The ability to customize small molecules—to make them better, safer, and easier to use—has long been a staple of pharmaceutical
development. But until recently, scientists had few options for enhancing biologics. San Diego-based Ambrx wants to change
Martin Mattingly has been president and CEO of Ambrx since September 2005. He joined the company from CancerVax, where he
was executive vice president and chief operating officer. He has also held leadership roles at Agouron Pharmaceuticals and
Pfizer, and oncology marketing positions at Eli Lilly. He holds a doctorate in pharmacy from the University of Kentucky.
The company's ReCODE (reconstituting chemically orthogonal-directed engineering) technology allows researchers to modify virtually
any amino acid, even those without their own chemical activity. In the past, it was only possible to make modifications to
a protein's 20 natural amino acids.
So, in essence, what Ambrx has done is create the "glue" that allows researchers to attach activity-enhancing molecules to
amino acids where they couldn't before. These attachment points have the potential to increase the length of time a protein
is active in the body, improve its safety profile, or make it more convenient for patients to use.
At just three years old, Ambrx has already forged its first partnership with Big Pharma: It teamed up with Roche to develop
the pharmaceutical giant's next-generation proteins and peptides. (It also has several other partnerships in the works.) Ambrx's
own lead protein—a weekly version of human growth hormone—is ready to enter the clinic.
Here, CEO Martin Mattingly discusses ReCODE in detail, explaining its potential to improve not only forthcoming biologics
but also those that already exist. He also answers a burning question: How did Ambrx develop this technology so quickly?
With small molecules, you have structure-based design, which allows you to customize. Is this what you're doing with biologics?
MATTINGLY: It's similar. We've used the term "protein medicinal chemistry" to describe what we do. In the past, the prevailing belief
was that natural substances have a set of amino acids that can't be modified. And what we now know is that they can be, and
we can improve on them. Roche has done it with a major product called Pegasys (pegylated interferon-alpha-2a). Amgen has done
it with several of their proteins. Eli Lilly has done it with insulin. We think of it as applying the traditional mindset
of medicinal chemistry, of making minor modifications to a small molecule to improve upon its characteristics.
But what Ambrx brings to the table for the first time is the ability to make a very precise and specific modification to a
protein, because what we have found is that the site of modification matters. So if you have a protein that has 200 amino
acids, we can pick any one of those amino acids and change it, and then confer new properties on the protein as a result of
that change. So, in a way, we do use a structure-based design approach because there are certain places you don't want to
modify the protein because you would inhibit it or you'd prevent it from being active. We know the general areas that we can
modify without affecting the activity of the protein.
The beauty of our technology is that once we go to a particular region of the protein, we can make changes anywhere within
that region; literally, we can make any amino acid change. We enable a level of control that's never been seen before.
Are you adding something to the amino acid through this technology?
Yes. We use an Ambrx amino acid that is specially designed to have certain properties. In the case of our first two products,
it is designed to make a chemical attachment point. We've referred to it variously as a Velcro-strip concept or glue. We're
creating a chemical attachment point—glue, if you will—that you can then use to put other things on the protein.