A nanobody (registered trademark of Ablynx NV, Sanofi), also known as a single domain antibody (sdAb) or VHH, is a recombinant, single-domain, variable fragment of camelid heavy chain-only antibodies, which can bind selectively to a specific antigen. Single domain antibodies have an approximate molecular weight of 15 kDa and are considered the smallest naturally derived antigen-binding fragment. Due to their size in the nm range, the term ‘nanobody’ was coined by the Belgian company Ablynx (now part of Sanofi), which refers to the VHH domain from Camelidae species.

At Cortalix, we initially created immune libraries from immunized llamas with combinations of purified extracellular domains of membrane receptors overexpressed in fibrosis and various cell types present in fibrotic tissue and fibrotic cancers.
From this we have been able to select a large number of attractive candidate nanobodies that we can upgrade to potential clinical candidates after various in vitro and in vivo studies.

Based on that experience, we recently invested in the design and production of some synthetic libraries. Based on these libraries, we chose backbones consisting of several humanized framework regions with as few potential liability sites as possible. The antigen-binding regions in the 3 CDRs have been subjected to random amino acid sequencing, avoiding, for example, unwanted stop codons.

In the early days, when recombinant antibody technology – mainly focused on scFvs – emerged, nanobodies did not attract much attention. However, over the years, a steadily growing number of publications illustrated the benefits of nanobodies in certain research niches. To identify practically applicable nanobodies, it is important to start from a high-quality gene bank of Nbs, focused on the final application and with a great diversity. Our screening and selection procedure using phage panning allows us to extract the best possible Nbs from this diverse library and then use a few engineering steps to tailor the Nb for its final application. We have various options for conjugating radionuclide chelators, including NOTA and DOTA derivatives. We use the latest techniques to control the PK and plasma clearance, which is different for a diagnostic and a therapeutic.

Nowadays, the technology to identify nanobodies and tailor them completely has become increasingly advanced and is also used by Cortalix and can also be offered by it to develop other nanobodies on request. Through 3D simulation we are able to make predictions, within certain limits, about the applicability of selected nanobodies.
Now that the first therapeutic nanobodies have been admitted to the market, other pharmaceutical companies will quickly join in and this will certainly lead to even broader applications, including in the field of radiopharmaceuticals.
At Cortalix we want to participate in this development and we will develop into a party that will accelerate the application of nanobodies and we want to contribute to solutions that offer prospects for patients who currently do not have them.