PYRROLOBENZODIAZEPINE ANTIBODY DRUG CONJUGATES AND METHODS OF USE

• US 20180326062A1
• Filed: 07/16/2018
• Published: 11/15/2018
• Est. Priority Date: 10/02/2015
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Dragovich, Peter, Pillow, Thomas, Sadowsky, Jack, Sliwkowski, Mark X., Wei, BinQing
• Granted Patent: US 10,639,373 B2
• Time in Patent Office: Days
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/40 characterized by post-translational modification
• CPC Class Codes: C07K 2317/522 CH1 domain
• CPC Class Codes: C07K 2317/567 Framework region [FR]

Abstract

The invention provides antibody-drug conjugates comprising an antibody conjugated to a pyrrolobenzodiazepine drug moiety via a disulfide linker, pyrrolobenzodiazepine linker-drug intermediates, and methods of using the antibody-drug conjugates.

Claims

1. A linker-drug intermediate of Formula I:

2. The linker-drug intermediate of claim 1 of Formula Ia:

3. The linker-drug intermediate of claim 1 of Formula Ib:

4. The linker-drug intermediate of claim 1 having Formula Ic:

5. The linker-drug intermediate of claim 1 of Formula Id:

6. The linker-drug intermediate of claim 1 wherein R⁴ and R⁵ are each H.

7. The linker-drug intermediate of claim 1 of Formula Ie:

8. The linker-drug intermediate of claim 1 wherein R⁴ and R⁵ are ═

O.

9. The linker-drug intermediate of claim 1 of Formula If:

10. The linker-drug intermediate of claim 1 wherein R¹ and R² along with the carbon atom to which they are attached form cyclopropyl or cyclobutyl ring.

30. A method of making an antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 11, the method comprising reacting an antibody with a linker-drug intermediate of Formula I of claim 1.

11. An antibody-drug conjugate compound of Formula II:

12. The antibody-drug conjugate compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1)-(53):

(1) BMPR1B (bone morphogenetic protein receptor-type IB);

(2) E16 (LAT1, SLC7A5);

(3) STEAP1 (six transmembrane epithelial antigen of prostate);

(4) MUC16 (0772P, CA125);

(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin);

(6) Napi2b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b);

(7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMASB, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B);

(8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene);

(9) ETBR (Endothelin type B receptor);

(10) MSG783 (RNF124, hypothetical protein FLJ20315);

(11) STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein);

(12) TrpM4 (BR22450, F1120041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member

     4);

(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor);

(14) CD21 (CR2 (Complement receptor

     2) or C3DR (C3d/Epstein Barr virus receptor) or Hs

     73792);

(15) CD79b (CD79B, CD7913, IGb (immunoglobulin-associated beta), B29);

(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C);

(17) HER2;

(18) NCA;

(19) MDP;

(20) IL20Rα

;

(21) Brevican;

(22) EphB2R;

(23) ASLG659;

(24) PSCA;

(25) GEDA;

(26) BAFF-R (B cell-activating factor receptor, BLyS receptor 3, BR3);

(27) CD22 (B-cell receptor CD22-B isoform);

(28) CD79a (CD79A, CD79α

, immunoglobulin-associated alpha);

(29) CXCR5 (Burkitt'"'"'s lymphoma receptor

     1);

(30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen));

(31) P2X5 (Purinergic receptor P2×

ligand-gated ion channel

     5);

(32) CD72 (B-cell differentiation antigen CD72, Lyb-2);

(33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family);

(34) FcRH1 (Fc receptor-like protein

     1);

(35) FcRH5 (IRTA2, Immunoglobulin superfamily receptor translocation associated

     2);

(36) TENB2 (putative transmembrane proteoglycan);

(37) PMEL17 (silver homolog;

SILV;

D12S53E;

PMEL17;

SI;

SIL);

(38) TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1;

Tomoregulin-1);

(39) GDNF-Ra1 (GDNF family receptor alpha 1;

GFRA1;

GDNFR;

GDNFRA;

RETL1;

TRNR1;

RET1L;

GDNFR-alpha1;

GFR-ALPHA-1);

(40) Ly6E (lymphocyte antigen 6 complex, locus E;

Ly67,RIG-E,SCA-2,TSA-1);

(41) TMEM46 (shisa homolog 2 (Xenopus laevis);

SHISA2);

(42) Ly6G6D (lymphocyte antigen 6 complex, locus G6D;

Ly6-D, MEGT1);

(43) LGR5 (leucine-rich repeat-containing G protein-coupled receptor 5;

GPR49, GPR67);

(44) RET (ret proto-oncogene;

MEN2A;

HSCR1;

MEN2B;

MTC1;

PTC;

CDHF12;

Hs.168114;

RET51;

RET-ELE1);

(45) LY6K (lymphocyte antigen 6 complex, locus K;

LY6K;

HSJ001348;

FLJ35226);

(46) GPR19 (G protein-coupled receptor 19;

Mm.4787);

(47) GPR54 (KISS1 receptor;

KISS1R;

GPR54;

HOT7T175;

AXOR12);

(48) ASPHD1 (aspartate beta-hydroxylase domain containing 1;

LOC253982);

(49) Tyrosinase (TYR;

OCAIA;

OCA1A;

tyrosinase;

SHEP3);

(50) TMEM118 (ring finger protein, transmembrane 2;

RNFT2;

FLJ14627);

(51) GPR172A (G protein-coupled receptor 172A;

GPCR41;

FLJ11856;

D15Ertd747e);

(52) CD33;

or

(53) CLL-1.

