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

Cell Rep

Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Center at Houston, Houston, TX 77054, USA. Electronic address:

Published: May 2022

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9195180PMC
http://dx.doi.org/10.1016/j.celrep.2022.110839DOI Listing

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