Chemoenzymatic Fc Glycan Engineering for Improving Antibody Immunotherapy

PhD Defense: Chong Ou, UMCP

Advisor: Dr. Lai-Xi Wang

Abstract: IgG antibodies contain a conserved N-glycan on the Fc domain. The structures of the glycan Play an important role in modulating antibody’s effector functions. This N-glycan also provides a suitable site for functionalization and conjugation of antibodies in a site-specific manner. We have recently developed a general chemoenzymatic method for Fc glycan remodeling through endoglycosidase-based deglycosylation and reglycosylation.

In my seminar, I will report an efficient method for site-specific antibody functionalization and drug conjugation using the glycan remodeling strategy. An efficient method was developed to functionalize therapeutical antibodies with different clickable groups including azide-, cyclopropene-, and norbornene-tags. Homogenous antibody-
drug conjugates (ADCs, with drug-antibody ratio of 4) were successfully obtained through three different click reactions on the tags introduced. A comparison cell-based
study indicates that the ADCs generated by the three click reactions all showed potent cancer cell killing activity and excellent serum stability. With this conjugation method,
we also constructed structurally well-defined antibody-αGal and antibody-rhamnose conjugates, which were designed to recruit natural anti-αGal and anti-rhamnose antibodies for complement-dependent cytotoxicity (CDC), using trastuzumab as a model antibody. Our preliminary in-vitro study indicates that the antibody-rhamnose cluster conjugates could mediate potent CDC activity against targeted cancer cell with high selectivity.