Radioimmunotherapy of Experimental Human Metastatic Melanoma with Melanin-Binding Antibodies and in Combination with Dacarbazine

• Published in: Clinical cancer research Vol. 15; no. 7; pp. 2373 - 2379
• Main Authors: REVSKAYA, Ekaterina, JONGCO, Artemio M, SELLERS, Rani S, HOWELL, Robertha C, KOBA, Wade, GUIMARAES, Allan J, NOSANCHUK, Joshua D, CASADEVALL, Arturo, DADACHOVA, Ekaterina
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2009
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Antineoplastic Agents, Alkylating - therapeutic use; Biological and medical sciences; Cell Line, Tumor; chemotherapy; combination therapy; Combined Modality Therapy; Dacarbazine - therapeutic use; Dermatology; Female; Humans; Medical sciences; melanin; Melanins - analysis; Melanins - immunology; Melanoma - drug therapy; Melanoma - radiotherapy; Melanoma - therapy; metastatic melanoma; Mice; Mice, Nude; Neoplasm Metastasis; Organometallic Compounds - immunology; Organometallic Compounds - therapeutic use; Pharmacology. Drug treatments; Positron-Emission Tomography; Radioimmunotherapy; Skin Neoplasms - drug therapy; Skin Neoplasms - radiotherapy; Skin Neoplasms - therapy; Tumors of the skin and soft tissue. Premalignant lesions; Antineoplastic agent; Human; Drug combination; Antibody; Malignant tumor; Metastasis; Radiotherapy; Dacarbazine; Alkylating agent; Treatment; Malignant melanoma; Immunoradiotherapy; Advanced stage; Melanin; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-2376

Purpose: Melanin has emerged as an attractive target for radioimmunotherapy (RIT) of melanoma, and a radiolabeled monoclonal antibody (mAb) 6D2 to melanin is currently in clinical evaluation. We investigated two approaches to improve the targeting of radiation to tumors using melanin-binding mAbs: ( a ) the use of an additional mAb to melanin could provide information on whether using antibodies to melanin can serve as a general approach to development of therapeutics for melanoma, and ( b ) as melanin targeting involves the antibody binding to extracellular melanin released from necrotic melanoma cells, we hypothesized that the administration of a chemotherapeutic agent followed by RIT would facilitate the delivery of radiation to the tumors due to the increased presence of free melanin. Experimental Design: We evaluated the therapeutic efficacy of two melanin-binding IgM mAbs labeled with 188 Re (6D2 and 11B11). We compared the efficacy of RIT with 188 Re-6D2 to chemotherapy with dacarbazine (DTIC) and to combined chemotherapy and RIT in human metastatic melanoma-bearing nude mice. Results: Therapeutic efficacy of 188 Re-labeled 6D2 and 11B11 was comparable despite differences in their affinity and binding site numbers. Comparison of chemotherapy with DTIC and RIT revealed that RIT was more effective in slowing tumor growth in mice. Administration of DTIC followed by RIT was more effective than either modality alone. Conclusions: These results provide encouragement for the development of RIT for melanoma with melanin-binding mAbs and suggest that combining chemotherapy and RIT may be a promising approach for the treatment of metastatic melanoma.