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Cited by 186Cancer Immunotherapy and BiomarkersMonoclonal and Polyclonal Antibodies ResearchT-cell and B-cell Immunology

The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index.

Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Dovedi, Simon J., Elder, Matthew J., Yang, Chunning, Sitnikova, Suzanne I., Irving, Lorraine, Hansen, Anna, Hair, James, Jones, Des C., Hasani, Sumati, Wang, Bo, Im, Seock-Ah, Tran, Ben, Subramaniam, Deepa S., Gainer, Shelby D., Vashisht, Kapil, Lewis, Arthur, Jin, Xiaofang, Kentner, Stacy, Mulgrew, Kathy, Wang, Yaya, Overstreet, Michael G., Dodgson, James, Wu, Yanli, Palazon, Asis, Morrow, Michelle, Rainey, Godfrey J., Browne, Gareth J., Neal, Frances, Murray, Thomas V., Toloczko, Aleksandra D., Dall'Acqua, William, Achour, Ikbel, Freeman, Daniel J., Wilkinson, Robert W., Mazor, Yariv·2021·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-1445

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Abstract

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1− T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells. Significance: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy. See related commentary by Burton and Tawbi, p. 1008. This article is highlighted in the In This Issue feature, p. 995

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Crossref · 10.1158/2159-8290.cd-20-1445

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Metadata

Authors
Dovedi, S. J., Elder, M. J., Yang, C., Sitnikova, S. I., Irving, L., Hansen, A., Hair, J., Jones, D. C., Hasani, S., Wang, B., Im, S.-A., Tran, B., Subramaniam, D. S., Gainer, S. D., Vashisht, K., Lewis, A., Jin, X., Kentner, S., Mulgrew, K., Wang, Y., Overstreet, M. G., Dodgson, J., Wu, Y., Palazon, A., Morrow, M., Rainey, G. J., Browne, G. J., Neal, F., Murray, T. V., Toloczko, A. D., Dall'Acqua, W., Achour, I., Freeman, D. J., Wilkinson, R. W., & Mazor, Y.
Affiliations
  • 1Early Oncology R&D, AstraZeneca.
  • 2Antibody Discovery and Protein Engineering, R&D, AstraZeneca.
  • 3Translational Science and Experimental Medicine, Respiratory and Immunology (RI), Biopharmaceuticals R&D, AstraZeneca.
  • Seoul National University (KR)
  • Peter MacCallum Cancer Centre (AU)
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-01-08
Volume
11
Issue
5
Pages
1100-1117
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-1445
OpenAlex
W3121059150
Cited by
186
References
63
Citations by year
2026: 20 · 2025: 35 · 2024: 48 · 2023: 38 · 2022: 31 · 2021: 14
FWCI
11.91
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
AstraZeneca
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
bispecific antibodies, PD-1, CTLA-4, immune checkpoint blockade, PD-1+ T cells, tumor-infiltrating lymphocytes, IL-2 secretion, tumor localization, solid tumors, cancer immunotherapy, immune-related adverse events
MeSH terms
Adenocarcinoma, Humans, Immunotherapy, Kidney Neoplasms, Male, Middle Aged, Stomach Neoplasms, T-Lymphocytes, Adenocarcinoma, Clear Cell, CTLA-4 Antigen, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized

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