CXCR4 in Primary Immunodeficiency Diseases

Primary Immunodeficiencies (PIs) are a group of rare, chronic disorders in which flaws in the immune system cause increased susceptibility to infections and, in some cases, increased risk of cancers. Within this broad disease classification, WHIM syndrome is one of a number PIs that are caused by the improper trafficking of immune cells. There are other PIs beyond WHIM syndrome that are also believed to be a result of immune trafficking dysregulation.

Therapeutic targeting of CXCR4 in WHIM syndrome

The figure below illustrates the mutation in the CXCR4 receptor in WHIM syndrome leading to abnormal signaling and retention of white blood cells in the bone marrow. It also depicts X4’s approach to blocking this abnormal signaling with a CXCR4 antagonist, enabling the white blood cells to release into the bloodstream, restoring normal immune function.

WHIM syndrome: Genetic Mutations in CXCR4 Create Abnormal Trafficking of White Blood Cells

[ click image to enlarge ]


By blocking the binding of CXCL12 ligand to the CXCR4 receptor, our therapeutics are designed to normalize the signaling from the mutant CXCR4 receptor. As a result, our therapeutics may promote normal release of neutrophils and leukocytes and restore normal immune surveillance.

For Physicians

The Jeffrey Modell Foundation (JMF), a non-profit organization for primary immunodeficiency diseases, and X4 Pharmaceuticals co-sponsored a genetic screening study to help identify patients who have WHIM syndrome, at no cost to patients or insurance.

CXCR4 genetic testing is also available at cost through other commercial or research laboratories.

Selected scientific references

  1. Hernandez PA, Gorlin RJ, Lukens JN, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nature Genetics 2003;34(1):70-74.
  2. Gulino AV, Moratto D, Sozzani S, et al. Altered leukocyte response to CXCL12 in patients with Warts Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome. Blood 2004;104(2):444-452.
  3. Kawai T and Malech, HL. WHIM Syndrome: Congenital Immune Deficiency Disease. Curr Opin Hematol. 2009; 16(1): 20–26.
  4. Dale DC, Bolyard AA, Kelley ML, et al. The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. Blood 2011;118(18):4963-4966.
  5. McDermott DH, Liu Q, Ulrick J, Kwatemaa N, Anaya-O’Brien S, Penzak SR, Filho JO, Priel DA, Kelly C, Garofalo M, Littel P, Marquesen MM, Hilligoss D, Decastro R, Fleisher TA, Kuhns DB, Malech HL, Murphy PM. The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome. Blood. 2011 Nov 3;118(18):4957-62. doi: 10.1182/blood-2011-07-368084.
  6. McDermott DH, Liu Q, Velez D, et al. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood. 2014 Apr 10;123(15):2308-16.

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