title: Complement-fixing CD45 monoclonal antibodies to facilitate stem cell transplantation in mouse and man.
abstract: Broadening the applicability of stem cell therapies requires safer preparative regimens for patients. The CD45 antigen is present on all cells of the hematopoietic lineage, and using a murine model, we determined whether a lytic CD45 monoclonal antibody could produce persistent aplasia and whether it could facilitate syngeneic or allogeneic stem cell engraftment. After its systemic administration, we found that all leukocyte subsets in peripheral blood were markedly diminished, but only the effect on the lymphoid compartment was sustained and marrow progenitor cells were spared from destruction. Given the transient effects of the monoclonal antibody on myelopoiesis and the more persistent effects on lymphopoiesis, we asked whether this agent could contribute to donor hemopoietic engraftment after subablative transplantation. Treatment with anti-CD45 alone did not enhance syngeneic engraftment, consistent with its inability to destroy progenitor cells and permit competitive repopulation with syngeneic donor stem cells. By contrast, the combination of anti-CD45 and an otherwise inactive dose of total-body irradiation allowed engraftment of H2 fully allogeneic donor stem cells. We attribute this result to the recipient immunosuppression produced by depletion of CD45-positive lymphocytes. We next assessed a pair of unconjugated rat anti-human CD45 monoclonal antibodies (MAbs), YTH54.12 and YTH25.4, in a clinical trial in patients who were to receive stem cell transplantation for acute leukemia. The maximum tolerated dose of these MAbs, 400 microg/kg/day, produced a pattern of response identical to that seen in the mice, with marked reductions in circulating lymphoid and myeloid cells and sparing of early marrow progenitors. In two of three patients with active leukemia, the MAbs also produced a decrease in the percentage of leukemic blast cells in bone marrow. These pre-clinical and clinical results warrant further evaluation of anti-CD45 MAbs in subablative preparative regimens for stem cell transplantation.
authors.affiliation: Center for Cell and Gene Therapy and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. mbrenner@bcm.tmc.edu
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Wulf
authors.forename: Donna R
authors.initials: DR
authors.lastname: Rill
authors.forename: Kang-Li
authors.initials: KL
authors.lastname: Luo
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
authors.forename: Zuyoung
authors.initials: Z
authors.lastname: Mei
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kuehnle
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
authors.forename: Martin
authors.initials: M
authors.lastname: Pule
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Robert A
authors.initials: RA
authors.lastname: Krance
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002455:Cell Division; D003167:Complement Activation / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D017493:Leukocyte Common Antigens / Q000276:immunology*; D051379:Mice; D051381:Rats; D033581:Stem Cell Transplantation / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D017493:Leukocyte Common Antigens