Recently we hosted The Eighth Annual Biologics Symposium (ABS) in London where industry thought leaders discussed the development of some of the most successful, and soon to be successful, biological drugs on the market. The event was held at the state-of-the-art IET London: Savoy place, seeped in cutting edge event technology - an inspiring venue where scientists could share their ideas, network, and explore practical ways to advance their drug development goals.
Dr Kirsty Harper, Head of Biologics at Envigo, kicked off the two day symposium by highlighting the importance of having a dedicated forum where drug developers could discuss recent advances in biological product development, and detail challenges with their development.
Dr Harper then went on to introduce the main topics of discussion that would take place. These included immunological assessment, species selection, drug delivery, efficacy, safety, and clinical aspects.
Here, you'll find five highlights from this year's thought-provoking event. Have a question for one of the speakers? Get in touch.
1. Advanced therapies and novel peptides - a new approach
Dr Keith Martin from Apitope looked at potential new ways to treat these diseases. Autoimmune diseases are caused by a break in immune tolerance. Unable to distinguish between foreign and self-antigens, the immune system attacks the patient’s own body.
Apitope, Dr Martin said, develops highly specific peptide-based therapeutics. Known as Apitopes®, they are antigen processing independent epitopes. Apitope’s proprietary discovery platform can select and develop Apitopes®, that target the immunological basis of autoimmune diseases directly.
The specific Apitopes® bind directly to the MHC II receptors on antigen presenting cells. They do this without inducing expression of any other co-stimulatory molecules. This causes T cells to:
- become inactive
- enter apoptosis
- become regulatory T cells
Typically, other current treatments induce a global immune suppression. As you can see, Apitopes® offer huge benefits compared to them. Dr Martin said that Apitopes® have the potential to both:
- treat a wide variety of autoimmune diseases
- treat undesired immune responses against biologic therapeutics
2. Gene therapies - challenges and safety considerations
Gene therapies are an exciting and evolving area of biopharmaceuticals. They aim to introduce genetic material into cells, to stop or reverse a specific disease. And it was these therapies that Dr Julie Tordo from The Cell and Gene Therapy Catapult covered in her popular presentation.
In particular, she looked at the challenges and safety considerations for adeno-associated virus (AAV) based gene therapies. AAV vectors have become a favorable choice of viral vectors. Viral vectors introduce the therapeutic genetic material into cells. Recent clinical trials have shown that AAV vectors are safe and effective. In addition, the first commercial gene therapy product has gained regulatory approval.
However, safety challenges remain with the development of these therapies. This is due to a lack of clinical experience. As a result, there is uncertainty about the nature and frequency of safety problems.
Dr Tordo set out some of these development challenges for AAV based gene therapies. She also offered solutions to overcome them. Dr Tordo highlighted potential solutions to immune responses that can occur when administering AAV vectors. Namely:
- those caused by patients with high levels of pre-existing anti-AAV neutralizing antibodies
- the subsequent impact of AAV to induce broad responses against both the capsid and or the transgene
Dr Tordo’s insightful presentation started a great discussion in the room. The delegates shared their current thoughts and experiences in the development of gene therapies.
3. Antibodies - library construction and potential re-investigation
Antibodies was the next big topic of the day. Dr Guy Hermans from Isogenica gave the first presentation. He outlined how Isogenica’s technologies enables the facile isolation of single domain (VVH) based antibody fragments from synthetic libraries.
Fully synthetic and largely humanized but based on camelid single domain structures, these fragments are engineered to:
- contain VHH framework ‘hallmark’ residues to enable good solubility
- but are humanized in other framework regions
Then Dr Hermans described Isogenica's Colibra™ DNA library construction. The methodology, he said, leads to a far higher percentage of CMC liability motif-free clones – further reducing the need for lead optimization.
Isogenica combines these VHH libraries with its proprietary in vitro CIS Display system, enabling rapid selections from repertoires order of magnitude larger than can be isolated from phage or yeast display methods.
Together, these two factors help produce an outstanding lead isolation solution. It means that lead molecules with single or double digit nM affinity can be selected rapidly, without the need for affinity maturation.
Dr Hermans finished by describing validation of the library to integral membrane proteins, including developments towards CD3 binding VHHs. He set out their potential for use in the exciting area of bi-specific T-cell engager molecules.
Dr Michael Dyson from IONTAS was the second antibodies speaker. Dr Dyson described the mammalian display technologies his company develop and use for human antibody discovery. Here gene editing technology is employed to efficiently direct site-specific integration of antibody genes into a single locus within the mammalian cell genome. This enables construction of libraries of tens of millions of monoclonal stable cell lines displaying IgG-formatted antibodies on their surface.
Using flow cytometry many millions of clones can be screened directly for high affinity and specificity. The technology can also identify and avoid clones with potential biophysical liabilities which could otherwise lead to costly delays or even product failure.
Dr Dyson gave examples of the use of the mammalian display technology for both de novo antibody discovery and antibody affinity maturation. Since screening is performed in a mammalian cell background in IgG format, with authentic post-translational modifications, the antibody characteristics are directly translatable to antibodies produced in production cell lines, thus dramatically reducing the time-lines for antibody development.
Then Dr Dyson looked at a previously problematic and shelved therapeutic antibody: Bococizumab. He showed how it could be rescued and made suitable for renewed clinical use by re-engineering and mammalian display selection. This approach, he said, could enable the potential re-investigation of molecules stopped due to issues with:
4. Vaccines - exciting developments
The next session looked at exciting developments in vaccines. Dr Rocky Cranenburgh from Prokarium, was on first. He talked about his company’s oral vaccine delivery platform, Vaxonella®. It combines patient compliance and the minimal requirement of healthcare professionals.
