title: Antibody targeting of stem cells to infarcted myocardium.
abstract: Hematopoietic stem cell (HSC) therapy for myocardial repair is limited by the number of stem cells that migrate to, engraft in, and proliferate at sites of injured myocardium. To alleviate this limitation, we studied whether a strategy using a bispecific antibody (BiAb) could target human stem cells specifically to injured myocardium and preserve myocardial function. Using a xenogeneic rat model whereby ischemic injury was induced by transient ligation of the left anterior descending artery (LAD), we determined the ability of a bispecific antibody to target human CD34+ cells to specific antigens expressed in ischemic injured myocardium. A bispecific antibody comprising an anti-CD45 antibody recognizing the common leukocyte antigen found on HSCs and an antibody recognizing myosin light chain, an organ-specific injury antigen expressed by infarcted myocardium, was prepared by chemical conjugation. CD34+ cells armed and unarmed with this BiAb were injected intravenously in rats 2 days postmyocardial injury. Immunohistochemistry studies showed that the armed CD34+ cells specifically localized to the infarcted region of the heart, colocalized with troponin T-stained cells, and colocalization with vascular structures. Compared to unarmed CD34+ cells, the bispecific antibody improved delivery of the stem cells to injured myocardium, and such targeted delivery was correlated with improved myocardial function 5 weeks after infarction (p < .01). Bispecific antibody targeting offers a unique means to improve the delivery of stem cells to facilitate organ repair and a tool to study stem cell biology.
authors.affiliation: Department of Medicine and Cardiovascular Research Institute, University of California-San Francisco, 500 Parnassus Avenue, San Francisco, CA 94143-1354, USA. lee@medicine.ucsf.edu
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Fang
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Davol
authors.forename: Yiping
authors.initials: Y
authors.lastname: Gu
authors.forename: Richard E
authors.initials: RE
authors.lastname: Sievers
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Grabert
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gall
authors.forename: Eric
authors.initials: E
authors.lastname: Tsang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Yee
authors.forename: Hubert
authors.initials: H
authors.lastname: Fok
authors.forename: Ngan F
authors.initials: NF
authors.lastname: Huang
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
authors.forename: James W
authors.initials: JW
authors.lastname: Larrick
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Lum
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D002469:Cell Separation; D004452:Echocardiography; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D017493:Leukocyte Common Antigens / Q000276:immunology; D009203:Myocardial Infarction / Q000628:therapy*; D051381:Rats; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D015395:Histocompatibility Antigens Class I; D017493:Leukocyte Common Antigens