Assessment of the Effects of Single-Domain Anti-Idiotypic Distribution Enhancers on the Disposition of Trastuzumab and on the Efficacy of a PE24-Trastuzumab Immunotoxin

Antibody-based therapies often exhibit limited distribution within solid tumors due to the "binding-site barrier" (BSB). Our group has developed and validated the use of anti-idiotypic distribution enhancers (AIDEs), which transiently block antibody binding, improving intra-tumoral distribution and efficacy. This study evaluated 1HE and LG1, model anti-trastuzumab AIDEs, in combination with trastuzumab-PE24, a highly potent immunotoxin. The effects of 1HE on the whole-body disposition of radiolabeled trastuzumab were assessed in NCI-N87 tumor-bearing mice. Mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling was employed to explore how AIDE binding kinetics influence antibody intra-tumoral distribution and immunotoxin potency. Trastuzumab-PE24 was developed by site-specific conjugation, enabled by self-splicing split intein, with cytotoxicity tested on various cell lines in vitro. The impact of 1HE and LG1 coadministration on trastuzumab-PE24 efficacy was evaluated in NCI-N87 xenograft-bearing mice. 1HE coadministration decreased trastuzumab tumor maximum concentration, reducing tumor terminal slope by 8% and overall tumor exposure by 2.6%, without negatively affecting selectivity. Modeling predicted the optimal AIDE dissociation rate constant for trastuzumab-PE24 to be between 0.015 and 0.3 h-1. The coadministration of trastuzumab-PE24 with 1HE and LG1 improved anti-tumor efficacy and extended median survival to 60 days (p = 0.0002). AIDE coadministration led to minimal negative impacts on overall tumor exposure, consistent with model simulations. AIDE coadministration improved the efficacy of trastuzumab-PE24 in NCI-N87 xenografts. Modeling further predicted that repeated AIDE administration with trastuzumab-PE24 could induce complete tumor regression. These findings highlight the advantages of the AIDE strategy, particularly when coadministered with highly potent immunotoxins.