Optimized Nonclinical Safety Assessment Strategies Supporting Clinical Development of Therapeutic Monoclonal Antibodies Targeting Inflammatory Diseases

Abstract

An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex-mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and reduced host defence against infection and cancer. Nonclinical strategies to facilitate clinical and market entry in the most efficient timeframe are presented.

Considerations Regarding the Future Use of Nonhuman Primates to Support the Clinical Development of Biopharmaceuticals

“…However, there are significant challenges in inclusion of fertility end points in toxicity studies, including irregular cycling, making cycle times difficult to calculate, effect of housing conditions on cycling, the long time required to establish baseline menstrual cycle, and the lack of information to aid decisions on what constitutes a significant effect [36]. There is also a concern that the increasing use of sexually mature primates for general toxicity studies for the sole purpose of assessing fertility will put a strain on animal supply and may not be sustainable in the long term [9].…”

“…The decision is based on a number of considerations, including the age of children to be included in trials, the risk/benefit to the intended juvenile patients, the duration of dosing, the mechanism of action and expression of the target in adults and juveniles, existing pharmacology/toxicology data in animals and humans (including the data from target knockout mice if available), and the timing of the trials during development. Other triggers for juvenile studies may include whether the target is known to be involved in postnatal development or known to be expressed in the developing tissue and whether any target organs identified in adult toxicology or clinical studies are developing organs in the proposed pediatric populations [9]. Cynomolgus monkeys aged 2-3 years (8-to 12-year-old human equivalents) used frequently to support adult clinical trials may not be sufficient to support early juvenile populations.…”

“…Cross-reactivity, or lack thereof, can be predicted by an in silico analysis of sequence and structural homology/identity between the human antigen protein or targeted epitopes and the cognate proteins in conventional species used for toxicology studies [9]. However, for most mAbs, TCR is generally used.…”

“…In most cases toxicity of biopharmaceuticals has been related to exaggerated pharmacology, which is related to their specific targets (e.g., serious infections, malignancies, cytokine release syndrome [CRS], tumor lysis syndrome, and autoimmunity). This is often based on an understanding of the pharmacology/ mechanism of action and data from preclinical studies in pharmacologically responsive species [9].…”

“…Collectively, these observations suggest that a prospective assessment of target gene variation may be warranted for cynomolgus monkeys (and other NHP species) in pharmacology and toxicology studies. A suggested complementary strategy would be to systematically archive blood/tissue DNA from each individual animal to enable retrospective investigation of a potential genotypic basis for unanticipated or variable pharmacological response [9].…”