‘Basic research is needed more than anything else’

Pharmaceutical company Gilead recently acquired German biotech startup Tubulis for $3.2 billion (£2.3 billion). The deal saw Gilead acquire two of Tubulis’ antibody–drug conjugates (ADCs) that have shown promising results in early-stage clinical trials.

One ADC treats platinum-resistant ovarian cancer, while the other targets various solid tumour types. At the heart of these drugs lies clever phosphorus chemistry that adds hydrophilic polyethylene glycol (PEG) polymers to antibodies to make them more soluble, stable and improve their pharmacokinetic properties.

‘We were fascinated by this area, this newborn field of bioorthogonal chemistry and bioconjugation,’ says one of Tubulis’ co-founders Christian Hackenberger at the Leibniz Research Institute for Molecular Pharmacology in Germany. He spun out the company in 2019, alongside Heinrich Leonhardt at LMU Munich in Germany and two other researchers from their labs.

‘I was particularly fascinated by phosphorus reactions, especially Staudinger reactions,’ says Hackenberger. His team initially used such reactions to link a phosphite carrying three PEG groups to azide-labelled proteins. Hackenberger explains that his team later developed this into a system called P5-labelling, creating phosphorus(v) compounds with various side groups – typically including a long-chain PEG polymer, an alkyne group and a drug compound. Cleaving disulfide bonds in antibodies then exposes cysteine groups to react with the phosphorus’ alkyne group to create an ADC.

‘With P5 labelling we could provide the chemistry and the bio-conjugation and make all the conjugates. And then in [Leonhardt’s] lab, they did the first evaluation of the cytotoxic activity,’ he says.

Hackenberger explains that his team’s ADCs – those now acquired by Gilead – were far more hydrophilic than those already on the market. The method also allowed for greater flexibility in choosing a payload drug, as well as higher drug loadings on each antibody without compromising solubility and other properties.

‘In retrospect, this all sounds like an autobahn, like a fast track to success,’ says Hackenberger. ‘But, of course, there were also struggles in between.’

He explains the first attempts to get funding for the company failed as ‘it was not necessarily a time where ADC research was fashionable’. A combination of basic research funding and support from the German Science Foundation for early stage start-ups helped get Tubulis off the ground. Investors later provided extra funding once the government’s two-year support programme had finished. ‘We were very fortunate that at each of these time points, we really had the data to be convincing,’ says Hackenberger.

He has since reflected on what the process of commercialising fundamental research has taught him: ‘I learned how to think about patents, how to think about publishing [studies] and still being able to drive innovation… [and] to think strategically in terms of when is a good time for funding the company and when not.’

‘To [now] be at the point where you really see these clinical results… it’s unbelievable,’ he says, adding that being able ‘to generate something that has a real translational impact [is] a dream coming true’.

‘The whole story really tells you that basic research is needed more than anything else,’ says Hackenberger. ‘When we work with some strategic thinking, with good innovation, with the right team, we can make impact. We should not forget that as scientists that it is in our hands to do that.’