We have recently shown that co-administration of monoclonal antibodies (mAb) with anti-idiotypic distribution enhancers (AIDEs) that inhibit mAb binding to tumor antigens enabled increased intra-tumoral mAb distribution and increased efficacy of an antibody-drug conjugate (trastuzumab emtansine, T-DM1). In the present work, a PK/PD model was applied to predict the impact of this optimization strategy on the within-tumor distribution and anti-tumor 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 co-administration of anti-trastuzumab AIDEs. Anti-tumor efficacy of trastuzumab-gelonin, with or without co-administration 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 nM). PK/PD simulations predicted that anti-idiotypic single-domain antibodies AIDEs with dissociation rate constants between 0.03-0.2 hour-1 would provide optimal enhancement of trastuzumab-gelonin efficacy. LE8 and 1HE, anti-trastuzumab AIDEs, were selected for evaluation in vivo. Co-administration of trastuzumab-gelonin with the inhibitors increased the portion of tumor area that stained positive for trastuzumab-gelonin by 58% (p=0.0059). Additionally, LE8 or 1HE co-administration 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 intra-tumoral distribution and efficacy of immunotoxins when applied for treatment of solid tumors.

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