CA2114156C - Elucidation and synthesis of selected pentapeptides - Google Patents
Elucidation and synthesis of selected pentapeptides Download PDFInfo
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- CA2114156C CA2114156C CA002114156A CA2114156A CA2114156C CA 2114156 C CA2114156 C CA 2114156C CA 002114156 A CA002114156 A CA 002114156A CA 2114156 A CA2114156 A CA 2114156A CA 2114156 C CA2114156 C CA 2114156C
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- dap
- och3
- dov
- val
- dil
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The sea hare Dolabella auricularia has yielded many structurally distinct peptides which possess antineoplastic activity. Presently the compound denominated "dolastatin 10" represents then most important of such peptides because of its demonstrated potential as an anticancer drug.
The present invention relates to the systematic creation of five unique pentapeptides by selectively coupling a tripeptide - trifluoroacetate salt with a preselected dipeptide-trifluoroacetate salt which provide active molecules capable of emulating the measured therapeutic effect of dolastatin 10. The pentapeptides hereof have the structure shown below:
wherein R is selected from the following group of substituents:
The present invention relates to the systematic creation of five unique pentapeptides by selectively coupling a tripeptide - trifluoroacetate salt with a preselected dipeptide-trifluoroacetate salt which provide active molecules capable of emulating the measured therapeutic effect of dolastatin 10. The pentapeptides hereof have the structure shown below:
wherein R is selected from the following group of substituents:
Description
2~i~~.~b ELUCIDATION AND ;aYNTHESIS OF
SELECTED PENT~1PEPTIDES
INTRODUC~1~; ION
This inv~ntion relates generaa.ly to ttxe field o~ anta.-neop:last:tc campounds, and more part:Lcularly 'to thQ elucidation and svynthesis of s~alected pentapeptides prepared by coupling dipeptide salts with the known tripeptide-trifluoroacetate salt.
More particularly, the present invention relates to :LO the synthesis of five pentapeptides by the coupling of a tri.peptide-trifluoroacetate salt with the respective dipeptide-trifluoroacetate salt, which was itself prepared by the coupling of dolaproine with the respective amino acid. This coupling results in compounds which are found to exhibit effective antineoplastic activity against various human cancerous tumor cell :Lines.
BACKGROUND OF THE INVENTTON
Ancient marine invertebrate species of the 20 Phyla Br~ozoa, Molluska, and Porifera have been well established in the oceans for over one billion years. Such organisms have undergone trillions of biosynthetic reactions in their evolutionary chemistry to reach their prEasent level of cellular organization, regulation and defense.
For example, marine sponges have changed minimally in physical appearance for nearly 500 million years. This suggests a very effective chemical resistance to evolution in response to 30 changing environmental conditions over that period of time. Recognition of the potential for utilizing this biologically potent marine animal for medicinal purposes was a.°ecorded in Egypt about 2,700 BC and by 200 BC sea hare extracts wez~e being used in Greece for their curative affect. This consideration along with the observation that marine animals, e.g. invertebrates and sharks, rarely develop cancer led to the systematic investigation of marine animal and plant anticancer compounds .
By 1~GF3 lmple cwidence had been obtaanec.~, bused on the U.S. National Dancer :Lnst3.tute's (NC:L) ltay experimenta:L cancer study systems, 'that certain marine organisms could provide new and antineoplastic and/or cytotoxic agents and might also lead to compounds which would be effective in the control and/or eradication of viral diseases.
Further, these marine organisms were believed to possess potentially useful drug candidates of unprecedented structure which had eluded discovery by other methods of medicinal chemistry.
Fortunately, these expectations have been realized, e.g, the discovery of the b:ryostatins, dolastatins and cephalostatins, many of which are now in preclinical development or human clinical studies.
Those researchers presently involved in medicinal chemistry know well the time lag between the isolation of a new compound and its introduction to the market. Often this procedure takes several years and may take decades. As a result, industry, in association with the U.S.
Government, has developed a system of testing criteria which serves two purposes. One is to eliminate those substances which are shown through testing to be economically counterproductive. The ~ second, more important purpose serves to identify those compounds which demonstrate a high likelihood of success and therefore warrant the further study and qualification, and attendant expense, necessary to meet the stringent regulatory requirements which control the ultimate market place.
The current cost to develop the necessary data approaches ten million dollars per compound. As such, economics dictate that such a huge investment will be made only when there is a reasonable opportunity for it to bye recovered. Absent such opportunity, there will be no investment and the research involving the discovery of these potentially life saving compounds will cease. Only two hundred years ago many diseases ravaged mankind. Many of these now have been controlled or eradicated. During the advancement of'means to treat or eliminate these diseases, work with appropriate animals was of critical importance.
Current research in,the control of cancer in the United States is coordinated by the National Cancer Institute (NCI). To determine whether a substance has anti-cancer properties, the NCI has established a systematic protocol. This protocol, which involves the testing of a substance against a _.--- standard sell line panel containing 60 human tumor cell lines, has been verified and has been accepted in scientific circles. The protocol, and the established statistical means for analyzing the results obtained by the standardized testing are fully described in the literature. See: Boyd, Dr.
Michael R., ,rincigles & Practice of Oncology, PPO
Updates, Volume 3, Number 10, October 1989, for an in depth description of the testing protocol; and Paull, K. D., "Display and Analysis of Patterns of Differential Activity of Drugs Against Human Tumor Cell Lines. Development of Mean Graph and COMPARE
- 30 Algorithm", Journal of the National Cancer Institute Reports, Vol. 81, No. 14, Page 1088, July 14, 1989 for a description of the methods of statistical analysis.
Numerous substances have been discovered which demonstrate significant antineoplastic or tumor inhibiting characteristics. As stated above, many of these compounds have been extracted, albeit with great difficulty, from marine animals such as the sponge and sea hare. Once isolation and testing of these compounds has been accomplished, a practical question remains, namely how to produce commercially significant quantities of the desired substance.
Quinine, which is available in practical quantities from the bark of the cinchona plant, differs from the compounds which are extracts of marine creatures possessing antineoplastic l0 qualities. The collection and processing of these later compounds from their natural sources ranges from grossly impractical,to the utterly impossible.
Ignoring the ecological impact, the population of these creatures and the cost of collection and extraction make the process unworkable. Artificial synthesis of the active compounds is the only possible solution.
Therefore, the elucidation of the structure of these antineoplastic compounds is essential. After 20 the structure has been determined, then a means of synthesis must be determined. This is often a long and arduous procedure due to the idiosyncratic complexity of these naturally occurring, ~- evolutionary modified compounds. In addition, research is necessary to determine whether any portion of the naturally occurring compound is irrelevant to the desired properties, so that focus can be on the simplest structure having the perceived properties.
SELECTED PENT~1PEPTIDES
INTRODUC~1~; ION
This inv~ntion relates generaa.ly to ttxe field o~ anta.-neop:last:tc campounds, and more part:Lcularly 'to thQ elucidation and svynthesis of s~alected pentapeptides prepared by coupling dipeptide salts with the known tripeptide-trifluoroacetate salt.
More particularly, the present invention relates to :LO the synthesis of five pentapeptides by the coupling of a tri.peptide-trifluoroacetate salt with the respective dipeptide-trifluoroacetate salt, which was itself prepared by the coupling of dolaproine with the respective amino acid. This coupling results in compounds which are found to exhibit effective antineoplastic activity against various human cancerous tumor cell :Lines.
BACKGROUND OF THE INVENTTON
Ancient marine invertebrate species of the 20 Phyla Br~ozoa, Molluska, and Porifera have been well established in the oceans for over one billion years. Such organisms have undergone trillions of biosynthetic reactions in their evolutionary chemistry to reach their prEasent level of cellular organization, regulation and defense.
For example, marine sponges have changed minimally in physical appearance for nearly 500 million years. This suggests a very effective chemical resistance to evolution in response to 30 changing environmental conditions over that period of time. Recognition of the potential for utilizing this biologically potent marine animal for medicinal purposes was a.°ecorded in Egypt about 2,700 BC and by 200 BC sea hare extracts wez~e being used in Greece for their curative affect. This consideration along with the observation that marine animals, e.g. invertebrates and sharks, rarely develop cancer led to the systematic investigation of marine animal and plant anticancer compounds .
By 1~GF3 lmple cwidence had been obtaanec.~, bused on the U.S. National Dancer :Lnst3.tute's (NC:L) ltay experimenta:L cancer study systems, 'that certain marine organisms could provide new and antineoplastic and/or cytotoxic agents and might also lead to compounds which would be effective in the control and/or eradication of viral diseases.
Further, these marine organisms were believed to possess potentially useful drug candidates of unprecedented structure which had eluded discovery by other methods of medicinal chemistry.
Fortunately, these expectations have been realized, e.g, the discovery of the b:ryostatins, dolastatins and cephalostatins, many of which are now in preclinical development or human clinical studies.
Those researchers presently involved in medicinal chemistry know well the time lag between the isolation of a new compound and its introduction to the market. Often this procedure takes several years and may take decades. As a result, industry, in association with the U.S.
Government, has developed a system of testing criteria which serves two purposes. One is to eliminate those substances which are shown through testing to be economically counterproductive. The ~ second, more important purpose serves to identify those compounds which demonstrate a high likelihood of success and therefore warrant the further study and qualification, and attendant expense, necessary to meet the stringent regulatory requirements which control the ultimate market place.
The current cost to develop the necessary data approaches ten million dollars per compound. As such, economics dictate that such a huge investment will be made only when there is a reasonable opportunity for it to bye recovered. Absent such opportunity, there will be no investment and the research involving the discovery of these potentially life saving compounds will cease. Only two hundred years ago many diseases ravaged mankind. Many of these now have been controlled or eradicated. During the advancement of'means to treat or eliminate these diseases, work with appropriate animals was of critical importance.
Current research in,the control of cancer in the United States is coordinated by the National Cancer Institute (NCI). To determine whether a substance has anti-cancer properties, the NCI has established a systematic protocol. This protocol, which involves the testing of a substance against a _.--- standard sell line panel containing 60 human tumor cell lines, has been verified and has been accepted in scientific circles. The protocol, and the established statistical means for analyzing the results obtained by the standardized testing are fully described in the literature. See: Boyd, Dr.
Michael R., ,rincigles & Practice of Oncology, PPO
Updates, Volume 3, Number 10, October 1989, for an in depth description of the testing protocol; and Paull, K. D., "Display and Analysis of Patterns of Differential Activity of Drugs Against Human Tumor Cell Lines. Development of Mean Graph and COMPARE
- 30 Algorithm", Journal of the National Cancer Institute Reports, Vol. 81, No. 14, Page 1088, July 14, 1989 for a description of the methods of statistical analysis.
Numerous substances have been discovered which demonstrate significant antineoplastic or tumor inhibiting characteristics. As stated above, many of these compounds have been extracted, albeit with great difficulty, from marine animals such as the sponge and sea hare. Once isolation and testing of these compounds has been accomplished, a practical question remains, namely how to produce commercially significant quantities of the desired substance.
Quinine, which is available in practical quantities from the bark of the cinchona plant, differs from the compounds which are extracts of marine creatures possessing antineoplastic l0 qualities. The collection and processing of these later compounds from their natural sources ranges from grossly impractical,to the utterly impossible.
Ignoring the ecological impact, the population of these creatures and the cost of collection and extraction make the process unworkable. Artificial synthesis of the active compounds is the only possible solution.
Therefore, the elucidation of the structure of these antineoplastic compounds is essential. After 20 the structure has been determined, then a means of synthesis must be determined. This is often a long and arduous procedure due to the idiosyncratic complexity of these naturally occurring, ~- evolutionary modified compounds. In addition, research is necessary to determine whether any portion of the naturally occurring compound is irrelevant to the desired properties, so that focus can be on the simplest structure having the perceived properties.
BRIEF SUMMARY OF THE INVENTION
The synthesis of potentially useful peptides presents one of the most essential and promising approaches to new types of anticancer and immunosuppressant drugs. The Dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cytostatic peptides isolated from Indian Ocean sea hare Dolabe» a au i >>a is represent excellent leads for synthetic modification. The very productive sea hare Dolabe~~a auriculariA has produced a number of structurally distinct peptides with .excellent antineoplastic activity. Presently Dolastatin 10, a linear pentapeptide represents the most important member and is a potentially useful antineoplastic agent. Dolastatin 10 shows one of the bast antineoplastic activity profiles against various cancer screens presently known.
This research has led to an effective method ~) i !R ~ ~~
da ~ ~'-for the synthesis of new and very potent anti-cancer pentapeptides related in structure to Dolastat:in 10. ~l'he presea~t :i.nventi.on involves the s'truc'ture and synthesis of :f:ive such pen ta,pe,ptides as shown below, I_I Cth ttsC
\N Co-N oo_N N ~c:o-R
CHI III , ( ~ OCf I3 CIh UCFI~ O
3(a-e) ,',' I;
\ c) R .= N COOCH3 ~) R =
~N COOCEI~ II3C CEt~
F-I d) R=
-N COOCIIs H
\ CH3 ~) R= ~ S
e) R=
-N CONC-i~
I-I
Accordingly, the primary object of the subject invention is the synthesi;~ of five pentapeptide derivatives of dolastat9_n 10 which exhibit effective antineoplastic activity against various human cancerous tumor cell lines.
Another obj ect of the :>ubj ect inventic>n is the synthesis of pentapeptide derivatives of dolastatin 10 through the coupling o:E respective tripeptide and dipeptide trifluoroacetate salts, whe:re.i.n the dipeptide salt was prepared by the coug~ling of dolaproine and the respective amino acid.
These and still further objects as shall .
hereinafter appear are readily fulfilled by the present invention in a remarkably unexpected manner as will be readily discerned from the fol:Lowing detailed description of an exemplary embodiment thereo:E .
DESGRIF'!,'ION OF THE PREFERRED EMBODIMEINT
The synthesis of potentially useful peptides presents one of the most ~assential and promising approaches to new types of anticancer and immunosuppressant drugs. The Dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cyto:;tatic peptides isolated from Indian Ocean sea hare Dolabella auricularia represent excellent leads fox synthetic modification. The very productive sea hare Dolabella auricularia has produced a number of structurally distinct peptides with esccellent antineoplastic activity. Presently Dolastatin 10, a linear pentapeptide represents the most important member and is a potentially useful antineoplastic agent. Dolastatin 10 shows one of the best antineoplastic activity profiles against various cancer screens presently known. Recently the total synthesis and absolute configuration of 'this structurally unique and bio:Logically active peptide was reported. This compound has been tested in vivo and demonstrated significant activity, as shown below.
Experimental Anticancer Acaivity of Dolastatin 10 in Murine in vivo Systems, T/C (~tg/kg) P388 L~ym~phocytic Leukemia Human Mammary Xenograph tC)X:LC (13.U) Ntlde MousQ
155 and 17% cures (6.5) Toxic (26) 146 anel 17% cures (3.25) 137 (13) 137 (1.63) 178 (6.25) T.1210 OVCAR-3 Human Ovary Xenograph Lymphocytic Leukemia 10152(13) Nude Mouse 135 (6.5) 300 (40) 139 (3.25) 120 (1.63) MX-1 Human Mammary Xenograft B16 Melanoma (Tumor Regression) 238 and 40% cures (11.11) 14 (52) 182 (6.67) 50 (26) 205 (4.0) 67. (13) 171 (3.4) 69 (6.25) 142 (1.44) 20M5076 Ovarv Sarcoma toxic (26) 166 (13) 142 (6.5) 151 (3.25) LOX Human Melanoma Xenograph to (Nude Mouse) toxic (52) 301 and 67% cures (26) 309. and 50% cures (13) 30206 and 33% cures (6.5) 170 and 17% cures (3.25) LOX in separate experiments 340 and 50% cures (43) 181 and 33% cures (26) 192 (15) 138 and 17% cures (9.0) ~~ ~~t~
Dolastatin 10 has also been tested against a minipanel from the NCt Primary screen. These results appear below, showing the amount of Dolastatin 10 required to attain GISO in ygJml, against 'the cell lines set forth below.
. 5 x:10 7 . 5 x:l2 . 5 x10' 3 . h x10-"
KM20L2 (E) SK-MEL-5 ~.7 x10 7.~ x10'a l0 From the foregoing, it can be seen that the in vitro activity of dolastatin 10 in the primary screen has been confirmed by in vivo animal tests.
For the compounds disclosed i.n this application, the in vitro tests disclosed above are reasonably accurate predictors of anticancer activity, and not mere indicators of the desirability for further testing.
These newly discovered pentapeptide Compounds (~a-3a), related to Dolastatin l0, are formed by 20 the coupling of the respective dipeptide fluoroacetate salts (2a-2e) with the known tripeptide-trifluoroacetate salt (.4). The dipeptides (1a-~.~) were in turn prepared by coupling dolaproine (5) with the respective amino acids. All compounds were characterized (physical and spectroscopic data) and tested against the marine lymphocytic P388 leukemia cell line as well as six major human cancer cell lines. The remarkable cancer cell growth inhibitory data are 30 shown in Table 1.
~~~4~'~~
'I'nblc 1. Intent inhibitinn of f:nnccr cell IIItes by I)entnpeptidcs :In-c 'ffl5'fCl.:!.1~'I'YI'L(:L'L,L.I.INIi~ 1'I'sN'fr\1'I:1''CIU!:
-StR/nti~ 3 :S ;) J 3 a a b c rl ~usoMouse L-EUKGbIfAP3R8 O.U6ti')O.Ol9S11.00880.0004410.11110389 ~
OvarianOVCr\R-:S<(l,Il0010.0076<0.0001<O.UU()l<(1.0001 .
CNS SF-29S<0.00(Il11,00085<0.1100)<O,OOOI<O,OOU1 OI-50Rcnai A-498 <O.U0010.00_097<O.OOOI<O.DOUI<0.0(lOl Lure-NSCNCI-II~460<O.OOOI0.000095<11,U001<O.OOUI<0,0001 Colon KM20L2<0.11001<0,(1(101<O.OOUI<0.0(lOt<0.0(10l MclanotnaSK-MEL-3<0.00010.00017<(1.0001<0.0001<0.0001 OvarianOVCAR-3U.DOII0.()077<O.OOOI<O.OOOI<0.0001 C~VS 29S 0.000170.049 0.(10240.17 (1.OS6 SP- -'COIRennl A498 0.0029O.U062(1.0054<0.0001>l Lunc-NSCNCI-11460O.Ol1O.OII 0.00130.0110890.13 Colon KM20I.211.00110.11190.0022<(1.OOOl0.00015 McinnomnSK-MEL-3(1.00068O.Ol2 <O,OUOI<0.0001>l OvnrinnOVC;1R-3>l 0.066 >l 0.043>1 (J1S SF-295>I >l >1 >l >l ' LC-50Renal A498 >l >I >l >l >l Lane-NSCNCI-H460>l >I >1 >i >I
Colon KM20L2>l O.OR3 >.l >l >i MelanomaSK-MEL-3>I >1 >l >I >l The human cancer cell lines results shown for pentapeptides 3a-a in Table I illustrate remarkably patent and selective activity against human ovary, CNS (brain), kidney, lung, colon and melanoma type cancers. In this respect, each compound parrots a pattern previously discovered for Dolastatin 10 and as such is reasonably expected to generate pn vivo data results comparable to those reported above for Dolastatin 10. .
The scheme and structures of these penta-peptides appear below:
~~~~~~.1 I-I CH3 H CI.I3 COOII Amino acid salt ~ \ TTIIfn0InilCCtiC
N ~ i . CO-l2 acid COQIInt OCI~Ig c OCEI
COOl3n L(n-e) I-I CI~I3 1 II~C
\N~ CO-N CO-N COON
CO-R III
/ ,\ ,,, CF~C00' Cf-I3 HI CII~ OCH3 Ei H
CF3C00' OCH3 ~
2(n~e) II CHI
H3C~ ,~
N 'CO-R
CO-i CO-N
CH3 H ~H3 OCI-h O OCI-I
3(a.e) s ~ 1, I3 c) R = N ~COOCH3 a) R = a ~N COOCH3 FI3C' \CII
H
R=
/ ~ ~N,r H COOCHj v b) R= ~ /CH3 S
e) R=
~,N~ CONI-IZ
s H SCIICMr I ~ I COOCFI3 21:x. 4 ~.
General Procedure for the Synthesis of Di;psptides (1a-9.e) To a solution of dolapro:ine tfa salt (:Lmmol) and 'the amino ac:Ld salt (lmmol) in dry dichloro-methane (2m1) , cooled to ice-bath temperature under an argon atmosphere was added dry triethy:lamine (3rnmo1) followed by diethylcyanophophonate ( 1. lmmol ) . The solution Hras stirred at the same ice bath temperature for 1.-2 hr. The salts that precipitated were collected, the solvent was evaporated (under reduced pressure) and the residue chromatographed over a SILICA GEL column with solvents noted to obtain the respective dipeptides.
i) Hoa-Dap-Phe-OCH3 (la):
Chromatographic separation on a SThICA GEL
column with 3:1 hexane-acetone as the eluent .resulted in the required dipeptide as a thick oil.
Crystallization from ether-hexane gave sparkling crystals of the pure compound (la, 96%) ~ m.p. -125°Cp [a]p 5 - -15.1° (c 0.41, CHC13) ; IR(~thin film): 3314, 2974, 2934, 2878, 1748, 1692, 1663, 1537, 1456, 1400, 1366, 1173, 1101 and 700; ~H NMR
(300MHz, CDC13): 1.163(d, J=7.OHz, 3H, CH3), 1. 4316 (s, 9H, t-Bu) , 1. 624-1. 850 (m, 4H, 2 x CHz) , 2.25-2.45(m, 1H, CHCO), 3.045(dd, J=13.9 and 7.8Hz, 1H, 1/2 CHz-Ph) , 3. 175 (dd, J=13. 8 and 5.55Hz, 1H, 1/2 CHz-Ph), 3.3642(x, 3H, OCH3), 3.3701(s, 3H, OCH3), 3.50-3.60(m, 1H, CH-OCH3), 3.7422(m, 2H, CHZ-N) , 3 . 85 (m, 1H, pro CH-N) , 4 . 80 (m, 1FI, phe ' CH-N), 6.10, 6.75(m, 1H, NH) and 7.10-7.32(:m, 5H, Ph); MS: m/z 416[M-CH30H], 375, 316, 264, 210, 170, 114(1000 and 70. Anal. Found: H: 8.12, N: 6.20.
Cz4H36NZ06 requires H: 8.09, N: 6.25.
ii) Boa-Dap-Phs-NHz (1b):
Chromatographic purification using a STLICA
GEL column with 1:1 hexane-acetone as the eluent 2~.~.4~1~i~
gave the required dipeptide: as a crystalline solid.
Recrystallization from aicetone gave sparkling crystals of the pure compound ( ~.b, 65 0 ) ; m. p.
199-200°C (acetone); [a]p2' _ -40° (c 0.15, CHCI~);
IR(thin film): 3302, 3198, 2974, 2934, 2878, 1669, 1539, 1456, 1404, 1366, 1169, 1111 and 700; ~H NMR
(300MHz, CDC13) : 1.019 (brs, 3H, CII3) , 1.426 (s, 9H, t-Bu) , 1. 55-1. 90 (m, 4H, 2 x CFIZ) , 2 . 30 (quintFt, 1H, CFI-CO) , 3. 00-3 . 25 (m, 3H, C;HZ-N, CH-OCHj) , 3. 349 (s, 3Ii, OCH~), 3.60-3.75(m, 1H, pro CH-N), 4.60-4.80(m, 1H, phe CH-N) , 5. 30 (brs, 1H, NH) , 6. 267 (d, J=7. 2I-Iz, 1H, NH), 6.90(brm, 1H, NH) and 7.164-7.306(m, 5H, CbHs); MS: m/z 433(M+), 401(M-MeOH), 360, 301, 247, 232, 210, 170, 154, 138, 114 and 70(100%). Anal.
Found: C: 63.75, H:8.18, N:9.62. C23H35N305 requires C: 63.72, H: 8.14, N: 9.69.
iii) Boc-Dap-Pro-OCH3 (1a);;
Chromatographic sepana~tion on a SILICA GEL
column with 3:2 hexane-aceaone as the eluent gave the required dipeptide as a thick oil (1a, 92% );
[a]p5 - -101.5° (c 0,2, CHC13); IR(neat): 2974, 2880, 1748, 1692, 1647, 1398, 1366, 1171andl 1098; ~H
NMR (300MHz, CDC13): 1.222(d, J=7.OHz, 3H, CH3), 1.440(s, 9H, t-Bu), 1.65-2.20(m, 8H, 4 x CHZ), 2.60-2.70(m, 1H, CH-CO), 3.10-3.22(m, 1H, CH-OCH3), 3 . 417 (s, 3H, CH3) , 3 . 45-3 . 65 (m, 4H, 2 x CHZ-N) , 3.675(s, 3H, OCH3), 3.74-3.83(m, 1H, CH-N) and 4.447 (dd, J=8. 55 and 3 . 5Hz, 1H, CH-COOCH3) . HRFABMS:
m/z 399.24880[M+H]ø. CzoH35N206 requires 399.26951.
' iv) Boc-Dap-Ile-OCH3 (1d):
Chromatographic purification on a SILICA GEL
column with 3:2 hexane-ethyl acetate, as the eluent yielded the required dipeptide as an oily liquid 1d, 720) ; m.p. -- 76-77°C (acetone) ; Ca]D S = -28°2°
(c 0.17, CHC13) ; IR(thin film) : 3325, 2971, 2936, 2878, 1746, 1694, 1667, :L530, 1478, 1398, 1254, 1175, 1105, 868 and 774; ~H NMR (300MHz, CDC13):
0.882(d, J=6.9Hz, 3H, CH3-CH), 0.9012(t, J=7.4Hz, 3H, CH3-CHZ) , 1. 05-1. 24 (m, 5H, CH3, CHz-CH3) , 1.4526(s, 9H, t-Bu), 1.65-2.00(m, 5FI, x CHZ
CIA-CH2~, 2 . 30-2 . 50 (m, 1FI, CH-CO) , 3 . 18-3 . 28 (:m, 1FI, C~-OCH3) , 3. 422 (s, 3FI, OCEI3) , 3 .48-3.1H, 60 (m, pro _C~,[-N) , 3 . 699 (s, 3FI, OCFI3) , 3.72-3.1FI, 82 (m, 1/2 CFIz-N) , 3 .88-3.98 (m, 1FI, 1/2 CFIz-N) , 4.44-4 . 58 (m, 1FI, ].le CH-N) and 6. 15, 6.7 (m, 1FI, MS:
NFI) ; m/z 382(M-MeOFI), 341, 282, 245, 230, 210, 170, 114, 70(100%) and 57. Anal. Found: C: 61.06,9.25, FI: N:
6.64. CZ~H3aN206 requires C: 60.84, H: N: 6.76.
9.24, v) Boo-Dap-Met-OCH3 (le):
Chromatographic separation on a SILICA GEL
column using 3:2 hexane-acetone as 'the eluent gave the required dipeptide as a solid (le, 83%); m.p. -68-70°C; [a]pzs = -27.6° (c, 0.59, CHC13); IR(neat):
3312, 2974, 2934, 2878, 1748, 1692, 1663, 1539, 1398, 1366, 1256, 1171, 1115, 866 and 774; ~H NMR
(CDC13) : 1. 223 (brs, 3H, CH-CFI3) , 1. 441 (brs, 9H, t-Bu), 1.6-1.2(m, 6H, 3xCHz), 2.070 (s, 3H, S-CH3), 2.3--2.55(m, 3H, CHZ-S, CH-CO), 3.15-3.35 (m, 2H, N-CHZ) , 3. 420 (s, 3H, OCH3) , 3.55 (m, 1H, CFI-OCH~) , 3.716(brs, 3H, COOCH3), 3.85-4.0(m, 1FI, pro CH-N), 4.6(brm, 1H, met CH-N), 6.3(brm, 1H, NH); MS (m/z):
432 (M+), 400, 359, 258, 210, 170,114(100%). Anal.
