Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells
| Autor: | Bo Wang, Frances Neal, Arthur Lewis, Kapil Vashisht, Deepa S. Subramaniam, Des C. Jones, Sumati Hasani, Daniel J. Freeman, Chunning Yang, Lorraine Irving, Michael G. Overstreet, Gareth J. Browne, Suzanne I. Sitnikova, James Hair, Robert W. Wilkinson, Yaya Wang, Ben Tran, Ikbel Achour, James Dodgson, Shelby D. Gainer, Xiaofang Jin, Seock-Ah Im, William F Dall'Acqua, Yariv Mazor, Godfrey Rainey, Asis Palazon, Anna Hansen, Yanli Wu, Matthew J. Elder, Stacy Kentner, Aleksandra D. Toloczko, Michelle Morrow, Murray Thomas Vincent, Simon J. Dovedi, Kathy Mulgrew |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
biology medicine.drug_class Chemistry medicine.medical_treatment media_common.quotation_subject Rational design chemical and pharmacologic phenomena Immunotherapy Monoclonal antibody Blockade 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology In vivo 030220 oncology & carcinogenesis medicine biology.protein Cancer research Secretion Antibody Internalization media_common |
| Zdroj: | Cancer Discovery. 11:1100-1117 |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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