Novel Igg To Melanin Is A Promising Reagent For Radioimmunotherapy Of Metastatic Melanoma With Superior Performance Over Immunotherapy

Despite several novel drugs for metastatic melanoma entering the market in the last few years, there is an enormous need for effective treatments that would not rely on patients’ specific genotypes, biochemical pathways, microbiomes or the variability of one’s immune system. Earlier we have conducted a successful Phase 1 Clinical trial in patients with metastatic melanoma of a murine antibody to melanin radiolabeled with beta emitter 188Rhenium (188Re). The trial demonstrated safety and was indicative of the efficacy targeting melanin with radiolabeled antibodies (1). However, the IgM isotype of the first generation antibody presented an impediment for its humanization and further clinical development. Recently, we identified an 8C3 murine antibody to melanin with IgG isotype which is amenable to humanization. The goal of this study was to evaluate the possibility of radiolabeling this new antibody with 188Re and alpha emitter 213Bismuth (213Bi), to assess its potential as a radioimmunotherapy (RIT) reagent for metastatic melanoma and to compare with the standard of care – an immune checkpoint inhibitor. Female C57Bl6 mice were injected with highly aggressive B16-F10 murine melanoma cells via tail vain to form metastases like lesions in the lungs. 8C8 was radiolabeled with 188Re or 213Bi “directly’ or via CHXA”-DTPA chelating agent, respectively. On day 4 after cells injections the groups of 5-7 mice were treated with either unlabeled 8C3 antibody, or 400 μCi 188Re-8C3 or 400 μCi 213Bi-8C3 mAb, or left untreated. On day 14 after cells injection the mice were sacrificed, their lungs removed and metastases-like lesions enumerated. In a separate series of experiments, mice given B16-F10 melanoma cells were treated with 3 consecutive doses of anti-murine CTLA4 mAb 9D9, or 150 μCi 213Bi-8C3, or combination of 9D9 and 150 μCi 213Bi-8C3, or left untreated. The number of melanoma lesions in the lungs was evaluated on Day 14 post cellular injection. There was statistically significant (P = 0.01) reduction of metastases-like lesions in the lungs of mice treated with either 400 μCi 188Re-8C3 or 400 μCi 213Bi-8C3 mAb in comparison with the untreated controls. The unlabeled 8C3 mAb did not have any effect on the number of the lesions. Direct comparison of an anti-CTLA4 mAb to RIT in C57Bl6 mice showed that RIT was much more effective in eliminating lung lesions than immunotherapy alone, and when the combination of RIT and immunotherapy was applied – the effect on the lesions came primarily from RIT. The 8C3, a second generation IgG to melanin, demonstrated impressive results in decreasing melanoma lung lesions in an aggressive murine melanoma. This novel molecular targeted systemic radiation therapy was not accompanied by any undesirable side effects. We conclude that 8C3 is a promising agent for development into a clinical RIT reagent for patients with metastatic melanoma refractory to standard of care checkpoint blockade immunotherapy and BRAF/MEK targeted drug treatment.