Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells
Published version of a preprint
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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Numerous bispecific antibodies have been developed, including CTLA-4 × PD-L1 (KN046), CTLA-4 × PD-1 (MGD019 and MEDI5752), LAG-3 × PD-L1 (IBI323), LAG-3 × PD-1 (Tebotelimab), TIM-3 × PD-L1 (LY3415244), TIM-3 × PD-1, and TIGIT×PD-L1.
“Numerous bispecific antibodies have been developed, including CTLA-4 × PD-L1 (KN046) [281], CTLA-4 × PD-1 (MGD019 and MEDI5752) [282, 283], LAG-3 × PD-L1 (IBI323) [284], LAG-3 × PD-1 (Tebotelimab) [285], TIM-3 × PD-L1 (LY3415244) [286], TIM-3 × PD-1 [305], TIGIT×PD-L1 [287].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [283]
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- 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
- Published
- 2021-01-08
- Volume
- 11
- Issue
- 5
- Pages
- 1100-1117
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- 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
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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