Claims for Patent: 10,004,812

Summary for Patent: 10,004,812

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 Endoglin; 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:	15/116,419
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 Endoglin; L is a linker; D is a drug comprising a cytolysin; and p is 1 to 10, wherein the cytolysin is of formula IV: ##STR00035## wherein: R.sup.2 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: ##STR00036## 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 is directly or indirectly attached to linker L; and q is 0, 1, 2 or 3. 2. The conjugate of claim 1, wherein A comprises 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. 3. The conjugate of claim 2, 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. 4. The conjugate of claim 2, 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. 5. The conjugate of claim 1, 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 1, 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 1, wherein D comprises a cytolysin having the following structure: ##STR00037## or ##STR00038## 12. The conjugate of claim 1, wherein L comprises an attachment group for attachment to A and protease cleavable portion. 13. The conjugate of claim 12, wherein L comprises maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate. 14. The conjugate of claim 1, wherein L-D has a structure selected from the group consisting of: ##STR00039## 15. A method of treating a tumor in a mammalian subject, wherein said tumor and/or stroma surrounding said tumor expresses endoglin, said method comprising administering a therapeutically effective amount of a conjugate as defined in claim 1 to the subject in need thereof. 16. The method of claim 15, wherein said conjugate is administered simultaneously, sequentially or separately with one or more other antitumor drugs. 17. The method of claim 16, wherein said one or more other antitumor drugs comprise a cytotoxic chemotherapeutic agent or an anti-angiogenic agent or an immunotherapeutic agent. 18. The method of claim 17, 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. 19. The method of claim 18, wherein said anti-PD-1 molecule or anti-PD-L1 molecule comprises nivolumab or pembrolizumab. 20. The method of claim 15, wherein the tumor is an endoglin-expressing blood neoplasm, pancreatic cancer, Ewing sarcoma, breast cancer, melanoma, lung cancer, head and neck cancer, ovarian cancer, bladder cancer or colon cancer. 21. A method of treating an endoglin-expressing inflammatory condition or an endoglin-expressing eye disease in a mammalian subject, said method comprising administering a therapeutically effective amount of the conjugate as defined in claim 1 to the subject in need thereof. 22. The method according to claim 21, wherein: said inflammatory condition is endoglin-expressing rheumatoid arthritis; and/or said eye disease is endoglin-expressing diabetic retinopathy or endoglin-expressing macular degeneration.

Details for Patent 10,004,812

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