Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties

Abstract

Several novel anti-CD20 monoclonal antibodies are currently in development with the aim of improving the treatment of B cell malignancies. Mutagenesis and epitope mapping studies have revealed differences between the CD20 epitopes recognized by these antibodies. Recently, X-ray crystallography studies confirmed that the Type I CD20 antibody rituximab and the Type II CD20 antibody obinutuzumab (GA101) differ fundamentally in their interaction with CD20 despite recognizing a partially overlapping epitope on CD20. The Type I CD20 antibodies rituximab and ofatumumab are known to bind to different epitopes. The differences suggest that the biological properties of these antibodies are not solely determined by their core epitope sequences, but also depend on other factors, such as the elbow hinge angle, the orientation of the bound antibody and differential effects mediated by the Fc region of the antibody. Taken together, these factors may explain differences in the preclinical properties and clinical efficacy of anti-CD20 antibodies.

Keywords: :

• Rituximab
• obinutuzumab
• ofatumumab
• GA101
• structure
• type I
• type II
• non-Hodgkin lymphoma
• immunotherapy
• leukemia

Potential Conflicts of interest

C.K., E.M. and P.U. are employees of Roche Glycart A.G., W.S., G.G., M.S., G.N. are employees of Roche Diagnostics GmbH, all other authors do not have a conflict of interest to declare. Writing support was provided by Zoe Crossman, Health Interactions, UK and Rachel Edwards, Prism Ideas, UK.

Acknowledgments

We thank all members and contributors in the GA101 preclinical team and the GA101 global life cycle team.