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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., (© 2017 S. Karger AG, Basel.)

We investigated the capacity of two glial tumor cell lines (CxT24neo3 and CxT3Cl5) to invade through reconstituted basement membrane (Matrigel, MG). The purpose of our experiments was to establish whether the number of cells or the mode of malignant progression would quantitatively modify the invasion of a brain tumor cell population. To accomplish this goal, we used a vital-dye method to assess the fraction of cells that invaded through 30 micrograms MG coated on a polycarbonate filter (8 microns pore size). Our experiments demonstrated that the fraction of invasive CxT24neo3 and CxT3Cl5 cells in vitro reproducibly differed as a function of the number of initially seeded cells. This showed that invasion through MG was subject to quantitative changes caused by the number of cells present. Since CxT24neo3 and CxT3Cl5 became malignant by transfection with different oncogenes, the results also indicated that the type of quantitative change was influenced by the mode of malignant progression.

We have implanted MO4 transformed mouse cells attached to a collagen matrix (artificial tumor) under the renal capsule of syngeneic mice. It was our purpose to evaluate whether or not the kidney invasion test (KIT) could be used for the determination in vivo of the invasive capacity of cultured cell populations. Invasion was expressed in terms of the proportion of the depth of the invasive part of the tumor to the total tumor thickness (invasion rate), both measured macroscopically after hemisection of the kidney. Macroscopic findings were confirmed by histology. For MO4 cells the invasion index changed in function of time after implantation. The relationship 'invasion index versus time after implantation' was demonstrated to be constant in 3 independent groups of mice. Therefore, we propose determination of the invasion rate versus time in the KIT as a method to compare the invasive capacity in vivo of different cell lines.