Large biotech firms are scurrying to exploit bi-specific antibodies as well. Novartis recently paid GenMab $2 million to tap into the latter’s DuoBody™ technology for creating bi-specific mAbs. The full value of the deal could reach $175 million for GenMab, which has its own development pipeline as well.
Bi-specific antibodies combine the affinities and activities of two different mAb fragments and target two distinct antigens simultaneously, for example a tumor target and a cytotoxic immune system cell.
“Bi-specific antibodies pose unique challenges in development and manufacturing and can require added effort and time in bringing new therapeutics to commercialization,” says Kevin Bailey, Ph.D., vp for preclinical manufacturing at Regeneron Pharmaceuticals. Regeneron develops monoclonal antibodies to block individual therapeutic targets in oncology, cardiovascular diseases, infectious diseases, and others.
A somewhat related approach is to administer two mAbs at once with the idea of delivering an orthogonal one-two punch to the therapeutic target. Such treatments would be prohibitively expensive unless the innovator companies collaborated on a designated combination product, an unlikely occurrence. An innovative way around this idea is to produce two or more mAbs simultaneously in the same cells.
That is the idea behind Oligoclonics® from Merus, which creates mixtures of mAbs with different specificities through co-transfection of cells for multiple antibodies. This approach essentially creates a combination therapy in one manufacturing process. Merus received the first European patent for the technology in June.
Engineered antibodies seek to improve the safety or efficacy of conventional antibodies or fragments through modification of glycosylation. In particular glyco-engineered antibodies containing low or no core fucose residues on the Fc N-glycan show improved affinity for Fc gamma receptor IIIa, and thus improve antibody-dependent cellular cytotoxicity—a critical factor in antitumor activity.
BioWa is one firm at the forefront of eliminating fucose from antibodies. The company’s Potelligent® technology enhances mAb activity, increases Fc binding, lowers the effective dose of an antibody therapeutic, and requires no change in the manufacturing process. In June, BioWa signed an agreement with Lonza to investigate the potential for reducing fucose residues in mAbs produced through Lonza’s GS Gene Expression™ system.
Improving mAbs through genetic engineering, manufacturing innovations, formulation, or some combination of the three is, of course, the idea behind “biobetters.” Formulation and preformulation are established strategies for improving prospects of development-stage small molecule drugs, for example by improving solubility.
The same is true for proteins and antibodies, notes Indu S. Javeri, Ph.D., CEO of CuriRx. “Preformulation is essential for mAbs, as it allows us to identify and understand the molecule’s strengths and weaknesses. This information, in turn, helps manufacturers develop high-yield purification processes and resolve manufacturing-related issues.”
Some enhancement strategies involve non-mammalian expression systems, others improve on CHO cells. All pose both advantages and disadvantages in terms of economics, productivity, and regulatory risk.
Some larger CMOs offer proprietary cell lines and expression systems for mAbs and other therapeutic proteins. But, according to Hetrick, proprietary technology “seems to add little value to the service offerings of smaller to mid-sized CMOs.”
He cites the limited reactor volumes and number of campaigns possible at such organizations, which would not support the infrastructure of proprietary expression systems. Since smaller CMOs operate mostly in Phase II and earlier, proprietary technologies would “not in most cases translate into a significant decision criterion for selecting that CMO. Moreover, CMOs tend to employ whatever cell line a client specifies.”
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So despite platforming and the familiarity it brings, the cutting edges of mAb development and manufacturing continue to evolve as this molecular category adapts to medical and market needs.
“Innovator companies are positioning themselves as developers of second- and third-generation therapeutics that address shortcomings of first-generation mAbs,” says Hetrick. “The claims for these molecules are impressive, yet it remains to be seen how they perform in the clinic and what additional developmental or manufacturing challenges they will pose.”
These challenges will be met, as they usually are. A more significant hurdle to innovation in mAbs, according to Hetrick, is early-stage funding. “Although there is an abundance of capacity, and pricing has not increased over the past couple of years, the number of underfunded early-stage clients remains constant. There is pressure for CMOs to do more for less and at some point you reach a wall in terms of acceptable margins.” Despite the “platforming” and mainstreaming of single-use process equipment, process development leading to a first clinical batch still takes 12 to 18 months, and success relies more than ever on resolving scientific and engineering issues.
Hetrick cautions developers to achieve phase-appropriate regulatory conformance and acquire sufficient clinical materials rather than pursuing the ultimate process during very early development. Organizations often spend too much effort attaining high-expression levels for Phase I and avoiding future process royalties, while the real value lies in the product and its performance in the clinic.
“The faster you can get there, the more value you build in a shorter period of time. I have literally seen projects get totally derailed for this reason alone. Sponsors need to approach risk, efficiency, cost, and regulatory compliance pragmatically.”
Regeneron’s Dr. Bailey concurs: “A key challenge continues to be achieving the right balance between speed-to-clinic versus having an optimized manufacturing process during clinical development, as well as the timing for making that transition.”