Patient-derived, vaccine-elicited MUC1 antibodies mediate immune effector functions against cancer cells

Abstract

Abstract Cancer cells undergo changes that the immune system recognizes, and this can be leveraged for therapy. Antibodies specific for such changes can exert anti-tumor effects via multiple mechanisms, including blocking oncogenic signaling, serving as Trojan horses carrying toxic compounds, coordinating innate immune engagement for cytotoxicity through cellular and non-cellular means, and promoting antigen uptake to jumpstart adaptive immunity for durable protection. We analyzed 12 high-affinity fully human IgG1 monoclonal antibodies that recognize a tumor-specific hypoglycosylated form of Mucin-1 (MUC1) that is overexpressed in >80% of all cancers. These antibodies are unique and different from humanized murine anti-MUC1 mAbs, having undergone selection and affinity maturation in individuals receiving the MUC1-100mer peptide vaccine (Lohmueller et al. Sci. Rep. 2016). Importantly, in all vaccinated individuals that generated antibodies to MUC1, there have been no adverse events in 8 years, increasing the likelihood that as therapeutic agents they would be safe. To test their immune effector capacity, we used these human anti-MUC1 antibodies in in vitro antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC) assays with different huMUC1-expressing cell lines, immune effector cells and serum. Several of the anti-MUC1 antibodies can mediate ADCC by NK cells and ADCP by macrophages, although there was very little or no CDC function. Notably, unlike in published studies on rituximab and alemtuzumab, the amount of antibody binding to cancer cells (MUC1) did not always correlate with increased effector function.