Vaxonella® uses attenuated strains of Salmonella enterica to deliver the vaccine antigen. He explained how the bacteria transits the stomach and enters Peyer’s patches. It does this via M-cells in the lining of the small intestine. Then salmonella is phagocytosed by antigen presenting cells. They express the vectored vaccine antigen, and stimulate humoral and cellular immune responses.
Prokarium, he said, are developing their vaccine platform for a number of indications. They include plague. As you may know, the WHO has classified plague as re-emerging disease. Africa has seen the biggest increases in cases. And in 2017, Madagascar recorded 195 deaths due to the plague.
Yersinia pestis, Dr Cranenburgh explained, is the bacteria that causes plague. This bacteria cultures easily, and the pneumonic form of plague is fatal. As such, this makes it a potential bio-terror pathogen. Prokarium's oral vaccine could be self-administered, he said, and deployed rapidly to affected areas.
The final vaccines speaker was Dr Peter Laing from Excivion. He described the challenges of developing vaccines against Zika and dengue, and how such vaccines might be designed to avoid priming for antibody-dependent enhancement.
Dr Laing said the first vaccine licensed only recently for dengue was Dengvaxia® which had run into a problem. In 2017, its manufacturer reported that dengue-seronegative children receiving Dengvaxia® had an elevated risk of hospitalization, possibly as a result of priming by the vaccine for severe dengue (encompassing dengue haemorrhagic fever and dengue shock syndrome).
Severe dengue is characterized by antibody-dependent enhancement of disease. Some scientists believe, he said, that the vaccine had acted in a subset of dengue-naïve subjects as a silent primary infection priming vaccinated subjects for severe dengue.
Excivion, he explained, has developed a new approach to flavivirus vaccines. Called glycan-cloaking, and had applied it to dengue and Zika vaccines. This approach allows the generation of protective neutralizing antibodies while minimizing the generation of cross-reactive antibodies against immunodominant sites that were particularly implicated in the generation of antibody-dependent enhancement.
5. Biologics - some special considerations
Dr Fiona Sewell from the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), presented the results from a recent survey, carried out by NC3Rs and in collaboration with the Association of British Pharmaceutical Industry (ABPI). The survey aimed to determine whether the biologics industry is exploiting the use of a single species for post first-in-human (FIH) studies allowed within ICHS6.
The ICHS6 guidance for preclinical safety evaluation of biotechnology-derived pharmaceuticals is clear. If two pharmacologically relevant species for a clinical candidate (one rodent and one non-rodent) are available, then both species should be used for short-term (usually up to FIH) general toxicology studies.
But if toxicological findings from these two species are similar, then it is considered appropriate to use only one species for the subsequent longer-term chronic dosing studies, with first consideration given to the rodent species.
Of course, often biopharmaceuticals use one species from the start of the general toxicology studies, as only one pharmacologically relevant species exists. Frequently, this is the non-human primate.
Dr Sewell’s data was collected from 18 organisations on 172 molecules, of which 80 were biological molecules:
- monoclonal antibodies (mAbs) (46)
- recombinant proteins (15)
- synthetic peptides (13)
- antibody-drug conjugates (6)
Whilst 45% of these biologicals (mainly mAbs) only used one species, this left a surprisingly high number (44 molecules) that did use two species. The FIH study toxicities were similar in both species for 57% of these molecules. Dr Sewell presented 11 molecules that had used two species for the FIH studies and, progressed to post FIH studies. Of these, six had similar FIH toxicities in both species (4 mAbs, 1 recombinant protein and 1 synthetic peptide). However, only two mAbs reduced to one species for the post-FIH studies (dropping the non-rodent and continuing in rodent only.
Dr Sewell accepted that:
- the data obtained for individual molecule types in this survey was minimal
- it would be useful to have more information on why some molecules continue with a two species approach
However, she said, the results show the potential to reduce further the use of animals in biopharmaceutical development. Interestingly, for those molecules that used two species when asked whether, in hindsight, decisions could have been made from a single species, the majority answered yes. There was an interesting discussion after Dr Sewell’s presentation. Delegates discussed how to balance the goals of the NC3Rs ,whilst ensuring that good quality scientific data is produced to support human safety.
Dr Vasanthi Mowat, EU Director of Pathology at Envigo, was our last speaker. She talked about the challenges of interpreting histopathology of biopharmaceuticals. Dr Mowat presented three interesting case studies. They included:
- acute hepatic necrosis in mice
- hepatic degeneration in rats
- immune-complex mediated disease in Cynomolgus monkeys
Summing them up, Dr Mowat said they illustrated specific challenges seen with biologics including:
- anti-drug antibodies and formation of immune complexes
- Lack of dose relationship for treatment related changes
- Unclear relationship between pharmacokinetics, histopathology and other parameters
She concluded that these cases showed the importance of using a weight of evidence approach and considering all data.Take home messages
Our hand-picked panel of industry experts presented insightful presentations about current biologics topics, all of which provided valuable take home messages. ABS 2018 provided an excellent forum for peers and fellow experts to engage in educational discussions and highlighted again the importance of bringing the industry together, to create meaningful and productive relationships that will advance drug development goals.
If you have a question for our speakers or would like more information on biological product development, contact us.