Radioimmunotherapy of experimental human metastatic melanoma with melanin-binding antibodies and in combination with dacarbazine.
OBJECTIVE
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.


METHODS
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.
Revskaya
Ekaterina
E
Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Jongco
Artemio M
AM
Sellers
Rani S
RS
Howell
Robertha C
RC
Koba
Wade
W
Guimaraes
Allan J
AJ
Nosanchuk
Joshua D
JD
Casadevall
Arturo
A
Dadachova
Ekaterina
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008543:Melanins / Q000032:analysis / Q000276:immunology*; D008545:Melanoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds / Q000276:immunology / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D016499:Radioimmunotherapy; D012878:Skin Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*
D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; D008543:Melanins; D009942:Organometallic Compounds; D003606:Dacarbazine