Abstract
Metastatic melanoma remains difficult to treat despite recent approvals of several new drugs. Recently we reported encouraging results of Phase I clinical trial of radiolabeled with 188Re murine monoclonal IgM 6D2 to melanin in patients with Stage III/IV melanoma. Subsequently we generated a novel murine IgG 8C3 to melanin. IgGs are more amenable to humanization and cGMP (current Good Manufacturing Practice) manufacturing than IgMs. We performed comparative structural analysis of melanin-binding IgM 6D2 and IgG 8C3. The therapeutic efficacy of 213Bi- and 188Re-labeled 8C3 and its comparison with anti-CTLA4 immunotherapy was performed in B16-F10 murine melanoma model. The primary structures of these antibodies revealed significant homology, with the CDRs containing a high percentage of positively charged amino acids. The 8C3 model has a negatively charged binding surface and significant number of aromatic residues in its H3 domain, suggesting that hydrophobic interactions contribute to the antibody-melanin interaction. Radiolabeled IgG 8C3 showed significant therapeutic efficacy in murine melanoma, safety towards healthy melanin-containing tissues and favorable comparison with the anti-CTLA4 antibody. We have demonstrated that antibody binding to melanin relies on both charge and hydrophobic interactions while the in vivo data supports further development of 8C3 IgG as radioimmunotherapy reagent for metastatic melanoma.
Highlights
Melanoma is a cancer with increasing incidence and is anticipated to affect roughly 73,380 new patients in the United States in 2016 and over 10,130 expected deaths this year[1]
In our search for new treatments for metastatic melanoma that would not rely on specific genotypes, biochemical pathways or the variability of an individual’s immune response, we turned to radioimmunotherapy (RIT) targeting melanin
The complementarity determining regions (CDRs) of both monoclonal antibody (mAb) contain high percentage of positively charged amino acids (Fig. 1). This finding suggests that these V regions were selected in part by negative charges on the fungal melanin molecules[28,29] and that electrostatic attractions contribute significantly to the binding of the mAbs to melanin
Summary
Melanoma is a cancer with increasing incidence and is anticipated to affect roughly 73,380 new patients in the United States in 2016 and over 10,130 expected deaths this year[1]. Melanin was not considered a target for RIT because it is an intracellular pigment contained in organelles called melanosomes, and assumed not to be accessible to Ab. melanomas are rapidly growing tumors with high rates of cellular turnover and cell necrosis releases melanin into the extracellular space, where it is accessible to radiolabeled mAbs to melanin. Melanomas are rapidly growing tumors with high rates of cellular turnover and cell necrosis releases melanin into the extracellular space, where it is accessible to radiolabeled mAbs to melanin Such antibodies deliver cytotoxic radiation to nearby malignant cells via the so called “cross-fire” effect. The IgMs are difficult to produce under the cGMP (current Good Manufacturing Practice) conditions, to purify and to radiolabel For this reason, the continuous development of RIT targeting melanin towards the clinical product calls for IgG isotype. We report the results of the comparative structural investigation of the novel 8C3 IgG and the previous generation 6D2 IgM and 8C3 evaluation as a potential RIT agent in aggressive murine melanoma
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