By James Netterwald, Ph. D.
Like all pharmaceuticals, biopharmaceuticals have a specific way in which they interact with their target molecule; this is called the pharmaceutical’s mechanism of action and is specific for a given drug or a class of drugs. Some biopharmaceuticals inhibit the activity of their target by directly binding to it, thus prohibiting the target from carrying out its biological function, while others promote the activity of a target through this binding action. A major mechanism of action for monoclonal antibodies is blocking the function of a specific protein referred to as an antigen. Typically, monoclonal antibodies do this by specifically binding to its antigen and inhibiting its antigen’s ability to interact with other cellular proteins, which may be located on the cell’s outer surface or may be inside the cell, depending on the specific antigen. For example, HUMIRA (adalimumab; produced by Abbott Laboratories) is a monoclonal antibody-based therapeutic that blocks the pro-inflammatory activity of TNF-alpha and is indicated for the treatment of Rheumatoid Arthritis.
MONOCLONALS GET CHALLENGED
One major complaint about biopharmaceuticals is that they are too expensive for patients. “Currently, monoclonal antibodies cost patients between $15,000 and $20,000 per year,” says Piers Whitehead, VP of corporate development at Neovacs (Paris, France). “Our products target a market that is today dominated by $18 billion plus worth of monoclonal antibodies and antibody-like products,” says Whitehead. A major reason biopharmaceuticals are more expensive for consumers than the small-molecule pharmaceutical is that they cost a lot more to develop and manufacture. Furthermore, with monoclonal antibodies, the cost differential is further increased by the need to manufacture monoclonal antibodies in low-yield and time-consuming mammalian cells. “Monoclonal antibodies typically need to be glycosylated, which in turn dictates the use of a high cost manufacturing system,” says Whitehead. Glycosylation is a biological process in which sugar molecules are chemically attached to proteins.
Founded in 1993, Neovacs specializes in the development of immunotherapies. But its products differ from the rest of the pack in that instead of injecting a monoclonal antibody into patients, antigens are injected that will trigger the production of polyclonal antibodies by the patient’s immune system. Neovacs’ products are called Kinoids, which are made of two main components: the target cytokine and a carrier protein. Cytokines are proteins produced in small quantities by immune cells and help to regulate the immune response. KLH, a foreign carrier protein, is used to boost the likelihood of immune response to the cytokine, and is conjugated — connected by strong chemical bonding — to the cytokine. “We could produce our products at a much lower cost per treatment course. These cost savings might allow more patients to be treated, which would significantly expand the market,” says Whitehead. “Our Kinoid antigens can be made in lower cost microbial systems.”
There are other reasons to challenge the market dominance of monoclonal antibodies. Current monoclonal antibody products used for chronic diseases often produce resistance over time, as the patient’s immune system recognizes the antibody administered as a foreign entity. As a result, it is common for these products to lose efficacy progressively. The Kinoids should not encounter this problem, since their mechanism of action relies on an antibody produced by the patient. A further difference is cost. In order for monoclonal antibodies to be effective, patients have to receive frequent injections at high doses. “If you look at Humira, that product has to be administered every two weeks,” says Guy-Charles Fanneau de La Horie, Ph.D., CEO of Neovacs. “Kinoids will need to be administered only three or four times a year. In addition, the Kinoid products, because they are antigens getting the patient’s immune system to make the antibodies, can be administered at significantly lower doses [in the 300 to 400 mcg range], as opposed to the gram scale for monoclonal antibody products. So we feel that we can have a huge advantage in cost of production for an annual treatment,” says de La Horie.
Neovacs’ lead kinoid product targets the cytokine TNF-alpha (tumor necrosis factor alpha), the dysregulation and/or overproduction of which has been shown to play a role in many auto-immune diseases such as Crohn’s Disease and rheumatoid arthritis. The product is designed to elicit anti-TNF antibodies that block its activity, thus reducing the damaging inflammation associated with autoimmunity. TNF-alpha Kinoid is currently in a Phase 1/2 trial in Crohn’s Disease and a Phase 2 clinical trial in Europe for the treatment of rheumatoid arthritis.
BIOPHARMACEUTICAL MANUFACTURING: TREND AND PREDICTIONS
Lonza, a contract pharmaceutical manufacturing and development company proving such services to biopharmaceutical companies for almost 30 years, is headquartered in Basel, Switzerland. The multinational company also is involved in helping to design molecules and helping predict the safety profile or the immunogenicity of a biologic, which all help its customers identify development problems very early in the process.
According to John Birch, Ph.D., chief scientific officer of biopharmaceuticals at Lonza, in terms of the future of biologics, there are many emerging trends. Just in the area of manufacturing, there are three major aspects that have emerged: the cost of goods, speed of development, and the design of the molecules themselves. “The cost of goods is a significant issue, and we continue to put a lot of work into designing processes that will be more cost-effective, such as extremely efficient fermentation processes,” says Birch. “But even with the front end improved, what we are seeing increasingly is that the most expensive part of the process is recovery and purification. So, it now becomes very significant for us to investigate more efficient downstream routes.” For speed and process development, he explains that, historically, it could have taken a couple of years to reach the point where a manufacturer could produce a sufficient quantity of a protein to actually start a clinical trial. One area of focus for Lonza and others in the space has been to develop more efficient cell lines for the production of biologics. Birch says, “One of the slowest parts of the development process is actually the development of mammalian cell strains for the production of monoclonal antibodies.” To meet this challenge, Lonza has developed its own proprietary expression technology called the GS Gene Expression System and fast track cell line constructions. “We are capable of screening for highly productive cell lines using highly automated systems, which have helped to dramatically reduce the amount of time it takes to generate the production strains,” says Birch. In terms of trends in molecular design, the discovery companies are putting a lot of effort into designing increasingly more potent molecules.
Birch also offered some predictions with regard to the abovementioned trends. “We can design cells that help produce molecules that are more potent. I think with regard to monoclonal antibodies, we will see a future in which, in addition to the classical monoclonals, we also will see fragment-based antibodies that have antibody-like binding properties, different biological effects, and can be manufactured in microbial cultures.” In terms of other predictions, “I think we will see the use of microbial cultures over mammalian cultures for the production of some of these proteins. I think with increased potency we can produce some of these molecules on a smaller scale. And this might increase the use of single-use systems, which in general are becoming more common,” says Birch.
In summary, biopharmaceuticals have truly revolutionized the pharmaceutical industry because of their targeted specificity and improved safety profile. However, traditional manufacturing of biopharmaceuticals has been inefficient, which has led to skyrocketing cost to the consumer and has stood in the way of complete market dominance. Improved manufacturing processes such as the use of more efficient cell lines for bioreactor-based manufacturing will likely lower the cost of manufacturing, which will, in turn, lower the cost of goods.