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 bet a, that possess a wide spectrum of biological effects. Two natural ant agonists of IL-1 action have been characterized: the IL-1 receptor ant agonist (IL-1Ra) and a soluble form of the type II IL-1 receptor. Neut ralizing autoantibodies to IL-1 alpha have also been detected in sera of healthy individuals and patients with autoimmune or inflammatory di seases. To characterize such antibodies molecularly, we attempted to g enerate B cell clones producing anti-IL-1 alpha human monoclonal antib ody (HuMAb) by combining Epstein-Barr virus-immortalization and CD40-a ctivation of B lymphocytes from individuals with circulating anti IL-1 alpha. We describe herein the generation and properties of a natural IgG(4)/kappa anti-IL-1 alpha monoclonal autoantibody, HuMAb X3, that b ound specifically to human IL-1 alpha, but not to IL-1 beta and IL-1Ra , with a high affinity (K-d=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 for m of HuMAb X3 was found to display identical specific IL-1 alpha antag onism. The presence of somatic mutations within X3 variable regions su ggests an antigen-driven affinity maturation. This study extends the d emonstration of the presence of high affinity neutralizing anti-IL-1 a lpha autoantibodies that can function as a third type of IL-1 antagoni st. Copyright (C) 1996 Elsevier Science Ltd.