Monovalent TNF receptor 1-selective antibody with improved affinity and neutralizing activity

Area of Science:

• Immunology
• Biotechnology
• Drug Discovery

Background:

• Tumor necrosis factor (TNF) signaling is crucial in inflammation and immunity.
• Current anti-TNF drugs inhibit both pro-inflammatory (TNFR1) and pro-survival (TNFR2) pathways, leading to side effects.
• Selective TNFR1 inhibition offers a therapeutic advantage by preserving TNFR2-mediated functions.

Purpose of the Study:

• To develop a TNFR1-specific antagonist with improved properties over existing antibodies.
• To engineer enhanced binding and inhibitory potential against TNFR1-mediated signaling.
• To optimize pharmacokinetic properties for potential clinical application.

Main Methods:

• Affinity maturation and re-engineering of a humanized antibody variable domain.
• Generation of a monovalent Fab derivative (Fab 13.7) with enhanced TNFR1 binding.
• Construction and evaluation of various Fab 13.7-derived formats (PEGylated Fab, albumin fusion, half-IgG, Fv-Fc).
• Assessment of binding kinetics, antagonistic activity, and pharmacokinetic profiles.

Main Results:

• Fab 13.7 demonstrated superior binding and potent inhibition of TNFR1 activation compared to the parental antibody.
• Engineered derivatives showed improved pharmacokinetic properties.
• The Fv13.7-Fc format exhibited the optimal balance of enhanced pharmacokinetics and sustained antagonistic activity.
• No agonistic activity was observed, even with cross-linking.

Conclusions:

• Selective TNFR1 inhibition is achievable and therapeutically relevant.
• Fab 13.7 represents a potent TNFR1-specific antagonist.
• The Fv13.7-Fc derivative shows significant promise for clinical development in inflammatory diseases.