Research

The Nanobody^® advantage

The unique and well characterised properties of Nanobodies^® enable them to outperform conventional therapeutic antibodies in several critical areas:

• recognising uncommon or hidden epitopes
• binding into cavities or active sites of protein targets
• drug format flexibility
• gastro-intestinal stability
• tailoring of half-life
• ease and speed of drug discovery
• ease of manufacture.

Recognition of uncommon & hidden epitopes

As a result of their small size, Nanobodies^® can recognise uncommon epitopes on targets hidden or shielded from the much larger conventional antibodies. Such recognition can be associated with improved biological activity compared to conventional antibodies in applications such as in parasite neutralisation.

Cavity binding - enzymes & receptors

Due to their unique 3-dimensional structure, Nanobodies^® have the potential to access cavities within molecular targets such as enzyme active sites and receptor clefts. These cavity structures are largely inaccessible to conventional antibodies but can be readily recognised by a long and protruding peptide loop as found in many Nanobodies^®. Importantly, while enzyme and receptor clefts are also binding sites for many small molecule drugs, these drugs typically engage such targets with a low affinity and low selectivity. This can result in unwanted side-effects and lack of potency. In contrast, Nanobodies^® have the potential to engage cavity structures with the same high affinity and selectivity as typically protein-protein interactions mediated by conventional antibodies. This is expected to yield highly potent molecules and minimise the likelihood of side-effects.

Exceptional drug formats

The Nanobody^® platform allows the ability to design modular drugs based on Nanobody^® building blocks combined with each other or with other protein domains or other molecules or drugs. These can combine more than one function in the final drug format. Ablynx has combined Nanobodies^® in a wide range of formats, including unique multivalent (multiple identical binding sites for the same antigen), biparatopic (two Nanobodies^® binding neighbouring epitopes on the same antigen), bispecific (Nanobodies^® binding to two different antigens) and bi-functional molecules. These formats are easy to construct and the modular proteins can often be expressed at high levels in bacteria or yeast. As a result of this formatting flexibility, the range of therapeutic applications for Nanobodies^® appears to be beyond that possible for conventional antibodies and antibody fragments.

Gastrointestinal stability & oral availability

Nanobodies^® are more resistant to extremes of pH and temperature and resist attack by proteases to a greater degree than conventional antibodies. Some Nanobodies^® have been shown to survive the harsh conditions of the stomach and remain biologically active in the gut. This creates opportunities for orally delivered Nanobodies^® to treat gastrointestinal disorders including Crohn’s disease and neutralization of viruses causing gastro-enteritis.

Tailored half-life

Nanobodies^® can be tailored for a half-life varying from 30 minutes to 3 weeks, by choosing from a variety of engineering methods. This versatility increases the range of therapeutic options available to Nanobodies^® ranging from acute to chronic indications.

Efficient drug discovery & development

Ablynx’s Nanobody^® platform can very rapidly deliver therapeutic leads for a wide range of targets. Based on naturally occurring antibodies that lack a light chain, Nanobodies^® obviate the need for construction and screening of large libraries, and for lengthy and unpredictable affinity maturation. As a result, Ablynx can generate panels of high-affinity Nanobodies^® ready for further analysis in 8 weeks of target access. As fast as within 10 months from accessing a target, high-affinity Nanobody^® leads can be progressed into pre-clinical development.

Ease of manufacture & formulation

Nanobodies^® are encoded by single genes and are efficiently produced in almost all prokaryotic and eukaryotic hosts including bacteria and yeast. The production process is scalable and multi-kilogram quantities of Nanobodies^® have been produced. Because Nanobodies^® typically exhibit a superior stability compared with conventional antibodies, they can be formulated as a long shelf-life, ready-to-use solution.