Monoclonal antibodies feature prominently in the recent wave of immunotherapy development due to their potential for high potency, long half-life and highly specific modulation of a single drug target. However, binding to non-target receptors could drive unexpected and potentially severe toxicities in newly-developed immunotherapies. If human off-target reactivity is not identified by in vitro screening or through classical pre-clinical toxicology, the issue may only be uncovered after lengthy and costly clinical development.
The anti-PD1 antibody SHR-1210 (also known as camrelizumab) has had the expected biological activity in early clinical studies for solid tumours; however, its toxicity profile is different to other anti-PD1 immunotherapies. The majority of patients receiving camrelizumab have developed capillary hemangioma, which is a benign tumour formed by a collection of excess blood vessels. This observation led the team at UltraHuman Eight Ltd to hypothesize that the target-binding domains of SHR-1210-IgG1 might interact with previously unidentified and unpredictable receptors that are associated with vascular development or tissue differentiation.