To demonstrate the utility of the competitive inhibition approach for immunotoxins, PK parameters specific for a recombinant immunotoxin were incorporated into the model structure. 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 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. 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.
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. Our group has developed and experimentally validated a strategy to increase antibody penetration in solid tumors through transient inhibition of antibody-antigen binding.