TY - JOUR
T1 - Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin
AU - Dadachova, Ekaterina
AU - Nosanchuk, Joshua D.
AU - Shi, Li
AU - Schweitzer, Andrew D.
AU - Frenkel, Annie
AU - Nosanchuk, Jerome S.
AU - Casadevall, Arturo
PY - 2004/10/12
Y1 - 2004/10/12
N2 - 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 (188Re) 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.
AB - 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 (188Re) 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.
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U2 - 10.1073/pnas.0406180101
DO - 10.1073/pnas.0406180101
M3 - Article
C2 - 15469923
AN - SCOPUS:6944253583
SN - 0027-8424
VL - 101
SP - 14865
EP - 14870
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 41
ER -