Transient Inhibition of Trastuzumab–Tumor Binding to Overcome the “Binding-Site Barrier” and Improve the Efficacy of a Trastuzumab–Gelonin Immunotoxin

Abstract

Abstract We have recently shown that coadministration of mAbs with anti-idiotypic distribution enhancers (AIDE) that inhibit mAb binding to tumor antigens enabled increased intratumoral mAb distribution and increased efficacy of an antibody–drug conjugate (trastuzumab emtansine, T-DM1). In this article, a pharmacokinetic/pharmacodynamic (PK/PD) model was applied to predict the impact of this optimization strategy on the within-tumor distribution and antitumor efficacy of trastuzumab–gelonin, where the released payload (gelonin) is expected to exhibit negligible bystander activity. Immunofluorescence histology was used to investigate trastuzumab–gelonin distribution in solid tumors following dosing with or without coadministration of anti-trastuzumab AIDEs. Antitumor efficacy of trastuzumab–gelonin, with or without coadministration of AIDEs, was also evaluated in tumor-bearing mice. Trastuzumab–gelonin efficiently induced cytotoxicity when applied to NCI-N87 cells in culture (IC50: 0.224 ± 0.079 nmol/L). PK/PD simulations predicted that anti-idiotypic single-domain antibodies AIDEs with dissociation rate constants between 0.03 and 0.2 per hour would provide optimal enhancement of trastuzumab–gelonin efficacy. LE8 and 1HE, anti-trastuzumab AIDEs, were selected for evaluation in vivo. Coadministration of trastuzumab–gelonin with the inhibitors increased the portion of tumor area that stained positive for trastuzumab–gelonin by 58% (P = 0.0059). In addition, LE8 or 1HE coadministration improved trastuzumab–gelonin efficacy in NCI-N87 xenograft-bearing mice by increasing the percent increase in life span (%ILS) from 27.8% (for trastuzumab–gelonin administered alone) to 62.5% when administered with LE8 (P = 0.0007) or 83.3% (P = 0.0007) when administered with 1HE. These findings support the hypothesis that transient, competitive inhibition of mAb-tumor binding can improve the intratumoral distribution and efficacy of immunotoxins when applied for treatment of solid tumors.