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- Title
Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3.
- Authors
Slaga, Dionysos; Ellerman, Diego; Lombana, T. Noelle; Vij, Rajesh; Li, Ji; Hristopoulos, Maria; Clark, Robyn; Johnston, Jennifer; Shelton, Amy; Mai, Elaine; Gadkar, Kapil; Lo, Amy A.; Koerber, James T.; Totpal, Klara; Prell, Rodney; Lee, Genee; Spiess, Christoph; Junttila, Teemu T.
- Abstract
T cell–dependent bispecific antibodies with bivalent low affinity binding to HER2 are more selective for tumor cells that overexpress the target. Less can be more for tumor targeting: HER2 is a receptor tyrosine kinase that is often overexpressed in breast cancer. Unfortunately, many normal tissues also express HER2, resulting in toxicity from HER2-targeted treatments. Slaga et al. have developed a T cell–dependent bispecific antibody that binds to both HER2 and the CD3 protein on T cells, helping redirect the T cells to recognize tumor cells. To improve treatment safety, the authors selected an antibody that binds two HER2 molecules at a time, but with low affinity for each one, making it selective for tumors that have a high density of surface HER2 relative to healthy tissues. 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.
- Subjects
HER2 protein; T cells; IMMUNOGLOBULINS; TUMOR treatment; TUMORS
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 463, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aat5775