Preclinical safety evaluation of monoclonal antibodies.

Monoclonal antibodies (mAbs) are a well-established product class of biotechnology-derived pharmaceuticals for treating multiple diseases. A growing number of mAbs are being tested in clinical trials worldwide. Many of the second generation mAbs entering the clinic today are highly engineered, produced from recombinant cell lines, and present new safety challenges for regulators and industry scientists responsible for their safety evaluation. The increasing complexity of antibodies and the variety of recombinant production cell systems used for antibody manufacturing require a well thought-out approach for preclinical safety evaluation of mAbs. The focus of this chapter is to provide the reader with a basic framework for preparing a scientifically sound preclinical package for safety evaluation of therapeutic mAbs. We outline the general considerations for planning a preclinical program and the issues critical for success. We describe the types of preclinical safety studies and the timing for their conduct in relation to clinical trials. We also share some of the lessons learned about toxicity of mAbs from previous antibody development programs. A list of relevant regulatory documents issued by various government agencies and selected references to other useful texts and publications are also provided in the chapter. We believe that applying the principles described in this chapter will improve the quality and relevance of the preclinical safety data generated to support the future development of mAbs therapeutics.