The European Union wants commercially available antibodies to be animal-free, what does the industry think?
Jun 30, 2021
Jun 30, 2021
In 2020 the European Commission published a report by its Joint Research Centre. Based on the EU Directive 2010/63/EU on the protection of animals used for scientific purposes. The EURL ECVAM Scientific Advisory Committee (ESAC) advised that animals should no longer be used for the development and production of antibodies for research, regulatory, diagnostic, and therapeutic applications. They made several recommendations to promote the use of non-animal-derived antibodies. These included refusing EU grant funding to projects involving animal-derived antibodies, restricting the publication of manuscripts in scientific journals using these products, and requesting the phasing out of animal-derived antibodies by manufacturers and suppliers. Although this is not law in the EU, these opinions are gaining traction within the scientific community.
To investigate the effects of this recommendation, a small study was performed with the assistance of Pivotal Scientific Limited to determine how the industry is changing. This was achieved through distributing two online surveys to antibody suppliers and distributors worldwide to gather their opinions on the topic. Life Science companies selling research use only (RUO) products were contacted and asked a number of questions relating to the EURL ECVAM recommendations. Forty antibody suppliers and forty antibody distributors based in Europe, the Americas and Asia responded anonymously to share their views.
Awareness within the industry of the EURL ECVAM report was surprisingly low, only 30% of global suppliers and 20% of distributors were familiar with its recommendations. When taking into account geographical location, this rose to 45% of suppliers based in Europe. Of the suppliers who responded to the survey, just under 60% already sell non-animal-derived antibodies. When asked if non-animal-derived antibodies are not only equivalent to animal-derived antibodies, but can offer significant scientific advantages and economic benefits, 60 % agreed. However, when asked if non-animal derived antibodies are ready to replace animal-derived antibodies, responses were much more cautious, 27.5% said yes, but a higher percentage of suppliers were unsure or disagreed. Similar responses were also obtained from the distributors, at 65% and 32.5% respectively. Interestingly, 10% of distributors had noticed an increase in demand and 22.5% an increase in supply for non-animal-derived antibodies over the past year.
Whilst working within the industry, PSL has observed that increasingly companies are focussing their portfolios on recombinant antibodies, with a number planning to remove non-recombinant antibodies entirely. Although recombinant antibodies are not always animal-free, synthetic or naive gene libraries allow antibody production without the need for animal immunization. Analysis of the survey results suggests that although there is a great deal of positivity towards the idea of non-animal derived antibodies, companies are far less receptive to the recommendation to replace current commercial antibodies with non-animal derived alternatives. A number of respondents raised concerns regarding the price and reliability of these antibodies.
Should the European Commission wish to see the removal of animals from the antibody generation and manufacturing process, a more proactive approach is required. Education of suppliers and customers to the advantages of non-animal derived antibodies may help generate awareness and customer demand. Without these, it is highly unlikely that the manufacture of animal-derived monoclonal and polyclonal antibodies will cease in the near future.
The seminal publication by Köhler and Milstein in 1975, describing the generation of antibody producing hybridomas, has led to what is now a billion-pound industry with antibodies developed as both key research tools and therapeutic agents. However, the very first antibodies used for research predate the invention of monoclonal antibody-producing hybridomas. Prior to this, the mixture of antibodies produced naturally as part of an immune response, were collected directly from the serum of animals and humans. These polyclonal antibodies, and their monoclonal counterparts, were the only source of commercially produced research antibodies until the advent of recombinant antibodies in the 1990s. When a technique called phage display made it possible for antibody manufacturers to easily harness DNA cloning technology to produce antibodies.
Each method of antibody generation and manufacture has its advantages and disadvantages. Polyclonal antibodies are high affinity and simple to produce, but due to the nature of their production, are only available in finite amounts and eventually run out. Hybridoma cells, which produce monoclonal antibodies in culture, can drift genetically. This can lead to problems reproducing key experiments and give misleading assay results. The hybridoma cells can also die or deteriorate in storage, leading to the permanent loss of key antibody clones. Issues with batch-to-batch variability are also well reported within the scientific community. Despite this, monoclonal antibodies produced by the in vitro method from hybridoma are an immensely useful tool, ubiquitous in research and quick and easy to manufacture in large amounts. Antibody manufacture from hybridoma by the in vivo method produces high yields of antibody contained within the ascitic fluid and is a very reliable method for difficult to produce antibodies. However, the use of ascites as a production method is declining, as many regions in Europe have discouraged its use due to animal welfare concerns.
Recombinant antibodies are less well established in the research reagent marketplace but have a number of advantages over their predecessors. Valuable antibodies cannot be lost as the DNA sequence is known, and antibody engineering becomes possible, allowing antibodies to be designed for specific applications. Recombinant antibody generation is not necessarily animal-free. Many recombinant antibodies are generated by inoculation of an animal, enabling the cloning of its B-cell repertoire to produce an antibody gene library. Non-animal derived recombinant antibodies can be created by cloning of the antibody gene repertoire from non-immunised human donors, or libraries can be derived synthetically. Additionally, sequencing technology can be utilised to reproduce antibodies produced by hybridoma, converting key monoclonal antibodies to recombinant antibodies.
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