Claims for Patent: 10,137,202

Summary for Patent: 10,137,202

Title:	Antibody-drug conjugates and immunotoxins
Abstract:	The present invention relates to conjugates, in particular antibody-drug conjugates and immunotoxins, having the formula I: A-(L-D)p (I) or a pharmaceutically acceptable salts or solvates thereof, wherein: A is an antibody that selectively binds FAP; L is a linker; D is a drug comprising a cytolysin or a Nigrin-b A-chain; and p is 1 to 10, and to use of such conjugates in the therapeutic treatment of tumors. Methods of producing such conjugates and components for use in such methods are disclosed.
Inventor(s):	Kontermann; Roland (Nurtingen, DE), Pfizenmaier; Klaus (Tiefenbronn, DE), Ferrer; Cristina (Madrid, ES), Fabre; Myriam (Barcelona, ES), Simon; Laureano (Derio, ES)
Assignee:	Oncomatryx Biopharma, S.L. (Derio, ES)
Application Number:	15/116,430
Patent Claims:	1. A conjugate having the formula I: A-(L-D).sub.p (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: A is an antibody that selectively binds fibroblast activation protein alpha (FAP), said antibody comprising heavy chain complementarity determining regions 1-3 (CDRH1-3) and light chain complementarity determining regions 1-3 (CDRL1-3) having the following amino acid sequences: (i) CDRH1: SEQ ID NO: 7; (ii) CDRH2: SEQ ID NO: 8; (iii) CDRH3: SEQ ID NO: 9; (iv) CDRL1: SEQ ID NO: 10; (v) CDRL2: SEQ ID NO: 11; and (vi) CDRL3: SEQ ID NO: 12; L is a linker; D is a drug comprising a cytolysin; and p is 1 to 10. 2. The conjugate of claim 1, wherein A comprises a heavy chain variable region (VH), comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 6. 3. The conjugate of claim 1, wherein A comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3, and a light chain comprising the amino acid sequence of SEQ ID NO: 4. 4. The conjugate of claim 1, wherein D is a cytolysin of formula IV: ##STR00031## wherein: R.sup.2 (i) is directly or indirectly attached to linker L or (ii) is H or C.sub.1-C.sub.4 alkyl; R.sup.6 is C.sub.1-C.sub.6 alkyl; R.sup.7 is C.sub.1-C.sub.6 alkyl, CH.sub.2OR.sup.19 or CH.sub.2OCOR.sup.20, wherein R.sup.19 is alkyl, R.sup.20 is C.sub.2-C.sub.6-alkenyl, phenyl, or CH.sub.2-phenyl; R.sup.9 is C.sub.1-C.sub.6 alkyl; R.sup.10 is H, OH, O-alkyl or O-acetyl; f is 1 or 2; R.sup.11 has the following structure: ##STR00032## wherein R.sup.21 is H, OH, halogen, NH.sub.2, alkyloxy, phenyl, alkyl amino or dialkyl amino; R.sup.16 is H or a C.sub.1-C.sub.6-alkyl group; R.sup.17 (i) is directly or indirectly attached to linker L or (ii) is CO.sub.2H, CO.sub.2R.sup.18, CONHNH.sub.2, OH, NH.sub.2, SH or a optionally substituted alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl group, wherein R.sup.18 is an optionally substituted alkyl, heteroalkyl or hetercycloalkyl group; and q is 0, 1, 2 or 3; and wherein the term "optionally substituted" relates to groups, wherein one or several H atoms can be replaced by F, Cl, Br or I or OH, SH, NH.sub.2, or NO.sub.2; the term "optionally substituted" further relates to groups, which can be exclusively or additionally substituted with unsubstituted C.sub.1-C.sub.6 alkyl, C.sub.2C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.2-C.sub.9 heterocycloalkyl, C.sub.6-C.sub.10 aryl, C.sub.1-C.sub.9 heteroaryl, C.sub.7-C.sub.12 aralkyl or C.sub.2-C.sub.11 heteroaralkyl groups. 5. The conjugate of claim 4, wherein R.sup.17 is C(O)X, CONHNHX, OX, NHX or SX, wherein X is a bond to linker L. 6. The conjugate of claim 4, wherein linker L further comprises a spacer. 7. The conjugate of claim 6, wherein the spacer has a chain length of 2 to 30 atoms. 8. The conjugate of claim 7, wherein the spacer comprises or consists of a group --(CH.sub.2).sub.n-- or --(OCH.sub.2CH.sub.2).sub.n--, wherein n=1 to 10. 9. The conjugate of claim 6, wherein the spacer is directly attached to group R.sup.17, or is attached to group R.sup.17 via a bridging group. 10. The conjugate of claim 9, wherein the spacer is attached to group R.sup.17 via a --C(O)X bridging group, wherein X is a bond to R.sup.17. 11. The conjugate of claim 10, wherein R.sup.17 is CONHNHX and the spacer is a --(OCH.sub.2CH.sub.2).sub.n-- attached to R.sup.17 via a --C(O)X bridging group, wherein n=2, 3 or 4, and wherein X represents the bond between the spacer and R.sup.17. 