| RRC ID |
78149
|
| 著者 |
Groothuis PG, Jacobs DCH, Hermens IAT, Damming D, Berentsen K, Mattaar-Hepp E, Stokman MEM, Boekel TV, Rouwette M, van der Vleuten MAJ, Sesink A, Dijcks FA, Coumans RGE, Schouten J, Glaudemans DH, Wijk DV, Blomenröhr M, Kappers WA, Ubink R, van der Lee MMC, Dokter WHA.
|
| タイトル |
Preclinical Profile of BYON3521 Predicts an Effective and Safe MET Antibody-Drug Conjugate.
|
| ジャーナル |
Mol Cancer Ther
|
| Abstract |
MET, the cell-surface receptor for the hepatocyte growth factor/scatter factor, which is widely overexpressed in various solid cancer types, is an attractive target for the development of antibody-based therapeutics. BYON3521 is a novel site-specifically conjugated duocarmycin-based antibody-drug conjugate (ADC), comprising a humanized cysteine-engineered IgG1 monoclonal antibody with low pmol/L binding affinity towards both human and cynomolgus MET. In vitro studies showed that BYON3521 internalizes efficiently upon MET binding and induces both target- and bystander-mediated cell killing. BYON3521 showed good potency and full efficacy in MET-amplified and high MET-expressing cancer cell lines; in moderate and low MET-expressing cancer cell lines good potencies and partial efficacy were observed. In mouse xenograft models, BYON3521 showed significant antitumor activity upon single-dose administration in multiple non-MET-amplified tumor types with low, moderate, and high MET expression, including complete tumor remissions in models with moderate MET expression. In the repeat-dose Good Laboratory Practice (GLP) safety assessment in cynomolgus monkeys, BYON3521 was well tolerated and based on the observed toxicities and their reversibility, the highest non-severely toxic dose was set at 15 mg/kg. A human pharmacokinetics (PK) model was derived from the PK data from the cynomolgus safety assessments, and the minimal efficacious dose in humans is estimated to be in the range of 3 to 4 mg/kg. In all, our nonclinical data suggests that BYON3521 is a safe ADC with potential for clinical benefit in patients. A first-in-human dose-escalation study is currently ongoing to determine the maximum tolerated dose and recommended dose for expansion (NCT05323045).
|
| 巻・号 |
22(6)
|
| ページ |
765-777
|
| 公開日 |
2023-6-1
|
| DOI |
10.1158/1535-7163.MCT-22-0596
|
| PII |
725725
|
| PMID |
37042205
|
| PMC |
PMC10233350
|
| MeSH |
Animals
Antibodies, Monoclonal*
Antibodies, Monoclonal, Humanized
Cell Line, Tumor
Humans
Immunoconjugates*
Immunoglobulin G
Mice
Xenograft Model Antitumor Assays
|
| リソース情報 |
| ヒト・動物細胞 |
EBC-1(RCB1965)
KP4(RCB1005) |
