US2021260210A1PendingUtilityA1

Anti-her2 biparatopic antibody-drug conjugates and methods of use

Assignee: ZYMEWORKS INCPriority: Mar 13, 2018Filed: Mar 12, 2019Published: Aug 26, 2021

Est. expiryMar 13, 2038(~11.7 yrs left)· nominal 20-yr term from priority

Inventors:Kevin Hamblett Rupert H. Davies James R. Rich Gerald J. Rowse Vincent K.C. Fung Stuart Daniel Barnscher

A61K 47/6855A61K 47/6811C07K 16/3069A61K 47/6817A61K 47/65A61K 47/6425A61K 47/6857C07K 16/3015A61K 47/6803A61K 47/6869C07K 2317/622C07K 2317/565C07K 16/32A61P 35/00A61K 47/6889C07K 16/3046C07K 2317/73A61K 38/00C07K 2317/55C07K 2317/526C07K 16/3023A61K 47/6863C07K 2317/31A61K 2039/505A61K 38/05

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Claims

Abstract

Anti-HER2 biparatopic antibody-drug conjugates (ADCs) in which the drug is an auristatin analogue and is conjugated to the antibody at a low average drug-to-antibody ratio (DAR), and methods of using the ADCs in the treatment of a HER2-expressing cancer. The low average DAR (<3.9) ADCs as described herein have improved tolerability and decreased toxicity as compared to a corresponding ADC having a DAR ≥3.9 when administered at the same toxin dose.

Claims

exact text as granted — not AI-modified

1 . An antibody-drug conjugate comprising an anti-HER2 biparatopic antibody conjugated to an auristatin analogue via a linker (L) at a low average drug-to-antibody ratio (DAR),
wherein the anti-HER2 biparatopic antibody comprises a first antigen-binding polypeptide construct which binds a first HER2 epitope and a second antigen-binding polypeptide construct which binds a second HER2 epitope, wherein the first and second HER2 epitopes are on different domains of HER2, wherein the auristatin analogue and linker have general Formula (X)

wherein:
R 1 is selected from:

L is the linker, and
represents the point of attachment of the linker to the anti-HER2 biparatopic antibody, and
wherein the low average DAR is an average DAR of between 1.5 and 2.5.

2 . (canceled)

3 . The antibody-drug conjugate according to claim 1 , wherein R 1 is:

4 . (canceled)

5 . The antibody-drug conjugate according to claim 1 , wherein R 1 is:

6 - 8 . (canceled)

9 . The antibody-drug conjugate according to claim 1 , wherein the average DAR is between 1.8 and 2.5.

10 - 11 . (canceled)

12 . The antibody-drug conjugate according to claim 1 , wherein the conjugate comprises between about 5% and about 50% DAR0 species.

13 . The antibody-drug conjugate according to claim 1 , wherein the conjugate comprises between about 10% and about 30% DAR0 species.

14 . The antibody-drug conjugate according to claim 1 , wherein the conjugate comprises between about 10% and about 25% DAR0 species.

15 . The antibody-drug conjugate according to claim 1 , wherein the conjugate comprises between about 15% and about 25% DAR0 species.

16 - 17 . (canceled)

18 . The antibody-drug conjugate according to claim 1 , wherein the conjugate comprises between 0% and about 15% DAR6 or greater species.

19 . The antibody-drug conjugate according to claim 1 , wherein the conjugate comprises between about 0% and about 10% DAR6 or greater species.

20 . The antibody-drug conjugate according to claim 1 , wherein L is a cleavable linker.

21 . The antibody-drug conjugate according to claim 20 , wherein L is a protease-cleavable linker.

22 . The antibody-drug conjugate according to claim 1 , wherein L has general Formula (VI):

wherein:
Z is a functional group capable of reacting with the target group on the anti-HER2 biparatopic antibody;
Str is a stretcher;
AA 1 and AA 2 are each independently an amino acid, wherein AA 1 -[AA 2 ] m forms a protease cleavage site;
X is a self-immolative group;
D is the point of attachment to the auristatin analogue;
s is 0 or 1;
m is an integer between 1 and 4, and
o is 0, 1 or 2.

23 . The antibody-drug conjugate according to claim 1 , wherein L has general Formula (VIII):

wherein:
A-S— is the point of attachment to the anti-HER2 biparatopic antibody;
Y is one or more additional linker components, or is absent, and
D is the point of attachment to the auristatin analogue.

24 . The antibody-drug conjugate according to claim 1 , wherein L has general Formula (X):

25 . The antibody-drug conjugate according to claim 1 , wherein the auristatin analogue-linker has the structure:

wherein A-S— is the point of attachment to the anti-HER2 biparatopic antibody.

26 - 27 . (canceled)

28 . The antibody-drug conjugate according to claim 25 , wherein the conjugate comprises between about 10% and about 30% DAR0 species.

29 . (canceled)

30 . The antibody-drug conjugate according to claim 25 , wherein the conjugate comprises between 0% and about 15% DAR6 or greater species.