12. The conjugate of claim 4, wherein D comprises a cytolysin having the following structure: ##STR00033## 13. The conjugate of claim 4, wherein D comprises a cytolysin having the following structure: ##STR00034## 14. The conjugate of claim 4, wherein L comprises an attachment group for attachment to A and a protease cleavable portion. 15. The conjugate of claim 14, wherein L comprises maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate. 16. The conjugate of claim 1, wherein L-D has a structure selected from the group consisting of: ##STR00035## ##STR00036## 17. A method of treating a tumor in a mammalian subject, wherein said tumor and/or stroma surrounding said tumor expresses fibroblast activation protein alpha (FAP), said method comprising administering a therapeutically effective amount of a conjugate as defined in claim 1 to a subject in need thereof. 18. The method of claim 17, wherein said conjugate is administered simultaneously, sequentially or separately with one or more other antitumor drugs. 19. The method of claim 18, wherein said one or more other antitumor drugs comprise a cytotoxic chemotherapeutic agent or an anti-angiogenic agent or an immunotherapeutic agent. 20. The method of claim 19, wherein said one or more other antitumor drugs comprise Gemcitabine, Abraxane, bevacizumab, itraconazole, or carboxyamidotriazole, an anti-PD-1 molecule or an anti-PD-L1 molecule. 21. The method of claim 20, wherein said anti-PD-1 molecule or anti-PD-L1 molecule comprises nivolumab or pembrolizumab. 22. The method of claim 17, wherein the tumor is an FAP-expressing tumor of pancreatic cancer, breast cancer, melanoma, lung cancer, head and neck cancer, ovarian cancer, bladder cancer or colon cancer. 23. A method of treating a fibroblast activation protein alpha (FAP) expressing inflammatory condition in a mammalian subject, comprising administering a therapeutically effective amount of a conjugate as defined in claim 1 to a subject in need thereof. 24. The method according to claim 23, wherein said FAP expressing inflammatory condition is FAP expressing rheumatoid arthritis. 25. A conjugate having the formula I: A-(L-D).sub.p (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: A is an antibody that selectively binds fibroblast activation protein alpha (FAP); L is a linker; D is a drug comprising a cytolysin; and p is 1 to 10, wherein L-D has a structure selected from the group consisting of: ##STR00037## ##STR00038## 26. A method of treating a tumor in a mammalian subject, wherein said tumor and/or stroma surrounding said tumor expresses fibroblast activation protein alpha (FAP), said method comprising administering a therapeutically effective amount of a conjugate as defined in claim 25 to a subject in need thereof. 27. The method of claim 26, wherein said conjugate is administered simultaneously, sequentially or separately with one or more other antitumor drugs. 28. The method of claim 27, wherein said one or more other antitumor drugs comprise a cytotoxic chemotherapeutic agent or an anti-angiogenic agent or an immunotherapeutic agent. 29. The method of claim 28, wherein said one or more other antitumor drugs comprise Gemcitabine, Abraxane, bevacizumab, itraconazole, or carboxyamidotriazole, an anti-PD-1 molecule or an anti-PD-L1 molecule. 30. The method of claim 29, wherein said anti-PD-1 molecule or anti-PD-L1 molecule comprises nivolumab or pembrolizumab. 31. The method of claim 26, wherein the tumor is an FAP-expressing tumor of pancreatic cancer, breast cancer, melanoma, lung cancer, head and neck cancer, ovarian cancer, bladder cancer or colon cancer. 32. A method of treating a fibroblast activation protein alpha (FAP) expressing inflammatory condition in a mammalian subject, comprising administering a therapeutically effective amount of a conjugate as defined in claim 25 to a subject in need thereof. 33. The method according to claim 32, wherein said FAP expressing inflammatory condition is FAP expressing rheumatoid arthritis.

Details for Patent 10,137,202

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2034-02-06
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	For Injection	125514	09/04/2014		2034-02-06
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	Injection	125514	01/15/2015		2034-02-06
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	12/22/2014		2034-02-06
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	10/04/2017		2034-02-06
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	08/27/2021		2034-02-06