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).

C-Met, the cell-surface receptor for HGF/SF which is widely overexpressed in various solid cancer types, is an attractive target for the development of antibody-based therapeutics. However, the apparently delicate balance between anti-tumor activity and target mediated-toxicities proved to be quite a challenge. As a result, there are currently no c-Met targeting antibodies or antibody-drug conjugates (ADCs) on the market. We developed BYON3521, a novel site-specifically conjugated, duocarmycin-based ADC, comprising a humanized, cysteine-engineered IgG1 monoclonal antibody with low pM binding affinity towards both human and cynomolgus c-Met. In vitro studies showed that BYON3521 internalizes efficiently upon c-Met binding, and induces both target- as well as bystander-mediated cell killing. BYON3521 showed good potency and full efficacy in MET-amplified and high c-Met-expressing cancer cell lines; in moderate and in low c-Met-expressing cancer cell lines partial efficacy was observed. PK/PD studies and a mouse clinical trial in patient-derived xenograft models showed significant anti-tumor activity of BYON3521 upon single dose administration in multiple tumor types. BYON3521 showed responses in non-MET-amplified tumors with low, moderate and high c-Met expression, with partial and complete tumor remission seen in several models with moderate c-Met expression. In the repeat-dose GLP safety assessment in cynomolgus monkeys BYON3521 was well tolerated. In all, BYON3521 was deemed a safe ADC with potential for clinical benefit in patients. Preparations are ongoing to start clinical Phase I in 2021. Citation Format: Patrick Groothuis, Danielle Jacobs, Inge Hermens, Desiree Damming, Ellen Mattaar, Myrthe Rouwette, Monique van der Vleuten, Aloys Sesink, Fred Dijcks, Ruud Coumans, Marion Blomenrohr, Ruud Ubink, Miranda van der Lee, Wim H.A. Dokter. BYON3521, a novel effective and safe c-Met targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 926.

Supplementary tables and figures

Supplementary tables and figures

Supplementary tables and figures

Supplementary tables and figures