Biosimilars are “copies” of the original large-molecule drug. Due to the large market share of approved biologics, there has been much interest in generating biosimilars with a view to accessing market share as soon as patent expiry or loss of exclusivity occurs [38]. With biosimilars becoming increasingly important, there is high demand for effective and efficient characterization techniques from both the biosimilar manufacturers and the governing bodies, who

mAbs are partially reduced to free cysteine residues from interchain disulfide bonds. The cytotoxic drug and linker are then conjugated via alkylation, with the drug loading ranging from zero to eight

Figure 10.3 mAbs are partially reduced to free cysteine residues from interchain disulfide bonds. The cytotoxic drug and linker are then conjugated via alkylation, with the drug loading ranging from zero to eight.

are concerned with ensuring that a product is as similar as possible to the original biologic. The US FDA and the European Medicines Agency (EMA) both acknowledge that each candidate biopharmaceutical requires individual review [64]. The innovator manufacturing processes and conditions are not made available to competitor companies seeking to produce biosimilars, meaning that no biosimilar is identical to that of the branded, reference therapeutic [46]. A proportion of dissimilarity is also introduced with the use of mammalian cells to produce the biosimilar protein; the DNA sequence is identified and inserted into a vector and then into the mammalian cells for replication. However, given that no two mammalian cells are identical, inter- and intrabatch variability is to be expected, particularly with respect to glycosylation [46, 65-67]. These variations are also present within the original mAb therapeutics due to the use of heterogeneous mammalian cells, and therefore realistic acceptance criteria limits need to be defined for the biosimilars, in line with the individual innovator drugs and their mechanism of action.

According to the EMA “Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues,” which became effective in 2012, the definition for a biosimilar is a biological medicinal product that has similar molecular and biological activity in terms of posology, efficacy, quality, safety, and administration. As a minimum, any biosimilar mAb candidate must contain an identical amino acid sequence, disulfide bond arrangement, and hence tertiary structure as the reference product. Deviations in folding can adversely affect antigen binding and immu- nogenicity [68, 69]. Due to the nature of mAb manufacturing, variability is inevitable, and PTMs can have significant or little effect upon the therapeutic mechanism of action [67]. Any deviations, however, highlighted during biosimilar comparability testing require justification using sound scientific rationale, which will then help deduce the extent of both nonclinical and clinical in vivo and in vitro studies required to demonstrate bio similarity. The requirements for testing are therefore generated on a case-by-case basis while adhering to guidelines [67]. The term biosimilar does not apply to next- generation mAbs, for example, glycoengineered mAbs designed to improve efficacy or potency as they are structurally and/or functionally altered. The world's first biosimilar mAb (infliximab, trade names Remsima® and Inflectra®, manufactured by Celltrion and Hospira, respectively) was approved by the EMA in September 2010 [70] and released to the market in February 2015 following patent expiration of the original. The FDA announced their first biosimilar approval, Zarxio® [Novartis AG], in March 2015, although this was not a mAb. With the approval of Remsima® and Inflectra®, it seems likely that competitor companies will acknowledge the potential of biosimilar mAb development, and therefore a quick, informative technique such as MS will offer data that can derisk biosimilar development programs, limiting investment in unsuitable candidates.

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