Antibody adjuvant conjugates

Patent metadata

Field	Value
Publication number	US-11547761-B1
Application number	US-202117466873-A
Country	US
Kind code	B1
Filing date	Sep 3, 2021
Priority date	Jul 7, 2016
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

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 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 2, Q is not present, 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 HER2.

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

4. The immunoconjugate of claim 1 , wherein the antibody is trastuzumab or a biosimilar thereof.

5. The immunoconjugate of claim 1 , 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.

6. The immunoconjugate of claim 1 , 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 —, wherein 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.

7. The immunoconjugate of claim 1 , 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.

8. The immunoconjugate of claim 7 , 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

9. The immunoconjugate of claim 7 , 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.

10. The immunoconjugate of claim 9 , wherein G is a bond.

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

12. The immunoconjugate of claim 11 , wherein is r is an integer from 1 to 5.

13. 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.

14. 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 —, wherein 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

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

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6851 Primary

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

• C07K16/30

  from tumour cells · CPC title

• C07K16/44

  against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids} · CPC title