Is this yet another Immunotherapy? How ADC’s work

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Antibody therapies have a little sister who is catching up in funding – and hype? In light of now five deaths from Juno’s CAR-T therapy, antibody drug conjugates are attracting a lot of interest in a resurgence after their debut 10 years ago. To feel out the field, we talked to two CEOs competing directly in the ADC space.

Jan Schmidt-Brand“Antibody drug conjugates were a really hot topic a few years ago, but they were overshadowed by immunotherapies. Now people are starting to realize that these therapies will not be the magic bullet,” says Jan Schmidt-Brand, CEO/CFO of Wilex, one of the leaders in the field of antibody drug conjugates. Some companies are upgrading immuno-oncology by combining antibodies with cytotoxins in what are known as antibody drug conjugates (ADCs).

While a magic bullet to cure cancer does not exist, ADCs might at least be an effective tool to fight it. “ADCs are highly efficient and, with adequate payloads, capable not only of overcoming tumor resistance but also killing dormant tumor cells that cause metastasis and tumor relapse,” says Schmidt-Brand. “Each ADC is something completely individual, regarding its target, indication, and chemistry: ADCs could theoretically be engineered to target just about any biological tumor target as long as it can be reached by internalizing antibodies.”

Moreover, ADCs stand to be easy to administer via infusion compared to CAR-T therapies, which entail a very complex procedure of blood withdrawal to extract T-cells, follow by genetic modification and amplification of these cells. This procedure amounts to financially and medically intensive care: the last estimated cost of the procedure was $500K per patient, and the patient needs to be closely monitored and cared for during the therapy. “It seems to be very effective in some indications, but still has a long way to go from a development perspective,” says Schmidt-Brand.

Are ADCs a good alternative? What are they exactly, and where are they going in Europe?

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Is this yet another Immunotherapy? How ADC’s work

adc-therapeutics-chris-martin-ceo“ADCs aren’t really an immunotherapy in the common understanding of the term these days,” says Chris Martin, CEO of ADC Therapeutics. “They’re more of a guided missile, where the antibody is the guiding system of a cytotoxic payload.” In an ADC, a toxin piggybacks on an antibody as it homes in on its target receptor protein. The antibody sticks to the cell surface and is then internalized, payload and all, so the toxin can be released inside the cell to induce apoptosis.

The cytotoxic therapy on its own is simply chemotherapy, which carries serious side effects as it indiscriminately kills sick and healthy cells. This toxicity could theoretically be avoided by directing the molecules exclusively to the cancer cells; while medicinal chemistry aims to solve this problem by altering the molecule, the intrinsic specificity of antibodies could also provide an answer. “This is very much a way to marry the next generation of highly potent chemical drugs and the new generation of biologicals,” says Martin.

Antibody or Toxin? Strategies in ADC Development

As antibody development has fallen under the purview of immuno-oncology, most companies are making their mark on the field via toxin development. For Martin, it seemed like a natural transition to the new generation of biological drugs from more traditional medicinal chemistry. Since founding Spirogen in 2000 to discover and develop new anticancer agents, Martin has built the company’s know-how into the strategy of ADC Therapeutics.

The company is known for its pyrrolobenzodiazepine (PBD) dimer toxins, which “block cell division without being caught by DNA repair mechanisms. This allows for long-term treatments,” explains Martin. Schmidt-Brand’s company, Wilex, focuses on amantin, which kills dividing and quiescent tumor cells by inhibiting RNA II Polymerase to effectively halt protein production.

Wilex is also looking at linkers. Schmidt-Brand says that “in most cases, you can use a certain toolbox of linkers, since linkers can change very different properties of the resulting ADCs in a sometimes unpredictable way. The best approach is to pick a small array of pre-selected linkers and then use the one yielding the best results.”