Precision Glycocalyx Editing for Cancer Immunotherapy

December 15, 2016
04:00 PM - 05:00 PM
Hutchison Hall 473

Dr. Han Xiao
Stanford University
Chemistry

Bioorganic Seminar, Abstract:  Cell surface glycans constitute a central axis of immune modulation that is exploited by tumors to evade immune destruction. Therapeutic strategies that target tumor-associated glycans may therefore potentiate anti-tumor immunity. In previous work, we identified hypersialylation, a common tumor phenotype, as a resistance mechanism against antibody-dependent cell-mediatedcytotoxicity (ADCC) by natural killer (NK) cells. Sialylated glycans on cancer cells engaged sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on NK cells, leading to enhanced inhibitory signaling. Here, we report the development of antibody-sialidase conjugates that enhance tumor cell susceptibility to ADCC by selective desialylation of the tumor cell glycocalyx. We chemically linked the monoclonal antibody cancer drug trastuzumab to a recombinant sialidase using a combination of bioorthogonal chemistry methods. The trastuzumab-sialidase conjugate desialylated tumor cells in a HER2-dependent manner, reduced binding by NK cell inhibitory Siglec receptors, and enhanced binding to the NK cell activating receptor NKG2D. Compared to the activity of trastuzumab alone, the trastuzumab-sialidase conjugate led to enhanced NK cell killing against tumor cells with moderate levels of HER2, suggesting potential clinical utility for treating cancer patients with low HER2 levels or trastuzumab resistance. Precision glycocalyx editing with antibody-enzyme conjugates is a promising avenue for cancer immune therapy.

Category: Seminars