Phase 1, first-in-human, open label, dose escalation ctudy of MGD009, a humanized B7-H3 x CD3 dual-affinity re-targeting (DART) protein in patients with B7-H3-expressing neoplasms or B7-H3 expressing tumor vasculature.

TPS3105 Background: MGD009 is a B7-H3 x CD3 Dual Affinity Re-Targeting (DART) protein. DART proteins are bispecific, antibody-based molecules that can bind two distinct antigens simultaneously. MGD009 is designed to redirect T cells to eliminate B7-H3-expressing target cells through co-engagement of B7-H3 on the target cell and CD3 on the T cell, each in a monovalent binding manner. MGD009 contains a mutated human IgG1 Fc domain to reduce / eliminate effector function via binding to Fc gamma receptors (FcγRs) and complement, but retains binding to the neonatal Fc receptor (FcRn) enabling use of the IgG salvage pathway to prolong circulating its half-life. B7-H3 protein expression is extremely limited in normal human tissues but is overexpressed in a broad range of tumor types, including melanoma (M), NSCLC (LC), SCCHN (HN), mesothelioma (MESO) and urothelial cancer (UC). By binding to B7-H3 on tumor cells and CD3 on T lymphocytes, MGD009 can recruit cytotoxic T cells, irrespective of their ability to recognize cancer cells, and trigger T-cell activation, expansion, and T-cell mediated killing of B7-H3- expressing tumors. The limited expression of B7-H3 on normal cells should restrict the potential for cytolytic activity directed at normal tissues, and unintended toxicity in patients treated with MGD009. Methods: This multi-center, open-label trial is a Phase 1 dose escalation / cohort expansion study (NCT02628535). All patients must have advanced B7-H3+ tumors. Prior checkpoint inhibitor therapy will be allowed. Dose escalation uses a 3+3+3 design, with patients treated every 2 weeks with escalating doses of IV MGD009 (starting dose 0.3 ug/kg). Cohort expansions (N = 16/cohort) treated at the maximum tolerated dose will include patients with M, HN, MESO, UC and LC. Major objectives include characterization of the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of MGD009 in this ongoing study. Clinical trial information: NCT02628535.