Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Oncology

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

  • Text
  • PDF
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

×

Full Text PDF | Download (5.06 MB)


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

Sign up for email alerts