13. The antibody-drug conjugate compound of claim 11, or a pharmaceutically acceptable salt thereof, of Formula IIa:

14. The antibody-drug conjugate compound of claim 11, or a pharmaceutically acceptable salt thereof, of Formula IIb:

15. The antibody-drug conjugate compound of claim 11, or a pharmaceutically acceptable salt thereof, of Formula IIc:

16. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 15 wherein R⁴ and R⁵ are each H.

17. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 15 wherein R⁴ and R⁵ are ═

O.

18. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 15 having Formula IId:

19. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 15 having Formula IIe:

20. The antibody-drug conjugate compound of claim 15, or a pharmaceutically acceptable salt thereof, having Formula IIf:

21. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 11, wherein Ab is a cysteine-engineered antibody.

22. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 21, wherein the cysteine-engineered antibody comprises LC K149C or HC A118C as the site of drug conjugation.

23. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 11, wherein Ab is selected from anti-HER2, anti-CD22, anti-CD33, anti-Napi2b, or anti-CLL-1.

24. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 11, wherein p is 1, 2, 3, or 4.

25. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 11, comprising a mixture of the antibody-drug conjugate compounds, wherein the average drug loading per antibody, p, in the mixture of antibody-drug conjugate compounds is about 2 to about 5.

26. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 11 and a pharmaceutically acceptable diluent, carrier or excipient.

27. The pharmaceutical composition of claim 26, further comprising a therapeutically effective amount of a chemotherapeutic agent.

28. A method of treating cancer comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of claim 26.

29. The method of claim 28 wherein the patient is administered a chemotherapeutic agent, in combination with the antibody-drug conjugate according to claim 11, or a pharmaceutically acceptable salt thereof.

31. An antibody-drug conjugate compound of Formula II:

32. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 31, wherein the anti-HER2 antibody comprises a light chain variable region comprising the sequence of SEQ ID NO:

17 and a heavy chain variable region comprising the sequence of SEQ ID NO;

18.

33. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 31 having Formula IIa:

34. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 31 having Formula IIb:

35. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 31 having Formula IIc:

36. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 35 wherein R⁴ and R⁵ are each H.

37. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 35 wherein R⁴ and R⁵ are ═

O.

38. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 35 having Formula IId:

39. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 35 having Formula IIe:

40. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 35 having Formula IIf:

41. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 31, wherein anti-HER2 antibody is a cysteine-engineered antibody.

42. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 41, wherein the cysteine-engineered antibody comprises LC K149C or HC A118C as the site of drug conjugation.

43. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 31, wherein p is 1, 2, 3, or 4.

44. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 31, comprising a mixture of the antibody-drug conjugate compounds, wherein the average drug loading per antibody, p, in the mixture of antibody-drug conjugate compounds is about 2 to about 5.

45. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 31 and a pharmaceutically acceptable diluent, carrier or excipient.

46. The pharmaceutical composition of claim 45, further comprising an additional therapeutic agent.

47. The pharmaceutical composition of claim 46, wherein the additional therapeutic agent is a chemotherapeutic agent.

48. The pharmaceutical composition of claim 46, wherein the additional therapeutic agent is an antibody or immunoconjugate that binds HER2.

49. The pharmaceutical composition of claim 48, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to domain II of HER2, and/or (ii) an antibody or immunoconjugate that binds to domain IV or HER2.

50. The pharmaceutical composition of claim 48, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to epitope 2C4, and/or (ii) an antibody or immunoconjugate that binds to epitope 4D5.

51. The pharmaceutical composition of claim 46, wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-MCC-DM1 (T-DM1), or pertuzumab.

52. The pharmaceutical composition of claim 46, further comprising (1) trastuzumab or T-DM1, and (2) pertuzumab.

53. A method of treating cancer comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of claim 45.

54. The method of claim 53, wherein the cancer is a HER2-positive cancer.

55. The method of claim 54, wherein the HER2-positive cancer is breast cancer or gastric cancer.

56. A method of treating cancer comprising administering to a patient a therapeutically effective amount of the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 31.

57. The method of claim 56, wherein the cancer is a HER2-positive cancer.

58. The method of claim 57, wherein the HER2-positive cancer is breast cancer or gastric cancer.

59. The method of claim 56, further comprising administering to a patient an additional therapeutic agent.

60. The method of claim 59, wherein the additional therapeutic agent is a chemotherapeutic agent.

61. The method of claim 59, wherein the additional therapeutic agent is an antibody or immunoconjugate that binds HER2.

62. The method of claim 61, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to domain II of HER2, and/or (ii) an antibody or immunoconjugate that binds to domain IV or HER2.

63. The method of claim 61, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to epitope 2C4, and/or (ii) an antibody or immunoconjugate that binds to epitope 4D5.

64. The method of claim 61, wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-MCC-DM1 (T-DM1), or pertuzumab.

65. The method of claim 61, further comprising administering to the patient (1) trastuzumab or T-DM1, and (2) pertuzumab.

66. An antibody drug conjugate, or a pharmaceutically acceptable salt thereof, of Formula IIf

67. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 66, wherein Ab is an anti-HER2 antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:

22;

(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO;

23;

(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO;

24;

(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO;

19;

(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO;

20; and

(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO;

21.

68. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 66, wherein the anti-HER2 antibody comprises a light chain variable region comprising the sequence of SEQ ID NO:

17 and a heavy chain variable region comprising the sequence of SEQ ID NO;

18.

69. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 66 to and a pharmaceutically acceptable diluent, carrier or excipient.