Efficacy and pharmacokinetics of EGFR-targeted antibody-drug conjugates following convection-enhanced delivery in mice with glioblastoma xenografts

Purpose: Antibody-drug conjugates (ADCs) provide specific delivery of potent toxins to cancers. Unfortunately, the clinical benefits these powerful therapeutics have not been realized in glioblastoma (GBM). The blood brain barrier (BBB) GBM can limit distribution ADCs into tumor tissue. To bypass BBB, we tested convection enhanced (CED) infusion orthotopic patient derived xenografts. Methods: Two EGFR-targeted with a similar antibody backbone but different were compared: depatuxizumab mafodotin (Depatux-M) has monomethyl auristatin F (MMAF) toxin, which is cell permeant once released, and Losatuxizumab vedotin (ABBV-221) E (MMAE) toxin. Efficacy was evaluated three PDX models amplified/mutant EGFRviii. Bioluminescence imaging survival used evaluate efficacy. MMAE levels quantified using LC-MS/MS, NeuN immunostaining neuronal loss. Results: compared across following treatment Depatux-M ABBV-221 delivered serial CED infusions (21 days apart) or seven intraperitoneal (IP) injections (7 apart). median survivals by group are shown table. For two more mature studies, data demonstrate consistent enhancement (60 mg) (66 as IP injection (5 mg/kg). C57BL6 non-tumor bearing mice at therapeutic dose well tolerated had no impact on NeuN+ density. At much higher concentrations, 740 mg also effect Neu+ density, while 274 resulted marked loss density lethal toxicity 5 days. Following 570 ng free MMAE, toxin relatively stable over four-hour sampling period an AUC 3860 ± 311 h*ng/g infused right hemisphere 2.4 0.6 h*ng/mL plasma. A exposure profile observed 60 for total 3073 635 131 h*ng/g. Surprisingly, high plasma 2924 449 h*ng/mL, below quantitation.Tabled 1TreatmentMedian survival, daysGBM6GBM39GBM108AB095 – CED4920NRAB095-MMAF CED>805818.5Depatux-M IP5768NRDepatux-M CED>80>100NRAB095-MMAE CED5719NRABBV-221 IP53>100NRABBV-221 CED>80>100NR Open table new tab Conclusions: either extend EGFR amplified PDXs. However, concentrations associated increased Depatux-M, suggesting broader window latter ADC. No conflict interest.