Enhanced Efficacy of GA101: A Third-Generation, Glycoengineered Type II CD20 Antibody for B-Cell Malignancies

The abstract discusses the development and testing of a third-generation type II CD20 antibody known as GA101, designed for the treatment of B-cell non-Hodgkin lymphoma (NHL). GA101 is distinguished by its enhanced antibody-dependent cellular cytotoxicity (ADCC) and its ability to induce caspase-independent apoptosis more effectively than existing CD20 monoclonal antibodies (MAbs). The process of humanizing GA101 involved incorporating CDR sequences from a murine antibody onto a fully human IgG1-kappa germline framework and optimizing the Fc region through glycoengineering to increase binding affinity to human FcgammaRIII receptors. This resulted in a significantly improved binding capacity and an amplified ADCC effect against NHL cell lines.

Experiments demonstrated that the modified GA101 had a nanomolar affinity for CD20 and induced strong apoptosis upon binding to target cells. Comparative studies showed that GA101 induced more potent apoptosis in NHL cell lines and patient samples than other CD20 antibodies. In comprehensive assays that included ADCC, complement-dependent cytotoxicity (CDC), and apoptosis, GA101 outperformed other antibodies, including rituximab and its Fc-variants.

In vivo studies in NHL xenograft models revealed that GA101 treatment led to complete tumor remission and long-term survival, contrasting with the tumor stasis observed with rituximab. The conclusion highlights GA101 as a promising therapeutic candidate for B-cell malignancies due to its superior efficacy in both in vitro and in vivo preclinical models.