Biotech Values

[DewDiligence]

MNTA – This 2003 article on glycobiology
from Signals Magazine is still a good read.
I’ve excerpted the part pertaining to MNTA.

http://www.signalsmag.com/signalsmag.nsf/0/3B9506A0682DD21688256DA6007B6B84

›Billions of Possibilities

“Inventive” certainly describes Momenta Pharmaceuticals Inc., one of the new crop of glycobiology companies. Founded in 2001 on technology developed at MIT, the privately held company [it IPO’d in 2004] is perfecting a high throughput method for the precise chemical characterization of complex sugars – both linear and branched. The Cambridge, MA firm’s technology involves breaking up these huge molecules into smaller fragments with specific enzymes, sorting the bits with high-pressure liquid chromatography and then characterizing the individual units within each piece by mass spectroscopy and NMR.

With the help of sophisticated computer algorithms that can simulate the massive number of theoretical sequences that might belong to the complex sugar being investigated and an iterative experimental process that systematically eliminates the possibilities, Momenta’s technology is capable of deriving the full sequence of the original complex.

According to chairman and CEO Alan Crane, “Momenta’s technology has three components: proprietary enzymes, equivalent to restriction enzymes, that chop sugars in very specific places; improvements on existing analytical technology (both MS and NMR), which have been adapted for use with sugars; and bioinformatics.” Moreover, the technology requires very small amounts of starting material and can even be used to analyze a mixture of different polysaccharides.

The company’s enzymes, all licensed from MIT, are absolutely critical for determining structure. The collection contains naturally occurring enzymes (such as heparin-degrading enzymes isolated from bacteria) as well as about 120 mutant enzymes with altered specificities that degrade polysaccharides at different places, explained Ganesh Venkataraman, Momenta’s VP of technology. The firm also has various enzymes that attach or remove side groups on the sugar molecules as well as transferases that it can use to build sugars, he added.

“Our technology allows us to sequence a sugar of any length, which used to be impossible.” For instance, using older methods, the time and labor needed to sequence even a hexasaccharide would be enough to constitute a graduate thesis, Venkataraman said. “Now, it takes 15 minutes.”

That’s good, because complex sugars can be much larger. Momenta has sequenced both deca- and dodeca-saccharides. And here, the possible combinations are staggering: 255 million for the 10-unit sugar and more than 12 billion for the 12-unit sugar. Why is this so? Because not only are there a number of different ways for monosaccharides – the basic building blocks of carbohydrates – to link to form disaccharides, but also as the chains continue to elongate the complexity increases enormously, introducing differential modifications, side chains, branches or the addition of sulfate groups, for instance.

With such a powerful technology, Momenta ought to be able to build a nice business for itself through a series of carefully crafted, product-focused partnerships. But the company wants more: It also intends to develop its own drugs – new therapeutics as well as enhanced versions of existing products. Armed with the ability to sequence complex sugars, company scientists will also be able to analyse how specific sequences and changes in structure affect the properties of drugs.

For instance, they’ve used the technology to understand the relationship between structure and activity for heparin, a complex, sulfated polysaccharide that blocks the formation of blood clots. “Then we designed a product with improved clinical properties for specific indications,” Venkataraman said.
In fact, the company is now developing an anti-coagulant drug candidate with superior efficacy, safety and pharmacokinetic properties [this is M118, now in phase-2].

Moreover, understanding sugars should open the door to new therapeutic approaches for treating cancer and other diseases. Because the sugar groups on cancerous cells are very different than those found on normal ones, for instance, it’s possible to analyze those differences and determine the effects that those changes have on disease biology. As well, since cell surface sugars modulate the access of growth factors to the cell, engineering sugars might be a way to block multiple pathways simultaneously in cancer cells, Venkataraman said.‹