Our group has developed and experimentally validated a strategy to increase antibody penetration in solid
tumors through transient inhibition of antibody-
antigen binding. In prior work, we demonstrated that 1HE, an anti-
trastuzumab single domain antibody that transiently inhibits
trastuzumab binding to HER2, increased the penetration of
trastuzumab and increased the efficacy of
ado-trastuzumab emtansine (T-DM1) in HER2+ xenograft bearing mice. In the present work, 1HE variants were developed using random mutagenesis and phage display to enable optimization of
tumor penetration and efficacy of
trastuzumab-based
therapeutics. To guide the rational selection of a particular 1HE mutant for a specific
trastuzumab-
therapy, we developed a mechanistic pharmacokinetic (PK) model to predict within-
tumor exposure of
trastuzumab/T-DM1. A pharmacodynamic (PD) component was added to the model to predict the relationship between intratumor exposure to T-DM1 and the corresponding
therapeutic effect in HER2+ xenografts. To demonstrate the utility of the competitive inhibition approach for
immunotoxins, PK parameters specific for a recombinant
immunotoxin were incorporated into the model structure. Dissociation half-lives for variants ranged from 1.1 h (for variant LG11) to 107.9 h (for variant HE10). Simulations predicted that 1HE co-administration can increase the
tumor penetration of T-DM1, with inhibitors with longer
trastuzumab binding half-lives relative to 1HE (15.5 h) further increasing T-DM1 penetration at the expense of total
tumor uptake of T-DM1. The PK/PD model accurately predicted the response of NCI-N87 xenografts to treatment with T-DM1 or T-DM1 co-administered with 1HE. Model predictions indicate that the 1HE mutant HF9, with a
trastuzumab binding half-life of 51.1 h, would be the optimal inhibitor for increasing T-DM1 efficacy with a modest extension in the median survival time relative to T-DM1 with 1HE. Model simulations predict that LG11 co-administration will dramatically increase
immunotoxin penetration within all
tumor regions. We expect that the mechanistic model structure and the wide range of inhibitors developed in this work will enable optimization of
trastuzumab-
cytotoxin penetration and efficacy in solid
tumors.