Generation of dual specific bivalent BiTEs (dbBIspecific T-cell engaging antibodies) for cellular immunotherapy
Posted on 2019-09-06 - 04:32
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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Kujawski, Maciej; Li, Lin; Bhattacharya, Supriyo; Wong, Patty; Lee, Wen-Hui; Williams, Lindsay; et al. (2019). Generation of dual specific bivalent BiTEs (dbBIspecific T-cell engaging antibodies) for cellular immunotherapy. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4656104.v1
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AUTHORS (13)
MK
Maciej Kujawski
LL
Lin Li
SB
Supriyo Bhattacharya
PW
Patty Wong
WL
Wen-Hui Lee
LW
Lindsay Williams
HL
Harry Li
JC
Junie Chea
KP
Kofi Poku
NB
Nicole Bowles
NV
Nagarajan Vaidehi
PY
Paul Yazaki
JS
John Shively