Innovations in hematopoietic stem-cell mobilization: a review of the novel CXCR4 inhibitor motixafortide.

Hematopoietic stem-cell transplantation (HCT) and stem-cell-based gene therapies rely on the ability to collect sufficient CD34+ hematopoietic stem and progenitor cells (HSPCs), typically via peripheral blood mobilization. Commonly used HSPC mobilization regimens include single-agent granulocyte colony-stimulating factor (G-CSF), plerixafor, chemotherapy, or a combination of these agents. These regimens, however, frequently require multiple days of injections and leukapheresis procedures to collect adequate HSPCs for HCT (minimum = >2 × 10⁶ CD34+ cells/kg; optimal = 5-6 × 10⁶ CD34+ cells/kg). In addition, these regimens frequently yield suboptimal CD34+ HSPC numbers for HSPC-based gene-edited therapies, given the significantly higher HSPC number needed for successful gene-editing and manufacturing. Meanwhile, G-CSF is associated with common adverse events such as bone pain as well as an increased risk of rare but potentially life-threatening splenic rupture. Moreover, G-CSF is unsafe in patients with sickle-cell disease, a key patient population that may benefit from autologous HSPC-based gene-edited therapies, where it has been associated with unacceptable rates of serious vaso-occlusive and thrombotic events. Motixafortide is a novel CXCR4 inhibitor with extended in vivo activity (>48 h) that has been shown in preclinical and clinical trials to rapidly mobilize robust numbers of HSPCs in preparation for HCT, while preferentially mobilizing increased numbers of more primitive HSPCs by immunophenotyping and single-cell RNA expression profiling. In this review, we present a history of stem-cell mobilization and update of recent innovations in novel mobilization strategies with a specific focus on the development of motixafortide, a long-acting CXCR4 inhibitor, as a novel HSPC mobilizing agent.