Research often requires staying power. This is particularly true for the development of new drugs, where not only the development in the laboratory, but also the ever-increasing official requirements and regulations cost time and money. Prof. Dr. Gundram Jung and Prof. Dr. Helmut Salih have experienced these developments first hand over the past 35 years. Jung has been working on cancer immunotherapy since the early 1980s. His focus has been on antibody constructs capable of recruiting one of the immune system’s most effective cells, T cells, against tumor cells. Helmut Salih joined the team in the 1990s, when he worked as a junior doctor on a clinical trial with bispecific antibodies developed by Jung. “I was immediately convinced by this approach’s potential, and I am honored that I was able to be there 25 years ago when we treated patients with leukemia and glioblastoma with Gundram Jung’s bispecific antibodies—quite successfully so,” recalls Salih, now Medical Director and Professor of Translational Immunology at the Tübingen University Hospital and the German Cancer Research Center (Deutschen Krebsforschungszentrum – DKFZ).
BISPECIFIC ANTIBODIES CAN STIMULATE AND DIRECT T CELLS TO ATTACK CANCER CELLS
“It is gratifying to see that T cell-based immunotherapy is now firmly established in cancer medicine,” says Gundram Jung. “So-called checkpoint inhibitors, CAR T cells, and bispecific antibodies have become cornerstones in the treatment of numerous cancers and are effective even in advanced stages of the disease. These approaches use antibodies either to directly or indirectly stimulate T cells or to direct them to attack cancer cells. Bispecific antibodies can do both, which makes them particularly promising.” However, like the other T cell-recruiting strategies, they currently only achieve lasting success in certain cancers and in a small number of patients. “The difficulties start with the seemingly simple question of how to get immune cells to leave the vasculature in sufficient numbers and migrate into a solid tumor,” says Helmut Salih. “We guide the process by directing our antibody constructs against ‘target molecules’ that are not only found on tumor cells themselves but also on the tumor’s specific blood vessels. In doing so, we can achieve the required influx of T cells.”
A second major improvement of Jung’s and Salih’s strategy concerns the efficiency and duration of T cell activation. For over 30 years, scientists have understood that T cells are activated (effectually as a safety maneuver) in a kind of two-key principle, meaning two different protein molecules on the cell surface have to be stimulated more or less simultaneously—first an antigen-specific receptor and then a costimulatory receptor. If the second, costimulatory signal is missing, the activation is relatively short and is quickly “switched off” again. The receptors involved can be specifically manipulated with antibodies or in CAR T cells. While modern CAR T cells are equipped with both signals (and have only been clinically effective since then), the available bispecific antibodies have, until now, only been able to simulate the first signal. “In Tübingen, we have developed a special combination of bispecific antibodies that stimulate both the first and second signals. The fact that the two bispecific antibodies used in combination are functionally dependent on each other and recognize two different target antigens on tumor cells and vessels allows us to kill two birds with one stone,” Jung explains.
TWO TARGET ANTIGENS AND TWO SIGNALS: TWYCE
“After decades of work, we think our concept can help achieve that quantum leap in bispecific antibody therapy,” says Helmut Salih. “However, since the first steps were taken in the 1990s, a new problem has emerged: the ever-increasing regulatory burden required for both manufacturing and clinical trials significantly slows down the process of getting new drugs, like our antibodies, out of the lab and to the patient. That is why I am even more happy that we are tackling this process in the Clinical Cooperation Unit Translational Immunology at the Tübingen University Hospital with the DKFZ Heidelberg, and that we are now testing more than ten new therapy concepts in clinical trials.” Dedicated staff members on the team with years of relevant experience are taking all the necessary steps in the manufacturing process and during clinical trials. Dr. Martin Pflügler, a trained pharmacist, is responsible for the manufacturing process; Dr. Jonas Heitmann, an internist and oncologist, organizes the clinical trials.
In 2019, the first trial with a bispecific antibody delivering signal 1 was initiated in patients with advanced prostate cancer. Patients responded, but only briefly. Based on the results, the antibody has been used since the end of 2022 in patients with a so-called biochemical recurrence of prostate cancer and thus lower tumor burden. In these patients, a relatively short activation of T cells may be enough for achieving an antitumor effect. For advanced stage patients, a study is planned in which this antibody will be used for the first time in combination with a bispecific co-stimulator (BiCo), which provides the second signal and therefore significantly prolongs T cell activation. This study is scheduled to begin in 2024. Additional bispecific antibodies that should make it possible to treat other cancers, like intestinal or lung cancers, are in advanced stages of development. They are intended to be effective on their own or in combination with other BiCos.
However, public funding alone would not be enough to realize all these ambitions. That is why Salih, Jung, and Pflügler recently founded TWYCE GmbH. Together with the Federal Agency for Disruptive Innovation and the SPRIND subsidiary BiconY, founded in May 2023, the team is taking greater steps towards overcoming the existing hurdles and achieving their goal of declaring war on cancer.
“Gundram Jung and I always wanted to be like Paul Ehrlich: Developing drugs and treating patients directly in the clinic with them. Nowadays, the capital required to do this can ultimately only be raised through a company spin-off, and we are glad that SPRIND is supporting us in these steps.”
THIS IS WHY WE ARE COMMITTED Because we care about the well-being of our patients. Because after years of intensive research, we have succeeded in developing a promising platform that has the potential to help a great number of patients. Because we believe we can successfully treat solid tumors with this approach.
WHAT WE DO Conduct toxicity studies. Prepare and conduct a Phase I clinical trial to test the efficacy of our innovative drug combination in patients with metastatic prostate cancer. Prepare and conduct a clinical phase I study in patients with metastatic lung cancer. Develop new and innovative drug combinations for other solid tumor diseases. Collect scientific results and make them available to society.
QUANTUM LEAP IN CANCER IMMUNOTHERAPY At the end of the project, a pipeline with potentially groundbreaking active substances will be available to combat solid tumors.
THIS IS THE POTENTIAL WE SEE New treatment options for cancer patients and replacement of standard therapies associated with many side effects.
