Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3.
Sci Transl Med
; 10(463)2018 10 17.
Article
em En
| MEDLINE
| ID: mdl-30333240
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Complexo CD3
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Receptor ErbB-2
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Citotoxicidade Imunológica
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Afinidade de Anticorpos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article