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Technical challenges in defining mAbs Posted 25/08/2010

Monoclonal antibodies (mAbs) are highly complex molecules with secondary and tertiary structures. The drug substance (the molecule itself) and drug product (the pharmaceutically formulated final product) are heterogeneous, i.e. a mixture of several slightly different structures. Although the molecular characterisation of a mAb molecule itself might have reached a high level of precision, reliability, quality and reproducibility, various possibilities for mAb heterogeneity exist. Variations to the mAb protein include alternative disulfide pairings/disulfide shuffling, deamidation, (methionine) oxidation, cyclisation of N-terminal glutamine residues and partial enzymatic cleavage during manufacturing. Variations of post-translational modifications such as glycosylation patterns include differential addition of sugars, alternative branching of sugar chains and others. Physicochemical characterisation of these characteristics currently remains cumbersome.

Besides the complexity of the mAb molecule itself, like other biologicals, mAbs usually contain process- and product-related impurities such as aggregates, heterogeneous structures and fragments. Despite manufacturing procedures being closely defined, fluctuations can considerably affect the final product. Although small changes—such as pH in cell cultures, temperature and culture media ingredients—may not seem significant, they can adversely affect the product. Each and every step of the production process is thus highly relevant, and any change in this process will inevitably affect the final product.

Therefore it is very possible that different batches of mAbs will have different clinical efficacy. This complexity is reflected in the amount of documentation that has to be submitted by developers at the time of applying for marketing authorisation. It has to include primary and higher-order structures, expression vectors, post-translational modifications; physicochemical characteristics and biological activity; a detailed description of the manufacturing, including in-process controls and product controls, changes in this manufacturing strategy that have already been implemented, and quality control. And this list is not exhaustive.

MAbs need to be considered on an individual basis

Thus, it is clear the ‘generic’ approach is not applicable to biotechnological products - especially mAbs, which are considerably more complex than currently developed biosimilars, such as human growth hormone, insulin or erythropoietin. It is entirely possible that, compared with a brand product, a biosimilar mAb might display subtle differences in molecular structure that cannot be detected by current methods. It will probably be challenging to demonstrate that such differences have no adverse impact on clinical efficacy and safety. (Even batches of a licensed product may vary, and the product may change if a manufacturing process is changed even slightly). Glycosylation patterns are likely to be among the most crucial issues for biosimilar mAb development, because these modifications can affect binding, immunogenicity and effector activity of a mAb molecule. Glycosylation can occur at several points in the manufacturing process or when a pilot process is scaled up for manufacturing.

(see also The current EU regulatory framework governing biosimilars, What clinical trials will be required for biosimilar mAbs? and How far does similarity go?)

Reference:

Schneider CK, Kalinke U. Toward biosimilar monoclonal antibodies. Nat Biotechnol. 2008;26(9):985-90

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