Over recent decades monoclonal antibody (mAb) therapy has developed from a standing start to become an established tool in the arsenal of human medicine. Last year the US FDA approved the 100th monoclonal antibody product – just 35 years on from the very first approval in 1986. The primary appeal of monoclonal antibodies is their specificity and affinity for their target, attributes which make these molecules particularly attractive for use in the treatment of cancers.
Given the large variety of monoclonal antibodies which are now available for treatment of human disease and the excellent results which have been achieved, it is perhaps surprising that this success has not been mirrored in veterinary medicine, which so often borrows tools developed in human practice. Indeed, the FDA gave their very first full approval of a monoclonal antibody treatment for any type of non-human animal earlier this year: Solensia™ (Frunevetmab) for the treatment of feline osteoarthritis.
Dogs and cats suffer from a range of chronic disorders that include cancer, lymphoma, arthritis, allergic disorders and chronic pain, so it is clear that antibody treatments could offer pets the same benefits found in the equivalent human applications. However, in contrast to chemical drugs, many of which have been repurposed effectively for veterinary applications, biologics such as monoclonal antibodies are in most cases species-specific. The species-specificity issue is two-fold: firstly, mAbs directed to a human target antigen generally do not cross-react with canine or feline target antigens, due to differences in antigen structure between species. Even more significantly, introduction of a human or humanised mAb will cause recognition of a foreign protein by the host immune system and induce an immune response in pets - potentially leading to significant side effects. Due to this, there is a need for development of monoclonal antibodies for veterinary use which are not simply repurposed from human medicine, but instead are designed or redesigned with the purpose of effectively treating pets in mind.
Market for veterinary monoclonal antibodies
Inevitably, pharmaceutical and biotech companies are aware that the market for expensive biologic therapies in canines and felines is limited in comparison with humans, which makes funding antibody development and clinical trials more challenging. The addressable market size is even smaller for less common types of pets, further amplifying the challenge. However, in recent years, there is a perception of increased willingness and expectation amongst pet owners to provide the best available care for their sick companions, in addition to increases in the numbers of pets, amount of money spent on pets, and pet life-span. This combination of economic factors, in addition to technological advances has led to increased activity in the veterinary antibody field.
In addition to financial drivers, there are a number of other factors contributing to the disparity in development of the human and veterinary monoclonal antibody fields.
Knowledge of the immune systems of companion animals
Crucially, our knowledge of the immune systems of companion animals is relatively poor compared to the human immune system. Several of the most effective human monoclonal antibody treatments target elements of the human immune system, such as the checkpoint molecules PD-1 and CTLA-4. These molecules were originally considered as potential therapeutic targets due to our knowledge of their role in human cancers. In contrast, we have limited knowledge about canine and feline target antigens and their mode of action. In part, this lack of information is due to the limited availability of species-specific reagents to characterise immune system components. It will also be important to improve our understanding of the mechanism of action of monoclonal antibodies in pets, as many human monoclonal antibodies utilise antibody-dependent cellular cytotoxicity (ADCC), mediated by the patients’ own immune cells, as a key mechanism of action. Research into the immune systems of our pets will be critical in enabling the efficacy of these therapies to be optimised in pets. Furthermore, compared to human tumours, tumours in pets have not been as well characterized with respect to genotype and phenotype1. These limitations hamper efforts to develop monoclonal antibodies and also mean there is a lack of biomarkers to determine which animals may benefit from a particular treatment.
Development of species-specific antibodies
As mentioned above, another key challenge facing the field of veterinary antibodies is how to produce monoclonal antibodies which have a high affinity for canine or feline target antigens and which do not induce potentially harmful immune responses when administered to pets - though this is not a challenge which is new to the field of antibody research in general.
In the early days of antibody research in human medicine, researchers started with rodent antibodies and generated ‘humanised’ antibodies by engineering elements of the protein sequence to increase similarity to antibodies produced naturally in humans, thus reducing the immune response generated by their administration.
