Decoding complement – IgG recruitment, Hexamerization, and C1q binding in Real-Time

The complement cascade, an integral part of the human immune system, is activated by pathogen-bound antibody complexes. However, the formation of these complexes is not well understood. The research team combines pharmaceutical expertise with specialized biophysical tools to study this process in order to make antibody-therapeutics more effective.

Eingereicht von: Dr. Johannes Preiner
Dr. Jürgen Strasser
Firma/Universität: FH OÖ Forschungs- und Entwicklungs GmbH
Kooperationspartner: Genmab; Leiden University Medical Center, Johannes Kepler Universität Linz

Topic and field of research - Foto: (c) Johannes PreinerThe human immune system protects us from invading pathogens and diseases like cancer by distinguishing “self” from “non-self”, and attacking the latter. It does so in a variety of ways, one of which is the human complement system. This cascade of proteins and enzymes in the bloodstream is activated by antibodies binding to potential threats in our bodies. Antibodies are Y-shaped molecules, which can recognize and bind to their target (so-called antigens on the surfaces of bacteria, viruses, or tumors) with high specificity. However, to ultimately activate complement, they must additionally arrange into ordered complexes on the pathogen surface consisting of six individual antibodies (=hexamers). It is these hexamers that the complement system recognizes (rather than single antibodies), ultimately leading to pathogen removal. How they form, however, is not well understood. This leaves physicians and pharmaceutical companies in a difficult position, as they have to rely on a degree of trial-and-error when designing new drugs and therapies based on complement activation. There have been great successes in the field, but truly targeted antibody design and formulation remains challenging.

Aims and goals

The research team consists of experts in the fields of pharmacology, biotechnology, immunology, and biophysics, which come together to study antibody hexamerization and complement activation in unprecedented detail. The goal is to fully characterize and understand the process in order to rationalize differences in drug potency between formulations as well as targeted disease types.

Approach and execution

Genmab is an expert in the field of biotechnology and focuses on the creation and development of antibody therapeutics. Their antibodies, both unmodified molecules and specially prepared versions with a variety of properties, are used in the project, ensuring the highest level of quality and relevance to the field. The team in Linz uses the provided material, along with data about their biological activity, in a range of biophysical assays. Antibody-antibody interactions are characterized on the single-molecule level using atomic force microscopy-based dynamic force spectroscopy, mimicking the situation in the bloodstream (that is, when no pathogen is present). The complementary situation, where antibodies bind to their target as well as to each other, is studied in ensemble measurements using quartz crystal microbalance. Together these approaches are able to describe and characterize molecular processes in the immune system, but the most direct evidence comes from high-speed atomic force microscopy, which enables the team to observe individual antibodies directly and without modification in real time. In this manner it becomes possible to “film” their binding and hexamerization behavior. This unique combination of fields and techniques – from biological activity to the single molecule level – holds great potential not only for the characterization of antibody hexamerization, but also for further studies of complex processes relevant for medicine and human health.

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