Enhancing Antibody-mediated Immune Response against Tumor-associated Carbohydrate Antigens

Sialyl Lewis A (sLeA, also known as CA19-9), a tetrasaccharide selectively and highly expressed on advanced adenocarcinomas has long been considered as an attractive therapeutic target. While progress in antibodies targeting tumor-associated protein antigens resulted in an impressive array of therapeutics, only one antibody targeting a tumor-associated carbohydrate antigen (TACA) has been FDA-approved.

Using syngeneic murine tumor model systems, Fc-engineering techniques, and our unique panel of transgenic immunocompetent mice carrying human Fc Receptors (FcRs), we demonstrated that anti-sLeA antibodies induce tumor clearance in vivo, relying on interactions between the Fc portion of anti-sLeA Antibodies and myeloid-expressed activating FcRs, resulting in ADCC. In contrast to protein-targeting antibodies, where hFcγRIIIA engagement was necessary and sufficient to mediate tumor clearance, a similar selective dependence was not seen for anti-sLeA antibodies. Thus, re-engineering the Fc portion of sLeA-targeting antibodies to enhance their affinity to activating FcRs led to an enhanced therapeutic effect.

This study reveals the underlying mechanisms of an anti-tumor immune response elicited by administration of carbohydrate-targeting antibodies in vivo. Our findings regarding the distinct FcR-engagement requirements may be applicable to other TACA-targeting antibodies, facilitating the development of more efficient anti-cancer therapies and further advancing this promising class of antibodies into clinical use.