title: Preliminary studies for an immunotherapeutic approach to the treatment of human myeloma using chimeric anti-CD38 antibody.
abstract: Multiple myeloma is a disease in which conventional chemotherapy has only limited value, but which may be ideal for treatment with passive antibody against a suitable cell surface antigen on the neoplastic plasma cell. The CD38 antigen is known to be present on the majority of neoplastic plasma cells, and this was confirmed by detailed examination of bone marrow aspirates from three patients. Strong expression of CD38 was confined to cells which, by the criteria of light-scattering profiles and possession of cytoplasmic Ig, were plasma cells. The vast majority of neoplastic plasma cells appeared to be involved. Using a cell line as a model, it was found that the CD38 antigen acts as a target for a chimeric antibody prepared from the antibody OKT10. The chimeric antibody consists of the Fab portion of the mouse monoclonal antibody linked by a stable thioether bond to an Fc molecule derived from human IgG1, thereby forming mouse Fab-human Fc. In contrast to the parent antibody, the chimeric molecule mediates antibody-dependent cellular cytotoxicity (ADCC) very efficiently with human blood mononuclear effector cells, and is effective at low concentration. Also, even though the CD38 antigen is present on natural killer cells, there appears to be little deleterious action of the antibody on effector cell function. The antibody also failed to affect the growth of progenitor cells of the granulocyte/macrophage or erythroid lineages present in normal bone marrows, despite the suspicion that these cells express the antigen. Other advantages of the CD38 molecule are that it is not found in the serum of patients with myeloma, and it does not appear to modulate in vitro. Fourteen patients with florid myeloma and on various chemotherapeutic regimes had an undiminished capacity to mediate ADCC with the chimeric antibody, when compared with normal individuals. The maintenance of ADCC activity, coupled with the known suppression of the antibody response in these patients, augers well for treatment with chimeric antibody.
authors.affiliation: Lymphoma Research Unit, Tenovus Research Laboratory, General Hospital, Southampton, UK.
authors.forename: F K
authors.initials: FK
authors.lastname: Stevenson
authors.forename: A J
authors.initials: AJ
authors.lastname: Bell
authors.forename: R
authors.initials: R
authors.lastname: Cusack
authors.forename: T J
authors.initials: TJ
authors.lastname: Hamblin
authors.forename: C J
authors.initials: CJ
authors.lastname: Slade
authors.forename: M B
authors.initials: MB
authors.lastname: Spellerberg
authors.forename: G T
authors.initials: GT
authors.lastname: Stevenson
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000368:Aged; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D004705:Endocytosis; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007518:Isoantibodies / Q000737:chemistry / Q000627:therapeutic use; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009101:Multiple Myeloma / Q000628:therapy*; D010950:Plasma Cells / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D007518:Isoantibodies; D008562:Membrane Glycoproteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1