PSMA-targeted bispecific Fab conjugates that engage T cells

Bioorg Med Chem Lett. 2017 Dec 15;27(24):5490-5495. doi: 10.1016/j.bmcl.2017.09.065. Epub 2017 Oct 6.

Abstract

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.

Keywords: Bioconjugation; Bispecific antibody; Click chemistry; Disulfide bridging; Fab.

MeSH terms

  • Antibodies, Bispecific / chemistry*
  • Antibodies, Bispecific / immunology
  • Antibodies, Bispecific / pharmacology
  • Antigens, Surface / immunology*
  • CD3 Complex / immunology
  • Cell Survival / drug effects
  • Cells, Cultured
  • Click Chemistry
  • Disulfides / chemistry
  • 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

Substances

  • Antibodies, Bispecific
  • Antigens, Surface
  • CD3 Complex
  • Disulfides
  • Immunoglobulin Fab Fragments
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II