#NxtGenADCs: So Many Possibilities

In the war against cancer, antibody-drug conjugates (ADCs) are on a covert search and destroy mission. Nicknamed “Trojan Horses,” ADCs are highly targeted biopharmaceutical drugs. They combine monoclonal antibodies (mAbs) specific to surface antigens present on particular tumor cells, with highly potent anti-cancer toxins joined by a chemical linker. Through the antibody, ADCs attach themselves to a receptor on the tumor cell, gain entry and once inside, release a cytotoxic drug.

ADCs originated in the late 1950s, when scientists began to explore ways to deliver a toxin directly to a cancer cell. They did this by “conjugating” or connecting different drugs to antibodies, hence the name, antibody-drug conjugates.

Early ADCs were ineffective and not very safe. Over the course of 50 years, several adaptations were made, including: the use of humanized or human antibodies to reduce immune system reactions; improvements in the site of conjugation and linker stability to enhance ADC stability; and the introduction of more potent toxins.

Continued modifications resulted in the first approved ADCs with improved targeting and cell killing. But they were unstable in the bloodstream, leading to premature release of the cytotoxic payload, impacting healthy tissue and narrowing the therapeutic window. The therapeutic window is the measure of the safety of a drug, and it indicates the difference between the dose at which you start to see beneficial effects and the dose at which you start to see serious side effects.

For more than 16 years, Byondis scientists have been working to create ADCs that kill cancer cells without killing healthy tissue. These next generation ADCs are 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. They are based on Byondis' distinctive, proprietary, linker-drug and site-specific conjugation technologies, novel mechanisms of action, and selected combination strategies.

A number of these next generation ADCs are in or entering the clinic. Last year, BYON3521, an ADC that targets c-MET, entered into a Phase I trial. c-MET is widely overexpressed in a variety of solid tumors, including renal cell cancer, uveal (ocular) melanoma, and head and neck squamous cell cancer. Another ADC, BYON4413, is preparing to enter the clinic later this year. This ADC is directed against CD123, expressed in acute myeloid leukemia (AML) and other hemato-oncological malignancies.

In its early discovery pipeline, building the company’s ADC capabilities, Byondis has identified three new platforms: a linker-drug technology to generate immuno-oncology ADCs; a linker-drug technology to generate ADCs with potential in both oncologic and other indications, such as autoimmune diseases; and a platform technology to increase the tumor-specificity of mAbs and ADCs.

“ADCs will continue to be an important part of our R&D strategy,” said Marco Timmers, Ph.D., Byondis CEO. “They offer the potential to treat cancers with high unmet need, and so many possibilities to explore in the way of new molecular targets, antibodies, toxins and mechanisms. Advancements in their discovery, design, development, and manufacturing will continue and we are excited to be a part of it.”