title: A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF.
abstract: The pro-inflammatory cytokine GM-CSF is aberrantly produced in many autoimmune and chronic inflammatory human diseases. GM-CSF neutralization by antibodies has been shown to have a profound therapeutic effect in animal models of rheumatoid arthritis, inflammatory lung diseases, psoriasis and multiple sclerosis. Moreover, the absence of GM-CSF in null mutant mice ameliorates or prevents certain of these diseases. Here we describe the biophysical and biological properties of a human anti-GM-CSF IgG1 antibody designated MT203, which was derived by phage display guided selection. MT203 bound with picomolar affinity to an epitope on human and macaque GM-CSF involved in high-affinity receptor interaction. As a consequence, the antibody potently prevented both GM-CSF-induced proliferation of TF-1 cells with a sub-nanomolar IC50 value and the production of the chemokine IL-8 by U937 cells. MT203 neutralized equally well recombinant (r) human (h) GM-CSF from Escherichia coli and yeast, and also normally glycosylated GM-CSF secreted by human lung epithelial cells in response to IL-1beta stimulation. Furthermore, MT203 significantly reduced both survival and activation of peripheral human eosinophils as may be required for effective treatment of inflammatory lung diseases. The antibody did not show a detectable loss of neutralizing activity after 5 days in human serum at 37 degrees C. Based on its favorable properties, MT203 has been selected for development as a novel anti-inflammatory human monoclonal antibody with therapeutic potential in a multitude of human autoimmune and inflammatory diseases.
authors.affiliation: Micromet AG, Staffelseestr. 2, D 81477 Munich, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Krinner
authors.forename: Tobias
authors.initials: T
authors.lastname: Raum
authors.forename: Silke
authors.initials: S
authors.lastname: Petsch
authors.forename: Sandra
authors.initials: S
authors.lastname: Bruckmaier
authors.forename: Ioana
authors.initials: I
authors.lastname: Schuster
authors.forename: Laetitia
authors.initials: L
authors.lastname: Petersen
authors.forename: Ronny
authors.initials: R
authors.lastname: Cierpka
authors.forename: Derege
authors.initials: D
authors.lastname: Abebe
authors.forename: Michael
authors.initials: M
authors.lastname: Mølhøj
authors.forename: Andreas
authors.initials: A
authors.lastname: Wolf
authors.forename: Poul
authors.initials: P
authors.lastname: Sørensen
authors.forename: Mathias
authors.initials: M
authors.lastname: Locher
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Julia
authors.initials: J
authors.lastname: Hepp
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D053583:Interleukin-1beta / Q000494:pharmacology; D016209:Interleukin-8 / Q000276:immunology; D037181:Lectins, C-Type; D008251:Macaca; D011994:Recombinant Proteins; D000099192:CD69 Antigens
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007074:Immunoglobulin G; D053583:Interleukin-1beta; D016209:Interleukin-8; D037181:Lectins, C-Type; D011994:Recombinant Proteins; D000099192:CD69 Antigens