Discovery and Phase 1 study of a novel monoclonal antibody against human IL-1β for the treatment of IL-1β-mediated diseases.

Abstract

Interleukin-1β (IL-1β) is a key mediator of innate immunity against pathogen infections. However, dysregulated IL-1β activity is associated with various autoinflammatory, autoimmune, degenerative, atherosclerotic diseases, and cancers. Biologic drugs that neutralize excess IL-1β activity, such as canakinumab, have been effective in treating IL-1β-mediated diseases. This article reports the discovery and development of a novel humanized anti-IL-1β antibody, designated as TAVO103A, which exhibited potent binding affinities to human and monkey IL-1β. TAVO103A demonstrated more potent neutralization of IL-1β activities compared to canakinumab in multiple assays, including tests on the IL-1β-driven signal transduction cascade, inflammatory cytokine release from MRC-5 cells, chemokine release from A549 cells, and the proliferation of D10.G4.1 helper T cells. Ex vivo studies showed that TAVO103A effectively neutralized IL-1β-mediated release of pro-inflammatory cytokines from peripheral blood mononuclear cells (PBMC). In addition, TAVO103A exhibited dose-dependent efficacy in a knee joint inflammation mouse model. TAVO103A underwent Fc engineering to reduce binding to Fcγ receptors, increase affinity to FcRn receptors, and enhance its resistance to proteolytic degradation. In a Phase 1 study, TAVO103A was found to be safe, well tolerated, and demonstrated a median half-life of 63 days in healthy subjects. By recognizing a different epitope, TAVO103A provided more potent neutralization of IL-1β activities, a longer circulating half-life, and improved safety profiles compared to canakinumab, positioning it to be a potential best-in-class therapeutic option for various IL-1β-mediated diseases.