Computational model predicts effective delivery of 188-Re-labeled melanin-binding antibody to metastatic melanoma tumors with wide range of melanin concentrations

Abstract

Metastatic melanoma is almost always deadly and new methods of treatment are urgently needed. Recently, we established the feasibility of radioimmunotherapy (RIT) for experimental melanoma in mice using a 188-rhenium (188Re)-labeled monoclonal antibody (mAb) 6D2 (IgM) to melanin. Our objective was to determine the effects of varying tumor melanin concentration and of different diffusivities and lymphatic clearance rates of the normal tissue, on the absorbed dose to the tumor in simulated therapy, in preparation for a clinical trial of RIT for melanoma. Using finite element analysis (FEA), we created a pharmacokinetic model that describes melanin-targeting RIT of a melanoma micrometastasis (1.3-mm radius) imbedded in normal tissue (14.3-mm radius). Our method incorporates antibody plasma kinetics, transcapillary transport, interstitial diffusion, and lymphatic clearance. Michaelis-Menten kinetics was used to model mAb binding to tumor melanin for melanin concentrations of 76, 7.6, 0.76, 0.076, and 0.0076 micromol/l. An absorbed dose was calculated, after accounting for direct and crossfire irradiation, on the basis of a 7.4-GBq intravenous dose of 188Re-6D2. The results showed that penetration of mAb into the tumor was inversely proportional to tumor melanin concentration. Decreased diffusivity and increased lymphatic clearance of the surrounding normal tissue decreased the dose to the tumor. The formation of mAb-melanin complex was remarkably similar within a 1000-fold range of melanin concentration, resulting in total doses of 2840, 2820, 2710, and 1990 cGy being delivered to tumors with melanin concentrations of 76, 7.6, 0.76, and 0.076 micromol/l, respectively. In conclusion, RIT of metastatic melanoma can be effective over a wide range of tumor melanin concentrations. The results can be useful in the design of a clinical trial of melanin-targeting RIT in patients with metastatic melanoma.