Lars Perk - Applied Research

While studying Molecular Science at the University of Wageningen in the Netherlands, Lars Perk (1977) discovered his passion for organic chemistry with a biological component. Perk: “After my internship at the University of Trondheim in Norway, I was sure that I wanted to follow the PhD trajectory. The only condition I set myself was that the results of my research had to have a practical use”.

PhD trajectory
In March 2003, just a few months after finishing his master’s degree, Perk found a PhD position at the ear, nose, and throat department at the VU University Medical Center in Amsterdam. Perk says: “The applied side of the research seemed very interesting to me because it covered topics in chemistry, biochemistry, and medicine. Besides that, the goal of the research caught my attention: improving technologies to demonstrate that the antibodies used for the treatment of cancer actually accumulate in the cells of a tumor”.
In the first year of his research, Perk gained basic knowledge about radiochemistry. After this first year, he shifted his focus to details, for example, the possible ways to localize cancerous growth with positron emission tomography (PET). This detection technique involves inserting a radioactive isotope — a ”radionuclide” — into the patient; while the isotope decays, it emits positrons. Usually these radionuclides are implanted or connected to another substance, for example, an antibody. The radioactive-labeled antibody at this point connects to tumor cells, which allows the isotope to attach to a cancer cell, which can then be localized by using a PET scanner.

Minimizing the half-life
Perk explains: “Especially the half-life of the radionuclide is important. In PET research the isotope [¹⁸F] is commonly bound to fluorodeoxyglucose. However, [¹⁸F] has a half-life of less than two hours. That works well if you want to see where the body consumes sugar, but if you want to use antibodies, then you are bound to the fact that it takes a few days before antibodies will have spread out over the body and been absorbed by or attached to the tumor cells. To match the biological dispersion time of an antibody, a different radionuclide is chosen, such as ⁸⁹Zr or ¹²⁴I, because it stays active for several days”.
“Before I started,” tells Perk, “two PhD students had already done research on these long-lived radionuclides. Both radionuclides are interesting because they have exactly the half-life needed to accumulate in tumors. That takes about three days.” Perk was now facing the challenge of how to prepare ⁸⁹Zr and ¹²⁴I for use on a larger scale, and how to develop ⁸⁹Zr in such a way that would be safe to be used on humans.

Biochemical puzzle
After Perk had studied the basic principles of working with radioactivity, he was prepared to tackle the question of how to connect ⁸⁹Zr to certain antibodies. This would allow for the radioactive-labeled antibody to be attached to a cancer cell as a marker. According to Perk: “It is much more complicated to connect zirconium to an antibody than iodine radionuclides, because the connections require a biochemical interface, a “chelate.” It was a complicated biochemical puzzle to master this connection”.
Together with the American company Macrocyclics, Perk searched for a widely applicable connection method. In the third year of his research, he managed to reduce the six steps of this technique to two simple steps. Since then, this method has been continuously refined.

Glowing tumor cells
The main question at this point was the applicability of this new way to connect ⁸⁹Zr to antibodies. To answer this question, ⁸⁹Zr-labeled antibodies were injected in mice with a minor malignant growth. Perk tells: “After a few days it is possible to see if radioactive-marked antibodies accumulate or not. Generally speaking, the tumor itself lights up on the screen of the PET scanner, the surrounding tissue does not”.
Perk’s preclinical results produced very clear images of glowing tumor cells, making a big impression on international colleagues. Yet, the method, referred to as “immuno-PET,” is not only recognized by researchers. The pharmaceutical industry is showing interest in the results as well, especially because these new antibodies are able to detect the malignant growths in a better and much faster way. That, of course, accelerates the development of new medicinal products.

Commercial application
What is remarkable for an academic researcher is that Perk himself keeps his eye on the commercial application of his findings: “The American company that collaborated with us immediately showed interest in the results and made the decision to start with the commercial production of this chelate. The scientific description of the substance is p-isothiocyanatobenzyl-desferrioxamine. Its commercial production now allows ⁸⁹Zr to be applied on a large scale, for the first time”.

Putting knowledge into action
“The first project after starting my position as head of research at BV Cyclotron VU was to set up the production of ¹²⁴I. We had a small test production site at the Radionuclide Center. The challenge was to set up a commercial production line based on their lab version. It is mainly a matter of cost and scale, while meeting all requirements of a GMP-compliant environment. I was given the task of coordinating everything from the initial plans to the construction of the new labs.
After I successfully completed that first commercial production line, I started working on a production line for ⁸⁹Zr. That was exciting, of course, as it allowed me to put knowledge from my PhD research into practice. Basically, we were building on the results of my PhD research. With the experience gained from setting up the ¹²⁴I production line, things went very smoothly.

New Production line
At the moment, I am setting up yet another production line. The nice thing about this kind of work is that I have contact with very different people: researchers, engineers, architects, and construction companies. As the research project manager, I must have knowledge on a very wide range of subjects”.
Perk hardly works in the lab himself anymore. With several new production lines coming up, several new cyclotrons being installed, and the move of BV Cyclotron VU to the new Imaging Center, he is now fully focused on project management. Perk says: “I am involved in the early ideas, the design phase, all debates with the local regulators, and so on. One thing that I learned from all this is that long-term collaboration with the same third-party contractors pay off: projects advance much faster, smoother, and the overall quality of the product is higher”.

Motivation
The future prospects for new diagnostic methods remain an important motivation for Perk: “In retrospect, the most memorable aspect of my PhD work was the variety of the research, stretching from the lab to clinical studies. I enjoyed the contact with doctors and patients. And now I still see my experience and knowledge being applied in clinical settings on a daily basis. I can’t think of a better motivation for doing my work”!

The PhD research of Lars Perk was financed as part of the Open Technology Program of the Dutch Technology Foundation STW.