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Better antibodies without using animals

EURL ECVAM Recommendation on non-aniaml derived antibodies
Better antibodies without using animals
May 15 2020

The JRC’s EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) has issued a Recommendation urging end-users and other stakeholders to recognise the scientific validity of non-animal-derived antibodies and to stop using animals for antibody development and production.

The Recommendation is based on the opinion of EURL ECVAM’s Scientific Advisory Committee (ESAC) and states that animals should no longer be used for the development and production of antibodies for research, regulatory, diagnostic and therapeutic applications. It also challenges misconceptions existing in the scientific community about non-animal-derived antibodies and highlights the scientific and economic benefits of their use.

Every year in the EU, close to 1 million animals are used for antibody generation and production despite the availability of technologies that do not necessitate the use of animals. Not only is this number high but the procedures employed often cause severe suffering. The Recommendation proposes concrete actions for key actors including end-users, commercial providers, authorities, research funding bodies and journal editors.

“The EU Directive 2010/63 on the protection of animals used for scientific purposes is very clear”, insists Maurice Whelan, JRC scientist and head of EURL ECVAM, “when a scientifically valid alternative is available, then it simply must be used. Authorisation should not be given for the development and production of antibodies through animal immunisation, where robust, legitimate scientific justification is lacking.”

Technologies to obtain antibodies without the use of animals

Antibodies are special proteins produced by our immune system to stop “intruders” such as bacteria or viruses from harming us when, for example, we cut ourselves or get the flu. They are also extensively used in biomedical research to identify and isolate molecules and to develop new drugs, and are of fundamental importance for diagnosing and treating disease.

Non-animal methods for generating and producing antibodies have been available for years. One such method, based on so-called ‘phage display’ technology, is extremely versatile and can be used to generate a near-infinite range of high quality antibodies in a very efficient way. The inventors of the technique received the 2018 Nobel Prize in Chemistry.

Antibodies produced by phage display are already widely used across several fields including therapeutics. The antibody adalimumab, for example, is an approved drug that recognises and binds to a particular biomolecule in the body to reduce inflammation, helping alleviate symptoms associated with many different conditions such as arthritis, psoriasis and Crohn's disease.

Addressing the reproducibility crisis in science

Non-animal-derived antibodies typically exhibit highly desirable characteristics such as being able to form a strong bond with targets (binding affinity), having a long shelf life (stability) and the ability to be very selective (specificity), usually outperforming animal-derived equivalents.

JRC scientist Marlies Halder, co-author of the EURL ECVAM Recommendation, states that “Animal-derived antibodies typically suffer from batch-to-batch variability and many show low specificity towards the target molecule. These problems can be easily solved through the use of non-animal-derived antibodies obtained by phage display technology. Their use will greatly improve reproducibility and relevance of scientific procedures and lead to more efficient and effective use of research funds.”

Poor reproducibility of experiments is bad news when it comes to time and money. In fact, it is estimated that many hundreds of millions of euro are inadvertently spent annually by the biomedical research community on non-specific and badly defined animal-derived antibodies. Moreover, significant losses are also being incurred as a consequence through associated waste of time and resources and the follow-up of potentially misleading research results.

Non-animal-derived antibodies can be reliably produced in unlimited amounts, which essentially ensures a life-time supply of antibodies with identical performance, a critical requirement for reproducibility of scientific experiments requiring affinity reagents.

Making the transition to non-animal derived antibodies

Several factors are contributing to a slow transition of the scientific community to non-animal-derived affinity reagents. For one, commercial availability of non-animal-derived affinity reagents is limited since the majority of providers still generate antibodies by animal immunisation.

Unfortunately too, many misconceptions exist in the scientific community about the quality and validity of non-animal-derived affinity reagents; a problem that is compounded by a lack of education and training opportunities for users to gain a better understanding and appreciation of non-animal-derived affinity reagents and how they can ultimately benefit their work.

According to João Barroso, JRC scientist and co-author of the EURL ECVAM Recommendation, “End-users need to better inform themselves about the advantages of using non-animal derived antibodies and should specifically request them from suppliers.”

With the right setup, selection of antibodies using a universal phage display library takes a matter of weeks, while the generation of animal-derived antibodies typically requires several months. Academic institutions therefore should coordinate efforts to establish non-animal-derived universal recombinant libraries and provide development and production services to support their research activities. In addition, manufacturers and suppliers should endeavour to offer non-animal-derived antibodies in their catalogues.

Editors, reviewers and publishers of scientific papers also have an important role to play. According to João, “Authors should be requested to state the source of the affinity reagents they’ve used, whether they are animal-derived or non-animal-derived, how they were characterised and how their quality (e.g. affinity, specificity) was properly checked.”

Background

ESAC Working Group on the scientific validity of replcements for animal-derived antibodies
ESAC Working Group on the scientific validity of replcements for animal-derived antibodies

©EU, 2018
The EURL ECVAM Recommendation is published as a JRC Science for Policy Report and is based on an independent scientific peer review conducted by EURL ECVAM’s Scientific Advisory Committee (ESAC). The ESAC Opinion on the "Scientific validity of replacements for animal-derived antibodies" and the accompanying ESAC Working Group report are annexed to the Recommendation report.

During the development of the Recommendation, EURL ECVAM consulted with other Commission services and relevant EU regulatory agencies, EURL ECVAM’s advisory body for Preliminary Assessment of Regulatory Relevance (PARERE), the EURL ECVAM Stakeholder Forum (ESTAF) and with partner organisations of the International Collaboration on Alternative Test Methods (ICATM).