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Next step: Building own sales force


Dr. Jan van de Winkel is Executive Vice President and Chief Scientific Officer of Genmab A/S, which he co-founded in February 1999. Prior to joining Genmab, van de Winkel served as Vice President and Scientific Director of Medarex Europe until 2000. He has been responsible for a number of patents and is the author of over 260 scientific publications. He received his M.Sc. in Biology (1985) and a Ph.D. in Immunology (1988) from the University of Nijmegen, The Netherlands, and has conducted postdoctoral work in the Netherlands and the USA. Dr. van de Winkel holds a part-time Professorship of Immunotherapy at the University Medical Center in Utrecht. He is a member of the scientific advisory boards of the Biotech Turnaround Fund and of Thuja Capital Healthcare Fund.

Professor van de Winkel, could you give us a brief outline of what Genmab is doing and which business model it uses?

Van de Winkel:
Genmab is a global biotechnology company focused on making human antibody therapeutics. From the beginning, we have decided to work on two types of scientifically and economically promising targets. The first type are validated targets, for which other antibody drugs have already been shown to work therapeutically in the clinic. In this field, Genmab tries to make human antibody therapeutics with better characteristics and simply competes for the original market. Examples would be targets such a CD20 and EGFR, where we have worked successfully. The second cate­gory of targets are novel ones, for which there is a compelling scientific and business rationale to make a human antibody therapeutic against, e.g. the inflammation target interleukin 15. On the basis of preclinical models, IL-15 is predicted to be a better target than TNF-alpha because it is situated near the apex of the cytokine cascade and it was envisaged that blocking IL-15 could well lead to a more prominent block at the inflammation level. So, we have always worked with a mix of new and validated targets. This was quite new at the time we started to do this. But it’s interesting to see that the so-called fourth-generation antibody companies are all using a similar business model to that which we have been using since 1999 – the last 8 years. Our burn rate has been somewhere around 70 million dollars. Ultimately, Genmab has been successful in raising capital – we have raised over one billion dollars in capital. In the last issued financial release, we informed the market that we still have 755 million in the bank, so this is one of the best capitalised biotechnology companies worldwide, definitely in Europe. Market capitalisation is the second biggest in Europe – it’s close to 3 billion dollars at this moment.

Could you please outline which platform technologies are essential for Genmab to produce antibodies; which are licensed-in and which are proprietary?

Van de Winkel:
The most important platform technology for us is the so-called UltiMab® platform, originally developed at Medarex, a US-based antibody company, which made that technology available to Genmab in exchange for equity. Originally, when we founded Genmab, Medarex had close to 45% of the shares in Genmab, in exchange for giving us access to their technology platform. Right now, because of the various financings, and also since Medarex has sold some shares, they have about 10.8% of our shares. The UltiMab® technology makes use of transgenic mice that express human genes. Most of our current antibodies in clinical development are based on the Ulti­Mab® platform. We have also developed a proprietary platform in-house called UniBody®. With this technology, we think we can generate very good antagonists, or blocking therapeutics for different responses. The drug candidates, created with the UniBody platform, are currently in the pre-clinical stage.
Can you please outline the features of the antibodies derived with help of the UltiMab and the UniBody platform? – One delivers full-length antibodies, I guess, the other provides fragments…

Van de Winkel:
Yes, the antibodies generated from UltiMab® mice are fully human. They are predicted to be very mildly immunogenic – if immunogenic at all –, so one can use such therapeutics repeatedly in patients – more readily than other types of antibody therapeutics. They tend to be of very high binding affinity. We generated antibodies with picomolar affinities, which are very difficult to make in normal mice. They compare favourably with antibodies produced with other platforms, such as phage display. Usually, the initial antibodies generated by phage display bind only poorly to disease targets. The best example is Humira (ada­limumab), which is an antibody against TNF-alpha, marketed by Abbott. That antibody had medio­cre binding qualities when it was first isolated, but after 2 years of molecular engineering, its affinity has been increased and now it’s a pretty decent TNF-alpha-blocking antibody. With the UltiMab technology, one needs no engineering to get well-binding antibodies that are also very similar to the molecules we have in our own bodies. We have given human antibodies to hundreds of patients and have never observed a significant antibody response against any of these.

Do you have some data on the immunogenicity of UltiMab antibodies for our readers?

Van de Winkel:
We are working together with the Belgian company Algonomics. We recently studied the predicted immunogenicity by analysing the sequences of human antibodies and then estimating the number of peptides specified by the human antibodies capable of binding to various MHC class II molecules. When one compares our antibodies with for instance chimeric antibodies or humanised antibodies, there is a far lower number of predicted binding peptides present in the human antibodies, and what we have then done is to validate this in-silico approach by looking at rheumatoid arthritis patients treated for a year with Humira. What we found is that we could predict over 90% of the immunogenicity of adali­mumab in individual patients correctly with the in-silico approach. When that is correct for Humira one would expect it to be also correct for other therapeutic antibodies. Thus, UltiMab antibodies are hardly immunogenic – if immunogenic at all. We intend to publish similar analyses of chimeric antibodies, such as Rituxan (rituximab), in peer-reviewed journals this year.

