The molecules are touted as a superior alternative to conventional monoclonal antibodies (mAbs) as they are cheaper and easier to manufacture, while retaining their selectivity and efficacy. Due to their reduced size, the antibody rivals can be administered in a variety of ways: injected, orally, in sprays or creams, as opposed to full size antibodies, which can only be delivered by injection. Boehringer Ingelheim will pay €75m upfront, which includes a €15m equity investment, followed by potential milestones payments of up to €125m per Nanobody. That puts the total potential value of the deal at a staggering €1.325bn and establishes the pharma company as a new major player in the world of antibody rivals. Currently, this sector of biologic therapies is dominated by Ablynx and GlaxoSmithKline (GSK), the latter through their £230m (€340m) acquisition of Domantis earlier this year. Domantis achieved this miniaturisation by only producing the small part of the antibody or domain that actually binds to the target, disregarding the extra part of the protein. The resultant domain fragments, dubbed Domain Antibodies (dAbs), are up to 13 times smaller than normal antibodies (around 110 amino acids long). The molecules entered the clinic for the first time in May of this year, through a Domantis licensee called Peptech. Its PN0621 drug targets tumour necrosis factor (TNF) to treat auto-immune inflammatory diseases such as rheumatoid arthritis. Ablynx, meanwhile, developed its alternative mini-antibodies following the discovery that camels and llamas (camelidae) possess fully functional antibodies that lack light chains. These heavy-chain antibodies contain a single variable domain (VHH) and two constant domains (CH2 and CH3). Importantly, the cloned and isolated VHH domain is a perfectly stable polypeptide harbouring the full antigen-binding capacity of the original heavy-chain antibody. These heavy chain VHH domains form the basis of Ablynx's Nanobodies and the molecules are slightly ahead of GSK's in terms of development: the final Phase I results of ALX-0081 are expected this month. This Ablynx drug targets von Willebrand Factor (vWF) to reduce the risk of thrombosis in patients with acute coronary syndrome. The collaboration between Ablynx and Boehringer Ingelheim will focus on multiple diseases, including immunology, oncology and respiratory, with both parties able to propose possible targets. Dr Edwin Moses, CEO of Ablynx, said: "This is by far the largest financial agreement that Ablynx has signed to discover and develop innovative Nanobody therapeutics. We are delighted to strengthen our existing relationship with Boehringer Ingelheim by working together to develop innovative products across multiple therapeutic areas. This strategic alliance may provide the opportunity to grow Ablynx's own product pipeline." A further advantage to mini-antibodies is that they can also address therapeutic needs beyond the reach of antibodies, for example targeting epitopes such as receptor clefts, enzyme active sites and viral canyon sites, according to Ablynx. They can also enter the central nervous system more easily and so treat a number of diseases that bigger molecules cannot. According to Domantis, another advantage can been seen in diseases where more than one antibody could be used; it is possible to stitch together two or more antibody domains in one product, which could then do the job of multiple traditional antibodies. A third alternative to antibodies is being developed by Molecular Partners. The Swiss Biotech recently raised CHF18.5m (€11.3m) in Series A financing, with investors attracted by its Designed Ankyrin Repeat Proteins (DARPins). DARPins comprise a single protein structural motif that is repeated several times and linked by a peptide loop. The structural units then stack together to form an elongated molecule.
