A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF.
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.
Krinner
Eva-Maria
EM
Micromet AG, Staffelseestr. 2, D 81477 Munich, Germany.
Raum
Tobias
T
Petsch
Silke
S
Bruckmaier
Sandra
S
Schuster
Ioana
I
Petersen
Laetitia
L
Cierpka
Ronny
R
Abebe
Derege
D
Mølhøj
Michael
M
Wolf
Andreas
A
Sørensen
Poul
P
Locher
Mathias
M
Baeuerle
Patrick A
PA
Hepp
Julia
J
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
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