多发性骨髓瘤
抗体
分子生物学
双特异性抗体
抗原
B细胞
细胞
T细胞
癌症研究
免疫学
生物
病毒学
单克隆抗体
免疫系统
遗传学
作者
Kodandaram Pillarisetti,Gordon Powers,Leopoldo Luistro,Alexander Babich,Eric T. Baldwin,Yingzhe Li,Xiaochun Zhang,Mark Mendonça,Nate Majewski,Rupesh Nanjunda,Diana Chin,Kathryn Packman,Yusri Elsayed,Ricardo M. Attar,François Gaudet
出处
期刊:Blood Advances
[Elsevier BV]
日期:2020-09-21
卷期号:4 (18): 4538-4549
被引量:105
标识
DOI:10.1182/bloodadvances.2020002393
摘要
Abstract B-cell maturation antigen (BCMA), a member of the tumor necrosis factor family of receptors, is predominantly expressed on the surface of terminally differentiated B cells. BCMA is highly expressed on plasmablasts and plasma cells from multiple myeloma (MM) patient samples. We developed a BCMAxCD3 bispecific antibody (teclistamab [JNJ-64007957]) to recruit and activate T cells to kill BCMA-expressing MM cells. Teclistamab induced cytotoxicity of BCMA+ MM cell lines in vitro (H929 cells, 50% effective concentration [EC50] = 0.15 nM; MM.1R cells, EC50 = 0.06 nM; RPMI 8226 cells, EC50 = 0.45 nM) with concomitant T-cell activation (H929 cells, EC50 = 0.21 nM; MM.1R cells, EC50 = 0.1 nM; RPMI 8226 cells, EC50 = 0.28 nM) and cytokine release. This activity was further increased in the presence of a γ-secretase inhibitor (LY-411575). Teclistamab also depleted BCMA+ cells in bone marrow samples from MM patients in an ex vivo assay with an average EC50 value of 1.7 nM. Under more physiological conditions using healthy human whole blood, teclistamab mediated dose-dependent lysis of H929 cells and activation of T cells. Antitumor activity of teclistamab was also observed in 2 BCMA+ MM murine xenograft models inoculated with human T cells (tumor inhibition with H929 model and tumor regression with the RPMI 8226 model) compared with vehicle and antibody controls. The specific and potent activity of teclistamab against BCMA-expressing cells from MM cell lines, patient samples, and MM xenograft models warrant further evaluation of this bispecific antibody for the treatment of MM. Phase 1 clinical trials (monotherapy, #NCT03145181; combination therapy, #NCT04108195) are ongoing for patients with relapsed/refractory MM.
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