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4401 Synergistic Activity of Belantamab Mafodotin (anti-BCMA immuno-conjugate) with PF-03084014 (gamma-secretase inhibitor) in Bcma-Expressing Cancer Cell Lines

Program: Oral and Poster Abstracts
Session: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Poster III
Hematology Disease Topics & Pathways:
multiple myeloma, Diseases, Lymphoma (any), Plasma Cell Disorders, Lymphoid Malignancies
Monday, December 9, 2019, 6:00 PM-8:00 PM
Hall B, Level 2 (Orange County Convention Center)

Stephen Eastman, BS, MS1*, Christopher Shelton2*, Ira Gupta, MD3, Julie Krueger1*, Christina Blackwell1* and Paul M Bojczuk3*

1Immuno-oncology and Combinations, GlaxoSmithKline, Collegeville, PA
2GlaxoSmithKline, Upper Providence, Collegeville, PA
3GlaxoSmithKline, Collegeville, PA

Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation of plasma cells within the bone marrow. B cell maturation antigen (BCMA) is a cell-surface receptor required for the survival of plasma cells and is also ubiquitously expressed on MM cells. Belantamab Mafodotin (GSK2857916) is a humanised monoclonal anti-BCMA antibody, which is afucosylated and conjugated to the microtubule-disrupting agent monomethyl auristatin-F (MMAF). Upon binding to BCMA on the cell surface, belatamab mafodotin is rapidly internalised and the cytotoxic moiety (cys-mcMMAF) is released, leading to direct cell death.

BCMA is directly shed from the plasma membrane by gamma-secretase, a type-I sheddase. In order to further enhance belantamab mafodotin activity, we sought to increase cell surface levels of BCMA by blocking shedding of BCMA with a gamma-secretase inhibitor (GSI). We then determined the effect on the activity of belantamab mafodotin by combining belantamab mafodotin with PF-03084014, a highly-selective GSI. In order to understand combination effects against immuno-conjugate activity, a 3-day proliferation assay on a panel of multiple myeloma and lymphoma cell lines with varying levels of BCMA expression was conducted. The assay showed a 50 to 3,000-fold EC50 shift in cell lines sensitive to belantamab mafodotin across multiple lymphoma cell types.

Antibody-dependent cellular cytotoxicity (ADCC) activity of belantamab mafodotin in combination with PF-03084014 was also examined. In a 24-hour ADCC Jurkat reporter assay, an EC50 shift across multiple BCMA-expressing cell lines was observed. Even cell lines with very low BCMA expression, such as Raji, showed a synergistic increase in ADCC activity in combination with PF-03084014. Cell lines that were non-responsive in the cell proliferation assay, showed activity in the ADCC assay, indicating low-expressing BCMA cell lines remain sensitive to belantamab mafodotin, alone and in combination with PF-03084014.

Synergistic effect from this preclinical work provided rationale to support clinical evaluation of belantamab mafodotin in combination with PF-03084014 in a planned clinical trial (DREAMM-5).

Disclosures: Eastman: GlaxoSmithKline: Employment, Equity Ownership. Shelton: GlaxoSmithKline: Employment, Equity Ownership. Gupta: Novartis: Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Krueger: GlaxoSmithKline: Employment, Equity Ownership. Blackwell: GlaxoSmithKline: Employment, Equity Ownership. Bojczuk: GlaxoSmithKline: Employment, Equity Ownership.

*signifies non-member of ASH