Found: C: 55.35, H: 8.33, N: 6.53, S: 7.23. CZOH36Nz06 S requires C: 55.53, H: 8.39, N: 6.48, S: 7.41.
Synthesis of phenylalanine amide trifluoroacetate salt:
' To a solution of t-boc-phenylalanine amide (3, 80mg, 0.303mmo1) in dichloromethane (0.5m1) was added trifluoroacetic acid (lml) at ice-bath temperature and the solution was stirred at the same temperature for 1.5 hr. under argon atmosphere. The solvents were removed under reduced pressure and the residue taken into toluene and toluene also removed under. reduced pressure to obtain a white solid of the trifluoroacetate salt 2~~ l~~'~)~
(80mg, 95~); ~H NMR (DMSO-d6, 300MHz): 2.95-3.10(m, 2H, C6H5-CHZ) , 3 . 3209 (brs, 2FI, NI-IZ) , 3 . 9408 (brs, 1I-I, CH-N), 7.236-7.317(m, 5H, C6H5) and 7.528, 7.862, 8.150 (brs, 3I-I, NH~~) .
DEPROTRCTIO~Y OF DTPEPTIDES 1a-a WTT~i TRTFLUOROACETIC ACID- aENERA1G PROCEDURE:
To a solution of the Boo-protected dipeptide (lmmol) in dry dichloromethane (2m1, cooled to ice-bath temperature, under an argon atmosphere) was added trifluoroacetic acid (2m1) and the solution was stirred at the same temperature fox 1-2 hr. After removing the solvent under reduced pressure, the residue was dissolved in toluene and solvent was again removed under reduced pressure.
The latter operation was repeated to remove all the :5,:
trifluoroacetic acid. The residue was dried (in vacuo) to obtain the trifluoroacetate salts of the respective dipeptides. Wherever possible, the trifluoroacetate salts were characterized from spectral data and physical constants recorded.
Synthesis of Dap-Phe-OCH3 Tfa (2a):
After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (2a, quantitative) as a colorless crystalline solid: IR(thin film): 3275, 2928, 1744, 1674, 1541, 1456, 1202, 1132 and 72,1; ~H
NMR (300MHz, CDC13): 1.107(brs, 3H, CH3), 1.60-2.10(m, 4H, 2 x CHZ), 2.60(m, 1H, CHCO), ' 2 . 90-3. 00 (m, 2H, CHZ-Ph) , 3 .10-3 > 35 (m, 3H, CfI-OCH3, CHZ-N) , 3 . 209 (s, 3H, OCH3) , 3 . 40-3 . 55 (m, 1H, pro CH-N), 3.712(s, 3H, COOCH3), 4.75(m, 1H, phe CH-N), 7.106(m, :LH, NH), 7.124-7.324(m, 5H, Fh) and 8.7(m, 1H, NH); HRFABMS: m/z 349.21350(100%, cation);
[C~9H29N204]'" requires 349.21273.
Synthesis of Dap-Phe-NHZ Tfa (2b):
r., :~. ~. .:~ ) Removal of toluene under reduced pressure left the trifluoroacetate salt (2b, 97% ) as a colorless solid.
&ynthesis of Dap-.lPro-OCH3 ~fa (20):
After removing toluene under reduced pressure, t h a residue obtained as a think oily mass was triturated with ether to obtain the trifluoroacetate salt (20, 99%) as a colorless crystalline solid: TR(thin film): 2980, 2890, 1746, 1680, 1626, 1437, 1287, 1200, 1094, 799 and 721; ~H
NMR (300MHz, CDC13): 1.307(d, J=6.9Hz, 3'H, CH3), 1. 85-2 . 30 (m, 8H, 4 x CHZ) , 2 . 85 (m, 1H, CH-CO) , 3 .20-3.40 (m, 1H, CH-OCH3) , 3. 485 (s, 3H, CHI) , 3.35-3.75(m, 3H, CH-N, CHZ-N), 3.687(s, 3H, COOOCH3) , 4 .165 (m, 2H, CHZ-N*) , 4 . 442 (m, 1FI, CH-N+) and 8.008(m, NH). HRFABMS: m/z 299.19770(100%, cation) t [C~SHZ~N204]+ requires 299.1971.
Synthesis of Dap-Il~-OCH3 Tfa (2d):
After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (2d, 97%) as a gummy mass:
IR(thin film): 3289, 2969, 2884, 1744, 16?4, 1541, 1458, 1383, 1202, 1136, 833, 799 and 721; ~H NMR
(300MHz, CDC13): 0.88(brs, 3H, CH3), 1.884(t, J=6.7Hz, 3H, CH3-CHZ) , 1. 209 (d, J=6.8Hz, CH3-CH) , 1.10-1.50(m, 2H, CHZ), 1.80-2.20(m, 5H, 2 X CHz, ' CH3-CH), 2.707(m, 1H, CH-CO), 3.10-3.41(m, 2H, CHZ-N), 3.470(s, 3H, OCH3), 3.60-3.70(M, 1H, CH-OCH3), 3.48-3.85-3.90(m, 1H, pro CH-N), 3.702(s, 3H, COOCH3), 4.43(dd, J=7.5 and 5.4Hz, 1H, ile CH-N), 6.926(d, J=7.9Hz, 1H, NH), 8.8(m, 1H, 1/2 NHz) and 10 (m, 1H, 1/2 NHZ): MS: HRFAE3: m/z 315.22890(100%. Cation) p (C~6H31N204]* requires 315.22838.
Synthesis of Dap-Met-OCH3 Tfa (2e);
Removal of toluene under reduced ;pressure left the trifluoroacetate salt (2e, quantitative) as a gummy mass.
SYNTHESIS OF PENTABEPTIDES 3a-a ~ ~3E1NERAL
PROCEDURE;
To a solution of the tripeptide tfa ;salt (4, lmmol) and the dipeptide tfa salt (lmmol) in dichloromethane (2m1, ice-bath and under argon) was added dry triethylamine (3mmol) followed by diethylcyanophosphonate (l.lmmol). The solution was stirred at the same temperature for 1-2hr.
After removing solvent under reduced pressure the residue was chromatographed on a SILICA GEL column using the solvent system given below as eluents to obtain the respective pentapeptides (3a-e).
Dov-Val-Dil-Dap-Phe-OCH3 (3a):
Chromatographic separation on a SIL~TCA GEL
column with 3:4 hexane-acetone as the eluent gave the required pentapeptide(3a, 87%); m.p. - 80-83°C
[a]p 5 = -35.3 ° (c 0.34, CHC13) ; IR(thin film) 3298, 2963, 2934, 2876, 2830, 2787, 1748, 1622, 1532, 1454, 1379, 1269, 1200, 1099, 1038, 737 arid 700; MS: m/z 759(Mi), 716, 481, 449, 433, 227, 186, 154, 128, 100(100%), 85 and 70. Anal. Found: C:
64.91, H: 9.33, N: 8.97. C4~H69N508 requires C: 64.71, H: 9.15, N: 9.22.
Dov-Val-Dil-Dap-Phe-NHZ(9b):
Chromatographic separation on a SILICA GEL
column with 1:3 hexane-acetone as the eluent resulted in the required pentapeptide as colorless powder (33~, 99 0) ; m.p. = 111-113 °C ; [a]p 5 = -42 ° (c 0.25, CHCl3) ; IR(thin film) : 3304, 3138, 3054, 2965, 2934, 2876, 2830, 2787, 1622, 1541, 1499, 1423, 1371, 1306, 1252, 1202, 1171, 1098, 1038, 756, 735 and 696; MS: m/z 744(M+), 701, 669, 519, 481, 418, 227, 206, 186, 170, 154, 128 and 114.
Dov-Val-Dil-Dap-Pro-OCH3 (3a):
Chromatographic purification using a SILICA
GEL column with 1:3 hexane-acetone as the eluent yielded the required pentapeptide as colorless powder (3a, 69%) ; m.p. = 75-77°C ; [a]p25 = _52.7° (c 0.11, CI-IC13) ; IR(thin film) : 3293, 2963, 2876, 2830, 2789, 1750, 1624, 1422, 1385, 1273, 1198, :L096, 1040 and 733; MS: m/z 709(:M"), 666, 581, 481, 449, 412, 383, 369, 297, 255, 227(100%), 199, 186, 170 and 155. Anal. Found: C: 62.51, H: 9.61, N: 9.72.
C3~H6~N508 requires C: 62.59, H: 9.51, N: 9.87.
Dov-val-Dil,-Dap-Ile-OCH3 (3~d) Chromatographic separation on a SILICA GEL
column with 1:2 hexane-acetone as the elu~ent gave the required pentapeptide .as colorless powder (3d, 80% ); m.p. - 80-82°C; [a]p25 = -39.3° (c 0.14, CHC13) ; IR(thin film) : 3300, 3050, 2965, 2878, 2830, 2787, 1746, 1622, 1530, :L454, 1383, 1267, 1120, 1099, 1038 and 735; MS: m/z 725(M+), 682, 481, 399, 227, 186, 170, 154 and 128. Anal. Found: C: 63.03, H: 10.01, N: 9.77. C38H7~N5t~8 requires C: 62.86, H:
9.86, N: 9.65.
Dov-va7.-Di1-Dap-Met-OCH3 (;De) ' Chromatographic separation using a SILICA GEL
column with 1:2 hexane-acetone as the eluent .resulted in the required pentapeptide as colorless powder (3e, 78%) ; m.p. = 63-65°C; [a]o 5 = -44.1" (C, 0.44, CHC13) ; IR(thin film) : 3297, 2963, 2934, 2876, 2830, 2787, 1750, 1620(br),. 1539, 1449, 1420, 1375, 1198 and 1098; MS (m/z) : '743 (M+) , 700, 611, 568, 481, 417, 311, 227 and 154. Anal. Found: C: 59.78, H: 9.14, N: 9.16, S: 4.39. C3~H69N5068S requires C:
,;::~
59.73, H: 9.35, N: 9.41, S: 4.31.
To further aid in the understanding of the present invezxtion, and not by way of l:Lm:i.tation, the following examples axe presented.
Example ~a - 8ynthas3s of Boc-Dap-Phe-OCH~ (:La):
The general procedure for the synthesis of dipeptides (1a-1e) was followed. The numerical identificate shown in Scheme 1 is followed herein.
Chromatographic separation on a SILICA GEL column with 3:1 hexane-acetone as the eluent resulted in the required dipeptide as a thick oil.
Crystallization from ether-hexane gave sparkling crystals of the pure compound (~.a, 96~) ; m.p. -125°C; [a]p 5 = -15.1 (c 0.41, CHC13) ; IR(thin film) 3314, 2974, 2934, 2878, 1748, 1692, 1663, 1537, 1456, 1400, 1366, 1173, 1101 arid 700; ~H NMR
(300MHz, CDC13): 1.163(d, J=7.OHz, 3H, CH3), 1. 4816 (s, 9H, t-Bu) , 1. 624-1. 850 (m, 4H, 2 x CHz) , 2.25-2.45(m, 1H, CHCO), 3.045(dd, J=13.9 and 7.8Hz, 1H, 1/2 CHz-Ph), 3.175(dd, J=13.8 and 5.55Hz, 1H, 1/2 CHz-Ph), 3.3642(s, 3H, OCH3), 3.3701(s, 3H, OCH3), 3.50-3.60(m, 1H, CH-OCH3), 3.7422(m, 2H, CHz-N), 3.85(m, 1H, pro CH-N), 4.80(m, 1H, phe CH-N), 6.10, 6.75(m, 1H, NH) and 7.10-7.32(m, 5H, Ph); MS: m/z 416(M-MeOH), 375, 316, 264, 210, 170, 114(100%) and 70. Anal. Found: H: 8.12, N: 6.20.
Cz~H3eN20s requires H: 8.09, N: 6.25.
' Example Ib - Synthesis of Boc-Dap-Phe-PIHZ (1b):
The general procedure for the synthe~;is of dipeptides (1a-1e) was followed. Chromatographic purification using a SILICA GEL column wii~h 1:1 hexane-acetone as the eluent gave the required dipeptide as a crystalline solid.
Recrystallization from acetone gave sparkling crystals of the pure compound (l.b, 65%); m.p. -2114'156 199-200°C (acetone) ; [a]pzs = -40 (c 0.15, CkiCl3) ;
IR(thin film): 3302, 3198, 2974, 2934, 2878, 1669, 1539, 1456, 1404, 1366, 11119, 1111 and 700; ~H NMR
(300MHz, CDC13) : 1. 019 (brs, 3kI, CkI3) , 1. 426 (s, 9kI, t-Eiu), 1.55-1.90(m, 4ki, 2 x CHz), 2.30(quintet, 1H, CH-CO) , 3 . 00-3. 25 (m, iii, C:FIz-N, CH-OCki3) , 3. 349 (s, Ski, OCi~I3) , 3 . 60-3 . 75 (m, 1k3, pro CkI-N) , 4. 60-4 . 80 (m, lkI, phe CH-N) , 5. 30 (brs, 1H, NFI) , 6. 287 (d,. J=7. 2kiz, lkl, NH) , 6. 90 (brm, lkI, NH) and 7. 164-7 . 306 (m, 5H, C6Hs) ; MS: m/z 433 (M*) , 401 ~;M-MeOH) , 360, 301, 247, 232, 210, 170, 154, 138, 114 and 70(1000 . Anal.
Found: C: 63.75, H:8.18, N:9.62. Cz3H3sN3Os requires C: 63.72, H: 8.14, N: 9.69.
Eacample Tc - Synthesis of lBoc-Dap-Pro-OCH~ (1c):
The general procedure for the synthesis of dipeptides was followed. Chromatographic separation on a SILICA GEL column with 3:2 hexane-acetone as the eluent gave the required dipeptide as a thick oil (7.c, 92~) ; [a]pz5 - _101.5 (c 0.2, CHC13) ; IR(neat) : 2974, 2880, 1748, 1692, 1647, 1398, 1366, 1171and. 1098; ~H NMR (300MHz, CDC13): 1.222(d, J=7.OHz, 3H, CH3), 1.440(x, 9H, t-Bu), 1.65-2.20(m, 8H, 4 x CHz), 2.60-2.70(m, 1H, CH-CO), 3.10-3.22(m, 1H, CH-OCH3), 3.417(x, 3H, CH3), 3.45-3.65(m, 4H, 2 x CHz-N), 3.675(x, 3H, OCH3), 3.74-3.83(m, 1H, CH--N) and 4.447(dd, J=8.55 and 3.5Hz, 1H, CH-COOCH3). HRFABMS: m/z 399.24880 (M+H)*; . [CZpH3sN206]* requires 399.24951.
Eacample Id - Synthesis of I3oo-Dap-ale-OOHS (sd) o The general procedurE~ for the synthesis of dipeptides (la-1e) was followed. Chromatographic purification on a SILICA. GEL column with 3:2 hexane-ethyl acetate as i~he eluent yielded the required dipeptide as an oily liquid (id, 72%);
m.p. - 76-77°C (acetone) : [a]pzs = -28.2 (c 0.17, CHC13) ; IR(thin film) : 3325,, 2971, 2936, 2878, 1746, 1694, 1667, 1530, 1478, 1398, 1254, 1175, 1105, 868 2I1i5 and 774; ~H NMR (300MHz, CDC13): 0.882 (d, J=6.9Hz, 3H, CH3-CH) , 0. 9012 (t, J=7. 4Hz, 3H, !CH;-CHZ) , 1. 05-1.24 (m, 5FI, CFI3, CHZ-CFI3) , 1, 4526 (s, 9H, t-Bu) , 1. 65-2 . 00 (m, SFI, 2 x CFIz, C~F~-CHZ) , 2 . 30-2 . 50 (m, 1FI, CFF-CO) , 3 . 18-3. 28 (m, 1FI, C~-OCFi~) , 3.422 (s, 3FI, OCFI3) , 3. 48-3. 60 (m, 1FI, pro ,~-N) , 3. 6951 (s, 3FI, OCFIj) , 3 . 72-3 .82 (m, 1FI, 1/2 CFIZ-r1) , 3 . 88-3 , 98 (m, 1FI, 1/2 CFIZ-N) , 4. 44-4 . 58 (m, 9.FI, i1e CFI-N) and 6. 15, 6.7(m, 1H, NFI); MS: m/z 382(M-MeOH), 341, 282, 245, 230, 210, 170, 114, 70(1000 and 57. Anal. Found:
C: 61. 06, H: 9. 25, N: 6. E.4. CZ~H38N206 requires C:
60.84, H: 9.24, N: 6.76.
Example Ie - Synthesis of ;Boc-Dap-Met-OCH3 (xe):
The general proaedur~a for the synthe:;is of dipeptides (1a-1e) was fo7.lowed. Chromatographic separation on a SILICA GEL column using 3:2 hexane-acetone as the eluent gave the required dipeptide as a solid (1e, 83~k) ~ m.p. - 68-70°C;
(a]pZS= -27.6 (c, 0.59, CHCl;s) ; IR(neat) : 3312, 2974, 2934, 2878, 1748, 1692, x.663, 1539, 1398, 1366, 1256, 1171, 1115, 866 anal 774; ~H NMR (CDC13):
1.223(brs, 3H, CH-CH3), 1.441(brs, 9H, t-Bu), 1.6-1.2 (m, 6H, 3xCHZ) , 2.070 (s, 3H, S-CH3) , 2.3-2.55(m, 3H, CHZ-S, CH-CO), 3.15-3.35 (m, 2H, N-CHZ) , 3. 420 (s, 3H, OCH3) , 3.55 (m, 1H, CH-°OCH3) , 3.716(brs, 3H, COOCH3), 3.85-4.0(m, 1H, pro CH-N), 4.6(brm, 1H, met CH-N), 6.3(brm, 1H, NH): MS (m/z):
432 (M+), 400, 359, 258, 210, 170, 114(100%). Anal.
Found: C: 55.35, H: 8.33, N: 6.53, S: 7.23. CZaH36N206 S requires C: 55.53, H: 8.39, N: 6.48, S: 7.41.
Example TIa - gynthesis of Dap-Phe-oCH3 Tfa~ (xa):
General procedure A was followed. After removing toluene under reduced pressure, the residue obtained as a thief oily mass was ti~trated with ether to obtain the trifluoroacetate salt (2a, quantitative) as a colorless crystalline: solid:
IR(thin film): 3275, 2928, 1744, 1674, 1541, 1456, zm4ms 1202, 1132 and 721; ~H NMR (300MHz, CDC13):
1. 107 (brs, 3H, CFI) , 1. 60-2 . 10 (m, 4H, 2 ~" CHZ) , 2 . 60 (m, 1FI, CFiCO) , 2 . 90-3 . 00 (m, 2FI, CII2-Ph) , 3. 10-3. 35 (m, 3FI, CFA-OCFI3, CHZ-N) , 3. 209 (s, 3FI, OCFI~) , 3 .40-3. 55 (m, 1II, pro CFI-N) , 3 . 712 (s, 3FI, COOCFI3) , 4 , 75 (m, 1H, phe CFI-N) , 7 .106 (m, 1FI, NFI) , 7. 124-~ 7. 324 (m, 5FI, Ph) and 8.7 (xa, 7.II, NFI) ; IiFtF~ABMS:
m/z 349.21350(100, nation) ; (G~9FI29N20~]* requires 399.21273.
Example IIb - 8ynthe~is of Dap-Ph~-NHZ Tfa (2b):
General procedure A was followed. Removal of toluene under reduced pressure left the trifluoroacetate salt (2b, 97~) as a co7.orless solid.
Exampl~ IIa - Synthesis of Dap-Pro-OCH3 Tfa (2a):
General procedure A was followed. After removing toluene under reduced pressure, residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (20, 990) as a colorless crystalline solid: IR(thin film):
2980, 2890, 1746, 1680, 1626, 1437, 1287, 1200, 1094, 799 and 721; ~H NMR (300MHz, CDC13): 1.307(d, J=6.9Hz, 3H, CH3), 1.85-2.30(m, 8H, 4 x CHZ), 2.85(m, 1H, CH-CO), 3.20-3.40(m, 1H, CH-OCH3), 3.485(s, 3H, CH3), 3.35-3.75(m, 3H, CH-N, CHz-N), 3. 687 (s, 3H, COOOCH3) , 4. 165 (m, 2H, CFIZ-N*) , 4 .442 (m, 1H, CH-N*) and 8.008(m, NH). HRFABMS: m/z 299.19770(100%, cation) ; [C~SHZ~Nz04]* requires 299.1971.
Exaanple IId - Synthesis of >aap-Ile-OCH3 Tfa (2d) :
General procedure A was followed. After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoro-acetate salt (2d, 970) as a gummy mass: IR(thin film): 3289, 2969, 2884, 1744, 1674, 1541, 1458, 1383, 1202, 1136, 833, 799 and 721; ~H NMR (300MHz, ~:~1~156 CDC13): 0.88(brs, 3H, CH3), 1.884(t, J=6.7Hz, 3H, CFI3-CHZ) , 1. 209 (d, J=6. 8Hz, CH3-CH) , 1. 10-1. 50 (m, 2H, CHz) , 1. 80-2. 20 (m, 5H, 2 X CFI2, CFi3-CFI) , 2 .707 (m, lFi, CFI-CO) , 3 . 10-3. 41 (m, 2FI, CFi2-N) , 3 . 470 (s, 3FI, 0CFI3) , 3 . 60-3 . 70 (M, 1FI, C~-OCFI~) , 3 . 85-3 . 90 (m, 1FI, pro ~-N) , 3.702 (s, 3FI, COOCFij) , 4. 43 (dd, J=7. 5 and 5.4Fiz, lFi, ile CFI-N) , 6.926 (d, J=7.9FIz, 1H, NH) , 8.8 (m, lFi, 1/2 NFiz) and 10 (m, 1FI, 1/2 NHz) ; MS:
HRFAB: m/z 315.22890(100. ration) ; [C,6FI31N204~*
requires 315.22838.
Example IIe - Synthesis of Dap-Mat-OCH3 Tfa (2e):
General procedure A was followed. Removal of toluene under reduced pressure left the trifluoro-acetate salt (2e~ quantitative) as a gummy mass.
Example IIIa - Synthesis o~ Dov-Val-Dil-Dap-Phs-OCIi~
(3a) Chromatographic separation on a STLICA GEL
column with 3:4 hexane-acetone as the eluent gave the required pentapeptide(3a, 87~); m.p. - 80-83°C
; [a]D 5= -35.3 (c 0.34, CHC13) ; IR(thin film) : 3298, 2963, 2934, 2876, 2830, 2787, 1748, 1622, 1532, 1454, 1379, 1269, 1200, 1099, 1038, 737 and 700;
MS: m/z 759(M+), 716, 481, 449, 433, 227, 186, 154, 128, 100(100%), 85 and 70. Anal. Found: <:: 64.91, H: 9.33, N: 8.97. C4~H69Ns08 requires C: 64.71, H:
9.15, N: 9.22.
Example IIIb - Synthesis o~ DoV-Val-Dil-Dap-Phe-iJgiz ' (3b) :
General procedure B was followed.
Chromatographic separation on a SILICA GEL column with 1:3 hexane-acetone as the eluent resulted in the: required pentapeptide as colorless powder (3b, 99~); m.p. = 111-113°C ; [a~pz5= -42 (c 0.25, CHC13);
IR(thin film): 3304, 3138, 3054, 2965, 2934, 2876, 2830, 2787, 1622, 1541, 1499, 1423, 1371, 1306, r z~~~156 1252, 1202, 1171, 1098, 1038, 756, 73°.> and 696; MS:
m/z 744 (M+) , 701, 669, 519, 481, 418, :?27, 206, 186, 170, 154, 128 and 114.
Example IIIa - synthesis of Dov-Val-Dill-Dap-pro-OCH3 (3a) s General procedure B was followed.
Chromatograph:Lc purification using a SILICA GEL
column with 1:3 hexane-acetone as the eluent yielded the required pentapeptide as co:Lorless powder (3a, 69~); m.p. = 75-77°C ; [a]p5= -52.7 (c 0.11, CHC13) ; IR(thin film) : 3293, 2963, 2876, 2830, 2789, 1750, 1624, 1422, 1385, 1273, 1198, 1096, 1040 and 733; MS: m/z 709(M+), 666, 581, 481, 449, 412, 383, 369, 297, 255, 227(1000), 199, 186, 170 and 155. Anal. Found: C: 62.51, H: 9.61, N: 9.72.
C37H67N5~a requires C: 62.59, H: 9.51, N: 9.87.
Example TIId - synthesis of Dov-Val-Dil-Dap-Ile-OCH3 (3d) General procedure B was followed.
Chromatographic separation on a SILTCA Gr~L column with 1:2 hexane-acetone as the eluent gave the required pentapeptide as colorless powder (3d, 80~); m.p. - 80-82°C ; [a]pz5= -39.3 (c 0.14, CHC13) ; IR(thin film) : 3300, 3050, 2965, 2878, 2830, 2787, 1746, 1622, 1530, 1454, 1383, 12Ei7, 1120, 1099, 1038 and 735; MS: m/z 725(M+), 682, 481, 399, 227, 186, 170, 154 and 128. Anal. Found: C: 63.03, H: 10.01, N: 9.77. C38H7~N5~08 requires C: 62.86, H:
' 9.86, N: 9.65.
Example IIIe - sgnthesis of Dov-Val-Dil-Da~u-Met-OCH3 (3e) General procedure B was followed.
Chromatographic separation using a SI:L7CCA GEL
column with 1:2 hexane-acetone as the eluent resulted in the required pentapeptide as c~o:iLorless ~~~i~s powder (3e, 78%); m.p. - 63-65°C; (a]pZS= -44.1 (c, 0.44, CHC13) ; IR(thin film) : 3297, 2963, 2934, 2876, 2830, 2787, 1750, 1620(br), 1539, 1449, 1420, 1375, 1198 and 1098; MS (m/z) : 743 (Nf~) , 700, 611, 568, 487., 417, 311, 227 and 154. Anal. T'ound: C: 59.78, I3: 9.14, N: 9.16, S: 4.39. C~~I~I69N506n8 rec~uiras C:
59.73, II: 9.35, N: 9.41, S: 4.31.
