Optimizing anti-CD3 affinity for effective T cell targeting against tumor cells.

Abstract:

:Bispecific antibodies binding to the TCR/CD3 complex and to a tumor-associated surface molecule can be used to target cytotoxic T lymphocytes against tumor cells. We reasoned that high-affinity binding to CD3 may reduce the efficiency of T cell stimulation and target the bispecific reagent to T cells rather than to tumor cells in vivo. We therefore mutated a bispecific single-chain antibody (BscAb) directed to human CD3 and EpCAM to generate variants that bind to CD3 with higher or lower affinity. When compared to the wild-type molecule, a mutant with increased binding to CD3 showed lower capacity to target T cells against an EpCAM+ tumour. In contrast, mutants with decreased binding to CD3, in spite of rapid dissociation, efficiently triggered T cell activation and cytotoxicity, especially when present on tumor cells at low copy number. These results are consistent with the TCR serial triggering model and suggest that BscAb with extremely low affinity for the TCR-CD3 complex could be exploited therapeutically because of their preferential localization to tumor cells.

journal_name

Eur J Immunol

authors

Bortoletto N,Scotet E,Myamoto Y,D'Oro U,Lanzavecchia A

doi

10.1002/1521-4141(200211)32:11<3102::AID-IMMU3102>

keywords:

subject

Has Abstract

pub_date

2002-11-01 00:00:00

pages

3102-7

issue

11

eissn

0014-2980

issn

1521-4141

journal_volume

32

pub_type

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