|Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma.
|Year of Publication
|Marin B-M, Porath KA, Jain S, Kim M, Conage-Pough JE, Oh J-H, Miller CL, Talele S, Kitange GJ, Tian S, Burgenske DM, Mladek AC, Gupta SK, Decker PA, McMinn MH, Stopka SA, Regan MS, He L, Carlson BL, Bakken K, Burns TC, Parney IF, Giannini C, Agar NYR, Eckel-Passow JE, Cochran JR, Elmquist WF, Vaubel RA, White FM, Sarkaria JN
|2021 12 01
|Antibodies, Monoclonal, Humanized, Blood-Brain Barrier, Brain Neoplasms, Cell Line, Tumor, ErbB Receptors, Glioblastoma, Humans, Immunoconjugates, Pharmaceutical Preparations
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.
|PubMed Central ID
|T32 EB025823 / EB / NIBIB NIH HHS / United States
U54 CA210180 / CA / NCI NIH HHS / United States
P41 EB015898 / EB / NIBIB NIH HHS / United States