Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory considerations for the development of next generation antibody-based therapeutics: Historical overview and quality requirements in the EU ***

Dr. Sonja Matt (Abschlußjahr: 2020)

Summary
Language: English
The rise of monoclonal antibody therapeutics began with the discovery of the hybridoma technology in 1975 by Georges Köhler and César Milstein. Simultaneously to the development of the first monoclonal antibody therapeutic, the European Economic Community laid down the requirements for the approval of so-called ‘high technology’ medicinal products in 1987 (Directive 87/22/EEC). Currently, the Community code Directive 2001/83/EC and Regulation (EC) 726/2004 are the legal basis for the authorization of monoclonal antibodies in the EU.
Until August 2020, over 80 original monoclonal antibody-based therapeutics for human use are authorized in the European Union. The majority is indicated for the treatment of cancer and autoimmune diseases. Monoclonal antibodies significantly differ from standard pharmaceuticals. They are huge protein molecules and every change in the manufacturing process can affect their molecular structure and, consequently, their biological function. Therefore, specific European and international regulatory guidelines exist, which mainly address aspects relating to the development of the manufacturing process and process controls, structural and functional characterization and control of the antibody molecule.
Over the last years, so-called ‘next generation’ antibodies have entered the market and account for 20-30% of authorized monoclonal antibodies. Next generation antibody formats are an improvement over conventional full size monoclonal antibodies and include glyco-engineered monoclonal antibodies, antibody fragments, nanobodies, bispecific antibodies, T cell engagers and immunoconjugates.
Fc-engineering and glyco-engineering techniques enabled the generation of monoclonal antibodies with altered biological activity or potency. For example, molecules with enhanced effector functions are more efficient in tumor cell killing and are an option for the treatment of cancer.
Generation of antigen binding fragments improved the ease of manufacturing. Antibody fragments are small in size and can be easily engineered, cloned and expressed. They can be produced in bacteria and yeast expression systems, which have a high production yield. When no effector functions are needed for the mechanism of action, antibody fragments are an option.
With the discovery of heavy-chain antibodies in camelids and the nurse shark, even the use of single variable domains for therapeutic (and diagnostic) purposes became possible. Due to their small size in the nanometre range, single domain antibodies are superior with regard to tissue distribution and penetration. Even inner zones of solid tumours or cryptic epitopes became accessible. Furthermore, targets located in the brain or inside a cell come into reach.
The aforementioned antibody fragments are also used as building blocks for bispecific antibodies. These molecules can bind to two different target antigens (or to two different epitopes on the same antigen) at the same time. There is often a strong scientific rationale to engage more than one target – especially for the treatment of cancer. Most prominent are bispecific T cell engagers, which are able to recruit immune effector cells to the tumour site.
Immunoconjugates, such as antibody-drug conjugates, represent another promising next generation antibody format. They are primarily developed for end-stage cancer patients and consist of a monoclonal antibody (or antibody fragment) which is armed with a cytotoxic payload. The monoclonal antibody is used as vehicle for the targeted delivery of its payload. Immunoconjugates combine the specificity of a monoclonal antibody with the cytotoxicity of a small molecule drug, toxin or radionuclide. For the development and authorization of antibody-drug conjugates, compliance with the regulatory guidelines and requirements for both biologics and small molecules needs to be demonstrated.
Overall, the development and authorization of next generation antibody formats follows the existing regulatory guidelines for monoclonal antibodies and biologics. Format-specific guidelines do not (yet?) exist. As for all monoclonal antibodies, the structure-function relationship of the molecule needs to be taken into account. The development of bispecific antibodies and immunoconjugates is particularly challenging since both formats combine different molecular entities. At least for these two formats more detailed guidance and harmonized regulatory requirements could simplify their development and authorization.
As the field of therapeutic monoclonal antibodies is developing fast, regulatory challenges will remain. Novel antibody formats and delivery approaches (e.g. probodies, brain shuttles and intrabodies) are already in the pipeline.
Pages: 160
Annexes: 01, Pages: 12