Adopting non-animal methods in drug development
The passing of the FDA Modernization Act 2.0 is a commitment to reducing the use of animals in drug testing.
The act allows researchers to use non-animal methods, such as cell-based assays and computer models, to study the safety and effectiveness of drugs at the preclinical trial phase. The FDA Modernization Act 2.0 also eliminates the use of animal testing to secure licences for biosimilar or interchangeable biological products.
This shift reflects the industry’s recognition of the lack of accuracy and predictive power of animal models. In line with this is an increasing demand for ethical compliance in development and the reduction of animals at all stages of discovery and development.
Why are the regulations changing?
In the world of drug development, animal testing has long been the go-to method for investigating the safety and effectiveness of new medicines. But testing drugs for humans in animal-based models can lead to both false negative and false positive results. Using organoids, organ-on-a-chip, cell and in silico models have been shown to offer increased precision which then should improve the clinical trial success rates.
Non-animal methods are already taking hold in drug development for the central nervous system. Diseases like Alzheimer’s, Parkinson’s and multiple sclerosis are difficult to study and treat in animal models, where it is challenging to reflect the complex nature of the human CNS. Consequently 99.6% of drugs for Alzheimer’s disease that are successful in animal testing are ineffective in humans.
Using non-animal methods enables a ‘fail early, fail often’ approach to testing, meaning drug candidates can be filtered out earlier in the discovery process, translating to less money being wasted on drugs that don’t deliver the desired effect.
Reducing reliance on animals through the pipeline
Increasing awareness of the ethical concerns and inaccuracies in using animal models has driven interest in replacing animal-derived products throughout the pipeline, including with affinity reagents.
Antibody generation relies on the immune response of animals. The isolated antibodies can be synthesised by in vitro methods of hybridoma generation or recombinant antibody generation, or continued isolation directly from the animal source for polyclonal antibodies.
In 2020, EURL ECVAM produced a report concluding that non-animal-derived antibodies are mature reagents that offer significant scientific advantages and economic benefits over animal-derived antibodies. Antibodies were considered the gold standard reagent in the life sciences, but they are associated with many limitations including stability, lack of ability to develop to some targets such as toxins and haptens, and the need for animals to generate them.
‘Non-animal-derived antibodies are mature reagents generated by proven technologies, that are not only equivalent to animal derived antibodies but in many respects can offer significant scientific advantages and economic benefits.’
European Union Reference Laboratory – European Centre for Validation of Alternative Methods
This recommendation to move towards non-animal-derived reagents applied to the development and production of affinity reagents for research, regulatory, diagnostic and therapeutic applications. In the EU, the provisions of Directive 2010/63/EU should be respected and EU countries should no longer authorise the development and production of antibodies through animal immunisation, where robust, legitimate scientific justification is lacking.
A recent review of antibody licences in the UK recommended to the Home Office that increased exploration of non-animal-derived methods with increased justification of the need for animal-derived reagents are required in licence applications.
But ethical considerations are not the only reason to move away from animal-derived antibodies. Assays using animal-derived antibodies can suffer from batch-to-batch variation, low specificity, high background and interference from cross-reactive proteins — all of which can compromise their reproducibility. If animal-derived antibodies are used to analyse human samples, in diagnostics or as bioanalytical reagents, further complications arise from HAMA-antibodies. These human anti-mouse antibodies are found endogenously within some people and interfere with the performance of animal-derives antibodies, leading to false positive or false negative results. In recognition of these problems, some researchers have started to engineer their antibody paratope sequences into humanised or human antibody scaffolds and use them as recombinant reagents. While this may lead to correctly performing antibodies in the end, high time and cost investment do not make this a simple approach, and the fact remains that researchers worldwide are thinking about ways to minimise animal use in their work.
Non-animal-derived antibody alternatives with Optimer
Optimer binders are an example of such non-animal-derived antibodies that are recommended by the Directive 2010/63/EU. As next generation aptamers these binders are developed entirely in vitro through multiple screening of diverse libraries. Not only does this offer the benefits of reducing animal use, but also allows tuning of affinity, selectivity, and stability within the process, reducing lengthy post-development engineering that is often needed with antibodies.
Optimer generation is performed entirely in vitro, removing the requirement for animals from this process. The isolated Optimer binders are synthesised by well-controlled, scalable chemical synthesis methods.
We are increasingly seeing our partners explore Optimer binder development to allow adherence to the regulatory directives and as a move to shift away from the use of animals at all stages of their discovery and development.
For toxic targets or small molecule / hapten targets in vitro development via aptamer-based or equivalent platforms has always been essential as toxins would kill the animal before an immune response can be raised to generate antibodies, while small molecules are often too small to generate an immune response. However, we are now seeing this approach being purposefully pursued by many to get ahead of the curve and move to non-animal based methods as soon as possible.
Beyond ethical concerns, the Optimer development process also aligns with the in vitro testing approach of offering ‘fail early’. We phase our development process with multiple go/no-go points and an initial feasibility phase in discovery that indicates the potential of success. This allows quick decisions to be made regarding Optimer development for each project. Also as payment is phased, this ‘pay-as-we-work’ strategy ensures projects that aren’t suitable for our innovative Optimer development platform to cost little up front, de-risking development for our partners.
In the last few years we have seen multiple new regulations and directives that increasingly aim to remove animal use in research, and critically, to replace this with more accurate and effective solutions. The aim of this is to increase the success rate in drug development and correspondingly to reduce cost. Removing the requirements for animals in drug testing and setting recommendations for alternatives to be used in affinity reagent generation shows a clear line of the progression in the industry to adopt more considered approaches that favour ethical considerations, improved science and hopefully better translation of the clinical pipeline for patients.
If you would like to discuss Optimer generation for your project to help overcome ethical considerations, improve stability, sensitivity or specificity, get in touch.