IP Library › Granted Patent US 11,261,259

Granted Patent B2

US 11,261,259 · App. 17/286,437 · Granted Mar 1, 2022

Anti-claudin 18.2 and anti-4-1BB bispecific antibodies and uses thereof

Inventors: Wenqing Jiang (Shanghai, CN); Lei Fang (Shanghai, CN); Zhengyi Wang (Shanghai, CN); Bingshi Guo (Shanghai, CN); Eunyoung Park (Seongnam-Si, KR); Eunsil Sung (Seongnam-Si, KR); Byungje Sung (Seongnam-Si, KR)

Assignees: I-Mab Biopharma US Limited; ABL Bio Inc.

C07K16/2878 A61P35/00 C07K16/28 A61K2039/505 C07K2317/31 C07K2317/52 C07K2317/622 C07K2317/92

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Quick Facts

Patent No.: US 11,261,259
App. No.: 17/286,437
Granted: Mar 1, 2022
Kind: B2

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Abstract

Provided are bispecific and multi-specific antibodies that target both claudin 18.2 (CLDN18.2) and 4-1BB. These antibodies, in the absence of CLDN18.2-expressing cells, can bind to 4-1BB but are unable to activate 4-1BB signaling. In the presence of CLDN18.2-expressing cells, however, these antibodies can trigger CLDN18.2-dependent 4-1BB signaling, leading to potent immune response to the CLDN18.2-expressing tumor cells.

Claims (80)

1. An antibody, comprising:

an anti-claudin 18.2 (CLDN18.2) unit having binding specificity to a CLDN18.2 protein; and

an anti-4-1BB unit having binding specificity to a 4-1BB protein,

wherein the anti-4-1BB unit comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3, wherein:

the CDRH1 comprises the amino acid sequence of SEQ ID NO:1;

the CDRH2 comprises the amino acid sequence of SEQ ID NO:2;

the CDRH3 comprises the amino acid sequence of SEQ ID NO:3, 56, 57, 58, or 59;

the CDRL1 comprises the amino acid sequence of SEQ ID NO:4;

the CDRL2 comprises the amino acid sequence of SEQ ID NO:5; and

the CDRL3 comprises the amino acid sequence of SEQ ID NO:6.

2. The antibody of claim 1 , wherein the binding of the anti-4-1BB unit to 4-1BB proteins on a cell does not result in clustering of the 4-1BB proteins, in the absence of the anti-CLDN18.2 unit binding to a CLDN18.2 protein.

3. The antibody of claim 1 , further comprising a Fc fragment that has reduced effector function.

4. The antibody of claim 3 , wherein the Fc fragment is selected from the group consisting of:

an IgG1 Fc fragment with a L235E mutation,

an IgG1 Fc fragment with a L234A and/or L235A mutation,

an IgG1 Fc fragment with a P329G or P329A mutation,

an IgG4 Fc fragment with a F234A and/or L235A or L235E mutation,

an IgG2 Fc fragment with a H268Q, V309L, A330S, and/or P331S mutation, and

an IgG2 Fc fragment with a V234A, G237A, P238S, H268A, V309L, A330S, and/or P331S mutation (EU numbering).

5. The antibody of claim 1 , wherein the VH of the anti-4-1BB unit comprises an amino acid sequence selected from the group consisting of SEQ ID NO:24, 46-50 and 63-66 and the VL of the anti-4-1BB unit comprises an amino acid sequence selected from the group consisting of SEQ ID NO:25, 52-53 and 69-74.

6. The antibody of claim 1 , wherein the anti-CLDN18.2 unit comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3, wherein:

(a) the CDRH1 comprises the amino acid sequence of SEQ ID NO:7;

the CDRH2 comprises the amino acid sequence of SEQ ID NO:8;

the CDRH3 comprises the amino acid sequence of SEQ ID NO:9;

the CDRL1 comprises the amino acid sequence of SEQ ID NO:10;

the CDRL2 comprises the amino acid sequence of SEQ ID NO:11; and

the CDRL3 comprises the amino acid sequence of SEQ ID NO:12,

(b) the CDRH1 comprises the amino acid sequence of SEQ ID NO:13;

the CDRH2 comprises the amino acid sequence of SEQ ID NO:14;

the CDRH3 comprises the amino acid sequence of SEQ ID NO:15;

the CDRL1 comprises the amino acid sequence of SEQ ID NO:16;

the CDRL2 comprises the amino acid sequence of SEQ ID NO:17; and

the CDRL3 comprises the amino acid sequence of SEQ ID NO:18, or

the CDRH2 comprises the amino acid sequence of SEQ ID NO:20;

the CDRH3 comprises the amino acid sequence of SEQ ID NO:21;

the CDRL1 comprises the amino acid sequence of SEQ ID NO:22;

the CDRL2 comprises the amino acid sequence of SEQ ID NO:11; and

the CDRL3 comprises the amino acid sequence of SEQ ID NO:23.

7. The antibody of claim 6 , wherein the VH of the anti-CLDN18.2 unit comprises an amino acid sequence selected from the group consisting of SEQ ID NO:26, 28 and 30, and the VL of the anti-CLDN18.2 unit comprises an amino acid sequence selected from the group consisting of SEQ ID NO:27, 29 and 31.

8. An antibody comprising two first polypeptides and two second polypeptides,

wherein each first polypeptide comprises, from N- to C-terminus, a heavy chain variable region (VH), a CH1, a CH2, a CH3, and a single chain fragment (scFv) having specificity to a 4-1BB protein;

wherein each second polypeptide comprises a light chain variable region (VL) and a CL;

wherein each VH is paired with one of the VL and have specificity to a claudin 18.2 (CLDN18.2) protein; and

wherein the scFv comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3, wherein: