Antibody targeting KIT as pretransplantation conditioning in immunocompetent mice.
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.
Xue
Xingkui
X
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
Pech
Nancy K
NK
Shelley
W Christopher
WC
Srour
Edward F
EF
Yoder
Mervin C
MC
Dinauer
Mary C
MC
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
D000906:Antibodies; D019009:Proto-Oncogene Proteins c-kit
Medicine (Baltimore). 2000 May;79(3):155-69
10844935
Exp Hematol. 2002 Nov;30(11):1324-32
12423686
Exp Hematol. 1993 Feb;21(2):206-19
8425559
Nat Genet. 1995 Feb;9(2):202-9
7719350
Blood. 2001 Jun 15;97(12):3738-45
11389011
Science. 2007 Nov 23;318(5854):1296-9
18033883
Stem Cells. 2007 Jun;25(6):1578-85
17347493
Expert Opin Biol Ther. 2004 Sep;4(9):1423-34
15335310
Curr Opin Hematol. 2007 Jan;14(1):29-36
17133097
Hematology Am Soc Hematol Educ Program. 2005;:89-95
16304364
Clin Cancer Res. 2008 Apr 1;14(7):1926-30
18381929
Blood. 2009 Oct 8;114(15):3309-15
19692703
J Exp Med. 1991 Jul 1;174(1):63-71
1711568