CD3-binding molecules capable of binding to human and non-human CD3

Inventors

Huang, Ling • Johnson, Leslie S.

Assignees

Macrogenics In • Macrogenics Inc

Abstract

The present invention relates to CD3-binding molecules capable of binding to human and non-human CD3, and in particular to such molecules that are cross-reactive with CD3 of a non-human mammal (e.g., a cynomolgus monkey). The invention also pertains to uses of such antibodies and antigen-binding fragments in the treatment of cancer, autoimmune and/or inflammatory diseases and other conditions.

Core Innovation

The invention provides cross-reactive CD3-binding molecules, including antibody antigen-binding fragments and CD3-specific diabodies, engineered so that an antigen-binding domain immunospecifically binds both an epitope of human CD3 and an epitope of the CD3 of a non-human mammal. The antigen-binding domain is formed by defined antibody CD3-specific VL and VH domains that together enable immunospecific binding across species.

The CD3-binding antigen-binding fragments define a CD3-specific VL domain comprising the three complementarity determining regions of SEQ ID NO:5 under Kabat numbering, and a CD3-specific VH domain comprising the three complementarity determining regions of SEQ ID NO:7 modified to include an amino acid substitution of D65G, also under Kabat numbering. This defines the cross-reactive binding interface using SEQ-ID-defined CDR identity and a defined Kabat-numbered VH modification.

The document further defines structural scope for CD3-binding molecules, including covalently linked diabody formats that generate an additional epitope binding site from other variable domains. It also states Fc engineering to reduce or abolish FcγR binding and effector functions, and provides an optional second-epitope targeting concept intended to redirect T-cell killing of tumor cells.

The disclosed intended therapeutic uses include treating cancer by administering the described CD3-binding molecules, as well as treatment of autoimmune and inflammatory diseases, including type I insulin-dependent diabetes.

Claims Coverage

The independent claims include one method claim directed to treating cancer by administering an effective amount of a CD3-binding antibody antigen-binding fragment with defined VL/VH CDR identity and a specified VH substitution, enabling immunospecific binding to both human CD3 and non-human mammal CD3.

The claim coverage centers on a CD3-binding antibody antigen-binding fragment defined by Kabat-numbered VL and VH CDR specifications, including a D65G VH substitution, that immunospecifically binds both human CD3 and non-human mammal CD3 epitopes for cancer treatment.

Stated Advantages

Documented Applications