Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment

Abstract

Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.

Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections

“…This threshold is not unreasonably high, as our analysis of a low-dose SHIV challenge study below showed that a few macaques got infected in spite of serum bnAb levels corresponding to 95–99% in vitro neutralization of the challenge pseudovirus [ 21 ]. In the ongoing Phase 2b VRC01 clinical trials, the minimum VRC01 in vivo serum concentrations are predicted to be 5–16 μg/ml [ 52 ]. Based on this, we chose the target minimum concentration of 10 μg/ml total for our modeling of Abs, individually or in combinations.…”

Challenges and Opportunities for the Subcutaneous Delivery of Therapeutic Proteins

“…This technique has been applied to a variety of IgG compounds as well as other therapeutic proteins 137 . There are very recent attempts at analyzing highly concentrated formulations using bioanalytical methods, however these methods are not used throughout industry 138,139 .…”

Strategies for Generating Diverse Antibody Repertoires Using Transgenic Animals Expressing Human Antibodies

“…The safety of therapeutic antibodies must be evaluated in a preclinical setting prior to human trials. This important step of drug development usually necessitates that the clinical candidate cross-reacts to the appropriate preclinical animal species chosen for toxicology ( 81 , 82 ). To ensure our lead candidates can meet this stringent design goal, we frequently incorporate the orthologous antigen from the toxicology species into our immunization protocols.…”