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European Biopharmaceutical Review

Tunable Half-Life Technology

As the industry looks to find new ways to treat chronic conditions such as diabetes, shifts in dosing paradigms from once daily to weekly, and even monthly, provide significant benefits to the patient.

To address the delivery challenges associated with biological molecules, the industry has developed a range of technologies that can be broadly categorised into three areas: protein engineering; increasing the hydrodynamic volume (PEGylation, Xtenylation); and through a neonatal Fc receptor (FcRn) mediated cellular recycling (Fc and albumin fusion proteins). Despite these significant technical advances, none of these solutions allow a drug developer to tune the pharmacokinetic (PK) profile of their drug substance to maximise the efficacy of the treatment.

In response to this, a breakthrough tunable half-life extension technology, based on existing albumin-based half-life extension technology Albufuse, has been created. This genetic fusion technology is based around the idea of combining the naturally long half-life of albumin with the therapeutic effect of a biological drug. The technology is now well proven with the first two molecules produced using it, Albiglutide and Neugranin, currently undergoing review by the regulatory authorities. The technology is well documented for its safety and ability to produce stable biologic formulations.

Through subtle modification of the albumin molecule, a range of albumin variants with both increased and decreased PK properties with respect to native sequence albumin has been engineered. The result is a technology that allows manufacturers to tune protein or peptide half-life to specific medical needs, and can also be made available as a conjugation option.

Natural Biology

Human albumin has a naturally long serum half-life of around 19 days that is a result of both its size and ability to undergo a pH-dependant recycling process via the neonatal FcRn receptor (see Figure 1). A detailed understanding of the key amino acids involved in the FcRn receptor binding process has been developed. Subsequently, numerous albumin variants have been generated with single and multiple amino acid substitutions that can both reduce and increase the interaction between albumin and the FcRn receptor. The result is a range of albumin variants with both increased and decreased plasma half-lives in relation to wild-type human albumin. This ability to modulate albumin half-life provides researchers with the opportunities to control the PK of their biological drug to maximise therapeutic effect.

Flexible Drug Delivery Platform

Depending on the specific attributes of the drug molecule or requirements of the drug company, this half-life extension technology can be made available through two distinct technology offerings: genetic fusion and chemical conjugation. A summary of the differences between these approaches is presented in Table 1.

Genetic fusion is best suited to natural peptides and proteins. The flexibility of the genetic fusion approach means that molecules can be located at either the C- or N- terminus of the albumin molecule, or both, generating fusion molecules with monovalent, bivalent or bispecific properties. Chemical conjugation is most appropriate for synthetic peptides that are heavily engineered or contain non-natural amino acids.

Chemical conjugation approaches typically utilise the free-thiol at Cys 34 to facilitate site specific conjugation onto the albumin molecule without interfering with the albumin molecules’ ability to bind to FcRn. Table 1 outlines the main features of each of these options.

Startling Industry Potential

Offering manufacturers a definite advantage over alternative solutions – the ability to tailor drug half-lives to specific medical indications – holds benefits on both patient-centric and commercial levels. The technology could lead to lower and less frequent dosage levels for patients who need to take regular medication, such as those with chronic conditions, resulting in increased patient compliance and the possibility for patients to administer their own drugs. On a commercial level, this breakthrough technology will allow manufacturers to establish a niche position in the market, with more innovative and flexible products which offer improved performance throughout the drug lifecycle.

Importantly, the technology has been shown to produce more stable blood levels in patients and also confers a reduced risk of side-effects as the drug dose remains within the therapeutic range, increasing the patient’s tolerance to the drug. Since some biopharmaceuticals have to be administered by a nurse at home or at a clinic, the number of visits can also be reduced dramatically.

As a result of these recent developments, pharmaceutical companies large and small are adopting and realising the benefits of half-life extension and tailoring solutions, especially for use in drugs treating chronic conditions such as diabetes, haemophilia and neutropenia.

Conclusion

The market demand for more effective drugs is growing, which has led to the recent development of a range of half-life extension platforms. Many of these platforms are limited by the synthetic materials from which they are developed; that is, drug half-life cannot be effectively adapted to fit the needs of specific medical conditions. In response to that challenge, the latest advancement provides a wide ranging and accessible platform that drug manufacturers can use to differentiate their own products from competing therapies – creating ‘biobetter’ products. Thanks to new knowledge of albumin’s relationship with its receptors, this technology could transform many products.

Following the launch of this half-life extension technology to market, pharmaceutical companies of all sizes have begun to draw on its benefits – for example, some using the technology for diabetes, haemophilia, and neutropenia treatments. Because this technology is based on albumin (a natural, non-immunogenic plasma protein already present in our bodies), it is safe for use in pharmaceutical development to help provide control and design flexibility. Reduced dose frequencies can offer patients more effective treatment plans and thus a higher quality of life.


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Mark Perkins is a Formulation Chemist with a PhD in Pharmaceutical Sciences from the University of Nottingham. As Customer Solution Manager, Mark works with partners who are evaluating Novozymes Biopharma’s recombinant albumin products and associated technologies in the areas of biopharmaceutical formulation and halflife extension. Prior to this position, he worked as a materials specialist at an inhaled drug development company and as a project manager within an analytical consultancy.
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