A recent article, published in Molecular Cancer Therapeutics, an American Association for Cancer Research (AACR) journal, suggests that BYON3521, a next-generation antibody-drug conjugate being developed by clinical-stage Dutch biopharmaceutical company Byondis, has an encouraging safety/efficacy window with potential for clinical benefit in patients. 
BYON3521 comprises the humanized IgG1 c-MET-targeting monoclonal antibody, SYD2884, and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA or SYD980).
The antibody part of BYON3521 binds to c-MET on the surface of the cancer cell and the ADC is internalized. After proteolytic cleavage of the linker in the lysosome, the inactivated cytotoxin is activated, binds to the DNA and DNA damage is induced, eventually resulting in tumor cell death.
BYON3521 incorporates Byondis’ distinctive, proprietary duocarmazine linker-drug technology called ByonZine® and its site-specific conjugation technology ByonShieLD®. The characteristic design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation and induces efficient release of the cytotoxin in the tumor.
Uptake of the activated payload by neighboring tumor cells with lower or no c-MET expression may improve the efficacy potential through the so-called bystander effect.
Dose escalation study
A First-in-Human dose escalation study is currently ongoing to determine the maximum tolerated dose and recommended dose for expansion (NCT05323045). The study is enrolling patients in leading oncology centers in Belgium, Italy, the Netherlands and the United Kingdom.
The data from in vitro and in vivo studies showed that BYON3521 potently and selectively kills tumor cells expressing c-MET, even at low c-MET-expressing levels. In addition, the nonclinical safety evaluation showed that BYON3521 is well tolerated, predicting a substantial clinical therapeutic window.
“The c-MET/HGF pathway is one of the most dysregulated pathways in human solid tumors and is generally associated with a poor prognosis,” said Wim Dokter, Ph.D., Byondis’ Chief Scientific Officer
“Being able to use that pathway to deliver clinical benefit to patients will therefore be extra rewarding,” Dokter added.
c-MET (also called tyrosine-protein kinase MET [Mesenchymal Epithelial Transition] factor or HGFR [Hepatocyte Growth Factor Receptor]) is a cell-surface receptor for the hepatocyte growth factor/scatter factor (HGF/SF), which is widely overexpressed in various solid cancer types. As a result, is an attractive target for the development of antibody-based therapeutics.
Binding of the growth factor HGF to c-MET leads to normal cell division, growth and differentiation, important in the generation of new tissue, e.g., during the development of a fetus, or during growth or wound repair.
But in many tumor cells, c-MET activation is dysregulated: too much c-MET is expressed, c-MET is mutated or c-MET is active even without the binding of HGF. c-MET is overexpressed in a variety of solid tumors, such as renal cell cancer, uveal (ocular) melanoma, non-small cell lung cancer and head and neck squamous cell cancer.
ADC Drug Map
A First-in-human Dose-escalation and Expansion Study With the Antibody-drug Conjugate BYON3521 – NCT05323045
 Groothuis PG, Jacobs DCH, Hermens IAT, Damming D, Berentsen K, Mattaar-Hepp E, Stokman MEM, Van Boekel T, Rouwette M, Van der Vleuten MAJ, Sesink A, Dijcks FA, Coumans RGE, Schouten J, Glaudemans DH, van Wijk D, Blomenröhr M, Kappers WA, Ubink R, Van der Lee MMC, Dokter WHA. Preclinical profile of BYON3521 predicts an effective and safe c-MET-antibody-drug conjugate. Mol Cancer Ther. 2023 Apr 12:MCT-22-0596. doi: 10.1158/1535-7163.MCT-22-0596. Epub ahead of print. PMID: 37042205.
 First Patient Dosed in Phase 1 Study of Next Generation Antibody-Drug Conjugate BYON3521. J. Antibody-drug Conjugates, August 26, 2022. Online. Last accessed on April 12, 2023.
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