Rational antibody design for undruggable targets using kinetically controlled biomolecular probes.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Many critical drug targets, including ion channels and G protein-coupled receptors, are challenging for current antibody-based therapies.
• Developing antibodies against these difficult targets requires innovative approaches to understand protein dynamics and binding sites.

Purpose of the Study:

• To explore kinetically controlled proteases as probes for identifying druggable epitopes on challenging protein targets.
• To develop a platform for generating high-affinity antibodies with specific pharmacological functions against difficult-to-drug targets.

Main Methods:

• Utilized low-Reynolds number flows to achieve controlled protease activity, enabling precise identification of antibody binding sites (epitopes).
• Translated identified epitopes into short-sequence antigens for antibody production.
• Characterized the epitope-paratope interactions at a molecular level.

Main Results:

• Successfully generated high-affinity monoclonal antibodies against difficult-to-drug targets.
• Demonstrated the first stimulus-selective antibodies targeting the Transient Receptor Potential Vanilloid 1 (TRPV1) channel.
• Developed apoptosis-inducing antibodies that selectively mediate cytotoxicity in KRAS-mutated cells.

Conclusions:

• The developed platform effectively identifies druggable epitopes and enables the production of functional antibodies against challenging targets.
• This method expands the potential of antibody therapeutics for previously undruggable targets, offering new hope for patients.
• The approach holds promise for developing novel treatments for pain and KRAS-mutated cancers.