Monoclonal antibodies – complex to produce, targeted in therapy
25.11.2014 21:48
30 years after the Nobel Prize was awarded for the development of the hybridoma process, monoclonal antibodies (mAbs) have become an integral part of the therapeutic landscape for chronic inflammatory diseases. The path from the development of the first mAb to the therapeutic use of these complex proteins was long and complex. This is not least due to the complex manufacturing processes, whereby the products can differ depending on the cell line used, the nutrient medium and the culture conditions. Since the patent protection for biopharmaceuticals expired, biological imitation products, so-called biosimilars, have come onto the market. The active ingredients of biosimilars - unlike generics - are similar to the original product, but never identical. As part of a press conference supported by AbbVie, experts examined the sensitive requirements for the production and therapeutic use of mAbs and discussed future developments due to the impending market entry of biological imitation products with a view to quality-assured therapy for patients
From basic research to today's therapeutic milestone
Only with the development of hybridoma technology did it become possible to produce identical mAbs in large quantities. For the discovery of this groundbreaking process, the scientists Niels K. Jerne, Georges JF Köhler and César Milstein received the Nobel Prize in Medicine in 1984.
While simple, recombinant proteins can be obtained from E. coli and yeast, complex, glycosylated proteins - such as monoclonal antibodies - use living mammalian cells for protein synthesis. However, the success of this innovative class of substances only came after a few detours. The first monoclonal antibody approved as a drug in 1986 was a non-genetically engineered, pure mouse antibody. In order to reduce the immunogenicity of mouse antibodies in humans and to improve the pharmacokinetics of the antibody, mAbs have been continuously developed over the last 20 years.
Since the 1980s, antibody research has also been carried out in the laboratories at the Ludwigshafen site for pharmaceutical research. “The challenge for us scientists was to develop a fully human antibody for safe use in humans. The antibody should selectively bind to TNF-*, which plays a central role in the inflammatory cascade, neutralize it and have a long half-life. This had never happened before,” explained Prof. Dr. med. Bianca Wittig, Medical Director at AbbVie Germany, pioneered the development of Humira®. The first clinical trials with adalimumab began in 1997, and in 2003 the TNF inhibitor was approved for the treatment of rheumatoid arthritis in Europe. Since then, approvals have followed for the treatment of nine additional chronic inflammatory diseases in adults and children.
“Humira’s success was largely due to its innovative development and effectiveness approach as well as the comprehensive documentation of its good effectiveness and tolerability,” says Prof. Wittig. With 15 years of global clinical trial experience, Humira is one of the most extensively studied biologics. A review article published in 2013, based on 71 clinical studies with 23,458 patients and over 36,730 patient-years in six indications, indicates good long-term tolerability without new and unexpected side effects even after twelve years of use.
New challenges for the therapy of chronic inflammatory diseases
In the coming years, more and more of these innovative active ingredients will lose their patent protection and biological imitation products will enter the market. “Biosimilars are very similar to their respective reference products, but never identical,” emphasized Prof. Dr. med. Raja Atreya from the University Hospital Erlangen. The reasons for this are the extremely complex manufacturing process, which consists of up to 5,000 individual steps, and the uniqueness of the cell line used. Exact copies are therefore impossible.
For the approval of biosimilars in a study program that is reduced compared to that of the originator, the EMA requires proof that biological imitation products are equivalent to the reference product in terms of their quality, safety and effectiveness. “The EMA approval process allows, in justified individual cases, for the clinical results in one indication, such as rheumatoid arthritis, to be extrapolated to other indications, such as ulcerative colitis, without carrying out additional studies in patients with chronic intestinal diseases. Despite all the similarities in the inflammatory cascade, there are relevant differences in these clinical pictures, both in the inflammatory process and in the side effect profile. “I therefore look at the aspect of extrapolation critically,” says Prof. Atreya.
Specialist societies such as the European Crohn's and Colitis Organization (ECCO) and the German Society for Rheumatology (DGRh) as well as the patient organization German Rheumatism League also expressed similar concerns and made it clear in their statements that patient safety was the top priority. The Rheumatism League demands that biosimilars have clearly distinguishable active ingredient names (INN) from the reference product and other biological imitation products and that therapy changes between the reference product and biosimilars should only be based on purely medical reasons.
Prof. Atreya also drew such a conclusion and emphasized that all decisions must be made by the treating doctor. Especially in complex clinical pictures such as chronic inflammatory bowel disease, the individual needs of the patient and patient safety must form the basis for the treatment decision.