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Supplementary Material for: A “Prozone-Like” Effect Influences the Efficacy of the Monoclonal Antibody ABT-700 against the Hepatocyte Growth Factor Receptor

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posted on 25.07.2017 by Vaidya K.S., Oleksijew A., Tucker L.A., Pappano W.N., Anderson M.G., Grinnell C.M., Zhang Q., Heighton S.J., Mitten M.J., Mishra S., Palma J.P., Wang J., Reilly E.B., Boghaert E.R.

ABT-700 is a therapeutic antibody against the hepatocyte growth factor receptor (MET). At doses or regimens that lead to exposures exceeding optimum in vivo, the efficacy of ABT-700 is unexpectedly reduced. We hypothesized that this reduction in efficacy was due to a “prozone-like” effect in vivo. A prozone-like effect, which is a reduction in efficacy beyond optimum exposure, is caused due a mechanism similar to the generation of false negative flocculation tests by excessive antibody titres. In vitro, we demonstrate that at higher ABT-700 concentrations, this “prozone-like” effect is mediated by a progressive conversion from bivalent to ineffective monovalent binding of the antibody. In vivo, the efficacy of ABT-700 is dependent on an optimum range of exposure as well. Our data suggest that the “prozone-like” effect is operative and independent of target expression. ABT-700 dose, regimen, exposure, and tumor burden are interdependent variables influencing the “prozone-like” effect and mediating and in vivo efficacy. By optimization of dosage and regimen we demonstrate that the “prozone-like” effect can be alleviated and ABT-700 efficacy at varying tumor loads can be further extended in combination with cisplatin. Our results suggest that optimization of exposure taking tumor burden into account may alleviate “prozone-like” effects without compromising efficacy.

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