JBH-492

CAP-100 is a novel therapeutic antibody directed against the ligand binding site of human CCR7. This chemokine receptor is overexpressed in chronic lymphocytic leukemia (CLL) and orchestrates the homing of CLL cells into the lymph node. Previous studies, on a very limited number of samples, hypothesized that the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib might induce loss of surface CCR7 levels in CLL cells. CAP-100 will be evaluated in clinical trials as a therapy for relapse/refractory CLL patients, who have received at least two systemic therapies (NCT04704323). As nowadays many relapse/refractory CLL patients will have received ibrutinib as a prior therapy, we aimed to investigate in a large cohort of CLL patients the impact of this BTKi on CCR7 expression and functionality as well as on the therapeutic activity of CAP-100. Our data confirm that ibrutinib moderately down-regulates the very high expression of CCR7 in CLL cells but has no apparent effect on CCR7-induced chemotaxis. Moreover, CLL cells are perfectly targetable by CAP-100 which led to a complete inhibition of CCR7-mediated migration and induced strong target cell killing through antibody-dependent cell-mediated cytotoxicity, irrespective of previous or contemporary ibrutinib administration. Together, these results validate the therapeutic utility of CAP-100 as a next-line single-agent therapy for CLL patients who failed to ibrutinib and confirm that CAP-100 and ibrutinib have complementary non-overlapping mechanisms of action, potentially allowing for combination therapy.

Accumulation of immune cells in adipose tissue promotes insulin resistance in obesity. Although innate and adaptive immune cells contribute to adipose inflammation, the processes that sustain these interactions are incompletely understood. Here we show that obesity promotes the accumulation of CD11c+ adipose tissue immune cells that express C-C chemokine receptor 7 (CCR7) in mice and humans, and that CCR7 contributes to chronic inflammation and insulin resistance. We identified that CCR7+ macrophages and dendritic cells accumulate in adipose tissue in close proximity to lymph nodes (LNs) (i.e., perinodal) and visceral adipose. Consistent with the role of CCR7 in regulating the migration of immune cells to LNs, obesity promoted the accumulation of CD11c+ cells in LNs, which was prevented by global or hematopoietic deficiency of Ccr7. Obese Ccr7−/− mice had reduced accumulation of CD8+ T cells, B cells, and macrophages in adipose tissue, which was associated with reduced inflammatory signaling. This reduction in maladaptive inflammation translated to increased insulin signaling and improved glucose tolerance in obesity. Therapeutic administration of an anti-CCR7 antibody phenocopied the effects of genetic Ccr7 deficiency in mice with established obesity. These results suggest that CCR7 plays a causal role in maintaining innate and adaptive immunity in obesity.