MGD011, Humanized CD19 x CD3 DART^® Protein with Enhanced Pharmacokinetic Properties, Demonstrates Potent T-Cell Mediated Anti-Tumor Activity in Preclinical Models and Durable B-Cell Depletion in Cynomolgus Monkeys Following Once-a-Week Dosing

CD19, a lymphocyte-specific marker expressed from early B-lymphocyte development through mature memory B cells, is highly represented in B-cell malignancies, making it attractive for targeted interventions. MGD011 is a Dual-Affinity Re-Targeting (DART®) protein designed to redirect T-cells to eliminate CD19-expressing cells through co-engagement of CD19 and CD3 in a monovalent binding fashion. MGD011 was engineered with a modified Fc domain that is inactivated for binding to FcγRs but retains binding to the neonatal Fc receptor (FcRn) of the immunoglobulin salvage pathway, allowing for extended pharmacokinetic (PK) properties and convenient dosing at a once-a-week or longer interval. To enable preclinical toxicokinetics and dose optimization, MGD00011 was also designed to cross-react with non-human primates. MGD011 demonstrates bispecific binding to B and T cells isolated from human and cynomolgus monkey blood. MGD011 mediates potent in vitro redirected T-cell killing of B-cell lymphoma cell lines and effective autologous B-cell depletion of human or cynomolgus monkey peripheral blood mononuclear cells (PBMCs). MGD011-mediated killing of CD19 target cells was accompanied by target-dependent T-cell expansion and activation, cytokine release and upregulation of perforin and granzyme B, consistent with the redirected T-cell mediated killing mechanism of action endowed in its design. Two tumor models in NOD/SCID/IL2 receptor gamma chain-deficient (NSG) or NSG/beta2-microglobulin-deficient (NSG/Bm2^-/-) mice were used to ascertain in vivo activity of MGD011. The growth of newly-implanted tumor xenografts of HBL-2 cells, a mantle cell lymphoma line, or Raji cells, a Burkitt’s lymphoma line, was efficiently inhibited by intravenous (IV) administration of MGD011 following the subcutaneous (SC) implantation of the target cells co-mixed with activated human T cells in Winn’s tumor models. Furthermore, in human PBMC-reconstituted mice bearing pre-established intradermal (ID) HBL-2 xenografts, MGD011 demonstrated potent anti-tumor activity with high complete response rates and no evidence of relapse over the study duration. To assess the safety and pharmacodynamic activity of MGD011, a dose-escalation study of MGD011 administered once weekly by 2-hour IV infusion was conducted in cynomolgus monkeys. MGD011 was well tolerated at doses up to 100 µg/kg, the highest dose tested, with no drug-related adverse findings and modest elevations in serum cytokines. MGD011-related pharmacological effects included marked decrease in circulating B cells at doses as low as 0.5 µg/kg, profound reduction of CD20⁺ cells in lymphoid organs and only modest recovery 4 weeks after the last dose. As expected, MGD011 displays prolonged PK properties, consistent with that of a human IgG1 in monkeys. In summary, the safety, activity and PK profiles of MGD011 support further investigation as a therapeutic candidate for treatment of B-cell malignancies.