RT Journal Article
SR Electronic
T1 Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.23.474044
DO 10.1101/2021.12.23.474044
A1 Yasuaki Anami
A1 Yoshihiro Otani
A1 Wei Xiong
A1 Summer Y. Y. Ha
A1 Aiko Yamaguchi
A1 Ningyan Zhang
A1 Zhiqiang An
A1 Balveen Kaur
A1 Kyoji Tsuchikama
YR 2021
UL http://biorxiv.org/content/early/2021/12/24/2021.12.23.474044.abstract
AB Glioblastoma multiforme (GBM) is characterized by aggressive growth and the poorest prognosis of all brain tumor types. Most therapies rarely provide clinically meaningful improvements in outcomes of patients with GBM. Antibody-drug conjugates (ADCs) are emerging chemotherapeutics with stunning success in cancer management. Although promising, clinical studies of three ADCs for treating GBM, including Depatux-M, have been discontinued because of safety concerns and limited therapeutic benefits. Here, we report that ADC homogeneity is a critical parameter to maximize the therapeutic potential in GBM therapy. We demonstrate that homogeneous conjugates generated using our linker show enhanced drug delivery to intracranial brain tumors. Notably, compared to heterogeneous ADCs, including a Depatux-M analog, our ADCs provide greatly improved antitumor effects and survival benefits in orthotopic brain tumor models, including a patient-derived xenograft model of GBM. Our findings warrant the future development of homogeneous ADCs as promising molecular entities toward cures for intractable brain tumors.Competing Interest StatementY.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; EU18804968.8-1109/3630189). The remaining authors declare no competing interests.