Hematopoietic and immunomodulatory effects of lytic CD45 monoclonal antibodies in patients with hematologic malignancy.
The CD45 antigen is present on all cells of the hematopoietic lineage. In some rodent models, lytic CD45 monoclonal antibodies (MAbs) induce complete marrow aplasia. In others, only transient myelolymphodepletion are observed, which are nonetheless sufficient to permit engraftment with fully allogeneic stem cells after otherwise ineffective doses of radiation. The in vivo effects of unconjugated cytolytic CD45 MAbs on myeloid and lymphoid cells in humans are unknown, so it is unclear if they could contribute in a similar way to conventional ablative or to nonmyeloablative preparative regimens used for stem cell transplantation (SCT). We therefore assessed the safety, myeloreductive activities, and lymphoreductive activities of the unconjugated rat anti-human CD45 MAbs, YTH25.4 and YTH54.12, in subjects who were to undergo SCT for advanced hematologic malignancy. The MAb pair bind to contiguous but nonoverlapping epitopes on CD45 and work synergistically to fix complement and recruit cellular lytic mechanisms. The MAbs were given in increasing doses up to 1600 microg/kg during 4 days, after which the patients began their conventional transplantation preparative regimen. The maximum tolerated dose of these MAbs, 400 microg/kg/d, produced marked reduction in circulating lymphoid and myeloid cells while largely sparing marrow progenitors. In 2 of 3 patients who had active leukemia at the time of study, the MAbs reduced the percentage of leukemic blast cells in bone marrow. Seven of 14 patients are disease free 610 to 1555 days post-SCT. The in vivo myeloreductive and lymphoreductive properties of lytic CD45 MAb in humans, therefore, closely parallel the activity seen in a murine model and, therefore, may be of similar value.
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. rakrance@txccc.org
Robert A
RA
Krance
Ingrid
I
Kuehnle
Donna R
DR
Rill
Zhuyong
Z
Mei
Carl
C
Pinetta
William
W
Evans
Michael P
MP
Brown
Martin
M
Pulé
Helen E
HE
Heslop
Malcolm K
MK
Brenner
D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology; D016465:Bone Marrow Purging / Q000379:methods; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D000939:Epitopes; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006410:Hematopoiesis / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007223:Infant; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D022423:Myeloid Cells / Q000187:drug effects; D010599:Pharmacokinetics; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000939:Epitopes; D017493:Leukocyte Common Antigens