Pre-clinical development of a 188Re-labeled melanin-binding antibody for phase I clinical trial in patients with metastatic melanoma

1388 Objectives: Effective methods of treatment of currently deadly metastatic melanoma are urgently needed. Previously we established the feasibility of targeting melanin in experimental human melanoma with 188-Rhenium (188Re)-labeled 6D2 mAb resulting in tumor regression. We carried out additional pre-clinical development of 188Re-6D2 for use in Phase I clinical trial in patients with metastatic melanoma. Methods: The developmental work included chemistry, pharmacokinetics, efficacy, and acute hematologic toxicity studies in an experimental human melanoma. Results: Tris(2-Carboxyethyl) Phosphine Hydrochloride (TCEP) was tested as potential agent for generation of –SH groups on 6D2 mAb for subsequent radiolabeling with 188Re. TCEP turned out to be both effective in generating a sufficient number of -SH groups on 6D2 mAb to ensure high radiolabeling yields and facile in preserving mAbs structural integrity. 188Re-6D2 cleared from the blood with the half-life of approximately 5 hrs and from the body – with the half-life of 10 hr. Therapy of A2058 melanoma tumor-bearing mice showed that while the lowest dose of 0.15 mCi per mouse had no effect on the tumor progression relative to untreated mice - doses of 0.5, 1.0 and 1.5 mCi significantly (P Conclusions: 188Re-6D2 was immunoreactive and stable over time, cleared fast from the blood and major organs and was therapeutic in experimental human melanoma. Research Support: Pain Therapeutics, Inc. and AECOM Cancer Center.