title: Bispecific monoclonal antibody regulation of Fc gamma RIII-directed tumor cytotoxicity by large granular lymphocytes.
abstract: Bispecific monoclonal antibodies (BsMAbs) prepared by somatic cell fusion bind monovalently to their targets and yet are extremely potent enhancers of target cell lysis by relevant effector cells. The mechanisms underlying this efficiency are not known. To investigate this property, we studied the ability of selected antibodies to modulate potentiation of tumor lysis by a bispecific antibody (CL158) which targets Fc gamma RIII-expressing cells, via the 3G8 epitope, to malignant cells expressing CA19-9 antigen. Antibodies directed against the 3G8 and B73.1 epitopes of Fc gamma RIII efficiently inhibited BsMAb-mediated SW948 tumor cell lysis by interleukin-2 (IL-2)-activated lymphocytes (PBLs). Unexpectedly, Leu 19 antibody reversed antibody-dependent but not antibody-independent lysis of 51Cr-labeled SW948 cells by IL-2-activated PBLs in a concentration-dependent fashion. Leu 19 binds to CD56, a neural cell adhesion molecule (N-CAM) isoform expressed by large granular lymphocytes (LGLs). The effects of Leu 19 on bispecific antibody promotion of lysis were due to competition for binding to the 3G8 epitope of Fc gamma RIII and led to inhibition of binding between LGLs and SW948 cells. Leu 19 did not inhibit antibody-dependent lysis by the monospecific, bivalent IgG2a variant of CA19-9 antibody. These studies show that competition assays can be useful in dissecting the relevant mechanisms underlying BsMAb-promoted lysis. Steric constraints between effector cell trigger molecules (i.e., Fc gamma RIII) and CAM such as N-CAM may regulate the function of these molecules. Understanding the roles of diverse CAM in this phenomenon will facilitate efforts to expand and use defined effector cell populations with maximal lytic potential and to identify potentially responsive tumor phenotypes.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: I G
authors.initials: IG
authors.lastname: de Palazzo
authors.forename: J
authors.initials: J
authors.lastname: Kitson
authors.forename: C
authors.initials: C
authors.lastname: Gercel-Taylor
authors.forename: S
authors.initials: S
authors.lastname: Adams
authors.forename: L M
authors.initials: LM
authors.lastname: Weiner
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D000943:Antigens, Differentiation / Q000276:immunology*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006098:Granulocytes / Q000276:immunology*; D006801:Humans; D011961:Receptors, Fc / Q000276:immunology*; D017452:Receptors, IgG; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D015295:Antigens, Tumor-Associated, Carbohydrate; D015815:Cell Adhesion Molecules; D011961:Receptors, Fc; D017452:Receptors, IgG