Utilization of immortalized B cells to identify SDCBP as a novel therapeutic target in ovarian carcinoma.

e14507 Background: We hypothesized that tumor-infiltrating B cells in endometriosis and endometriosis-associated ovarian cancer can be used to identify novel, targetable antigen domains to inhibit the progression of ovarian carcinomas. We aimed to identify targets that are spontaneously recognized by B-cell-derived antibodies within ovarian clear cell carcinoma (CCC), endometrioid carcinoma (EC), and endometriosis and to determine the preclinical anti-cancer efficacy of a candidate antibody that recognizes the extracellular domain of an identified target. Methods: B cells from freshly dissociated CCC (n = 2), EC (n = 2), and endometriomas (n = 2) were isolated, activated, and EBV-immortalized. Antibodies were purified from B cell supernatants and used for screening in a proteome array. Targets were prioritized based on accessibility (transmembrane or secreted proteins), expression in endometriosis and cancer, and concurrent IgA and IgG responses. Tumor-promoting syndecan binding protein (SDCBP) was identified and SDCBP-reactive B cells were FACS-sorted and subjected to single cell B cell receptor sequencing to determine the variable heavy and light chain sequences of enriched clonotypes. We then generated a recombinant IgG4 antibody targeting SDCBP with the dominant VH/VL matching sequences. Immunoblots and qPCR were performed to assess SDCBP expression in ovarian cancer cell lines and tumor samples. In vivo studies compared anti-tumor potential of the α-SDCBP IgG4 with controls using immunodeficient mouse models of human CCC and high-grade serous ovarian carcinoma (HGSOC). Results: Nine accessible proteins were detected by both IgA and IgG in all samples, including SDCBP. SDCBP is expressed in ovarian cancer cell lines and tumor samples of multiple histologies, including CCC, EC, and HGSOC. Administration of α-SDCBP IgG4 in TOV21G (CCC) tumor-bearing mice significantly decreased tumor volume compared to non-antigen-specific irrelevant IgG4 (iIgG4, p = 0.002) and vehicle (0.001), and correspondingly trended toward decreased tumor weight compared to vehicle (p = 0.06). Likewise, administration of α-SDCBP IgG4 in OVCAR3 (HGSOC) tumor-bearing mice significantly decreased tumor volume compared to iIgG4 (p = 0.03) and trended toward decreased tumor weight (p = 0.06). Conclusions: An α-SDCBP IgG4 has demonstrated anti-tumor efficacy in SDCBP+ CCC and HGSOC, and SDCBP-targeted therapy for endometriosis and associated malignant conditions, as well as HGSOC, warrants further investigation.