Abstract
Due to the microheterogeneity of the macromolecules produced in biological systems, only the high degree of similarity but not the structural identity of the follow-on biological active agents can be proven. In case of monoclonal antibodies (mAbs) the proof of similarity is much more difficult due to the large molecular weight, complicated structure and complex biological effects of the IgG molecule. The identity of the amino acid sequence is the basic requirement of biosimilarity. Smaller changes in the carbohydrate side chains attached to the protein molecule can be accepted if they do not cause significant functional changes. On the other hand, the alteration of some carbohydrate side chain(s) located at strategically important sites might significantly influence the biological properties of the mAbs. Besides the antigen binding the pharmacological effects of the antibodies depend on several other effector functions related to the Fc fragment such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and phagocytosis. Hence several biological functions must be measured and evaluated in their totality for stating the degree of biosimilarity. According to the concordant strict requirements of the European Medicines Agency (EMA) and the American Food and Drug Administration (FDA), the proof of similar efficacy and safety must be based on the results obtained in the most sensitive and suitable in vitro and in vivo experimental designs. The fundamental proofs are provided by the comparison of the pharmacokinetic and pharmacodynamic measurements, as well as the similarity of the dose-effect relationships. These observations are complemented by the comparative clinical therapeutic trials which eventually support the similar therapeutic use of the follow-on medicinal products in the clinical practice. The final judgement of biosimilarity is a case-by-case decision based on the joint evaluation of all the data available.
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