Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

The therapeutic antibody eculizumab caught in action

06.06.2016

In collaboration with Alexion Pharmaceuticals, Inc., scientists from Aarhus University have used X-rays to understand how the therapeutic antibody eculizumab prevents our immune system from destroying red blood cells and damaging kidney tissue.

The scientists in Aarhus studied an important protein from the innate immune system called C5 which is cleaved by enzymes when pathogens invade our body as a defense mechanism. The two C5 fragments formed through this cleavage recruit immune cells to fight the pathogen and may directly kill it.


The atomic structure of C5 (blue) bound to the C5-binding part of eculizumab (yellow) shows how eculizumab blocks the cleavage of C5 in blood circulation. This rescues the red blood cells (red disks) from disruption. In real life the proteins are 500 times smaller than the red blood cells.

Credit: Janus Asbjørn Schatz-Jakobsen

Our own cells are protected against damage caused by cleavage of the C5 protein. But in two rare diseases called paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), this protection is lost due to mutations in our DNA. Patients suffer as their red blood cells and cells in the kidney are continuously damaged, and the diseases are life-threatening.

The global biopharmaceutical company Alexion, headquartered in the U.S., has developed a therapeutic antibody called eculizumab that prevents the cleavage of C5 and thereby treats the two diseases.

The research was performed by PhD student Janus Asbjørn Schatz-Jakobsen and Professor Gregers Rom Andersen at the Department of Molecular Biology and Genetics at Aarhus University in Denmark in collaboration with scientists at Alexion and is now published in The Journal of Immunology with a figure from the article on the cover of the July issue.

Description of tthe research project

Janus first purified C5 from human blood plasma and then mixed it with a fragment of the eculizumab antibody prepared by Alexion solely for this collaboration. After many attempts, Janus managed to form crystals containing the complex between C5 and the antibody fragment. In the following year, more than 200 crystals were investigated by Janus using very intense X-ray radiation at large international facilities in France.

After a total of 18 months with careful and tedious work, Janus was finally able to describe the atomic structure of C5 bound to the eculizumab fragment. This structure revealed that the antibody creates a physical barrier that prevents the cleaving enzymes from forming contacts with C5.

On the other side of the Atlantic Ocean, scientists at Alexion in parallel performed biochemical experiments in which the function of antibodies carrying mutations in regions responsible for binding to C5 were compared to the normal eculizumab antibody.

Janus Asbjørn Schatz-Jakobsen explains: "When I had finished my atomic model and was awaiting the results from Alexion for comparison, I felt almost like a small child waiting for X-mas eve. When the result arrived by email, I could quickly confirm that there was an excellent agreement between my results and those obtained by the Alexion scientists, which confirmed that my model was correct. It was quite a relief and the results from Alexion also made me discover new exciting aspects of my atomic structure that I had not noticed yet."

The new research has also helped the scientists at Aarhus University to better understand the mechanism by which C5 is cleaved by enzymes in the absence of eculizumab. At Alexion, the atomic structure is now used as a framework to understand in details how their therapeutic antibody works and treats the two diseases.

Read the article published in The Journal of Immunology.

For further information, please contact

Professor Gregers Rom Andersen
gra@mbg.au.dk
mobile: 45-3025-6646

PhD student Janus Asbjørn Schatz-Jakobsen
janusasj@mbg.au.dk
Tel. 45-8715-4201
Department of Molecular Biology and Genetics
Aarhus University, Denmark

http://www.au.dk 

Professor Gregers Rom Andersen | EurekAlert!

More articles from Life Sciences:

nachricht What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Simple processing technique could cut cost of organic PV and wearable electronics

06.12.2016 | Materials Sciences

3-D printed kidney phantoms aid nuclear medicine dosing calibration

06.12.2016 | Medical Engineering

Robot on demand: Mobile machining of aircraft components with high precision

06.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>