Immunogenicity of Innovative and Biosimilar Medicinal Products
in collaboration with…
Scendea Author:
Erik Doevendans
Technical Head (NL) & Principal Consultant
Chime Authors:
Dr. Guangxi Feng, Dr. Matt (Jiun-Ming) Wu
Protein Science Group
Introduction
The first regulation and guidance for copy biotech products (biosimilars), pioneered by the EMA, not only enabled the introduction of biosimilars in the EU, but also were a model for regulatory regions worldwide.
Currently, over 100 biosimilars are used in clinical practice and the total clinical experience with biosimilar medicines exceeds two billion treatment days [Mysler et al, 2021]. There are around forty biosimilar of nine originator mAbs authorized in the EU and US [September 2023, EMA website/FDA] and there is no evidence of differences in safety, immunogenicity, and efficacy between biosimilar and originator products [a.o. Bielsky et al, 2019]. Recent data show that there are no concerns with interchangeability either.
Comparative Immunogencity
One of the main reasons behind a dedicated regulatory pathway for similar biological medicinal products was the potential immunogenicity of biopharmaceuticals. Due to their complexity and heterogeneity, biopharmaceuticals have been considered too challenging to be comprehensively characterized. Original products and their copies could, therefore, never be shown to be identical. To obtain a marketing authorization as a biosimilar, the copy must be similar in physicochemical and biological characteristics and this similarity needs to be confirmed by (pre)clinical studies, although there is scientific and regulatory consensus that preclinical safety studies are not required if similar biological function has been demonstrated in vitro [Van Aerts et al, 2014]. A clinical evaluation of immunogenicity was deemed necessary as current in-silico and in-vitro assays have insufficient predictive value and sensitivity to detect potential for clinical immunogenicity and differences in clinical immunogenicity between originator and biosimilar (candidate).
Now, biosimilars and originator biopharmaceuticals share the same amino acid sequence, secondary and tertiary structure are similar as well. Hence, the intrinsic immunogenicity of a biosimilar (candidate) will be comparable to the originator. If differences in immunogenicity were to show in comparative clinical studies, it is probable that they will be due to differences in extrinsic factors, such as the nature and degree of glycosylation and impurities, particularly the amount and nature of aggregates.
To date, glycosylation can be controlled to the extent that clinically relevant differences will not occur between originator and biosimilar and certainly non-human glycosylation structures will not be present. Any alteration of tertiary structure or creation of novel epitopses due to post translational modifications such as deamidation, oxidation and glycosylation will be discovered at early stages of process development and would disqualify a candidate biosimilar (cell line) [M. G. Tovey et al, 2011, Van Beers et al, 2012; Anshu et al, 2016].
Process and product-related impurities, such as host cell proteins (HCP), may pose a risk to either safety and/or efficacy of biological products, however, over forty years of clinical experience with biotech products learns that HCPs, when adequately controlled to below 100 ppm, hardly ever led to clinical safety issues in clinical development and never when glycoproteins where on the market [Park JH et al, 2017., Vanderlaan et al, 2014].
It is known that aggregates are the most important risk factor in relation to immunogenicity. It is safe to state that in the absence of non-human glycan structures, aggregates are the only important risk factor present, as other potential factors contributing to the risk of immunogenicity of biopharmaceuticals are -per definition- not relevant for biosimilars as there are no differences in intrinsic immunogenicity, target disease, target population and treatment regimen (route of administration, dose, frequency and/or duration of treatment).
Whether comparative clinical PK studies or efficacy studies (as currently requested by regulators) are sensitive enough to detect small differences in immunogenicity is unlikely though; immunogenicity is best followed post marketing.
Chime, Experts in Biosimilar Development
Based on the physicochemical and biological/pharmacodynamic (in-vitro) characteristics of the innovator product [Reference (Medicinal Product) -RMP/RP-], the acceptance criteria of (critical) quality attributes are set for the biosimilar candidate, collectively the Quality Target Product Profile (QTTP). Subsequently a manufacturing process is developed aiming at a biosimilar candidate meeting the QTTP.
Biosimilar developers demonstrate that candidate is within the batch-to-batch variation of the RMP for all quality attributes. Clinical studies are performed to confirm the biosimilarity in terms of pharmacokinetics, safety, and efficacy. The size and extent of clinical studies is determined by the level of similarity, as demonstrated through physicochemical and in vitro biological characterization.
In summary, ensuring similar primary, secondary, and tertiary structures, a comparable glycosylation profile (for glycoproteins), and a similar, or lower, level of aggregates are the key requirements in developing a biosimilar.
Chime offers services for the development and manufacturing of biosimilar monoclonal antibodies.
Establishing QTTP
Reverse engineering
Determination of (critical) quality attributes
Determining critical process parameters
See Table 1 for quality attributes to be evaluated when assessing biosimilar candidates. Quality attributes may vary for different molecules and should be considered on a case-by-case basis.
Table 1.
Quality Attributes Considerations and Tests for Biosimilar Development
Structural quality attributes are the integral critical quality elements that are related to the expression, and these require testing on a side-by-side comparison with a reference product to confirm biosimilarity.
The primary structure must match 100%, notwithstanding any terminal amino acid difference allowed. The secondary and tertiary structure test profile should be superimposable, without any statistical treatment of data. All test methods should be fit-for-purpose, but not necessarily fully validated, as side-by-side testing of RMP and candidate biosimilar removes bias. All of the above tests only need to be done on one batch of the reference product and of the biosimilar candidate.
Glycosylation can be a critical quality attribute in biologic manufacturing.
In particular, it could affect immunogenicity and pharmacokinetics of therapeutic monoclonal antibodies (mAbs) and other therapeutic (glyco-) proteins, and must therefore be closely monitored throughout drug development and manufacturing. To address this, advances have been made primarily in upstream processing, including mammalian cell line engineering (Elizabeth Edwards et al., Biotechnol Bioeng, 2022). Host cell line engineering and optimization of bioreactor conditions (fed batch vs perfusion, growth media selection, pH and osmolality) are important approaches to modify and tailor glycan profiles [Giddens et al, 2018].
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