Comparative Radioimmunotherapy of Experimental Melanoma with Novel Humanized Antibody to Melanin Labeled with 213Bismuth and 177Lutetium

Abstract

Melanoma is a cancer with increasing incidence and there is a need for alternatives to immunotherapy within effective approaches to treatment of metastatic melanoma. We performed comparative radioimmunotherapy (RIT) of experimental B16-F10 melanoma with novel humanized IgG to melanin h8C3 labeled with a beta emitter, ¹⁷⁷Lu, and an alpha-emitter, ²¹³Bi, as well as biodistribution, microSPECT/CT imaging, and mouse and human dosimetry calculations. microSPECT/CT imaging showed that a humanized antibody that targets "free" melanin in the tumor microenvironment had high tumor uptake in B16F10 murine melanoma in C57Bl/6 mice, with little to no uptake in naturally melanized tissues. Extrapolation of the mouse dosimetry data to an adult human demonstrated that doses delivered to major organs and the whole body by ¹⁷⁷Lu-h8C3 would be approximately two times higher than those delivered by ²¹³Bi-h8C3, while the doses to the tumor would be almost similar. RIT results indicated that ²¹³Bi-h8C3 was more effective in slowing down the tumor growth than ¹⁷⁷Lu-h8C3, while both radiolabeled antibodies did not produce significant hematologic or systemic side effects. We concluded that h8C3 antibody labeled with ²¹³Bi is a promising reagent for translation into a clinical trial in patients with metastatic melanoma.

Keywords: 177Lutetium; 213Bismuth; B16-F10 melanoma; humanized antibody; melanin; radioimmunotherapy.

Figure 1

microSPECT/CT imaging of ¹¹¹In-h8C3 in B16-F10 tumor-bearing mice. The red arrows indicate tumor location. Images presented are presented as maximum intensity projections (MIP) for clarity. Slice imaging of the 24 h time point is shown in Figure S2 to show tumor location more clearly.

Figure 2

Detailed biodistribution of ¹¹¹In-h8C3 in B16-F10 tumor-bearing mice.

Figure 3

Tumor volumes and body weights of B16-F10 melanoma-bearing mice treated with ¹⁷⁷Lu-h8C3 and ²¹³Bi-h8C3. (A) Tumor volume and (B) body weight. Low dose—7.4 MBq; high dose—14.8 MBq. * indicate statistical significance.

Figure 4

Blood chemistry (white blood cells, red blood cells and platelet) of B16-F10 melanoma-bearing mice treated with ¹⁷⁷Lu-h8C3 and ²¹³Bi-h8C3. (A–C)—WBC, RBC and PLT, respectively. Low dose—7.4 MBq; high dose—14.8 MBq. ** indicate statistical significance P = 0.001.