BYON3521, a new ADC targeting c-Met, has entered phase 1 (BYON3521.001/NCT05323045) clinical development when, earlier this week, a first patients had been dosed with the investigational drug being developed by Byondis, an independent, clinical stage biopharmaceutical company creating precision medicines.

“The protein c-MET is widely overexpressed in a variety of solid tumors. Based on preclinical findings, we were keen to start the Phase 1 study of BYON3521, with the hope of finding another option for patients in need,” said Byondis Chief Medical Officer Jan Schellens, M.D., Ph.D.

c-MET, also known as tyrosine-protein kinase MET [Mesenchymal Epithelial Transition] factor or HGFR [Hepatocyte Growth Factor Receptor]), is a proto-oncogene active in normal cell division, growth and differentiation. Mutations may cause it to become an oncogene, which can promote cancer cell growth and multiplication.[1][2]

Despite the importance of the MET oncogene in a variety of malignancies, clinical strategies targeting c-Met have only benefitted relatively small subsets of patients with tumors driven by signaling through the c-Met pathway. In order to benefit patients, selection of patients with MET amplification and/or c-Met activation most likely to respond was required. To overcome these observed limitations, an ADC designed to specifically target c-Met may overcome observed limitations.

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“Pre-clinical data showed selective and potent killing of c-MET expressing tumors and a safety profile that indicated a favorable therapeutic index,” said Byondis Chief Scientific Officer Wim Dokter, Ph.D.

Based on (early) pre-clinical studies, BYON3521 represents am innovative therapeutic strategy to deliver a potent cytotoxin to c-Met-overexpressing cancer cells enabling cell killing regardless of reliance on MET signaling.

Study design
The clinical study, BYON3521.00, is designed to evaluate the safety, pharmacokinetics and preliminary efficacy of BYON3521 in up to 150 patients aged 18 or over with histologically confirmed c-MET-expressing, MET-amplified or MET-mutated (except exon 14 mutated) locally advanced or metastatic solid tumors. Eligible patients are those who have progressed on standard therapy or for whom no standard therapy exists.

The study is scheduled to be conducted in two parts, including Dose Escalation and Dose Expansion.

  • Part 1, the dose escalation phase, should enroll up to 30 patients with solid tumors to evaluate the therapy’s safety and determine the Maximum Tolerated Dose (MTD) and Recommended Dose for Expansion (RDE).
  • Part 2, dose expansion, should enroll up to 120 patients with specific solid tumors and documented c-MET pathway activation in four cohorts — renal cell cancer, uveal (ocular) melanoma, head and neck squamous cell cancer and other cancers. These patients will receive the RDE determined in Part 1 to evaluate the objective tumor response rate (ORR) and safety of BYON3521 in these cohorts. All patients in both parts of the study will receive BYON3521 infusions every three weeks until disease progression or unacceptable side effects.

The study is currently enrolling patients in leading oncology centers in Belgium, Italy, the Netherlands and the United Kingdom.

A second ADC
BYON3521 is the second ADC being developed by Byondis ADC. The company’s most advanced ADC, [vic-]trastuzumab duocarmazine (SYD985), which targets HER2-expressing cancers such as metastatic breast and endometrial (uterine) cancer, is being reviewed by the U.S. Food and Drug Administration following the company’s Biologics License Application (BLA) to the FDA and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA).

The BLA was based on positive results from its pivotal Phase III TULIP® trial of [vic-]trastuzumab duocarmazine (SYD985) in metastatic breast cancer. A current Phase II trial evaluates the safety and efficacy of SYD985 as a standalone therapy for HER2-expressing recurrent, advanced, or metastatic endometrial cancers.

Mechanism of Action
BYON3521 is comprised of the humanized IgG1 monoclonal antibody SYD2884, targeting c-MET, and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA or SYD980). The investigational agent employs site-specific conjugation to an engineered cysteine residue located on heavy chain position 41 of the antibody.

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, resulting in tumor cell death. Treatment with BYON3521 is considered a form of targeted therapy.

While earlier generation of ADCs were designed to improved targeting and cell killing, they generally were unstable in the bloodstream, leading to premature release of the cytotoxic payload. This early release of the cytotoxic payload directly impacts healthy tissue and narrowing the therapeutic window.

To solve this problem, scientists at Byondis developed a next generation ADCs which has show to be highly stable in circulation and carry an intricate, inactivated and potent cytotoxic drug that rapidly self-destructs if prematurely released, limiting damage to healthy tissue and improving the therapeutic window.

The differentiating linker-drug, vc-seco-DUBA, owes its potent anti-tumor activity to a synthetic duocarmycin-based cytotoxin. Duocarmycins, first isolated from Streptomycesbacteria in the 1970s, bind to the minor groove of DNA and disrupt the nucleic acid architecture, which subsequently leads to tumor cell death.

BYON3521 incorporates Byondis’ distinctive, proprietary duocarmazine linker-drug (LD) technology ByonZine® and its site-specific conjugation technology ByonShieLD®.

The distinctive 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 c-MET expression may improve the efficacy potential through the so-called bystander effect.

In pre-clinical studies, the site-specific conjugation of the linker-drug resulted in enhanced in vivo anti-tumor activity. In addition, the manufacturing of BYON3521 relies on a single-step selective reduction of the engineered cysteines, instead of a two-step reduction/oxidation protocol that is commonly used for these types of site-specifically conjugated ADCs and that can lead to undesired side-products.

The ByonShieLD® technology greatly improves manufacturability of ADCs and yields products with improved physicochemical properties.

Clinical trials
A First-in-human Dose-escalation and Expansion Study With the Antibody-drug Conjugate BYON3521 – NCT05323045

[1] Fu J, Su X, Li Z, Deng L, Liu X, Feng X, Peng J. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene. 2021 Jul;40(28):4625-4651. doi: 10.1038/s41388-021-01863-w. Epub 2021 Jun 18. PMID: 34145400.
[2] Mughal A, Aslam HM, Sheikh A, Khan AM, Saleem S. c-Met inhibitors. Infect Agent Cancer. 2013 Apr 8;8(1):13. doi: 10.1186/1750-9378-8-13. PMID: 23566349; PMCID: PMC3626853.

Featured image courtesy © 2022 Byondis, Used with permission.

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