Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)

  • Sci Rep. 2017 Aug 4;7(1):7305. doi: 10.1038/s41598-017-07848-8.
Yanyan Zhang  1  2  3  4 ,  Erika Saavedra  1  2  3  4 ,  Ruoping Tang  5  6  7  8 ,  Yin Gu  9 ,  Patrick Lappin  10 ,  Dusko Trajkovic  10 ,  Shu-Hui Liu  11 ,  Tod Smeal  9 ,  Valeria Fantin  9 ,  Stephane De Botton  1  12  13 ,  Ollivier Legrand  5  6  7  8 ,  Francois Delhommeau  5  6  7  14 ,  Flavia Pernasetti  15 ,  Fawzia Louache  16  17  18  19
Affiliations
  • 1. INSERM, UMR 1170, 114 rue Edouard Vaillant, 94805, Villejuif, France.
  • 2. Université Paris-Saclay, Gustave Roussy, Villejuif, France.
  • 3. Gustave Roussy, 94805, Villejuif, France.
  • 4. CNRS, GDR 3697, MicroNIT, Villejuif, France.
  • 5. Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.
  • 6. INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.
  • 7. Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012, Paris, France.
  • 8. AP-HP, Hôpital St Antoine, Service d'Hématologie clinique et de thérapie cellulaire, F-75012, Paris, France.
  • 9. Oncology Research & Development, Pfizer Worldwide Research & Development, San Diego, CA, USA.
  • 10. Drug Safety Research & Development, Pfizer, San Diego, CA, USA.
  • 11. Oncology Research & Development, Pfizer Worldwide Research & Development, San Francisco, San Diego, CA, USA.
  • 12. Gustave Roussy, Université Paris-Saclay, Service d'Hématologie Clinique, Villejuif, France.
  • 13. Faculté de médecine Paris-Sud, Kremlin-Bicêtre, France.
  • 14. AP-HP, Hôpital Saint-Antoine, Service d'hématologie biologique, F-75012, Paris, France.
  • 15. Oncology Research & Development, Pfizer Worldwide Research & Development, San Diego, CA, USA. [email protected].
  • 16. INSERM, UMR 1170, 114 rue Edouard Vaillant, 94805, Villejuif, France. [email protected].
  • 17. Université Paris-Saclay, Gustave Roussy, Villejuif, France. [email protected].
  • 18. Gustave Roussy, 94805, Villejuif, France. [email protected].
  • 19. CNRS, GDR 3697, MicroNIT, Villejuif, France. [email protected].
PMID: 28779088 DOI: 10.1038/s41598-017-07848-8
Abstract

The Chemokine Receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25-30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17CXCR4-low and P15CXCR4-high models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated Animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.

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