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01.12.2019 | Technical advance | Ausgabe 1/2019 Open Access

BMC Cancer 1/2019

Generation of dual specific bivalent BiTEs (dbBIspecific T-cell engaging antibodies) for cellular immunotherapy

Zeitschrift:
BMC Cancer > Ausgabe 1/2019
Autoren:
Maciej Kujawski, Lin Li, Supriyo Bhattacharya, Patty Wong, Wen-Hui Lee, Lindsay Williams, Harry Li, Junie Chea, Kofi Poku, Nicole Bowles, Nagarajan Vaidehi, Paul Yazaki, John E. Shively
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12885-019-6056-8) contains supplementary material, which is available to authorized users.
Maciej Kujawski, Lin Li and Supriyo Bhattacharya contributed equally to this work.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abstract

Background

Bispecific T-cell engaging antibodies (BiTES), comprising dual anti-CD3 and anti-tumor antigen scFv fragments, are important therapeutic agents for the treatment of cancer. The dual scFv construct for BiTES requires proper protein folding while their small molecular size leads to rapid kidney clearance.

Methods

An intact (150 kDa) anti-tumor antigen antibody to CEA was joined in high yield (ca. 30%) to intact (150 kDa) anti-murine and anti-human CD3 antibodies using hinge region specific Click chemistry to form dual-specific, bivalent BiTES (dbBiTES, 300 kDa). dbBiTEs were tested in vitro by EM, flow cytometry and cell cytoxicity and in vivo by PET tumor imaging and redirected T-cell therapy.

Results

The interlocked hinge regions are compatible with a structural model that fits the electron micrographs of 300 kDa particles. Compared to intact anti-CEA antibody, dbBiTES exhibit high in vitro cytotoxicity, high in vivo tumor targeting as demonstrated by PET imaging, and redirected dbBiTE coated T-cells (1 microgram/10 million cells) that kill CEA+ target cells in vivo in CEA transgenic mice.

Conclusion

dbBiTE redirected T-cell therapy is a promising, efficient approach for targeting and killing cancer cells.
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