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Nanobodies®: small magical molecules for big difficult diseases

Written by DS on in the category Interviews with the tags , , , .


One of Belgium’s established biotech companies, Ablynx, has developed an innovative platform to produce small therapeutic proteins, called Nanobodies. These Nanobodies are being developed for the treatment of several diseases with high unmet medical need such as for example RSV (respiratory syncytial virus) infection, TTP (thrombotic thrombocytopenic purpura - an orphan blood disease), rheumatoid arthritis, lupus and cancer. The therapeutic proteins can be tailor-made and the possibilities are tremendous. We spoke with Johan Heylen, Chief Commercial Officer (CCO), about the technology and the potential of these innovative therapeutics.

What are Nanobodies exactly and how are they produced?
Johan Heylen: Nanobodies are very small antibodies, based on the smallest functional part of a special kind of antibodies from llamas. Nanobodies are about 10 times smaller than classical antibodies. As a starting point, we immunise llamas with the therapeutic target of interest (you can compare this with a vaccination). After a few weeks, we isolate the special llama antibodies from their blood from which we then further make our Nanobodies in the labs. The binding site of the Nanobodies is sequenced and the DNA behind the sequence is synthetized. Subsequently, the Nanobodies are produced via expression of the DNA in microbial cells.

What is so unique about this technology?
Johan Heylen: The Nanobodies are very small, so they can reach places and bind with targets that classical antibodies cannot reach or bind to, for example ion channels. They are very stable, heat-resistant and easy to produce. To modify their half-life, they can be attached to a Nanobody that binds with human serum albumin; as such the half-life extended Nanobody circulates longer. This allows controlling the administration frequency. Furthermore, administration of Nanobodies is not limited to intravenous injection. Thanks to the Nanobodies’ robustness and stability, administration through inhalation is also possible as is subcutaneous injection. 

Another important feature is the possibility to connect several Nanobodies as Lego® blocks together, using a glycine-serine linker within the same microbial production step. This multi-formatting allows combination of Nanobodies with agonistic and antagonistic activity and, combining Nanobodies that bind with different disease targets or Nanobodies that bind to the same target to increase their potency. This “mix & match” approach is a unique advantage and is of particular interest in the field of immune-oncology.

With which biochemical targets do Nanobodies bind? Can you give some examples of your products?
Johan Heylen: One of our flagships is the Nanobody (ALX-0171) to treat RSV virus infection in infants. This Nanobody is administered through inhalation and thus directly reaches the site of infection, i.e. the respiratory tract including the lungs. The Nanobody binds to the F-protein of the virus, inhibiting virus replication and uptake in the cells at the site of infection. Currently, a FPhase IIa study in infants is on-going and we hope to bring this product to the market in 2020/2021.

Another example is the Nanobody that binds to von Willebrand fFactor (vWF), a blood glycoprotein involved in haemostasis (bleeding process). TTP is a rare, potentially life threatening blood disease with high unmet medical need. In patients with TTP, ultra-large, multimeric precursors of vWF (UL-vWF) are present in the blood, which spontaneously bind platelets leading to the formation of unwanted characteristic string-like clots in small blood vessels. Our Nanobody, caplacizumab, binds to vWF and thereby inhibits these platelet string formations A Phase III registration studyis expected to start later this year.

We also have a Nanobody (ALX-0061) that binds to interleukin-6-receptor (IL-6R), which plays a role in inflammation. This Nanobody is being developed in partnership with AbbVie for the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We are responsible for Phase II clinical development of this Nanobody and two Phase IIb studies in patients with RA are currently on-going. A Phase II study in SLE patients is expected to start in the summer.

Also, Nanobodies for cancer immunotherapy are in early development both in partnership with Merck & Co, Inc., and as part of our proprietary pipeline.

Many biotech companies focus all their resources on one target or programme, but the downside of this approach is that if this doesn’t work, this could mean the end. Ablynx has multiple shots on goal with more than 30 programmes in our product pipeline of which six are in clinical development.
 

How do you develop your products?
Johan Heylen: Some of our products are fully owned, for others we partner with pharmaceutical companies including Novartis, Merck & Co, Inc., Merck Serono, Boehringer Ingelheim, AbbVie, Genzyme and Eddingpharm. These partnerships have to date generated more than €340 million in non-refundable, non-dilutive cash to Ablynx.

How do you see Ablynx’s future?
Johan Heylen: Ablynx is one of Belgium’s showpieces. Next is to maximize the potential of the pipeline, as programmes move through the clinic and towards the market. It’s an extremely exciting time, and I feel privileged to co-guide Ablynx into its next phase in its life cycle. The ambition is to build a leading international biopharmaceutical company generating significant return for shareholders and bringing drugs on the market which will make a real difference to the lives of patients.

Johan Heylen joined Ablynx in 2014 and brings more than 20 years of experience in pharma/biotech sales, marketing, project management and business development. One of his major realizations was has been the global launch of a number of paediatric vaccines, of which the blockbuster Rotarix, through which infant mortality in emerging countries decreased significantly. During his stay in the USA, he took an innovative cancer immunotherapy from Proof-of-Concept to end of Phase III, defined the launch plan and business model and set up the organizational structure, people and processes to support strategy and implementation. In his current role as CCO, Johan has responsibility for Business Development, Project Planning and Portfolio Management of the late stage assets, and Commercial, anticipating the commercialisation of the first Nanobody-based therapeutics.

We interviewed Johan the day after the Leuven’s half IronMan triathlon contest. A needed preparation for his 2015 sports challenge, the IronMan in Cologne. Mens sana in corpore sano…

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