PSMA with Multiple Single-Chain and Domain Binders Treats Prostate Cancer
The prostate specific membrane antigen (PSMA) is an integral membrane protein normally expressed on the basal side of the cell. In prostate cancer, PSMA is transferred to the luminal side of the prostate ducts and its expression level is increased up to 1000 times. This high level of expression is indicative of advanced disease stage and poor prognosis. Pitt researchers have identified new generation antibodies that are specifically designed to be suitable for development of novel antibody-based therapeutics such as CAR T-cells, bispecific antibodies for ADCC, or ADCs. Pitt’s PSMA antibodies target one of the extracellular domains (the apical domain) of the protein and do not need to be internalized. The goal in developing these antibodies was to discover antibodies with comparable or better performance of the known PSMA antibodies in clinical trials. Researchers successfully generated a properly folded recombinant PSMA protein and used it for selecting high affinity PSMA-specific VH-antibody domains binders from large-size phage display libraries. These binders can play a significant role in advancing current treatments for prostate cancer.
Description
This innovation regarding PSMA antibodies has several unique features. Researchers used the small format of the VH-antibody domains binders, which provides the opportunity for developing ADCs with better tumor penetration compared to the full IgG, or Fab, or scFv formatted ADCs. The antibodies developed in the invention are derived from fully human phage display libraries, which provides for low risk of inducing immune response. The selection of binders competing with the antibodies J591 and VH-PSMA from TNB585 ensured targeting distinct epitopes on the PSMA surface. The affinities of the selected binders span two orders of magnitude including the affinities of the reference binders. This provided for a tuning capability of the developed antibody-based pharmaceuticals. The developed PSMA antibodies can be used for targeting PSMA expressing cells with high selectivity using either ADC, or ADCC, or CAR T cells.Applications
For use in treatment of prostate cancerAdvantages
• Small format of antibody domains antibodies provides opportunity for better tumor penetration• Targeting distinct epitopes on the PSMA surface allows for selective targeting of PSMA expressing cells.