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Cited by 48Multiple Myeloma Research and TreatmentsMonoclonal and Polyclonal Antibodies ResearchProtein Degradation and Inhibitors

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Preclinical Efficacy and Safety Comparison of CD3 Bispecific and ADC Modalities Targeting BCMA for the Treatment of Multiple Myeloma

Panowski, Siler H., Kuo, Tracy C., Zhang, Yi, Chen, Amy, Geng, Tao, Aschenbrenner, Laura, Kamperschroer, Cris, Pascua, Edward, Chen, Wei, Delaria, Kathy, Farias, Santiago, Bateman, Marjorie, Dushin, Russell G., Chin, Sherman M., Van Blarcom, Thomas J., Yeung, Yik Andy, Lindquist, Kevin C., Chunyk, Allison G., Kuang, Bing, Han, Bora, Mirsky, Michael, Pardo, Ingrid, Buetow, Bernard, Martin, Thomas G., Wolf, Jeffrey L., Shelton, David, Rajpal, Arvind, Strop, Pavel, Chaparro-Riggers, Javier, Sasu, Barbra J.·2019·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-19-0007

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Abstract

The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody–drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both in vitro and in vivo with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent in vitro and in vivo, causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on on-target elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.

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Metadata

Authors
Panowski, S. H., Kuo, T. C., Zhang, Y., Chen, A., Geng, T., Aschenbrenner, L., Kamperschroer, C., Pascua, E., Chen, W., Delaria, K., Farias, S., Bateman, M., Dushin, R. G., Chin, S. M., Van Blarcom, T. J., Yeung, Y. A., Lindquist, K. C., Chunyk, A. G., Kuang, B., Han, B., Mirsky, M., Pardo, I., Buetow, B., Martin, T. G., Wolf, J. L., Shelton, D., Rajpal, A., Strop, P., Chaparro-Riggers, J., & Sasu, B. J.
Affiliations
  • Allogene Therapeutics (United States) (US)
  • ALX Oncology Inc. (United States) (US)
  • Pfizer (United States) (US)
  • 4Covance, Inc., Early Phase Development Solutions, Madison, Wisconsin.
  • Grifols (United States) (US)
  • CytomX Therapeutics (United States) (US)
  • Five Prime Therapeutics (United States) (US)
  • 10RGD Solutions, LLC, Medicinal Chemistry, Old Lyme, Connecticut.
  • 1Allogene Therapeutics, Research, South San Francisco, California.
  • Aptevo Therapeutics (United states) (US)
  • 12Unity Biotechnology, Safety and DMPK, Brisbane, California.
  • University of California, San Francisco (US)
  • Bristol-Myers Squibb (United States) (US)
  • 3Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, South San Francisco, California.
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2019-11-01
Volume
18
Issue
11
Pages
2008-2020
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-19-0007
OpenAlex
W2969569086
Cited by
48
References
2
Citations by year
2026: 7 · 2025: 11 · 2024: 7 · 2023: 2 · 2022: 8 · 2021: 8 · 2020: 3 · 2019: 1
FWCI
3.56
Type
journal article
Language
en
Open access
closed
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Funders
Pfizer (Pfizer Inc.) (NA)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
multiple myeloma, BCMA, CD3 bispecific antibody, antibody-drug conjugates, antibody affinity, tumor-associated antigens, orthotopic xenograft, cynomolgus monkey toxicity, on-target toxicity
MeSH terms
Animals, Antibody Affinity, Cell Survival, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Female, Humans, Multiple Myeloma, Signal Transduction, Gene Expression Regulation, Neoplastic, CD3 Complex, Antibodies, Bispecific, Immunoconjugates, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, B-Cell Maturation Antigen

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