THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
Report Now Available

Excerpt of Chapter 1

… Combining in vivo and in vitro discovery and molecular engineering technologies allows exquisite control of the antibody sequences and properties that was not possible twenty years ago. New approaches for the rapid production of cell lines suitable for large scale commercial production have also enabled the development of monoclonal antibody therapies to treat a myriad of diseases and made these products available to an increasing number of patients. In addition to enabling the more efficient and economic production of monoclonal antibodies, the above antibody engineering technologies coupled with advances in understanding and controlling the behavior of mammalian production cells in the bioreactor have greatly increased our ability to control or alter the properties of the resulting antibodies. For example, the extent and type of glycosylation, which can impact product efficacy, can be controlled by both cell line engineering and cell culture technologies. However, all of the above improvements come at a cost. Many of the discovery and engineering technologies used to generate monoclonal antibody products are covered by one or more patents related to such areas as host cell lines, antibody design, molecular biology, and cell culture technology.

…Numerous monoclonal antibody-related products (which include full length monoclonal antibodies as well as antibody fragments, Fc fusion proteins, conjugated monoclonal antibody products, etc.) currently on the market are approved for the treatment of a variety of diseases, ranging from cardiovascular indications (e.g., ReoPro, a Fab product) to infectious diseases (e.g., Synagis) to several different cancers. The diseases for which monoclonal antibody products have been approved as therapeutic treatments are quite varied with patient populations ranging from a few thousand or less for such orphan indications as paroxysmal nocturnal hemoglobinuria or the cryopyrin-associated periodic syndromes to much larger patient populations for other indications. The number of patients treated with some monoclonal antibodies for some cancers and multiple sclerosis is in the hundreds of thousands while millions of patients are treated with monoclonal antibody products used to treat such diseases as asthma and rheumatoid arthritis. In some cases, the market penetration for monoclonal antibody products is quite large with most of the potentially treatable patients receiving the antibody therapy.

…As shown in Figure 1.2, as of July 2009, the total number of monoclonal antibody-related products (full length antibodies, Fc fusion proteins, and antibody fragments) approved in the United States and Europe has now reached 44. Of the 44 monoclonal antibody-related products, 34 are full-length monoclonal antibodies; five are Fab fragments and five are Fc fusion proteins containing the antibody constant region fused to some other binding protein. While a total of 44 monoclonal antibody-related products have been approved by the FDA, 11 products have been withdrawn leaving 33 monoclonal antibody-related products currently approved and on the market. Note also that while most biopharmaceutical companies seek approval for their monoclonal antibody products in both the United States and Europe (and, increasingly, Japan), several monoclonal antibody products are currently approved only in the United States or Europe.

Figure 1.2.  Total Annual Approval of Monoclonal Antibody Products in the US and Europe

...Monoclonal antibodies are currently the dominant class of biologic products in development generating much interest and excitement regarding the promise and potential of these biopharmaceutical products. There are many factors that will enable the continued cost effective development of new antibody products in the coming years, especially the advancements in manufacturing technologies and processes described in this report. This report is intended to provide a general roadmap for the development of an antibody product from initial discovery through the filing of an Investigational New Drug Application (IND) or Investigational Medicinal Product Dossier (IMPD) or equivalent for first in human clinical trials. The primary focus is on those specific issues related to process development, manufacturing, quality control, and analysis of full length single specificity antibody products produced in mammalian cell culture although much of the discussion is relevant to the production of antibody related products such as Fc-fusion proteins and to antibody products produced in other mammalian hosts or even non-mammalian hosts. We do not include discussions on target identification, selection of appropriate disease indications or antibody formats, or designing preclinical or clinical programs.

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