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

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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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Background
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See all 186

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: Dovedi, Simon J.
Yang, Chunning
Sitnikova, Suzanne I.
Irving, Lorraine
Hansen, Anna
Jones, Des C.
Hasani, Sumati
Wang, Bo
Im, Seock-Ah
Tran, Ben
Gainer, Shelby D.
Vashisht, Kapil
Lewis, Arthur
Jin, Xiaofang
Mulgrew, Kathy
Wang, Yaya
Overstreet, Michael G.
Wu, Yanli
Palazon, Asis
Morrow, Michelle
Rainey, Godfrey J.
Browne, Gareth J.
Neal, Frances
Murray, Thomas V.
Achour, Ikbel
Wilkinson, Robert W.
Mazor, Yariv
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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Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

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