E-006 - CXCR4 ANTAGONISM CORRECTS PERIPHERAL NEUTROPENIA IN A MOUSE MODEL OF WHIM SYNDROME.

C. Nguyen¹, L. Roland², K. Zmajkovicova¹, H. Monticelli¹, B. Maierhofer¹, S. Taplin³, M. Defontis⁴, J. Bledsoe⁵, R. Johnson⁶, A. Taveras⁶, M. Espéli², K. Balabanian²; ¹X4 Pharmaceuticals (Austria) GmbH, Vienna, Austria, Vienna, Austria, ²Université Paris Cité, Institut de Recherche Saint-Louis, INSERM U1160, Paris, France, Paris, France, ³Integrated Biologix GmbH, Steinenvorstadt 33, CH-4051, Basel, Switzerland, Basel, Switzerland, ⁴Defontis Veterinary Clinical Pathology, Bully, France, Bully, France, ⁵Department of Pathology, Boston Children's Hospital, Boston, MA, USA, Boston, MA, United States, ⁶X4 Pharmaceuticals Inc., Boston, MA, USA, Boston, MA, United States.

Background: WHIM syndrome is a rare chronic neutropenic disorder and primary immunodeficiency predominantly caused by autosomal dominant gain-of-function variants in Cxcr4. Mavorixafor, an oral, selective CXCR4 antagonist, demonstrated clinical efficacy in patients with WHIM syndrome in a phase 3 trial (NCT03995108). There are limited data on the impact of CXCR4 antagonism on granulopoiesis, function and cytomorphology of neutrophils in WHIM syndrome. We characterized the impact of CXCR4 antagonism on neutrophils in a mouse model of WHIM syndrome.

Methods: Cxcr4+/1013 and Cxcr4WT mice received the orally bioavailable CXCR4 antagonist X4-185 or vehicle daily for 7 or 28 days. Blood and bone marrow (BM) samples were collected for numeration, flow cytometry, and morphology. Peripheral neutrophil effector functions (phagocytosis and oxidative burst) were assessed.

Results: Cxcr4+/1013 mice presented with moderate peripheral blood neutropenia without an accumulation of mature neutrophils in BM, or impairment of neutrophil granulopoiesis. CXCR4 antagonism did not affect myeloid progenitor cell counts but decreased mature neutrophil counts in BM while increasing mature neutrophils in blood (P <.001), suggesting coordinated migration of these cells between BM and blood mediated by CXCR4. Myelokathexis-like neutrophils comprised 26% of blood neutrophils in CXCR4+/1013 mice. Their frequency inversely correlated with blood neutrophil counts and did not change with CXCR4 antagonism. Whole blood neutrophils in Cxcr4+/1013 mice treated with a CXCR4 antagonist were functional and similar to those in control Cxcr4WT mice.

Conclusion: CXCR4 antagonism corrected peripheral neutropenia and mobilized functional neutrophils without impairing BM granulopoiesis or altering the frequency of myelokathexis-like neutrophils in the blood of Cxcr4+/1013 mice.