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

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.