The most effective medicines in the world are of limited value if they can’t be produced in bulk, and at a reasonable cost.  Therapeutic antibodies take years to develop. Without good oversight, each stage of development risks operating in a vacuum, with teams concentrating solely on their task before passing the candidate antibody onto the next team. An antibody developed with this “pass the parcel” approach may tick all the boxes for moving into clinical trials; it may even ace clinical trials. But if production cannot be scaled up for bulk manufacturing at a reasonable cost, the antibody is simply not commercially viable. Early engagement with manufacturing and commercialization experts and a helicopter view of the whole project from start to finish keeps the focus on developing an antibody that’s fit for purpose.

Scaling up determines cost of goods

Developers should look further than affinity alone when selecting a lead antibody. It would be a cruel twist of irony to develop a safe and effective antibody that cannot be manufactured in sufficient supply to treat all patients. Therapeutic antibodies are administered in high quantities to achieve the therapeutic effect – this can be in the range of milligrams to grams per patient per treatment cycle. For example, patients treated with the therapeutic antibody adalimumab (Humira™) take 80 mg on day one and then 40 mg every other week. The manufacturing process must keep up with the demand created by such dosing requirements.

Production is a key factor determining the ultimate cost of goods. Antibodies are churned out by genetically modified mammalian cells, grown in suspension in bioreactors. The antibody sequence is a critical “part” for the recombinant cell line “machinery”. As any mechanic will tell you, simple robust parts allow the machinery to run smoothly. In this case, well designed antibody sequence “parts” are easier for the cellular “machinery” to churn out in quantity.

Ideally, affinity maturation and sequence optimisation should optimise the antibody for ease of expression by mammalian cells. The yield, or titre, of antibody produced by these cells determines the ease of manufacturing and therefore the cost of goods.  A yield of 2 g of antibody per litre of cell suspension is the threshold for a commercially viable antibody (1). Titre up to 4-5 g/L and higher have been reported by some companies.

The titre determines how many cells are needed to harvest enough antibody – this in turn determines the size and number of bioreactors needed and the size of the factory needed to house them. Bioreactors typically range from containing 1,000 litres of cell culture up to 20,000 litres. The cost and time required to purify the antibody out of the cell suspension is another factor in scaling up production, and the ultimate cost of goods.

Production for clinical trials versus the market

Drug development is a race against the clock. Time and investment pressure means that antibodies are first produced in small batches for clinical trials before, or alongside, technology transfer, production scale-up and stability studies. Ideally the small batch production for clinical trials should form the basis for the scaled up bulk manufacturing. For example, changing the cell line to achieve higher titres for bulk production would require validation in additional clinical trials, setting timelines back by years. Similarly, a shelf life of one year may be sufficient for clinical trials, but stability of 3 years is needed for the market. Drug development timelines don’t always allow for a 3-year stability study before clinical trials – but doing things the other way around can lead to a commercially unusable antibody, even if efficacy and safety are good.

Development strategies

One of the main business decisions in antibody development is whether to make or buy, i.e. whether to perform all steps of the process in-house, or outsource certain tasks to specialist providers. A third option is to partner with providers, in a risk-sharing agreement. Whatever route is chosen, teams should start seeking and integrating expert advice about scale-up and commercialisation from the early days of the drug development process.

RAMP™, our rational affinity maturation platform, accelerates and optimizes selection of lead antibody candidates that are “pre-screened” for manufacturing suitability. Our proprietary rational library design introduces mutations in both the CDR and framework regions, inspired by how B cells use somatic hypermutation to generate antibody diversity. In silico modelling then screens out variants with sequence liabilities known to compromise expression and stability.

Contact us to see how RAMPTM can generate lead candidates that are manufacture-ready

References

1            https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759494/

Fusion Antibodies have named A-Frontier as their exclusive supplier in South Korea enabling Biotech companies to access premium antibody discovery and engineering and cell line development services from a trusted supplier.

Fusion Antibodies have been delivering services for drug discovery companies for over 20 years and have developed several proprietary platforms for Humanization and Affinity Maturation.

