Abstract 1201: Anti-B7-H3 antibody-drug conjugates as potential therapeutics for solid cancer

Abstract

Introduction: Monoclonal antibodies (mAbs) were generated via a target-unbiased approach based on intact cell immunization with cell lines, fetal progenitor cells, and cancer stem cells. An immunohistochemical (IHC) screen for cancer-specific candidates identified a panel of anti-B7-H3 (CD276) mAbs with highly differential tumor-versus-normal tissue binding. B7-H3 expression was observed in tumor epithelium as well as tumorassociated vasculature and stroma. Consistent with our findings, B7-H3 has been reported to be overexpressed in a growing number of solid cancers, including breast, lung, pancreatic, prostate, kidney, and colon cancer, as well as melanoma and glioblastoma. Furthermore, overexpression of B7-H3 has been correlated with disease severity and poor outcome in a number of these cancer types. A humanized version of an anti-B7-H3 mAb engineered with an enhanced Fc domain (enoblituzumab or MGA271 1) and a humanized Dual-Affinity Re-Targeting (DART ®) protein that recognizes both B7-H3 and CD3 and redirects T cells to kill B7-H3-expressing cells (MGD009) are being investigated in Phase 1 clinical studies. In this nonclinical study, we evaluated the therapeutic potential of anti-B7-H3 antibody-drug conjugates (ADCs) toward B7-H3-expressing solid cancers. Methods: A panel of anti-B7-H3 mAbs was screened for internalization and a subset of mAbs that were efficiently internalized by tumor cells was identified. These mAbs were converted to ADCs via chemical conjugation; in vitro and in vivo activity studies were then conducted with a range of tumor cell lines representing human cancer types that overexpress B7-H3. Results: The anti-B7-H3 ADCs exhibited specific, dose-dependent cytotoxicity toward B7-H3-positive tumor cell lines in vitro, including breast, lung, ovarian, pancreatic, and prostate cancer lines, with IC 50 values generally in the sub-nM range. Cytotoxicity was not observed with cell lines lacking B7-H3 expression. The anti-B7-H3 ADCs exhibited potent antitumor activity in vivo, resulting in tumor stasis and tumor regression in mice bearing B7-H3-positive human breast, lung, and ovarian tumor xenografts. Conclusion: Anti-B7-H3 ADCs exhibited dose-dependent cytotoxicity in vitro and potent antitumor activity in vivo toward a range of B7-H3-expressing tumor cell lines representing cancer types that overexpress B7-H3. Our findings demonstrate that ADCs targeting B7-H3 may serve as potential therapeutics for B7-H3-expressing solid cancers.

Preclinical Development of MGC018, a Duocarmycin-based Antibody–drug Conjugate Targeting B7-H3 for Solid Cancer

“…Using this approach, we identified B7-H3 as a cell surface protein with limited expression on normal tissues but overexpressed on the epithelium and tumor-associated vasculature in solid cancers. Validation studies showed that ligation of B7-H3 by several mAbs in our panel led to mAb internalization and antitumor activity toward B7-H3-expressing tumor cells when the mAbs were conjugated to auristatin (25). Based on these results, we selected a lead candidate mAb and sought to develop an ADC targeting B7-H3 for the treatment of cancer.…”

“…A pool of anti-B7-H3 mAbs was generated from a series of intact cell immunizations (13). The anti-B7-H3 mAb PRCA157 was selected as an ADC candidate from the pool of anti-B7-H3 mAbs based on its characteristics, including affinity, tumor versus normal tissue cross-reactivity profile, cynomolgus monkey B7-H3 cross-reactivity, cell internalization, and antitumor activity from screens as monomethyl auristatin E-based ADCs (25). PRCA157 was humanized by CDR grafting and fused to human C-kappa and gamma 1 constant regions, yielding the precursor MGA017 mAb, which retained the B7-H3 binding affinity of the parental murine mAb.…”