A combination of anti-CD15 monoclonal antibody PM-81 and 4-hydroperoxycyclophosphamide augments tumor cytotoxicity while sparing normal progenitor cells.
A cyclophosphamide congener, 4-hydroperoxycyclophosphamide (4HC), has been used to purge bone marrow (BM) of residual leukemia cells ex vivo for use in support of high-dose chemotherapy for patients with acute myeloid leukemia (AML) undergoing autologous BM transplantation (ABMT). The efficacy and toxicity of 4HC are dose-related. The maximally tolerated concentration, 60-100 micrograms/ml, is toxic to tumor cells but also to normal committed hematopoietic progenitor cells. The anti-CD15 monoclonal antibody (mAb) PM-81 has also been employed for purging BM in patients with AML. In some patients, all tumor cells may not be lysed due to antigenic heterogeneity. Because the two agents used individually are associated with potential limitations in terms of toxicity to normal cells and efficacy of tumor cell purging, using these agents together might have advantages. In fact, in this study the use of these two agents together in subtherapeutic concentration ranges as single agents revealed killing of cells from the HL60 and NB4 promyelocytic leukemia cell lines in addition to cells from patients with AML while sparing normal progenitor cells. Surprisingly, not only did the combination enhance killing of tumor cells, but the order of addition of the two agents was important in maximizing toxicity to tumor cells. Adding mAb+complement (C') first or simultaneously to 4HC was less effective than adding 4HC first followed by mAb + C'. This combination regimen was toxic to HL60 and NB4 leukemia cells that may not be killed by the mAb alone due to antigen-negative tumor cells or by low concentrations of 4HC.(ABSTRACT TRUNCATED AT 250 WORDS)
Rubin
J
J
Department of Medicine, University of Pittsburgh Medical Center, PA 15213.
Malley
V
V
Ball
E D
ED
D000208:Acute Disease; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016465:Bone Marrow Purging / Q000379:methods*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007938:Leukemia / Q000628:therapy; D007951:Leukemia, Myeloid / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D016256:Lewis X Antigen / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D016256:Lewis X Antigen; D003520:Cyclophosphamide; C011272:perfosfamide