Tuesday, November 13, 2007

Biolex: a preview

What if a slow-to-launch company could now be public?

Biolex Therapeutics is a clinical-stage biopharmaceutical company who filed for an IPO in August 2007. I wrote the following article shortly thereafter, expecting an imminent pricing. Interestingly, aside from some phase II results on their lead therapeutic candidate there hasn't been much in the way of information concerning either the company or the expected IPO date. Furthermore, the Biolex website has been curiously "under construction" since shortly after their S-1 filing. Regardless of whether Biolex plans to stay private, is talking to potential acquirers, or just dragging their feet and waiting for better market timing, I decided to post my research anyway because it was a good time learning the story.

The intriguing aspect of Biolex is that they employ a proprietary and very novel protein expression system (the LEX system), enabling the production of biologic candidates otherwise difficult to make through traditional commercial means. The LEX system utilizes the aquatic plant Lemna, known commonly as duckweed, as an expression host to produce these difficult proteins.

I decided to look in to Biolex for a multitude of reasons, not least of which because I personally spend most of my own waking hours expressing and purifying difficult proteins. However pursuing this analysis quickly opened up a Pandora's box of necessary prior research. This research has been absolutely indispensable to understanding Biolex in a proper context and will be needed ultimately to make any kind of a educated financial judgment, should IPO follow through. In any event however, I can guarantee that comprehension of Biolex story will prove to be highly a enriching experience to those interested in the zeitgeist of multi-disciplinary biotechnology. Lets get started at as logical place as any, the duckweed itself.

The Duckweeds: A Valuable Plant for Biomanufacturing ?

Lemna, commonly called duckweed is one 4 genera in the monocotyledonous family Lemnaceae, which grow floating in still or slow-moving fresh water around the globe. This family are also the smallest known and most morphologically reduced flowering plants. For those interested in an intimate understanding of the family I can recommend any number of the duckweed fansites or information pages. For the sake of brevity however, I will sum up those aspects of the genus which make it an amenable organism for production of recombinant proteins and biologics.
  • Lemna can be proliferated in an aqueous medium cheaply and clonally, and doubling times are 20-24hours.
  • The plants can tolerate a broad pH range and a number of organic buffers and protein stabilizing coupounds. (MES, MOPS, EDTA,PVP)
  • Duckweed cells can be processed easily as they contain no lignin (woody material), and can be homogenized readily by commercially available methods.
  • Lemna species, among others are amenable to genetic manipulation, reliable and relatively expedient methods can generate transgenic lines in 6 weeks or less.
  • Lemna cells are eukaryotic, and have glycosylation machinery.
Those interested in the nuts and bolts of plant genetic engineering will be unsurprised to discover that tranformation and creation of stable transgenic duckweed lines is performed in a more or less classical manner, using Agrobacterium tumefaciens and plating the recombinant callus on appropiate media with growth hormone and selection antibiotic.

It is also important to mention that plants in general all share some advantages as organisms for biopharmaceutical production. The most obvious is that transfer of human viruses and other contaminations is effectively impossible, either from the outside environment to the culture or from the culture to the biologic itself. This is not only beneficial from a cGMP perspective, but it also cuts orders of magnitude off the cost of production. Plant based expression systems are also easily scalable and have a potential of far less capital and operating costs than even existing bacterial systems. Finally not only are all plants and mosses able to glycosylate their proteins, there has been initial success with actual secretion of the therapeutic protein of interest into the media from either the root system (rhizosecretion) or directly from moss protoplasts, eliminating the need for homogenization and greatly simplifying the purification procedure.

The major challenges facing the usage of plants to produce biopharmaceuticals are largely twofold. The first is that there are major structural differences between plant and mammalian n-linked glycans. Therefore proteins glycosylated by the endogenous plant machinery elict an immunogenic response in humans when administered parenterally. This problem has been overcome somewhat in transgenic tobacco expression systems by engineering the plants to produce human galactosyltransferase. Alternatively this problem has been addressed in the moss expression system Physcomitrella patens by knocking out the genes encoding for the plant specific sugar transferases (developed commerically by Greenovation). Biolex themselves followed a similar concept by using RNAi to inhibit two undesirable endogenous Lemna sugar transferases, giving rise to a single species of non-immunogenic glycosylated antibody that performed better in vitro than those produced in CHO cells.

The second challenge facing those in the business of producing biologics in plant based systems is that of public opinion. In 2001, the Prodigene incident, where corn genetically modified to produce trypsin acidentally cross-pollenated a nearby field in Iowa, caused a public outcry and eventually sunk the company. This, and numerous other debacles concerning GM food crops have fueled the fire of public concerns to which the demise of several biotech business models of plant-made products (PMPs) can be attributed. Because of this, the current front runners of biotech PMP manufacturing are sidestepping this hot-button issue by using highly contained, non-food plants such as tobacco, moss, or duckweed. In this manner, it would seem Biolex has chosen a less controversial organism which is propigated under easily controlled, and highly contained conditions.

So far so good. Biolex has a proprietary method of making their therapeutic proteins, which as has been mentioned elsewhere on this blog, is a very good strategy indeed for potential acquisition or competition. I'll leave the analysis here for the time being, and in the case of a IPO pricing, I'll continue on with Biolex's lead therapeutics, patent positioning, partnerships and financials.

2 comments:

Anonymous said...

Hi. Your blog is great. I found it while researching Helicos as a possible investment. Good info.

Can you tell me what you think of Nanosphere? They went public a couple weeks ago (NSPH) and their Verigene system seems very interesting. I'd appreaciate your assessment. I'm wondering, among other things, if this system overlaps/competes with the HeliScope.

Thank you very much in advance.

Greg
email:gpickles@bain.com

P.S.: Here's the Nanosphere S-1/A -
http://ipo.nasdaq.com/ViewFiling_frames.asp?filename=0000950134%2D07%2D022102%2Etxt&filepath=%5C2007%5C10%5C29%5C

Anonymous said...

BTW, Nanosphere's web site is http://nanosphere.us/ (not .com)