IgG2m4, an engineered antibody isotype with reduced Fc function

By Z. An, Gail Forrest, Renée Moore, Michael Cukan, Peter Haytko, Lingyi Huang, Salvatore Vitelli, J. Zhao, P. Lu, Jin Hua and 6 more. 2009

95 citations recorded by the source corpus.

The Fc region of an antibody mediates effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and plays a key role in the in vivo half-life of an antibody. In designing antibody therapeutics, it is sometimes desirable that the antibody has altered Fc-mediated properties. In the case of a "benign blocker" antibody, it is often desirable to diminish or abolish the ADCC and CDC functions while retaining its PK profile. Here, we report a novel engineered IgG isotype, IgG2m4, with reduced Fc functionality. IgG2m4 is based on the IgG2 isotype with four key amino acid residue changes derived from IgG4 (H268Q, V309L, A330S and P331S). An IgG2m4 antibody has an overall reduction in complement and Fcγ receptor binding in in vitro binding analyses while maintaining the normal in vivo serum half-life in rhesus.

Subfields: Genetics, Molecular Biology, Radiology, Nuclear Medicine and Imaging