THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 2

…There are many different technologies currently available for the discovery and development of new monoclonal antibody products and to optimize these products for their intended therapeutic use… To maximize the probability of overall success of the product and the value of the program, discovery efforts today also include an assessment of the properties of the antibody that may inhibit or enhance manufacturability, formulation, or stability so that the most effective product that can be manufactured and delivered to the patient at a reasonable cost is selected and introduced into the development program.

…In the latest advance in antibody discovery, novel technologies have made it possible to generate fully human monoclonal antibodies that can be produced in cell culture using CHO or other cell lines. The technologies that enable generation of human antibodies are accessible through partnerships or licensing, enabling most companies to focus discovery programs on human antibody products. Today’s medical and regulatory expectation is that companies will use the best approach for their product to discover and develop humanized or fully human antibody products unless there is a compelling reason to develop a murine or other antibody type.

…Current approaches to discovery of fully human monoclonal antibodies include in vitro and in vivo methods, and these are often combined to accelerate discovery and enable the best candidate to be identified. One in vitro technology widely used today in antibody discovery and optimization is phage display in which libraries containing millions of variations of human antibody sequences are synthesized, expressed, and screened to identify those antibodies that bind to the intended target… Another technology that enables discovery of fully human antibodies is generation of transgenic mice in which the murine immunoglobulin genes are replaced by human antibody genes.

…All of the discovery techniques discussed here are capable of generating tens to hundreds of potential monoclonal antibody candidates for development. Each of these potential product candidates must be evaluated to identify a lead candidate for clinical development making the selection of a specific antibody candidate for development one of the most critical activities in the discovery and optimization of an antibody product. The success or failure of an entire product development program can hinge on selection of the correct antibody candidate from the many possibilities. For efficacy, antibodies with the necessary properties including the desired functional activity, appropriate binding affinity and specificity, and suitable pharmacokinetics should be identified and developed. In addition, companies are starting to incorporate an assessment of manufacturability and stability into final candidate selection.

… Advanced molecular engineering technologies have enabled development of a large number of antibody-related products that maintain the high selectivity and affinity target binding properties of whole monoclonal antibodies but that impart additional desired features or remove functions that are not required for some applications. In one type of engineered antibody product, the Fc region of the antibody is removed, thereby eliminating effector function and the ability of the antibody product to activate the immune system. Additionally, engineered, smaller antibody fragments containing just the antigen binding regions of an antibody can penetrate certain body tissues better than full length antibodies offering a potentially different therapeutic profile than the whole antibody. Engineered antibody products that do not contain the Fc domain include the Fab region alone, single chain variable region antibodies (sFv), and camelid variable heavy chain products (VHH). Fab products contain the entire light chain paired with the VH and CH1 of the heavy chain but do not include the dimerization domain of CH and therefore contain only a monovalent antigen binding domain. Fab products have a molecular weight of approximately 45 kDa and may be produced either directly in cell culture or may be produced by proteolytic cleavage of the intact whole antibody.

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