Testing more antibodies with fewer lab mice
Researchers at the University of Zurich (UZH) have developed a technology that can be used to test 25 antibodies simultaneously in a single laboratory mouse, which should not only speed up the research and development pipeline for new drugs but also hugely reduce the number of laboratory animals required. Their work has been published in the journal PNAS.
Many modern drugs are based on antibodies. These proteins very specifically identify a certain structure on the surface of cells or molecules and bind onto it — this may be a receptor protruding from the cell envelope. For antibodies and other protein-based biotherapeutics, extensive preclinical tests need to be conducted on animals before they can be tested on humans.
Currently, antibody candidates are analysed individually in animal models. A large number of laboratory animals are normally used to conduct each test; this is why preclinical tests account for a large proportion of the animals used in the pharmaceutical industry. One possible solution would be to test several substances simultaneously in a single animal; however, up until now this method was restricted to a maximum of four active ingredients per animal. The UZH researchers have now managed to overcome this restriction, developing an approach that allows them to test 25 different antibodies simultaneously in a single mouse.
To allow individual analysis of the properties of the antibodies from the complex plasma or tissues samples from the mice, the researchers developed a form of barcodes. They are made up of defined protein fragments — known as flycodes — that can be used to mark each antibody individually. Once they have been administered to the mouse, the individual antibody candidates can be separated from the mixture and analysed separately.
“Our results show that the flycode technology delivers high-quality preclinical data on the investigated antibodies,” said Markus Seeger, who co-led the research. “We get much more data with fewer mice and the data is of a better quality because the analyses can be compared directly.”
The researchers also demonstrated that the antibodies find their target structures correctly in the animals’ body: for example, two of the antibodies used in cancer medicine reliably identified the EGF receptor which the tumour cells primarily carry on the surface. The targeted accumulation in the tumour tissue also worked in a mixture with 20 other antibodies; this demonstrates that flycodes do not compromise the efficacy of the antibodies in a living organism. In addition, the team used flycodes to analyse the properties and data for a series of 80 drug-like synthetic biomolecules — known as sybodies — efficiently in a single experiment.
“Using minimal resources, the flycode technology allows a direct comparison of drug candidates under identical experimental conditions,” Seeger said. “It is set to advance preclinical discovery pipelines much more efficiently in the future.”
All the data in the study originates from just 18 mice. In principle, this new method can reduce the number of animals required by a factor of up to 100.
Image caption: The new technology allows 25 drug candidates to be tested simultaneously in a single mouse. Image credit: Frank Brüderli, UZH.