Targeted pyrrolobenzodiazapine conjugates

• US 9,242,013 B2
• Filed: 04/15/2011
• Issued: 01/26/2016
• Est. Priority Date: 04/15/2010
• Status: Active Grant

• Current Assignee: MedImmune Ltd. (Astrazeneca PLC), Seagen Inc.
• Original Assignee: MedImmune Ltd. (Astrazeneca PLC), Seattle Genetics Incorporated
• Inventors: Howard, Philip Wilson, Jeffrey, Scott, Burke, Patrick, Senter, Peter
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/641,219
• Publication Number:
  US 20130028919A1
• Time in Patent Office: 1,747 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/68035 the drug being a pyrrolobenzodiazepine
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6861 the tumour determinant being from kidney or bladder cancer cell
• CPC Class Codes: A61K 47/6867 the tumour determinant being from a cell of a blood cancer
• CPC Class Codes: A61K 47/6871 the antibody targeting an enzyme
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2812 against CD4
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/3038 Kidney, bladder
• CPC Class Codes: C07K 16/3061 : Blood cells
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided are Conjugate comprising PBDs conjugated to a targeting agent and methods of using such PBDs.

Claims

1. A conjugate having formula I:

L-(LU-D)_p 

 

(I)

or a pharmaceutically acceptable salt thereof;

wherein L is a Ligand unit selected from an antibody, an antigen-binding fragment of an antibody or a Fc fusion protein,

LU is a Linker unit which is of formula 1a;

-A¹-L¹-, 

 

(1a)

wherein;

-A¹- is selected from the group consisting of;

2. The conjugate according to claim 1, wherein R⁷ is selected from the group consisting of H, OH and OR.

3. The conjugate according to claim 2, wherein R⁷ is a C_1-4 alkyloxy group.

4. The conjugate according to claim 2, wherein Y and Y′

are O.

5. The conjugate according to claim 4, wherein R″

is C_3-7 alkylene.

6. The conjugate according to claim 5, wherein R⁹ is H.

7. The conjugate according to claim 6, wherein R⁶ is selected from the group consisting of H and halo.

8. The conjugate according to claim 1, wherein A is phenyl, X is selected from the group consisting of —

O—

, —

S—

, and —

NH—

, and Q¹ is a single bond.

9. The conjugate according to claim 8, wherein X is NH.

10. The conjugate according to claim 9, wherein Q¹ is a single bond and Q² is a single bond.

11. The conjugate according to claim 1, wherein R¹² is a C_5-7 aryl group optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C_1-7 alkoxy, C_5-20 aryloxy, C_3-20 heterocyclyoxy, C_1-7 alkyl, C_3-7 heterocyclyl and bis-oxy-C_1-3 alkylene wherein the C_1-7 alkoxy group is optionally substituted by an amino group, and if the C_3-7 heterocyclyl group is a C₆ nitrogen containing heterocyclyl group, it is optionally substituted by a C_1-4 alkyl group.

12. The conjugate according to claim 11, wherein the C_5-7 aryl group is an optionally substituted phenyl group.

13. The conjugate according to claim 12, wherein R¹² bears one to three substituent groups.

14. The conjugate according to claim 1, wherein R¹⁰ and R¹¹ form a nitrogen-carbon double bond.

15. The conjugate according to claim 1, wherein R^6′

, R^7′

, R^9′

, and Y′

are the same as R⁶, R⁷, R⁹, and Y respectively.

16. The conjugate of claim 1, wherein A¹ is:

17. The conjugate of claim 16, wherein n is 5.

18. The conjugate of claim 1, wherein L¹ is a dipeptide.

19. The conjugate of claim 18, wherein L¹ is selected from the group consisting of valine-alanine, valine-citrulline and phenylalanine-lysine.

20. The conjugate of claim 1 wherein D has the formula:

21. The conjugate of claim 1 wherein LU-D has the formula:

22. The conjugate of claim 21 wherein the Ligand unit is an antibody or antigen binding fragment thereof that specifically binds to a target antigen on the surface of a target cell.

23. The conjugate of claim 22 wherein the antibody is a monoclonal antibody.

24. The conjugate of claim 22 wherein the connection between the antibody or antigen binding fragment thereof and the Linker is formed between a thiol group of a cysteine residue of the antibody or antigen binding fragment thereof and a maleimide group of the Linker unit.

25. The conjugate of claim 24 wherein the cysteine residue is an introduced into the heavy chain or light chain of the antibody or antigen binding fragment thereof.

26. The conjugate of claim 20 wherein D has the formula:

27. The conjugate of claim 20 wherein D has the formula:

28. The conjugate of claim 26 wherein the Ligand unit is an antibody.

29. The conjugate of claim 28 wherein the connection between the antibody and the Linker unit is formed between a thiol group of a cysteine residue of the antibody and a maleimide group of the Linker unit.

30. The conjugate of claim 29 wherein the cysteine residue is an introduced cysteine residue in the heavy chain or light chain of the antibody or antigen binding fragment thereof.

31. The conjugate of claim 30 wherein the antibody is attached to the Linker unit via an introduced cysteine at amino acid heavy chain position 239, according to the EU numbering system.

32. The conjugate of claim 23 wherein the antibody is attached to the Linker unit via a thiol group of a cysteine reside of the antibody wherein the cysteine residue is an introduced cysteine at amino acid heavy chain position 239, according to the EU numbering system and a maleimide group of the Linker unit.

33. The conjugate of claim 31 wherein the antibody is a humanized 1F6 antibody.

34. The conjugate of claim 32 wherein the antibody is a humanized 1F6 antibody.

40. A method of treating a mammal having a proliferative disease wherein the cell surface antigen bound by the Ligand unit is expressed by proliferative cells of the proliferative disease comprising administering an effective amount of the conjugate of claim 1, wherein the proliferative disease treated is selected from the group consisting of renal cell carcinoma, Hodgkin Lymphoma, anaplastic large cell lymphoma and acute myeloid leukemia.

35. A pharmaceutical composition comprising a conjugate having formula I:

L-(LU-D)_p 

 

(I)

or a pharmaceutically acceptable salt thereof;

wherein L is an antibody,

LU-D has the formula;

36. The pharmaceutical composition of claim 35 wherein p is about 2.

37. The pharmaceutical composition of claim 36 wherein the antibody is a humanized 1F6 antibody.

38. A Drug Linker having the formula:

G¹-L¹-D

or a pharmaceutically acceptable salt thereof;

wherein G¹ is seletected from the group consisting of;

39. The Drug Linker of claim 38 having the formula:

41. The Drug Linker of claim 38 having the formula: