Labtimes 2017-06

page 42 Lab Times 6-2017 Biobusiness Antibody-drug conjugates (ADCs) raise high expectations The Next Big Thing? Switzerland’s ADC Therapeutics gains a whopping €170 million in venture financing but the ADC market is highly competitive. É palinges, a decent but somewhat stuffy suburb in the North of Laus- anne, Switzerland, has a population of 9,300, a daffy looking duck as a heral- dic animal, and Ingvar Kamprad, one of the world’s wealthiest people, as a former res- ident. Popular hobbies here include play- ing golf and driving Porsches. The most im- portant hobby is, of course, making money. So, it wasn’t the talk of the town when, in October 2017, the local drug developer ADC Therapeutics (ADCT), headquartered in Épalinges, announced that its fourth pri- vate funding round was closed, yielding an- other breathtaking €170 million to acceler- ate the development of their cancer drug pipeline. Taken together, ADCT has raised €390 million in venture capital since the company’s foundation only six years ago. ADCT’s CEO, Chris Martin, is certainly flush with money. Targeting cancer antigens ADCT develops site-directed biophar- maceutical drugs for the treatment of cir- culating and solid cancers, using proprie- tary antibody drug conjugates (ADCs). The big advantage of ADCs, compared to classi- cal chemotherapy approaches, is to specifi- cally target only cancer cell antigens while leaving healthy cells unharmed (if we be- lieve the company’s claims). In order to achieve this, cytostat- ic drugs are coupled to monoclonal anti- bodies. ADCT uses pyrrolobenzodiazepine (PBD) as a cytotoxin, a substance developed by Spirogen (London, UK), which was ac- quired by Astrazeneca’s R&D department Medimmune (Maryland, USA) in 2013. Di- meric PBD binds to and cross-links double- stranded DNA and thereby blocks cell divi- sion. Because the DNA helix is not disrupt- ed, the cancer cell DNA repair process is not activated, thus leading to cell death. ADCT’s two leading drug candidates for haematological cancers are on the thresh- old of registration trials. ADCT-301 targets CD25, a marker for activated and regulato- ry T-cells, and is suggested as a treatment for Hodgkin’s lymphoma (HL) as well as non-Hodgkin’s lymphoma (NHL). Addi- tionally, ADCT plans to use ADCT-301 in combinational studies for solid tumours. ADCT-402 is thought to attack B-cell mark- er CD19-expressing non-Hodgkin’s lympho- ma and B-cell leukaemia. Discontinued for safety reasons Other PBD-based ADCs are under way, too. For instance CD33-targeting drug Va- dastuximab talirine, which was developed by Seattle Genetics (Washington, USA) and studied for treatment of acute myeloid leukemia (AML) and myelodysplastic syn- drome (MDS). The PBD-ADC entered phase III clinical trials, but was discontinued in June 2017 for safety reasons; more precise- ly, due to a higher death rate in patients compared to control treatment. The reason for this phenomenon still remains unclear, but authorities will probably keep tabs on ADCT’s drug candidates. Only a few ADCs have received market approval so far, one of them being orphan drug brentuximab vedotin (trade name Ad- cetris), also marketed by Seattle Genetics. Adcetris entered the pharmaceutical mar- ket in 2011 (USA) and 2012 (Europe) and is used for the treatment of HL as well as NHL cells expressing tumour antigen CD30. Can- cer cells are attacked by the cytostatic drug monomethyl auristatin E (MMAE), which interferes with mitotic spindle assembly and thus leads to cell apoptosis. Other approved ADCs are, for instance, Inotuzumab ozogamicin (trade name Be- sponsa; Pfizer/Wyeth) against CD22-pos- itive acute lymphoblastic leukaemia (ALL) and Trastuzumab emtansine (trade name Kadcyla; Genentech/Roche) for the treat- ment of HER2-positive metastatic breast cancer. ADCT’s phase I drug candidate Photo: Pymouss An idyllic scene close to the Lake Geneva. Between golf courses, the country houses of billionaires and the town hall (see picture), a biotech company is trying to develop sophisticated cancer medicines.

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