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Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibody
Karin Staflin, … , Rodney Prell, Teemu T. Junttila
Karin Staflin, … , Rodney Prell, Teemu T. Junttila
Published April 9, 2020
Citation Information: JCI Insight. 2020;5(7):e133757. https://doi.org/10.1172/jci.insight.133757.
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Research Article Oncology

Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibody

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Abstract

Systemic cytokine release and on-target/off-tumor toxicity to normal tissues are the main adverse effects limiting the clinical utility of T cell–redirecting therapies. This study was designed to determine how binding affinity for CD3 and tumor target HER2 impact the efficacy and nonclinical safety of anti-HER2/CD3 T cell–dependent antibodies (TDBs). Affinity was found to be a major determinant for the overall tolerability. Higher affinity for CD3 associated with rapidly elevated peripheral cytokine concentrations, weight loss in mice, and poor tolerability in cynomolgus monkeys. A TDB with lower CD3 affinity was better tolerated in cynomolgus monkeys compared with a higher CD3–affinity TDB. In contrast to tolerability, T cell binding affinity had only limited impact on in vitro and in vivo antitumor activity. High affinity for HER2 was critical for the tumor-killing activity of anti-HER2/CD3 TDBs, but higher HER2 affinity also associated with a more severe toxicity profile, including cytokine release and damage to HER2-expressing tissues. The tolerability of the anti-HER2/CD3 was improved by implementing a dose-fractionation strategy. Fine-tuning the affinities for both the tumor target and CD3 is likely a valuable strategy for achieving maximal therapeutic index of CD3 bispecific antibodies.

Authors

Karin Staflin, Christina L. Zuch de Zafra, Leah K. Schutt, Vanessa Clark, Fiona Zhong, Maria Hristopoulos, Robyn Clark, Ji Li, Mary Mathieu, Xiaocheng Chen, Jennifer Johnston, Justin Low, Ryan Ybarra, Dionysos Slaga, Jihong Yang, Meric Ovacik, Noël O. Dybdal, Klara Totpal, Melissa R. Junttila, Diego Ellerman, Genee Lee, Mark S. Dennis, Rodney Prell, Teemu T. Junttila

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Figure 1

CD3 affinity does not impact in vitro activity of anti-HER2/CD3 TDB.

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CD3 affinity does not impact in vitro activity of anti-HER2/CD3 TDB.
(A)...
(A) Representation of anti-HER2/CD3 TDB. (B) Binding to human CD8+ cells was analyzed by flow cytometry (n = 1). (C) TDB-induced (1 μg/mL TDBs) TCR signaling pathway activation in splenic CD8+ cells extracted from huCD3 transgenic mice was analyzed by phos–SLP-76 Western blot (see complete unedited blots in the supplemental material; lanes were run on the same gel but were noncontiguous; n = 1). (D) TDB-induced activation of human CD8+cells was analyzed by flow cytometry (n = 1). (E) In vitro killing activity of HER2-amplified SKBR3 (solid lines) and low-HER2–expressing MCF7 (dotted lines) cells was analyzed by Cell Titer Glo viability assay (n = 3). Data presented as mean ± SD.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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