Powered by

Testing a new antibody therapy for treating blood cancer

The fight against acute myeloid leukaemia is a long one. Cancer cells that cause the disease to recur may remain despite initially successful destruction of the tumour with chemotherapy drugs. Now researchers from Tübingen have identified an antibody that could potentially prevent cancer recurrence.

Prof. Dr. Helmut Salih is an internal medicine expert and specialised in haematology/internistic oncology. He has been professor for translational immunology at the DKFZ's partner institute in Tübingen, the German Consortium for Translational Cancer Research (DKTK), since 2014. © Tobias Schwerdt / DKTK

In March 2017, doctors from Tübingen University Hospital joined forces with a company called SYNIMMUNE GmbH to carry out a phase I clinical trial that may usher in a new era for leukaemia treatment. The trial assesses the safety and efficacy of the new immunotherapy treatment in a cohort of patients with acute myeloid leukaemia (AML). The new therapy involves an antibody called FLYSYN that binds to a protein called FLT3 present on the surface of leukaemia cells. After binding to FLT3, the FLYSYN antibodies are able to stimulate immune system cells, in particular natural killer (NK) cells, with the antibody portion that points away from the cell. Stimulation enables NK cells to recognise and destroy cancer cells. The development of this therapeutic approach and the antibody are a hard-won research success that owes a great deal to the long-term commitment of the Tübingen researchers. The unusual cooperation between science and industry also played a crucial role in the development of the antibody therapy.

FLYSYN is an antibody for treating AML patients at the minimum residual disease stage. The antibody binds highly specifically to FLT3 receptor proteins on the surface of leukaemia cells. The FC fragment of FLYSYN was optimised to bind and stimulate natural killer (NK) cells of the human immune system. © SYNIMMUNE GmbH

Glossary

  • Antigens are foreign substances that stimulate the immune system to produce antibodies.
  • Antibodies are blood proteins (immunoglobulins) which are produced by the B lymphocytes in response to disease. They recognise foreign substances that have entered the body (e.g. bacteria) and help the body fight against a particular disease and develop an immunity to that disease.
  • A gene is a hereditary unit which has effects on the traits and thus on the phenotype of an organism. Part on the DNA which contains genetic information for the synthesis of a protein or functional RNA (e.g. tRNA).
  • Immunology is a scientific discipline dealing amongst others with the defence reactions of humans and animals against organisms such as bacteria, fungi, and viruses, but also with the defence reactions against foreign (non-self) cells and tissue or own (self) cells and tissue (autoimmune reactions).
  • Selection in a biological context means the assortment of organisms due to their characteristics. On the one hand, this could be natural selection ("survival of the fittest") like in evolutionary processes. On the other hand, selection by man, e.g. breeding, is called artificial selection. Artificial selection is also used in genetic engineering to identify a genetically modified organism due to its new characteristics (e.g. resistance to antibiotics).
  • Stem cells are cells from the embryo, fetus or adult that that have the ability to divide for indefinite periods in culture and give rise to specialized cells. In Germany it is illegal to extract the stem cells from embryos.
  • Immunotherapy is a kind of treatment for diseases, which involves and utilises the immune system. Immunotherapeutical methods are applied amongst others to treat allergies, cancer, infections and autoimmune diseases.
  • In general, dysplasia is a malformation, e.g. of a body part. In a histological context, dysplasias are abnormal tissue structures, which can be pre-stages of cancer.
  • Expression means the biosynthesis of a gene product. Usually, DNA is transcribed into mRNA and subsequently translated into proteins.
  • Leukaemia is a malign disease (cancer) of the hematopoietic system. It disturbs the generation of blood cells in the bone marrow by increased formation of degenerated white blood cells and their precursor cells. Other components of the blood are displaced. This leads to anaemia, infections and bleedings and finally to the death of the affected person, if leukaemia remains untreated.
  • Haematopoiesis is the process of the generation and maturation of blood cells. This process takes place in the red bone marrow in the human body, where the haematopoietic stem cells are located. The decision which type of blood cell (e.g. platelets, red or white blood cells) develops from the blood stem cells mainly depends on the growth factors that are present during maturation.
  • Plasticity is the attribute of organisms to change their characteristic values under the influence of environmental factors. Therefore, neuroplasticity is the characteristic of neurons to change their response behaviour dependent from their activity. In most cases, the strength of the synaptic transmission is influenced (synaptic plasticity). The neuroplasticity or synaptic plasticity, respectively, is considered to be the basic mechanism in learning processes and in the formation of memories.
  • Aggregation is the forming of a functional cluster of cells or molecules.
  • Good Manufacturing Practise.
  • Biomolecules which can bind active agents are called targets. They can be receptors, enzymes or ion channels. If agent and target interact with each other the term agent-target-specific effect is used. The identification of targets is very important in biomedical and pharmaceutical research because a specific interaction can help to understand basic biomolecular processes. This is essential to identify new points of application.
  • Engrafting cells, tissue or organs from a donor into a recipient is called transplantation. There exist several types of transplantation which are classified in three categories: function, location and derivation. Engrafting an organ of a different species into a recipient is called xenogenic transplantation, whereas an allogenic transplantation describes the tranfer of grafts from a donor into a recipient being a member of the same species. If donor and recipient are the same individual, the transplantion is called autogenic. Furthermore there exists a syngenic transplantation which is characterized by grafts originating from the uniovular twin. Furthermore, engrafting artificial material is called alloplastic transplantation. To suppress the natural immune response being raised by the transplanted organs, recipients have to be administered immunosuppressants. Since 1997 in Germany the legitimacy of organ donation is regulated by the Transplantation Law. In the case of brain death, an organ donor card has to be available or relatives have to agree with the organ donation. Today, the most frequently transplanted organs are heart, liver, kidney and cornea.

