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Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma
Author(s) -
Lee Lydia,
Bounds Danton,
Paterson Jennifer,
Herledan Gaelle,
Sully Katherine,
SeestallerWehr Laura M.,
Fieles William E.,
Tunstead James,
McCahon Lee,
Germaschewski Fiona M.,
Mayes Patrick A,
Craigen Jenny L.,
RodriguezJusto Manuel,
Yong Kwee L.
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14145
Subject(s) - cytotoxicity , antigen , flow cytometry , cancer research , antibody , multiple myeloma , clonogenic assay , plasma cell , medicine , immunology , biology , cell , in vitro , biochemistry
Summary B‐cell maturation antigen ( BCMA , also termed TNFRSF 17) is an attractive therapeutic target due to its restricted expression on normal and malignant plasma cells ( PC ). GSK 2857916 (or J6M0‐ MMAF ) is a BCMA ‐specific antibody conjugated to the microtubule‐disrupting agent monomethyl auristatin F ( MMAF ) via a protease‐resistant linker. To evaluate the clinical potential of this agent, tumour cells from seventy multiple myeloma ( MM ) patients were assessed for BCMA expression by immunohistochemistry and flow cytometry. All patients tested expressed BCMA , at varying levels, and both surface and intracellular expression were observed. BCMA expression is maintained through relapse, extramedullary spread and in residual disease post therapy. BCMA levels may also be prognostically useful as higher levels of BCMA were associated with poorer outcomes, even taking into account genetic risk. We observed rapid internalization of surface BCMA and newly expressed protein by 1 h, suggesting a mechanism for J6M0‐ MMAF activity even with low surface antigen. J6M0‐ MMAF mediated cytotoxicity of MM cells varied with dose and antigen levels, with clonogenic progenitors killed at lower doses than mature cells. In comparison, J6M0‐ MMAF killing of primary CD 138 + myeloma cells occurred with slower kinetics. Our observations support BCMA to be a promising therapeutic target in MM for novel therapies such as J6M0‐ MMAF .