Human Anti-Muc1 Antibodies Elicited by A Prophylactic Cancer Vaccine for Mab and Car-Modified T Cell Immunotherapies

Abstract Hypoglycosylated MUC1 is a tumor-associated protein that is expressed on over 80% of all human cancers including adenocarcinomas of the colon, pancreas, breast, lung, prostate, and ovary, and multiple myeloma. In our recent clinical trial, individuals at-risk for colon adenocarcinoma received a prophylactic MUC1 cancer vaccine. Many individuals responded producing high titers of anti-MUC1 IgG antibodies with no detectable toxicity. This trial provided a rare source of human antibodies elicited and affinity-matured in a healthy human host to abnormal MUC1. Using our recently developed proteomics method, we isolated and identified 13 anti-MUC1 antibodies representing 7 different clonotypes. These antibodies bind to several different epitopes on the MUC1 vaccine peptide with a range of affinities (15.7μM to 130pM). They also stain MUC1 on human cancer cell lines and colon, breast, lung, and pancreas adenocarcinoma tissue sections while showing no reactivity against a large panel of normal tissues that express MUC1. We constructed lentiviral vectors encoding chimeric antigen receptors (CARs) using scFv’s of several of the antibodies as antigen binding regions and a variety of co-signaling domain architectures. Several of the scFv’s were able to retarget human primary T cells to become activated and produce cytokines in a MUC1-dependent manner and to lyse a variety of MUC1+ human tumor cell lines. Preclinical testing in mouse tumor xenograftgrafts is underway. Being of fully human origin and showing a high-degree of tumor specificity and efficacy in preclinical experiments, these antibodies will be tested in future clinical trials for potential approval for therapy of cancer patients.