Research | FMP | 02-03-2021

Cytotoxin-carrying backpacks

Professor Christian Hackenberger conducts research into protein-based biopharmaceuticals that can be used as a targeted approach to treat cancer and viral infections. At the Berlin Science Week in early November, the FMP researcher received the “Breakthrough of the Year” award.

The new technology enables a simple way of connecting the cytsteine residues (SH) of a tumor-sensing antibody (yellow) to toxic drug molecules. The emerging linker is highly stable during blood circulation and enables therefore a safe transport to the tumor side. | Visualization: Barth van Rossum/FMP

Professor Hackenberger, congratulations on the award. I suppose you were not able to properly celebrate this distinction due to the current situation. Did this put a damper on your spirits?

It all took place online, but no, it didn’t dampen my spirits at all. I was really delighted, particularly because I received the award in the Life Sciences category, despite being a chemist. This was completely unexpected.

And yet you have already managed to block the flu virus using a kind of molecular superglue. Now you’re hoping to tackle the coronavirus. Is there hope of antiviral treatment against COVID-19 any time soon? 

We are working hard to adapt our phage capsids to the coronavirus, and I can say that the first results look very promising. However, this approach is so very new that we will need a lot more time before we can enter the clinical phase. So, I‘d rather not raise unrealistic expectations for the current pandemic. But I am confident that our concept is applicable to other viral infections caused by coronaviruses as well as the flu virus. And then we would have a platform that could also be transferred to any other virus.

Your approach is based on the use of harmless viruses to combat dangerous viruses. How does the whole thing work?

The basic concept is that we chemically modify empty, non-infectious shells of a phage virus so that the dangerous virus is completely enveloped and can no longer infect human cells. These phage capsids function like a kind of superglue that sticks perfectly to the binding sites of the virus. It is also our virus-specific design that makes the approach so special. It has enabled us to render influenza viruses harmless in human lung models from Charité. The challenge with the coronavirus is finding out the routes it uses to bind to lung cells or other cells of the body. We’re dependent on ongoing findings from the community for this – but, as I said, we are on the right track.

Your second breakthrough of the year – the development of antibody-drug conjugates, or ADCs for short – also concerns targeted design.

The award refers to a technology we have developed that enables antibodies in cancer immunotherapy to be loaded with a drug that is then released in the cancer cell exactly where it is needed. The basic idea is to spare patients the side effects of chemotherapy. The results were so successful that, together with our partner Ludwig-Maximilians-Universität München (LMU), we founded Tubulis as a spin-off in 2019. Within this company, ADCs are now being further developed and brought to the market, with Dominik Schumacher, a former PhD student of mine, in the role of CEO.

Tubulis succeeded in attracting almost eleven million euro in capital this summer. What was it that inspired the investors?

I reckon the decisive factor was our ability to demonstrate that our preparations are better than a drug that has already been approved. But that’s not all. I also think we were able to convince them as an entire team. After all, there is still close collaboration between Tubulis, LMU and FMP.

Better than an approved drug – what do you mean by this?

We conducted a comparative study with the antibody-drug conjugate Adcetris®, which is approved for the treatment of Hodgkin lymphoma. We reconstructed this drug 1:1, the only difference being that we linked the antibody and the active agent to our patented P5 technology. Subsequent preclinical trials showed that our “P5-Adcetris” is much more stable and effective than the original version. Ultimately, survival time doubled in our in-vivo experiment.

What makes the approach so superior?

It is the way we bind drug molecules to an antibody. To do this, we developed a chemical process and another process that works with a natural enzyme. If you imagine the antibody as a sniffer dog that is able to recognize cancer cells based on certain characteristics – whether receptors on the cell surface or certain sugar structures – then we have redesigned the backpack it uses to deliver the cell toxin, as it were. And this backpack is attached so securely to the sniffer dog’s back that the payload is not dropped en route, but is released at the right time, in the right place. Chemotherapy can therefore act directly where it is needed, leaving healthy cells intact. The weakness of previous conjugates was their lack of stable linkage between antibody and drug, which in some cases led to nasty side effects.

When will you be able to show in humans that your technology is better?

I think we will be able to achieve this more quickly than the antiviral drugs. A time horizon of a few years would be conceivable for our lead candidate for treatment of lymphatic diseases. It is too early to say anything about other tumor entities because the whole system has to be readjusted each time. You need the right antibody and the specific drug, which will then be effective against this precise tumor. This is far from trivial.

To clarify matters: you don’t develop the antibodies yourself, do you?

No, we don’t. What we do in my research group is add functionality to an existing antibody. The possibilities go far beyond the delivery of chemotherapeutic agents. But our partners at LMU, and in particular Professor Heinrich Leonhardt’s research group, develop new antibodies. In other words, we are working on all fronts to keep our pipeline filled.

What other plans do you have besides cytotoxin-carrying backpacks?

In the area of targeted drug delivery, we are also addressing how to get antibiotics to bacterial infections that are difficult to access. In addition, antibodies can also be used for diagnostic purposes by displaying a kind of warning blue light that enables a physician to view cancer cells that have been detected. A whole range of other new methods and fields of application are also at the planning stage, but these cannot be revealed yet.

You are a chemist and now also an entrepreneur. How do you feel in this dual role?

I am merely part of a large scientific community, rather than seeing myself as a chemist or an entrepreneur. It fills me with pride and motivation to collaborate with colleagues from other areas, especially in industry, to find solutions that add value to society. And by the way, despite being one of the four co-founders of Tubulis and contributing to strategic planning, I am not involved with day-to-day operations. Dominik is so good at it that I can only applaud in the background.

And what wishes does Christian Hackenberger, the researcher, have for his own future?

That we can successfully finish off what we have started, of course. Personally, I hope to be able to retain my scientific curiosity and creativity, so that I can keep tackling new challenges. And, of course, that my enthusiasm for our research will continue to attract such fantastic students and staff as in the past. This is, and remains, one of the greatest gifts that a university lecturer can hope to receive!

The interview was conducted by Beatrice Hamberger.
Translation: Teresa Gehrs

 

Contact

Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)

Prof. Dr. Christian Hackenberger
Phone +49 30 94793-181
Email hackenbe@fmp-berlin.de
https://www.leibniz-fmp.de/hackenbe
Twitter @PhosphorusFive

Silke Oßwald
Public Relations
Phone +49 30 94793-104
Email osswald@fmp-berlin.de
Twitter @LeibnizFMP
https://www.leibniz-fmp.de/