Despite the potential for the
chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many
chemokines can bind to multiple receptors and many receptors have multiple
ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002-a humanized
IgG1 monoclonal antibody against human CCL20-was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ
inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of
inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or
intravenous injection. Histomorphological changes resembled an
immune complex-mediated pathology, which is often due to formation of anti-
drug antibodies in monkeys receiving a human
protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of
inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue
inflammation was greater than the numbers of associated
immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight
protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of
GSK3050002, that was not predicted by in vitro assays. The aggregates also contained
complement components. These findings support the hypothesis that
immune complexes of
drug aggregates, not necessarily including anti-
drug antibodies, can fix
complement, accumulate over time, and trigger
immune complex disease. A situation which may have increased clinical relevance than typical anti-
drug antibody-associated
immune complex disease in monkeys administered human antibody
proteins.