A novel chemical strategy to harness the tumor specific biochemistry of human kallikrein 2 for prostate cancer theranostics

The recent FDA approvals (Lutathera, Azedra, Pluvicto) and the swell of promising experimental agents in clinical trials underscore the surging enthusiasm to investigate molecularly targeted radiotherapy (TRT) as a treatment modality for many cancers. However, the clinical experience shows that tumor responses to TRTs are often transient and/or variable among patients. Thus, there is an urgent unmet need to develop new strategies to maximize the therapeutic benefit of TRT for cancer patients. We have approached this challenge by developing a new class of radiopharmaceuticals termed “restricted interaction peptides” (RIPs) which are low molecular weight (MW) peptides that are internally cleaved by a tumor endoprotease to unmask a radiolabeled membrane binding peptide. After RIP proteolysis, the membrane binding peptide adopts a helical conformation and immediately attaches to a nearby plasma membranes in the tumor. Using PET, we have found that RIPs may have several properties advantageous for TRT. we hypothesize that RIPs may be a mutually safe and effective platform for TRT. During this project, we will test this hypothesis over three Specific Aims. During Aim 1, we will perform antitumor assessment studies with a radiolabeled RIP targeting human kallikrein 2 (hK2). We are prioritizing hK2 as the kallikreins are selectively produced by prostate cancer cells in patients with metastatic castration resistant prostate cancer (mCPRC), it is a highly efficient serine protease, and it is more highly and broadly expressed than PSMA. A promising lead (termed KRIP2.1) has been developed, validated as an hK2 substrate, radiolabeled with Cu-64, and confirmed via PET to target prostate cancer xenografts with no off target activation. During Aim 1, DOTA-KRIP2.1 will be conjugated to a representative β- (Lu-177) or alpha (Ac-225) emitter and its antitumor effects will be studied in mice bearing various tumor types with endogenous hK2 expression. During Aim 2, we will ask whether patient imaging with 64Cu-KRIP2.1 is feasible. A first in human study will be performed in 6 subjects (3 male, 3 female) to assess the safety, dosimetry, and pharmacokinetics of 64Cu-KRIP2.1. During Aim 3, we will ask whether tumor imaging with 64Cu-KRIP2.1 is feasible. Two cohorts representing patients with castration sensitive prostate cancer (n = 20) or mCRPC patients (n = 20) will receive 64Cu-KRIP2.1 PET/CT and the rate of detection will be benchmarked against anatomical imaging and immunohistochemical analysis for hK2 expression in biopsies. This project represents the first use of a conditionally activated membrane binding probe for TRT, which may overcome the well documented and significant shortcomings of conventional RLT. We are optimistic the data from these studies will provide a compelling rationale to initiate a drug trial for radiolabeled KRIP2.1 as well as to expand this platform to treat tumors overexpressing other extracellular endoproteases. Project Number: 1R01CA308884-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Michael Evans (+2 co-PIs) | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $575,178 | Activity Code: R01 | Study Section: Clinical Translational Imaging Science Study Section[CTIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11276346