Melanoma the fastest growing cancer incidence in the world today and the American Cancer Society reports that death rates for melanoma continue to rise. Alarmingly, melanoma is the most common cancer in young adults under 30. One characteristic of metastatic melanoma cells that is recognized as a potential target for new therapies is upregulation of cell-surface receptor melanocortin subtype I (MCR1). However, there are no agents currently available that exploit this identifiable difference between melanoma and normal cells. This proposal is focused on development, validation and commercialization of an automated system for the preparation of [203/212Pb]-labeled peptides that bind with high affinity and specificity to MCR1 for targeted imaging and therapy of metastatic melanoma. Our innovative approach enlists matched-pair isotopes 203Pb/212Pb to enable quantitative dosimetry based on 203Pb-SPECT imaging for 212Pb-alpha-particle therapy. Viewpoint Molecular Targeting, LLC has developed a strong-strategic business-partnerships that are driving our commercialization of diagnostic/therapeutic agents [203Pb]DOTA-VMT-MCR1/[212Pb]DOTA-VMT-MCR1. Matched pair isotopes 203Pb/212Pb is also attractive due to a relatively long half-life (51 h) of 203Pb, which is favorable for centralied manufacturing of radiotracers for their direct shipment to imaging facilities. Our overall objectie is to develop effective image-guided therapy for metastatic melanoma that will improve outcomes for melanoma patients with fewer-milder side effects than current therapies. To achieve these objectives, we propose the following specific aims: 1. Determine the feasibility of an automated cassette- based fluid handling system for clinical manufacturing of 203/212Pb labeled chelator-modified VMT-MCR1; and 2. Determine the feasibility of [203/212Pb]TCMC-VMT-MCR1 and [203/212Pb]C2N2-VMT-MCR1 for molecular imaging and radionuclide therapy for metastatic melanoma. With success in our Aims, we expect to determine the feasibility of an automated system to produce high specific activity 203/212Pb VMT-MCR1 under Aim 1. We further expect to have determined the feasibility of three VMT-MCR1 compositions to advance to clinical imaging trials via an eIND under Aim 2. We expect these successes to have the positive impact of advancing VMT-MCR1 through initial commercial risk-mitigating milestones to a first in humans imaging trial with 203Pb VMT-MCR1. We expect this to lead to 212Pb VMT-MCR1 therapy, which has the potential to circumvent drug resistance that limits the effectiveness of current treatments for metastatic melanoma.
This proposal is aimed to establish the feasibility of a novel automated system for the preparation of 203Pb and 212Pb - labeled peptide conjugates for clinical imaging and image guided therapy of metastatic melanoma. No other agents are available that are based on this approach for metastatic melanoma imaging and therapy.
| Li, Mengshi; Zhang, Xiuli; Quinn, Thomas P et al. (2017) Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer. Appl Radiat Isot 127:52-60 |
