amd-070 and Agammaglobulinemia

Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in CXCR4 C-terminus. We assessed genotype-phenotype correlations for known pathogenic CXCR4 variants and in vitro response of each variant to mavorixafor, an investigational CXCR4 antagonist. We used cell-based assays to analyze CXCL12-induced receptor trafficking and downstream signaling of 14 pathogenic CXCR4 variants previously identified in patients with WHIM syndrome. All CXCR4 variants displayed impaired receptor trafficking, hyperactive downstream signaling, and enhanced chemotaxis in response to CXCL12. Mavorixafor inhibited CXCL12-dependent signaling and hyperactivation in cells harboring CXCR4

Topics: Agammaglobulinemia; Aminoquinolines; Benzimidazoles; Biomarkers; Butylamines; Genetic Association Studies; Humans; Immunoglobulin A; Immunologic Deficiency Syndromes; Neutropenia; Primary Immunodeficiency Diseases; Proto-Oncogene Proteins c-akt; Receptors, CXCR4; Warts