Research Project
9680950
The melanocortin 1 receptor (MC1R) is over-expressed on uveal and cutaneous melanoma cells, but not in healthy normal tissues. We have developed a proprietary ligand, MTI-201, that binds to MC1R in melanoma cells with high affinity and specificity. Through our SBIR Phase I contract, we demonstrated that MC1R targeted 225Ac-DOTA-MTI-201 lacks of overt toxicity at single doses that produce significant efficacy against uveal and cutaneous melanoma in vivo using xenograft mouse models. Biodistribution, radiodosimetry, and PK studies also show rapid blood clearance with predominant distribution to the targeted tumor or to clearance organs with no organ specific pathology. We are currently executing a funded Phase II SBIR effort to complete a Phase I dose escalation clinical trial of 225Ac-DOTA-MTI- 201 in metastatic uveal melanoma patients that will focus on safety and initial tumor response. Looking ahead, it is critical for subsequent clinical evaluations of 225Ac-DOTA-MTI-201 to develop an analogous MC1R selective imaging agent to assist with patient selection and to confirm expression of target after the initial treatment to assist in the design of multiple dose trials. Such an agent may eventually serve as a companion diagnostic for 225Ac-DOTA-MTI-201 or other therapies that target MC1R. There is no available Actinium radioisotope that provides predominant gamma or positron emission that can perfectly mimic 225Ac-DOTA-MTI-201, but there are several plus three metal ion radioisotopes that similarly bind DOTA that should perform well as SPECT or PET imaging agents. The 111In, 67Ga and 68Ga analogs should mimic the overall PK of the radiotherapeutic. Herein, we pursue 67Ga analogs in our initial studies because its longer radiodecay half-life better mimics the expected biological half-life of 225Ac. If our initial Phase I studies support the use of 67Ga-DOTA-MTI-201 as an acceptable companion imaging agent, then we can further pursue development of the 67Ga- DOTA-MTI-201 as a SPECT imaging agent or we can consider the development of the 68Ga-MTI-201 as a PET imaging agent in follow-on Phase II SBIR funded studies. In addition, an imaging probe analogous to 225Ac-DOTA-MTI-201 might be used to estimate 225Ac-DOTA-MTI-201 radiation dose in patients. This proposal addresses the initial translational work required to confirm 67Ga-DOTA-MTI-201 as an MC1R imaging agent and potential companion diagnostic to support future 225Ac-DOTA-MTI-201 trials. Specific aims include optimization of 67Ga-DOTA-MTI-201 synthesis and measurement of 67Ga-DOTA-MTI-201 pharmacokinetics (PK), tumor to tissue ratios, mechanism of uptake and dosimetry in preclinical melanoma models. If successful, subsequent funding will be sought to complete the translational work and to submit an IND for phase 1 clinical imaging trials.
