What bioprocessing challenges are faced in the development and manufacture of a new Protein C therapeutic?

Over the past few days, we've seen Dr. Mike Ultee has shared with us the differences between a biobetter and a biosimilar and the why the current molecule he's working on is a biobetter.  Today, he takes a deeper look into the development and manufacturing of this therapeutic.

Well, we’ve faced a number of them. I’ll start with just the properties of the particular protein itself. It is an enzyme, but beyond that it’s a proteases. What that means is that enzyme that digests protein. When a proteases has had it purified, it has no sub-strength other than molecules of itself. So, you get auto digestion of the molecule. So, you start to get clips and breaks in the peptide chain as the result of the proteases attacking itself. So, that was one of the challenges that we faced.

Half way through the purification process, the pre-enzyme is activated with another enzyme called “PROM-IN” that results in an active protease – a Protein C material – activated Protein C, sometimes called APC. That is what you need to purify carefully under conditions that minimize any auto digestion.

Some other challenges we faced were the post-translational modification, known as gamma-carboxyglutamic acid, sometimes abbreviated GLA. This is a necessary part of the structure of Protein C and some other proteins that allow it to bind to specific receptors on cells and its targets. We need to ensure that there were good substitutions with the gamma-carboxyglutamic acid. Specifically, this enzyme has nine GLA residues on it. So, looking at the structure we were able to confirm that we got good, effective gamma-carboxyglutamic acid modification on this amino acid sequence as originally produced by the protein. It’s just amino acids and then additional modifications are put on, such as this one.

Download Dr. Ultee's full podcast here.

Dr. Ultee will be further examining this topic with with Kent E. Pryor, Ph.D., Chief Operating Officer,ZZ Biotech during the presentation A New Biobetter Therapeutic – Development and Manufacturing: A Collaboration Case Study at Biopharmaceutical Development and Production Week. For more information on this session and the rest of the program, download the agenda.  If you'd like to join us March 24-27, 2014 in San Diego, as a reader of this blog, register to join us and mention code BDP14BLOG and you can save 20% off the standard rate.

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Creating a Protein C Biobetter

Yesterday, Biopharmaceutical Development and Production Week speaker Dr. Michiel Ultee shared with us the different between a biosimilar and a biobetter.  This March, he will be addressing how to develop and manufacture an biobetter therapeutic.

Today, he takes an in-depth look at the biobetter he'll be presenting about:

It’s a version of Protein C, an analogue that has some amino acid changes to change the property very slightly, but significantly. Protein C is a protease that was initially marketed by Eli Lilly under the name “Xigris”. It was taken off the market a couple of years ago because of one particular side effect that was difficult – that was induced bleeding in some patients. That’s because it had an efficacy that would inhibit coagulation. It had other properties that were desirable, but that was one that caused some bleeding episodes in some patients being treated for medical conditions such as stroke.

ZZ Biotech, the company that Gallus has worked with on this project, developed a new form that was re-engineered where three amino acids have been changed so that this former Protein C no longer has the ability to inhibit blood coagulation. Therefore, it does not affect bleeding that was seen before. But it retains the cytoprotective qualities of the Protein C, allowing it to be an effective therapy for stroke victims and other disease states.

So, it’s really a biobetter because it’s an improved or second generation version of the first drug, but based on the same general protein, in this case Protein C – that enzyme.

Listen to Dr. Ultee's podcast and other insights from the speakers of BDP Week here.

Dr. Ultee will be presenting the case study A New Biobetter Therapeutic – Development and Manufacturing: A Collaboration Case Study with Kent E. Pryor, Ph.D., Chief Operating Officer, ZZ Biotech at BDP Week.  For more information on this session and the rest of the program, download the agenda.  If you'd like Mike this March 24-27, 2014 in San Diego, as a reader of this blog when you register to join us and mention code BDP14BLOG, you'll save 20% off the standard rate!

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