CD3-targeting and DLL3-targeting multispecific antigen-binding molecules and uses thereof

Patent metadata

Field	Value
Publication number	US-11274151-B2
Application number	US-202117216981-A
Country	US
Kind code	B2
Filing date	Mar 30, 2021
Priority date	Mar 31, 2020
Publication date	Mar 15, 2022
Grant date	Mar 15, 2022

Abstract

The disclosure provides multispecific antigen-binding molecules that comprise a first antigen-binding moiety and a second antigen-binding moiety, each of which is capable of binding to CD3 and CD137, but does not bind to CD3 and CD137 at the same time; and a third antigen-binding moiety that is capable of binding to DLL3, preferably human DLL3, which induce T-cell dependent cytotoxity more efficiently whilst circumventing adverse toxicity concerns or side effects that other multispecific antigen-binding molecules may have. The present invention provides multispecific antigen-binding molecules and pharmaceutical compositions that can treat various cancers, especially those associated with DLL3, by comprising the antigen-binding molecule as an active ingredient.

First claim

The invention claimed is:

1. A multispecific antigen-binding molecule that comprises:
(a) a first antigen-binding moiety and a second antigen-binding moiety, at least one of which binds to human CD3 and comprises
an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 20, a heavy chain CDR 2 comprising SEQ ID NO: 34, a heavy chain CDR 3 comprising SEQ ID NO: 48, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73;

and
(b) a third antigen-binding moiety that binds to human Delta-like 3 (DLL3) and comprises an antibody variable region comprising a heavy chain CDR1 comprising SEQ ID NO: 233, a heavy chain CDR 2 comprising SEQ ID NO: 234, a heavy chain CDR 3 comprising SEQ ID NO: 235, a light chain CDR 1 comprising SEQ ID NO: 237, a light chain CDR 2 comprising SEQ ID NO: 238, and a light chain CDR 3 comprising SEQ ID NO: 239.

