Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors

Yasuaki Anami, Yoshihiro Otani, Wei Xiong, Summer Y.Y. Ha, Aiko Yamaguchi, Kimberly A. Rivera-Caraballo, Ningyan Zhang, Zhiqiang An, Balveen Kaur, Kyoji Tsuchikama

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Article number110839
JournalCell Reports
Volume39
Issue number8
DOIs
Publication statusPublished - May 24 2022
Externally publishedYes

Keywords

  • antibody
  • antibody-drug conjugate
  • blood-brain barrier
  • brain tumor
  • chemotherapy
  • CP: cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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