Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy

  • J Med Chem. 2016 Mar 24;59(6):2660-73. doi: 10.1021/acs.jmedchem.5b01881.
Afaf R Genady  1  2 ,  Nancy Janzen  1 ,  Laura Banevicius  1 ,  Mahmoud El-Gamal  1 ,  Mohamed E El-Zaria  1 ,  John F Valliant  1  3
Affiliations
  • 1. Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
  • 2. Department of Chemistry, Faculty of Science, Tanta University , 31527 Tanta, Egypt.
  • 3. Centre for Probe Development and Commercialization , 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
PMID: 26894427 DOI: 10.1021/acs.jmedchem.5b01881
Abstract

The feasibility of developing a single agent that can deliver radioactive iodine and also direct cellular immune function by engaging endogenous antibodies as an antibody-recruiting small molecule (ARM) was determined. A library of new prostate-specific membrane antigen (PSMA)-binding ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP) groups and iodine were synthesized and screened in vitro and in vivo. A lead compound (9b) showed high affinity for PSMA and the ability to bind anti-DNP antibodies. Biodistribution studies of the iodine-125 analogue showed 3% ID/g in LNCaP xenograft tumors at 1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of 10:1 and 44:1, respectively. The radiolabeled analogue was bound and internalized by LNCaP cells, with both functions blocked using a known PSMA Inhibitor. A second candidate showed high tumor uptake (>10% ID/g) but had minimal binding to anti-DNP antibodies. The compounds reported represent the first examples of small molecules developed specifically for combination immunotherapy and radiotherapy for prostate Cancer.

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