31 - 33 . (canceled)

34 . The antibody-drug conjugate according to claim 1 , wherein the first and second antigen-binding polypeptide constructs are independently an scFv or a Fab.

35 . The antibody-drug conjugate according to claim 34 , wherein the first antigen-binding polypeptide construct is an scFv, and the second antigen-binding polypeptide construct is a Fab.

36 - 37 . (canceled)

38 . The antibody-drug conjugate according to claim 1 , wherein the first HER2 epitope is on ECD4 of HER2 and the second HER2 epitope is on ECD2 of HER2.

39 . The antibody-drug conjugate according to claim 38 , wherein the first antigen-binding polypeptide construct competes with trastuzumab for binding to HER2.

40 . The antibody-drug conjugate according to claim 38 , wherein the second antigen-binding polypeptide construct competes with pertuzumab for binding to HER2.

41 . The antibody-drug conjugate according to claim 38 , wherein the first antigen-binding polypeptide construct comprises the CDR sequences from the ECD4-binding arm of any one of v5019, v5020, v7091, v10000, v6902, v6903 or v6717, and the second antigen-binding polypeptide construct comprises the CDR sequences from the ECD2-binding arm of any one of v5019, v5020, v7091, v10000, v6902, v6903, v6717, v7133, v15079, v15080, v15081, v15082, v15083, v15084 or v15085.

42 . (canceled)

43 . The antibody-drug conjugate according to claim 41 , wherein the second antigen-binding polypeptide construct comprises the CDR sequences from the ECD2-binding arm of v10000.

44 . (canceled)

45 . The antibody-drug conjugate according to claim 38 , wherein the first antigen-binding polypeptide construct comprises a set of six CDRs that have 90% or greater sequence identity to a set of CDRs from the ECD4-binding arm of v10000, wherein the antigen-binding polypeptide construct retains the ability to bind ECD4, and the second antigen-binding polypeptide construct comprises a set of six CDRs that have 90% or greater sequence identity to a set of CDRs from the ECD2-binding arm of v10000, wherein the antigen-binding polypeptide construct retains the ability to bind ECD2.

46 . (canceled)

47 . The antibody-drug conjugate according to claim 1 , wherein the first antigen-binding polypeptide construct comprises the CDR sequences set forth in SEQ ID NOs: 27, 28, 29, 39, 40 and 41, and the second antigen-binding polypeptide construct comprises the CDR sequences set forth in SEQ ID NOs: 67, 68, 69, 70, 71 and 72.

48 - 49 . (canceled)

50 . The antibody-drug conjugate according to claim 491 , wherein the anti-HER2 biparatopic antibody comprises an IgG Fc region that is a heterodimeric Fc region comprising a modified CH3 domain.

51 . (canceled)

52 . The antibody-drug conjugate according to claim 50 , wherein the modified CH3 domain comprises a first polypeptide sequence and a second polypeptide sequence, and wherein:
(a) the first polypeptide sequence of the modified CH3 domain comprises the amino acid modifications L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T366L, K392M and T394W; or (b) the first polypeptide sequence of the modified CH3 domain comprises the amino acid modifications L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T366L, K392L and T394W; or (c) the first polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T350V, L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T350V, T366L, K392M and T394W; or (d) the first polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T350V, L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T350V, T366L, K392L and T394W; or (e) the first polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T350V, L351Y, S400E, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T350V, T366L, N390R, K392M and T394W.

53 . A pharmaceutical composition comprising the antibody-drug conjugate according to claim 1 and a pharmaceutically acceptable carrier or diluent.

54 . (canceled)

55 . A method of treating a HER2-expressing cancer comprising administering to a subject having a HER2-expressing cancer an effective amount of the antibody-drug conjugate according to claim 1 .

56 . The method according to claim 55 , wherein the HER2-expressing cancer is a breast cancer, ovarian cancer, lung cancer or gastric cancer.

57 . The method according to claim 55 , wherein the HER2-expressing cancer is a breast cancer.

58 . The method according to claim 55 , wherein the HER2-expressing cancer is an ovarian cancer.

59 . The method according to claim 55 , wherein the HER2-expressing cancer is scored as HER2 negative by immunohistochemistry.

60 - 71 . (canceled)

72 . The antibody-drug conjugate according to claim 1 , wherein the average DAR is about 2.0.

73 . The antibody-drug conjugate according to claim 22 , wherein s is 1, and o is 0.

74 . The antibody-drug conjugate according to claim 52 , wherein the first polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T350V, L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain comprises the amino acid modifications T350V, T366L, K392L and T394W.

75 . The method according to claim 55 , wherein the HER2-expressing cancer is a HER2 high cancer.

76 . The method according to claim 55 , wherein the HER2-expressing cancer is a HER2 low cancer.

77 . The method according to claim 55 , wherein the subject has relapsed from prior therapy.

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