Immune complex disease in a chronic monkey study with a humanised, therapeutic antibody against CCL20 is associated with complement-containing drug aggregates

Abstract

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 doseresponsive 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

The Contribution of Liver Sinusoidal Endothelial Cells to Clearance of Therapeutic Antibody

“…In the liver this presented as moderate inflammation with immune deposits localized within the sinusoids. Target antigen did not appear to be contained in these deposits and importantly anti-human antibodies were not detected or were present at a level too low to explain the findings (Laffan et al, 2020). This would suggest that localization of FcR [or CCL20 (Shields et al, 1999)] on the LSEC may have provided a focus for immune complex deposition and complement mediated toxicity toward the LSEC.…”

“…GSK305002 is a humanized IgG antibody that neutralizes the soluble chemokine CCL20 and was in development as a potential therapy for inflammatory disease (Laffan et al, 2020). Although no safety signatures appeared in a phase 1 study in humans, subsequent longer term escalating dose toxicity studies in cynomolgus monkeys highlighted a significant vascular inflammation in most subjects which is unexpected for an antibody targeting soluble antigen.…”

Skin Barrier Dysregulation in Psoriasis

“…Targeting chemokines has been effective in reducing psoriatic inflammation in several mouse models [ 253 ], and an anti-CCL20 antibody was effective at reducing chemokine receptor 6 positive cell infiltration into skin blisters in a human trial [ 254 ]. However, this antibody induced severe vascular and organ inflammation when used over 26 weeks in a monkey model, so novel antichemokine biologics may be needed [ 255 ].…”

Structure and Functional Characterization of a Humanized Anti-CCL20 Antibody following Exposure to Serum Reveals the Formation of Immune Complex That Leads to Toxicity

“…Additionally, an extended 6-mo toxicology study of GSK3050002 in cynomolgus monkeys was also performed via s.c. or i.v. injection, in which animal toxicity including vascular inflammation was observed after 26 wk, and the project was terminated (23). In this study, histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of antidrug Abs.…”