From the foregoing, it is readily apparent that a useful embodiment of the present invention has been herein described and illustrated which i fulfills all of the aforestated objectives in a remarkably unexpected fashion. It is of course understood that such modifications, alterations and adaptations as may readily occur to the artisan confronted with this disclosure are intended within the spirit of this disclosure which is limite=d only by the scope of the claims appended hereto.
i
The synthesis of potentially useful peptides presents one of the most essential and promising approaches to new types of anticancer and immunosuppressant drugs. The Dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cytostatic peptides isolated from Indian Ocean sea hare Dolabe» a au i >>a is represent excellent leads for synthetic modification. The very productive sea hare Dolabe~~a auriculariA has produced a number of structurally distinct peptides with .excellent antineoplastic activity. Presently Dolastatin 10, a linear pentapeptide represents the most important member and is a potentially useful antineoplastic agent. Dolastatin 10 shows one of the bast antineoplastic activity profiles against various cancer screens presently known.
This research has led to an effective method ~) i !R ~ ~~
da ~ ~'-for the synthesis of new and very potent anti-cancer pentapeptides related in structure to Dolastat:in 10. ~l'he presea~t :i.nventi.on involves the s'truc'ture and synthesis of :f:ive such pen ta,pe,ptides as shown below, I_I Cth ttsC
\N Co-N oo_N N ~c:o-R
CHI III , ( ~ OCf I3 CIh UCFI~ O
3(a-e) ,',' I;
\ c) R .= N COOCH3 ~) R =
~N COOCEI~ II3C CEt~
F-I d) R=
-N COOCIIs H
\ CH3 ~) R= ~ S
e) R=
-N CONC-i~
I-I
Accordingly, the primary object of the subject invention is the synthesi;~ of five pentapeptide derivatives of dolastat9_n 10 which exhibit effective antineoplastic activity against various human cancerous tumor cell lines.
Another obj ect of the :>ubj ect inventic>n is the synthesis of pentapeptide derivatives of dolastatin 10 through the coupling o:E respective tripeptide and dipeptide trifluoroacetate salts, whe:re.i.n the dipeptide salt was prepared by the coug~ling of dolaproine and the respective amino acid.
These and still further objects as shall .
hereinafter appear are readily fulfilled by the present invention in a remarkably unexpected manner as will be readily discerned from the fol:Lowing detailed description of an exemplary embodiment thereo:E .
DESGRIF'!,'ION OF THE PREFERRED EMBODIMEINT
The synthesis of potentially useful peptides presents one of the most ~assential and promising approaches to new types of anticancer and immunosuppressant drugs. The Dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cyto:;tatic peptides isolated from Indian Ocean sea hare Dolabella auricularia represent excellent leads fox synthetic modification. The very productive sea hare Dolabella auricularia has produced a number of structurally distinct peptides with esccellent antineoplastic activity. Presently Dolastatin 10, a linear pentapeptide represents the most important member and is a potentially useful antineoplastic agent. Dolastatin 10 shows one of the best antineoplastic activity profiles against various cancer screens presently known. Recently the total synthesis and absolute configuration of 'this structurally unique and bio:Logically active peptide was reported. This compound has been tested in vivo and demonstrated significant activity, as shown below.
Experimental Anticancer Acaivity of Dolastatin 10 in Murine in vivo Systems, T/C (~tg/kg) P388 L~ym~phocytic Leukemia Human Mammary Xenograph tC)X:LC (13.U) Ntlde MousQ
155 and 17% cures (6.5) Toxic (26) 146 anel 17% cures (3.25) 137 (13) 137 (1.63) 178 (6.25) T.1210 OVCAR-3 Human Ovary Xenograph Lymphocytic Leukemia 10152(13) Nude Mouse 135 (6.5) 300 (40) 139 (3.25) 120 (1.63) MX-1 Human Mammary Xenograft B16 Melanoma (Tumor Regression) 238 and 40% cures (11.11) 14 (52) 182 (6.67) 50 (26) 205 (4.0) 67. (13) 171 (3.4) 69 (6.25) 142 (1.44) 20M5076 Ovarv Sarcoma toxic (26) 166 (13) 142 (6.5) 151 (3.25) LOX Human Melanoma Xenograph to (Nude Mouse) toxic (52) 301 and 67% cures (26) 309. and 50% cures (13) 30206 and 33% cures (6.5) 170 and 17% cures (3.25) LOX in separate experiments 340 and 50% cures (43) 181 and 33% cures (26) 192 (15) 138 and 17% cures (9.0) ~~ ~~t~
Dolastatin 10 has also been tested against a minipanel from the NCt Primary screen. These results appear below, showing the amount of Dolastatin 10 required to attain GISO in ygJml, against 'the cell lines set forth below.
. 5 x:10 7 . 5 x:l2 . 5 x10' 3 . h x10-"
KM20L2 (E) SK-MEL-5 ~.7 x10 7.~ x10'a l0 From the foregoing, it can be seen that the in vitro activity of dolastatin 10 in the primary screen has been confirmed by in vivo animal tests.
For the compounds disclosed i.n this application, the in vitro tests disclosed above are reasonably accurate predictors of anticancer activity, and not mere indicators of the desirability for further testing.
These newly discovered pentapeptide Compounds (~a-3a), related to Dolastatin l0, are formed by 20 the coupling of the respective dipeptide fluoroacetate salts (2a-2e) with the known tripeptide-trifluoroacetate salt (.4). The dipeptides (1a-~.~) were in turn prepared by coupling dolaproine (5) with the respective amino acids. All compounds were characterized (physical and spectroscopic data) and tested against the marine lymphocytic P388 leukemia cell line as well as six major human cancer cell lines. The remarkable cancer cell growth inhibitory data are 30 shown in Table 1.
~~~4~'~~
'I'nblc 1. Intent inhibitinn of f:nnccr cell IIItes by I)entnpeptidcs :In-c 'ffl5'fCl.:!.1~'I'YI'L(:L'L,L.I.INIi~ 1'I'sN'fr\1'I:1''CIU!:
-StR/nti~ 3 :S ;) J 3 a a b c rl ~usoMouse L-EUKGbIfAP3R8 O.U6ti')O.Ol9S11.00880.0004410.11110389 ~
OvarianOVCr\R-:S<(l,Il0010.0076<0.0001<O.UU()l<(1.0001 .
CNS SF-29S<0.00(Il11,00085<0.1100)<O,OOOI<O,OOU1 OI-50Rcnai A-498 <O.U0010.00_097<O.OOOI<O.DOUI<0.0(lOl Lure-NSCNCI-II~460<O.OOOI0.000095<11,U001<O.OOUI<0,0001 Colon KM20L2<0.11001<0,(1(101<O.OOUI<0.0(lOt<0.0(10l MclanotnaSK-MEL-3<0.00010.00017<(1.0001<0.0001<0.0001 OvarianOVCAR-3U.DOII0.()077<O.OOOI<O.OOOI<0.0001 C~VS 29S 0.000170.049 0.(10240.17 (1.OS6 SP- -'COIRennl A498 0.0029O.U062(1.0054<0.0001>l Lunc-NSCNCI-11460O.Ol1O.OII 0.00130.0110890.13 Colon KM20I.211.00110.11190.0022<(1.OOOl0.00015 McinnomnSK-MEL-3(1.00068O.Ol2 <O,OUOI<0.0001>l OvnrinnOVC;1R-3>l 0.066 >l 0.043>1 (J1S SF-295>I >l >1 >l >l ' LC-50Renal A498 >l >I >l >l >l Lane-NSCNCI-H460>l >I >1 >i >I
Colon KM20L2>l O.OR3 >.l >l >i MelanomaSK-MEL-3>I >1 >l >I >l The human cancer cell lines results shown for pentapeptides 3a-a in Table I illustrate remarkably patent and selective activity against human ovary, CNS (brain), kidney, lung, colon and melanoma type cancers. In this respect, each compound parrots a pattern previously discovered for Dolastatin 10 and as such is reasonably expected to generate pn vivo data results comparable to those reported above for Dolastatin 10. .
The scheme and structures of these penta-peptides appear below:
~~~~~~.1 I-I CH3 H CI.I3 COOII Amino acid salt ~ \ TTIIfn0InilCCtiC
N ~ i . CO-l2 acid COQIInt OCI~Ig c OCEI
COOl3n L(n-e) I-I CI~I3 1 II~C
\N~ CO-N CO-N COON
CO-R III
/ ,\ ,,, CF~C00' Cf-I3 HI CII~ OCH3 Ei H
CF3C00' OCH3 ~
2(n~e) II CHI
H3C~ ,~
N 'CO-R
CO-i CO-N
CH3 H ~H3 OCI-h O OCI-I
3(a.e) s ~ 1, I3 c) R = N ~COOCH3 a) R = a ~N COOCH3 FI3C' \CII
H
R=
/ ~ ~N,r H COOCHj v b) R= ~ /CH3 S
e) R=
~,N~ CONI-IZ
s H SCIICMr I ~ I COOCFI3 21:x. 4 ~.
General Procedure for the Synthesis of Di;psptides (1a-9.e) To a solution of dolapro:ine tfa salt (:Lmmol) and 'the amino ac:Ld salt (lmmol) in dry dichloro-methane (2m1) , cooled to ice-bath temperature under an argon atmosphere was added dry triethy:lamine (3rnmo1) followed by diethylcyanophophonate ( 1. lmmol ) . The solution Hras stirred at the same ice bath temperature for 1.-2 hr. The salts that precipitated were collected, the solvent was evaporated (under reduced pressure) and the residue chromatographed over a SILICA GEL column with solvents noted to obtain the respective dipeptides.
i) Hoa-Dap-Phe-OCH3 (la):
Chromatographic separation on a SThICA GEL
column with 3:1 hexane-acetone as the eluent .resulted in the required dipeptide as a thick oil.
Crystallization from ether-hexane gave sparkling crystals of the pure compound (la, 96%) ~ m.p. -125°Cp [a]p 5 - -15.1° (c 0.41, CHC13) ; IR(~thin film): 3314, 2974, 2934, 2878, 1748, 1692, 1663, 1537, 1456, 1400, 1366, 1173, 1101 and 700; ~H NMR
(300MHz, CDC13): 1.163(d, J=7.OHz, 3H, CH3), 1. 4316 (s, 9H, t-Bu) , 1. 624-1. 850 (m, 4H, 2 x CHz) , 2.25-2.45(m, 1H, CHCO), 3.045(dd, J=13.9 and 7.8Hz, 1H, 1/2 CHz-Ph) , 3. 175 (dd, J=13. 8 and 5.55Hz, 1H, 1/2 CHz-Ph), 3.3642(x, 3H, OCH3), 3.3701(s, 3H, OCH3), 3.50-3.60(m, 1H, CH-OCH3), 3.7422(m, 2H, CHZ-N) , 3 . 85 (m, 1H, pro CH-N) , 4 . 80 (m, 1FI, phe ' CH-N), 6.10, 6.75(m, 1H, NH) and 7.10-7.32(:m, 5H, Ph); MS: m/z 416[M-CH30H], 375, 316, 264, 210, 170, 114(1000 and 70. Anal. Found: H: 8.12, N: 6.20.
Cz4H36NZ06 requires H: 8.09, N: 6.25.
ii) Boa-Dap-Phs-NHz (1b):
Chromatographic purification using a STLICA
GEL column with 1:1 hexane-acetone as the eluent 2~.~.4~1~i~
gave the required dipeptide: as a crystalline solid.
Recrystallization from aicetone gave sparkling crystals of the pure compound ( ~.b, 65 0 ) ; m. p.
199-200°C (acetone); [a]p2' _ -40° (c 0.15, CHCI~);
IR(thin film): 3302, 3198, 2974, 2934, 2878, 1669, 1539, 1456, 1404, 1366, 1169, 1111 and 700; ~H NMR
(300MHz, CDC13) : 1.019 (brs, 3H, CII3) , 1.426 (s, 9H, t-Bu) , 1. 55-1. 90 (m, 4H, 2 x CFIZ) , 2 . 30 (quintFt, 1H, CFI-CO) , 3. 00-3 . 25 (m, 3H, C;HZ-N, CH-OCHj) , 3. 349 (s, 3Ii, OCH~), 3.60-3.75(m, 1H, pro CH-N), 4.60-4.80(m, 1H, phe CH-N) , 5. 30 (brs, 1H, NH) , 6. 267 (d, J=7. 2I-Iz, 1H, NH), 6.90(brm, 1H, NH) and 7.164-7.306(m, 5H, CbHs); MS: m/z 433(M+), 401(M-MeOH), 360, 301, 247, 232, 210, 170, 154, 138, 114 and 70(100%). Anal.
Found: C: 63.75, H:8.18, N:9.62. C23H35N305 requires C: 63.72, H: 8.14, N: 9.69.
iii) Boc-Dap-Pro-OCH3 (1a);;
Chromatographic sepana~tion on a SILICA GEL
column with 3:2 hexane-aceaone as the eluent gave the required dipeptide as a thick oil (1a, 92% );
[a]p5 - -101.5° (c 0,2, CHC13); IR(neat): 2974, 2880, 1748, 1692, 1647, 1398, 1366, 1171andl 1098; ~H
NMR (300MHz, CDC13): 1.222(d, J=7.OHz, 3H, CH3), 1.440(s, 9H, t-Bu), 1.65-2.20(m, 8H, 4 x CHZ), 2.60-2.70(m, 1H, CH-CO), 3.10-3.22(m, 1H, CH-OCH3), 3 . 417 (s, 3H, CH3) , 3 . 45-3 . 65 (m, 4H, 2 x CHZ-N) , 3.675(s, 3H, OCH3), 3.74-3.83(m, 1H, CH-N) and 4.447 (dd, J=8. 55 and 3 . 5Hz, 1H, CH-COOCH3) . HRFABMS:
m/z 399.24880[M+H]ø. CzoH35N206 requires 399.26951.
' iv) Boc-Dap-Ile-OCH3 (1d):
Chromatographic purification on a SILICA GEL
column with 3:2 hexane-ethyl acetate, as the eluent yielded the required dipeptide as an oily liquid 1d, 720) ; m.p. -- 76-77°C (acetone) ; Ca]D S = -28°2°
(c 0.17, CHC13) ; IR(thin film) : 3325, 2971, 2936, 2878, 1746, 1694, 1667, :L530, 1478, 1398, 1254, 1175, 1105, 868 and 774; ~H NMR (300MHz, CDC13):
0.882(d, J=6.9Hz, 3H, CH3-CH), 0.9012(t, J=7.4Hz, 3H, CH3-CHZ) , 1. 05-1. 24 (m, 5H, CH3, CHz-CH3) , 1.4526(s, 9H, t-Bu), 1.65-2.00(m, 5FI, x CHZ
CIA-CH2~, 2 . 30-2 . 50 (m, 1FI, CH-CO) , 3 . 18-3 . 28 (:m, 1FI, C~-OCH3) , 3. 422 (s, 3FI, OCEI3) , 3 .48-3.1H, 60 (m, pro _C~,[-N) , 3 . 699 (s, 3FI, OCFI3) , 3.72-3.1FI, 82 (m, 1/2 CFIz-N) , 3 .88-3.98 (m, 1FI, 1/2 CFIz-N) , 4.44-4 . 58 (m, 1FI, ].le CH-N) and 6. 15, 6.7 (m, 1FI, MS:
NFI) ; m/z 382(M-MeOFI), 341, 282, 245, 230, 210, 170, 114, 70(100%) and 57. Anal. Found: C: 61.06,9.25, FI: N:
6.64. CZ~H3aN206 requires C: 60.84, H: N: 6.76.
9.24, v) Boo-Dap-Met-OCH3 (le):
Chromatographic separation on a SILICA GEL
column using 3:2 hexane-acetone as 'the eluent gave the required dipeptide as a solid (le, 83%); m.p. -68-70°C; [a]pzs = -27.6° (c, 0.59, CHC13); IR(neat):
3312, 2974, 2934, 2878, 1748, 1692, 1663, 1539, 1398, 1366, 1256, 1171, 1115, 866 and 774; ~H NMR
(CDC13) : 1. 223 (brs, 3H, CH-CFI3) , 1. 441 (brs, 9H, t-Bu), 1.6-1.2(m, 6H, 3xCHz), 2.070 (s, 3H, S-CH3), 2.3--2.55(m, 3H, CHZ-S, CH-CO), 3.15-3.35 (m, 2H, N-CHZ) , 3. 420 (s, 3H, OCH3) , 3.55 (m, 1H, CFI-OCH~) , 3.716(brs, 3H, COOCH3), 3.85-4.0(m, 1FI, pro CH-N), 4.6(brm, 1H, met CH-N), 6.3(brm, 1H, NH); MS (m/z):
432 (M+), 400, 359, 258, 210, 170,114(100%). Anal.
Found: C: 55.35, H: 8.33, N: 6.53, S: 7.23. CZOH36Nz06 S requires C: 55.53, H: 8.39, N: 6.48, S: 7.41.
Synthesis of phenylalanine amide trifluoroacetate salt:
' To a solution of t-boc-phenylalanine amide (3, 80mg, 0.303mmo1) in dichloromethane (0.5m1) was added trifluoroacetic acid (lml) at ice-bath temperature and the solution was stirred at the same temperature for 1.5 hr. under argon atmosphere. The solvents were removed under reduced pressure and the residue taken into toluene and toluene also removed under. reduced pressure to obtain a white solid of the trifluoroacetate salt 2~~ l~~'~)~
(80mg, 95~); ~H NMR (DMSO-d6, 300MHz): 2.95-3.10(m, 2H, C6H5-CHZ) , 3 . 3209 (brs, 2FI, NI-IZ) , 3 . 9408 (brs, 1I-I, CH-N), 7.236-7.317(m, 5H, C6H5) and 7.528, 7.862, 8.150 (brs, 3I-I, NH~~) .
DEPROTRCTIO~Y OF DTPEPTIDES 1a-a WTT~i TRTFLUOROACETIC ACID- aENERA1G PROCEDURE:
To a solution of the Boo-protected dipeptide (lmmol) in dry dichloromethane (2m1, cooled to ice-bath temperature, under an argon atmosphere) was added trifluoroacetic acid (2m1) and the solution was stirred at the same temperature fox 1-2 hr. After removing the solvent under reduced pressure, the residue was dissolved in toluene and solvent was again removed under reduced pressure.
The latter operation was repeated to remove all the :5,:
trifluoroacetic acid. The residue was dried (in vacuo) to obtain the trifluoroacetate salts of the respective dipeptides. Wherever possible, the trifluoroacetate salts were characterized from spectral data and physical constants recorded.
Synthesis of Dap-Phe-OCH3 Tfa (2a):
After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (2a, quantitative) as a colorless crystalline solid: IR(thin film): 3275, 2928, 1744, 1674, 1541, 1456, 1202, 1132 and 72,1; ~H
NMR (300MHz, CDC13): 1.107(brs, 3H, CH3), 1.60-2.10(m, 4H, 2 x CHZ), 2.60(m, 1H, CHCO), ' 2 . 90-3. 00 (m, 2H, CHZ-Ph) , 3 .10-3 > 35 (m, 3H, CfI-OCH3, CHZ-N) , 3 . 209 (s, 3H, OCH3) , 3 . 40-3 . 55 (m, 1H, pro CH-N), 3.712(s, 3H, COOCH3), 4.75(m, 1H, phe CH-N), 7.106(m, :LH, NH), 7.124-7.324(m, 5H, Fh) and 8.7(m, 1H, NH); HRFABMS: m/z 349.21350(100%, cation);
[C~9H29N204]'" requires 349.21273.
Synthesis of Dap-Phe-NHZ Tfa (2b):
r., :~. ~. .:~ ) Removal of toluene under reduced pressure left the trifluoroacetate salt (2b, 97% ) as a colorless solid.
&ynthesis of Dap-.lPro-OCH3 ~fa (20):
After removing toluene under reduced pressure, t h a residue obtained as a think oily mass was triturated with ether to obtain the trifluoroacetate salt (20, 99%) as a colorless crystalline solid: TR(thin film): 2980, 2890, 1746, 1680, 1626, 1437, 1287, 1200, 1094, 799 and 721; ~H
NMR (300MHz, CDC13): 1.307(d, J=6.9Hz, 3'H, CH3), 1. 85-2 . 30 (m, 8H, 4 x CHZ) , 2 . 85 (m, 1H, CH-CO) , 3 .20-3.40 (m, 1H, CH-OCH3) , 3. 485 (s, 3H, CHI) , 3.35-3.75(m, 3H, CH-N, CHZ-N), 3.687(s, 3H, COOOCH3) , 4 .165 (m, 2H, CHZ-N*) , 4 . 442 (m, 1FI, CH-N+) and 8.008(m, NH). HRFABMS: m/z 299.19770(100%, cation) t [C~SHZ~N204]+ requires 299.1971.
Synthesis of Dap-Il~-OCH3 Tfa (2d):
After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (2d, 97%) as a gummy mass:
IR(thin film): 3289, 2969, 2884, 1744, 16?4, 1541, 1458, 1383, 1202, 1136, 833, 799 and 721; ~H NMR
(300MHz, CDC13): 0.88(brs, 3H, CH3), 1.884(t, J=6.7Hz, 3H, CH3-CHZ) , 1. 209 (d, J=6.8Hz, CH3-CH) , 1.10-1.50(m, 2H, CHZ), 1.80-2.20(m, 5H, 2 X CHz, ' CH3-CH), 2.707(m, 1H, CH-CO), 3.10-3.41(m, 2H, CHZ-N), 3.470(s, 3H, OCH3), 3.60-3.70(M, 1H, CH-OCH3), 3.48-3.85-3.90(m, 1H, pro CH-N), 3.702(s, 3H, COOCH3), 4.43(dd, J=7.5 and 5.4Hz, 1H, ile CH-N), 6.926(d, J=7.9Hz, 1H, NH), 8.8(m, 1H, 1/2 NHz) and 10 (m, 1H, 1/2 NHZ): MS: HRFAE3: m/z 315.22890(100%. Cation) p (C~6H31N204]* requires 315.22838.
Synthesis of Dap-Met-OCH3 Tfa (2e);
Removal of toluene under reduced ;pressure left the trifluoroacetate salt (2e, quantitative) as a gummy mass.
SYNTHESIS OF PENTABEPTIDES 3a-a ~ ~3E1NERAL
PROCEDURE;
To a solution of the tripeptide tfa ;salt (4, lmmol) and the dipeptide tfa salt (lmmol) in dichloromethane (2m1, ice-bath and under argon) was added dry triethylamine (3mmol) followed by diethylcyanophosphonate (l.lmmol). The solution was stirred at the same temperature for 1-2hr.
After removing solvent under reduced pressure the residue was chromatographed on a SILICA GEL column using the solvent system given below as eluents to obtain the respective pentapeptides (3a-e).
Dov-Val-Dil-Dap-Phe-OCH3 (3a):
Chromatographic separation on a SIL~TCA GEL
column with 3:4 hexane-acetone as the eluent gave the required pentapeptide(3a, 87%); m.p. - 80-83°C
[a]p 5 = -35.3 ° (c 0.34, CHC13) ; IR(thin film) 3298, 2963, 2934, 2876, 2830, 2787, 1748, 1622, 1532, 1454, 1379, 1269, 1200, 1099, 1038, 737 arid 700; MS: m/z 759(Mi), 716, 481, 449, 433, 227, 186, 154, 128, 100(100%), 85 and 70. Anal. Found: C:
64.91, H: 9.33, N: 8.97. C4~H69N508 requires C: 64.71, H: 9.15, N: 9.22.
Dov-Val-Dil-Dap-Phe-NHZ(9b):
Chromatographic separation on a SILICA GEL
column with 1:3 hexane-acetone as the eluent resulted in the required pentapeptide as colorless powder (33~, 99 0) ; m.p. = 111-113 °C ; [a]p 5 = -42 ° (c 0.25, CHCl3) ; IR(thin film) : 3304, 3138, 3054, 2965, 2934, 2876, 2830, 2787, 1622, 1541, 1499, 1423, 1371, 1306, 1252, 1202, 1171, 1098, 1038, 756, 735 and 696; MS: m/z 744(M+), 701, 669, 519, 481, 418, 227, 206, 186, 170, 154, 128 and 114.
Dov-Val-Dil-Dap-Pro-OCH3 (3a):
Chromatographic purification using a SILICA
GEL column with 1:3 hexane-acetone as the eluent yielded the required pentapeptide as colorless powder (3a, 69%) ; m.p. = 75-77°C ; [a]p25 = _52.7° (c 0.11, CI-IC13) ; IR(thin film) : 3293, 2963, 2876, 2830, 2789, 1750, 1624, 1422, 1385, 1273, 1198, :L096, 1040 and 733; MS: m/z 709(:M"), 666, 581, 481, 449, 412, 383, 369, 297, 255, 227(100%), 199, 186, 170 and 155. Anal. Found: C: 62.51, H: 9.61, N: 9.72.
C3~H6~N508 requires C: 62.59, H: 9.51, N: 9.87.
Dov-val-Dil,-Dap-Ile-OCH3 (3~d) Chromatographic separation on a SILICA GEL
column with 1:2 hexane-acetone as the elu~ent gave the required pentapeptide .as colorless powder (3d, 80% ); m.p. - 80-82°C; [a]p25 = -39.3° (c 0.14, CHC13) ; IR(thin film) : 3300, 3050, 2965, 2878, 2830, 2787, 1746, 1622, 1530, :L454, 1383, 1267, 1120, 1099, 1038 and 735; MS: m/z 725(M+), 682, 481, 399, 227, 186, 170, 154 and 128. Anal. Found: C: 63.03, H: 10.01, N: 9.77. C38H7~N5t~8 requires C: 62.86, H:
9.86, N: 9.65.
Dov-va7.-Di1-Dap-Met-OCH3 (;De) ' Chromatographic separation using a SILICA GEL
column with 1:2 hexane-acetone as the eluent .resulted in the required pentapeptide as colorless powder (3e, 78%) ; m.p. = 63-65°C; [a]o 5 = -44.1" (C, 0.44, CHC13) ; IR(thin film) : 3297, 2963, 2934, 2876, 2830, 2787, 1750, 1620(br),. 1539, 1449, 1420, 1375, 1198 and 1098; MS (m/z) : '743 (M+) , 700, 611, 568, 481, 417, 311, 227 and 154. Anal. Found: C: 59.78, H: 9.14, N: 9.16, S: 4.39. C3~H69N5068S requires C:
,;::~
59.73, H: 9.35, N: 9.41, S: 4.31.
To further aid in the understanding of the present invezxtion, and not by way of l:Lm:i.tation, the following examples axe presented.
Example ~a - 8ynthas3s of Boc-Dap-Phe-OCH~ (:La):
The general procedure for the synthesis of dipeptides (1a-1e) was followed. The numerical identificate shown in Scheme 1 is followed herein.
Chromatographic separation on a SILICA GEL column with 3:1 hexane-acetone as the eluent resulted in the required dipeptide as a thick oil.
Crystallization from ether-hexane gave sparkling crystals of the pure compound (~.a, 96~) ; m.p. -125°C; [a]p 5 = -15.1 (c 0.41, CHC13) ; IR(thin film) 3314, 2974, 2934, 2878, 1748, 1692, 1663, 1537, 1456, 1400, 1366, 1173, 1101 arid 700; ~H NMR
(300MHz, CDC13): 1.163(d, J=7.OHz, 3H, CH3), 1. 4816 (s, 9H, t-Bu) , 1. 624-1. 850 (m, 4H, 2 x CHz) , 2.25-2.45(m, 1H, CHCO), 3.045(dd, J=13.9 and 7.8Hz, 1H, 1/2 CHz-Ph), 3.175(dd, J=13.8 and 5.55Hz, 1H, 1/2 CHz-Ph), 3.3642(s, 3H, OCH3), 3.3701(s, 3H, OCH3), 3.50-3.60(m, 1H, CH-OCH3), 3.7422(m, 2H, CHz-N), 3.85(m, 1H, pro CH-N), 4.80(m, 1H, phe CH-N), 6.10, 6.75(m, 1H, NH) and 7.10-7.32(m, 5H, Ph); MS: m/z 416(M-MeOH), 375, 316, 264, 210, 170, 114(100%) and 70. Anal. Found: H: 8.12, N: 6.20.
Cz~H3eN20s requires H: 8.09, N: 6.25.
' Example Ib - Synthesis of Boc-Dap-Phe-PIHZ (1b):
The general procedure for the synthe~;is of dipeptides (1a-1e) was followed. Chromatographic purification using a SILICA GEL column wii~h 1:1 hexane-acetone as the eluent gave the required dipeptide as a crystalline solid.
Recrystallization from acetone gave sparkling crystals of the pure compound (l.b, 65%); m.p. -2114'156 199-200°C (acetone) ; [a]pzs = -40 (c 0.15, CkiCl3) ;
IR(thin film): 3302, 3198, 2974, 2934, 2878, 1669, 1539, 1456, 1404, 1366, 11119, 1111 and 700; ~H NMR
(300MHz, CDC13) : 1. 019 (brs, 3kI, CkI3) , 1. 426 (s, 9kI, t-Eiu), 1.55-1.90(m, 4ki, 2 x CHz), 2.30(quintet, 1H, CH-CO) , 3 . 00-3. 25 (m, iii, C:FIz-N, CH-OCki3) , 3. 349 (s, Ski, OCi~I3) , 3 . 60-3 . 75 (m, 1k3, pro CkI-N) , 4. 60-4 . 80 (m, lkI, phe CH-N) , 5. 30 (brs, 1H, NFI) , 6. 287 (d,. J=7. 2kiz, lkl, NH) , 6. 90 (brm, lkI, NH) and 7. 164-7 . 306 (m, 5H, C6Hs) ; MS: m/z 433 (M*) , 401 ~;M-MeOH) , 360, 301, 247, 232, 210, 170, 154, 138, 114 and 70(1000 . Anal.
Found: C: 63.75, H:8.18, N:9.62. Cz3H3sN3Os requires C: 63.72, H: 8.14, N: 9.69.
Eacample Tc - Synthesis of lBoc-Dap-Pro-OCH~ (1c):
The general procedure for the synthesis of dipeptides was followed. Chromatographic separation on a SILICA GEL column with 3:2 hexane-acetone as the eluent gave the required dipeptide as a thick oil (7.c, 92~) ; [a]pz5 - _101.5 (c 0.2, CHC13) ; IR(neat) : 2974, 2880, 1748, 1692, 1647, 1398, 1366, 1171and. 1098; ~H NMR (300MHz, CDC13): 1.222(d, J=7.OHz, 3H, CH3), 1.440(x, 9H, t-Bu), 1.65-2.20(m, 8H, 4 x CHz), 2.60-2.70(m, 1H, CH-CO), 3.10-3.22(m, 1H, CH-OCH3), 3.417(x, 3H, CH3), 3.45-3.65(m, 4H, 2 x CHz-N), 3.675(x, 3H, OCH3), 3.74-3.83(m, 1H, CH--N) and 4.447(dd, J=8.55 and 3.5Hz, 1H, CH-COOCH3). HRFABMS: m/z 399.24880 (M+H)*; . [CZpH3sN206]* requires 399.24951.
Eacample Id - Synthesis of I3oo-Dap-ale-OOHS (sd) o The general procedurE~ for the synthesis of dipeptides (la-1e) was followed. Chromatographic purification on a SILICA. GEL column with 3:2 hexane-ethyl acetate as i~he eluent yielded the required dipeptide as an oily liquid (id, 72%);
m.p. - 76-77°C (acetone) : [a]pzs = -28.2 (c 0.17, CHC13) ; IR(thin film) : 3325,, 2971, 2936, 2878, 1746, 1694, 1667, 1530, 1478, 1398, 1254, 1175, 1105, 868 2I1i5 and 774; ~H NMR (300MHz, CDC13): 0.882 (d, J=6.9Hz, 3H, CH3-CH) , 0. 9012 (t, J=7. 4Hz, 3H, !CH;-CHZ) , 1. 05-1.24 (m, 5FI, CFI3, CHZ-CFI3) , 1, 4526 (s, 9H, t-Bu) , 1. 65-2 . 00 (m, SFI, 2 x CFIz, C~F~-CHZ) , 2 . 30-2 . 50 (m, 1FI, CFF-CO) , 3 . 18-3. 28 (m, 1FI, C~-OCFi~) , 3.422 (s, 3FI, OCFI3) , 3. 48-3. 60 (m, 1FI, pro ,~-N) , 3. 6951 (s, 3FI, OCFIj) , 3 . 72-3 .82 (m, 1FI, 1/2 CFIZ-r1) , 3 . 88-3 , 98 (m, 1FI, 1/2 CFIZ-N) , 4. 44-4 . 58 (m, 9.FI, i1e CFI-N) and 6. 15, 6.7(m, 1H, NFI); MS: m/z 382(M-MeOH), 341, 282, 245, 230, 210, 170, 114, 70(1000 and 57. Anal. Found:
C: 61. 06, H: 9. 25, N: 6. E.4. CZ~H38N206 requires C:
60.84, H: 9.24, N: 6.76.
Example Ie - Synthesis of ;Boc-Dap-Met-OCH3 (xe):
The general proaedur~a for the synthe:;is of dipeptides (1a-1e) was fo7.lowed. Chromatographic separation on a SILICA GEL column using 3:2 hexane-acetone as the eluent gave the required dipeptide as a solid (1e, 83~k) ~ m.p. - 68-70°C;
(a]pZS= -27.6 (c, 0.59, CHCl;s) ; IR(neat) : 3312, 2974, 2934, 2878, 1748, 1692, x.663, 1539, 1398, 1366, 1256, 1171, 1115, 866 anal 774; ~H NMR (CDC13):
1.223(brs, 3H, CH-CH3), 1.441(brs, 9H, t-Bu), 1.6-1.2 (m, 6H, 3xCHZ) , 2.070 (s, 3H, S-CH3) , 2.3-2.55(m, 3H, CHZ-S, CH-CO), 3.15-3.35 (m, 2H, N-CHZ) , 3. 420 (s, 3H, OCH3) , 3.55 (m, 1H, CH-°OCH3) , 3.716(brs, 3H, COOCH3), 3.85-4.0(m, 1H, pro CH-N), 4.6(brm, 1H, met CH-N), 6.3(brm, 1H, NH): MS (m/z):
432 (M+), 400, 359, 258, 210, 170, 114(100%). Anal.
Found: C: 55.35, H: 8.33, N: 6.53, S: 7.23. CZaH36N206 S requires C: 55.53, H: 8.39, N: 6.48, S: 7.41.
Example TIa - gynthesis of Dap-Phe-oCH3 Tfa~ (xa):
General procedure A was followed. After removing toluene under reduced pressure, the residue obtained as a thief oily mass was ti~trated with ether to obtain the trifluoroacetate salt (2a, quantitative) as a colorless crystalline: solid:
IR(thin film): 3275, 2928, 1744, 1674, 1541, 1456, zm4ms 1202, 1132 and 721; ~H NMR (300MHz, CDC13):
1. 107 (brs, 3H, CFI) , 1. 60-2 . 10 (m, 4H, 2 ~" CHZ) , 2 . 60 (m, 1FI, CFiCO) , 2 . 90-3 . 00 (m, 2FI, CII2-Ph) , 3. 10-3. 35 (m, 3FI, CFA-OCFI3, CHZ-N) , 3. 209 (s, 3FI, OCFI~) , 3 .40-3. 55 (m, 1II, pro CFI-N) , 3 . 712 (s, 3FI, COOCFI3) , 4 , 75 (m, 1H, phe CFI-N) , 7 .106 (m, 1FI, NFI) , 7. 124-~ 7. 324 (m, 5FI, Ph) and 8.7 (xa, 7.II, NFI) ; IiFtF~ABMS:
m/z 349.21350(100, nation) ; (G~9FI29N20~]* requires 399.21273.
Example IIb - 8ynthe~is of Dap-Ph~-NHZ Tfa (2b):
General procedure A was followed. Removal of toluene under reduced pressure left the trifluoroacetate salt (2b, 97~) as a co7.orless solid.
Exampl~ IIa - Synthesis of Dap-Pro-OCH3 Tfa (2a):
General procedure A was followed. After removing toluene under reduced pressure, residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (20, 990) as a colorless crystalline solid: IR(thin film):
2980, 2890, 1746, 1680, 1626, 1437, 1287, 1200, 1094, 799 and 721; ~H NMR (300MHz, CDC13): 1.307(d, J=6.9Hz, 3H, CH3), 1.85-2.30(m, 8H, 4 x CHZ), 2.85(m, 1H, CH-CO), 3.20-3.40(m, 1H, CH-OCH3), 3.485(s, 3H, CH3), 3.35-3.75(m, 3H, CH-N, CHz-N), 3. 687 (s, 3H, COOOCH3) , 4. 165 (m, 2H, CFIZ-N*) , 4 .442 (m, 1H, CH-N*) and 8.008(m, NH). HRFABMS: m/z 299.19770(100%, cation) ; [C~SHZ~Nz04]* requires 299.1971.
Exaanple IId - Synthesis of >aap-Ile-OCH3 Tfa (2d) :
General procedure A was followed. After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoro-acetate salt (2d, 970) as a gummy mass: IR(thin film): 3289, 2969, 2884, 1744, 1674, 1541, 1458, 1383, 1202, 1136, 833, 799 and 721; ~H NMR (300MHz, ~:~1~156 CDC13): 0.88(brs, 3H, CH3), 1.884(t, J=6.7Hz, 3H, CFI3-CHZ) , 1. 209 (d, J=6. 8Hz, CH3-CH) , 1. 10-1. 50 (m, 2H, CHz) , 1. 80-2. 20 (m, 5H, 2 X CFI2, CFi3-CFI) , 2 .707 (m, lFi, CFI-CO) , 3 . 10-3. 41 (m, 2FI, CFi2-N) , 3 . 470 (s, 3FI, 0CFI3) , 3 . 60-3 . 70 (M, 1FI, C~-OCFI~) , 3 . 85-3 . 90 (m, 1FI, pro ~-N) , 3.702 (s, 3FI, COOCFij) , 4. 43 (dd, J=7. 5 and 5.4Fiz, lFi, ile CFI-N) , 6.926 (d, J=7.9FIz, 1H, NH) , 8.8 (m, lFi, 1/2 NFiz) and 10 (m, 1FI, 1/2 NHz) ; MS:
HRFAB: m/z 315.22890(100. ration) ; [C,6FI31N204~*
requires 315.22838.
Example IIe - Synthesis of Dap-Mat-OCH3 Tfa (2e):
General procedure A was followed. Removal of toluene under reduced pressure left the trifluoro-acetate salt (2e~ quantitative) as a gummy mass.
Example IIIa - Synthesis o~ Dov-Val-Dil-Dap-Phs-OCIi~
(3a) Chromatographic separation on a STLICA GEL
column with 3:4 hexane-acetone as the eluent gave the required pentapeptide(3a, 87~); m.p. - 80-83°C
; [a]D 5= -35.3 (c 0.34, CHC13) ; IR(thin film) : 3298, 2963, 2934, 2876, 2830, 2787, 1748, 1622, 1532, 1454, 1379, 1269, 1200, 1099, 1038, 737 and 700;
MS: m/z 759(M+), 716, 481, 449, 433, 227, 186, 154, 128, 100(100%), 85 and 70. Anal. Found: <:: 64.91, H: 9.33, N: 8.97. C4~H69Ns08 requires C: 64.71, H:
9.15, N: 9.22.
Example IIIb - Synthesis o~ DoV-Val-Dil-Dap-Phe-iJgiz ' (3b) :
General procedure B was followed.
Chromatographic separation on a SILICA GEL column with 1:3 hexane-acetone as the eluent resulted in the: required pentapeptide as colorless powder (3b, 99~); m.p. = 111-113°C ; [a~pz5= -42 (c 0.25, CHC13);
IR(thin film): 3304, 3138, 3054, 2965, 2934, 2876, 2830, 2787, 1622, 1541, 1499, 1423, 1371, 1306, r z~~~156 1252, 1202, 1171, 1098, 1038, 756, 73°.> and 696; MS:
m/z 744 (M+) , 701, 669, 519, 481, 418, :?27, 206, 186, 170, 154, 128 and 114.
Example IIIa - synthesis of Dov-Val-Dill-Dap-pro-OCH3 (3a) s General procedure B was followed.
Chromatograph:Lc purification using a SILICA GEL
column with 1:3 hexane-acetone as the eluent yielded the required pentapeptide as co:Lorless powder (3a, 69~); m.p. = 75-77°C ; [a]p5= -52.7 (c 0.11, CHC13) ; IR(thin film) : 3293, 2963, 2876, 2830, 2789, 1750, 1624, 1422, 1385, 1273, 1198, 1096, 1040 and 733; MS: m/z 709(M+), 666, 581, 481, 449, 412, 383, 369, 297, 255, 227(1000), 199, 186, 170 and 155. Anal. Found: C: 62.51, H: 9.61, N: 9.72.
C37H67N5~a requires C: 62.59, H: 9.51, N: 9.87.
Example TIId - synthesis of Dov-Val-Dil-Dap-Ile-OCH3 (3d) General procedure B was followed.
Chromatographic separation on a SILTCA Gr~L column with 1:2 hexane-acetone as the eluent gave the required pentapeptide as colorless powder (3d, 80~); m.p. - 80-82°C ; [a]pz5= -39.3 (c 0.14, CHC13) ; IR(thin film) : 3300, 3050, 2965, 2878, 2830, 2787, 1746, 1622, 1530, 1454, 1383, 12Ei7, 1120, 1099, 1038 and 735; MS: m/z 725(M+), 682, 481, 399, 227, 186, 170, 154 and 128. Anal. Found: C: 63.03, H: 10.01, N: 9.77. C38H7~N5~08 requires C: 62.86, H:
' 9.86, N: 9.65.
Example IIIe - sgnthesis of Dov-Val-Dil-Da~u-Met-OCH3 (3e) General procedure B was followed.
Chromatographic separation using a SI:L7CCA GEL
column with 1:2 hexane-acetone as the eluent resulted in the required pentapeptide as c~o:iLorless ~~~i~s powder (3e, 78%); m.p. - 63-65°C; (a]pZS= -44.1 (c, 0.44, CHC13) ; IR(thin film) : 3297, 2963, 2934, 2876, 2830, 2787, 1750, 1620(br), 1539, 1449, 1420, 1375, 1198 and 1098; MS (m/z) : 743 (Nf~) , 700, 611, 568, 487., 417, 311, 227 and 154. Anal. T'ound: C: 59.78, I3: 9.14, N: 9.16, S: 4.39. C~~I~I69N506n8 rec~uiras C:
59.73, II: 9.35, N: 9.41, S: 4.31.
From the foregoing, it is readily apparent that a useful embodiment of the present invention has been herein described and illustrated which i fulfills all of the aforestated objectives in a remarkably unexpected fashion. It is of course understood that such modifications, alterations and adaptations as may readily occur to the artisan confronted with this disclosure are intended within the spirit of this disclosure which is limite=d only by the scope of the claims appended hereto.
i
Claims (23)
1. A compound having the structural formula designated 3(a-e):
wherein R is selected from the following group of substituents:
wherein R is selected from the following group of substituents:
2. A compound according to claim 1 in which R
is the substituent designated a.
is the substituent designated a.
3. A compound according to claim 1 in which R
is the substituent designated b.
is the substituent designated b.
4. A compound according to claim 1 in which R
is the substituent designated c.
is the substituent designated c.
5. A compound according to claim 1 in which R
is the substituent designated d.
is the substituent designated d.
6. A compound according to claim 1 in which R is the substituent designated e.
7. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as defined in any one of claims 1 to 6, and a pharmaceutically acceptable carrier.
8. Use of a compound as defined in any one of claims 1 to 6, for inhibiting the growth of human cancer cells responsive thereto.
9. A method of synthesizing a pentapeptide as defined in claim 1, which comprises: selecting dolaproine tfa salt;
selecting an amino acid salt; dissolving said amino acid salt in cooled dry dichloromethane and triethylamine;
adding said dolaproine tfa salt to said amino acid salt solution to produce a solution; adding diethylcyanophosphonate (DECP) to said solution; cooling said DECP-containing solution to cause precipitation in the solution;
evaporating the solvents from said precipitate-containing solution under reduced pressure to leave a residue;
chromatographing said residue over a SILICA GEL column with solvents to isolate the respective dipeptide; dissolving said dipeptide in cooled dry dichloromethane and adding trifluoroacetic acid thereto to create a second solution;
stirring said second solution, removing solvent from said second solution, under reduced pressure to provide a second residue; repeatedly dissolving said second residue in toluene and thereafter evaporating said solvent therefrom to remove all trifluoroacetic acid from said second residue; drying said second residue in vacuo thereby to obtain the trifluoroacetate salt of the respective dipeptide; admixing the respective tripeptide tfa salt to said dipeptide salt; dissolving said salts in dichloromethane in an ice-bath under an argon atmosphere to form a third solution; adding dry triethylamine to said third solution and thereafter; adding diethylcyanopho- phonate thereto to form a resultant fourth solutions stirring said fourth solution; removing solvent from said fourth solution under reduced pressure to leave a third residue; and chromatographing said third residue on a SILICA GEL column to isolate the desired pentapeptide.
selecting an amino acid salt; dissolving said amino acid salt in cooled dry dichloromethane and triethylamine;
adding said dolaproine tfa salt to said amino acid salt solution to produce a solution; adding diethylcyanophosphonate (DECP) to said solution; cooling said DECP-containing solution to cause precipitation in the solution;
evaporating the solvents from said precipitate-containing solution under reduced pressure to leave a residue;
chromatographing said residue over a SILICA GEL column with solvents to isolate the respective dipeptide; dissolving said dipeptide in cooled dry dichloromethane and adding trifluoroacetic acid thereto to create a second solution;
stirring said second solution, removing solvent from said second solution, under reduced pressure to provide a second residue; repeatedly dissolving said second residue in toluene and thereafter evaporating said solvent therefrom to remove all trifluoroacetic acid from said second residue; drying said second residue in vacuo thereby to obtain the trifluoroacetate salt of the respective dipeptide; admixing the respective tripeptide tfa salt to said dipeptide salt; dissolving said salts in dichloromethane in an ice-bath under an argon atmosphere to form a third solution; adding dry triethylamine to said third solution and thereafter; adding diethylcyanopho- phonate thereto to form a resultant fourth solutions stirring said fourth solution; removing solvent from said fourth solution under reduced pressure to leave a third residue; and chromatographing said third residue on a SILICA GEL column to isolate the desired pentapeptide.
10. An in vitro method for inhibiting the growth of human cancer cells in an environment which comprise administering a pharmaceutically acceptable carrier combined with an amount of an active agent which is selected from the compounds claimed in any one of claims 1 to 6 effective to inhibit the growth and effects of tumor cells in human cancer cells within the environment to which the administration is effected.
11. An in vitro method for inhibiting the growth of human cancer cells wherein said cancer is selected from the group consisting of leukemia, ovarian cancer, CNS cancer, mammary cancer, non-small cell lung cancer, renal cancer, colon cancer, and melanoma consisting of administering an active ingredient selected from the group consisting of:
Dov-Val-Dil-Dap-Phe-OCH3, Dov-Val-Dil-Dap-Phe-NH2, Dov-Val-Dil-Dap-Pro-OCH3, Dov-Val-Dil-Dap-Ile-OCH3, and Dov-Val-Dil-Dap-Met-OCH3, to said cells in a quantity sufficient to inhibit the growth of said cells.
Dov-Val-Dil-Dap-Phe-OCH3, Dov-Val-Dil-Dap-Phe-NH2, Dov-Val-Dil-Dap-Pro-OCH3, Dov-Val-Dil-Dap-Ile-OCH3, and Dov-Val-Dil-Dap-Met-OCH3, to said cells in a quantity sufficient to inhibit the growth of said cells.
12. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-OCH3.
13. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-NH2.
14. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Pro-OCH3.
15. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Ile-OCH3.
16. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Met-OCH3.
17. An in vitro method according to claim 11 for inhibiting the growth of human cancer cells selected from the group of cell lines consisting of P388 Lymphotic Leukemia, L1210 Lumphatic Leukemia, B16 Melanoma, M5076 Ovary Sarcoma, LOX Human Melanoma, Human Mammary MX-7, and OVCAR-3, consisting of administering an active ingredient selected from the group consisting of Dov-Val-Dil-Dap-Phe-OCH3, Dov-Val-Dil-Dap-Phe-NH2, Dov-Val-Dil-Dap-Pro-OCH3, Dov-Val-Dil-Dap-Ile-OCH3, and Dov-Val-Dil-Dap-Met-OCH3, to said cells in a quantity sufficient to inhibit the growth of said cells.
18. An in vitro method according to claim 11 wherein said cancer is selected from the group of cell lines consisting of P388, OVCAR-3, SF-295, A498, NCI-H460, KM20L2, and SK-MEL-3.
19. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-OCH3.
20. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-NH2.
21. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Pro-OCH3.
22. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Ile-OCH3.
23. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Met-OCH3.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8288352B2 (en) | 2004-11-12 | 2012-10-16 | Seattle Genetics, Inc. | Auristatins having an aminobenzoic acid unit at the N terminus |
| US10494432B2 (en) | 2007-07-16 | 2019-12-03 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
| US10544218B2 (en) | 2008-01-31 | 2020-01-28 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
| US10981987B2 (en) | 2007-07-16 | 2021-04-20 | Genentech, Inc. | Humanized anti-CD79b antibodies and immunoconjugates and methods of use |
| US11000510B2 (en) | 2014-09-23 | 2021-05-11 | Genentech, Inc. | Methods of using anti-CD79b immunoconjugates |
Families Citing this family (680)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69434136T2 (en) * | 1993-10-01 | 2005-12-01 | Teikoku Hormone Mfg. Co., Ltd. | Dolastatin DERIVATIVES |
| US6686445B1 (en) | 1997-09-24 | 2004-02-03 | Arizona Board Of Regents, Acting For And On Behalf Of Arizona State University | Synthetic antineoplastic agents derived from dolastatin 15 and methods of making same |
| CA2298639C (en) * | 1997-09-24 | 2005-07-05 | Erik J. Flahive | Synthetic antineoplastic agents derived from dolastatin 15 and methods of making same |
| JP4776843B2 (en) | 1999-10-01 | 2011-09-21 | イムノゲン インコーポレーティッド | Cancer composition and method using immunoconjugate and chemotherapeutic agent |
| US7256257B2 (en) | 2001-04-30 | 2007-08-14 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
| US6884869B2 (en) * | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
| US20100056762A1 (en) | 2001-05-11 | 2010-03-04 | Old Lloyd J | Specific binding proteins and uses thereof |
| PT1392359E (en) | 2001-05-11 | 2010-01-27 | Ludwig Inst For Cancer Res Ltd | Specific binding proteins and uses thereof |
| SI2357006T1 (en) * | 2002-07-31 | 2016-01-29 | Seattle Genetics, Inc. | Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease |
| AU2004213053C1 (en) | 2003-02-20 | 2009-07-16 | Seagen Inc. | Anti-CD70 antibody-drug conjugates and their use for the treatment of cancer and immune disorders |
| CA2543888C (en) | 2003-11-06 | 2016-01-19 | Seattle Genetics, Inc. | Monomethylvaline compounds capable of conjugation to ligands |
| CN101065151B (en) | 2004-09-23 | 2014-12-10 | 健泰科生物技术公司 | Cysteine engineered antibodies and conjugates |
| ATE476994T1 (en) | 2004-11-30 | 2010-08-15 | Curagen Corp | ANTIBODIES TO GPNMB AND THEIR USES |
| FR2883873B1 (en) | 2005-03-31 | 2009-07-10 | Pharmamens Sarl | AGE INHIBITORS |
| EP1871418B1 (en) | 2005-04-19 | 2014-03-19 | Seattle Genetics, Inc. | Humanized anti-cd70 binding agents and uses thereof |
| EP3498289A1 (en) | 2005-07-07 | 2019-06-19 | Seattle Genetics, Inc. | Monomethylvaline compounds having phenylalanine side-chain modifications at the c-terminus |
| WO2007008848A2 (en) * | 2005-07-07 | 2007-01-18 | Seattle Genetics, Inc. | Monomethylvaline compounds having phenylalanine carboxy modifications at the c-terminus |
| WO2007011968A2 (en) | 2005-07-18 | 2007-01-25 | Seattle Genetics, Inc. | Beta-glucuronide-linker drug conjugates |
| ES2547689T3 (en) | 2005-12-02 | 2015-10-08 | Genentech, Inc. | Compositions and methods for the treatment of diseases and disorders associated with cytokine signaling that involve antibodies that bind to IL-22 and IL-22R |
| KR101538521B1 (en) | 2005-12-15 | 2015-07-22 | 제넨테크, 인크. | Methods and compositions for targeting polyubiquitin |
| BRPI0706840A2 (en) | 2006-01-05 | 2011-04-05 | Genentech Inc | polynucleotide isolated anti-ephb4 antibodies, vector, host cell, method for producing an anti ephb4 antibody, method for producing an anti ephb4 immunoconjugate, method for detecting ephb4, method for diagnosing a composition disorder, method for inhibiting angiogenesis, method for treating a cancer, tumor and / or cell proliferation disorder and use of an antibody |
| CN101410413B (en) | 2006-01-20 | 2013-04-24 | 健泰科生物技术公司 | Anti-EPHRINB2 antiboies and methods using same |
| US7750116B1 (en) * | 2006-02-18 | 2010-07-06 | Seattle Genetics, Inc. | Antibody drug conjugate metabolites |
| AR059851A1 (en) | 2006-03-16 | 2008-04-30 | Genentech Inc | ANTIBODIES OF EGFL7 AND METHODS OF USE |
| KR101454508B1 (en) | 2006-05-30 | 2014-11-04 | 제넨테크, 인크. | Antibodies and immunoconjugates and uses therefor |
| WO2007143600A2 (en) * | 2006-06-05 | 2007-12-13 | Incyte Corporation | Sheddase inhibitors combined with cd30-binding immunotherapeutics for the treatment of cd30 positive diseases |
| JP2010503407A (en) | 2006-09-12 | 2010-02-04 | ジェネンテック・インコーポレーテッド | Methods and compositions for diagnosis and treatment of cancer |
| WO2008052187A2 (en) | 2006-10-27 | 2008-05-02 | Genentech. Inc. | Antibodies and immunoconjugates and uses therefor |
| CA2699837C (en) | 2006-12-01 | 2017-06-13 | Seattle Genetics, Inc. | Variant target binding agents and uses thereof |
| MX338185B (en) | 2007-01-25 | 2016-04-05 | Dana Farber Cancer Inst Inc | Use of anti-egfr antibodies in treatment of egfr mutant mediated disease. |
| US7834154B2 (en) | 2007-02-09 | 2010-11-16 | Genentech, Inc. | Anti-ROBO4 antibodies and uses therefor |
| JP5618549B2 (en) | 2007-03-15 | 2014-11-05 | ルードヴィッヒ インスティテュート フォー キャンサーリサーチ リミテッド | Method of treatment using EGFR antibody and SRC inhibitor and related preparation |
| US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
| AU2008251608B2 (en) | 2007-05-08 | 2014-03-27 | Genentech, Inc. | Cysteine engineered anti-MUC16 antibodies and antibody drug conjugates |
| PE20090321A1 (en) | 2007-06-04 | 2009-04-20 | Genentech Inc | ANTI-NOTCH1 NRR ANTIBODIES, METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITION |
| CA2696360C (en) | 2007-08-14 | 2018-11-20 | Ludwig Institute For Cancer Research | Monoclonal antibody targeting the egfr receptor and uses thereof |
| DK3059246T3 (en) | 2007-09-26 | 2018-10-01 | Chugai Pharmaceutical Co Ltd | Modified constant region of an antibody |
| AU2008308509B2 (en) | 2007-10-04 | 2014-10-23 | Zymogenetics, Inc. | B7 family member zB7H6 and related compositions and methods |
| JP5727786B2 (en) | 2007-10-19 | 2015-06-03 | シアトル ジェネティクス，インコーポレーテッド | CD19 binding substance and use thereof |
| US7892760B2 (en) | 2007-11-19 | 2011-02-22 | Celera Corporation | Lung cancer markers, and uses thereof |
| TWI580694B (en) | 2007-11-30 | 2017-05-01 | 建南德克公司 | Anti-vegf antibodies |
| AU2009205995B2 (en) | 2008-01-18 | 2014-04-03 | Medimmune, Llc | Cysteine engineered antibodies for site-specific conjugation |
| DK2842575T3 (en) | 2008-03-18 | 2017-11-27 | Seattle Genetics Inc | Auristatin drug linker conjugates |
| WO2009124090A1 (en) * | 2008-03-31 | 2009-10-08 | Genentech, Inc. | Compositions and methods for treating and diagnosing asthma |
| PL2279412T3 (en) | 2008-04-09 | 2017-12-29 | Genentech, Inc. | Novel compositions and methods for the treatment of immune related diseases |
| JP5624535B2 (en) | 2008-05-02 | 2014-11-12 | シアトル ジェネティクス，インコーポレーテッド | Methods and compositions for preparing antibodies and antibody derivatives having low core fucosylation |
| DK2318832T3 (en) | 2008-07-15 | 2014-01-20 | Academia Sinica | Glycan arrays on PTFE-like aluminum coated slides and related methods |
| ES2541726T3 (en) | 2008-10-01 | 2015-07-23 | F. Hoffmann-La Roche Ag | Anti-Notch2 antibodies and methods of use |
| UA109633C2 (en) | 2008-12-09 | 2015-09-25 | HUMAN ANTIBODY AGAINST TISSUE FACTOR | |
| TW201438739A (en) | 2009-03-20 | 2014-10-16 | Genentech Inc | Anti-HER antibodies |
| BRPI1006448B1 (en) * | 2009-03-25 | 2021-08-17 | Genentech, Inc | ANTI-FGFR3 ANTAGONIST ANTIBODY, MONOCLONAL ANTIBODY, POLYNUCLEOTIDE, VECTOR, TRANSGENIC MICROORGANISM, METHOD FOR THE PRODUCTION OF AN ANTI-FGFR3 ANTIBODY, PHARMACEUTICAL FORMULATION AND USES OF ANTI-FR3 ANTAGONIST ANTIBODY |
| CN103755808B (en) | 2009-03-25 | 2016-02-10 | 霍夫曼-拉罗奇有限公司 | Anti-alpha 5 beta 1 antibodies and application thereof |
| WO2010120561A1 (en) | 2009-04-01 | 2010-10-21 | Genentech, Inc. | Anti-fcrh5 antibodies and immunoconjugates and methods of use |
| BRPI1014089A2 (en) | 2009-04-02 | 2016-04-19 | Roche Glycart Ag | multispecific antibodies comprising full length antibodies and single chain fab fragments |
| CA2758964A1 (en) | 2009-04-16 | 2010-10-21 | Abbott Biotherapeutics Corp. | Anti-tnf-.alpha. antibodies and their uses |
| KR101763808B1 (en) | 2009-06-04 | 2017-08-16 | 노파르티스 아게 | METHODS FOR IDENTIFICATION OF SITES FOR IgG CONJUGATION |
| UA104626C2 (en) | 2009-06-17 | 2014-02-25 | Эббви Биотерапеутикс Инк. | Anti-vegf antibodies and their uses |
| RU2012101999A (en) | 2009-06-22 | 2013-07-27 | МЕДИММЬЮН, ЭлЭлСи | Fc RECOMBINED SITES FOR SITE-SPECIFIC CONJUGATION |
| US9493578B2 (en) | 2009-09-02 | 2016-11-15 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
| CA2772715C (en) | 2009-09-02 | 2019-03-26 | Genentech, Inc. | Mutant smoothened and methods of using the same |
| SG10201408401RA (en) | 2009-09-16 | 2015-01-29 | Genentech Inc | Coiled coil and/or tether containing protein complexes and uses thereof |
| MX2012004647A (en) | 2009-10-22 | 2012-06-19 | Genentech Inc | Anti-hepsin antibodies and methods using same. |
| TWI583394B (en) | 2009-10-23 | 2017-05-21 | 千禧製藥公司 | Anti-gcc antibody molecules and related compositions and methods |
| WO2011056502A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Bone morphogenetic protein receptor type ii compositions and methods of use |
| WO2011056497A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor type iib compositions and methods of use |
| WO2011056494A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor-like kinase-1 antagonist and vegfr3 antagonist combinations |
| US8658175B2 (en) | 2009-10-28 | 2014-02-25 | Abbvie Biotherapeutics Inc. | Anti-EGFR antibodies and their uses |
| BR112012010153B1 (en) | 2009-11-05 | 2022-05-03 | Genentech, Inc | Method of producing an antibody |
| CA2781887C (en) | 2009-11-30 | 2018-03-27 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
| US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
| US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
| EP3778917A3 (en) | 2009-12-04 | 2021-06-09 | F. Hoffmann-La Roche AG | Multispecific antibodies, antibody analogs, compositions, and methods |
| PT2510011E (en) | 2009-12-09 | 2014-12-12 | Inst Nat Santé Et De La Rech Médicale | Monoclonal antibodies that bind b7h6 and uses thereof |
| BR112012013717B1 (en) | 2009-12-10 | 2020-01-28 | Hoffmann La Roche | antibodies binding to human csf-1r, pharmaceutical composition and uses of the antibody |
| US8486397B2 (en) | 2009-12-11 | 2013-07-16 | Genentech, Inc. | Anti-VEGF-C antibodies and methods using same |
| ES2594893T3 (en) | 2009-12-16 | 2016-12-23 | Abbvie Biotherapeutics Inc. | Anti HER2 antibodies and their uses |
| AU2010336485B2 (en) | 2009-12-23 | 2015-03-26 | Genentech, Inc. | Anti-Bv8 antibodies and uses thereof |
| UA115517C2 (en) | 2010-02-08 | 2017-11-27 | Ейдженсіс, Інк. | Antibody drug conjugates (adc) that bind to 161p2f10b proteins |
| ES2519348T3 (en) | 2010-02-18 | 2014-11-06 | Genentech, Inc. | Neurregulin antagonists and their use in cancer treatment |
| EP2538981B1 (en) | 2010-02-23 | 2017-12-20 | F. Hoffmann-La Roche AG | Compositions and methods for the diagnosis and treatment of tumor |
| EP2542588A1 (en) | 2010-03-05 | 2013-01-09 | F. Hoffmann-La Roche AG | Antibodies against human csf-1r and uses thereof |
| RU2617971C2 (en) | 2010-03-05 | 2017-04-28 | Ф.Хоффманн-Ля Рош Аг | Antibodies to human csf-1r and use thereof |
| ES2550060T3 (en) | 2010-03-12 | 2015-11-04 | Abbvie Biotherapeutics Inc. | CTLA4 proteins and their uses |
| BR112012022044A2 (en) | 2010-03-24 | 2020-08-25 | Genentech Inc | ''antibody, immunoconjugate, pharmaceutical formulation, antibody use, treatment method, isolated bispecific antibody and host cell''. |
| TW201138821A (en) | 2010-03-26 | 2011-11-16 | Roche Glycart Ag | Bispecific antibodies |
| SG183947A1 (en) | 2010-03-31 | 2012-10-30 | Boehringer Ingelheim Int | Anti-cd40 antibodies |
| WO2011130332A1 (en) | 2010-04-12 | 2011-10-20 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
| MX346731B (en) | 2010-04-23 | 2017-03-30 | Genentech Inc * | Production of heteromultimeric proteins. |
| MA34291B1 (en) | 2010-05-03 | 2013-06-01 | Genentech Inc | COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING A TUMOR |
| NZ602840A (en) | 2010-06-03 | 2014-11-28 | Genentech Inc | Immuno-pet imaging of antibodies and immunoconjugates and uses therefor |
| US9000130B2 (en) | 2010-06-08 | 2015-04-07 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
| RS59769B1 (en) | 2010-06-09 | 2020-02-28 | Genmab As | Antibodies against human cd38 |
| HUE035599T2 (en) | 2010-06-15 | 2018-05-28 | Genmab As | Human antibody drug conjugates against tissue factor |
| CN103080136B (en) | 2010-06-18 | 2015-08-12 | 霍夫曼-拉罗奇有限公司 | Anti-Axl antibody and using method |
| WO2011161119A1 (en) | 2010-06-22 | 2011-12-29 | F. Hoffmann-La Roche Ag | Antibodies against insulin-like growth factor i receptor and uses thereof |
| WO2011161189A1 (en) | 2010-06-24 | 2011-12-29 | F. Hoffmann-La Roche Ag | Anti-hepsin antibodies and methods of use |
| CN105585630B (en) | 2010-07-29 | 2020-09-15 | Xencor公司 | Antibodies with modified isoelectric points |
| EP2600895A1 (en) | 2010-08-03 | 2013-06-12 | Hoffmann-La Roche AG | Chronic lymphocytic leukemia (cll) biomarkers |
| EA037977B1 (en) | 2010-08-13 | 2021-06-18 | Роше Гликарт Аг | Anti-fap antibodies, methods of production and use thereof |
| CN103154032A (en) | 2010-08-13 | 2013-06-12 | 弗·哈夫曼-拉罗切有限公司 | Antibodies to IL-1beta and IL-18, for treatment of disease |
| WO2012020038A1 (en) | 2010-08-13 | 2012-02-16 | Roche Glycart Ag | Anti-tenascin-c a2 antibodies and methods of use |
| WO2012025530A1 (en) | 2010-08-24 | 2012-03-01 | F. Hoffmann-La Roche Ag | Bispecific antibodies comprising a disulfide stabilized - fv fragment |
| RU2013114360A (en) | 2010-08-31 | 2014-10-10 | Дженентек, Инк. | BIOMARKERS AND TREATMENT METHODS |
| TWI651096B (en) | 2010-09-29 | 2019-02-21 | 美商艾澤西公司 | Antibody drug conjugate (ADC) that binds to the 191P4D12 protein |
| EP3828205A1 (en) | 2010-10-01 | 2021-06-02 | Oxford BioTherapeutics Ltd | Anti-ror1 antibodies |
| US8481680B2 (en) | 2010-10-05 | 2013-07-09 | Genentech, Inc. | Mutant smoothened and methods of using the same |
| JP6121906B2 (en) | 2010-10-22 | 2017-04-26 | シアトル ジェネティクス，インコーポレーテッド | Synergistic effect between auristatin antibody drug conjugate and PI3K-AKTmTOR pathway inhibitor |
| TW201300417A (en) | 2010-11-10 | 2013-01-01 | Genentech Inc | Methods and compositions for neural disease immunotherapy |
| EP2637692A4 (en) | 2010-11-12 | 2014-09-10 | Scott & White Healthcare | Antibodies to tumor endothelial marker 8 |
| BR122020012255B1 (en) | 2010-12-16 | 2022-08-09 | Genentech, Inc | USE OF AN ANTI-IL-13 ANTIBODY, USES OF A TH2 PATHWAY INHIBITOR AND ANTI-PERIOSTIN ANTIBODIES |
| AU2011349443B2 (en) | 2010-12-20 | 2015-12-24 | Genentech, Inc. | Anti-mesothelin antibodies and immunoconjugates |
| KR20130118925A (en) | 2010-12-22 | 2013-10-30 | 제넨테크, 인크. | Anti-pcsk9 antibodies and methods of use |
| WO2012085111A1 (en) | 2010-12-23 | 2012-06-28 | F. Hoffmann-La Roche Ag | Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery |
| JOP20210044A1 (en) | 2010-12-30 | 2017-06-16 | Takeda Pharmaceuticals Co | Anti-cd38 antibodies |
| WO2012092539A2 (en) | 2010-12-31 | 2012-07-05 | Takeda Pharmaceutical Company Limited | Antibodies to dll4 and uses thereof |
| AR085138A1 (en) | 2011-02-04 | 2013-09-11 | Genentech Inc | Fc VARIATIONS AND METHODS FOR PRODUCTION |
| US10689447B2 (en) | 2011-02-04 | 2020-06-23 | Genentech, Inc. | Fc variants and methods for their production |
| WO2012109624A2 (en) | 2011-02-11 | 2012-08-16 | Zyngenia, Inc. | Monovalent and multivalent multispecific complexes and uses thereof |
| MY163539A (en) | 2011-03-29 | 2017-09-15 | Roche Glycart Ag | Antibody fc variants |
| MX342240B (en) | 2011-04-07 | 2016-09-21 | Genentech Inc | Anti-fgfr4 antibodies and methods of use. |
| KR20140031217A (en) | 2011-04-20 | 2014-03-12 | 로슈 글리카트 아게 | Method and constructs for the ph dependent passage of the blood-brain-barrier |
| CA2832387A1 (en) | 2011-04-20 | 2012-10-26 | Genmab A/S | Bispecifc antibodies against her2 |
| CA2835203A1 (en) | 2011-05-09 | 2012-11-15 | University Of Virginia Patent Foundation | Compositions and methods for treating cancer |
| WO2012155019A1 (en) | 2011-05-12 | 2012-11-15 | Genentech, Inc. | Multiple reaction monitoring lc-ms/ms method to detect therapeutic antibodies in animal samples using framework signature pepides |
| SG194917A1 (en) | 2011-05-16 | 2013-12-30 | Genentech Inc | Fgfr1 agonists and methods of use |
| AU2012257418B2 (en) | 2011-05-16 | 2017-08-03 | Tagworks Pharmaceuticals B.V. | Bio-orthogonal drug activation |
| ES2643694T3 (en) | 2011-05-19 | 2017-11-23 | Inserm (Institut National De La Santé Et De La Recherche Medicale) | Human anti-HER3 antibodies and their uses |
| EP2714738B1 (en) | 2011-05-24 | 2018-10-10 | Zyngenia, Inc. | Multivalent and monovalent multispecific complexes and their uses |
| CA2833820C (en) | 2011-05-27 | 2019-10-29 | Glaxo Group Limited | Bcma (cd269/tnfrsf17) -binding proteins |
| BR112013031819B1 (en) | 2011-06-10 | 2022-05-03 | Mersana Therapeutics, Inc | Polymeric support, pharmaceutical composition, compound and support use |
| BR112013032899A2 (en) | 2011-06-22 | 2017-01-24 | Inserm Inst Nat De La Santé Et De La Rech Médicale | anti-axl antibodies and uses thereof |
| EP2723376B1 (en) | 2011-06-22 | 2018-12-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anti-axl antibodies and uses thereof |
| BR112013030472A2 (en) | 2011-06-30 | 2019-09-24 | Genentech Inc | pharmaceutical formulation, article of manufacture and method |
| UA117901C2 (en) | 2011-07-06 | 2018-10-25 | Ґенмаб Б.В. | Antibody variants and uses thereof |
| WO2013022855A1 (en) | 2011-08-05 | 2013-02-14 | Xencor, Inc. | Antibodies with modified isoelectric points and immunofiltering |
| KR20140057326A (en) | 2011-08-17 | 2014-05-12 | 제넨테크, 인크. | Neuregulin antibodies and uses thereof |
| JP6060162B2 (en) | 2011-08-23 | 2017-01-11 | ロシュ グリクアート アーゲー | Fc-free antibody comprising two Fab fragments and methods of use |
| US20130058936A1 (en) | 2011-08-23 | 2013-03-07 | Peter Bruenker | Bispecific antibodies specific for t-cell activating antigens and a tumor antigen and methods of use |
| WO2013040433A1 (en) | 2011-09-15 | 2013-03-21 | Genentech, Inc. | Methods of promoting differentiation |
| AU2012312515A1 (en) | 2011-09-19 | 2014-03-13 | Genentech, Inc. | Combination treatments comprising c-met antagonists and B-raf antagonists |
| EP2758435A1 (en) | 2011-09-23 | 2014-07-30 | Roche Glycart AG | Bispecific anti-egfr/anti igf-1r antibodies |
| EP2764351B1 (en) | 2011-09-29 | 2018-11-07 | Seattle Genetics, Inc. | Intact mass determination of protein conjugated agent compounds |
| US20130089562A1 (en) | 2011-10-05 | 2013-04-11 | Genenthech, Inc. | Methods of treating liver conditions using notch2 antagonists |
| EP3611187A1 (en) | 2011-10-10 | 2020-02-19 | Xencor, Inc. | A method for purifying antibodies |
| US10851178B2 (en) | 2011-10-10 | 2020-12-01 | Xencor, Inc. | Heterodimeric human IgG1 polypeptides with isoelectric point modifications |
| ES2687951T3 (en) | 2011-10-14 | 2018-10-30 | F. Hoffmann-La Roche Ag | Anti-HtrA1 antibodies and procedures for use |
| WO2013056054A2 (en) | 2011-10-14 | 2013-04-18 | Genentech, Inc | Peptide inhibitors of bace1 |
| MX2014004426A (en) | 2011-10-15 | 2014-07-09 | Genentech Inc | Scd1 antagonists for treating cancer. |
| MX2014004991A (en) | 2011-10-28 | 2014-05-22 | Genentech Inc | Therapeutic combinations and methods of treating melanoma. |
| WO2013078170A1 (en) | 2011-11-21 | 2013-05-30 | Genentech, Inc. | Purification of anti-c-met antibodies |
| MX356337B (en) | 2011-12-15 | 2018-05-23 | Hoffmann La Roche | Antibodies against human csf-1r and uses thereof. |
| EP3539982A3 (en) | 2011-12-23 | 2020-01-15 | Pfizer Inc | Engineered antibody constant regions for site-specific conjugation and methods and uses therefor |
| JP6684490B2 (en) | 2012-01-09 | 2020-04-22 | ザ・スクリップス・リサーチ・インスティテュート | Ultralong complementarity determining regions and uses thereof |
| US20150011431A1 (en) | 2012-01-09 | 2015-01-08 | The Scripps Research Institute | Humanized antibodies |
| KR20140119114A (en) | 2012-01-18 | 2014-10-08 | 제넨테크, 인크. | Methods of using fgf19 modulators |
| SG11201404198TA (en) | 2012-01-18 | 2014-08-28 | Genentech Inc | Anti-lrp5 antibodies and methods of use |
| JP2015505537A (en) | 2012-01-20 | 2015-02-23 | シー レーン バイオテクノロジーズ， エルエルシー | Binding molecule conjugate |
| CA2861124A1 (en) | 2012-02-10 | 2013-08-15 | Genentech, Inc. | Single-chain antibodies and other heteromultimers |
| US20130209473A1 (en) | 2012-02-11 | 2013-08-15 | Genentech, Inc. | R-spondin translocations and methods using the same |
| BR112014018005B1 (en) | 2012-02-15 | 2021-06-29 | F. Hoffmann-La Roche Ag | USE OF A NON-COVALENT IMMOBILIZED COMPLEX |
| WO2013130093A1 (en) | 2012-03-02 | 2013-09-06 | Genentech, Inc. | Biomarkers for treatment with anti-tubulin chemotherapeutic compounds |
| AR090549A1 (en) | 2012-03-30 | 2014-11-19 | Genentech Inc | ANTI-LGR5 AND IMMUNOCATE PLAYERS |
| US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
| US9156915B2 (en) | 2012-04-26 | 2015-10-13 | Thomas Jefferson University | Anti-GCC antibody molecules |
| KR20150006000A (en) | 2012-05-01 | 2015-01-15 | 제넨테크, 인크. | Anti-pmel17 antibodies and immunoconjugates |
| WO2013170191A1 (en) | 2012-05-11 | 2013-11-14 | Genentech, Inc. | Methods of using antagonists of nad biosynthesis from nicotinamide |
| WO2013173391A1 (en) | 2012-05-15 | 2013-11-21 | Concortis Biosystems, Corp | Drug-conjugates, conjugation methods, and uses thereof |
| WO2013174783A1 (en) | 2012-05-23 | 2013-11-28 | Pieris Ag | Lipocalin muteins with binding-affinity for glypican-3 (gpc-3) and use of lipocalin muteins for target-specific delivery to cells expressing gpc-3 |
| EP2859017B1 (en) | 2012-06-08 | 2019-02-20 | Sutro Biopharma, Inc. | Antibodies comprising site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
| CA2875096A1 (en) | 2012-06-15 | 2013-12-19 | Genentech, Inc. | Anti-pcsk9 antibodies, formulations, dosing, and methods of use |
| MX359449B (en) | 2012-06-19 | 2018-09-28 | Ambrx Inc | Anti-cd70 antibody drug conjugates. |
| EP3135690A1 (en) | 2012-06-26 | 2017-03-01 | Sutro Biopharma, Inc. | Modified fc proteins comprising site-specific non-natural amino acid residues, conjugates of the same, methods of their preparation and methods of their use |
| RU2015100656A (en) | 2012-06-27 | 2016-08-20 | Ф. Хоффманн-Ля Рош Аг | METHOD FOR PRODUCING ANTIBODY FC-FRAGMENT CONNECTING, INCLUDING AT LEAST ONE CONNECTING GROUP, WHICH SPECIALLY RELATED TO THE TARGET, AND THEIR APPLICATION |
| CN104395339A (en) | 2012-06-27 | 2015-03-04 | 弗·哈夫曼-拉罗切有限公司 | Method for selection and production of tailor-made highly selective and multi-specific targeting entities containing at least two different binding entities and uses thereof |
| RU2644263C2 (en) | 2012-06-27 | 2018-02-08 | Ф. Хоффманн-Ля Рош Аг | Method for selection and production of selective and multispecific therapeutic molecules with specified properties, including, at least two, different target groups, and their applications |
| EP3138578B1 (en) | 2012-07-04 | 2022-01-12 | F. Hoffmann-La Roche AG | Anti-theophylline antibodies and methods of use |
