Pyrrolobenzodiazepine antibody drug conjugates and methods of use

• US 10,632,196 B2
• Filed: 02/20/2018
• Issued: 04/28/2020
• Est. Priority Date: 10/02/2015
• Status: Expired due to Fees

• 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
• Primary Examiner(s): Huff, Sheela J.
• Application Number:
  US15/899,612
• Publication Number:
  US 20180185486A1
• Time in Patent Office: 798 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 47/68035 the drug being a pyrrolobenzodiazepine
• 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. An antibody-drug conjugate compound of Formula II:

2. The antibody-drug conjugate compound of claim 1, 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, SEMA5B, 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, FLJ20041, 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, CD79β

, 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 P2X 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-alphal;

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.

3. The antibody-drug conjugate compound of claim 1, or a pharmaceutically acceptable salt thereof, of Formula IIa:

4. The antibody-drug conjugate compound of claim 1, or a pharmaceutically acceptable salt thereof, of Formula IIb:

5. The antibody-drug conjugate compound of claim 1, or a pharmaceutically acceptable salt thereof, of Formula IIc:

6. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 5 wherein R⁴ and R⁵ are each H.

7. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 5 wherein R⁴ and R⁵ are ═

O.

8. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 5 having Formula IId:

9. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 5 having Formula IIe:

10. The antibody-drug conjugate compound of claim 5, or a pharmaceutically acceptable salt thereof, having Formula IIf:

11. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein said Ab is a cysteine-engineered antibody.

12. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 11, wherein the cysteine-engineered antibody comprises K149C substitution in the light chain according to Kabat numbering;

or A118C substitution in the heavy chain according to EU numbering as the site of drug conjugation.

13. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Ab is selected from anti-HER2, anti-CD 22, anti-CD33, anti-Napi2b, or anti-CLL-1.

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

15. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1, 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.

16. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1 and a pharmaceutically acceptable diluent, carrier or excipient.

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

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

19. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 18, 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.

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

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

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

23. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 22 wherein R⁴ and R⁵ are each H.

24. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 22 wherein R⁴ and R⁵ are ═

O.

25. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 22 having Formula IId:

26. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 22 having Formula IIe:

27. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 22 having Formula IIf:

28. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 18, wherein anti-HER2 antibody is a cysteine-engineered antibody.

29. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 28, wherein the cysteine-engineered antibody comprises K149C substitution in the light chain according to Kabat numbering;

or A118C substitution in the heavy chain according to EU numbering as the site of drug conjugation.

30. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 18, wherein p is 1, 2, 3, or 4.

31. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 18, 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.

32. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 18 and a pharmaceutically acceptable diluent, carrier or excipient.

33. The pharmaceutical composition of claim 32, further comprising an additional therapeutic agent.

34. The pharmaceutical composition of claim 33, wherein the additional therapeutic agent is a chemotherapeutic agent.

35. The pharmaceutical composition of claim 33, wherein the additional therapeutic agent is an antibody or immunoconjugate that binds HER2.

36. The pharmaceutical composition of claim 35, 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.

37. The pharmaceutical composition of claim 35, 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.

38. The pharmaceutical composition of claim 33, wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-MCC-DM1 (T-DM1), or pertuzumab.

39. The pharmaceutical composition of claim 33, further comprising (1) trastuzumab or T-DM1, and (2) pertuzumab.

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

41. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 40, wherein the anti-HER2 antibody is a cysteine-engineered antibody.

42. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 40 and a pharmaceutically acceptable diluent, carrier or excipient.

43. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 40, wherein the anti-HER2 antibody comprises:

(i) the heavy chain sequence of SEQ ID NO;

26 and the light chain sequence of SEQ ID NO;

30;

or (ii) the heavy chain sequence of SEQ ID NO;

31 and the light chain sequence of SEQ ID NO;

25.

44. The antibody drug conjugate compound of claim 40 wherein p is about 2.

45. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 41 wherein the cysteine-engineered antibody comprises K149C substitution in the light chain according to Kabat numbering;

or A118C substitution in the heavy chain according to EU numbering as the site of drug conjugation.

46. An antibody drug conjugate, or a pharmaceutically acceptable salt thereof, of Formula IIe:

47. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 46, wherein the anti-HER2 antibody comprises:

(i) the heavy chain sequence of SEQ ID NO;

26 and the light chain sequence of SEQ ID NO;

30;

or (ii) the heavy chain sequence of SEQ ID NO;

31 and the light chain sequence of SEQ ID NO;

25.

48. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 46, wherein the anti-HER2 antibody is a cysteine-engineered antibody.

49. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 46 wherein the cysteine-engineered antibody comprises K149C substitution in the light chain according to Kabat numbering;

or A118C substitution in the heavy chain according to EU numbering as the site of drug conjugation.

50. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 46 and a pharmaceutically acceptable diluent, carrier or excipient.

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

52. The antibody drug conjugate compound of claim 51 wherein p is about 2.

53. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 51 and a pharmaceutically acceptable diluent, carrier or excipient.

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

55. The antibody drug conjugate compound of claim 54 wherein p is about 2.

56. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 54 and a pharmaceutically acceptable diluent, carrier or excipient.

57. The antibody drug conjugate compound of claim 54 wherein the anti-HER2 antibody comprises the heavy chain sequence of SEQ ID NO:

26 and the light chain sequence of SEQ ID NO;

30.

58. The antibody drug conjugate compound of claim 54 wherein the anti-HER2 antibody comprises the heavy chain sequence of SEQ ID NO:

31 and the light chain sequence of SEQ ID NO;

25.