Enhanced IgG Hexamerization Mediates Efficient C1q Docking and Complement-Dependent Cytotoxicity; Preclinical Proof Of Concept On Primary CLL and Burkitt Lymphoma.
Beurskens FJ, de Jong RN, Verploegen S, et al.
Key Points:
Role of Fc-mediated intermolecular contacts in complement-dependent cytotoxicity (CDC) of cancer cells by therapeutic IgG antibodies in biological relevant in vitro and in vivo model systems.
Authors generated Fc mutations predicted to influence Fc:Fc interactions between IgG antibodies and screened for improved C’ activation.
Authors identified critical amino acid residues in the Fc:Fc contacts.
Enhancing mutation resulted in significant increase in inhibition of in vivo tumor growth by a CD20 antibody in subcutaneous Raji xenograft model in SCID mice.
Implications:
- Novel insight into mechanism of complement-dependent lysis; found mutations that improved formation of Fc:Fc-mediated resulted in strongly increased CDC in primary CLL cells and improved efficacy in Burkitt lymphoma cell line.
View the original abstract on the ASH website.
