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

The efficacy of antibody-based therapies applied to solid tumors is often limited by the “binding-site barrier” (BSB). Our group has developed anti-idiotypic distribution enhancers (AIDEs), which enhance antibody intra-tumoral distribution and efficacy. This study evaluates 1HE and LG1, model anti-trastuzumab AIDEs, and trastuzumab–PE24, a site-specific conjugated immunotoxin with high potency. Mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to investigate relationships between AIDE binding characteristics and effects on antibody distribution and immunotoxin potency. AIDE coadministration led to negligible negative impacts on overall exposure and pharmacokinetic selectivity. Consistent with prior work demonstrating that AIDEs improve intra-tumoral antibody distribution and anti-cancer efficacy, 1HE and LG1 enhanced the anti-tumor efficacy of trastuzumab-PE in NCI-N87 xenografts. In addition, the PK/PD model predicted that the repeated administration of AIDEs with trastuzumab–PE24 could lead to complete tumor regression. This model prediction implies that the benefits of the AIDE approach increase with the increasing potency of immunotoxins.