Preclinical Activity of JNJ-7957, a Novel BCMAxCD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab
- 1 May 2020
- journal article
- conference paper
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (9), 2203-2215
- https://doi.org/10.1158/1078-0432.CCR-19-2299
Abstract
Purpose: Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action. Experimental Design: We evaluated the anti-MM activity of the fully human BCMAxCD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated. Results: We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957-mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naive MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect. Conclusions: JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.Other Versions
Funding Information
- Janssen Research and Development
This publication has 47 references indexed in Scilit:
- Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple MyelomaPLOS ONE, 2012
- How I treat plasma cell leukemiaBlood, 2012
- The Crystal Structures of Dystrophin and Utrophin Spectrin Repeats: Implications for Domain BoundariesPLOS ONE, 2012
- The therapeutic human CD38 antibody daratumumab improves the anti-myeloma effect of newly emerging multi-drug therapiesBlood Cancer Journal, 2011
- Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumabHaematologica, 2010
- MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumorsMolecular Immunology, 2006
- Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infectionsLeukemia & Lymphoma, 2006
- BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasoneBlood, 2004
- Engineering an APRIL-specific B Cell Maturation AntigenOnline Journal of Public Health Informatics, 2004
- BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma CellsThe Journal of Experimental Medicine, 2004