| CN104428006B (en) | 2012-07-04 | 2017-09-08 | 弗·哈夫曼-拉罗切有限公司 | The antigen-antibody conjugate of covalent attachment |
| RU2630296C2 (en) | 2012-07-04 | 2017-09-06 | Ф. Хоффманн-Ля Рош Аг | Antibodies to biotin and application methods |
| SG11201408646VA (en) | 2012-07-06 | 2015-01-29 | Genmab Bv | Dimeric protein with triple mutations |
| EP3632462A1 (en) | 2012-07-06 | 2020-04-08 | Genmab B.V. | Dimeric protein with triple mutations |
| CA2874554C (en) | 2012-07-13 | 2019-12-03 | Roche Glycart Ag | Bispecific anti-vegf/anti-ang-2 antibodies and their use in the treatment of ocular vascular diseases |
| CA2880701A1 (en) | 2012-08-18 | 2014-02-27 | Academia Sinica | Cell-permeable probes for identification and imaging of sialidases |
| UA118251C2 (en) | 2012-08-23 | 2018-12-26 | Ейдженсіс, Інк. | Antibody drug conjugates (adc) that bind to 158p1d7 proteins |
| EP3584255B1 (en) | 2012-08-31 | 2022-02-16 | Sutro Biopharma, Inc. | Modified amino acids comprising an azido group |
| PL2897978T3 (en) | 2012-09-19 | 2017-08-31 | Abbvie Biotherapeutics Inc. | Methods for identifying antibodies with reduced immunogenicity |
| JP6444874B2 (en) | 2012-10-08 | 2018-12-26 | ロシュ グリクアート アーゲー | Fc-free antibody comprising two Fab fragments and methods of use |
| EP2914628A1 (en) | 2012-11-01 | 2015-09-09 | Max-Delbrück-Centrum für Molekulare Medizin | An antibody that binds cd269 (bcma) suitable for use in the treatment of plasma cell diseases such as multiple myeloma and autoimmune diseases |
| JP6302476B2 (en) | 2012-11-08 | 2018-03-28 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | HER3 antigen binding protein that binds to the HER3 beta hairpin |
| EP3461501A1 (en) | 2012-11-13 | 2019-04-03 | F. Hoffmann-La Roche AG | Anti-hemagglutinin antibodies and methods of use |
| EP4245744A2 (en) | 2012-11-22 | 2023-09-20 | Tagworks Pharmaceuticals B.V. | Chemically cleavable group |
| ES2701076T3 (en) | 2012-11-24 | 2019-02-20 | Hangzhou Dac Biotech Co Ltd | Hydrophilic linkers and their uses for the conjugation of drugs to molecules that bind to cells |
| US20140154255A1 (en) | 2012-11-30 | 2014-06-05 | Abbvie Biotherapeutics Inc. | Anti-vegf antibodies and their uses |
| WO2014093379A1 (en) | 2012-12-10 | 2014-06-19 | Mersana Therapeutics, Inc. | Auristatin compounds and conjugates thereof |
| JP6334553B2 (en) | 2012-12-10 | 2018-05-30 | メルサナ セラピューティクス，インコーポレイティド | Protein-polymer-drug conjugate |
| US9872918B2 (en) | 2012-12-12 | 2018-01-23 | Mersana Therapeutics, Inc. | Hydroxyl-polymer-drug-protein conjugates |
| WO2014107739A1 (en) | 2013-01-07 | 2014-07-10 | Eleven Biotherapeutics, Inc. | Antibodies against pcsk9 |
| EA201500741A1 (en) | 2013-01-10 | 2016-01-29 | Генмаб Б.В. | HUMAN FG IGG1 OPTIONS AND THEIR APPLICATION |
| US11053316B2 (en) | 2013-01-14 | 2021-07-06 | Xencor, Inc. | Optimized antibody variable regions |
| US9605084B2 (en) | 2013-03-15 | 2017-03-28 | Xencor, Inc. | Heterodimeric proteins |
| US10487155B2 (en) | 2013-01-14 | 2019-11-26 | Xencor, Inc. | Heterodimeric proteins |
| LT2943511T (en) | 2013-01-14 | 2019-11-11 | Xencor Inc | Novel heterodimeric proteins |
| US10131710B2 (en) | 2013-01-14 | 2018-11-20 | Xencor, Inc. | Optimized antibody variable regions |
| US10968276B2 (en) | 2013-03-12 | 2021-04-06 | Xencor, Inc. | Optimized anti-CD3 variable regions |
| US9701759B2 (en) | 2013-01-14 | 2017-07-11 | Xencor, Inc. | Heterodimeric proteins |
| EP2945969A1 (en) | 2013-01-15 | 2015-11-25 | Xencor, Inc. | Rapid clearance of antigen complexes using novel antibodies |
| MX2015010791A (en) | 2013-02-22 | 2015-11-26 | Hoffmann La Roche | Methods of treating cancer and preventing drug resistance. |
| KR20150123811A (en) | 2013-02-26 | 2015-11-04 | 로슈 글리카트 아게 | Anti-mcsp antibodies |
| WO2014138364A2 (en) | 2013-03-06 | 2014-09-12 | Genentech, Inc. | Methods of treating and preventing cancer drug resistance |
| US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
| JP2016516046A (en) | 2013-03-14 | 2016-06-02 | ジェネンテック， インコーポレイテッド | Methods for treating cancer and methods for preventing cancer drug resistance |
| EP3299391B1 (en) | 2013-03-14 | 2019-12-04 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
| BR112015023120A2 (en) | 2013-03-15 | 2017-11-21 | Genentech Inc | method for identifying an individual with a disease or dysfunction, method for predicting the responsiveness of an individual with a disease or dysfunction, method for determining the likelihood that an individual with a disease or dysfunction will exhibit benefit from treatment, method for selecting a therapy, Uses of a pd-11 Axis Binding Antagonist, Assay to Identify an Individual with a Disease, Diagnostic Kit, Method to Evaluate a Treatment Response, and Method to Monitor the Response of a Treated Individual |
| US10858417B2 (en) | 2013-03-15 | 2020-12-08 | Xencor, Inc. | Heterodimeric proteins |
| WO2014145000A2 (en) | 2013-03-15 | 2014-09-18 | Abbvie Biotherapeutics Inc. | Anti-cd25 antibodies and their uses |
| US10519242B2 (en) | 2013-03-15 | 2019-12-31 | Xencor, Inc. | Targeting regulatory T cells with heterodimeric proteins |
| KR20150130451A (en) | 2013-03-15 | 2015-11-23 | 제넨테크, 인크. | Methods of treating cancer and preventing cancer drug resistance |
| AU2014228172B2 (en) | 2013-03-15 | 2018-12-06 | Abbvie Deutschland Gmbh & Co.Kg | Anti-EGFR antibody drug conjugate formulations |
| SG11201507619PA (en) | 2013-03-15 | 2015-10-29 | Ct For Drug Res And Dev | Cytotoxic and anti-mitotic compounds, and methods of using the same |
| CA2906927C (en) | 2013-03-15 | 2021-07-13 | Xencor, Inc. | Modulation of t cells with bispecific antibodies and fc fusions |
| US10106624B2 (en) | 2013-03-15 | 2018-10-23 | Xencor, Inc. | Heterodimeric proteins |
| AU2014233528B2 (en) | 2013-03-15 | 2019-02-28 | Abbvie Biotherapeutics Inc. | Fc variants |
| SG11201507432XA (en) | 2013-03-15 | 2015-10-29 | Abbvie Inc | Antibody drug conjugate (adc) purification |
| CA2902739C (en) | 2013-03-15 | 2022-11-22 | Xencor, Inc. | Heterodimeric proteins |
| WO2014151866A1 (en) | 2013-03-15 | 2014-09-25 | Genentech, Inc. | Compositions and methods for diagnosis and treatment of hepatic cancers |
| CN105143258B (en) | 2013-03-15 | 2020-06-23 | Ac免疫有限公司 | anti-Tau antibodies and methods of use |
| MX2015012563A (en) | 2013-03-15 | 2016-10-26 | Abbvie Biotechnology Ltd | Anti-cd25 antibodies and their uses. |
| EA038918B1 (en) | 2013-03-15 | 2021-11-09 | Зинджения, Инк. | Peptide binding an epidermal growth factor receptor, multispecific complexes comprising peptide and antibodies and use thereof |
| AR095517A1 (en) | 2013-03-15 | 2015-10-21 | Genentech Inc | ANTIBODIES AGAINST THE CHEMIOATRAYENT RECEIVER EXPRESSED IN T HELPER 2 CELLS (ANTI-CRTh2) AND METHODS OF USE |
| AR095882A1 (en) | 2013-04-22 | 2015-11-18 | Hoffmann La Roche | ANTIBODY COMBINATION THERAPY AGAINST HUMAN CSF-1R WITH A TLR9 AGONIST |
| GB2513405A (en) | 2013-04-26 | 2014-10-29 | Adc Biotechnology Ltd | Method of synthesising ADCs using affinity resins |
| MX2015015060A (en) | 2013-04-29 | 2016-02-25 | Hoffmann La Roche | Fc-receptor binding modified asymmetric antibodies and methods of use. |
| KR102293064B1 (en) | 2013-05-20 | 2021-08-23 | 제넨테크, 인크. | Anti-transferrin receptor antibodies and methods of use |
| EP3013365B1 (en) | 2013-06-26 | 2019-06-05 | Academia Sinica | Rm2 antigens and use thereof |
| WO2014210564A1 (en) | 2013-06-27 | 2014-12-31 | Academia Sinica | Glycan conjugates and use thereof |
| ES2865473T3 (en) | 2013-07-10 | 2021-10-15 | Sutro Biopharma Inc | Antibodies Comprising Multiple Site-Specific Unnatural Amino Acid Residues, Methods for Their Preparation, and Methods of Use |
| EP3022224A2 (en) | 2013-07-18 | 2016-05-25 | Fabrus, Inc. | Antibodies with ultralong complementarity determining regions |
| CN111518199A (en) | 2013-07-18 | 2020-08-11 | 图鲁斯生物科学有限责任公司 | Humanized antibodies with ultralong complementarity determining regions |
| EP3738611A1 (en) | 2013-07-31 | 2020-11-18 | BioNTech AG | Diagnosis and therapy of cancer involving cancer stem cells |
| JP6510518B2 (en) | 2013-08-01 | 2019-05-08 | アジェンシス，インコーポレイテッド | Antibody-drug conjugate (ADC) that binds to the CD37 protein |
| WO2015035044A2 (en) | 2013-09-04 | 2015-03-12 | Abbvie Biotherapeutics Inc. | Fc VARIANTS WITH IMPROVED ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY |
| US9782476B2 (en) | 2013-09-06 | 2017-10-10 | Academia Sinica | Human iNKT cell activation using glycolipids with altered glycosyl groups |
| KR20160055253A (en) | 2013-09-12 | 2016-05-17 | 할로자임, 아이엔씨 | Modified anti-epidermal growth factor receptor antibodies and methods of use thereof |
| AR097584A1 (en) | 2013-09-12 | 2016-03-23 | Hoffmann La Roche | ANTIBODY COMBINATION THERAPY AGAINST HUMAN CSF-1R AND ANTIBODIES AGAINST HUMAN PD-L1 |
| RU2016109247A (en) | 2013-09-17 | 2017-10-19 | Дженентек, Инк. | WAYS OF APPLICATION OF ANTIBODIES TO LGR5 |
| CA2926586C (en) | 2013-10-11 | 2020-04-07 | Mersana Therapeutics, Inc. | Polymeric scaffold based on phf for targeted drug delivery |
| KR102355745B1 (en) | 2013-10-11 | 2022-01-26 | 아사나 바이오사이언시스 엘엘씨 | Protein-polymer-drug conjugates |
| CN105813654B (en) | 2013-10-11 | 2019-05-31 | 美国政府(由卫生和人类服务部的部长所代表) | TEM8 antibody and application thereof |
| AU2014333563B9 (en) | 2013-10-11 | 2020-04-02 | Oxford Biotherapeutics Ltd | Conjugated antibodies against LY75 for the treatment of cancer |
| US9840493B2 (en) | 2013-10-11 | 2017-12-12 | Sutro Biopharma, Inc. | Modified amino acids comprising tetrazine functional groups, methods of preparation, and methods of their use |
| EP3057610B1 (en) | 2013-10-15 | 2021-09-22 | Sorrento Therapeutics, Inc. | Drug-conjugates with a targeting molecule and two different drugs |
| CN105744954B (en) | 2013-10-18 | 2021-03-05 | 豪夫迈·罗氏有限公司 | anti-RSPO 2 and/or anti-RSPO 3 antibodies and uses thereof |
| US9644037B2 (en) | 2013-10-18 | 2017-05-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Antibodies that specifically bind ataxia telangiectasia-mutated and RAD3-related kinase phosphorylated at position 1989 and their use |
| WO2015069922A2 (en) | 2013-11-06 | 2015-05-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Alk antibodies, conjugates, and chimeric antigen receptors, and their use |
| CA2929386C (en) | 2013-11-07 | 2023-01-03 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Neuregulin allosteric anti-her3 antibody |
| JP6590803B2 (en) | 2013-11-21 | 2019-10-16 | ゲンマブ エー／エス | Antibody-drug conjugate lyophilized formulation |
| EP3080164B1 (en) | 2013-12-13 | 2019-01-16 | Genentech, Inc. | Anti-cd33 antibodies and immunoconjugates |
| TWI670283B (en) | 2013-12-23 | 2019-09-01 | 美商建南德克公司 | Antibodies and methods of use |
| WO2015095953A1 (en) | 2013-12-27 | 2015-07-02 | The Centre For Drug Research And Development | Sulfonamide-containing linkage systems for drug conjugates |
| CA2935064C (en) | 2013-12-27 | 2023-06-27 | Zymeworks Inc. | Var2csa-drug conjugates |
| MX2016008187A (en) | 2014-01-03 | 2016-09-29 | Hoffmann La Roche | Bispecific anti-hapten/anti-blood brain barrier receptor antibodies, complexes thereof and their use as blood brain barrier shuttles. |
| JP6521464B2 (en) | 2014-01-03 | 2019-05-29 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Covalently linked polypeptide toxin-antibody conjugates |
| MX2016008189A (en) | 2014-01-03 | 2016-09-29 | Hoffmann La Roche | Covalently linked helicar-anti-helicar antibody conjugates and uses thereof. |
| WO2015103549A1 (en) | 2014-01-03 | 2015-07-09 | The United States Of America, As Represented By The Secretary Department Of Health And Human Services | Neutralizing antibodies to hiv-1 env and their use |
| WO2015108998A2 (en) | 2014-01-15 | 2015-07-23 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Cartilage targeting agents and their use |
| US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
| WO2015109180A2 (en) | 2014-01-16 | 2015-07-23 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
| EP3096797A1 (en) | 2014-01-24 | 2016-11-30 | F. Hoffmann-La Roche AG | Methods of using anti-steap1 antibodies and immunoconjugates |
| EP3102197B1 (en) | 2014-02-04 | 2018-08-29 | Genentech, Inc. | Mutant smoothened and methods of using the same |
| CA2936565C (en) | 2014-02-12 | 2020-08-11 | Genentech, Inc. | Anti-jagged1 antibodies and methods of use |
| CN106029693A (en) | 2014-02-21 | 2016-10-12 | 豪夫迈·罗氏有限公司 | Anti-IL-13/IL-17 bispecific antibodies and uses thereof |
| EP3122757B1 (en) | 2014-02-28 | 2023-09-06 | Hangzhou Dac Biotech Co., Ltd | Charged linkers and their uses for conjugation |
| ES2897765T3 (en) | 2014-03-14 | 2022-03-02 | Hoffmann La Roche | Methods and compositions for the secretion of heterologous polypeptides |
| KR20220123560A (en) | 2014-03-21 | 2022-09-07 | 애브비 인코포레이티드 | Anti-egfr antibodies and antibody drug conjugates |
| KR20160137599A (en) | 2014-03-24 | 2016-11-30 | 제넨테크, 인크. | Cancer treatment with c-met antagonists and correlation of the latter with hgf expression |
| CN106415244B (en) | 2014-03-27 | 2020-04-24 | 中央研究院 | Reactive marker compounds and uses thereof |
| UA119167C2 (en) | 2014-03-28 | 2019-05-10 | Зенкор, Інк. | Bispecific antibodies that bind to cd38 and cd3 |
| PT3126394T (en) | 2014-03-31 | 2019-12-19 | Hoffmann La Roche | Anti-ox40 antibodies and methods of use |
| AU2015241038A1 (en) | 2014-03-31 | 2016-10-13 | Genentech, Inc. | Combination therapy comprising anti-angiogenesis agents and OX40 binding agonists |
| CN106232139A (en) | 2014-04-11 | 2016-12-14 | 免疫医疗有限责任公司 | Bispecific HER2 antibody |
| FR3020063A1 (en) | 2014-04-16 | 2015-10-23 | Gamamabs Pharma | ANTI-HER4 HUMAN ANTIBODY |
| EP3140392B1 (en) | 2014-05-06 | 2023-07-26 | F. Hoffmann-La Roche AG | Production of heteromultimeric proteins using mammalian cells |
| EP3146071B1 (en) | 2014-05-23 | 2020-09-02 | F. Hoffmann-La Roche AG | Mit biomarkers and methods using the same |
| CA2950440A1 (en) | 2014-05-27 | 2015-12-03 | Academia Sinica | Anti-her2 glycoantibodies and uses thereof |
| JP6894239B2 (en) | 2014-05-27 | 2021-06-30 | アカデミア シニカＡｃａｄｅｍｉａ Ｓｉｎｉｃａ | Compositions and methods for universal glycoforms for enhanced antibody efficacy |
| CA2950415A1 (en) | 2014-05-27 | 2015-12-03 | Academia Sinica | Anti-cd20 glycoantibodies and uses thereof |
| US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
| TWI732738B (en) | 2014-05-28 | 2021-07-11 | 中央研究院 | Anti-tnf-alpha glycoantibodies and uses thereof |
| ES2883023T3 (en) | 2014-05-28 | 2021-12-03 | Agensys Inc | Cytotoxic dolaproin-dolaisoleuin peptide derivatives for the treatment of cancer |
| WO2015191986A1 (en) | 2014-06-13 | 2015-12-17 | Genentech, Inc. | Methods of treating and preventing cancer drug resistance |
| MX2016015280A (en) | 2014-06-26 | 2017-03-03 | Hoffmann La Roche | Anti-brdu antibodies and methods of use. |
| MX2017000363A (en) | 2014-07-11 | 2017-04-27 | Genentech Inc | Notch pathway inhibition. |
| HUE048667T2 (en) | 2014-07-11 | 2020-08-28 | Genmab As | Antibodies binding axl |
| CA2956178A1 (en) | 2014-07-24 | 2016-01-28 | Xencor, Inc. | Rapid clearance of antigen complexes using novel antibodies |
| US10934360B2 (en) | 2014-07-31 | 2021-03-02 | The Hong Kong University Of Science And Technology | Human monoclonal antibodies against EPHA4 and their use |
| BR112017003835A2 (en) | 2014-08-28 | 2018-04-10 | Bioatla Llc | chimeric antigen receptor, expression vector, genetically engineered cytotoxic cell, pharmaceutical composition, and methods for producing a chimeric antigen receptor and for treating a disease in an individual. |
| TWI751102B (en) | 2014-08-28 | 2022-01-01 | 美商奇諾治療有限公司 | Antibodies and chimeric antigen receptors specific for cd19 |
| WO2016040369A2 (en) | 2014-09-08 | 2016-03-17 | Academia Sinica | HUMAN iNKT CELL ACTIVATION USING GLYCOLIPIDS |
| US9751946B2 (en) | 2014-09-12 | 2017-09-05 | Genentech, Inc. | Anti-CLL-1 antibodies and immunoconjugates |
| CN113698488A (en) | 2014-09-12 | 2021-11-26 | 基因泰克公司 | anti-B7-H4 antibodies and immunoconjugates |
| BR112017004631A2 (en) | 2014-09-12 | 2018-01-30 | Genentech, Inc. | antibody, nucleic acid, host cell, antibody production method, immunoconjugate, pharmaceutical formulation, methods of treatment, cell proliferation inhibition and human her2 detection and method for cancer detection |
| EP3388449A3 (en) | 2014-09-12 | 2018-10-24 | F. Hoffmann-La Roche AG | Cysteine engineered antibodies and conjugates |
| DK3194421T3 (en) | 2014-09-17 | 2022-02-14 | Zymeworks Inc | CYTOTOXIC AND ANTIMITOTIC COMPOUNDS AND PROCEDURES FOR USE |
| EP3200829B1 (en) | 2014-10-01 | 2023-12-06 | Medimmune, LLC | Method of conjugating a polypeptide |
| US9732148B2 (en) | 2014-10-16 | 2017-08-15 | Genentech, Inc. | Anti-α-synuclein antibodies and methods of use |
| GB201419185D0 (en) | 2014-10-28 | 2014-12-10 | Adc Biotechnology Ltd | Method of synthesising ADCs using affinity resin |
| WO2016070062A2 (en) | 2014-10-31 | 2016-05-06 | Genentech, Inc. | Anti-il-17a and il-17f cross reactive antibody variants and compositions comprising and methods of making and using same |
| AU2015343339A1 (en) | 2014-11-03 | 2017-06-15 | Genentech, Inc. | Methods and biomarkers for predicting efficacy and evaluation of an OX40 agonist treatment |
| CN106796235B (en) | 2014-11-03 | 2021-01-29 | 豪夫迈·罗氏有限公司 | Assays for detecting T cell immune subsets and methods of use thereof |
| WO2016073789A2 (en) | 2014-11-05 | 2016-05-12 | Genentech, Inc. | Anti-fgfr2/3 antibodies and methods using same |
| MX2017005148A (en) | 2014-11-06 | 2017-08-08 | Hoffmann La Roche | Fc-region variants with modified fcrn-binding and methods of use. |
| WO2016073157A1 (en) | 2014-11-06 | 2016-05-12 | Genentech, Inc. | Anti-ang2 antibodies and methods of use thereof |
| EA201791029A1 (en) | 2014-11-10 | 2017-12-29 | Дженентек, Инк. | ANTIBODIES AGAINST INTERLEUKIN-33 AND THEIR APPLICATION |
| WO2016081640A1 (en) | 2014-11-19 | 2016-05-26 | Genentech, Inc. | Anti-transferrin receptor / anti-bace1 multispecific antibodies and methods of use |
| CN107108745B (en) | 2014-11-19 | 2021-01-12 | 基因泰克公司 | Antibodies against BACE1 and their use for immunotherapy of neurological diseases |
| US10508151B2 (en) | 2014-11-19 | 2019-12-17 | Genentech, Inc. | Anti-transferrin receptor antibodies and methods of use |
| IL252480B2 (en) | 2014-11-26 | 2023-12-01 | Xencor Inc | Heterodimeric antibodies that bind cd3 and tumor antigens |
| CA2968878A1 (en) | 2014-11-26 | 2016-06-02 | Xencor, Inc. | Heterodimeric antibodies that bind cd3 and cd38 |
| US10259887B2 (en) | 2014-11-26 | 2019-04-16 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and tumor antigens |
| CN107001482B (en) | 2014-12-03 | 2021-06-15 | 豪夫迈·罗氏有限公司 | Multispecific antibodies |
| CN107108739B (en) | 2014-12-05 | 2022-01-04 | 豪夫迈·罗氏有限公司 | anti-CD 79b antibodies and methods of use |
| ES2764299T3 (en) | 2014-12-09 | 2020-06-02 | Inst Nat Sante Rech Med | Human monoclonal antibodies against AXL |
| BR112017011234A2 (en) | 2014-12-10 | 2018-03-27 | Genentech Inc | antibodies to the blood-brain barrier receptor and methods of use |
| SG10201710322VA (en) | 2014-12-19 | 2018-02-27 | Chugai Pharmaceutical Co Ltd | Anti-c5 antibodies and methods of use |
| WO2016105450A2 (en) | 2014-12-22 | 2016-06-30 | Xencor, Inc. | Trispecific antibodies |
| US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
| US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
| KR20170128234A (en) | 2015-01-16 | 2017-11-22 | 주노 쎄러퓨티크스 인코퍼레이티드 | Antibodies specific for ROR1 and chimeric antigen receptors |
| WO2016117346A1 (en) | 2015-01-22 | 2016-07-28 | Chugai Seiyaku Kabushiki Kaisha | A combination of two or more anti-c5 antibodies and methods of use |
| CN107430127B (en) | 2015-01-24 | 2020-08-28 | 中央研究院 | Cancer markers and methods of use thereof |
| WO2016118191A1 (en) | 2015-01-24 | 2016-07-28 | Academia Sinica | Novel glycan conjugates and methods of use thereof |
| CN107849090A (en) | 2015-01-28 | 2018-03-27 | 索伦托医疗有限公司 | Antibody drug conjugates |
| US10330683B2 (en) | 2015-02-04 | 2019-06-25 | Genentech, Inc. | Mutant smoothened and methods of using the same |
| CN114773469A (en) | 2015-02-05 | 2022-07-22 | 中外制药株式会社 | Antibodies comprising an ion concentration-dependent antigen-binding domain, FC region variants, IL-8-binding antibodies and uses thereof |
| US20180030095A1 (en) | 2015-02-13 | 2018-02-01 | George Robert Pettit | Silstatin compounds |
| EP3261665A1 (en) | 2015-02-24 | 2018-01-03 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Middle east respiratory syndrome coronavirus immunogens, antibodies, and their use |
| WO2016141387A1 (en) | 2015-03-05 | 2016-09-09 | Xencor, Inc. | Modulation of t cells with bispecific antibodies and fc fusions |
| BR112017019062A2 (en) | 2015-03-09 | 2018-04-17 | Agensys Inc | antibody-drug (adc) conjugates that bind to flt3 proteins |
| HUE048111T2 (en) | 2015-03-23 | 2020-05-28 | Bayer Pharma AG | Anti-ceacam6 antibodies and uses thereof |
| WO2016165762A1 (en) | 2015-04-15 | 2016-10-20 | Ganymed Pharmaceuticals Ag | Drug conjugates comprising antibodies against claudin 18.2 |
| JP7044553B2 (en) | 2015-04-24 | 2022-03-30 | ジェネンテック， インコーポレイテッド | How to identify bacteria containing bound polypeptides |
| AU2016252773B2 (en) | 2015-04-24 | 2022-06-02 | Genentech, Inc. | Multispecific antigen-binding proteins |
| EP3778640A1 (en) | 2015-05-01 | 2021-02-17 | Genentech, Inc. | Masked anti-cd3 antibodies and methods of use |
| EP3091033A1 (en) | 2015-05-06 | 2016-11-09 | Gamamabs Pharma | Anti-human-her3 antibodies and uses thereof |
| EA201792441A2 (en) | 2015-05-06 | 2018-06-29 | Янссен Байотек, Инк. | FIBRONECTIN TYPE III DOMAINS CONNECTING WITH A PROSTATSPECIFIC MEMBRANE ANTIGEN |
| US20160346387A1 (en) | 2015-05-11 | 2016-12-01 | Genentech, Inc. | Compositions and methods of treating lupus nephritis |
| DK3294770T3 (en) | 2015-05-12 | 2020-12-07 | Hoffmann La Roche | Therapeutic and diagnostic methods for cancer |
| US10591465B2 (en) | 2015-05-12 | 2020-03-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and kits for labeling, detection and isolation of Foxp3+ regulatory T cells, isolated population of Foxp3+ regulatory T cells thus obtained and uses thereof |
| JP6770533B2 (en) | 2015-05-22 | 2020-10-14 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | A human monoclonal antibody fragment that inhibits both the catalytic activity of Cath-D and its binding to the LRP1 receptor. |
| US20180134788A1 (en) | 2015-05-26 | 2018-05-17 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and Pharmaceutical Compositions (NTSR1 Inhibitors) for the Treatment of Hepatocellular Carcinomas |
| WO2016189118A1 (en) | 2015-05-28 | 2016-12-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of prognosis and treatment of patients suffering from acute myeloid leukemia |
| IL294138A (en) | 2015-05-29 | 2022-08-01 | Genentech Inc | Therapeutic and diagnostic methods for cancer |
| CN107771182A (en) | 2015-05-29 | 2018-03-06 | 豪夫迈·罗氏有限公司 | The anti-Ebola virus glycoproteins antibody of humanization and application method |
| AU2016274584A1 (en) | 2015-06-08 | 2018-01-04 | Genentech, Inc. | Methods of treating cancer using anti-OX40 antibodies and PD-1 axis binding antagonists |
| JP2018521019A (en) | 2015-06-08 | 2018-08-02 | ジェネンテック， インコーポレイテッド | Method of treating cancer using anti-OX40 antibody |
| EP3845557B1 (en) | 2015-06-12 | 2023-08-02 | Lentigen Technology, Inc. | Method to treat cancer with engineered t-cells |
