A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma.

Abstract

Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identify the most highly expressed cell surface proteins. We annotate candidate protein expression in many healthy tissues and validate the expression of promising targets in 30+ patient samples with relapsed/refractory MM, as well as in primary healthy hematopoietic stem cells and T cells by flow cytometry. Six candidates (ILT3, SEMA4A, CCR1, LRRC8D, FCRL3, IL12RB1) and B cell maturation antigen (BCMA) present the most favorable profile in malignant and healthy cells. We develop a bispecific T cell engager targeting ILT3 that shows potent killing effects in vitro and decreased tumor burden and prolonged mice survival in vivo, suggesting therapeutic relevance. Our study uncovers MM-associated antigens that hold great promise for immune-based therapies of MM.

• Authors: Francesco Di Meo, Anjushree Iyer, Keith Akama, Rujin Cheng, Christina Yu, Annamaria Cesarano, Noriyoshi Kurihara, Hirofumi Tenshin, Arafat Aljoufi, Silvia Marino, Rajesh K Soni, Julie Roda, James Sissons, Ly P Vu, Monica Guzman, Kun Huang, Tamara Laskowski, Hal E Broxmeyer, David G Roodman, Fabiana Perna
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 4 Issue 7 Pg. 101110 (07 18 2023) ISSN: 2666-3791 [Electronic] United States
• PMID: 37467717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Topics

• Animals
• Mice
• Multiple Myeloma (drug therapy, pathology)
• Immunotherapy (methods)
• T-Lymphocytes
• Plasma Cells (metabolism)