Targeting Direct Hits to Cancer Cells

An increased understanding of tumor biology allows researchers to explore new ways to target cancer cells by combining toxins with antibodies.

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Diseased cells can be tricked into ingesting targeted medicines.

Advances in the treatment of cancer have been remarkable in the past decade. For many cancer types, chemotherapy remains the standard of care. The problem is that chemotherapy is delivered in a way that damages not only cancer cells but also healthy ones.
A deepening understanding of the biology of tumors has given rise to new compounds that target specific tumors at the molecular level. That, combined with innovative technologies to deliver those drugs, aims to reduce the impact of chemotherapy on healthy cells.
The pursuit of more targeted therapies includes the development of antibody drug conjugates (ADCs), a platform AbbVie has been working to advance with partner Seattle Genetics since 2011.
“Antibodies are very targeted molecules, and each binds to a specific protein in the body,” says Jochen Salfeld, Ph.D., vice president of global biologics discovery, based at the AbbVie Bioresearch Center in Worcester, Massachusetts. “The goal with antibody drug conjugates is to deliver a medicine to diseased tissue in a precise way that does not damage the healthy tissue.”

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Marrying antibody, toxin and chemical

Each ADC has three parts – the antibody, which targets a particular protein; the toxin, which is meant to attack the diseased tissue; and a chemical that connects the two, called a linker. The linker is important because it allows the toxin to be released only once it reaches the target cell.
In addition to reducing the impact of chemotherapy on healthy cells, ADCs would also reduce the amount of drug needed for treatment.
“To be effective against cancer cells, the drug itself has to be very toxic. By directly focusing the drug to the cancer cell, we would reduce the amount of drug circulating in the body,” Salfeld says. “It’s essentially enhancing the drug’s effects inside of the cancer cell while using less drug overall.”
The ADC platform could also breathe life into molecules that are too toxic to be given on their own. “If we introduce them into a cell via an ADC, they may have a very different profile because the efficacy of the compound is specifically directed to the diseased tissue,” Salfeld says.

Seeking only cancer cells

Beyond small molecules, there also is potential to develop ADCs that can target two proteins at once.
“Some of the target proteins exist both on cancer cells and healthy cells, so it can be challenging to make them specific enough to seek out only the cancer cells,” Salfeld says. “Our dual variable domain (DVD) antibody technology could allow us to make ADCs with dual-targeting capabilities.”
For example, a particular tumor cell may carry two targets – target A and target B. To get full efficacy would require a targeting molecule that attacks both at the same time without attacking healthy cells that carry only A or B.
AbbVie is studying an ADC for use in patients with an aggressive form of brain cancer, with several other ADCs in earlier stages of investigation in cancer and in other therapeutic areas.