ABSTRACT
A human anti-CD19 antibody was expressed in fucosyltransferase-deficient CHO cells to generate nonfucosylated MDX-1342. Binding of MDX-1342 to human CD19-expressing cells was similar to its fucosylated parental antibody. However, MDX-1342 exhibited increased affinity for FcγRIIIa-Phe158 and FcγRIIIa-Val158 receptors as well as enhanced effector cell function, as demonstrated by increased potency and efficacy in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis assays. MDX-1342 showed dose-dependent improvement in survival using a murine B-cell lymphoma model in which Ramos cells were administered systemically. In addition, low nanomolar binding to cynomolgus monkey CD19 and increased affinity for cynomolgus monkey FcγRIIIa was observed. In vivo administration of MDX-1342 in cynomolgus monkeys revealed potent B-cell depletion, suggesting its potential utility as a B-lymphocyte depletive therapy for malignancies and autoimmune indications.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antigens, CD19/immunology , B-Lymphocytes/immunology , Lymphocyte Depletion , Lymphoma, B-Cell/therapy , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibody Affinity , CHO Cells , Cricetinae , Cricetulus , Humans , Macaca fascicularis , Mice , Mice, SCID , Mice, Transgenic , Phagocytosis , Receptors, IgG/immunology , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: This study was undertaken to evaluate the effects of MDX-1401, a nonfucosylated fully human monoclonal antibody that binds to human CD30, and to determine whether it exhibits greater in vitro and in vivo activity than its parental antibody. EXPERIMENTAL DESIGN: Assays measuring antibody binding to CD30-expressing cells and FcgammaRIIIa (CD16) transfectants as well as antibody-dependent cellular cytotoxicity (ADCC) were conducted. Antitumor activity was determined using a Karpas-299 systemic model. RESULTS: The binding of MDX-1401 to CD30 antigen was identical to fucose-containing parental anti-CD30 antibody (MDX-060). In contrast, MDX-1401 showed increased binding affinity to FcgammaRIIIa-transfected cells resulting in increased effector function. MDX-1401 greatly improved ADCC activity as evidenced by a decrease in half-maximal effective concentration (EC(50)) and an increase in maximum cell lysis when compared with MDX-060. Increased ADCC activity was observed among a panel of cell lines, including one with very low CD30 antigen expression in which parental antibody failed to induce any detectable ADCC. MDX-1401 activity with all FcgammaRIIIa polymorphic variants, including less active Phe/Phe158 and Phe/Val158 effector cells, was shown. Furthermore, MDX-1401 was efficacious in inhibiting tumor growth in CD30(+) lymphoma xenografts. CONCLUSIONS: The low doses of antibody required for ADCC activity irrespective of donor genotype, the ability to mediate ADCC in target cells expressing low levels of CD30, and increased in vivo efficacy support the development of MDX-1401 for treatment of malignant lymphoma.
Subject(s)
Antibodies, Monoclonal/pharmacology , Lymphoma/drug therapy , Xenograft Model Antitumor Assays , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Humanized , Antibody Affinity/drug effects , Antibody Affinity/immunology , Antibody-Dependent Cell Cytotoxicity/drug effects , Binding Sites, Antibody/immunology , CHO Cells , Carbohydrates/chemistry , Carbohydrates/immunology , Cell Line, Tumor , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Fucose/chemistry , Fucose/immunology , Humans , Ki-1 Antigen/immunology , Lymphoma/immunology , Lymphoma/pathology , Male , Mice , Mice, SCID , Receptors, IgG/chemistry , Receptors, IgG/immunologyABSTRACT
Eighteen participants in a rural Appalachian community were interviewed to learn about their mystical experiences in the context of health care. Semistructured interviews addressed factors initiating mystical experience and essential qualities of mystical experience. Nursing process and the nurse's response were examined. Data were analyzed using the immersion/crystallization method and concept mapping. Mystical experience was conceptualized as a process incorporating initiation, occurrence, maturation, and integration of mystical experience. Essential qualities included sensory-motor perception, interaction with the supernatural, interaction with family members, conviction of reality, cognition, dynamic tension and emotional intensity. Nursing interventions included listening and support. Subjective nursing responses included tension, intimacy and empathy, sense of awe, autonomic responses, and appreciation of the mystical in everyday life. Various stressors are associated with mystical experience. Patients having mystical experiences may benefit from nursing support.
