Abstract
Biosimilar development involves a target-directed iterative process to ensure a similar product to the originator. Here we report the preclinical development of the proposed biosimilar rituximab (GP2013). Post-translational modifications and bioactivities of GP2013 versus originator rituximab were engineered and monitored to ensure similar pharmacological profiles. Antibody-dependent cellular cytotoxicity (ADCC) was used to illustrate how different glycosylation patterns and structure–function relationships were controlled during process development. Pharmacological comparability between GP2013 and originator rituximab were confirmed in preclinical studies using clinical scale drug product. Similar in vitro ADCC potency was demonstrated when compared in a dose–response manner against two lymphoma cell lines using freshly purified human natural killer (NK) cells. In vivo efficacy was demonstrated in two well characterized mouse xenograft models, testing at sensitive sub-therapeutic dose levels. Pharmacokinetics and pharmacodynamics (CD20 cell depletion) were likewise comparable in cynomolgus monkeys. This preclinical comparability exercise confirms that GP2013 and originator rituximab are pharmacologically similar.
Highlights
Derived therapeutics have revolutionized modern medicine, significantly improving health care outcomes for patients since they were first introduced in the 1980s [1,2]
Target-directed biosimilar development: linking a-fucosylated glycans to in vitro Antibody-dependent cellular cytotoxicity (ADCC) activity Glycosylation of the antibody Fc fragment is essential for Fc receptor-mediated activity and complement binding [21]
Human IgG1s carry two N-linked complex-type glycans, which influence the conformation of the Fc domain via multiple non-covalent interactions with the CH2 domain
Summary
Derived therapeutics have revolutionized modern medicine, significantly improving health care outcomes for patients since they were first introduced in the 1980s [1,2]. Biosimilars provide a comparable level of efficacy and safety with that of the originator product with the added advantage of being more affordable, thereby expanding patient access to therapies that otherwise may be restricted for cost reasons [3]. Regulatory approval is provided on the basis of comparable quality, safety and efficacy to an originator product [4,5]. In Europe, the European Medicines Agency (EMA) has developed a specific regulatory pathway and recently issued guidelines that describe non-clinical and clinical requirements for the development of biosimilar mAbs [6]. Second-generation drugs, such as biobetters, cannot be approved via the biosimilar regulatory pathways [4]
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