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How to Build Better Proteins

By Aileen Ruff, Catalent | March 9, 2016

Advancing the next generation of biologics

Biologics have become a vital component of the medicines war chest in recent years, having already revolutionized the treatment of diseases from rheumatoid arthritis to cancer. The biggest selling medicine in 2014, AbbVie’s Humira, is a monoclonal antibody, and in all, 11 of the top 20 bestsellers are biologically derived. A huge amount of research effort is being put into developing the next generation of biologics, and ways to make proteins better are being explored.

Combination antibody therapies are gaining in importance in a variety of indications in oncology, immunooncology and infectious diseases. They can attack multiple targets at the same time, which may make them more effective in treating these diseases.
However, as they contain multiple actives, they are even more expensive to make than a single antibody drug. Excelimmune is one company looking to further antibody combination therapy (ACT) technology and its technology platform is designed to allow the consistent manufacture of multiple recombinant proteins such as antibodies within a single culture batch.

The key innovation behind Excelimmune’s technology platform is the use of stable pools of cells that are generated via multiple directed gene insertions. Creating cells in this way, rather than using traditional clonal cell lines, gives a quick, flexible and stable culture system to create mixtures of cells that generate different antibodies in the same batch.

Catalent is working with Excelimmune under a license agreement to further evolve the platform, using its own proprietary GPEx cell line engineering technology to improve the production capability of the cells. The ability to create antibody combinations consistently and cost-effectively will be crucial if this type of complex antibody therapeutic is to succeed in the clinic, and will allow investigators to study the effects of combinations earlier in the development cycle.

Technologies such as the GPEx cell line engineering offer faster access to reliable and productive cell lines. These are extremely important when developing better biologics as they speed up the development time, and reduce the cost of production, allowing successful antibodies to reach patients more quickly and cheaply. GPEx technology is a proprietary vector technology used to make the desired biologic in a highly productive and efficient way by incorporating several different new genes.

Stable cell lines are also important, and the technology has been demonstrated up to 100 generations. Development is fast, as stable pools of cells that produce the target proteins are generated from the outset, with no need for stability testing. GPEx technology is already being used in the manufacture of five marketed products, including biosimilars, and many more antibodies and fusion proteins are under development with multiple clients.

Several antibody drug conjugates (ADCs) are already on the market, and many more are under development. These combine the targeting and extended half-life properties of a monoclonal antibody with the cell-killing activity of a highly potent chemotherapeutic agent. The result is a more directed and potentially effective cancer treatment. ADCs are notoriously variable in structure, with first generation manufacturing techniques giving a wide distribution in terms of the number and location of API molecules attached to the antibody. Other issues include the inherent stability of the chemical linkers used to join the two components together, and poor production efficiency. All of these issues can affect the product’s efficacy and increase costs.

The SMARTag technology, originally licensed from Redwood Bioscience before being acquired by Catalent in 2014, allows a more uniform drug–antibody ratio to be achieved, alongside an ability to direct the sites of attachment more accurately. By employing a naturally occurring enzyme to introduce a specific chemical group at directed points along the protein chain of the antibody, the number and location of the API molecules can be more carefully controlled. Only minimal cell line engineering is required. The novel linker technology employed is more stable when travelling through the body to the site of action, and thus, the API is much less likely to be lost in transit. It also means that it is less likely to cause side effects by damaging cells elsewhere. Importantly, the final ADC is much more homogeneous in nature than first generation products, which is important when satisfying the regulators that its efficacy and side effect profiles will be reproducible.

Analytical technology is also moving on at a pace. State-of-the-art techniques that prove the activity, stability and reproducibility of the biologics are essential if the increasingly strict demands of the regulators are to be met. The recent licensing of the first biosimilars in the U.S.—almost a decade after biosimilars reached the market in Europe—is going to increase demand for analytical services, as rigorous analysis is a vital part of the process to prove biosimilarity to satisfy regulatory authorities.

Aileen Ruff
Vice President, Business Unit Strategy and Marketing, Advanced Delivery Technologies, Catalent
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