Coming back to the UniBody platform and the features of its antibody fragments…

Van de Winkel:
UniBodies are based on so-called IgG4 antibodies. In contrast, most therapeutic antibodies are based on the IgG1 isotype, which is a subclass of antibodies which can very readily interact with the human immune system, e.g. via immune cells that bind antibodies via their antibody- (or Fc-) receptors. Additionally, complement proteins are activated via the Fc part of an IgG1 antibody. IgG4 antibodies do not activate complement and interact only poorly with cells of the immune system. Genmab has created a variant from normal IgG4. Normally, antibodies have two arms. UniBodies are fully human 72 kDa-halves of antibodies with a half-life comparable to that of a normal IgG and they are predicted to be non-immunogenic in patients. That is different to other antibody fragments, e.g. nanobodies, domain antibodies or single-chain antibodies, which all need to be engineered to provide them with an appropriate in-vivo half life. We are going to confirm these results from ani­mal studies in man in the near future.

In what indications these fragments

will come to clinical trials in the next time?

Van de Winkel:
We have not detailed this at conferences. But I can tell you that we already have a number of UniBodies generated against solid tumour targets as well as against haematological and inflammatory targets. For a number of these, we have already demonstrated proof of concept. We will be giving the market an update on these developments this year.

What administration routes Genmab has chosen for its UniBody fragments?

Van de Winkel:
For a number of indications, UniBodies will be injected like other antibodies. But we believe that they may be well administered also via aerosols because they are smaller than other antibodies.
How Genmab is going to produce its UniBody fragments and what about the manu­facturing costs?

Van de Winkel:
We consider the size of UniBodies to be small enough to allow manufacturing in prokaryotic systems. This is different from other antibodies that need to be produced in eukaryotic cells. We believe that this could represent a manufacturing advantage. If we can produce them in prokaryotes this would affect manufacturing costs significantly, making it possible to also compete for markets with approved antibodies. Currently, we are in the process of comparing different production platforms. We are also in active discussions with big-biotech and pharma companies that are interested in getting access to the UniBody platform. This is because there are a lot of targets one cannot target easily with a normal antibody. We see this as an expansion of our presence in this therapeutic space.

Genmab has a lot of immunological targets in its pipeline. Can you tell us something about cross-linking characteristics of UniBodies?

Van de Winkel:
Unibodies do not cluster together. There are a number of targets we already have identified for which a non-clustering and non-cross-linking therapeutic could represent a more successful approach than conventional antibodies, which could lead to unintended agonistic effects due to target cross-linking

Coming back to UltiMab antibodies; recently, Genmab announced a significant deal with GlaxoSmithKline on HuMax-CD20™ (ofatumumab), which is currently in clinical trials for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL), non-Hodgkin’s lymphoma (NHL) and rheumatoid arthritis. What seemed unusual was that it was one of the first times that a biotech company asked a big pharma for the US co-distribution rights – and had succeeded…

Van de Winkel:
In the new era of biotech, we can now read about the pipeline problems of big pharma literally every day. And now we have a drug-candidate against one of the best-validated antibody targets in the world, with a predicted market potential of over US$ 6 billion. The chimeric CD20 antibody Rituxan brought in over US$ 4 billion last year. And CD20 antibodies have the potential for further growth in both the cancer and autoimmune markets. On the one hand, we have a validated therapeutic target for significant diseases. On the other hand, one already knows that there are significant problems with the existing therapeutic, i.e. that is not good enough for chronic use in autoimmune patients. We have generated a CD20 antibody that binds to the same target as Rituxan but in a different manner, and which has provided excellent early clinical data in rheumatoid arthritis. Our antibody can kill target cells expressing lower levels of CD20 than Rituxan can. We could make it clear to Glaxo – and to a number of other pharma companies – that HuMax-CD20 has better thera­peutic characteristics than Rituxan and should be excellently-positioned to take up market space from Rituxan. This situation led to a kind of bidding war that was very valuable in the promotion of one of the next steps in the development of Genmab: To create the possibility of co-promoting/selling our own antibodies with the help of a very experienced marketing and sales partner such as GlaxoSmithKline. Now, Genmab has the option to set up a sales force for the CD20 antibody and also to sell two of Glaxo’s products. This creates the opportunity to keep sales of future human antibodies completely in our hands that are interesting to the same doctors as HuMax­-CD20 –the next one could be our HuMax-CD38 therapeutic antibody for Multiple Myeloma. So, the co-marketing rights for HuMax-CD20 in North America and the Nordic region represent a nice first step with a look to this strategy.

How strongly will HuMax-CD20 compete with other innovative RA antibodies such as BristolMyers Squibbs’ CTLA4-Ig therapeutic Orencia, which already is approved in the US?

Van de Winkel:
The future in autoimmune diseases – as well as in cancer therapy – will be combination therapies. To achieve better efficacy, demonstrated by a higher percentage of ACR50 or ACR70 responses in diseases like rheumatoid arthritis, it would be ideal to combine a CD20 antibody like HuMax-CD20 with a TNFalpha blocker or a T cell-blocking drug like Orencia. B



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