2. The multispecific antigen-binding molecule of claim 1 , wherein
(i) the first antigen-binding moiety binds to human CD3 and comprises an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 20, a heavy chain CDR 2 comprising SEQ ID NO: 34, a heavy chain CDR 3 comprising SEQ ID NO: 48, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73; and
(ii) the second antigen-binding moiety binds to human CD3 and comprises an antibody variable region selected from the group consisting of (I) to (XIV):
(I) an antibody variable region comprising a heavy chain complementarity determining region (CDR) 1 comprising SEQ ID NO: 17, a heavy chain CDR 2 comprising SEQ ID NO: 31, a heavy chain CDR 3 comprising SEQ ID NO: 45, a light chain CDR 1 comprising SEQ ID NO: 64, a light chain CDR 2 comprising SEQ ID NO: 69, and a light chain CDR 3 comprising SEQ ID NO: 74;
(II) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 18, a heavy chain CDR 2 comprising SEQ ID NO: 32, a heavy chain CDR 3 comprising SEQ ID NO: 46, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73;
(III) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 19, a heavy chain CDR 2 comprising SEQ ID NO: 33, a heavy chain CDR 3 comprising SEQ ID NO: 47, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73;
(IV) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 19, a heavy chain CDR 2 comprising SEQ ID NO: 33, a heavy chain CDR 3 comprising SEQ ID NO: 47, a light chain CDR 1 comprising SEQ ID NO: 65, a light chain CDR 2 comprising SEQ ID NO: 70, and a light chain CDR 3 comprising SEQ ID NO: 75;
(V) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 22, a heavy chain CDR 2 comprising SEQ ID NO: 36, a heavy chain CDR 3 comprising SEQ ID NO: 50, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73;
(VI) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 23, a heavy chain CDR 2 comprising SEQ ID NO: 37, a heavy chain CDR 3 comprising SEQ ID NO: 51, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73;
(VII) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 23, a heavy chain CDR 2 comprising SEQ ID NO: 37, a heavy chain CDR 3 comprising SEQ ID NO: 51, a light chain CDR 1 comprising SEQ ID NO: 66, a light chain CDR 2 comprising SEQ ID NO: 71, and a light chain CDR 3 comprising SEQ ID NO: 76;
(VIII) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 24, a heavy chain CDR 2 comprising SEQ ID NO: 38, a heavy chain CDR 3 comprising SEQ ID NO: 52, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73;
(IX) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 25, a heavy chain CDR 2 comprising SEQ ID NO: 39, a heavy chain CDR 3 comprising SEQ ID NO: 53, a light chain CDR 1 comprising SEQ ID NO: 66, a light chain CDR 2 comprising SEQ ID NO: 71, and a light chain CDR 3 comprising SEQ ID NO: 76;
(X) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 26, a heavy chain CDR 2 comprising SEQ ID NO: 40, a heavy chain CDR 3 comprising SEQ ID NO: 54, a light chain CDR 1 comprising SEQ ID NO: 66, a light chain CDR 2 comprising SEQ ID NO: 71, and a light chain CDR 3 comprising SEQ ID NO: 76;
(XI) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 26, a heavy chain CDR 2 comprising SEQ ID NO: 40, a heavy chain CDR 3 comprising SEQ ID NO: 54, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73;
(XII) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 27, a heavy chain CDR 2 comprising SEQ ID NO: 41, a heavy chain CDR 3 comprising SEQ ID NO: 55, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73;
(XIII) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 28, a heavy chain CDR 2 comprising SEQ ID NO: 42, a heavy chain CDR 3 comprising SEQ ID NO: 56, a light chain CDR 1 comprising SEQ ID NO: 63, a light chain CDR 2 comprising SEQ ID NO: 68, and a light chain CDR 3 comprising SEQ ID NO: 73; and
(XIV) an antibody variable region comprising a heavy chain CDR 1 comprising SEQ ID NO: 82, a heavy chain CDR 2 comprising SEQ ID NO: 83, a heavy chain CDR 3 comprising SEQ ID NO: 84, a light chain CDR 1 comprising SEQ ID NO: 65, a light chain CDR 2 comprising SEQ ID NO: 70, and a light chain CDR 3 comprising SEQ ID NO: 75.

3. A multispecific antigen-binding molecule that comprises:
(a) a first antigen-binding moiety and a second antigen-binding moiety, at least one of which binds to human CD3 and comprises
an antibody variable region comprising a VH comprising SEQ ID NO: 6 and a VL comprising SEQ ID NO: 58;

and
(b) a third antigen-binding moiety comprising an antibody variable region comprising a VH comprising SEQ ID NO: 232 and a VL comprising SEQ ID NO: 236.

4. The multispecific antigen-binding molecule of claim 1 , wherein the antibody variable regions of the first and second antigen binding moieties are identical.

5. The multispecific antigen-binding molecule of claim 3 , wherein the antibody variable regions of the first and second antigen binding moieties are identical.

6. The multispecific antigen-binding molecule of claim 4 , wherein each of the first and second antigen-binding moieties is a Fab that has a cysteine residue at EU numbering position 191, and wherein a disulfide bond links these two cysteine residues.

7. The multispecific antigen-binding molecule of claim 5 , wherein each of the first and second antigen-binding moieties is a Fab that has a cysteine residue at EU numbering position 191, and wherein a disulfide bond links these two cysteine residues.

8. The multispecific antigen-binding molecule of claim 6 , wherein each of the first, second and third antigen binding moieties is in the form of a Fab comprising a VH, a VL, a CH1 domain and a light chain constant (CL) domain, and wherein the C-terminus of the CH1 domain of the third antigen-binding moiety is fused, directly or via a peptide linker, to the N-ter

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Naoi Sotaro
• Feng Shu
• Igawa Tomoyuki
• Ho Shu Wen Samantha

Classifications

• C07K2317/92

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

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• C07K2317/526

  CH3 domain · CPC title