Journal article
Discovery and Phase 1 study of a novel monoclonal antibody against human IL-1β for the treatment of IL-1β-mediated diseases
Clinical and experimental immunology, v 219(1), uxaf009
21 Jan 2025
PMID: 39964852
Featured in Collection : UN Sustainable Development Goals @ Drexel
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. 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.
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Details
- Title
- Discovery and Phase 1 study of a novel monoclonal antibody against human IL-1β for the treatment of IL-1β-mediated diseases
- Creators
- Minseon Cho - Integrated BioTherapeutics (United States)Susan H Tam - Integrated BioTherapeutics (United States)Lihua Shi - Integrated BioTherapeutics (United States)Isa Fung - Integrated BioTherapeutics (United States)Mark Tornetta - Integrated BioTherapeutics (United States)Gabriela A Canziani - Drexel UniversityMan-Cheong Fung - Tavotek Biotherapeutics Inc., Ambler, PA, USAMark L Chiu - Integrated BioTherapeutics (United States)Chao Han - Integrated BioTherapeutics (United States)Di Zhang (Corresponding Author) - Integrated BioTherapeutics (United States)
- Publication Details
- Clinical and experimental immunology, v 219(1), uxaf009
- Publisher
- Oxford University Press
- Grant note
- S10 OD027009 / NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001447666200001
- Scopus ID
- 2-s2.0-105001591554
- Other Identifier
- 991022197407304721
UN Sustainable Development Goals (SDGs)
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Source: SDGs in the Output
InCites Highlights
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- Web of Science research areas
- Immunology