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A Target Discovery Pipeline Identified ILT3 as a Target for Immunotherapy of Multiple Myeloma

34 Pages Posted: 23 Nov 2022 Publication Status: Published

See all articles by Francesco Di Meo

Francesco Di Meo

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

Anjushree Iyer

NGM Biopharmaceuticals

Keith Akama

NGM Biopharmaceuticals

Rujin Cheng

NGM Biopharmaceuticals

Christina Yu

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

Annamaria Cesarano

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

Noriyoshi Kurihara

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

Hirofumi Tenshin

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

Arafat Aljoufi

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

Silvia Marino

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

Rajesh Kumar Soni

Columbia University - Proteomics and Macromolecular Crystallography Shared Resource

Julie Roda

NGM Biopharmaceuticals

James Sissons

NGM Biopharmaceuticals

Ly Vu

British Columbia Cancer Research Centre

Monica Guzman

Cornell University - Weill Cornell Medicine

Kun Huang

Indiana University - Department of Medicine

Tamara Laskowski

Lonza Group AG

David G. Roodman

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

Hal Broxmeyer

Indiana University - Department of Microbiology and Immunology

Fabiana Perna

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine

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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

Suggested Citation

Di Meo, Francesco and Iyer, Anjushree and Akama, Keith and Cheng, Rujin and Yu, Christina and Cesarano, Annamaria and Kurihara, Noriyoshi and Tenshin, Hirofumi and Aljoufi, Arafat and Marino, Silvia and Soni, Rajesh Kumar and Roda, Julie and Sissons, James and Vu, Ly and Guzman, Monica and Huang, Kun and Laskowski, Tamara and Roodman, David G. and Broxmeyer, Hal and Perna, Fabiana, A Target Discovery Pipeline Identified ILT3 as a Target for Immunotherapy of Multiple Myeloma. Available at SSRN: https://ssrn.com/abstract=4283169 or http://dx.doi.org/10.2139/ssrn.4283169
This version of the paper has not been formally peer reviewed.

Francesco Di Meo

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

Anjushree Iyer

NGM Biopharmaceuticals ( email )

Keith Akama

NGM Biopharmaceuticals ( email )

Rujin Cheng

NGM Biopharmaceuticals ( email )

Christina Yu

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

Annamaria Cesarano

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

Noriyoshi Kurihara

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

Hirofumi Tenshin

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

Arafat Aljoufi

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

Silvia Marino

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

Rajesh Kumar Soni

Columbia University - Proteomics and Macromolecular Crystallography Shared Resource ( email )

New York, NY 10032
United States

Julie Roda

NGM Biopharmaceuticals ( email )

James Sissons

NGM Biopharmaceuticals ( email )

Ly Vu

British Columbia Cancer Research Centre ( email )

Vancouver
Canada

Monica Guzman

Cornell University - Weill Cornell Medicine ( email )

New York, NY
United States

Kun Huang

Indiana University - Department of Medicine ( email )

IN
United States

Tamara Laskowski

Lonza Group AG ( email )

David G. Roodman

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

Hal Broxmeyer

Indiana University - Department of Microbiology and Immunology ( email )

Fabiana Perna (Contact Author)

Indiana University Purdue University Indianapolis (IUPUI) - Indiana University School of Medicine ( email )

Riley Hospital for Children
705 Riley Hospital Dr.
Indianapolis, ID 46202
United States

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