Cytotoxicity-inducing therapeutic agent

Patent metadata

Field	Value
Publication number	US-12522669-B2
Application number	US-202418590651-A
Country	US
Kind code	B2
Filing date	Feb 28, 2024
Priority date	Nov 30, 2010
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

Disclosed are bispecific antibodies with heavy chain constant regions having the sequence of an IgG1 constant region with one or more mutations including one or more substitutions that reduce the ability of the heavy chain constant regions to bind to a human Fcγ receptor.

First claim

The invention claimed is:

1 . A bispecific antibody that comprises:
a first light chain comprising a first light chain variable region (VL) and a first light chain constant region; a second light chain comprising a second VL and a second light chain constant region; a first heavy chain comprising a first heavy chain variable region (VH) and a first heavy chain constant region, wherein the first heavy chain constant region is a non-wild-type heavy chain constant region comprising the sequence of SEQ ID NO: 23 with one or more amino acid substitutions and optionally a deletion of one or both of the amino acids at EU numbering positions 446 and 447; and a second heavy chain comprising a second VH and a second heavy chain constant region, wherein the second heavy chain constant region is a non-wild-type heavy chain constant region comprising the sequence of SEQ ID NO: 23 with one or more amino acid substitutions and optionally a deletion of one or both of the amino acids at EU numbering positions 446 and 447,
wherein the first light chain and the first heavy chain associate to form a first antigen-binding domain that binds to CD3,
wherein the second light chain and the second heavy chain associate to form a second antigen-binding domain that binds to CD20,
wherein the first VL and second VL each contains a light chain CDR1, a light chain CDR2, and a light chain CDR3,
wherein the first VH and second VH each contains a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3,
wherein the first heavy chain constant region associates with the second heavy chain constant region,
wherein, when assessed by surface plasmon resonance, the ability of the associated first and second heavy chain constant regions to bind to a given human Fcγ receptor is reduced, compared to the ability of a wild-type human IgG1 antibody to bind to the human Fcγ receptor, as a result of at least one of the one or more amino acid substitutions within the first and second heavy chain constant regions,
wherein at least one of the amino acid substitutions that result in the reduced ability to bind to the human Fcγ receptor is selected from L234F, L235E, and D265A in each of the first and second heavy chain constant regions, wherein all positions are by EU numbering, and
wherein the human Fcγ receptor is a human FcγRI receptor, a human FcγRIIA receptor, or a human FcγRIIIA receptor.

2 . The bispecific antibody of claim 1 , wherein at least two of the following amino acid substitutions are present in both the first and second heavy chain constant regions:
(a) L234F; (b) L235E; and (c) D265A, wherein all position numbers are by EU numbering.

3 . The bispecific antibody of claim 1 , wherein all three of the following amino acid substitutions are present in both the first and second heavy chain constant regions:
(a) L234F; (b) L235E; and (c) D265A, wherein all position numbers are by EU numbering.

4 . The bispecific antibody of claim 3 , further comprising one or more additional amino acid substitutions, compared to SEQ ID NO: 23, in the CH3 domain of one or both of the first and second heavy chain constant regions.

5 . The bispecific antibody of claim 4 , wherein the one or more additional amino acid substitutions include a substitution, compared to SEQ ID NO: 23, at EU numbering position 356 in the first heavy chain constant region.

6 . The bispecific antibody of claim 5 , wherein the one or more additional amino acid substitutions further include a substitution, compared to SEQ ID NO: 23, at EU numbering position 356 in the second heavy chain constant region.

7 . The bispecific antibody of claim 6 , wherein the sequence of the CH3 domain of the first heavy chain constant region differs from the sequence of the CH3 domain of the second heavy chain constant region at one or more positions, and the difference results in a higher percentage of heterodimers formed in a mixture of the first and second heavy chains than if the first and second heavy chains comprise identical CH3 domains.

8 . The bispecific antibody of claim 7 , wherein the amino acid at EU numbering position 409 in the first heavy chain constant region is different from the amino acid at EU numbering position 409 in the second heavy chain constant region.

9 . A bispecific antibody that comprises:
a first light chain comprising a first VL and a first light chain constant region; a second light chain comprising a second VL and a second light chain constant region; a first heavy chain comprising a first VH and a first heavy chain constant region, wherein the first heavy chain constant region comprises the sequence of SEQ ID NO: 23 with (a) amino acid substitutions comprising a Phe substitution at EU numbering position 234, a Glu substitution at EU numbering position 235, and substitutions at EU numbering positions 265 and 356, and (b) optionally a deletion of one or both of the amino acids at EU numbering position 446 and 447; and a second heavy chain comprising a second VH and a second heavy chain constant region, wherein the second heavy chain constant region comprises the sequence of SEQ ID NO: 23 with (A) amino acid substitutions comprising a Phe substitution at EU numbering position 234, a Glu substitution at EU numbering position 235, and substitutions at EU numbering positions 265, 356, and 409; and (B) optionally a deletion of one or both of the amino acids at EU numbering positions 446 and 447,
wherein the first heavy chain constant region associates with the second heavy chain constant region,
wherein, when assessed by surface plasmon resonance, the ability of the associated first and second heavy chain constant regions to bind to a given human Fcγ receptor is reduced, compared to the ability of a wild-type human IgG1 antibody to bind to the human Fcγ receptor,
wherein the human Fcγ receptor is a human FcγRI receptor, a human FcγRIIA receptor, or a human FcγRIIIA receptor,
wherein the first VL and second VL each contains a light chain CDR1, a light chain CDR2, and a light chain CDR3,
wherein the first VH and second VH each contains a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, and
wherein the bispecific antibody is a T cell engager.

10 . The bispecific antibody of claim 9 , wherein each of the first and second heavy chain constant regions comprises an Ala substitution at EU numbering position 265.

11 . The bispecific antibody of claim 9 , wherein the sequence of the CH3 domain of the first heavy chain constant region differs from the sequence of the CH3 domain of the second heavy chain constant region at one or more positions, and the difference results in a higher percentage of heterodimers formed in a mixture of the first and second heavy chains than if the first and second heavy chains comprise identical CH3 domains.

12 . The bispecific antibody of claim 11 , wherein the amino acid at EU numbering position 409 in the first heavy chain constant region is different from the amino acid at EU numbering position 409 in the second heavy chain constant region.

13 . The bispecific antibody of claim 9 , wherein each of the first and second heavy chain constant regions comprises a deletion of one or both of the amino acids at EU numbering positions 446 and 447.

14 . An antibody that comprises:
a first heavy chain constant region associated with a second heavy chain constant region, each comprising the sequence of SEQ ID NO: 23 with at least one mutation, including one or more mutations selected from a Phe substitution at EU numbering position 234, a Glu substitution at EU numbering position 235, and an Ala substitution at EU numbering

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Nezu Junichi
• Ishiguro Takahiro
• Narita Atsushi
• Sakamoto Akihisa
• Kawai Yumiko
• Igawa Tomoyuki
• Kuramochi Taichi

Classifications

• C07K16/00

  Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies · CPC title

• C07K16/468

  Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K16/18

  against material from animals or humans · CPC title

• C07K16/28

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