A Theranostic Approach to Imaging and Treating Melanoma with 203Pb/212Pb-Labeled Antibody Targeting Melanin

Abstract

Metastatic melanoma is a deadly disease that claims thousands of lives each year despite the introduction of several immunotherapeutic agents into the clinic over the past decade, inspiring the development of novel therapeutics and the exploration of combination therapies. Our investigations target melanin pigment with melanin-specific radiolabeled antibodies as a strategy to treat metastatic melanoma. In this study, a theranostic approach was applied by first labeling a chimeric antibody targeting melanin, c8C3, with the SPECT radionuclide 203Pb for microSPECT/CT imaging of C57Bl6 mice bearing B16-F10 melanoma tumors. Imaging was followed by radioimmunotherapy (RIT), whereby the c8C3 antibody is radiolabeled with a 212Pb/212Bi “in vivo generator”, which emits cytotoxic alpha particles. Using microSPECT/CT, we collected sequential images of B16-F10 murine tumors to investigate antibody biodistribution. Treatment with the 212Pb/212Bi-labeled c8C3 antibody demonstrated a dose-response in tumor growth rate in the 5–10 µCi dose range when compared to the untreated and radiolabeled control antibody and a significant prolongation in survival. No hematologic or systemic toxicity of the treatment was observed. However, administration of higher doses resulted in a biphasic tumor dose response, with the efficacy of treatment decreasing when the administered doses exceeded 10 µCi. These results underline the need for more pre-clinical investigation of targeting melanin with 212Pb-labeled antibodies before the clinical utility of such an approach can be assessed.

Theranostic Imaging Surrogates for Targeted Alpha Therapy: Progress in Production, Purification, and Applications

“…Phantom imaging of 203 Pb has been performed, with imaging spatial-resolution results comparable to 99m Tc for 1.6-4.8 mm diameter fillable rod regions [72]. In vivo preclinical and clinical SPECT imaging of uncomplexed and chelated 203 Pb has been performed [71,73]. Studies have included 203/212 Pb-labeled PSMA and gastrin-releasing peptide receptortargeting agents for imaging and radiotherapy of prostate-cancer-bearing mice [60,61,74,75], and 203/212 Pb-labeled anti-melanin antibodies and melanocortin subtype 1 receptor targeting ligands for imaging and therapy of melanoma-bearing mice [59,72,73,[76][77][78][79].…”

“…In vivo preclinical and clinical SPECT imaging of uncomplexed and chelated 203 Pb has been performed [71,73]. Studies have included 203/212 Pb-labeled PSMA and gastrin-releasing peptide receptortargeting agents for imaging and radiotherapy of prostate-cancer-bearing mice [60,61,74,75], and 203/212 Pb-labeled anti-melanin antibodies and melanocortin subtype 1 receptor targeting ligands for imaging and therapy of melanoma-bearing mice [59,72,73,[76][77][78][79]. As shown in Figure 4, a PSMA-targeting 203 Pb agent, [ 203 Pb]Pb-CA012, exhibited a comparable biodistribution to [ 177 Lu]Lu-PSMA 617 with high tumor uptake relative to other tissues [74].…”