@article{755422d5126746de84be71dea0f95c11,
title = "Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors",
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.",
keywords = "antibody, antibody-drug conjugate, blood-brain barrier, brain tumor, chemotherapy, CP: cancer",
author = "Yasuaki Anami and Yoshihiro Otani and Wei Xiong and Ha, {Summer Y.Y.} and Aiko Yamaguchi and Rivera-Caraballo, {Kimberly A.} and Ningyan Zhang and Zhiqiang An and Balveen Kaur and Kyoji Tsuchikama",
note = "Funding Information: We gratefully acknowledge the following researchers for providing the cells used in this study: U87ΔEGFR from Dr. Erwin G. Van Meir (Emory University), Gli36δEGFR from Dr. E. Antonio Chiocca (Brigham and Women's Hospital), JIMT-1-BR3 from Dr. Patricia S. Steeg (the National Cancer Institute), and GBM12 from Dr. Jann N. Sarkaria (Mayo Clinic). We thank Dr. Chisato M. Yamazaki for providing scientific input and Travis J. Roeder for technical assistance. This work was supported by the National Institutes of Health (R35GM138264 to K.T.; R61NS112410 and P01CA163205 to B.K.), the Department of Defense Breast Cancer Research Program (W81XWH-18-1-0004 and W81XWH-19-1-0598 to K.T.), the Cancer Prevention and Research Institute of Texas (RP150551 and RP190561 to Z.A.), the Welch Foundation (AU-0042-20030616 to Z.A.), and the Japan Society for the Promotion of Science (postdoctoral fellowship to Y.A. and A.Y.). Conceptualization, K.T.; methodology, Y.A. Y.O. W.X. N.Z. Z.A. B.K. and K.T.; validation, Y.A. Y.O. and W.X.; formal analysis, Y.A. Y.O. S.Y.Y.H. and K.A.R.-C.; investigation, Y.A. Y.O. W.X. S.Y.Y.H. A.Y. K.A.R.-C. and K.T.; resources, N.Z. Z.A. B.K. and K.T.; writing – original draft, Y.A. Y.O. and K.T.; writing – review & editing, Y.A. Y.O. A.Y. Z.A. and K.T.; visualization, Y.A. and Y.O.; supervision, K.T.; project administration, K.T.; funding acquisition, Y.A. A.Y. Z.A. B.K. and K.T. Y.A. N.Z. Z.A. and K.T. are named inventors on a patent application relating to the work filed by the Board of Regents of the University of Texas System (PCT/US2018/034363, US-2020-0115326-A1, and EU18804968.8-1109/3630189). The remaining authors declare no competing interests. Funding Information: We gratefully acknowledge the following researchers for providing the cells used in this study: U87ΔEGFR from Dr. Erwin G. Van Meir (Emory University), Gli36δEGFR from Dr. E. Antonio Chiocca (Brigham and Women{\textquoteright}s Hospital), JIMT-1-BR3 from Dr. Patricia S. Steeg (the National Cancer Institute), and GBM12 from Dr. Jann N. Sarkaria (Mayo Clinic). We thank Dr. Chisato M. Yamazaki for providing scientific input and Travis J. Roeder for technical assistance. This work was supported by the National Institutes of Health ( R35GM138264 to K.T.; R61NS112410 and P01CA163205 to B.K.), the Department of Defense Breast Cancer Research Program ( W81XWH-18-1-0004 and W81XWH-19-1-0598 to K.T.), the Cancer Prevention and Research Institute of Texas ( RP150551 and RP190561 to Z.A.), the Welch Foundation ( AU-0042-20030616 to Z.A.), and the Japan Society for the Promotion of Science (postdoctoral fellowship to Y.A. and A.Y.). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = may,
day = "24",
doi = "10.1016/j.celrep.2022.110839",
language = "English",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}
