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Mar 1, 2011 (Vol. 31, No. 5)

Strategies to Advance mAb Production

New Approaches to Process Challenges Help Push the Industry Forward

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    MorphoSys recently introduced arYla™, which combines HuCAL technology with an additional solid-phase technology for high-throughput gene synthesis to accelerate and speed up the antibody-optimization process. The solid-phase method is based on a DNA-engineering platform that enables the controlled synthesis of DNA-fragments that represent all possible permutations.

    While approval of new therapeutic antibodies has not progressed as rapidly as was forecast 10 years ago, new products are moving through the pipeline. As always, bioprocessing, critical to antibody manufacture, is a key factor in the cost and efficiency of production.

    Interviews with company officials and researchers engaged in bioprocessing showed how novel approaches to these challenges are moving the industry forward. All of the experts GEN spoke to will discuss new scientific developments and recent technological advances at BIT’s “International Congress of Antibodies” meeting in Beijing later this month.

    “We have more than 60 programs in progress with our partners; the majority of these programs are building on IgG-type antibodies,” states Bodo Brocks, Ph.D., director and group leader of analytics and head of quality control at MorphoSys. “This is our preferred direction and our customers’ favored format. Moreover, our high-throughput systems are designed to move in this direction, producing large quantities of antibody.”

    HuCAL, Morphosys’ antibody-development platform, HuCAL, is a phage display technology consisting of a library of 40 billion possible human antibody sequences. Unlike earlier antibody-development platforms, it does not rely on immunization of mice or other animals.

    In a typical run, a panel of a few thousand possible candidates can be selected and further analyzed. “We examine biological potency, specificity, and affinity of the antibody, while on the other side we look at the physical chemical properties like thermal stability or aggregation to make the antibodies fit for our pipeline,” explains Dr. Brocks.

    The antibodies from the library can be reconfigured, removing and replacing pieces so as to change their binding affinity or biological function without changing their overall human structure. “The strength of our technology is that we can do affinity maturation, bringing antibodies from nanomolar to picomolar affinity. By grafting alternative complementarity determining regions into promising candidates, we can develop highly potent antibodies.”

    Alternative scaffolds, based on protein families such as the ankyrins, have been the subject of considerable attention in recent years but have not yet resulted in FDA-approved products. “These are interesting from the standpoint of ease of production in bacterial systems,” Dr. Brocks adds, “but in recent years mammalian upstream systems have improved significantly for antibody production, so that’s not an area that we are pursuing at this time.”

  • Single-Use Rapid Scale-Up

    “We are moving from the era of blockbuster drugs to that of niche busters,” says Paul Chapman, Ph.D., vp at EMD Millipore. “There’s probably not a single antibody production company that doesn’t carry over capacity based on business plans developed in the last decade.”

    The implications of this transformation within the bioprocessing industry, especially with respect to antibody production, are portentous. A decade ago many pharmas and biotechs built large-scale antibody-production facilities with elaborate and costly hardware for the purpose of generating kilogram quantities of a single recombinant protein.

    Now much of this capacity is idle, as demand has shifted due to the pursuit of therapies guided by the demands of personalized medicine, in which the amount of material required to meet the needs of a restricted market may be orders of magnitude less. EMD Millipore is one of a number of companies developing single-use processing systems and technologies to meet this exigency.

    Single-use modules are ideal for therapeutics whose demand will be measured in milligrams to kilograms rather than tons. “In moving from the lab bench to the bedside, we are deploying a range of single-use technologies for antibody manufacture,” Dr. Chapman continues. “This allows us to remove labor-intensive steps and obtain the same quality with a much higher level of flexibility and overall plant productivity.”

    According to Dr. Chapman, the Mobius CellReady 3L Bioreactor is the first single-use benchtop bioreactor designed to mimic the characteristics and performance of traditional glass stirred-tank bioreactors. The Mobius CellReady bioreactor reduces turnaround time from days to hours, improving operational efficiency and scheduling flexibility for process-development labs.

    Currently, cost savings are a significant consideration for antibody-production companies. “Earlier on, I don’t think companies were that hard-pressed to optimize every step as the industry is today,” Dr. Chapman suggests. “But now we can shrink the template and remove labor-intensive steps, while still retaining the same quality and manufacturing capacity. This means that we can drive down costs with a faster turn-around time. Moreover, we can run two to three different products at the same time, which would not have been possible without the flexibility of these single-use processing technologies.”

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