Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing
By Ji Li, N. Stagg, Jennifer Johnston, Michael J Harris, Sam A. Menzies, D. Dicara, Vanessa L. Clark, Maria Hristopoulos, Ryan Cook, Dionysos Slaga and 14 more. 2017
281 citations recorded by the source corpus.
Summary The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD-1/PD-L1 signaling, in the treatment of MM and other B cell malignancies.
Subfields: Genetics, Hematology, Radiology, Nuclear Medicine and Imaging
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Citations in the corpus
- Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors (2020, background): “The impact of epitope location on effector functions engaged by Abs has recently been highlighted using CD20 and CD307 as targets in B cell malignancies, demonstrating increased ADCC activity with Abs targeting epitopes closer to the cell surface.(11,15) Although it is accepted that different Abs bi”