Prostrate-specific membrane antigen (PSMA) is a glycoprotein highly restricted to prostate secretory epithelial cell membranes ubiquitously expressed in prostate adenocarcinoma. In prostate cancer, the expression of PSMA is primarily extracellular, while expression in normal tissue is cytoplasmic. PSMA is also expressed on the (neo)vasculature that supplies blood to many other tumors.
Novel anti-PSMA ADCs are being developed for indications in prostate cancer and glioblastoma multiforme. PSMA has been the focus of several antibody-drug conjugate development programs.
- Researchers at Progenics Pharmaceuticals, Inc. (Tarrytown NY USA) are developing an antibody-drug conjugate consisting of a monoclonal antibody conjugated with monomethyl auristatin E (MMAE) via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker.
- This novel ADCs has the potential to demonstrate increased potency in cancer patients while decreasing the toxicity that is usually seen in other ADCs due to the heterogeneity of the random conjugation approach used to generate these molecules.
- In prostate cancer, expression of PSMA is primarily extracellular, whereas expression is cytoplasmic in normal prostate. In vitro Progenies’ ADC displayed picomolar PSMA-dependent cytotoxic potency.
- Progenies PSMA ADC in clinical trials
PSMA is not expressed on non-prostatic solid tumors themselves, however, it is widely expressed on the neovasculature of these tumors. Researchers at Progenics performed a large immunohistochemical (IHC) analysis of solid tumor samples and found staining across a broad range of solid tumors (e.g., lung, ovarian, pancreatic), with 90% of the samples exhibiting moderate to strong neovascular staining. The ‘universal’ expression of PSMA on tumor neovasculature points to a potential utility for the development of an PSMA ADC for a broad range of solid tumors.
Researchers at Ambrx are developing an alphaPSMA antibody-anti-androgenic conjugate. Ambrx is using a proprietary Protein Medicinal Chemistry platform to optimize the therapeutic potential of ADCs. By creating homogeneous, novel ADCs with defined drug-to-antibody ratios (DAR), and sites of conjugation rationally selected to preserve antibody structure and function, scientists at Ambrx are able to perform quantitative experiments to identify the best monoclonal antibody, DAR, linker design, mechanism of action and site(s) of conjugation for several cancer targets.
Last Editorial Review: May 10, 2016