Dead Cells in Melanoma Tumors Provide Abundant Antigen for Targeted Delivery of Ionizing Radiation by a mAb to Melanin

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 41; pp. 14865 - 14870
• Main Authors: Dadachova, Ekaterina, Nosanchuk, Joshua D., Shi, Li, Schweitzer, Andrew D., Frenkel, Annie, Nosanchuk, Jerome S., Casadevall, Arturo, Scharff, Matthew D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.10.2004; National Acad Sciences
• Subjects: Animals; Antibodies, Monoclonal; Antigens; Antigens, Neoplasm - immunology; Biological Sciences; Cell Death; Cell Line, Tumor; Cells; Dose-Response Relationship, Radiation; Humans; Imaging; Ions; Kidneys; Medical treatment; Melanin; Melanins - immunology; Melanoma; Melanoma - pathology; Melanoma - radiotherapy; Mice; Mice, Nude; Pigments; Radiation; Radiation, Ionizing; Radioimmunotherapy - methods; Radiotherapy; Transplantation, Heterologous; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0406180101

Melanoma is a cancer with a rising incidence, and metastatic disease is almost always lethal. We investigated the feasibility of targeting melanin, an intracellular melanocyte pigment, to deliver cytotoxic radiation to human melanoma cells in vivo by using a melanin-binding mAb (6D2). Nude mice bearing MNT1 pigmented human melanoma tumors were treated with mAb 6D2 labeled with 1.5 mCi (1 Ci = 37 GBq) of the β-emitter 188-Rhenium (188 Re) and manifested inhibition of tumor growth and prolonged survival. mAb 6D2 bound tumor melanin and demonstrated no crossreactivity with normal melanized tissues in black mice. The mechanism of melanin targeting involved Ab binding to extracellular melanin released during tumor cell turnover or to dying cells with permeable membranes. In this approach, the cytotoxic radiation emanating from labeled Ab bound to melanin is presumably delivered by "crossfire" effect to the adjacent viable tumor cells. Our results establish the feasibility of targeting melanin released from dead melanoma cells in tumors with radiolabeled Abs to achieve a therapeutic effect. In contrast to conventional tumor antigens, melanin is insoluble, resistant to degradation, and can be expected to accumulate in targeted tissues, suggesting that the efficacy of therapy could increase with each subsequent treatment cycle.