Heterogeneous Delivery Across the Blood-Brain Barrier Limits the Efficacy of an EGFR-Targeting Antibody Drug Conjugate in Glioblastoma

Citation:

Marin B-M, Porath KA, Jain S, Kim M, Conage-Pough JE, Oh J-H, Miller CL, Talele S, Kitange GJ, Tian S, et al. Heterogeneous Delivery Across the Blood-Brain Barrier Limits the Efficacy of an EGFR-Targeting Antibody Drug Conjugate in Glioblastoma. Neuro Oncol. 2021;23 (12) :2042-53. Copy at http://www.tinyurl.com/yxn2s6zd

Date Published:

2021 Dec 01

Abstract:

BACKGROUND: Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important. METHODS: PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH, and phosphoproteomics. RESULTS: Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment. CONCLUSIONS: Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.

Last updated on 12/06/2021