Antibody-Drug Conjugates as Radiopharmaceutical Theranostics for Cancer

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 months Phase II: up to $2,250,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Antibody-drug conjugates (ADCs) are a new class of targeted drugs consisting of monoclonal antibodies (mAbs) chemically linked to cytotoxic drugs (payload). However, there are inherent limitations of ADCs: (i) acquired cancer resistance to the ADC's payload; (ii) heterogeneity of target expression; and (iii) ineffective intracellular trafficking of the payload. These limitations can be circumvented by loading ADCs with diagnostic and therapeutic radionuclides. First, diagnostic radionuclides emitting gamma radiation (e.g., Flourine-18 or Technetium-99m) detectable by positron Page 95 emission tomography (PET) or single-photon emission tomography (SPECT) will allow monitoring of the pharmacokinetics and biodistribution of ADCs. This will help select patients with tumors expressing adequate numbers of targeted antigens for effective treatment. Compared to current immunohistochemistry approaches for patient selection, the radiopharmaceutical approach has the advantage that it allows whole body imaging of target antigen expression on metastases. Second, therapeutic radionuclides emitting cytotoxic beta (e.g., Lutetium-177) or alpha particles (e.g., Lead-212) will increase the therapeutic potential of ADCs in patients pre-selected based on radiopharmaceutical imaging. This will add a second therapeutic agent of radiation in addition to the chemical therapeutic already present, with independent mechanisms of action. Development of resistance to both therapeutics will be less likely than resistance to one, and neighboring tumor cells that do not express the targeted antigens can still be eliminated by radiation over distances of several cell-diameters (alphaparticles) to a few millimeters (beta particles) by a crossfire killing effect. Taken together, conjugating radionuclides to ADCs to reconfigure them as radiopharmaceuticals represents a new theranostic treatment strategy for diagnostic imagingbased patient selection followed by two-armed (chemical- and radiation-based) therapy.