Rapid Mobilization Of CD34+ Progenitor Cells With TG0054-03, a novel CXC Chemokine Receptor 4 (CXCR4) Antagonoist

Abstract

Background TG-0054 (burixafor) is a potent and specific antagonist of the human CXCR4 chemokine receptor. TG-0054 blocks the interaction between CXCR4 and stromal cell-derived factor-1 (SDF-1), thus causing a rapid mobilization of stem cells from the bone marrow into peripheral blood within 1-3 hours of intravenous administration of the drug. Materials and Methods: An early phase II trial was conducted in patients with multiple myeloma (MM), non-Hodgkin lymphoma (NHL) or Hodgkin disease (HD) to evaluate the safety and stem cell mobilization of TG-0054 alone or in combination with G-CSF. 12 patients (1 HL, 7 MM, and 4 NHL patients) received an i.v. dose of 3.14 mg/kg TG-0054, and peripheral blood CD34 counts were assessed at 2, 4 and 6 hours post drug infusion. Patients who achieved at least 10 CD34 cell/ul in the peripheral blood were collected by large volume leukapheresis (24L) for 1-4 days to obtain a predetermined target of >2.5 x 106 CD34 cells /kg. Results: Seven patients (1 HD, 6 MM) were successfully mobilized with TG-0054 as a single agent achieving a cumulative CD34+ stem cell collection of 4.0 to 10.4 x106 cells /kg over 2-4 leukapheresis sessions. Patients who failed to mobilize with TG0054 as a single agent on day +1 were placed on the second arm of the study, where they received 5 doses of granulocyte colony stimulating factor (G-CSF) at a dose of 10 ug/kg beginning on day +4 with TG-0054added back in combination on day +8. These remaining five patients (1 MM, 4 NHL) who did not mobilize with TG0054 alone on day +1 and received G-CSF plus TG-0054 were leukapheresed on day +8. Those patients achieved a cumulative CD34 peripheral blood stem cell collection of of 3.2-21.0 x106 cells /kg over 1-4 leukaphereses sessions. Conclusion: TG-0054 exhibited potent and rapid mobilization of CD34+ stem cells, with favorable safety profile in patients. Engraftment All 12 patients received conditioning regimens (BEAM for the lymphoma patients and melphalan for the myeloma patients) followed by a stem cell infusion of at least 3.0 x106 CD34+ cells/kg. All patients engrafted without delay compared to historical controls. Median days to WBC engraftment were 12. Median days to platelet recovery of 20,000 and 50,000 were 20 and 20.5 days, respectively. Engraftment results of TG-0054 mobilized patients are similar to those seen in a matched group of historical controls. We have observed that mobilization with TG-0054 caused a preferential mobilization of mononuclear cells (MNC) component of the graft. Percent MNC in TG-0054 mobilized patients‘ grafts were 78.9+15.2 (median 81.5) as compared to percent of MNC in G-CSF mobilized patients‘ grafts of 62.6+27.7 (median 69.6). Disclosures: Schuster: TaiGen Biotechnology Co., Ltd: Research Funding. Tsai:TaiGen Biotechnology Co., Ltd: Employment. Hsu:TaiGen Biotechnology Co., Ltd: Employment, Equity Ownership. Chang:TaiGen Biotechnology Co., Ltd: Employment. Hsu:TaiGen Biotechnology Co., Ltd: Employment.

The Biological and Clinical Relevance of G Protein-Coupled Receptors to the Outcomes of Hematopoietic Stem Cell Transplantation: A Systematized Review

“…Examining these varied studies, an extension of plerixafor indications is to be expected in the coming years, as are new pharmacological alternatives. Indeed, new compounds targeting CXCR4 are in development: small molecules (TG-0054 [60,61,62]) such as plerixafor, but also peptides (BL-8040 [63], (BK)T140 [64], POL6326 [65], LY2510924 [66]), or oligonucleotides (NOX-A12 [67]). All have already been tested in humans as part of phase I or early phase II clinical trials.…”

“…The use of anti-CXCR4 compounds for mobilization in the donor did not preclude engraftment in humans [61,85,94,95,110,111] or mice [112], with some studies reporting even better engraftment in mice [113,114] (Table 2). Targeting CXCR4 could also improve engraftment by vacating the hematopoietic niches in the recipient before HSCT, either via chimeric antigen receptor (CAR) T cells co-expressing CXCR4 and C-kit or via plerixafor [115,116,117].…”

Peripheral Blood Stem Cell Mobilization: a Look Ahead

“…This led to the development of plerixafor, a CXCR4 antagonist, for clinical use in patients who mobilize poorly to G-CSF. Following on from plerixafor, additional CXCR4 antagonists, including POL636 [26–28], BKT140 [29;30], LY2510924 [31–33], TG-0054 [34], and ALT-1188 [35] are in preclinical and/or clinical development, although what their benefit above plerixafor might be is yet to be determined. NOX-A12 an anti-SDF-1 Spiegelmer, a first in class mirror-image oligonucleotide inhibitor of SDF-1 mobilizes HSPC [36].…”