Anatomy of a #NxtGenADC

Another Byondis antibody-drug conjugate, BYON3521, has progressed to First-in-Human (Phase I) study. Here’s a look at how it got there.

Over the last two decades, targeted therapies – drugs that target cancer cells by homing in on specific molecular changes seen primarily in those cells – have become standard of care for many cancers. Among the most promising are antibody-drug conjugates or ADCs. ADCs combine monoclonal antibodies specific to surface antigens on particular tumor cells, with highly potent cytotoxins joined via a chemical linker.

While earlier generation ADCs improved targeting and cell killing, they were unstable in the bloodstream, leading to premature release of the cytotoxic payload, impacting healthy tissue and narrowing the therapeutic window. Byondis’ next generation ADCs are highly stable in circulation and carry an intricate, inactivated, and potent cytotoxin that rapidly self-destructs if prematurely released, limiting damage to healthy tissue, and improving the therapeutic window.

BYON3521 targets c-MET, the cell-surface receptor for Hepatocyte Growth Factor/Scatter Factor (HGF/SF). c-MET is a proto-oncogene active in normal cell division, growth and differentiation. When mutated or overexpressed it can become an oncogene and promote cancer cell growth and multiplication.

c-MET is widely 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. It is generally associated with a poor prognosis.

Despite c-MET being an excellent target, creating a suitable therapy is far from easy. A wide range of ????c-MET inhibitors, ranging from small molecules to antibodies, have been in clinical development. But the results have been disappointing. In some cases, therapies have even aggravated the patient’s condition.

In finding the best antibody for a c-MET-targeting ADC, it was important to avoid those antibodies that have the opposite of the desired effect, that is, cause cancer cells to divide and the tumor to grow bigger instead of smaller. Of the final set of 125 humanized antibodies that Byondis tested, we eventually narrowed it down to three and finally, one.

BYON3521 is comprised of 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. Preclinical results showed that BYON3521 potently and selectively kills tumor cells expressing c-MET, even at low levels of c-MET on the cell membrane.

The “First-in-Human Dose-Escalation and Expansion Trial With the Antibody-Drug Conjugate BYON3521 to Evaluate the Safety, Pharmacokinetics and Efficacy in Patients with c-MET-Expressing Locally Advanced or Metastatic Solid Tumors” (BYON3521.001/NCT05323045) is currently enrolling patients in leading oncology centers in Belgium, Italy, the Netherlands and the U.K.

Byondis continues to employ the latest insights in tumor biology and immunology to search for new molecular targets and develop new mechanisms for ADCs, monoclonal antibodies (mAbs) and small molecule programs. We are driven by one goal: providing novel treatments with high efficacy and low systemic toxicity to improve the standard of care for patients with an unmet medical need.