Discovery Process for Antibody-Based Therapeutics

Medicilon's medicinal chemistry involves the application of a number of specialized disciplinary approaches all focused on the ultimate goal of drug discovery. Drug target identification and validation, rational (target-based) drug design, structural biology, computational-based drug design, methods development (chemical, biochemical and computational), and “Hit-to-lead” development are all aspects of medicinal chemistry. The techniques and approaches of chemical biology, synthetic organic chemistry, combinatorial (bio)chemistry, mechanistic enzymology, computational chemistry, chemical genomics and high-throughput screening are all used and applied by medicinal chemists towards drug discovery. Email:marketing@medicilon.com.cn web:www.medicilon.com

Drug discovery is a sophisticated process that integrates scientific innovation with cutting-edge technologies. Development of novel protein therapeutics or biologics has gained significant momentum in the biopharmaceutical sector in recent years. Additionally, the approval process for biosimilars and generic biological drugs is not well-defined and is currently under evaluation. Due to the complex molecular and functional properties associated with protein drugs, establishing pharmaceutical equivalency in terms of both safety and efficacy for biosimilars relative to their brand name counterparts is complex. Moreover, the regulatory path for approval of these agents is yet to be clearly defined. Although the biosimilar industry is growing aggressively, the major players in the biopharmaceutical sector continue to invest significant resources in discovery and development of new and novel biotherapeutics (Genazzani et al. 2007). The shift in emphasis toward development of biotherapeutics is in part manifested by the growing preponderance of biologic agents in the portfolios of major biopharmaceutical companies. For antibody-based therapeutics, which include monoclonal antibodies, antibody-derived variants (e.g. camelid nanobody), and Fc fusion proteins, close to 40 drugs are on the market with another 30 in the late clinical phase . With the flurry of industrial activities focusing on developing novel biologics, a major effort in the biopharmaceutical industry is devoted to establishing sophisticated industrial processes for preclinical discovery and manufacturing of viable therapeutics. The overall process for developing antibody-based therapeutics can be divided into five phases, i.e., target selection and validation, screening preparation, generation of early candidates (‘‘hits’’), selection of advanced candidates (‘‘leads’’), lead optimization, and clinical candidate selection. An overview of the drug discovery process prior to the selection of a clinical candidate is shown in Fig. 2.1. As with traditional small molecule drugs, the discovery process typically begins with selection of a validated target and a proposal for therapeutic modulation of the intended target. During the screening phase, all relevant reagents and assays are developed and tested. Screening is then carried out to generate candidate antibodies with desirable molecular and functional attributes that can be potentially translated for application in the anticipated therapeutic indication(s). At the end of this phase, a successful screen will result in the identification of one or more promising leads deemed favorable for further development. Next, the lead antibody is optimized to endow drug-like properties such as optimal target-binding affinity, manufacturability, and other biopharmaceutical properties when possible. The optimized candidate is subjected to broad and stringent in vitro and in vivo evaluation in order to determine whether it is suitable for further development. This chapter provides an overview of the preclinical drug discovery process.