Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors
Year: 2022
Type: article
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.
Source: Cell Reports
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Defense, Mayo Clinic, Welch Foundation, California Breast Cancer Research Program, Cancer Prevention and Research Institute of Texas, Brigham and Women's Hospital, Emory University, University of Texas System, National Institutes of Health, Japan Society for the Promotion of Science, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: G1017714130, G1241018968, Therapeutic Monoclonal Antibody Lead Optimization and Development Core, G2049212056, G2311883909, G2423594639, CHEMICALLY GENERATED BISPECIFIC ANTIBODY-DRUG CONJUGATES FOR TREATING TRIPLE-NEGATIVE BREAST CANCER, G4119534169, DUAL-LOADING ADCS FOR COMBATING CANCER DRUG RESISTANCE AND HETEROGENEITY, Optimizing oncolytic virus therapy for glioblastoma, Advanced Cancer Antibody Drug Modalities Core Facility, G5850682332, G5893650929, G8166743225, Chemical approaches for generating blood-brain barrier-permeable antibody conjugates, Next Gen Virotherapy for GBM, Circumventing Barriers to Effective Oncolytic Virotherapy of Malignant Gliomas
OpenAlex ID: W4281398334