The use of pharmacokinetic and pharmacodynamic data to optimize the dose and schedule of an EphA2 antibody drug conjugate in-vivo

B61 The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously demonstrated that the EphA2 on tumor cells can be targeted by monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. Monoclonal antibodies that selectively bind and internalize into tumor cells provide a vehicle for targeted delivery of cytotoxics. Thus, antibody-drug conjugates (ADC) increase the therapeutic index of the attached cytotoxics by reducing systemic toxicity and enhancing tumor targeting and efficacy. Here we explore the relationship between the pharmacokinetics of the EphA2 ADC, the pharmacodynamics of EphA2 in the prostate tumor (PC3) and tumor efficacy.
 The EphA2 ADC has a serum half life of approximately 50 hours and a tumor half life of approximately 60 hours. The tumor exposures were approximately dose proportional while the serum exposures were not.
 Following treatment with the EphA2 ADC, the EphA2 receptor is degraded in a time and dose dependent manner. We used this observation as our pharmacodynamic marker. A single dose of the EphA2 ADC at the 1, 5 and 10 mg/kg dose levels resulted in rapid and prolonged degradation of the EphA2 receptor in a PC3 tumor xenograft model, which began one hour post dose and lasted for at least six days at the higher doses. The 10 mg/kg dose of the EphA2 ADC did not result enhanced degradation of EphA2, thus setting our dosing limits between 1 and 5 mg/kg.
 We show that once/week administration of the EphA2 ADC gave comparable efficacy to a twice/week dosing schedule in the PC3 tumor model. In conclusion we report that the use of pharmacokinetic and pharmacodynamic data can provide guidance in the planning of tumor efficacy studies using the EphA2 ADC.