Researchers of the Paul-Ehrlich-Institut have developed a humanised mouse model that can be used to predict severe adverse immune reactions after administration of the monoclonal antibody TGN1412. A few years ago, the antibody led to severe immune reactions as a result of a cytokine storm in a clinical trial with healthy volunteers. The humanised mouse model can contribute to increasing the safety in first-in-man use of certain antibodies. PLOS ONE reports on the research results in his online version of March 9, 2016.
TGN1412 – the effects of the clinical trial with this humanised "superagonistic" monoclonal antibody can still be felt today. TGN1412 was developed for the treatment of rheumatoid arthritis and a particular form of leukaemia.
In 2006, the antibody was administrated in a first-in-man study to six healthy volunteers in the UK. All volunteers developed massive release of immunological messenger substances (cytokine storm) with life-threatening symptoms only a short time after they received TGN1412.
In the preliminary animal experiments – an important component of the required studies before first use in humans – no risks became apparent. The severe immunological reactions thus came as a surprise.
For this reason, since this event, researchers have been seeking methods of studying and estimating such severe adverse effects as a result of immunological reactions before first use in humans. Immunologists of the Paul-Ehrlich-Institut (PEI) who are supervised by and collaborating with Priv.-Doz. (associate professor) Dr Zoe Waibler, head of a temporary research group, investigated whether a humanised mouse model could be suitable for this.
They used so-called knock-out mice, in which specific genes of the immune system of the mouse are deactivated. These mice are substituted with cells of the immune system from human blood.
In addition to TGN1412, the scientists also used the monoclonal antibody OKT3, of which it is also known that it can cause severe cytokine storms. The scientists were able to detect cytokine release in the blood samples of the animals for both antibodies. Thus, for instance interferon-gamma levels increased considerably after the administration of the antibody.
Besides, the scientists observed additional effects equivalent to those observed in humans. These included the loss of leucocytes (white blood cells) after the administration of TGN1412 and the typical loss of particular surface markers (CD3) on T cells typically observed after the administration of OKT3. These cells play an important part in the human immune system.
However, what was a lot more obvious related to the clinical symptoms: The body temperature of the animals decreased. This is a sure sign of disease in mice comparable to high temperatures in humans. The general state of health of the mice, too, deteriorated significantly in only few hours. "Based on the symptoms and the blood samples in this mouse model, we can see adverse effects at an early stage without having to know in detail in advance what exactly we are looking for. This is a significant use of the mouse model", as Ms Waibler explained the results.
This animal model, above all, makes immunological effects visible which are mediated via T cells of the immune system. Even though the animal model involves a high workload, it opens up options of approaches to improving safety before first use in humans during clinical trials of monoclonal antibodies, for which a T-cell-mediated reaction could be expected and for which a severe immune reaction must be ruled out.
Weißmüller S, Bauer S, Kreuz D, Schnierle B, Kalinke U, Kirberg J, Hanschmann KM, Waibler Z (2016): TGN1412 induces lymphopenia and human cytokine release in a humanized mouse model.
PLOS ONEMar 9 [Epub ahead of print].
http://dx.plos.org/10.1371/journal.pone.0149093 - Online-Version of the Publication
http://www.pei.de/EN/information/journalists-press/press-releases/2016/07-mouse-... This press release on the PEI-Website
Dr. Susanne Stöcker | Paul-Ehrlich-Institut - Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel
Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory
Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
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:...
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...
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...
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...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine