Mesothelin-targeted CD40 agonistic multispecific antibody constructs for the treatment of solid tumors

Patent metadata

Field	Value
Publication number	US-11926672-B2
Application number	US-202017127629-A
Country	US
Kind code	B2
Filing date	Dec 18, 2020
Priority date	Dec 20, 2019
Publication date	Mar 12, 2024
Grant date	Mar 12, 2024

Abstract

The present invention relates to a human agonistic CD40 multispecific antibody construct for treatment of solid tumors by engineering a molecule that specifically targets the CD40 pathway on tumor-associated APCs, without systemic CD40 activation.

First claim

What is claimed is:

1. An antigen binding protein that specifically binds and agonizes human CD40 (SEQ ID NO: 1), the antigen binding protein comprising a light chain variable region (VL) and a heavy chain variable region (VH), wherein
the VL and VH are selected from the group consisting of:
a) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 58, 59, and 60, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 136, 137, and 138, respectively;
b) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 64, 65, and 66, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 142, 143, and 144, respectively;
c) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 70, 71, and 72, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 148, 149, and 150, respectively;
d) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 76, 77, and 78, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 154, 155, and 156, respectively;
e) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 82, 83, and 84, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 160, 161, and 162, respectively;
f) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 88, 89, and 90, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 166, 167, and 168, respectively;
g) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 94, 95, and 96, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 172, 173, and 174, respectively;
h) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 100, 101, and 102, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 178, 179, and 180, respectively;
i) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 106, 107, and 108, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 184, 185, and 186, respectively;
j) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 112, 113, and 114, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 190, 191, and 192, respectively;
k) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 118, 119, and 120, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 196, 197, and 198, respectively;
l) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 124, 125, and 126, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 202, 203, and 204, respectively;
m) a VL comprising a CDRL1, a CDRL2, and a CDRL3 selected from the group consisting of SEQ ID NOs: 130, 131, and 132, respectively; and a VH comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of SEQ ID NOs: 208, 209, and 210, respectively; and
n) a VL comprising a CDRL1 comprising SEQ ID NO:100, a CDRL2 comprising SEQ ID NO:101, and a CDRL3 comprising the CDRL3 of SEQ ID NO: 370; and a VH comprising a CDRH1 comprising SEQ ID NO:178, a CDRH2 comprising SEQ ID NO: 179, and a CDRH3 comprising SEQ ID NO: 180.

2. The antigen binding protein according to claim 1 , wherein: the VL and VH are selected from the group consisting of:
a) a VL comprising SEQ ID NO: 5 and a VH comprising SEQ ID NO: 6;
b) a VL comprising SEQ ID NO: 9 and a VH comprising SEQ ID NO: 10;
c) a VL comprising SEQ ID NO: 13 and a VH comprising SEQ ID NO: 14;
d) a VL comprising SEQ ID NO: 17 and a VH comprising SEQ ID NO: 18;
e) a VL comprising SEQ ID NO: 21 and a VH comprising SEQ ID NO: 22;
f) a VL comprising SEQ ID NO: 25 and a VH comprising SEQ ID NO: 26;
g) a VL comprising SEQ ID NO: 29 and a VH comprising SEQ ID NO: 30;
h) a VL comprising SEQ ID NO: 33 and a VH comprising SEQ ID NO: 34;
i) a VL comprising SEQ ID NO: 37 and a VH comprising SEQ ID NO: 38;
j) a VL comprising SEQ ID NO: 41 and a VH comprising SEQ ID NO: 42;
k) a VL comprising SEQ ID NO: 45 and a VH comprising SEQ ID NO: 46;
l) a VL comprising SEQ ID NO: 49 and a VH comprising SEQ ID NO: 50;
m) a VL comprising SEQ ID NO: 53 and a VH comprising SEQ ID NO: 54; and
n) a VL comprising the VL sequence of SEQ ID NO: 370 and a VH comprising SEQ ID NO: 34.

3. The antigen binding protein according to claim 1 , wherein the heavy chain comprises an amino acid substitution selected from the group consisting of:
(i) N297G or N297A;
(ii) L234A and L235A; and
(iii) R292C and V302C;
wherein the amino acid numbering is EU numbering according to Kabat.

4. The antigen binding protein according to claim 3 , wherein the heavy chain comprises N297G, R292C, and V302C mutations, wherein the amino acid numbering is EU numbering according to Kabat.

5. The antigen binding protein according to claim 1 , wherein the antigen binding protein further comprises a light chain constant domain (CL) polypeptide linked to the VL, wherein the CL polypeptide is selected from the group consisting of SEQ ID NO: 883 and SEQ ID NO: 884.

6. The antigen binding protein according to claim 1 , wherein the antigen binding protein further comprises a heavy chain CH1-hinge-CH2-CH3 polypeptide wherein the CH1-hinge-CH2-CH3 polypeptide is selected from the group consisting of SEQ ID NO: 885 and SEQ ID NO: 886.

7. The antigen binding protein according to claim 1 , wherein said VH comprises a human framework (FR) sequence, and said VL comprises a human framework (FR) sequence.

8. The antigen binding protein according to claim 1 , wherein said antigen binding protein comprises a human constant domain.

9. The antigen binding protein according to claim 1 , wherein said antigen binding protein comprises a human light chain constant domain (CL).

10. The antigen binding protein according to claim 9 , wherein said CL is a kappa CL or lambda CL.

11. The antigen binding protein according to claim 1 , wherein said antigen binding protein comprises a human heavy chain constant domain CH1.

12. The antigen binding protein according to claim 11 , wherein said CH1 is an IgG CH1.

13. The antigen binding protein according to claim 11 , wherein said CH1 is an IgG1 CH1.

14. The antigen binding protein according to claim 1 , wherein said antigen binding protein comprises a human heavy chain Fc domain.

15. The antigen binding protein according to claim 14 , wherein said Fc is an IgG Fc.

16. The antigen binding protein according to claim 14 , wherein said Fc is an IgG1 Fc.

17. The antigen binding protein according to claim 1 , comprising a VH and a VL, wherein said VL comprises a CDRL1 comprising SEQ ID NO:100, a CDRL2 comprising SEQ ID NO:101, and a CDRL3 comprising the CDRL3 of SEQ ID NO: 370; and said VH comprises a CDRH1 comprising SEQ ID NO:178, a CDRH2 comprising SEQ I

Assignees

• Amgen Inc

Inventors

• Yu Xin
• Egen Jackson
• Garces Fernando
• Takenaka Shunsuke
• Kim Aeryon
• Sawant Deepali

Classifications

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/52

  Constant or Fc region; Isotype · CPC title

• C07K2317/522

  CH1 domain · CPC title

• C07K2317/567

  Framework region [FR] · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title