title: Antibody targeting KIT as pretransplantation conditioning in immunocompetent mice.
abstract: Inherited hematologic defects that lack an in vivo selective advantage following gene correction may benefit from effective yet minimally toxic cytoreduction of endogenous hematopoietic stem cells (HSCs) prior to transplantation of gene-modified HSCs. We studied the efficacy of administering a novel sequential treatment of parenteral ACK2, an antibody that blocks KIT, followed by low-dose irradiation (LD-IR) for conditioning of wild-type and X-linked chronic granulomatous disease (X-CGD) mice. In wild-type mice, combining ACK2 and LD-IR profoundly decreased endogenous competitive long-term HSC repopulating activity, and permitted efficient and durable donor-derived HSC engraftment after congenic transplantation. ACK2 alone was ineffective. The combination of ACK2 and LD-IR was also effective conditioning in X-CGD mice for engraftment of X-CGD donor HSCs transduced ex vivo with a lentiviral vector. We conclude that combining ACK2 with LD-IR is a promising approach to effectively deplete endogenous HSCs and facilitate engraftment of transplanted donor HSCs.
authors.affiliation: Herman B Wells Center for Pediatric Research, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Xingkui
authors.initials: X
authors.lastname: Xue
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Pech
authors.forename: W Christopher
authors.initials: WC
authors.lastname: Shelley
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D007121:Immunocompetence; D051379:Mice; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology*; D014161:Transduction, Genetic; D019172:Transplantation Conditioning / Q000379:methods*; D014916:Whole-Body Irradiation
chemical_list: D000906:Antibodies; D019009:Proto-Oncogene Proteins c-kit
references.citation: Medicine (Baltimore). 2000 May;79(3):155-69
references.pmid: 10844935
references.citation: Exp Hematol. 2002 Nov;30(11):1324-32
references.pmid: 12423686
references.citation: Exp Hematol. 1993 Feb;21(2):206-19
references.pmid: 8425559
references.citation: Nat Genet. 1995 Feb;9(2):202-9
references.pmid: 7719350
references.citation: Blood. 2001 Jun 15;97(12):3738-45
references.pmid: 11389011
references.citation: Science. 2007 Nov 23;318(5854):1296-9
references.pmid: 18033883
references.citation: Stem Cells. 2007 Jun;25(6):1578-85
references.pmid: 17347493
references.citation: Expert Opin Biol Ther. 2004 Sep;4(9):1423-34
references.pmid: 15335310
references.citation: Curr Opin Hematol. 2007 Jan;14(1):29-36
references.pmid: 17133097
references.citation: Hematology Am Soc Hematol Educ Program. 2005;:89-95
references.pmid: 16304364
references.citation: Clin Cancer Res. 2008 Apr 1;14(7):1926-30
references.pmid: 18381929
references.citation: Blood. 2009 Oct 8;114(15):3309-15
references.pmid: 19692703
references.citation: J Exp Med. 1991 Jul 1;174(1):63-71
references.pmid: 1711568