A-Frontier is a leading supplier in Korea distributing diverse products and service, and have their own R&D center delivering custom antibody and protein related service.

This new partnership will strengthen Fusion Antibodies’ presence in the Asia- Pacific region and build upon existing collaborations in South Korea, Japan and China.

Paul Kerr, CEO, Fusion Antibodies said, “We are delighted to announce this partnership with A-Frontier. We recognize their quality organization and service provision; and extensive network in the Biotech field and are excited to have our platforms offered to their customers. This partnership will connect us with companies carrying out innovative work in drug discovery in South Korea. We look forward to working closely with companies to help them get to the clinic as quickly as possible without compromising the quality of their antibody.”

Eonjung Kim, CEO, A-Frontier said, “We are pleased to be able to offer these unrivalled platforms to our customers and are happy that Fusion Antibodies have selected us to deliver their services in this region.”

Fusion Antibodies have named BioTickle as their exclusive distributor in India to provide local biotherapeutic developers access to proprietary antibody discovery, engineering and cell line development technologies.

Fusion Antibodies, based in Belfast, Northern Ireland, are experts in antibody development and offer a seamless array of end-to-end services to get their client’s molecules GMP ready with a focus on quality and commercial viability. The partnership with BioTickle will allow Fusion Antibodies to extend its reach to R&D organisations in India that have a need for unique and innovative technology to give them an edge in an increasingly competitive region. BioTickle’s local knowledge and expertise, particularly with respect to biosimilars, perfectly underpins Fusion Antibodies global outreach.

Paul Kerr, CEO, Fusion Antibodies, “We recognize that India is a world leader when it comes to biosimilars and BioTickle definitely have their finger on the pulse. With the patents on a number of blockbuster biologics approaching expiry, we only expect the intensity in this area to grow. A lot of expertise has been gained since the first biosimilar was approved and working with BioTickle, we are also seeing this expertise being applied with increasing interest to novel molecules. We believe Fusion Antibodies could greatly benefit the local industry and we’ve found the perfect partner in BioTickle to underpin our growth.”

Uday Ulhe, Chief Technology Leader, BioTickle, commented: “We are excited to be able to offer the services of Fusion Antibodies to our vast customer base in India and Asia-Pacific. Getting the foundations right at early stages of antibody development ensures a much more successful outcome and certainly streamlines downstream process development. Once the molecule makes it to the manufacturing and clinical stages the economies of those early decisions can really be felt.. We look forward to delivering a packaged service with Fusion Antibodies that helps our clients get to the clinic with the best biologic possible.”

About Fusion Antibodies

Fusion Antibodies delivers new technology and innovation throughout early-stage antibody discovery. As a drug discovery and research partner, our scientists increase the pace to the clinic by guiding clients to develop the best antibodies possible. Through the early stages of drug discovery, we enable biotechnology and pharmaceutical organisations towards their end-goal – the provision of treatments that improve the lives of patients throughout the world.

About BioTickle

Established in 2012 with a vision to make biosimilars available and affordable to approximately 5 billion people living in the Asia Pacific region. BioTickle began with with populating single use bioreactors and the automation of bioprocesses to now offer end to end solutions for biotherapeutic development with impact analysis.

BioTickle’s expertise is in end-to-end processing and the company offers solutions to improve efficiencies at both the research & development level and the industrial production level. BioTickle navigates new technologies and runs it through a panel of scientists with simulations in labs and impact analysis on full operations, offering recommendations to improve bioprocess efficiency.

Therapeutic antibodies have revolutionized the treatment of numerous diseases, but not every antibody has what it takes to become a licensed medicine. Finding a high-affinity antibody that binds to your target is only the first step. The ideal therapeutic antibody must have good efficacy, safety, pharmacokinetics (PK) and stability, and in addition, be easy to manufacture to ensure commercial viability.

Safety first

Safety is the first requirement for any medicine, and this is no different for therapeutic antibodies. Perhaps most importantly, a good therapeutic antibody should bind to its target with high specificity. For example, an antibody that is designed to target tumour cells should ignore healthy cells, as off-target binding might lead to unexpected side effects.

It’s also crucial to fine-tune the antibody’s affinity – how tightly it binds to its target. If the affinity is too low and the antibody binds its target only weakly, the therapeutic effect may not be achieved. Conversely, if the affinity is too high, the antibody dose could be “used up” too quickly, and the likelihood of off-target activity might increase.

Another important step is to minimise the risk of the antibody generating an immunogenic reaction. If an antibody is unstable, it can aggregate, misfold or even give rise to potentially dangerous metabolites such as charge variants (which occur when an amino acid has been oxidised or deaminated). These seemingly minor changes can render an antibody immunogenic, as well as reducing its efficacy.

Optimising efficacy and PK

When it comes to optimising the efficacy of an antibody, one of the major challenges is fine-tuning its affinity. The antibody needs to have sufficiently high affinity to ensure that it works as intended, but not high enough that it binds to off-target molecules and causes unintended side effects. In some cases, reducing the antibody’s affinity might actually increase its functionality, particularly in the case of multi-specific antibodies that bind two or more antigens at once (1).

Therapeutic antibodies also need to be delivered efficiently to where they’re needed in the body, and hang around for long enough to have an effect. At the same time, there should be a focus on minimising the number of doses the patient requires. The PK of the antibody can be optimised by careful screening for liabilities in its sequence that could, for example, make it unstable, meaning greater and more frequent doses are required.

Cost of goods

With increasing numbers of approvals, the therapeutic antibody market is getting crowded and competitive. Healthcare payers need to control costs, a pressure that is passed onto manufacturers. Thus, cost control should be part of every antibody development programme from the beginning.

Optimising antibody expression and considering the “manufacturability” of antibody sequences is fundamental to developing any therapeutic antibody, and ultimately also has an impact on cost. A functionally perfect antibody that becomes overly modified or degraded during large scale manufacture will not make it to the clinic. For example, manufacturability can be affected by free cysteines, formation of interchain disulphide bond formation and aggregation. Less dramatic self-interaction may still only be evident at the high concentrations required for a clinical production batch.

Stability is another cost factor. Optimizing the antibody for longer shelf life and reducing the need for cold storage can help to keep costs down.

Help from a trusted partner

Fusion Antibodies’ rational affinity maturation platform – RAMPTM – produces functional antibodies that are optimised to jump the hurdles littering the path to the clinic, helping to control costs along the way. Rational library design reduces the risk of sequence liabilities and the downstream risks of aggregation and immunogenicity (2). This can increase yield, optimise affinity and promote stability. The best candidates are screened out in silico from the library and expressed in mammalian cells for further characterisation – including manufacturability.

References

1 Mazor, Y., Sachsenmeier, K., Yang, C. et al. Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence. Sci. Rep. 7, 40098 (2017).

2 Tabasinezhad, M., Talebkhan, Y., Wenzel, W. et al. Trends in therapeutic antibody affinity maturation: From in-vitro towards next-generation sequencing approaches. Immunol. Lett.212, 106–113 (2019).

Fusion Antibodies (AIM: FAB), specialists in pre-clinical antibody discovery, engineering and supply, announces that the Company is working with Queen’s University Belfast (“QUB”) as part of The Northern Ireland Coronavirus Antibody Development Alliance (“NICADA”), which has been established to seek new therapeutic and diagnostic approaches to help in the global fight against the coronavirus pandemic.

NICADA aims to develop new therapeutic molecules that can be evaluated for their ability to neutralize SARS-CoV-2, the virus that causes COVID-19 disease.

Working with Professor Ultan Power in the Wellcome-Wolfson Institute of Experimental Medicine, Professor Chris Scott in The Patrick G Johnston Centre for Cancer Research and Dr Fuquan Lui in the School of Biological Sciences, at QUB, it is intended that Fusion will prepare antibodies that will potentially neutralise the virus. There is a shortage of key reagents for testing globally and, although not a core service currently offered by the Company, Fusion Antibodies will be using their expertise in the development of key antibody related reagents

Fusion and QUB have not agreed to any financial arrangements in respect of the research alliance, and the arrangement is not expected to impact Fusion’s revenue or working capital position.

