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discovered_01_2015

discovered 01.15 FOCUS WWW.HZDR.DE An add-on system with a one-size-fits-all module Instead of working with just one ‘Lego brick’, Arndt uses two of them – a target module and an effector module. The target module is an adapted (monospecific) antibody that can connect with a molecule on the cancer cell on one side and features an easily detected structure on the other – a unique ‘peptide-epitope’ created by the research group. The effector module is a bispecific antibody, which means it connects with this peptide-epitope as well as the immune cell. ‘The outcome is the same: tumor and T-cells are connected,’ Arndt says. ‘The advantage is that we can use the effector module universally and combine it with any target module.’ It is no longer necessary to run complicated tests to see whether the bispecific antibody has changed during its adaptation to a new cancer target. This offers great advantages for patients. The modular system can target several structures on the cancer cell. ‘We simply combine the effector module with two, three or more target modules that can detect various target structures on the cancer cells,’ Arndt explains. This greatly increases the chances of therapy success because tumor cells are adaptable, and when they alter the surface structure at which a regular bispecific antibody is supposed to dock, the therapy is no longer effective. ‘Yet it is less likely that a tumor will change several of our targeted surface structures at the same time.’ Immunotherapy plus radiation The modular system is so flexible that it can also be combined with conventional cancer therapies such as radiation. When tumor cells are irradiated and destroyed, proteins are Researchers are seeking to redeploy antibodies as cancer drugs because they are the tools of the body’s own immune system. Normally, antibodies only fit one specific target structure – a molecule on the surface of a virus, a bit of pollen or a protein on a cancer cell. Each immune cell generates only one type of antibody, which binds to only one single target – the same way a Lego brick fits onto another. Upon docking on their target, the antibodies sit on the surface of the immune cell like the spines of a hedgehog, immediately causing the cell and the antibodies to multiply rapidly, spawning innumerous antibodies of a particular type, which can grab on to a foreign body. Scavenger cells can then annihilate it. Researchers had the idea that this immune reaction could be improved by constructing bispecific antibodies that can simultaneously identify two targets, just as a Lego brick can be connected at the top and at the bottom. When an artificial bispecific antibody connects with both a cancer cell and an immune cell, an immune reaction is triggered in the patient, leading to the destruction of the tumor. Promising drugs Patients already benefit from this principle. At the end of last year, US authorities approved ‘Blinatumomab’ as the first bispecific antibody cancer treatment. The drug, which was initially developed in Germany by Micromet, detects a structure named CD3 on defense cells and the receptor CD19 on cancerous blood cells in patients with acute lymphocytic leukemia (ALL), triggering a defense reaction that fights back the cancer. The system is so promising that pharmaceutical companies are currently developing many families of bispecific antibodies. But the drug isn’t perfect, which is why pharmaceutical researcher and cancer immunologist Michael Bachmann and his research group, of which Claudia Arndt is a member, are on a mission to further improve the mechanism. Arndt never envisioned a career in the medical field as such. ‘But the idea of doing research close to human subjects has always fascinated me.’ Immunobiology is ‘a great way to combine biology and medicine,’ the young researcher says. She is undaunted by the fact that it involves long hours of wielding pipettes and lengthy experiments that often lead to dead ends. ‘You know why you’re doing all this, you know that it could eventually save a patient’s life.’ And it could also help improve an effective therapeutic principle. ‘When you’re looking to develop a new bispecific antibody, you could actually keep the part that binds the immune cell and only change the part that detects the specific type of cancer,’ says Arndt. But altering one end could in fact affect the binding properties of the other end, because the entire structure of the molecule changes. If you hold a lighter to one side of a Lego brick, the other side is deformed, as well. Which is why so far, it has been necessary to create new bispecific antibodies from scratch. ‘Each new bispecific antibody must be tested to see whether it genuinely binds the T-cell,’ says Arndt. This is a real nuisance. ‘To address this, we have developed a modular system.’ Claudia Arndt The 28-year-old completed both her biology degree at TU Dresden and her four-year dissertation in the field of tumor immunobiology at the Medical Faculty Carl Gustav Carus with distinction. The talented junior researcher’s name is on a total of 16 publications. Adding up the impact factors of the individual papers - that is a point value attributed to the status of the journal where a paper is published – she garners a whopping 80 points. In 2015, Arndt won third place in the ‘Young Investigator Award’ at the ‘Tumor Immunology meets Oncology XI’ conference. Her future work at the HZDR Institute of Radiopharmaceutical Cancer Research will continue to revolve around universal antibodies for the immunotherapeutic treatment of cancers.

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