Practical considerations for nonclinical safety evaluation of therapeutic monoclonal antibodies

Abstract

Monoclonal antibodies (mAbs) are a well established class of therapeutics as evidenced by a large number of FDA approved mAbs for the treatment of cancers and autoimmune diseases. Monoclonal antibodies that are molecularly engineered for enhanced functions and pharmacokinetic properties are routinely being considered for development by many biotechnology companies. Safety evaluation of current generation of mAbs poses new challenges due to the highly complex nature of engineering aspects and variability induced by the diverse recombinant cell systems to generate them. This review provides a basic outline for nonclinical safety evaluation of therapeutic antibodies. Important considerations for planning a preclinical program, the types of nonclinical safety studies, and a general timeline for their conduct in relation to clinical trials are described. A list of relevant regulatory documents issued by government agencies is also provided. Adoption of these principles will greatly enhance the quality and relevance of the nonclinical safety data generated and will facilitate future development of mAb therapeutics.

Society of Toxicologic Pathology Position Paper on Best Practices on Recovery Studies

“…Some biopharmaceuticals (e.g., monoclonal antibodies) have lengthy half-lives resulting in continued exposure following the end of the dosing period (Dong et al 2011;Lobo, Hansen, and Balthasar 2004). When recovery evaluations are conducted for biologics, the length of the recovery period should take the half-life of the biologic into consideration and should be sufficient for the biologic to be cleared adequately for evaluation of recovery (Lynch, Hart, and Grewal 2009;Pandher, Leach, and Burns-Naas 2012). The addition of a recovery period solely to assess immunogenicity of a biologic is not warranted (ICH 2011).…”

Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

“…It is noteworthy that monoclonal antibodies represent a promising class of biotherapeutics for the treatment of autoimmune diseases and cancers, and more than 20 mAbs have been approved for therapy or are in clinical trials (Lynch et al, 2009). Rituximab, a chimeric monoclonal antibody directed against CD20, which is present primarily on B cells and is currently used in the treatment of nonHodgkin's lymphoma and rheumatoid arthritis (Plosker and Figgitt, 2003;Fleischmann, 2009), significantly decreases the level of anti PR3 autoantibodies, resulting in patient clinical remission (Ferraro et al, 2008) that is possibly related to a lower neutrophil activation.…”

Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

“…Although the relevance of species selection is judged carefully based on pharmacological/toxicological as well as pharmacokinetic property of each drug, species difference in response to drugs frequently makes it difficult to extrapolate animal toxicity to human ADRs. Selection of relevant animal species for biotechnology-derived pharmaceuticals is especially problematic since they are generally highly specific to target molecules, and are sometimes immunogenic to species other than humans (Lynch et al, 2009). Also, toxicology testing is often conducted in homogenous and healthy animals at extremely high drug exposures.…”