Prof. Dr. Helmut Salih from the Department of Internal Medicine II in Tübingen is coordinating the FLYSYN trial and was also involved in the development of the antibody therapy. Salih comments on initial difficulties: “The problem is that hardly any antigens are expressed solely on malignant cells. The binding of antibodies to healthy cells would lead to severe adverse drug effects. The objective is therefore to reduce off-target binding by selecting suitable and highly selective target antigens. For me, FLT3 is one of the best antigens available for treating acute leukaemias. This is because high amounts of FLT3 are measured on leukaemic blast cells while only low amounts are expressed on healthy immune system and haematopoietic progenitor cells. We have not yet observed any destruction of haematopoietic cells by the antibody either in vitro or in patients treated in experimental treatment settings.”

Salih went on to credit those who were instrumental in identifying FLT3 as an anti-cancer antigen: “Prof. Dr. Gundram Jung and Dr. Ludger Große-Hovest from the Department of Immunology at the University of Tübingen have made an outstanding contribution to the identification of FLT3. They have been working on the identification of antibodies for treating cancer for many years. The three of us selected FLT3 for treating AML.”

Exemplary cooperation between industry and academia

Dr. Martin Steiner has been the CEO of the biotechnology company SYNIMMUNE GmbH from Tübingen since March 2016. © SYNIMMUNE GmbH

Jung, along with Große-Hovest (CSO of SYNIMMUNE GmbH), has also been actively involved in the development of FLYSYN. The development of the AML antibody therapy was strongly supported with funds from the German government in the form of two successful GO-Bio proposals submitted between 2008 and 2015. These funds contributed to spinning out SYNIMMUNE GmbH from the Department of Immunology at the University of Tübingen. FLYSYN is now the young company’s lead product. Dr. Martin Steiner, CEO of SYNIMMUNE GmbH, explains: “The development of FLYSYN was given priority in the second GO-Bio phase and used up most of our funding. Amongst other things, the money was used to develop the antibody production process under GMP conditions.” Salih points out that this was something very special: “This was the first time that a therapeutic antibody had been developed in an academic setting. This was made possible because the University of Tübingen had established its own GMP building.” In 2015, SYNIMMUNE produced the first FLYSYN batch in this GMP laboratory. This batch has been approved for use in the ongoing phase I clinical trial.

The trial is for AML patients who have undergone standard treatment and are in complete haematological remission. Steiner explains: “From a medical point of view, these patients are considered healthy as no leukaemia cells are detectable under the microscope. The trial treats patients in whom genetic markers for leukaemia-specific mutations can still be detected, and who therefore have a high probability of suffering a relapse. A few weeks after standard therapy when blood formation has recovered, these AML patients are given the FLYSYN antibody to eliminate potentially remaining leukaemia cells.” The researchers hope that this “relapse strategy” will prevent the disease from recurring.

Salih explains why the new drug is not used for primary treatment: “Immunotherapies generally work better the lower the tumour burden. Although the NK cells of the immune system are activated by FLYSYN, their efficiency nevertheless depends on the number of malignant cells – the fewer the better. This is why the optimum point to apply antibody treatment is thought to be after standard chemotherapy treatment, i.e. when treatment has reduced the tumour burden, leaving just a small number of tumour cells. In addition, there is a clearly recognised legal reason for this: the use of completely new drugs is not generally permitted before the patient has undergone established standard cancer therapy."

SYNIMMUNE expands antibody development with platform technology

Producing the FLYSYN antibody under GMP conditions requires specifically trained GMP personnel. The photo shows two SYNIMMUNE employees performing sterile filtration. © SYNIMMUNE GmbH

Volunteers are still needed for the phase I clinical trial. Suitable patients must not, amongst other things, already have received stem cell transplants. The trial is designed as a multicentre trial and is therefore being carried out in Tübingen, Heidelberg and Ulm. Steiner also mentioned that there is a plan to take further study centres on board. Meaningful interim results are expected for the second half of 2018. SYNIMMUNE will be in charge of marketing the antibody in future, potentially in collaboration with a sales partner. In addition to the clinical trial, SYNIMMUNE and its clinical partners are also working on expanding the therapeutic principle. “The cancer cells of acute lymphatic leukaemia (ALL) patients also express FLT3. And FLT3 is also found on the surface of malignant cells in patients with MDS*, which is a pre-leukaemia stage. We want to use the antibody for treating these diseases as well,” says Salih.

SYNIMMUNE is not entirely reliant on FLYSYN. Steiner outlines the company’s long-term platform strategy: "We are also working on a platform technology for bispecific antibodies in which the antibodies are structurally modified to form no or very few aggregations. Aggregations can prevent antigen detection and cause side effects. If such aggregations can be excluded, higher dosages could be given, which in turn should improve treatment efficiency. "The company's overall goal is to develop even more potent, better antibodies that can also be used, for example, in combination therapies and for other types of cancer.

*MDS: myelodysplastic syndrome (ed. note)

 


Recruitment – information about the phase I trial with FLYSYN:

Recruitment of patients is not yet closed. Interested and suitable AML patients can still be included in the trial (as of October 2017). In addition to Tübingen, the trial will also be carried out in Heidelberg and Ulm. For further information, please visit:

http://www.uniklinikum-tuebingen-studien.de/aml-studie

 

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/testing-a-new-antibody-therapy-for-treating-blood-cancer/