Pharmacodynamics of SEA-BCMA, a Nonfucosylated Antibody Targeting BCMA, in Patients with Relapsed/Refractory Multiple Myeloma

Abstract

Patients with relapsed/triple class refractory (refractory to a proteasome inhibitor, immunomodulatory drug or anti-CD38 antibody) multiple myeloma (MM) have limited treatment options. Versatile therapies, such as unconjugated antibodies (Abs), that are well tolerated and can be combined with multiple modalities are critical for the MM treatment landscape. SEA-BCMA is an investigational, humanized, nonfucosylated IgG1 monoclonal Ab targeting B-cell maturation antigen (BCMA) on malignant plasma cells. Preclinical data show that SEA-BCMA blocks BCMA-mediated pro-survival and proliferative cell signaling and mediates antibody-dependent cellular phagocytosis and enhanced antibody-dependent cellular cytotoxicity via increased binding to activating Fc receptor, FcγRIIIa (Van Epps 2018). A phase 1, open-label, multicenter study to evaluate the safety, tolerability, and antitumor activity of SEA-BCMA in adults with relapsed or refractory MM (SGNBCMA-001; NCT03582033) is ongoing. To support maximal ligand blocking and immune effector engagement by SEA-BCMA, we investigated its binding and saturation pharmacodynamics (PD) in patients enrolled in dose escalation and currently recruiting dose expansion cohorts.Novel quantitative assays were developed to assess the BCMA target and the availability of SEA-BCMA in patients enrolled in the study. These assessments include: a liquid chromatography-mass spectrometry (LC-MS) soluble BCMA (sBCMA) assay, a BCMA receptor occupancy assay on malignant plasma cells in bone marrow aspirates, and a receptor binding assay to assess the direct binding and saturation capacity of SEA-BCMA in patients' serum samples and bone marrow aspirates to a BCMA-expressing cell in vitro. Results reported as median (min-max) values unless specified.At baseline, the median sBCMA level from patients enrolled in SGNBCMA-001 was 8.5(0.5-217.0) ng/mL. After the first dose of SEA-BCMA, a rapid and sustained increase in sBCMA was observed [32.0 (3.0-139.0) fold]. Mechanistically, because SEA-BCMA can bind to sBCMA, accumulation of sBCMA may occur due to formation of the sBCMA:SEA-BCMA complex, resulting in reduced clearance. Importantly, for patients at the dose selected for expansion (1600mg), the molar ratio of SEA-BCMA to sBCMA remained in excess (10:1-400:1), thereby overcoming the liabilities of this complex formation and supporting malignant plasma cell drug exposure. Results of a receptor binding assay using patients' serum samples also demonstrated a dose-dependent ability to saturate BCMA-expressing cells. Evaluation of receptor occupancy in patient bone marrow aspirates showed that at baseline, median unoccupied membrane BCMA (unbound by ligand) was 3,500(1,500-30,000) copies per cell with one excluded outlier that exhibited 270,000 copies per cell. On-treatment, unoccupied membrane BCMA reductions were observed ranging from 50% to 100% from baseline in majority of evaluable patients at the 1600mg dose. An on-treatment increase in total BCMA expression was also observed, which is being further investigated.Maximal ligand blocking and immune effector engagement is best achieved through saturation of a target receptor. Overall, these PD results provide insight into the saturation potential of plasma cell membrane BCMA by SEA-BCMA and informed the dose selection and schedule in expansion cohorts. Further evaluation of these relationships to patient response is ongoing as the Phase 1 study continues to enroll. DisclosuresTaft: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Henderson: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. O'Day: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Li: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Van Epps: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company.