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

Dovedi, SJ; Elder, MJ; Yang, C; Sitnikova, SI; Irving, L; Hansen, A; Hair, J; Jones, DC; Hasani, S; Wang, B; Im, SA; Tran, B; Subramaniam, DS; Gainer, SD; Vashisht, K; Lewis, A; Jin, X; Kentner, S; Mulgrew, K; Wang, Y; Overstreet, MG; Dodgson, J; Wu, Y; Palazon, A; Morrow, M; Rainey, GJ; Browne, GJ; Neal, F; Murray, TV; Toloczko, AD; Dall&#39;Acqua, W; Achour, I; Freeman, DJ; Wilkinson, RW; Mazor, Y

Author(s): Dovedi, SJ; Elder, MJ; Yang, C; Sitnikova, SI; Irving, L; Hansen, A; Hair, J; Jones, DC; Hasani, S; Wang, B; Im, SA; Tran, B; Subramaniam, DS; Gainer, SD; Vashisht, K; Lewis, A; Jin, X; Kentner, S; Mulgrew, K; Wang, Y; Overstreet, MG; Dodgson, J; Wu, Y; Palazon, A; Morrow, M; Rainey, GJ; Browne, GJ; Neal, F; Murray, TV; Toloczko, AD; Dall'Acqua, W; Achour, I; Freeman, DJ; Wilkinson, RW; Mazor, Y;
Details: Publication Year 2021-05,Volume 11,Issue #5,Page 1100-1117
Journal Title: Cancer Discovery
Publication Type: Research article
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.
Keywords: Adenocarcinoma/drug therapy; Adenocarcinoma, Clear Cell/drug therapy; Antibodies, Monoclonal, Humanized/*therapeutic use; CTLA-4 Antigen/metabolism; Humans; Immunotherapy; Kidney Neoplasms/drug therapy; Male; Middle Aged; Programmed Cell Death 1 Receptor/metabolism; Stomach Neoplasms/drug therapy; T-Lymphocytes/immunology
Department(s): Medical Oncology
PubMed ID: 33419761
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-20-1445
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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