Selective Activation of a Perforin-Granzyme B Fusion Protein Toxin by PSA as Therapy for Metastatic Prostate Cancer
Abstract
Protein toxins represent a class of agents that can kill cells in a proliferation independent manner. Many such proteins,derived primarily from bacterial sources, have been identified that are highly potent cytotoxins. While this approach has great potential, the major limitation is the fact that the protein toxin proves to be highly immunogenic and not amenable to repeated dosing to achieve maximal antitumor effect. This obstacle can be overcome through the use of human protein toxins. The goal of this proposal, therefore, is to develop a targeted cytotoxic agent that can selectively kill both proliferating and non-proliferating prostate cancer cells within a metastatic site without significant host toxicity. To achieve this goal, we propose to modify Granzyme B, the major cell-killing components present in cytotoxic T lymphocyte (CTL) granules to a form that is selectively targeted to prostate cancer cells. Granzyme B is a zymogen that must be proteolytically activated and then must penetrate cell membranes to proteolytically activate intracellular pro-apoptotic factors. We describe a targeting approach that recapitulates this dual activation but redirects it to prostate cancer cells. We will replace the native two amino acid propeptide of granzyme B with a peptide recognized as a substrate by PSA. To facilitate granzyme B internalization, we will couple a potent small molecule inhibitor of PSMA to the C-terminus of granzyme B. This granzyme B toxin will only be activated in the prostate cancer microenvironment while remaining inactive against normal tissues lacking both PSA and
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2019
- Accession Number
- AD1102993
Entities
People
- Samuel Denmeade
Organizations
- Johns Hopkins University