RGD-modified anti-CD3 antibodies redirect cytolytic capacity of cytotoxic T lymphocytes toward alphavbeta3-expressing endothelial cells

International Journal of Cancer. Journal International Du Cancer
Astrid J SchraaGrietje Molema

Abstract

To redirect the lytic activity of cytotoxic T lymphocytes (CTL) toward tumor vascular endothelial cells, we prepared bifunctional proteins with specificity for both alphavbeta3 and CD3. Monocyclic RGD peptides (cRGDfK) were covalently coupled to an anti-CD3 monoclonal antibody at different peptide:protein ratios. The resulting RGDpep-anti-CD3 conjugates bound specifically to alphavbeta3-expressing endothelial cells. Displacement studies with radiolabeled alphavbeta3 ligand demonstrated that the alphavbeta3 binding affinity of RGDpep-anti-CD3 conjugates was elevated as compared to the non-conjugated RGDpep. IC50 values ranged from 150-1.1 nM, depending on the amount of coupled RGDpep molecules per antibody molecule. RGD modification did not affect the ability of anti-CD3 antibodies to bind to CTL. Furthermore, RGDpep-anti-CD3 was fully capable of activating T cells upon CD3 binding as was shown in a Jurkat/NFAT reporter-gene activation assay. All RGDpep-anti-CD3 conjugates were able to induce RGDpep, CD3-dependent lysis of human primary endothelial cells by anti-CD3/IL-2 activated human peripheral blood mononuclear cells (PBMC), with a significant induction of cytotoxicity observed at an E/T ratio as low as 10. Redirecting cytol...Continue Reading

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Nov 15, 2002·International Journal of Cancer. Journal International Du Cancer·Astrid J SchraaGrietje Molema

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Citations

May 7, 2011·Theranostics·Kai Chen, Xiaoyuan Chen
Apr 10, 2013·Journal of Biomedical Materials Research. Part a·Eun-Kyung LimYong-Min Huh
Nov 29, 2005·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Kai TemmingRobbert J Kok
Jun 28, 2005·Journal of Controlled Release : Official Journal of the Controlled Release Society·Raymond M SchiffelersMartin C Woodle
Jan 23, 2021·Bioorganic & Medicinal Chemistry·Aiko YamaguchiKyoji Tsuchikama
Sep 21, 2006·Bioconjugate Chemistry·Alison A McCormickGregory P Pogue

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