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Antibody-Drug Conjugates (ADCs) are a class of therapeutic compounds designed to target cancer cells. They combine the cancer-killing (oncolytic) properties of potent cytotoxic drugs with the targeting capabilities of monoclonal antibodies, meaning that the drug can be delivered to diseased tissue and not to healthy cells, limiting the customary side effects that are traditionally associated with anti-cancer therapies while also extending the therapeutic window. Due to the complex and sensitive nature of antibodies and the potent nature of cytotoxic drugs, together with the requirement to maintain the structural “linker” between these 2 components when they are conjugated together in an ADC, it is easy to understand how such a chemical entity may not possess significant levels of stability in an aqueous solution for injection, or during the traditional – and usually aggressive – drying methods that are often used to create a powder suitable for tableting.
Freeze-drying has long since been used on antibodies and cytotoxic drugs, and can be used to stabilise ADCs in order to provide a longer shelf life; however, with the freeze-concentration effects that occur during lyophilisation, and the potential sensitivity of molecules to dehydration, it is unlikely that suitable combination of formulation and process conditions will be hit upon by trial and error. Specifically, a number of challenges need to be met for freeze-drying to be successful:
- Antibodies (or even antibody fragments) may need to be protected from the potentially damaging effects of freezing and the removal of water by the use of “lyoprotectants” in order to maintain their 3D structure and function,
- The cytotoxic element of the ADC means that special handling precautions are necessary, particularly when dealing with the freeze-dried material, which may be friable unless formulated appropriately to give a cohesive product,
- The linker between the antibody and the drug may also be sensitive to processing; some ADCs are designed with cleavable linkers to work on a broad range of targets, while others comprise linkers that are designed to be uncleavable in order for the drug to remain more specifically targeted. It is essential that the lyophilisation process does not adversely affect the nature of the linker molecule.
BTL has worked with more than 1,000 products since 1997, not just therapeutic materials but also vaccines and medical diagnostics. Through its extensive knowledge of protein / antibody stabilisation, its dedicated negative-pressure freeze-drying R&D lab and its range of cutting edge characterisation technologies, BTL possesses the know-how and the technical capability to provide clients with a high degree of assurance that its logical and scientific approach will lead to a successfully formulated, lyophilised and shelf-stable ADC product.
Tags: active drug conjugates, antibodies, cytotoxic, stability
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