Antibody adjuvant conjugates

Patent metadata

Field	Value
Publication number	US-10675358-B2
Application number	US-201816140309-A
Country	US
Kind code	B2
Filing date	Sep 24, 2018
Priority date	Jul 7, 2016
Publication date	Jun 9, 2020
Grant date	Jun 9, 2020

Abstract

The invention provides an immunoconjugate comprising an antibody construct which includes an antigen binding domain and an Fc domain, an adjuvant moiety, and a linker, wherein each adjuvant moiety is covalently bonded to the antibody via the linker. Methods for treating cancer with the immunoconjugates of the invention are also described.

First claim

The invention claimed is:

1. An immunoconjugate according to Formula IVb:

or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody comprising (i) an antigen binding domain and (ii) an Fc domain, Adj is an adjuvant moiety of formula:

wherein R 4 is an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, each J is hydrogen, each U is N, each t is 2, Q is not present, the dashed line (“ ”) represents a point of attachment of the adjuvant to G 1 , and G 1 is a bond; subscript a is an integer from 1 to 40; and subscript r is an integer from 1 to 10.

2. The immunoconjugate of claim 1 , wherein the antibody comprises a modified Fc region.

3. The immunoconjugate of claim 2 , wherein the modified Fc region contains at least one amino acid insertion, deletion, or substitution.

4. The immunoconjugate of claim 2 , wherein the modified Fc region is deglycosylated or afucosylated.

5. The immunoconjugate of claim 1 , wherein a is an integer from 1 to 20.

6. The immunoconjugate of claim 1 , wherein a is an integer from 1 to 10.

7. The immunoconjugate of claim 1 , wherein R 4 is a heteroalkyl group comprising from 1 to 8 carbons.

8. The immunoconjugate of claim 1 , wherein R 4 is an alkyl group comprising from 1 to 8 carbons.

9. The immunoconjugate of claim 1 , wherein R 4 is butyl.

10. The immunoconjugate of claim 1 , wherein r is an integer from 1 to 4.

11. The immunoconjugate of claim 1 , wherein the antigen binding domain binds to an antigen selected from the group consisting of CDH1, CD19, CD20, CD29, CD30, CD38, CD40, CD47, EpCAM, MUC1, MUC16, EGFR, VEGF, HER2, SLAMF7, PDGFRa, gp75, CTLA4, PD-1, PD-L1, PD-L2, LAG-3, B7-H4, KIR, TNFRSF4, OX40L, IDO-1, IDO-2, CEACAM1, BTLA, TIM3, A2Ar, VISTA, CLEC4C (BDCA-2, DLEC, CD303, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (Dectin-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), and CLEC7A (Dectin-1).

12. The immunoconjugate of claim 1 , wherein the antigen binding domain binds to HER2.

13. The immunoconjugate of claim 8 , wherein the antigen binding domain binds to HER2.

14. The immunoconjugate of claim 1 , wherein the antigen binding domain binds to PD-L1.

15. The immunoconjugate of claim 5 , wherein the antigen binding domain binds to PD-L1.

16. The immunoconjugate of claim 1 , wherein the antibody is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, avelumab, ipilimumab, obinutuzumab, trastuzumab, cetuximab, rituximab, pertuzumab, bevacizumab, daratumumab, etanercept, olaratumab, elotuzumab, margetuximab, and a biosimilar thereof.

17. The immunoconjugate of claim 8 , wherein the antibody is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, avelumab, ipilimumab, obinutuzumab, trastuzumab, cetuximab, rituximab, pertuzumab, bevacizumab, daratumumab, etanercept, olaratumab, elotuzumab, margetuximab, and a biosimilar thereof.

18. The immunoconjugate of claim 1 , wherein the antibody is trastuzumab.

19. The immunoconjugate of claim 8 , wherein the antibody is trastuzumab.

20. The immunoconjugate of claim 1 , wherein the antibody is a biosimilar of trastuzumab.

21. The immunoconjugate of claim 8 , wherein the antibody is a biosimilar of trastuzumab.

22. A composition comprising a plurality of immunoconjugates according to claim 1 .

23. The composition of claim 22 , wherein the composition further comprises one or more pharmaceutically acceptable excipients.

24. An immunoconjugate according to Formula IVb:

or a pharmaceutically acceptable salt thereof, wherein Ab is trastuzumab, Adj is an adjuvant moiety of formula:

wherein R 4 is butyl, each J is hydrogen, each U is N, each t is 2, Q is not present, the dashed line (“ ”) represents a point of attachment of the adjuvant to G 1 , and G 1 is a bond; subscript a is an integer from 1 to 40; and subscript r is an integer from 1 to 4.

25. The immunoconjugate of claim 24 , wherein the antibody comprises a modified Fc region.

26. The immunoconjugate of claim 25 , wherein the modified Fc region (1) contains at least one amino acid insertion, deletion, or substitution or (2) is deglycosylated or afucosylated.

27. The immunoconjugate of claim 24 , wherein a is an integer from 1 to 20.

28. The immunoconjugate of claim 24 , wherein a is an integer from 1 to 10.

29. A composition comprising a plurality of immunoconjugates according to claim 24 .

30. The composition of claim 29 , wherein the composition further comprises one or more pharmaceutically acceptable excipients.

Assignees

• Univ Leland Stanford Junior
• Bolt Biotherapeutics Inc

Inventors

• Alonso Michael Nathaniel
• Engleman Edgar George
• Ackerman Shelley Erin
• Kenkel Justin
• Lee Arthur
• Jackson David Y

Classifications

• A61K47/6855 Primary

  the tumour determinant being from breast cancer cell · CPC title

• C07K16/30

  from tumour cells · CPC title

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K47/6801 Primary

  Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent · CPC title