Abstract
Glioblastoma multiforme (GBM) is the most aggressive and fatal disease of all brain tumor types. Most therapies rarely provide clinically meaningful outcomes in the treatment of GBM. Although antibody-drug conjugates (ADCs) are promising anticancer drugs, no ADCs have been clinically successful for GBM, primarily because of poor blood-brain barrier (BBB) penetration. Here, we report that ADC homogeneity and payload loading rate are critical parameters contributing to this discrepancy. Although both homogeneous and heterogeneous conjugates exhibit comparable in vitro potency and pharmacokinetic profiles, the former shows enhanced payload delivery to brain tumors. Our homogeneous ADCs provide improved antitumor effects and survival benefits in orthotopic brain tumor models. We also demonstrate that overly drug-loaded species in heterogeneous conjugates are particularly poor at crossing the BBB, leading to deteriorated overall brain tumor targeting. Our findings indicate the importance of homogeneous conjugation with optimal payload loading in generating effective ADCs for intractable brain tumors.
Original language | English (US) |
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Article number | 110839 |
Journal | Cell Reports |
Volume | 39 |
Issue number | 8 |
DOIs | |
State | Published - May 24 2022 |
Externally published | Yes |
Keywords
- CP: cancer
- antibody
- antibody-drug conjugate
- blood-brain barrier
- brain tumor
- chemotherapy
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology