Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey.

Abstract

Nectin-2 is a transmembrane glycoprotein which is involved in the process of Ca2+-independent cell-cell adhesion. In our previous study, we have demonstrated that Nectin-2 is over-expressed in breast and ovarian cancer tissues by using gene expression analysis and immunohistochemistry. Furthermore, we discovered multiple anti-Nectin-2 fully human monoclonal antibodies which inhibited tumor growth in in vivo subcutaneous xenograft models with antibody-dependent cellular cytotoxicity (ADCC) as the principal mechanism of action. In this report, we assessed the toxicity of Y-443, a fully human IgG1/kappa anti-Nectin-2 monoclonal antibody exhibiting strong in vitro ADCC and in vivo anti-tumor activity in cynomolgus monkeys (Macaca fascicularis (Cynos)). Unexpectedly, upon administration, Y-443 induced strong thrombocytopenia through Nectin-2 expressed on Cyno platelets, presumably followed by phagocytosis in the mononuclear phagocytic system. To mitigate the adverse safety profile, we mutated the Fc region of Y-443 to reduce the Fc binding activity to Fcγ receptor I, which is the primary receptor for phagocytosis on macrophages. Moreover, we further engineered the Fc through defucosylation to maintain ADCC activity. The resultant Fc engineered antibody, termed Y-634, demonstrated diminished thrombocytopenia in Cyno toxicological studies and maintained anti-tumor activity in a mouse xenograft model. These findings suggest that Y-634 may have a therapeutic potential for the treatment of Nectin-2 positive cancers, and moreover, Fc engineering is a potential mitigation strategy to ameliorate safety liabilities in antibody induced thrombocytopenia while maintaining antibody potency.

• Authors: Tsutomu Oshima, Hideaki Miyashita, Yoshimasa Ishimura, Yuki Ito, Yoko Tanaka, Akira Hori, Toshio Kokubo, Tomofumi Kurokawa
• Journal: PloS one (PLoS One) Vol. 13 Issue 5 Pg. e0196422 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 29723247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Immunoglobulin Fc Fragments
• Nectins
• Recombinant Proteins

Topics

• Animals
• Antibodies, Monoclonal (adverse effects, genetics, immunology)
• Antibody-Dependent Cell Cytotoxicity
• Cell Line, Tumor
• Female
• Humans
• Immunoglobulin Fc Fragments (adverse effects, genetics, immunology)
• Macaca fascicularis
• Male
• Mice
• Mice, SCID
• Nectins (antagonists & inhibitors, genetics, immunology)
• Protein Engineering
• Recombinant Proteins (adverse effects, genetics, immunology)
• Thrombocytopenia (etiology, prevention & control)
• Xenograft Model Antitumor Assays