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Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3.

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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Slaga D,Ellerman D,Lombana TN,Vij R,Li J,Hristopoulos M,Clark R,Johnston J,Shelton A,Mai E,Gadkar K,Lo AA,Koerber JT,Totpal K,Prell R,Lee G,Spiess C,Junttila TT

doi

10.1126/scitranslmed.aat5775

subject

Has Abstract

pub_date

2018-10-17 00:00:00

issue

463

eissn

1946-6234

issn

1946-6242

pii

10/463/eaat5775

journal_volume

10

pub_type

杂志文章

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