A Target Discovery Pipeline Identified ILT3 as a Target for Immunotherapy of Multiple Myeloma
34 Pages Posted: 23 Nov 2022 Publication Status: Published
More...Abstract
Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we developed an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and 900+ patients. Starting from 4000+ candidates, we identified the most highly expressed cell surface proteins. We annotated candidate protein expression in many normal tissues and validated the expression of promising targets in 30+ patient samples with relapsed/refractory MM, including patients who relapsed after BCMA Chimeric Antigen Receptor T-cell therapy, as well as in primary normal hematopoietic stem cells and T cells by flow-cytometry. Seven candidates presented the most favorable profile in malignant and normal cells. We developed a novel bi-specific T-cell engager targeting ILT3 showing potent killing effects in vitro and decreased tumor burden and prolonged mice survival in vivo, suggesting therapeutic relevance. Our study uncovered novel MM-associated antigens that hold great promise for immune-based therapies of MM.
Note:
Funding Information: FP is supported by a grant from the Leukemia Research Foundation, three internal grants from IUSM and research grants from Lonza and NGM Biopharmaceuticals.
Declaration of Interests: The authors have no conflict of interest.
Ethics Approval Statement: We obtained primary patient samples from the Indiana University School of Medicine biobank. Informed consent was obtained from all the participants, and the procedure was approved by the institutional review board (IRB).
All animal procedures were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of Indiana University School of Medicine. INCOMPLETE
Keywords: Mass-spectrometry, target discovery strategy, ILT3, Bivalent antibodies, T cells engager: Myeloma
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