Background Biologics, in particular monoclonal antibodies (mAbs), transformed treatment of autoimmune diseases such as rheumatoid arthritis (RA) by selectively targeting pathogenesis and modifying disease course. Many biosimilars are being developed–products similar to innovator based on quality, safety, and efficacy. Unlike generics, biosimilars are not exact copies of the innovator. Small changes in product characteristics (quality attributes [QAs]) could impart clinically important differences.
Objectives We present a series of QAs for Humira® (adalimumab) from >500 drug substance batches produced from 4 facilities and 5 production scales from 2001-2013. Humira is approved for 10 indications by EMA, including RA, ankylosing spondylitis, and psoriatic arthritis.
Methods Proportions of charged species act as markers for overall molecular charge, a feature sensitive to manufacturing process changes. To assess surface charge profile of Humira drug substance, weak cation exchange HPLC was used to separate charge isoforms containing 0, 1, or 2 C-terminal lysines and other acidic species. Identity and quantification of oligosaccharides on conserved N-linked glycosylation site of Humira was evaluated by normal phase HPLC. For binding and functional assays, surface plasmon resonance was used to assess TNFα binding. Anti-TNF ELISA was used to determine relative binding capacity of Humira in solution. A meta-analysis of clinical efficacy data over time considered potential differentiating factors to facilitate comparison across and within studies.
Results Manufacturing changes for Humira primarily targeted scale increases, improvements in process robustness, and control across manufacturing sites. Charge microheterogeneity of Humira has been consistent as measured by proportion of lysines species over the product's history. Glycosylation patterns contribute to the unique structural signature of mAbs, influence function and are considered important product QAs when determining comparability. Identity and quantity of oligosaccharides on the conserved N-linked glycosylation site of Humira was evaluated on batches manufactured each year. Relative quantity of the agalactosyl fucosylated biantennary oligosaccharide forms of Humira has remained consistent through time, as have proportions of galactose-containing fucosylated biantennary oligosaccharides and detectable high mannose glycoforms. Concurrent to the molecule's structural consistency, potency of antibody for ligand binding was maintained through time. In addition, the structural consistency exhibited by Humira parallels the clinical performance of the mAb in the early and established RA trials that have been performed to support regulatory approval and commitments.
Conclusions Humira has demonstrated a highly consistent quality attribute profile, exhibiting minimal variability through >500 batches produced over 12 years, globally aligned and maintained across multiple sites/process scales. The consistency of the structural attributes of Humira provides the foundation for consistency in clinical performance. Collectively, these data contribute to the ongoing scientific debate on criteria necessary to establish and maintain biosimilarity.
Acknowledgements The authors and AbbVie designed the study and analyzed/interpreted the data. All authors contributed to the development of the content and reviewed/approved the abstract.
Disclosure of Interest J. Venema Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., P. Tebbey Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., A. Varga Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., M. Naill Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., X. Wang Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., L. Cui Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., J. Clewell Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc.