MGD011: A Humanized DART Protein for Potent Anti-Tumor Activity and Sustained B-Cell Depletion in Preclinical Studies

CD19 is a marker that is prevalent in B-cell malignancies, which makes it a promising target for treatment. MGD011 is a DART protein that aims to destroy CD19-expressing cells by engaging both CD19 and CD3 on T-cells. The protein has been designed to have an extended half-life due to its modified Fc domain, which interacts with the FcRn receptor but not FcγRs, allowing for less frequent dosing. MGD011 was also made to be cross-reactive with non-human primates for preclinical studies.

The protein has shown to bind to both human and cynomolgus monkey B and T cells and has demonstrated its ability to induce T-cell-mediated killing of B-cell lymphoma cells in vitro. It has also shown to deplete autologous B-cells from human and monkey peripheral blood mononuclear cells. The mechanism of action involves T-cell expansion and activation, cytokine release, and the upregulation of perforin and granzyme B.

In vivo studies using two different mouse models have shown that MGD011 can efficiently inhibit the growth of implanted tumor xenografts when administered intravenously. Additionally, in mice with pre-established xenografts, the protein has shown potent anti-tumor activity with high complete response rates and no relapse.

A dose-escalation study in cynomolgus monkeys has shown that MGD011 is well tolerated and exhibits a marked decrease in circulating B cells even at low doses. It also causes a significant reduction in CD20+ cells in lymphoid organs with only a modest recovery weeks after the last dose. The pharmacokinetic profile of MGD011 in monkeys is consistent with that expected of a human IgG1.

The findings from the studies suggest that MGD011 is a potential therapeutic candidate for B-cell malignancies, with a favorable safety profile and pharmacokinetic properties. The disclosures indicate that the authors are affiliated with MacroGenics Inc., with various forms of employment and equity ownership.