The Binding of CD38 Therapeutics to Red Blood Cells and Platelets Subverts Depletion of Target Cells

Introduction: The CD38 antigen is a target for treating multiple myeloma and is being investigated for disorders caused by plasma cells. Therapeutics bind to CD38 on red blood cells and platelets in the vasculature, prior to myeloma and plasma cells in the bone marrow and this initial activity could compromise downstream binding to target cells. Methods: We hypothesized that selectively targeting myeloma and plasma cells by circumventing CD38 expressed on RBCs and platelets could improve the potency of next generation therapeutics. We selected the human antibody TAK-079 (IgG1) because it demonstrated relatively low binding to CD38 on RBCs and platelets, in comparison to the first-generation antibody daratumumab (IgG1) in vitro, and characterized the pharmacokinetics and pharmacodynamics in relapsed/refractory multiple myeloma (RRMM) patients (NCT03439280). Results: TAK-079 and daratumumab bind to distinct amino acids of CD38 and exhibit similar affinities to recombinant CD38 protein, immobilized on a silicon chip (e.g. KD of 0.45 & 0.69 nM, respectively) and to endogenously expressed CD38 on a clonal cell line (e.g. EC50s = 0.30 & 0.34 nM, respectively). In contrast, these antibodies bound differently to components of human blood. Daratumumab bound 610% more intensively to a subpopulation of RBCs than TAK-079. Similarly, daratumumab bound 622% more intensively to a subpopulation of platelets than TAK-079. Conversely, TAK-079 bound 181% more potently than daratumumab to CD38 expressed on blood B lymphocytes (e.g. MFI mean EC50 =3.6 & 6.6 nM, respectively) and 259% more potently to blood T lymphocytes (e.g. MFI mean EC50 = 9.3 & 24.2 nM, respectively). Consistent with these data, trough exposures of TAK-079 were approximately 200% higher than those reported for daratumumab (NCT02519452) in RRMM patients, when compared at equivalent subcutaneous doses. Furthermore, bone marrow myeloma and plasma cells were completely saturated by TAK-079 and reduced at subcutaneous doses ≥ 300mg administered weekly. Conclusion: An effective strategy for developing more potent therapeutics may be to circumvent binding to CD38 on circulating RBCs and PLTs because the magnitude of CD38 antibody binding to leukocytes is inversely related to binding of circulating RBCs and PLTs in vitro. In addition, lower binding to RBCs and PLTs is associated with higher availability of CD38 antibody for binding target cells in RRMM patients, as well as target saturation and depletion by TAK-079 when administered subcutaneously at relatively low doses (eg, 300mg). Disclosures Fedyk: Millennium, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Idamakanti:Takeda: Employment. Chen:Takeda: Employment. Estevam:Takeda: Employment. Hernandez:Takeda: Employment. Wagoner:Takeda: Employment. Carsillo:Takeda: Employment. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Allikmets:Takeda: Employment, Patents & Royalties. Lahu:Think AQ: Consultancy. Palumbo:Millennium, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties.