Antibody adjuvant conjugates

Patent metadata

Field	Value
Publication number	US-11110178-B2
Application number	US-202016817864-A
Country	US
Kind code	B2
Filing date	Mar 13, 2020
Priority date	Jul 7, 2016
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

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 comprising
(a) an antibody construct comprising (i) an antigen binding domain and (ii) an Fc domain,
(b) an adjuvant moiety of formula:

wherein each J independently is hydrogen, OR 4 , or R 4 , each R 4 independently is hydrogen, or an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, each U independently is CH or N wherein at least one U is N, each subscript t independently is an integer from 1 to 3, Q is optionally present and is an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, and the dashed line (“ ”) represents the point of attachment of the adjuvant, and
(c) a linker,

wherein the adjuvant moiety is covalently bonded to the antibody construct via the linker.

2. 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, OX4OL, 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).

3. The immunoconjugate of claim 1 , wherein the antigen binding domain binds to EGFR, HER2, or PD-L1.

4. The immunoconjugate of claim 1 , wherein the antibody construct is an antibody.

5. The immunoconjugate of claim 4 , 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 biosimilars thereof.

6. The immunoconjugate of claim 4 , wherein the antibody comprises a modified Fc region.

7. The immunoconjugate of claim 4 , wherein immunoconjugate has a structure according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein
Ab is the antibody with

being an amino acid residue of the antibody, wherein A is a modified or unmodified sidechain of the amino acid residue,
Z is the linker,
Adj is the adjuvant moiety, and
subscript r is an integer from 1 to 10.

8. The immunoconjugate of claim 4 , wherein the immunoconjugate has a structure according to Formula II:

or a pharmaceutically acceptable salt thereof, wherein
Ab is the antibody with

being an amino acid residue of the antibody, wherein A is a lysine sidechain, thiol-modified lysine sidechain, or cysteine sidechain of the amino acid residue,
Adj is the adjuvant moiety,
subscript r is an integer 1 to 10,
Z 1 is selected from —C(O)—, —C(O)NH—, and —CH 2 —,
Z 2 and Z 4 are each independently selected from a bond, C 1-30 alkylene, and 3- to 30-membered heteroalkylene, wherein
one or more groupings of adjacent atoms in the C 1-30 alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by —C(O)—, —NR a C(O)—, or C(O)NR a —, w herein each R a is independently selected from H and C 1-6 alkyl,
one or more groupings of adjacent atoms in the C 1-30 alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by a 4- to 8-membered divalent carbocycle, and
one or more groupings of adjacent atoms in the C 1-30 alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by a 4- to 8-membered divalent heterocycle having one to four heteroatoms selected from O, S, and N,

Z 3 is a bond, a divalent peptide moiety, or a divalent polymer moiety, and
Z 5 is selected from an amine-bonded moiety and a thiol-bonded moiety.

9. The immunoconjugate of claim 4 , wherein the immunoconjugate has a structure according to Formula III:

or a pharmaceutically acceptable salt thereof, wherein
Ab is the antibody with

being a lysine residue of the antibody,
Adj is the adjuvant moiety,
G is CH 2 , C═O, or a bond,
L is a linking moiety, and
subscript r is an integer from 1 to 10.

10. The immunoconjugate of claim 9 , wherein L is selected from:

wherein R is optionally present and is a linear or branched, cyclic or straight, saturated or unsaturated alkyl, heteroalkyl, aryl, or heteroaryl chain comprising from 1 to 8 carbons, a is an integer from 1 to 40, each A is independently selected from any amino acid, subscript c is an integer from 1 to 20, the dashed line (“ ″) represents the point of attachment to

and the wavy line (“ ”) represents the point of attachment to

11. The immunoconjugate of claim 9 , wherein L is:

a is an integer from 1 to 40; the dashed line (“ ”) represents the point of attachment to

and the wavy line (“ ”) represents the point of attachment to

wherein each adjuvant moiety is covalently bonded to the antibody via the linker.

12. The immunoconjugate of claim 11 , wherein G is a bond.

13. The immunoconjugate of claim 12 , wherein a is an integer from 1 to 10.

14. The immunoconjugate of claim 13 , wherein is r is an integer from 1 to 5.

15. The immunoconjugate of claim 1 , wherein Q is not present.

16. The immunoconjugate of claim 15 , wherein each U is N and each subscript t is 2.

17. The immunoconjugate of claim 1 , wherein each U is N and each subscript t is 2.

18. The immunoconjugate of claim 1 , wherein the adjuvant moiety is of formula:

19. The immunoconjugate of claim 4 , wherein the antibody is trastuzumab or a biosimilar thereof.

20. The immunoconjugate of claim 19 , wherein Q is not present.

21. The immunoconjugate of claim 20 , wherein each U is N and each subscript t is 2.

22. The immunoconjugate of claim 19 , wherein each U is N and each subscript t is 2.

23. The immunoconjugate of claim 19 , wherein the adjuvant moiety is of formula:

Assignees

• Univ Leland Stanford Junior
• Bolt Biotherapeutics Inc
• The Board Of Trustees Of The Leland Standford Junior Univ

Inventors

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

Classifications

• C07K16/30

  from tumour cells · CPC title

• C07K16/28

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

• A61K47/6801 Primary

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

• A61K47/6851 Primary

  the antibody targeting a determinant of a tumour cell · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title