Structure-based Development of Human Interleukin-1β-Specific Antibody That Simultaneously Inhibits Binding to Both...

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Interleukin-1β (IL-1β) is a key cytokine in immune responses and inflammation.
• Dysregulation of IL-1β signaling is implicated in various diseases, including cancer.
• Current therapies target IL-1β by blocking its receptor interaction or co-receptor recruitment.

Purpose of the Study:

• To develop and characterize a novel neutralizing antibody against IL-1β.
• To investigate the dual-action inhibitory mechanism of the antibody.
• To evaluate the therapeutic potential of the antibody in preclinical models.

Main Methods:

• Screening and optimization of a human anti-IL-1β antibody (IgG26AW) using phage display.
• Structural analysis of the antibody-antigen complex (26-Fab/IL-1β).
• In vivo validation in mouse models for IL-6 inhibition, tumor growth, and metastasis reduction.
• Surface Plasmon Resonance (SPR) to assess binding kinetics and complex formation.

Main Results:

• IgG26AW demonstrated sub-nanomolar binding affinity to human IL-1β.
• The antibody successfully inhibited IL-1β-induced IL-6 elevation in vivo.
• Treatment with IgG26AW led to tumor shrinkage and reduced metastasis in xenograft models.
• Structural and SPR data confirmed IgG26AW blocks both IL-1RI and IL-1RAcP binding sites.

Conclusions:

• IgG26AW functions by preventing the assembly of the IL-1β/IL-1RI/IL-1RAcP ternary complex.
• The antibody exhibits high affinity, potent neutralization, and a novel binding epitope.
• IgG26AW represents a promising candidate for treating inflammatory diseases and as a complementary cancer therapy.