| WO2016204966A1 (en) | 2015-06-16 | 2016-12-22 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
| JP6996983B2 (en) | 2015-06-16 | 2022-02-21 | ジェネンテック， インコーポレイテッド | Anti-CLL-1 antibody and how to use |
| CN114507289A (en) | 2015-06-16 | 2022-05-17 | 豪夫迈·罗氏有限公司 | Humanized and affinity matured antibodies to FcRH5 and methods of use |
| CN107787331B (en) | 2015-06-17 | 2022-01-11 | 豪夫迈·罗氏有限公司 | anti-HER 2 antibodies and methods of use |
| KR20180020169A (en) | 2015-06-24 | 2018-02-27 | 에프. 호프만-라 로슈 아게 | Anti-transferrin receptor antibody with adjusted affinity |
| CA2989936A1 (en) | 2015-06-29 | 2017-01-05 | Genentech, Inc. | Type ii anti-cd20 antibody for use in organ transplantation |
| AU2016292762B2 (en) | 2015-07-10 | 2022-07-28 | Genmab A/S | AXL-specific antibody-drug conjugates for cancer treatment |
| EP3319936A4 (en) | 2015-07-12 | 2019-02-06 | Suzhou M-conj Biotech Co., Ltd. | Bridge linkers for conjugation of cell-binding molecules |
| US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
| MX2018001522A (en) | 2015-08-05 | 2018-03-15 | Janssen Biotech Inc | Anti-cd154 antibodies and methods of using them. |
| CN105384825B (en) | 2015-08-11 | 2018-06-01 | 南京传奇生物科技有限公司 | A kind of bispecific chimeric antigen receptor and its application based on single domain antibody |
| CN116987187A (en) | 2015-09-23 | 2023-11-03 | 豪夫迈·罗氏有限公司 | Optimized variants of anti-VEGF antibodies |
| CN108289954B (en) | 2015-09-24 | 2022-05-31 | 阿布维特罗有限责任公司 | HIV antibody compositions and methods of use |
| KR20180054837A (en) | 2015-09-30 | 2018-05-24 | 얀센 바이오테크 인코포레이티드 | Functional antibodies specifically binding to human CD40 and methods of use |
| CN114057885A (en) | 2015-10-02 | 2022-02-18 | 豪夫迈·罗氏有限公司 | Bispecific anti-human CD 20/human transferrin receptor antibodies and methods of use |
| BR112018005164A2 (en) | 2015-10-02 | 2019-10-01 | Hoffmann La Roche | antibodies, nucleic acid, host cell, method for producing an antibody, pharmaceutical formulation, use of the antibody and method of treating an individual who has cancer |
| AR106189A1 (en) | 2015-10-02 | 2017-12-20 | Hoffmann La Roche | BIESPECTIFIC ANTIBODIES AGAINST HUMAN A-b AND THE HUMAN TRANSFERRINE RECEIVER AND METHODS OF USE |
| KR102431342B1 (en) | 2015-10-02 | 2022-08-10 | 에프. 호프만-라 로슈 아게 | Bispecific antibodies specific for pd1 and tim3 |
| AU2016335750B2 (en) | 2015-10-07 | 2023-05-25 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | IL-7R-alpha specific antibodies for treating acute lymphoblastic leukemia |
| WO2017060397A1 (en) | 2015-10-09 | 2017-04-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of subjects suffering from melanoma metastases |
| JP6821688B2 (en) | 2015-10-09 | 2021-01-27 | ミルテニー・バイオテク・テクノロジー・インコーポレイテッドＭｉｌｔｅｎｙｉ Ｂｉｏｔｅｃ Ｔｅｃｈｎｏｌｏｇｙ， Ｉｎｃ． | Chimeric antigen receptor and usage |
| US10556953B2 (en) | 2015-10-12 | 2020-02-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Agent capable of depleting CD8 T cells for the treatment of myocardial infarction or acute myocardial infarction |
| MA43354A (en) | 2015-10-16 | 2018-08-22 | Genentech Inc | CONJUGATE DRUG CONJUGATES WITH CLOUDY DISULPHIDE |
| WO2017066714A1 (en) | 2015-10-16 | 2017-04-20 | Compugen Ltd. | Anti-vsig1 antibodies and drug conjugates |
| WO2017067944A1 (en) | 2015-10-19 | 2017-04-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of subjects suffering from triple negative breast cancer |
| EP3184547A1 (en) | 2015-10-29 | 2017-06-28 | F. Hoffmann-La Roche AG | Anti-tpbg antibodies and methods of use |
| PL3368579T3 (en) | 2015-10-30 | 2022-03-21 | F. Hoffmann-La Roche Ag | Hinge modified antibody fragments and methods of making |
| AU2016348391A1 (en) | 2015-11-03 | 2018-05-17 | Janssen Biotech, Inc. | Antibodies specifically binding TIM-3 and their uses |
| CN108602884A (en) | 2015-11-08 | 2018-09-28 | 豪夫迈·罗氏有限公司 | The method for screening multi-specificity antibody |
| CN106674327A (en) * | 2015-11-10 | 2017-05-17 | 复旦大学 | Dolastatin 10 derivative and its preparation method and application |
| US10227410B2 (en) | 2015-12-07 | 2019-03-12 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and PSMA |
| MX2018005229A (en) | 2015-12-09 | 2019-04-29 | F HoffmannLa Roche Ag | Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies. |
| EP3178848A1 (en) | 2015-12-09 | 2017-06-14 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies |
| AU2016371034A1 (en) | 2015-12-17 | 2018-05-31 | Janssen Biotech, Inc. | Antibodies specifically binding HLA-DR and their uses |
| TWI597292B (en) | 2015-12-18 | 2017-09-01 | 中外製藥股份有限公司 | Anti-c5 antibodies and methods of use |
| EP3402465B1 (en) | 2016-01-13 | 2024-03-13 | Genmab A/S | Formulation for antibody and drug conjugate thereof |
| CN108495653A (en) | 2016-01-27 | 2018-09-04 | 免疫医疗有限责任公司 | The method for being used to prepare glycosylation pattern antibody with definition |
| RU2018130757A (en) | 2016-01-27 | 2020-02-27 | Сутро Биофарма, Инк. | ANTIBODY CONJUGATES TO CD74, COMPOSITIONS CONTAINING AN ANTIBODY CONJUGATES TO CD74, AND METHODS FOR USING ANTIBODY ANTIBODIES TO CD74 |
| AU2017213826A1 (en) | 2016-02-04 | 2018-08-23 | Curis, Inc. | Mutant smoothened and methods of using the same |
| EP3419655A1 (en) | 2016-02-27 | 2019-01-02 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Peptide vaccines comprising self-assembling polymer nanoparticles |
| MX2018010361A (en) | 2016-02-29 | 2019-07-08 | Genentech Inc | Therapeutic and diagnostic methods for cancer. |
| TW201740979A (en) | 2016-02-29 | 2017-12-01 | 瑪德瑞高製藥公司 | HSP90 inhibitor drug conjugates |
| JP2019515876A (en) | 2016-03-08 | 2019-06-13 | アカデミア シニカＡｃａｄｅｍｉａ Ｓｉｎｉｃａ | Methods for module synthesis of N-glycans and their arrays |
| WO2017161206A1 (en) | 2016-03-16 | 2017-09-21 | Halozyme, Inc. | Conjugates containing conditionally active antibodies or antigen-binding fragments thereof, and methods of use |
| KR102438140B1 (en) | 2016-03-22 | 2022-08-31 | 엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔 | Humanized anti-claudin-1 antibodies and uses thereof |
| BR112018069273A2 (en) | 2016-03-25 | 2019-01-22 | Seattle Genetics Inc | methods for preparing a compound and treating a subject with a hematological malignancy, compound, composition, and drug binding intermediate or drug binding compound |
| EP3443004A1 (en) | 2016-04-14 | 2019-02-20 | H. Hoffnabb-La Roche Ag | Anti-rspo3 antibodies and methods of use |
| EP3443120A2 (en) | 2016-04-15 | 2019-02-20 | H. Hoffnabb-La Roche Ag | Methods for monitoring and treating cancer |
| MX2018012418A (en) | 2016-04-15 | 2019-07-10 | Bioatla Llc | Anti-axl antibodies, antibody fragments and their immunoconjugates and uses thereof. |
| EP3443350B1 (en) | 2016-04-15 | 2020-12-09 | H. Hoffnabb-La Roche Ag | Methods for monitoring and treating cancer |
| UA123323C2 (en) | 2016-05-02 | 2021-03-17 | Ф. Хоффманн-Ля Рош Аг | The contorsbody - a single chain target binder |
| WO2017196847A1 (en) | 2016-05-10 | 2017-11-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Variable new antigen receptor (vnar) antibodies and antibody conjugates targeting tumor and viral antigens |
| WO2017194441A1 (en) | 2016-05-11 | 2017-11-16 | F. Hoffmann-La Roche Ag | Modified anti-tenascin antibodies and methods of use |
| HRP20221298T1 (en) | 2016-05-13 | 2022-12-23 | Bioatla, Inc. | Anti-ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
| EP3465221B1 (en) | 2016-05-27 | 2020-07-22 | H. Hoffnabb-La Roche Ag | Bioanalytical method for the characterization of site-specific antibody-drug conjugates |
| EP3252078A1 (en) | 2016-06-02 | 2017-12-06 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer |
| CN110603266A (en) | 2016-06-02 | 2019-12-20 | 豪夫迈·罗氏有限公司 | Type II anti-CD 20 and anti-CD 20/CD3 bispecific antibodies for the treatment of cancer |
| WO2017214182A1 (en) | 2016-06-07 | 2017-12-14 | The United States Of America. As Represented By The Secretary, Department Of Health & Human Services | Fully human antibody targeting pdi for cancer immunotherapy |
| BR112018075653A2 (en) | 2016-06-08 | 2019-08-27 | Abbvie Inc | anti-b7-h3 antibodies and drug antibody conjugates |
| JP2019524651A (en) | 2016-06-08 | 2019-09-05 | アッヴィ・インコーポレイテッド | Anti-CD98 antibodies and antibody drug conjugates |
| CN109641962A (en) | 2016-06-08 | 2019-04-16 | 艾伯维公司 | Anti- B7-H3 antibody and antibody drug conjugates |
| TW202304996A (en) | 2016-06-08 | 2023-02-01 | 美商艾伯維有限公司 | Anti-b7-h3 antibodies and antibody drug conjugates |
| US20200147235A1 (en) | 2016-06-08 | 2020-05-14 | Abbvie Inc. | Anti-cd98 antibodies and antibody drug conjugates |
| MA45255A (en) | 2016-06-14 | 2019-04-17 | Xencor Inc | BISPECIFIC CONTROL POINT INHIBITORS ANTIBODIES |
| WO2018004338A1 (en) | 2016-06-27 | 2018-01-04 | Tagworks Pharmaceuticals B.V. | Cleavable tetrazine used in bio-orthogonal drug activation |
| WO2018005706A1 (en) | 2016-06-28 | 2018-01-04 | Xencor, Inc. | Heterodimeric antibodies that bind somatostatin receptor 2 |
| MA45625A (en) | 2016-07-08 | 2019-05-15 | Genmab As | NEW DOSAGE REGIMES FOR ANTIBODY-ANTIBODY-BASED CONJUGATE ANTI-AXL |
| AU2017301887A1 (en) | 2016-07-29 | 2019-02-07 | Juno Therapeutics, Inc. | Anti-idiotypic antibodies against anti-CD19 antibodies |
| CA3031559A1 (en) | 2016-08-02 | 2018-02-08 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies targeting glypican-2 (gpc2) and use thereof |
| CN116271014A (en) | 2016-08-05 | 2023-06-23 | 中外制药株式会社 | Compositions for preventing or treating IL-8 related diseases |
| AU2017316663B2 (en) | 2016-08-22 | 2024-02-22 | CHO Pharma Inc. | Antibodies, binding fragments, and methods of use |
| JP7138094B2 (en) | 2016-08-25 | 2022-09-15 | エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト | Intermittent administration of anti-CSF-1R antibody in combination with macrophage activator |
| US10793632B2 (en) | 2016-08-30 | 2020-10-06 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
| WO2018045325A1 (en) | 2016-09-02 | 2018-03-08 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with duocars |
| SG10201607778XA (en) | 2016-09-16 | 2018-04-27 | Chugai Pharmaceutical Co Ltd | Anti-Dengue Virus Antibodies, Polypeptides Containing Variant Fc Regions, And Methods Of Use |
| CN116731197A (en) | 2016-09-19 | 2023-09-12 | 豪夫迈·罗氏有限公司 | Complement factor based affinity chromatography |
| US10517958B2 (en) | 2016-10-04 | 2019-12-31 | Zymeworks Inc. | Compositions and methods for the treatment of platinum-drug resistant cancer |
| WO2018068028A1 (en) | 2016-10-06 | 2018-04-12 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
| SG11201903302UA (en) | 2016-10-14 | 2019-05-30 | Xencor Inc | Bispecific heterodimeric fusion proteins containing il-15/il-15ralpha fc-fusion proteins and pd-1 antibody fragments |
| CA3080270A1 (en) | 2016-10-25 | 2018-05-03 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Monoclonal antibodies binding to the cd160 transmembrane isoform |
| CN110267678A (en) | 2016-10-29 | 2019-09-20 | 霍夫曼-拉罗奇有限公司 | Anti- MIC antibody and application method |
| WO2018083126A1 (en) | 2016-11-01 | 2018-05-11 | Genmab B.V. | Polypeptide variants and uses thereof |
| KR20220147721A (en) | 2016-11-14 | 2022-11-03 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | Conjugation linkers, cell binding molecule-drug conjugates containing the likers, methods of making and uses such conjugates with the linkers |
| CN109923128A (en) | 2016-11-15 | 2019-06-21 | 基因泰克公司 | Administration for being treated with anti-CD20/ AntiCD3 McAb bispecific antibody |
| TW201829463A (en) | 2016-11-18 | 2018-08-16 | 瑞士商赫孚孟拉羅股份公司 | Anti-hla-g antibodies and use thereof |
| US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
| AU2017382883A1 (en) | 2016-12-21 | 2019-06-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibodies specific for FLT3 and uses thereof |
| JP7304287B2 (en) | 2016-12-22 | 2023-07-06 | エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト | Treatment of tumors with anti-CSF-1R antibodies in combination with anti-PD-L1 antibodies after unsuccessful anti-PD-L1/PD1 therapy |
| CA3096798A1 (en) | 2017-01-09 | 2018-07-12 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-mesothelin immunotherapy |
| JP7341060B2 (en) | 2017-02-10 | 2023-09-08 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | Methods and pharmaceutical compositions for the treatment of cancer associated with MAPK pathway activation |
| MY197534A (en) | 2017-02-10 | 2023-06-21 | Genentech Inc | Anti-tryptase antibodies, compositions thereof, and uses thereof |
| AU2018228873A1 (en) | 2017-03-01 | 2019-08-29 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
| SG11201908325PA (en) | 2017-03-24 | 2019-10-30 | Seattle Genetics Inc | Process for the preparation of glucuronide drug-linkers and intermediates thereof |
| WO2018175988A1 (en) | 2017-03-24 | 2018-09-27 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd33 immunotherapy |
| WO2018195302A1 (en) | 2017-04-19 | 2018-10-25 | Bluefin Biomedicine, Inc. | Anti-vtcn1 antibodies and antibody drug conjugates |
| TWI791519B (en) | 2017-04-27 | 2023-02-11 | 美商提薩羅有限公司 | Antibody agents directed against lymphocyte activation gene-3 (lag-3) and uses thereof |
| AU2018268970A1 (en) | 2017-05-19 | 2019-10-24 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibody targeting tnfr2 for cancer immunotherapy |
| AR111963A1 (en) | 2017-05-26 | 2019-09-04 | Univ California | METHOD AND MOLECULES |
| AU2018282094A1 (en) | 2017-06-05 | 2019-12-12 | Janssen Biotech, Inc. | Antibodies that specifically bind PD-1 and methods of use |
| JP7320458B2 (en) | 2017-06-22 | 2023-08-03 | メルサナ セラピューティクス インコーポレイテッド | Methods of making drug-loaded polymer scaffolds and protein-polymer-drug conjugates |
| US20210403573A1 (en) | 2017-06-22 | 2021-12-30 | INSERM (Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of fibrosis with agents capable of inhibiting the activation of mucosal-associated invariant t (mait) cells |
| WO2019005208A1 (en) | 2017-06-30 | 2019-01-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human mesothelin antibodies and uses in cancer therapy |
| CA3067603A1 (en) | 2017-06-30 | 2019-01-03 | Xencor, Inc. | Targeted heterodimeric fc fusion proteins containing il-15/il-15ra and antigen binding domains |
| WO2019004943A1 (en) | 2017-06-30 | 2019-01-03 | Aslan Pharmaceuticals Pte Ltd | Method of treatment using il-13r antibody |
| WO2019006280A1 (en) | 2017-06-30 | 2019-01-03 | Lentigen Technology, Inc. | Human monoclonal antibodies specific for cd33 and methods of their use |
| TWI823859B (en) | 2017-07-21 | 2023-12-01 | 美商建南德克公司 | Therapeutic and diagnostic methods for cancer |
| WO2019023316A1 (en) | 2017-07-26 | 2019-01-31 | Sutro Biopharma, Inc. | Methods of using anti-cd74 antibodies and antibody conjugates in treatment of t-cell lymphoma |
| WO2019028051A1 (en) | 2017-07-31 | 2019-02-07 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd19/cd20 immunotherapy |
| JP7250766B2 (en) | 2017-08-25 | 2023-04-03 | ヤンセン バイオテツク，インコーポレーテツド | FCγRII-Binding Fibronectin Type III Domains, Conjugates Thereof, and Multispecific Molecules Comprising Them |
| US10501539B2 (en) | 2017-09-15 | 2019-12-10 | Lentigen Technology Inc. | Compositions and methods for treating cancer with anti-CD19 immunotherapy |
| US10596270B2 (en) | 2017-09-18 | 2020-03-24 | Sutro Biopharma, Inc. | Anti-folate receptor antibody conjugates, compositions comprising anti-folate receptor antibody conjugates, and methods of making and using anti-folate receptor antibody conjugates |
| US10543263B2 (en) | 2017-10-16 | 2020-01-28 | Lentigen Technology Inc. | Compositions and methods for treating cancer with anti-CD22 immunotherapy |
| JP7232190B2 (en) | 2017-10-20 | 2023-03-02 | 中外製薬株式会社 | Methods for Measuring Uptake of Molecules into Cells |
| AU2018358883A1 (en) | 2017-10-30 | 2020-04-23 | F. Hoffmann-La Roche Ag | Method for in vivo generation of multispecific antibodies from monospecific antibodies |
| MA49911A (en) | 2017-11-01 | 2020-06-24 | Juno Therapeutics Inc | ANTIBODIES AND CHEMERICAL ANTIGENIC RECEPTORS SPECIFIC TO THE B-LYMPHOCYTE MATURATION ANTIGEN |
| EP3704146B1 (en) | 2017-11-01 | 2021-12-15 | F. Hoffmann-La Roche AG | Trifab-contorsbody |
| JP2021500930A (en) | 2017-11-01 | 2021-01-14 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | COMP Body-Multivalent Target Binding Substance |
| TW201923089A (en) | 2017-11-06 | 2019-06-16 | 美商建南德克公司 | Diagnostic and therapeutic methods for cancer |
| US11312770B2 (en) | 2017-11-08 | 2022-04-26 | Xencor, Inc. | Bispecific and monospecific antibodies using novel anti-PD-1 sequences |
| US10981992B2 (en) | 2017-11-08 | 2021-04-20 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
| US11629167B2 (en) | 2017-11-09 | 2023-04-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Betulastatin compounds |
| GB201719646D0 (en) | 2017-11-27 | 2018-01-10 | Bivictrix Therapeutics Ltd | Therapy |
| EP3717007A1 (en) | 2017-11-30 | 2020-10-07 | Bayer Aktiengesellschaft | Ildr2 antagonists and combinations thereof |
| EP3498293A1 (en) | 2017-12-15 | 2019-06-19 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Treatment of monogenic diseases with an anti-cd45rc antibody |
| SG11202005732XA (en) | 2017-12-19 | 2020-07-29 | Xencor Inc | Engineered il-2 fc fusion proteins |
| WO2019126464A2 (en) | 2017-12-20 | 2019-06-27 | Lentigen Technology, Inc. | Compositions and methods for treating hiv/aids with immunotherapy |
| US11667713B2 (en) | 2017-12-28 | 2023-06-06 | Chugai Seiyaku Kabushiki Kaisha | Cytotoxicity-inducing therapeutic agent |
| EP3740505A1 (en) | 2018-01-16 | 2020-11-25 | Lakepharma Inc. | Bispecific antibody that binds cd3 and another target |
| CR20200391A (en) | 2018-02-08 | 2020-10-19 | Genentech Inc | Bispecific antigen-binding molecules and methods of use |
| TW202000702A (en) | 2018-02-26 | 2020-01-01 | 美商建南德克公司 | Dosing for treatment with anti-TIGIT and anti-PD-L1 antagonist antibodies |
| US20200040103A1 (en) | 2018-03-14 | 2020-02-06 | Genentech, Inc. | Anti-klk5 antibodies and methods of use |
| KR20200132938A (en) | 2018-03-15 | 2020-11-25 | 추가이 세이야쿠 가부시키가이샤 | Anti-dengue virus antibodies with cross-reactivity against Zika virus and methods of use |
| EP3778639A4 (en) | 2018-04-02 | 2021-06-09 | Mab-Venture Biopharm Co., Ltd. | Lymphocyte activation gene-3 (lag-3) binding antibody and use thereof |
| CA3096052A1 (en) | 2018-04-04 | 2019-10-10 | Xencor, Inc. | Heterodimeric antibodies that bind fibroblast activation protein |
| TW202011029A (en) | 2018-04-04 | 2020-03-16 | 美商建南德克公司 | Methods for detecting and quantifying FGF21 |
| US11648317B2 (en) | 2018-04-13 | 2023-05-16 | Genentech, Inc. | Stable anti-CD79B immunoconjugate formulations |
| AR114789A1 (en) | 2018-04-18 | 2020-10-14 | Hoffmann La Roche | ANTI-HLA-G ANTIBODIES AND THE USE OF THEM |
| AU2019256529A1 (en) | 2018-04-18 | 2020-11-26 | Xencor, Inc. | TIM-3 targeted heterodimeric fusion proteins containing IL-15/IL-15Ra Fc-fusion proteins and TIM-3 antigen binding domains |
| US11524991B2 (en) | 2018-04-18 | 2022-12-13 | Xencor, Inc. | PD-1 targeted heterodimeric fusion proteins containing IL-15/IL-15Ra Fc-fusion proteins and PD-1 antigen binding domains and uses thereof |
| WO2019212357A1 (en) | 2018-05-04 | 2019-11-07 | Tagworks Pharmaceuticals B.V. | Compounds comprising a linker for increasing transcyclooctene stability |
| AU2019262520A1 (en) | 2018-05-04 | 2021-01-14 | Tagworks Pharmaceuticals B.V. | Tetrazines for high click conjugation yield in vivo and high click release yield |
| AU2019266203A1 (en) | 2018-05-07 | 2020-11-26 | Genmab A/S | Methods of treating cancer with a combination of an anti-PD-1 antibody and an anti-tissue factor antibody-drug conjugate |
| JP2021523158A (en) | 2018-05-07 | 2021-09-02 | ゲンマブ エー／エス | Cancer treatment method using a combination of anti-PD-1 antibody and anti-tissue factor antibody-drug conjugate |
| BR112020023167A2 (en) | 2018-05-14 | 2021-02-09 | Werewolf Therapeutics, Inc. | activatable cytokine polypeptides and methods of using these |
| CA3100007A1 (en) | 2018-05-14 | 2019-11-21 | Werewolf Therapeutics, Inc. | Activatable interleukin-2 polypeptides and methods of use thereof |
| JOP20200303A1 (en) | 2018-05-24 | 2020-11-23 | Janssen Biotech Inc | Psma binding agents and uses thereof |
| EA202190094A1 (en) | 2018-06-29 | 2021-04-21 | Бёрингер Ингельхайм Интернациональ Гмбх | ANTIBODIES AGAINST CD40 FOR USE IN THE TREATMENT OF AUTOIMMUNE DISEASE |
| WO2020010079A2 (en) | 2018-07-02 | 2020-01-09 | Amgen Inc. | Anti-steap1 antigen-binding protein |
| EP3820909B1 (en) | 2018-07-11 | 2023-03-01 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Monoclonal antibody for the detection of the antiretroviral drug emtricitabine (ftc, 2',3'-dideoxy-5-fluoro-3'-thiacytidine) |
| CA3105694A1 (en) | 2018-07-12 | 2020-01-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Affinity matured cd22-specific monoclonal antibody and uses thereof |
| CN112585163A (en) | 2018-08-08 | 2021-03-30 | 美国政府(由卫生和人类服务部的部长所代表) | High-affinity monoclonal antibody targeting glypican-2 and application thereof |
| AU2019318031A1 (en) | 2018-08-10 | 2021-02-25 | Chugai Seiyaku Kabushiki Kaisha | Anti-CD137 antigen-binding molecule and utilization thereof |
| JP2022500454A (en) | 2018-09-17 | 2022-01-04 | ストロ バイオファーマ インコーポレーテッド | Combination therapy with antifolate receptor antibody conjugate |
| US20220073638A1 (en) | 2018-09-19 | 2022-03-10 | INSERM (Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical composition for the treatment of cancers resistant to immune checkpoint therapy |
| MX2021003214A (en) | 2018-09-19 | 2021-05-12 | Genentech Inc | Therapeutic and diagnostic methods for bladder cancer. |
| WO2020061498A1 (en) | 2018-09-20 | 2020-03-26 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd123 immunotherapy |
| EP3626265A1 (en) | 2018-09-21 | 2020-03-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anti-human cd45rc antibodies and uses thereof |
| AU2019350865A1 (en) | 2018-09-26 | 2021-04-29 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with Anti-CD19/CD22 immunotherapy |
| BR112021005907A2 (en) | 2018-09-27 | 2021-08-10 | Xilio Development, Inc. | masked cytokines, nucleic acid, vector, host cell, methods for producing a masked cytokine, for treating or preventing a neoplastic disease and for treating or preventing a neoplastic inflammatory or autoimmune disease, composition, pharmaceutical composition and kit |
| KR20210069641A (en) | 2018-10-03 | 2021-06-11 | 젠코어 인코포레이티드 | IL-12 heterodimeric Fc-fusion protein |
| EP3867646A1 (en) | 2018-10-18 | 2021-08-25 | F. Hoffmann-La Roche AG | Diagnostic and therapeutic methods for sarcomatoid kidney cancer |
| JP2022513400A (en) | 2018-10-29 | 2022-02-07 | メルサナ セラピューティクス インコーポレイテッド | Cysteine-manipulated antibody with peptide-containing linker-drug conjugate |
| TW202034958A (en) | 2018-10-30 | 2020-10-01 | 丹麥商珍美寶股份有限公司 | Methods of treating cancer with a combination of an anti-vegf antibody and an anti-tissue factor antibody-drug conjugate |
| JP2022512860A (en) | 2018-11-06 | 2022-02-07 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | Methods and Pharmaceutical Compositions for the Treatment of Acute Myeloid Leukemia by Eradication of Leukemia Stem Cells |
| US11103533B2 (en) | 2018-11-30 | 2021-08-31 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-CD38 immunotherapy |
| CA3119798A1 (en) | 2018-12-06 | 2020-06-11 | Genentech, Inc. | Combination therapy of diffuse large b-cell lymphoma comprising an anti-cd79b immunoconjugates, an alkylating agent and an anti-cd20 antibody |
