IP Library › Granted Patent US 12,357,701
Granted Patent B2
US 12,357,701 · App. 17/210,081 · Granted Jul 15, 2025

Anti-HER2 biparatopic antibody-drug conjugates and methods of use

Inventors: Kevin Hamblett (Seattle, WA); Rupert H. Davies (Seattle, WA); James R. Rich (Vancouver, CA); Gerald J. Rowse (New Westminster, CA); Vincent K. C. Fung (Vancouver, CA); Stuart D. Barnscher (Vancouver, CA)
Assignee: Zymeworks BC Inc.
A61K47/6425A61K47/65A61K47/6817A61K47/6855A61K47/6857A61K47/6863A61K47/6869A61P35/00C07K16/3015C07K16/3023C07K16/3046C07K16/3069C07K16/32A61K38/00A61K2039/505C07K2317/31C07K2317/526C07K2317/55C07K2317/565C07K2317/622C07K2317/73
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Quick Facts
Patent No.
US 12,357,701
App. No.
17/210,081
Granted
Jul 15, 2025
Kind
B2
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 (70)

1. A method of treating a HER2-expressing cancer comprising administering to a subject having a HER2-expressing cancer an effective amount of 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 comprising the CDR sequences set forth in SEQ ID NOs: 67, 68, 69, 70, 71 and 72, and a second antigen-binding polypeptide construct comprising the CDR sequences set forth in SEQ ID NOs: 27, 28, 29, 39, 40 and 41, wherein the auristatin analogue and linker have general Formula (X):

wherein:

R 1 is

L is a protease-cleavable 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. The method according to claim 1 , wherein the HER2-expressing cancer is a breast cancer, ovarian cancer, lung cancer or gastric cancer.

3. The method according to claim 1 , wherein the HER2-expressing cancer is scored as HER2 negative by immunohistochemistry.

4. The method according to claim 1 , wherein the HER2-expressing cancer is scored as HER2 3+ by immunohistochemistry.

5. The method according to claim 1 , wherein the HER2-expressing cancer is scored as HER2 1+ or HER2 1+/2+ by immunohistochemistry.

6. The method according to claim 1 , wherein the average DAR is between 1.8 and 2.5.

7. The method according to claim 1 , wherein the conjugate comprises between about 10% and about 30% DAR0 species.

8. The method according to claim 1 , wherein the conjugate comprises between about 10% and about 25% DAR0 species.

9. The method according to claim 1 , wherein the conjugate comprises between about 15% and about 25% DAR0 species.

10. The method according to claim 1 , wherein the conjugate comprises between 0% and about 15% DAR6 or greater species.

11. The method according to claim 1 , wherein the conjugate comprises between about 0% and about 10% DAR6 or greater species.

12. The method according to claim 6 , 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.

13. The method according to claim 1 , wherein L has general Formula (VIII) or general Formula (IX):

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.

14. The method according to claim 1 , wherein the auristatin analogue and linker have the structure:

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

15. The method according to claim 14 , wherein the conjugate comprises between about 10% and about 30% DAR0 species.

16. The method according to claim 14 , wherein the conjugate comprises between 0% and about 15% DAR6 or greater species.

17. The method according to claim 1 , wherein the first and second antigen-binding polypeptide constructs are each independently an scFv or a Fab.

18. The method according to claim 1 , wherein the first antigen-binding polypeptide construct is an scFv, and the second antigen-binding polypeptide construct is a Fab.

19. The method according to claim 1 , wherein the anti-HER2 biparatopic antibody comprises an IgG Fc region that is a heterodimeric Fc region comprising a modified CH3 domain.

20. The method according to claim 19 , 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.

21. The method according to claim 19 , 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.

22. The method according to claim 1 , wherein the anti-HER2 biparatopic antibody comprises:

(i) a first heavy chain (H1) comprising the CDR sequences as set forth in SEQ ID NOs: 39, 40 and 41,

(ii) a second heavy chain (H2) comprising the CDR sequences as set forth in SEQ ID NOs: 67, 68, 69, 70, 71 and 72, and

(iii) a light chain (L1) comprising the CDR sequences as set forth in SEQ ID NOs: 27, 28 and 29, and

the auristatin analogue and linker have the structure:

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

wherein the low average DAR is an average DAR of between 1.8 and 2.5, and

wherein the conjugate comprises between about 10% and about 25% DAR0 species.

23. The method according to claim 22 , wherein the average DAR is about 2.0.

24. The method according to claim 22 , wherein:

(i) the H1 comprises the VH sequence as set forth in SEQ ID NO: 38,

(ii) the H2 comprises the VH sequence as set forth in SEQ ID NO: 66 and the VL sequence as set forth in SEQ ID NO: 65, and

(iii) the L1 comprises the VL sequence as set forth in SEQ ID NO: 26.

25. The method according to claim 22 , wherein the H1 comprises the sequence as set forth in SEQ ID NO: 36, the H2 comprises the sequence as set forth in SEQ ID NO: 63, and the L1 comprises the sequence as set forth in SEQ ID NO: 24.

26. The method according to claim 22 , wherein the H1 consists of the sequence as set forth in SEQ ID NO: 36, the H2 consists of the sequence as set forth in SEQ ID NO: 63, and the L1 consists of the sequence as set forth in SEQ ID NO: 24.

27. The method according to claim 22 , wherein the HER2-expressing cancer is a breast cancer, ovarian cancer, lung cancer or gastric cancer.

28. The method according to claim 22 , wherein the HER2-expressing cancer is a breast cancer.

29. The method according to claim 22 , wherein the HER2-expressing cancer is an ovarian cancer.

30. The method according to claim 22 , wherein the HER2-expressing cancer is a HER2 high cancer.

31. The method according to claim 22 , wherein the HER2-expressing cancer is a HER2 low cancer.

32. The method according to claim 22 , wherein the subject has relapsed from prior therapy.

33. The method according to claim 6 , wherein:

the first antigen-binding polypeptide construct comprises the VH sequence as set forth in SEQ ID NO: 66 and the VL sequence as set forth in SEQ ID NO: 65, and

the second antigen-binding polypeptide construct comprises the VH sequence as set forth in SEQ ID NO: 38 and the VL sequence as set forth in SEQ ID NO: 26.

Assignments (5)
CHANGE OF NAME Recorded Dec 12, 2022
From: ZYMEWORKS INC.
To: ZYMEWORKS BC INC.
Reel/Frame 062116/0071 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 1, 2021
From: ZYMEWORKS BIOPHARMACEUTICALS INC.
To: ZYMEWORKS INC.
Reel/Frame 055790/0581 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 1, 2021
From: BARNSCHER, STUART DANIEL
To: ZYMEWORKS INC.
Reel/Frame 055790/0593 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 1, 2021
From: HAMBLETT, KEVIN; DAVIES, RUPERT H.
To: ZYMEWORKS BIOPHARMACEUTICALS INC.
Reel/Frame 055790/0598 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 1, 2021
From: RICH, JAMES R.; ROWSE, GERALD JAMES; FUNG, VINCENT K.C.
To: ZYMEWORKS INC.
Reel/Frame 055790/0609 →
Continuity (6)
Division 16594728 · Oct 7, 2019
Continuation PCTCA2019050303 · Mar 12, 2019
Provisional Application 62743884 · Oct 10, 2018
Provisional Application 62658477 · Apr 16, 2018
Provisional Application 62642483 · Mar 13, 2018
Related Publication 20210346508A1 · Nov 11, 2021
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