Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma.
B-cell maturation antigen (BCMA, also termed TNFRSF17) is an attractive therapeutic target due to its restricted expression on normal and malignant plasma cells (PC). GSK2857916 (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 CD138(+) 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.
Haematology, UCL Cancer Institute, London, UK.
Lydia
L
Lee
Haematology, UCL Cancer Institute, London, UK.
Danton
D
Bounds
Department of Histopathology, UCL, London, UK.
Jennifer
J
Paterson
Haematology, UCL Cancer Institute, London, UK.
Gaelle
G
Herledan
BioPharm R&D, GlaxoSmithKline, Stevenage, UK.
Katherine
K
Sully
Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA.
Laura M
LM
Seestaller-Wehr
Platform Technology Sciences, GlaxoSmithKline, Collegeville, PA, USA.
William E
WE
Fieles
Platform Technology Sciences, GlaxoSmithKline, Collegeville, PA, USA.
James
J
Tunstead
BioPharm R&D, GlaxoSmithKline, Stevenage, UK.
Lee
L
McCahon
BioPharm R&D, GlaxoSmithKline, Stevenage, UK.
Fiona M
FM
Germaschewski
Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA.
Patrick A
PA
Mayes
BioPharm R&D, GlaxoSmithKline, Stevenage, UK.
Jenny L
JL
Craigen
Department of Histopathology, UCL, London, UK.
Manuel
M
Rodriguez-Justo
Haematology, UCL Cancer Institute, London, UK.
Kwee L
KL
Yong
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D053301:B-Cell Maturation Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis
D000911:Antibodies, Monoclonal; D053301:B-Cell Maturation Antigen; D018796:Immunoconjugates
B-cell maturation antigen; immunotherapy; monoclonal antibody; multiple myeloma