Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mouse model suitable for predicting cytokine storm by antibodies such as TGN1412

10.03.2016

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 the focus: T-cell-mediated immune-reactions caused by monoclonal antibodies such as TGN1412

Source: PEI

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.

Original Publication

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].
DOI: 10.1371/journal.pone.0149093

Weitere Informationen:

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

More articles from Life Sciences:

nachricht Tag it EASI – a new method for accurate protein analysis
20.06.2018 | Max-Planck-Institut für Biochemie

nachricht How to track and trace a protein: Nanosensors monitor intracellular deliveries
19.06.2018 | 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: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Creating a new composite fuel for new-generation fast reactors

20.06.2018 | Materials Sciences

Game-changing finding pushes 3D-printing to the molecular limit

20.06.2018 | Materials Sciences

Could this material enable autonomous vehicles to come to market sooner?

20.06.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>