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 Immunoljournal_title
European journal of immunologyauthors
Bortoletto N,Scotet E,Myamoto Y,D'Oro U,Lanzavecchia Adoi
10.1002/1521-4141(200211)32:11<3102::AID-IMMU3102>keywords:
subject
Has Abstractpub_date
2002-11-01 00:00:00pages
3102-7issue
11eissn
0014-2980issn
1521-4141journal_volume
32pub_type
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