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 cancers. However, tumor responses to TRTs are often transient and/or variable among patients. We hypothesize that alternative delivery strategies to radiolabeled small molecule or biologic ligands may confer more durable tumor responses, as radioligands are undermined by heterogeneous target expression among tumors, dissociation or degradation of ligand/receptor complexes, and incomplete target saturation due to low mass doses and infrequent repeat dosing. We have approached this challenge by developing a new class of radiopharmaceuticals termed “restricted interaction peptides” (RIPs) which are linear and unstructured low molecular weight peptides that are internally cleaved by a tumor endoprotease of interest to unmask a radiolabeled, helical membrane binding peptide. Once liberated, the radiolabeled helical peptide immediately and irreversibly attaches to a nearby phospholipid membrane in the tumor. Using PET, we have found that RIPs may have several properties advantageous for TRT, including catalytic amplification of tumor uptake and long persistence of the radioisotope in tumors due to the stability of the peptide/lipid membrane interaction. Thus, RIPs offer an unusual combination of the desirable safety profile characteristic of a low MW RLT with a high tumoral uptake more typical of a large MW TRT. Our initial experience with RIPs labeled with Cu-64/67, Lu-177, or Ac-225 have shown profound antitumor effects at well tolerated doses. Clinical translation of a <sup>64</sup>Cu-labeled RIP targeting human granzyme B is currently underway to assess the safety, pharmacokinetics, and dosimetry of this new drug class.

Maximizing tumor responses to targeted radiotherapies with conditionally activated membrane binding probes

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.