EU directives and animal welfare initiatives keep challenging scientists and industry leaders to change conventional practices. Far from hindering scientific and technological progress, this urge for change has fostered innovation in the biotech industry on a global scale. ProteoGenix share how these directives continue to support the development of integrated solutions to reduce animal use in biopharmaceuticals.
For the past decade, biopharmaceuticals have been gradually gaining ground over small molecules as the drugs of choice for the treatment of cancer, autoimmune, metabolic and infectious diseases. But, compared to their smaller counterparts, these biomolecules bring a completely different set of challenges to the table.
Challenges stem from the structural complexity and biological origin of these drugs. Factors that make the process of discovering, producing and testing them far more time-consuming and labour-intensive than the development of small molecules.
Unlike small drugs, biopharmaceuticals are prized for their specificity and reduced toxicity. Indeed, many of these biomolecules, in specific antibodies, can interact with precise targets and elicit a strong protective response with minimal side effects to patients. These unique characteristics continue to prompt the development of more robust technologies and infrastructures to accommodate the unique needs of biopharmaceutical drug development.
But even today, one of the most important bottlenecks in antibody development is the use of animals during the early stages of discovery. This creates very unique challenges and hinders the intensification of the process. Moreover, animal use has been cited by many researchers as one of the hidden and unreasonable costs of antibody production.
The need to use animals for antibody discovery and production
Statistical data regarding animal use for antibody production is scarce. Yet, according to the latest EU statistics, animal use for research in Europe could have exceeded 2.7 million animals in 2013 alone. Numbers provided by the UK and The Netherlands in that same year, indicate that at least 35,000 of these animals were used for antibody production in these countries alone.
The lack of global data regarding animal use in antibody production hinders the determination of global trends in this sector. However, numbers at the EU level suggest we may still have a considerable margin for reducing animal use in the sector.
Several reasons explain this dependency on animals for antibody production. The first one stems from historical preferences and pre-existing infrastructures, and the second one from the high costs still associated with animal-free technologies.
Moreover, although most antibodies currently used for therapy are obtained and produced by recombinant methods, there is still a fraction of these molecules that cannot yet be produced by this type of technology.
This fraction consists of polyclonal antibodies. Typically obtained in animals through immunisation, serum harvesting, and purification, these antibodies are still invaluable reagents for research and diagnostics. In some cases, polyclonal antibodies are often considered the most viable solution to counter the effects of snake, scorpion and venomous spider bites. The reason for the preference of these molecules for research and diagnostics derives from the inherent limitations of typical monoclonal antibody therapies.
Indeed, unlike typical monoclonal molecules, polyclonal antibodies consist of a mixture of antibodies with different specificities. Due to their inherent diversity, they are prized for their high sensitivity and ability to bind multiple regions of the same foreign molecule.
In contrast, monoclonal antibodies can only bind a single region of a foreign molecule. This specificity can sometimes act as a hindrance when these molecules are developed to target highly complex targets or proteins with high mutation rates.
Recently, scientists proposed the use of antibody cocktails (mixtures of two or more different monoclonal antibodies) as a way to overcome the limited sensitivity of these molecules. But, for this approach to work, the entire sector must reform its practices and shift from animal-dependent to animal-free antibody production methods. The latter may be used to reduce turnaround times in antibody production, and accelerate the discovery of new biopharmaceuticals.
Animal-free technologies for antibody generation
From a biological perspective, our ability to predict and mimic the natural immune response is still limited. And although many scientists are now leveraging artificial intelligence to create completely new biomolecules, we are still very far from finding a viable commercial application.
Instead of attempting to recreate the complex response of our immune system, most existing animal-free approaches rely on recombinant technologies to tap directly into the immunological diversity stored in our genes.
One of the first technologies that allowed researchers to capitalise on this natural diversity and reduce animal use in biopharmaceutical discovery was the phage display technology. First described in the 1980s, the technology has since allowed the development of countless new antibodies for therapy, research and diagnostics.
Adalimumab (Humira®) was the first antibody approved for therapy obtained by phage display technologies. Approved in 2002 and developed by AbbVie Inc., Adalimumab is a fully human antibody obtained by screening highly diverse libraries of human antibodies. Presently, it is used for the treatment of rheumatoid arthritis.
Although other display technologies have been developed and applied for antibody production, phage display is still considered the most robust of these technologies. It leverages the natural interaction between Escherichia coli and M13 bacteriophage, to produce a large number of different antibody variants that can be quickly screened for affinity, and subsequently multiplied in the high-performing bacterial host.
According to the latest data available in the IMGT/mAb-DB (Montpellier, France), there are at least 30 monoclonal antibodies developed by phage display technologies in Phase I/II clinical trials. Allied with its track record of approvals, phage display provides the unique opportunity to discover new biopharmaceuticals with reduced or even inexistent animal use.