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US 11,952,422 B2Granted
Antigen-binding molecule comprising altered antibody variable region binding CD3 and CD137
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsShun Shimizu, Shu Wen Samantha Ho, Naoka Hironiwa, Mika Sakurai, Taro Miyazaki, Tomoyuki Igawa
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Abstract
Antigen-binding domains that are capable of binding to CD3 and CD137 but do not bind to CD3 and CD137 at the same time and methods of using the same are provided. Methods to obtain antigen binding domains which bind to two or more different antigen more efficiently are also provided.
Claims15
A tri-specific IgG antibody comprising:
- a dual-binding Fab comprising a first variable region that binds to human CD3 epsilon and human CD137, but does not bind to human CD3 epsilon and human CD137 at the same time;
- a second Fab comprising a second variable region that binds to a third antigen different from human CD3 epsilon and human CD137, wherein the third antigen is a cancer antigen;
- and
- an Fc region,
- wherein the first variable region comprises a heavy chain variable domain (VH) and a light chain variable domain (VL) selected from the VH and VL of (a) to (e) below:
- (a) a VH comprising the amino acid sequence of SEQ ID NO:
- 30 and a VL comprising the amino acid sequence of SEQ ID NO:
- 51,
- (b) a VH comprising the amino acid sequence of SEQ ID NO:
- 46 and a VL comprising the amino acid sequence of SEQ ID NO:
- 53,
- (c) a VH comprising the amino acid sequence of SEQ ID NO:
- 40 and a VL comprising the amino acid sequence of SEQ ID NO:
- 56,
- (d) a VH comprising the amino acid sequence of SEQ ID NO:
- 30 and a VL comprising the amino acid sequence of SEQ ID NO:
- 58, and
- (e) a VH comprising the amino acid sequence of SEQ ID NO:
- 40 and a VL comprising the amino acid sequence of SEQ ID NO:
- 61.
17 more elements
A tri-specific IgG antibody comprising:
- a dual-binding Fab comprising a first variable region that binds to human CD3 epsilon and human CD137, but does not bind to human CD3 epsilon and human CD137 at the same time;
- a second Fab comprising a second variable region that binds to a third antigen different from human CD3 epsilon and human CD137, wherein the third antigen is a cancer antigen;
- and
- an Fc region,
- wherein:
- the first variable region comprises a VH and a VL;
- the amino acid sequence of the VH has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:
- 41, 30, 46, or 40;
- and
- the amino acid sequence of the VL has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:
- 51, 52, 53, 54, 55, 56, or 57.
8 more elements
A tri-specific IgG antibody comprising:
- a dual-binding Fab comprising a first variable region that binds to human CD3 epsilon and human CD137, but does not bind to human CD3 epsilon and human CD137 at the same time;
- a second Fab comprising a second variable region that binds to a third antigen different from human CD3 epsilon and human CD137, wherein the third antigen is a cancer antigen;
- and
- an Fc region,
- wherein the first variable region comprises:
- (1) a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:
- 51, 52, 53, 54, 55, 56, or 57, and
- (2) a VH that comprises an amino acid sequence comprising SEQ ID NO:
- 135 with a substitution at 2 to 10 positions, and wherein the VH comprises, at one or more positions selected from the following Kabat numbering positions, one of the amino acids indicated for that position:
- Ile, Asn, or Ser at position 31;
- Arg or Lys at position 52b;
- Ala, Gly, Leu, Gln, Val, or Ser at position 52c;
- Gln, Ser, or Asn at position 53;
- Ala, Gly, Leu, Gln, Ser, or Asn at position 54;
- Leu, Asn, or Ala at position 56;
- Ala, Asn, or Thr at position 57;
- Pro or Glu at position 61;
- Ala, Gly, Pro, Ser, Thr, Gln, or His at position 98;
- Ala, Leu, Ser, Gln, or Thr at position 99;
- Ala, Val, Gly, Ser, Thr, Tyr, or Phe at position 100;
- Ala, Val, Gly, Ser, Thr, Tyr, Phe, or Asp at position 100a;
- Gly, Ser, Thr, Tyr, Phe, or Asp at position 100b;
- Ala, Val, Leu, Gly, Ser, Tyr, or Phe at position 100c;
- Leu, Gly, Ser, Tyr, or Phe at position 100d;
- Pro, Gly, Ser, Tyr, or Phe at position 100e;
- Ala, Ser, Gln, Lys, Tyr, or Gly at position 100f;
- Tyr, Phe, or Gly at position 100g.
24 more elements
Dependencies are inferred from the claim text.