Generation and characterization of a human monoclonal autoantibody that acts as a high affinity interleukin-1 alpha specific inhibitor.
Interleukin-1 (IL-1) defines two polypeptides, IL-1 alpha and IL-1 beta, that possess a wide spectrum of biological effects. Two natural antagonists of IL-1 action have been characterized: the IL-1 receptor antagonist (IL-1Ra) and a soluble form of the type II IL-1 receptor. Neutralizing autoantibodies to IL-1 alpha have also been detected in sera of healthy individuals and patients with autoimmune or inflammatory diseases. To characterize such antibodies molecularly, we attempted to generate B cell clones producing anti-IL-1 alpha human monoclonal antibody (HuMAb) by combining Epstein-Barr virus-immortalization and CD40-activation of B lymphocytes from individuals with circulating anti-IL-1 alpha. We describe herein the generation and properties of a natural IgG4/kappa anti-IL-1 alpha monoclonal autoantibody, HuMAb X3, that bound specifically to human IL-1 alpha, but not to IL-1 beta and IL-1Ra, with a high affinity (Kd = 1.2 x 10(-10)M). HuMAb X3 inhibited IL-1 alpha binding to IL-1 receptors and neutralized biological activities of both recombinant and natural forms of IL-1 alpha. A recombinant form of HuMAb X3 was found to display identical specific IL-1 alpha antagonism. The presence of somatic mutations within X3 variable regions suggests an antigen-driven affinity maturation. This study extends the demonstration of the presence of high affinity neutralizing anti-IL-1 alpha autoantibodies that can function as a third type of IL-1 antagonist.
Garrone
P
P
Schering-Plough, Laboratory for Immunological Research, Dardilly, France.
Djossou
O
O
Fossiez
F
F
Reyes
J
J
Ait-Yahia
S
S
Maat
C
C
Ho
S
S
Hauser
T
T
Dayer
J M
JM
Greffe
J
J
Miossec
P
P
Lebecque
S
S
Rousset
F
F
Banchereau
J
J
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology*; D000915:Antibody Affinity; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins