Mavorixafor

WHIM syndrome is a rare primary immunodeficiency disorder predominantly linked to heterozygous gain-of-function mutations in the C-terminus of the C-X-C chemokine receptor 4 (CXCR4), which is a chemokine receptor that regulates immune cell trafficking and homeostasis. CXCR4 is a G protein-coupled receptor (GPCR) that activates downstream pathways such as G-protein signalling, calcium mobilization, and ERK/AKT activation. CXC Chemokine Ligand 12 (CXCL12), previously known as stromal-derived factor-1α (SDF-1α), is a sole ligand of CXCR4 that binds to the receptor and promotes the trafficking and homing of leukocytes to and from the bone marrow compartment. Gain-of-function mutations in the CXCR4 receptor gene result in desensitization defects and increased responsiveness to CXCL12, overactivation of CXCR4 downstream pathways, and the retention of leukocytes in the bone marrow. Due to a reduced number of mature neutrophils and lymphocytes, patients with WHIM syndrome experience a variety of manifestations of the disorder, including panleukopenia and an increased susceptibility to infections and malignancy.

Mavorixafor is an orally bioavailable CXCR4 antagonist that blocks the binding of CXCL12 to CXCR4. Mavorixafor inhibits the response to CXCL12 in both wild-type and mutated CXCR4 variants associated with WHIM syndrome. Treatment with mavorixafor results in increased mobilization of neutrophils and lymphocytes from the bone marrow into the peripheral circulation.