PSMA-targeted bispecific Fab conjugates that engage T cells

[Display omitted] Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2017-12, Vol.27 (24), p.5490-5495
Hauptverfasser:	Patterson, James T., Isaacson, Jason, Kerwin, Lisa, Atassi, Ghazi, Duggal, Rohit, Bresson, Damien, Zhu, Tong, Zhou, Heyue, Fu, Yanwen, Kaufmann, Gunnar F.
Format:	Artikel
Sprache:	eng
Schlagworte:	Antibodies, Bispecific - chemistry Antibodies, Bispecific - immunology Antibodies, Bispecific - pharmacology Antigens, Surface - immunology Bioconjugation Bispecific antibody CD3 Complex - immunology Cell Survival - drug effects Cells, Cultured Click Chemistry Disulfide bridging Disulfides - chemistry Fab Glutamate Carboxypeptidase II - immunology Humans Immunoglobulin Fab Fragments - chemistry Immunoglobulin Fab Fragments - immunology Immunoglobulin Fab Fragments - pharmacology Leukocytes, Mononuclear - cytology T-Lymphocytes - cytology T-Lymphocytes - drug effects T-Lymphocytes - metabolism
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Zusammenfassung:	[Display omitted] Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an αPSMA Fab (BisFab) by covalent linkage. Optimization of the reducing conditions was critical for selective interchain disulfide reduction and good bioconjugate yield. Activity of αPSMA/CD3 Fab conjugates was tested by in vitro cytotoxicity assays using prostate cancer cell lines. Both bispecific formats demonstrated excellent potency and antigen selectivity.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2017.09.065