| WO2020123275A1 (en) | 2018-12-10 | 2020-06-18 | Genentech, Inc. | Photocrosslinking peptides for site specific conjugation to fc-containing proteins |
| WO2020120786A1 (en) | 2018-12-14 | 2020-06-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Isolated mhc-derived human peptides and uses thereof for stimulating and activating the suppressive function of cd8+cd45rclow tregs |
| WO2020127411A1 (en) | 2018-12-19 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d |
| WO2020127968A1 (en) | 2018-12-20 | 2020-06-25 | Marino Stephen F | Protein-drug conjugate comprising a monomeric form of proteinase 3 |
| CN113227131A (en) | 2018-12-20 | 2021-08-06 | 豪夫迈·罗氏有限公司 | Modified antibody Fc and methods of use thereof |
| MX2021007768A (en) | 2018-12-26 | 2021-08-24 | Xilio Dev Inc | Anti-ctla4 antibodies and methods of use thereof. |
| AU2020206308A1 (en) | 2019-01-08 | 2021-07-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Cross-species single domain antibodies targeting mesothelin for treating solid tumors |
| TW202043256A (en) | 2019-01-10 | 2020-12-01 | 美商健生生物科技公司 | Prostate neoantigens and their uses |
| MX2021008621A (en) | 2019-01-22 | 2021-08-19 | Genentech Inc | Immunoglobulin a antibodies and methods of production and use. |
| AU2020212534A1 (en) | 2019-01-22 | 2021-07-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | High affinity monoclonal antibodies targeting glypican-1 and methods of use |
| US20220089770A1 (en) | 2019-01-24 | 2022-03-24 | Chugai Seiyaku Kabushiki Kaisha | Novel cancer antigens and antibodies of said antigens |
| WO2020160050A1 (en) | 2019-01-29 | 2020-08-06 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1) |
| CN113710706A (en) | 2019-02-27 | 2021-11-26 | 豪夫迈·罗氏有限公司 | Administration for anti-TIGIT antibody and anti-CD 20 antibody or anti-CD 38 antibody treatment |
| US11472890B2 (en) | 2019-03-01 | 2022-10-18 | Xencor, Inc. | Heterodimeric antibodies that bind ENPP3 and CD3 |
| WO2020181164A1 (en) | 2019-03-06 | 2020-09-10 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with self-driving chimeric antigen receptors |
| JP2022524074A (en) | 2019-03-14 | 2022-04-27 | ジェネンテック， インコーポレイテッド | Treatment of cancer with HER2xCD3 bispecific antibodies in combination with anti-HER2 MAB |
| BR112021020867A2 (en) | 2019-04-19 | 2022-01-04 | Genentech Inc | Antibodies, nucleic acid, vector, host cell, method of producing an antibody, immunoconjugate, pharmaceutical formulation, uses of the antibody, method of treating an individual with cancer, and method of reducing clearance |
| MX2021012767A (en) | 2019-04-19 | 2021-11-18 | Janssen Biotech Inc | Methods of treating prostate cancer with an anti- psma/cd3 antibody. |
| EP3962951A1 (en) | 2019-05-03 | 2022-03-09 | Sutro Biopharma, Inc. | Anti-bcma antibody conjugates |
| MX2021013766A (en) | 2019-05-14 | 2022-02-21 | Werewolf Therapeutics Inc | Separation moieties and methods and use thereof. |
| KR20220007136A (en) | 2019-05-14 | 2022-01-18 | 제넨테크, 인크. | Methods of Use of Anti-CD79b Immunoconjugates to Treat Follicular Lymphoma |
| KR20220016865A9 (en) | 2019-05-15 | 2022-02-21 | 추가이 세이야쿠 가부시키가이샤 | Antigen Binding Molecules, Pharmaceutical Compositions, and Methods |
| US11052112B2 (en) | 2019-05-30 | 2021-07-06 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-BCMA immunotherapy |
| CA3143925A1 (en) | 2019-06-17 | 2020-12-24 | Tagworks Pharmaceuticals B.V. | Compounds for fast and efficient click release |
| IL289094A (en) | 2019-06-17 | 2022-02-01 | Tagworks Pharmaceuticals B V | Tetrazines for high click release speed and yield |
| MX2022000174A (en) | 2019-07-02 | 2022-05-20 | Us Health | Monoclonal antibodies that bind egfrviii and their use. |
| KR20220033493A (en) | 2019-07-10 | 2022-03-16 | 추가이 세이야쿠 가부시키가이샤 | Claudine 6 Binding Molecules and Their Uses |
| WO2021010326A1 (en) | 2019-07-12 | 2021-01-21 | 中外製薬株式会社 | Anti-mutation type fgfr3 antibody and use therefor |
| MX2022001049A (en) | 2019-07-26 | 2022-05-03 | Janssen Biotech Inc | Proteins comprising kallikrein related peptidase 2 antigen binding domains and their uses. |
| MX2022001732A (en) | 2019-08-12 | 2022-05-06 | Purinomia Biotech Inc | Methods and compositions for promoting and potentiating t-cell mediated immune responses through adcc targeting of cd39 expressing cells. |
| PE20220299A1 (en) | 2019-08-15 | 2022-03-07 | Janssen Biotech Inc | MATERIALS AND METHODS FOR ENHANCED SINGLE-CHAIN VARIABLE FRAGMENTS |
| EP4048693A1 (en) | 2019-09-27 | 2022-08-31 | F. Hoffmann-La Roche AG | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
| US20220363776A1 (en) | 2019-10-04 | 2022-11-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of ovarian cancer, breast cancer or pancreatic cancer |
| BR112022007216A2 (en) | 2019-10-18 | 2022-08-23 | Genentech Inc | METHODS FOR TREATMENT OF DIFFUSE LYMPHOMA, KIT AND IMMUNOCONJUGATE |
| US20220380471A1 (en) | 2019-10-22 | 2022-12-01 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | High affinity nanobodies targeting b7-h3 (cd276) for treating multiple solid tumors |
| EP3812008A1 (en) | 2019-10-23 | 2021-04-28 | Gamamabs Pharma | Amh-competitive antagonist antibody |
| EP4055388A1 (en) | 2019-11-06 | 2022-09-14 | Genentech, Inc. | Diagnostic and therapeutic methods for treatment of hematologic cancers |
| TW202131954A (en) | 2019-11-07 | 2021-09-01 | 丹麥商珍美寶股份有限公司 | Methods of treating cancer with a combination of a platinum-based agent and an anti-tissue factor antibody-drug conjugate |
| AU2020380732A1 (en) | 2019-11-07 | 2022-06-02 | Genmab A/S | Methods of treating cancer with a combination of an anti-pd-1 antibody and an anti-tissue factor antibody-drug conjugate |
| JP2023504740A (en) | 2019-12-06 | 2023-02-06 | ジュノー セラピューティクス インコーポレイテッド | Anti-idiotypic antibodies against BCMA target binding domains and related compositions and methods |
| WO2021113780A1 (en) | 2019-12-06 | 2021-06-10 | Juno Therapeutics, Inc. | Anti-idiotypic antibodies to gprc5d-targeted binding domains and related compositions and methods |
| AU2020402752A1 (en) | 2019-12-12 | 2022-06-30 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Antibody-drug conjugates specific for CD276 and uses thereof |
| CN114867494B9 (en) | 2019-12-13 | 2024-01-12 | 基因泰克公司 | anti-LY 6G6D antibodies and methods of use |
| PE20221585A1 (en) | 2019-12-27 | 2022-10-06 | Chugai Pharmaceutical Co Ltd | ANTI-ANTIGEN-4 ANTIBODY ASSOCIATED WITH THE CYTOTOXIC T LYMPHOCYTE (CTLA-4) AND USE THEREOF |
| TW202138388A (en) | 2019-12-30 | 2021-10-16 | 美商西根公司 | Methods of treating cancer with nonfucosylated anti-cd70 antibodies |
| CN110818795B (en) | 2020-01-10 | 2020-04-24 | 上海复宏汉霖生物技术股份有限公司 | anti-TIGIT antibodies and methods of use |
| WO2022050954A1 (en) | 2020-09-04 | 2022-03-10 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
| WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
| TW202144395A (en) | 2020-02-12 | 2021-12-01 | 日商中外製藥股份有限公司 | Anti-CD137 antigen-binding molecule for use in cancer treatment |
| TW202144389A (en) | 2020-02-14 | 2021-12-01 | 美商健生生物科技公司 | Neoantigens expressed in multiple myeloma and their uses |
| TW202144388A (en) | 2020-02-14 | 2021-12-01 | 美商健生生物科技公司 | Neoantigens expressed in ovarian cancer and their uses |
| US20230095053A1 (en) | 2020-03-03 | 2023-03-30 | Sutro Biopharma, Inc. | Antibodies comprising site-specific glutamine tags, methods of their preparation and methods of their use |
| CA3174680A1 (en) | 2020-03-13 | 2021-09-16 | Genentech, Inc. | Anti-interleukin-33 antibodies and uses thereof |
| TW202144418A (en) | 2020-03-13 | 2021-12-01 | 美商健生生物科技公司 | Materials and methods for sialic acid binding ig-like lectin binding |
| WO2021188749A1 (en) | 2020-03-19 | 2021-09-23 | Genentech, Inc. | Isoform-selective anti-tgf-beta antibodies and methods of use |
| JP2023520515A (en) | 2020-04-03 | 2023-05-17 | ジェネンテック， インコーポレイテッド | Therapeutic and diagnostic methods for cancer |
| IL297541A (en) | 2020-04-24 | 2022-12-01 | Genentech Inc | Methods of using anti-cd79b immunoconjugates |
| WO2021222167A1 (en) | 2020-04-28 | 2021-11-04 | Genentech, Inc. | Methods and compositions for non-small cell lung cancer immunotherapy |
| WO2021231976A1 (en) | 2020-05-14 | 2021-11-18 | Xencor, Inc. | Heterodimeric antibodies that bind prostate specific membrane antigen (psma) and cd3 |
| US20230302050A1 (en) | 2020-05-20 | 2023-09-28 | Institut Curie | Single Domain Antibodies and Their Use in Cancer Therapies |
| CN116249714A (en) | 2020-05-27 | 2023-06-09 | 詹森生物科技公司 | Protein comprising CD3 antigen binding domain and uses thereof |
| WO2021252977A1 (en) | 2020-06-12 | 2021-12-16 | Genentech, Inc. | Methods and compositions for cancer immunotherapy |
| CA3181672A1 (en) | 2020-06-18 | 2021-12-23 | Shi Li | Treatment with anti-tigit antibodies and pd-1 axis binding antagonists |
| CA3171101A1 (en) | 2020-06-22 | 2021-12-30 | Dina SCHNEIDER | Compositions and methods for treating cancer with tslpr-cd19 or tslpr-cd22 immunotherapy |
| CN116322787A (en) | 2020-06-29 | 2023-06-23 | 展马博联合股份有限公司 | Anti-tissue factor antibody-drug conjugates and their use in cancer treatment |
| TW202204895A (en) | 2020-07-13 | 2022-02-01 | 美商建南德克公司 | Cell-based methods for predicting polypeptide immunogenicity |
| US20230296612A1 (en) | 2020-07-29 | 2023-09-21 | Chugai Seiyaku Kabushiki Kaisha | Method for measuring pharmacokinetics of agent labeled with non-radioactive substance |
| MX2023001256A (en) | 2020-07-29 | 2023-05-16 | Janssen Biotech Inc | Proteins comprising hla-g antigen binding domains and their uses. |
| EP4189071A1 (en) | 2020-08-03 | 2023-06-07 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Population of treg cells functionally committed to exert a regulatory activity and their use for adoptive therapy |
| WO2022029660A1 (en) | 2020-08-05 | 2022-02-10 | Juno Therapeutics, Inc. | Anti-idiotypic antibodies to ror1-targeted binding domains and related compositions and methods |
| EP4192942A1 (en) | 2020-08-07 | 2023-06-14 | Genentech, Inc. | T cell-based methods for predicting polypeptide immunogenicity |
| TW202221016A (en) | 2020-08-07 | 2022-06-01 | 美商建南德克公司 | Flt3 ligand fusion proteins and methods of use |
| CN112062855A (en) | 2020-08-26 | 2020-12-11 | 康诺亚生物医药科技（成都）有限公司 | Development and application of medicinal therapeutic agent containing adapter |
| US20220089759A1 (en) | 2020-09-21 | 2022-03-24 | Boehringer Ingelheim International Gmbh | Use of anti-cd40 antibodies for treatment of inflammatory conditions |
| JP2023544407A (en) | 2020-10-05 | 2023-10-23 | ジェネンテック， インコーポレイテッド | Administration for treatment with anti-FcRH5/anti-CD3 bispecific antibodies |
| TW202231292A (en) | 2020-10-13 | 2022-08-16 | 美商健生生物科技公司 | Bioengineered t cell mediated immunity, materials and other methods for modulating cluster of differentiation iv and/or viii |
| EP4229090A1 (en) | 2020-10-16 | 2023-08-23 | Université d'Aix-Marseille | Anti-gpc4 single domain antibodies |
| AU2021363766A1 (en) | 2020-10-22 | 2023-06-15 | Janssen Biotech, Inc. | Proteins comprising delta-like ligand 3 (dll3) antigen binding domains and their uses |
| US20230391852A1 (en) | 2020-10-26 | 2023-12-07 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies targeting sars coronavirus spike protein and uses thereof |
| CA3196076A1 (en) | 2020-11-04 | 2022-05-12 | Chi-Chung Li | Subcutaneous dosing of anti-cd20/anti-cd3 bispecific antibodies |
| KR20230095119A (en) | 2020-11-04 | 2023-06-28 | 제넨테크, 인크. | Dosing for Treatment with Anti-CD20/Anti-CD3 Bispecific Antibodies |
| EP4240493A2 (en) | 2020-11-04 | 2023-09-13 | Genentech, Inc. | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies and anti-cd79b antibody drug conjugates |
| EP4240397A1 (en) | 2020-11-05 | 2023-09-13 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd19/cd22 immunotherapy |
| CN114524878A (en) | 2020-11-23 | 2022-05-24 | 康诺亚生物医药科技（成都）有限公司 | Bispecific antibody and application thereof |
| CN114573703A (en) | 2020-12-02 | 2022-06-03 | 康诺亚生物医药科技（成都）有限公司 | Development and application of T cell adaptor therapeutic agent |
| CN114573702A (en) | 2020-12-02 | 2022-06-03 | 康诺亚生物医药科技（成都）有限公司 | Development and application of novel tumor adaptor treatment drug |
| TW202237638A (en) | 2020-12-09 | 2022-10-01 | 日商武田藥品工業股份有限公司 | Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof |
| GB202020572D0 (en) | 2020-12-23 | 2021-02-03 | Bivictrix Therapeutics Ltd | Novel methods of therapy |
| GB202020573D0 (en) | 2020-12-23 | 2021-02-03 | Bivictrix Therapeutics Ltd | Novel methods of therapy |
| CN114685657A (en) | 2020-12-31 | 2022-07-01 | 康诺亚生物医药科技（成都）有限公司 | Development and application of function-enhanced antibody blocking agent |
| JP2024505428A (en) | 2021-01-14 | 2024-02-06 | アンスティテュ キュリー | HER2 single domain antibody variants and their CARs |
| AR124681A1 (en) | 2021-01-20 | 2023-04-26 | Abbvie Inc | ANTI-EGFR ANTIBODY-DRUG CONJUGATES |
| KR20230137393A (en) | 2021-01-28 | 2023-10-04 | 얀센 바이오테크 인코포레이티드 | PSMA binding protein and its uses |
| WO2022172085A2 (en) | 2021-02-15 | 2022-08-18 | Takeda Pharmaceutical Company Limited | Cell therapy compositions and methods for modulating tgf-b signaling |
| AU2022222386A1 (en) | 2021-02-16 | 2023-07-20 | Glykos Finland Oy | Linker-payloads and conjugates thereof |
| TW202246324A (en) | 2021-03-01 | 2022-12-01 | 美商艾希利歐發展股份有限公司 | Combination of masked ctla4 and pd1/pdl1 antibodies for treating cancer |
| US20220306743A1 (en) | 2021-03-01 | 2022-09-29 | Xilio Development, Inc. | Combination of ctla4 and pd1/pdl1 antibodies for treating cancer |
| JP2024511319A (en) | 2021-03-09 | 2024-03-13 | ゼンコア インコーポレイテッド | Heterodimeric antibody that binds to CD3 and CLDN6 |
| US11859012B2 (en) | 2021-03-10 | 2024-01-02 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and GPC3 |
| EP4313317A1 (en) | 2021-03-23 | 2024-02-07 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the diagnosis and treatment of t cell-lymphomas |
| WO2022201052A1 (en) | 2021-03-24 | 2022-09-29 | Janssen Biotech, Inc. | Antibody targeting cd22 and cd79b |
| AR125212A1 (en) | 2021-03-24 | 2023-06-28 | Janssen Biotech Inc | PROTEINS INCLUDING CD3 ANTIGEN-BINDING DOMAINS AND THEIR USES |
| JP2024512633A (en) | 2021-03-30 | 2024-03-19 | バイエル・アクチエンゲゼルシヤフト | Anti-SEMA3A antibody and its uses |
| WO2022214681A1 (en) | 2021-04-09 | 2022-10-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the treatment of anaplastic large cell lymphoma |
| AR125344A1 (en) | 2021-04-15 | 2023-07-05 | Chugai Pharmaceutical Co Ltd | ANTI-C1S ANTIBODY |
| WO2022232612A1 (en) | 2021-04-29 | 2022-11-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Lassa virus-specific nanobodies and methods of their use |
| WO2022228706A1 (en) | 2021-04-30 | 2022-11-03 | F. Hoffmann-La Roche Ag | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibody |
| WO2022232488A1 (en) | 2021-04-30 | 2022-11-03 | Celgene Corporation | Combination therapies using an anti-bcma antibody drug conjugate (adc) in combination with a gamma secretase inhibitor (gsi) |
| WO2022228705A1 (en) | 2021-04-30 | 2022-11-03 | F. Hoffmann-La Roche Ag | Dosing for combination treatment with anti-cd20/anti-cd3 bispecific antibody and anti-cd79b antibody drug conjugate |
| BR112023023622A2 (en) | 2021-05-12 | 2024-02-06 | Genentech Inc | METHODS TO TREAT DIFFUSE LYMPHOMA, KITS, IMMUNOCONJUGATES, POLATUZUMABE VEDOTIN AND IMMUNOCONJUGATE FOR USE |
| CN117321219A (en) | 2021-05-19 | 2023-12-29 | 中外制药株式会社 | Method for predicting in vivo pharmacokinetics of molecules |
| CN117396513A (en) | 2021-05-28 | 2024-01-12 | 葛兰素史密斯克莱知识产权发展有限公司 | Combination therapy for the treatment of cancer |
| CN117480184A (en) | 2021-06-04 | 2024-01-30 | 中外制药株式会社 | anti-DDR 2 antibodies and uses thereof |
| AU2022291120A1 (en) | 2021-06-09 | 2023-11-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Cross species single domain antibodies targeting pd-l1 for treating solid tumors |
| WO2022270611A1 (en) | 2021-06-25 | 2022-12-29 | 中外製薬株式会社 | Anti–ctla-4 antibody |
| AU2022297107A1 (en) | 2021-06-25 | 2024-01-18 | Chugai Seiyaku Kabushiki Kaisha | Use of anti-ctla-4 antibody |
| CA3221281A1 (en) | 2021-06-29 | 2023-01-05 | Seagen Inc. | Methods of treating cancer with a combination of a nonfucosylated anti-cd70 antibody and a cd47 antagonist |
| US11807685B2 (en) | 2021-08-05 | 2023-11-07 | The Uab Research Foundation | Anti-CD47 antibody and uses thereof |
| WO2023019092A1 (en) | 2021-08-07 | 2023-02-16 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
| CA3230117A1 (en) | 2021-09-02 | 2023-03-09 | Mark Trautwein | Anti-cecam6 antibodies with reduced side-effects |
| AU2022338463A1 (en) | 2021-09-03 | 2024-03-21 | Toray Industries, Inc. | Pharmaceutical composition for cancer treatment and/or prevention |
| WO2023031445A2 (en) | 2021-09-06 | 2023-03-09 | Veraxa Biotech Gmbh | Novel aminoacyl-trna synthetase variants for genetic code expansion in eukaryotes |
| CA3231944A1 (en) | 2021-09-16 | 2023-03-23 | Carole GUILLONNEAU | Anti-human cd45rc binding domains and uses thereof |
| WO2023046322A1 (en) | 2021-09-24 | 2023-03-30 | Janssen Pharmaceutica Nv | Proteins comprising cd20 binding domains, and uses thereof |
| WO2023056403A1 (en) | 2021-09-30 | 2023-04-06 | Genentech, Inc. | Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists |
| CA3233953A1 (en) | 2021-10-05 | 2023-04-13 | Matthew Bruce | Combination therapies for treating cancer |
| WO2023089587A1 (en) | 2021-11-22 | 2023-05-25 | Janssen Biotech, Inc. | Compositions comprising enhanced multispecific binding agents for an immune response |
| WO2023094525A1 (en) | 2021-11-25 | 2023-06-01 | Veraxa Biotech Gmbh | Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion |
| EP4186529A1 (en) | 2021-11-25 | 2023-05-31 | Veraxa Biotech GmbH | Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion |
| WO2023104941A1 (en) | 2021-12-08 | 2023-06-15 | European Molecular Biology Laboratory | Hydrophilic tetrazine-functionalized payloads for preparation of targeting conjugates |
| WO2023110937A1 (en) | 2021-12-14 | 2023-06-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Depletion of nk cells for the treatment of adverse post-ischemic cardiac remodeling |
| US20230227545A1 (en) | 2022-01-07 | 2023-07-20 | Johnson & Johnson Enterprise Innovation Inc. | Materials and methods of il-1beta binding proteins |
| WO2023144303A1 (en) | 2022-01-31 | 2023-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Cd38 as a biomarker and biotarget in t-cell lymphomas |
| EP4314031B1 (en) | 2022-02-15 | 2024-03-13 | Tagworks Pharmaceuticals B.V. | Masked il12 protein |
| GB202202171D0 (en) | 2022-02-17 | 2022-04-06 | Bivictrix Ltd | Novel methods of therapy |
| GB202202170D0 (en) | 2022-02-17 | 2022-04-06 | Bivictrix Ltd | Novel methods of therapy |
| US20230338424A1 (en) | 2022-03-02 | 2023-10-26 | Lentigen Technology, Inc. | Compositions and Methods for Treating Cancer with Anti-CD123 Immunotherapy |
| US11590169B1 (en) | 2022-03-02 | 2023-02-28 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-CD123 immunotherapy |
| US20230414750A1 (en) | 2022-03-23 | 2023-12-28 | Hoffmann-La Roche Inc. | Combination treatment of an anti-cd20/anti-cd3 bispecific antibody and chemotherapy |
| WO2023191816A1 (en) | 2022-04-01 | 2023-10-05 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
| WO2023198648A1 (en) | 2022-04-11 | 2023-10-19 | Institut National de la Santé et de la Recherche Médicale | Methods for the diagnosis and treatment of t-cell malignancies |
| WO2023198727A1 (en) | 2022-04-13 | 2023-10-19 | F. Hoffmann-La Roche Ag | Pharmaceutical compositions of anti-cd20/anti-cd3 bispecific antibodies and methods of use |
| WO2023201299A1 (en) | 2022-04-13 | 2023-10-19 | Genentech, Inc. | Pharmaceutical compositions of therapeutic proteins and methods of use |
| WO2023198874A1 (en) | 2022-04-15 | 2023-10-19 | Institut National de la Santé et de la Recherche Médicale | Methods for the diagnosis and treatment of t cell-lymphomas |
| US20230346862A1 (en) | 2022-05-02 | 2023-11-02 | Athanor Biosciences, Inc. | Cancer eradicating - bio-nanoparticles (ce-bnp) |
| WO2023213960A1 (en) | 2022-05-06 | 2023-11-09 | Genmab A/S | Methods of treating cancer with anti-tissue factor antibody-drug conjugates |
| WO2023219613A1 (en) | 2022-05-11 | 2023-11-16 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
| WO2023240058A2 (en) | 2022-06-07 | 2023-12-14 | Genentech, Inc. | Prognostic and therapeutic methods for cancer |
| WO2024003310A1 (en) | 2022-06-30 | 2024-01-04 | Institut National de la Santé et de la Recherche Médicale | Methods for the diagnosis and treatment of acute lymphoblastic leukemia |
| US20240058465A1 (en) | 2022-06-30 | 2024-02-22 | Sutro Biopharma, Inc. | Anti-ror1 antibody conjugates, compositions comprising anti ror1 antibody conjugates, and methods of making and using anti-ror1 antibody conjugates |
| WO2024015897A1 (en) | 2022-07-13 | 2024-01-18 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
| WO2024013724A1 (en) | 2022-07-15 | 2024-01-18 | Pheon Therapeutics Ltd | Antibody-drug conjugates |
| WO2024020432A1 (en) | 2022-07-19 | 2024-01-25 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
| WO2024020564A1 (en) | 2022-07-22 | 2024-01-25 | Genentech, Inc. | Anti-steap1 antigen-binding molecules and uses thereof |
| WO2024018046A1 (en) | 2022-07-22 | 2024-01-25 | Institut National de la Santé et de la Recherche Médicale | Garp as a biomarker and biotarget in t-cell malignancies |
| WO2024026107A2 (en) | 2022-07-28 | 2024-02-01 | Lentigen Technology, Inc. | Chimeric antigen receptor therapies for treating solid tumors |
| WO2024023283A1 (en) | 2022-07-29 | 2024-02-01 | Institut National de la Santé et de la Recherche Médicale | Lrrc33 as a biomarker and biotarget in cutaneous t-cell lymphomas |
| US20240075142A1 (en) | 2022-08-26 | 2024-03-07 | Lentigen Technology, Inc. | Compositions and Methods for Treating Cancer with Fully Human Anti-CD20/CD19 Immunotherapy |
| WO2024049949A1 (en) | 2022-09-01 | 2024-03-07 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
Family Cites Families (1)
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| US4978744A (en) * | 1989-01-27 | 1990-12-18 | Arizona Board Of Regents | Synthesis of dolastatin 10 |
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| US8288352B2 (en) | 2004-11-12 | 2012-10-16 | Seattle Genetics, Inc. | Auristatins having an aminobenzoic acid unit at the N terminus |
| US10494432B2 (en) | 2007-07-16 | 2019-12-03 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
| US10981987B2 (en) | 2007-07-16 | 2021-04-20 | Genentech, Inc. | Humanized anti-CD79b antibodies and immunoconjugates and methods of use |
| USRE48558E1 (en) | 2007-07-16 | 2021-05-18 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
| US11866496B2 (en) | 2007-07-16 | 2024-01-09 | Genentech, Inc. | Humanized anti-CD79B antibodies and immunoconjugates and methods of use |
| US10544218B2 (en) | 2008-01-31 | 2020-01-28 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
| US11000510B2 (en) | 2014-09-23 | 2021-05-11 | Genentech, Inc. | Methods of using anti-CD79b immunoconjugates |
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| EP0612762B1 (en) | 1997-12-17 |
| US5780588A (en) | 1998-07-14 |
| DE69407322T2 (en) | 1998-06-04 |
| ATE161270T1 (en) | 1998-01-15 |
| CA2114156A1 (en) | 1994-07-27 |
| EP0612762A1 (en) | 1994-08-31 |
| JPH08119990A (en) | 1996-05-14 |
| DE69407322D1 (en) | 1998-01-29 |
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