166Ho and 90Y labeled 6D2 monoclonal antibody for targeted radiotherapy of melanoma: comparison with 188Re radiolabel

Abstract

Introduction: An approach to radioimmunotherapy (RIT) of metastatic melanoma is the targeting of melanin pigment with monoclonal antibodies (mAbs) to melanin radiolabeled with therapeutic radionuclides. The proof of principle experiments were performed using a melanin-binding antibody 6D2 of IgM isotype radiolabeled with a β emitter (188)Re and demonstrated the inhibition of tumor growth. In this study we investigated the efficacy of 6D2 antibody radiolabeled with two other longer lived β emitters (90)Y and (166)Ho in treatment of experimental melanoma, with the objective to find a possible correlation between the efficacy and half-life of the radioisotopes which possess high energy β (E(max)>1.5 MeV) emission properties.

Methods: 6D2 was radiolabeled with longer lived β emitters (90)Y and (166)Ho in treatment of experimental melanoma in A2058 melanoma tumor-bearing nude mice. The immunoreactivity of the radiolabeled 6D2 mAb, its in vitro binding to the MNT1 human melanoma cells, the biodistribution and therapy in A2058 human melanoma bearing nude mice as well as dosimetry calculations were performed.

Results: When labeled with the longer lived (90)Y radionuclide, the 6D2 mAb did not produce any therapeutic effect in tumor bearing mice while the reduction of the tumor growth by (166)Ho-6D2 was very similar to the previously reported therapy results for (188)Re-6D2. In addition, (166)Ho-labeled mAb produced the therapeutic effect on the tumor without any toxic effects while the administration of the (90)Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect.

Conclusions: (166)Ho-labeled mAb to melanin produced some therapeutic effect on the tumor without any toxic effects while the administration of the (90)Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. We concluded that the serum half-life of the 6D2 carrier antibody matched well the physical half-life of (166)Ho to deliver the tumoricidal absorbed dose to the tumor. Further investigation of this radionuclide for RIT of melanoma is warranted.

Keywords: Antibody; Melanoma; Radioisotopes; Radiotherapy.

Figure 1

Immunoreactivity of complex CHX-A″ DTPA -6D2 antibody as a function of varying the initial ratios of CHX-A″ DTPA to 6D2 antibody.

Figure 2

¹⁶⁶Ho- CHX-A″ DTPA -6D2 antibody serum stability at 0 and 12 hrs. The ¹⁶⁶Ho-CHX”ADTPA-6D2 mAb elutes at 7.8 min.

Figure 3

In vitro binding of ¹⁶⁶Ho- CHX-A″ DTPA -6D2 to MNT1 human melanoma cells. The blocked MNT1 samples were incubated with 6D2 antibody prior to incubation with ¹⁶⁶Ho- CHX-A″ DTPA -6D2.

Figure 4

Therapy of A2058 tumor bearing mice with ¹⁶⁶Ho- CHX-A″ DTPA -6D2 and ⁹⁰Y- CHX-A″ DTPA 6D2. The ¹⁸⁸Re-6D2 therapy data from is also included into the graph for comparative purposes.