Antigen-binding molecule containing modified Fc region
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsTomoyuki Igawa, Naoka Hironiwa, Shojiro Kadono, Atsushi Matsuo, Taichi Kuramochi, Futa Mimoto
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Abstract
The present inventors have successfully prepared an antibody Fc region dimer that has binding activity against each of an antigen and FcγR, but does not bind to the antigen and the FcγR at the same time, and a polypeptide comprising the Fc region dimer. The present invention enables the preparation of a multispecific binding polypeptide capable of avoiding an adverse reaction that may be caused by its binding to an antigen and FcγR at the same time. Thus, the present invention provides a polypeptide suitable as a drug.
Claims53
A method for producing an antibody, the method comprising:
- (A) providing a polypeptide library comprising a plurality of polypeptide dimer molecules having diverse amino acid sequences, each of the polypeptide dimer molecules comprising a first polypeptide chain comprising an IgG CH2 domain comprising at least one substitution or insertion, compared to a naturally occurring human IgG CH2 domain, at one or more CH2 loop region positions selected from EU numbering positions 231-239, 265-271, 295-300, and 324-337 and a second polypeptide chain comprising an IgG CH2 domain that can be the same as or different from the CH2 domain of the first polypeptide chain;
- (B) selecting from the library a polypeptide dimer molecule comprising a first CH2 domain and a second CH2 domain and that binds, via its CH2 domains, to
- (1) a target molecule that is naturally expressed on an immunocyte or on both a tumor cell and a normal cell, and is not an FcγR, and
- (2) an FcγR selected from the group consisting of FcγRIa, FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb,
- wherein the selected polypeptide dimer molecule does not bind to (1) and (2) at the same time;
- and
- (C) producing an antibody comprising an Fc region dimer, wherein the Fc region dimer comprises a CH2 domain identical in amino acid sequence to the first CH2 domain and a CH2 domain identical in amino acid sequence to the second CH2 domain of the polypeptide dimer molecule selected in (B).
A screening method comprising:
- (A) providing a polypeptide library comprising a plurality of polypeptide dimer molecules having diverse amino acid sequences, each of the polypeptide dimer molecules comprising a first polypeptide chain comprising an IgG CH2 domain comprising at least one substitution or insertion, compared to a naturally occurring human IgG CH2 domain, at one or more CH2 loop region positions selected from EU numbering positions 231-239, 265-271, 295-300, and 324-337 and a second polypeptide chain comprising an IgG CH2 domain that can be the same as or different from the CH2 domain of the first polypeptide chain;
- and
- (B) selecting from the library a polypeptide dimer molecule comprising a first CH2 domain and a second CH2 domain and that binds, via its CH2 domains, to
- (1) a target molecule that is naturally expressed on an immunocyte or on both a tumor cell and a normal cell, and is not an FcγR, and
- (2) an FcγR selected from the group consisting of FcγRIa, FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb,
- wherein the selected polypeptide dimer molecule does not bind to (1) and (2) at the same time.
Dependencies are inferred from the claim text.