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

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
doi: https://doi.org/10.1101/559427
Maciej Kujawski
1Department of Molecular Imaging and Therapy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Lin Li
1Department of Molecular Imaging and Therapy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Supriyo Bhattacharya
2Department of Computational and Quantitative Medicine, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Patty Wong
1Department of Molecular Imaging and Therapy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Wen-Hui Lee
1Department of Molecular Imaging and Therapy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Lindsay Williams
1Department of Molecular Imaging and Therapy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Harry Li
1Department of Molecular Imaging and Therapy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Junie Chea
3Radiopharmacy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Kofi Poku
3Radiopharmacy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Nicole Bowles
3Radiopharmacy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Nagarajan Vaidehi
2Department of Computational and Quantitative Medicine, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Paul Yazaki
1Department of Molecular Imaging and Therapy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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John E. Shively
1Department of Molecular Imaging and Therapy, Beckman Research Institute City of Hope, Duarte, CA, USA 91010
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Abstract

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

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Posted February 24, 2019.
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Generation of dual specific bivalent BiTEs (dbBIspecific T-cell Engaging antibodies) for cellular immunotherapy
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
bioRxiv 559427; doi: https://doi.org/10.1101/559427
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Generation of dual specific bivalent BiTEs (dbBIspecific T-cell Engaging antibodies) for cellular immunotherapy
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
bioRxiv 559427; doi: https://doi.org/10.1101/559427

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