Paul Kerr, Chief Executive Officer of Fusion Antibodies said: “We are delighted to be able assist in the global battle against coronavirus. In the first instance we’ll work with Queen’s University Belfast to use our expertise in the development of any key reagents.”

Professor Chris Scott, Director of the Patrick G Johnston Cancer Centre, Queen’s University Belfast, said: “By bringing together diverse researchers from virology, biological sciences and cancer research we are rapidly contributing to the development of new reagents that could not only neutralize the virus, but also aid diagnostic efforts; both of which are needed to inform decisions on lifting the current lockdown. We are delighted to initiate this alliance with Fusion Antibodies and to direct our research capabilities towards tackling this global pandemic.”

Ultan Power, Professor of Molecular Virology, Queen’s University Belfast said: “The NICADA alliance provides an excellent opportunity to generate novel therapeutics and diagnostics to help the global fight against SARS-CoV-2.”

The NICADA alliance is actively harnessing leading scientific talent to assist with tackling the global coronavirus pandemic.

Enquiries:

Dr Paul Kerr, Chief Executive Officer Via Walbrook PR

James Fair, Chief Financial Officer

Fusion Antibodies, a leading antibody discovery and development company, and Queen’s University Belfast, (173rd ranked University worldwide) have launched a fourth collaboration through a Knowledge Transfer Partnership (KTP). The new programme will allow for the development of an innovative software solution for the design of antibody libraries. The solution will be integrated into the service offering provided by Fusion Antibodies in antibody engineering, to transform capabilities and competitiveness in the antibody discovery space.

Knowledge Transfer Partnerships (KTP) is a UK-wide programme that has been helping businesses in the UK to innovate and grow for over 40 years. KTPs are funded by UKRI through Innovate UK with the support of co-funders, including the Scottish Funding Council, Welsh Government, Invest Northern Ireland, Defra and BEIS. Innovate UK manages the KTP Programme and facilitates its delivery through a range of partners including the Knowledge Transfer Network (KTN), Knowledge Bases and Businesses.

Queen’s University Belfast has partnered with businesses through the KTP initiative for over 25 years, and in May 2019 was the winner of the National Award for ‘Outstanding Contribution from a KTP Support Team’.

Paul Kerr, CEO of Fusion Antibodies commented “We are delighted to partner with Queen’s University through their Knowledge Transfer Partnership programme.  We have worked with Queen’s on multiple KTPs that have provided us with extraordinary talent and resources. Linking with the brightest minds in academia allows us to add another dimension to the knowledge-based service that we offer in the early stages of antibody discovery and development.”

Through the KTP programme, the partnership aims to recruit a suitably qualified software graduate to work in Fusion Antibodies on a collaborative project over an 18-month period.

“I am delighted that Fusion Antibodies are continuing their commitment to the KTP programme and Queen’s University. Their commitment to helping biotech companies deliver treatments for previously unmet medical needs offers graduates an opportunity to learn from both academic and industry experts. KTP sets them on the path to become future industry leaders, bringing to life the strategic plans of an innovative company such as Fusion Antibodies.” Lorraine Marks, Head of KTP and Business Engagement Programmes at Queens University Belfast.

About Fusion Antibodies

Fusion Antibodies delivers new technology and innovation throughout early-stage antibody discovery. As a drug discovery and research partner, our scientists increase the pace to the clinic by guiding clients to develop the best antibodies possible. Through the early stages of drug discovery, we enable biotechnology and pharmaceutical organisations towards their end-goal – the provision of treatments that improve the lives of patients throughout the world.

About Queen’s University, Belfast

Queen’s University Belfast is one of the leading universities in the UK and Ireland, with a distinguished heritage and history. With over 24,000 students, 4,200 staff and an annual turnover of some £300m, Queen’s University Belfast plays a unique leadership role in Northern Ireland. As a member of the Russell Group of UK research-intensive universities, Queen’s University Belfast combines excellence in research and education with a student-centred ethos.