- Chapter 1: Current regulatory landscape for biosimilars approval
- Chapter 2: Overview of biosimilars development
- Chapter 3: Case Studies: EU Regulatory Guidelines and how to interpret them
- Chapter 4: Analytical Comparability (chemistry, manufacturing and controls related product attributes)
- Chapter 5: Key factors that influence biosimilar in vitro and in vivo nonclinical testing strategies
- Chapter 6: Immunogenicity assessment for biosimilars: assay development, validation and interpretation
- Chapter 7: Case studies: challenges of developing and validating PK and immunogenicity assays to support pre-clinical and clinical comparability studies for biosimilars
- Chapter 8: Biosimilar monoclonal antibodies
Laboratory for Therapeutic & Diagnostic Antibodies
Department of Pharmaceutical & Pharmacological Sciences
KU Leuven, Campus GHB, ON2,
PB 820, 3000 Leuven, Belgium
Tel. +32 16 323431
About the Author
Professor Paul J Declerck, obtained his Ph.D. in Pharmaceutical Sciences from the University of Leuven (Leuven, Belgium) in 1984. After post-doctoral training in the Laboratory of Biochemical Cytology at the Rockefeller University (New York, USA) with Professor C de Duve, he joined the Center for Molecular and Vascular Biology with Prof D Collen, at the University of Leuven, in 1986. In 1991, he was appointed Professor of Pharmaceutical Biotechnology at the Faculty of Pharmaceutical Sciences, and then became full Professor in 1997. He is currently Research Director of the Laboratory for Therapeutic and Diagnostic Antibodies at the Department of Pharmaceutical and Pharmacological Sciences (University of Leuven). His research is focused on structure–function relationships of (recombinant) proteins and on the development of monoclonal antibodies for research, diagnostic and therapeutic purposes. He has expertise in the area of recombinant proteins, monoclonal antibody technology, biotechnology, drug development, structure–function relationship in proteins and biosimilars.
Prof. Declerck has given numerous invited lectures at international meetings and has authored over 220 scientific papers in peer-reviewed journals. He is President of the Commission of Medicines for human use of the Belgian Federal Agency for Medicines and Health Products, Dean of the faculty of Pharmaceutical Sciences of the University of Leuven, President of the International Society for Fibrinolysis and Proteolysis, and member of various international scientific advisory boards.
Biosimilar monoclonal antibodies
Monoclonal antibodies (MAs) are complex biotherapeutics as their molecular mechanism of action depends on multiple domains each contributing to the pharmacological and therapeutic properties of the molecule as well as to the safety profile. Consequently, biosimilar monoclonal antibodies constitute a unique class of biosimilars requiring specific guidelines for regulatory approval. An extensive comparative in vitro characterization to evaluate the biosimilarity of the various functional domains is required. Apart from typical protein analysis, evaluation of the glycosylation profile is of utmost importance. The exquisite species specificity of MAs precludes reliable in vivo nonclinical evaluations and means that adequately designed clinical studies are extremely critical to confirm the biosimilarity.
Monoclonal antibodies: a unique class of highly complex biologicals
The therapeutic potential of monoclonal antibodies (MAs) resides in three aspects. Firstly, MAs are directed against a single epitope in a particular target molecule and therefore they are highly specific (‘magic bullet’); secondly, MAs exhibit particular effector functions through the Fc region; and thirdly, MAs can be raised and selected against virtually any putative target. The first approved therapeutic monoclonal antibody was Muromonab-CD3 (Orthoclone Okt3®, anti-CD-3) authorized for the reversal of kidney transplant rejection .The concept of hybridoma technology  is based on the fusion between antibody producing B-cells (isolated from an immunized mouse) and a murine myeloma cell. Resulting hybrid cells may possess the antibody production properties from the original B-cell and the immortality from the myeloma cell. Hybridoma technology is mainly restricted to cells of mouse origin thereby leading to mouse monoclonal antibodies. Hybridoma technology combined with rDNA technology has allowed the generation of chimeric MA’s (e.g., abciximab, rituximab and infliximab) comprising the murine antigen-binding part of the monoclonal and a human Fc part. Further developments subsequently led to the generation of ‘humanized’ antibodies, in which the CDR-regions of the murine monoclonal are grafted into a human framework (e.g., palivizumab, trastuzumab and alemtuzumab). Developments in ‘transgenic’ technology led to the generation of transgenic mice containing the corresponding human antibody genes. Combination of the latter with hybridoma technology then allowed the generation of fully human antibodies (e.g., panitumumab). Alternatively, phage-displayed human antibody fragment libraries combined with cloning technology also allows the construction of fully human MAs (e.g., adalimumab).