Single Chelator-Minibody Conjugate for PET and Therapy Radionuclides

Abstract The overall goal of this SBIR is to develop an innovative theranostic agent for imaging and treatment of cancer, by combining PET imaging and targeted radionuclide therapy (TRT) agents via a single chelator-minibody conjugate precursor. The novel theranostic agent described here employs a chelator, Lumi804, that can quickly and stably chelate the most widely used positron emitter for antibodies (Zr-89) and the most widely used therapeutic beta-emitting radionuclide (Lu-177), and an alpha emitting isotope (Th-227) currently undergoing clinical evaluation in multiple phase I efficacy trials. To our knowledge, there are no chelator-antibody or chelator-minibody conjugates that are in human trials or used clinically that can be labeled with both Zr-89 (PET imaging) and Lu-177 (TRT) quickly at room temperature. Small molecule peptide analogues based on a dipeptide urea motif such as F-18-PSMA-1007 or Ga-68-PSMA-11 have recently improved imaging of prostate cancer, and analogues such as Lu-177-PSMA-617 and Ac-225-PSMA-617 are showing significant efficacy in patients. However, patients treated with Lu-177-PSMA-617 often recur, and salvage therapy with Ac-225-PSMA- 617, while effective, is limited due to salivary gland toxicity. Use of radiolabeled antibodies has been shown to avoid salivary gland localization, but can lead to bone marrow suppression due to the longer biological half-life of antibodies. The Zr-89-DFO-IAB2M minibody has been evaluated in Phase I clinical study and found to display low salivary gland localization while exhibiting a biological half-life that is much shorter than the corresponding Zr-89-DFO-J591 antibody conjugate. The proposed research in this SBIR Phase I project will develop the synthesis and evaluate the performance of a novel Zr-89, Lu-177, and Th-227 labeled anti- prostate specific membrane antigen (PSMA) intact minibody construct, leveraging a single chelator suitable for all three radiometals, for lesion detection, treatment, and monitoring patient response to radionuclide therapy. These studies will enable the development in Phase II of the first theranostic agent to target positron, beta particle, and alpha particle radiation to PSMA expressing tumors.Narrative Small molecule peptide analogue radiopharmaceuticals have recently improved imaging of prostate cancer, and are showing significant efficacy in patients. However, patients often recur, and salvage therapy is limited due to salivary gland toxicity. The proposed research in this SBIR Phase I project will develop the synthesis and evaluate the performance of a novel Zr-89, Lu- 177, and Th-227 labeled anti-prostate specific membrane antigen (PSMA) intact minibody theranostic agent that will minimize bone marrow suppression and salivary gland toxicity.