Oncolytics Biotech Inc ONCY

RE:RE:RE:RE:RE:RE:Resistance to ADCs in the treatment of solid tumors

[Noteable]

May 29, 2024 - " Chemotherapy drugs are well suited to killing cancer cells, but they’re bad at killing only cancer cells — the destruction of healthy tissue has been an inevitable outcome. This toxicity is why chemotherapies come with significant side effects, pushing some people to discontinue the drugs in favour of palliative care. 

Decades of work to develop less burdensome alternatives are now coming to fruition. One approach is to use even more potent anticancer drugs, but package them in a way that makes them more selective of the cells they kill — meaning they are both more effective and have fewer side effects as compared with conventional chemotherapy. 

This is the promise of antibody–drug conjugates (ADCs), which consist of three key parts. The first is an antibody, which is engineered to dock at specific receptors on a cancer cell’s membrane. The second is a highly toxic cancer-killing drug. And the third is the chemical scaffold that connects the antibody to the drug. 

“It’s a simple structure on paper,” says Kyoji Tsuchikama, a medical chemist at the University of Texas Health Science Center at Houston. But because of the delicate balance between efficacy and safety, he adds, “we’ve needed a complex understanding of cancer biology to make them”.

Scientists have been working to determine the best combination of these components, spurred on by renewed interest in ADCs from investors and pharmaceutical companies. 

ADCs still have their imperfections. “We do still see toxicity and sometimes that’s because of improper design,” says Tsuchikama. “It’s not like they cause instant death, but in terms of patient quality of life, it can be disruptive.” For example, if ADCs mistakenly shed their payloads in normal cells or in the bloodstream, rather than directly into the cancer cells, then the kinds of side effect that typify conventional chemotherapy are likely to persist. 

As with most new cancer treatments, ADCs are expensive. It’s perhaps not surprising, therefore, that drug companies are betting a lot of money on them in anticipation of handsome returns. Market research analysts valued the ADC market at US$9.25 billion in 2022, and forecast it to increase to $20.5 billion by 2030. One 2023 paper estimated that it costs about €120,000 ($128,000) to treat someone with breast cancer with ADCs for one year3. The authors of the study question whether insurance companies and public health-care systems will be prepared to spend that kind of money on the millions of people diagnosed with the disease each year. 

The question of cost, however, is yet to be resolved. Regulators require drug developers to investigate each component of an ADC: the payload, the antibody and the chemical scaffold. “That doubles or triples the cost” compared with a conventional and comparatively simple small-molecule drug, says Tsuchikama.

https://www.nature.com/articles/d41586-024-01426-5