Abstract LB179: Patient-derived, vaccine-elicited, anti-MUC1 antibodies directly target tumor cells for elimination via multiple immune mechanisms

Abstract

During premalignant and malignant transformation, cells undergo antigenic changes that can be recognized by the immune system, and this can be leveraged both for immune prevention and therapy. One such change occurs with MUC1, or Mucin-1, a large variable number tandem repeat (VNTR)-containing transmembrane protein that is overexpressed and hypoglycosylated on a majority of precancerous and adenocarcinoma cells, including those of the colon, lung, breast, pancreas and ovaries. This tumor form of MUC1 is recognized by both cellular and humoral immunity. Healthy individuals at high risk of developing colon cancer due to a history of colonic polyps were enrolled in a clinical trial testing the feasibility of prophylactic vaccination against the tumor form of MUC1, also expressed on polyps (Kimura et al., 2013). Half the participants generated high levels of anti-MUC1 IgG antibodies, some of which were cloned to further analyze their tumor specificity and to potentially develop them as therapeutics for patients with cancer (Lohmueller et al., 2016). As these fully human IgG1 monoclonal antibodies (mAbs) were selected and affinity matured in healthy individuals who experienced no negative side effects to the vaccine in >10 years, it increases the likelihood that as therapeutics they will be safe. To study anti-tumor efficacy and mechanism(s) of action of 12 of these mAbs, tumor cells were co-incubated with immune cells in the presence of the mAbs, and each mAb’s ability to mediate antibody-dependent cellular cytotoxicity (ADCC) by NK cells, antibody-dependent cellular phagocytosis (ADCP) by monocytes, antibody-dependent trogocytosis/trogoptosis (ADCT) by neutrophils, antibody-dependent cytokine release (ADCR) and complement dependent cytotoxicity (CDC) was assessed. Several MUC1 mAbs examined could mediate ADCC, ADCP, ADCT and ADCR, with some mechanisms being cell-line dependent. One mAb was selected for in vivo testing and found to delay breast cancer growth and prolong survival in immunocompromised mice lacking T cells, B cells and NK cells, pointing to ADCP and ADCT as important anti-tumor functions. Additionally, the relationship between epitope location and immune effector functions was explored by creating different MUC1 constructs that vary epitope distance from the cell surface, number of epitopes, etc, to test properties of the target antigen that may affect antibody efficacy. These latter experiments revealed an increased efficiency in phagocytosis and trogocytosis when the mAbs bound an epitope that was both proximal to and anchored to the membrane. Notably, unlike published studies of rituximab and alemtuzumab, the amount of MUC1 mAb binding did not always correlate with increased effector function. Our results may inform not only the development of these MUC1-based therapies but more broadly future therapeutic mAb design against a variety of targets. Citation Format: Michelle L. McKeague, Jason Lohmueller, Matthew T. Dracz, Najla Saadallah, Jia Xue, Eric D. Ricci, William Lu, Olivera J. Finn. Patient-derived, vaccine-elicited, anti-MUC1 antibodies directly target tumor cells for elimination via multiple immune mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB179.