Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3 - PubMed (original) (raw)
. 2018 Oct 17;10(463):eaat5775.
doi: 10.1126/scitranslmed.aat5775.
Diego Ellerman 1, T Noelle Lombana 1, Rajesh Vij 1, Ji Li 1, Maria Hristopoulos 1, Robyn Clark 1, Jennifer Johnston 1, Amy Shelton 1, Elaine Mai 1, Kapil Gadkar 1, Amy A Lo 1, James T Koerber 1, Klara Totpal 1, Rodney Prell 1, Genee Lee 1, Christoph Spiess 1, Teemu T Junttila 2
Affiliations
- PMID: 30333240
- DOI: 10.1126/scitranslmed.aat5775
Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3
Dionysos Slaga et al. Sci Transl Med. 2018.
Abstract
A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab-immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell-directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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