Veterinary antibody researchers have taken a similar approach, using engineering to make antibodies more dog-like (caninization) or cat-like (felinization). Engineering antibodies in this way is time intensive, costly, can affect the target specificity, and the remaining rodent portion of a hybrid antibody can nonetheless be recognised as foreign, causing a reduction in efficacy. For example, the caninized mAbs Blontress™ and Tactress™ developed by Aratana Therapeutics have received conditional approval in the US and are commercially available for the treatment of lymphoma2. However, in 2015 Aratana stated that scientific studies suggest these caninized mAbs are not as specific to their targets as expected. There is also currently a lack of peer-reviewed evidence of clinical efficacy of these mAbs in treating canine lymphoma.
Again learning from the lessons of human antibody research, veterinary antibody researchers are now developing fully canine and feline antibodies, which advantageously have a lower risk of inducing immune responses in patients than either rodent or caninized/felinized antibodies. The first use of a fully canine therapeutic antibody in a dog trial was recently carried out by PetMedix. To achieve this, PetMedix transferred a large section of canine antibody DNA into the mouse genome. The Ky9™ mice generated through this genetic engineering process can be used to produce fully canine antibodies in vivo. Production of these antibodies in vivo has the further advantage of exposing the antibodies to natural immune selection processes, which cannot be replicated through protein engineering techniques. PetMedix is also developing an analogous Felyne™ platform for the discovery of antibodies for cats, based on the same concept.
The advantages of fully canine and feline antibodies are also being pursued by Adivo, who established CAESARTM, which is the first fully canine phage display platform, named after their founder’s dog who fought cancer for many years. Phage display uses libraries of genes encoding proteins of interest (in this case antibodies), and inserts these genes into phage genomes, resulting in phages displaying the proteins of interest. The proteins of interest displayed by the phages can then be screened for binding activity and other characteristics, enabling identification of promising candidate antibodies. The phage display technique revolutionised the field of antibody discovery in human medicine, by providing an in vitro method for rapidly selecting and evolving antibodies with high functionality and low risk of immunogenicity, and this platform has been used to develop some of the most successful antibody pharmaceuticals in the world. CAESARTM uses a fully canine antibody library, harnessing the power of the phage display platform for the benefit of dogs. Adivo has also recently launched FELIXTM, a similar platform for the selection of fully feline therapeutic antibody candidates for the treatment of cats. In vitro platform technologies such as these have the benefit of not requiring the use of animals during the antibody generation process.
Outlook
Veterinarians, researchers, and pet owners have reason to hope that the breakthroughs in monoclonal antibody research in human medicine will soon benefit pets as well. However, it is clear that due to species-specificity, simply repurposing monoclonal antibodies used in human medicine without comprehensive knowledge of the specifics of the pet’s immune system is unlikely to deliver optimal results. Instead, a bespoke veterinary-focused approach is needed, which will require expensive research and development – often with uncertain outcomes. Ensuring that IP generated through this research is well-protected will therefore have a key role in driving innovation in this field towards the eventual goal of unlocking the potential of monoclonal antibodies for dogs, cats, and other pets who deserve access to the benefits of this class of therapy.
References
- Hans Klingemann Front Immunol. 2018; 9: 133
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807660/ -
Hans Klingemann Front Immunol. 2021; 12
https://doi.org/10.3389/fimmu.2021.665784
About the authors
This blog was co-authored by Thomas Lonsdale, Anja Koller, and Alex Galbraith.
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Thomas Lonsdale
Thomas is an associate patent attorney with experience in drafting and prosecution of patent applications for a range of European and international clients in the fields of chemistry, biochemistry, pharmaceuticals and materials. He has also worked on FTOs and attended proceedings before the EPO. Thomas holds a Masters (MChem) and doctorate (DPhil) from the University of Oxford in which he specialised in biocatalysis.
Email: thomas.lonsdale@mewburn.com
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Anja Koller
Anja is a member of our life sciences patent team specialising in biotechnology and pharmaceuticals. She is experienced in prosecuting patent applications before the EPO and DPMA as well as in offensive and defensive oppositions before the EPO. Anja has a Bachelor’s degree in molecular biotechnology, a Master’s degree in industrial biotechnology and a PhD in biochemical engineering from the Technical University of Munich, Germany.
Email: anja.koller@mewburn.com
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