A bio-inspired computational pipeline for antibody screening and repurposing

Area of Science:

• Biochemistry and Molecular Biology
• Computational Biology and Bioinformatics
• Immunology and Infectious Diseases

Background:

• Conventional therapeutic antibody discovery methods (hybridoma, phage display) are slow, inefficient, and expensive.
• Current computational approaches like mutagenesis and deep learning have limitations in affinity gains, expression, and validation rates.
• Activin A is a key cytokine involved in fibrosis, oncology, and muscle-wasting disorders, making it a target for therapeutic intervention.

Purpose of the Study:

• To develop and validate a multi-scale computational screening pipeline for high-throughput in silico prioritization of structure-resolved therapeutic antibodies.
• To identify novel antibody candidates targeting Activin A with potential therapeutic applications.
• To demonstrate the integration of AI-driven prediction with physics-based simulations for accelerated antibody screening.

Main Methods:

• A multi-scale computational screening pipeline integrating structure-based docking (ZDock), graph neural network interaction prediction, and accelerated molecular dynamics (MDs) with metadynamics free-energy profiling.
• Screening of approximately 5000 antibody structures against Activin A.
• Experimental validation of computationally identified antibody candidates.

Main Results:

• The pipeline identified 11 potential antibody candidates from ~5000 screened structures.
• Experimental validation confirmed two binders, with one antibody (Ab4) exhibiting sub-nanomolar affinity (KD = 0.38 nM) and potent neutralizing activity against Activin A.
• The validated antibody shows therapeutic potential for fibrodysplasia ossificans progressiva (FOP) and related diseases.

Conclusions:

• The developed computational pipeline effectively accelerates structure-guided antibody screening and repurposing.
• The integration of AI and physics-based simulations offers a powerful approach to therapeutic antibody discovery, paralleling aspects of immune selection.
• The identified Activin A binders hold significant therapeutic promise for fibrotic and related conditions.