De novo design of high-affinity single-domain antibodies
De novo design of high-affinity single-domain antibodies
Abstract Developing antibodies is complex and resource-intensive, and methods for designing antibodies targeting specific epitopes are lacking. We introduce a de novo antibody design approach leveraging the empirical force field FoldX to design complementarity determining regions (CDRs). Starting from a scaffold VHH, we tackled three challenges of increasing difficulty: 1) design the CDRs to optimize VHH stability and affinity for its original target; 2) design the CDRs for high affinity to the human ortholog; 3) design the CDRs for low nanomolar affinity for a pre-defined epitope on the unrelated human Interleukin-9 receptor alpha, for which no antibodies were previously developed. For each challenge we reached single digit nanomolar affinity in a single design cycle. Our approach allows de novo design of high-affinity VHHs while ensuring specificity and stability.
Rousseau Frederic、van der Kant Rob、Zhang Zhongyao、Markovi? Iva、Maragkou Katerina、Blanco Javier Delgado、Cianferoni Damiano、Carolis Carlo、Schymkowitz Joost、Savvides Savvas N.、Dewilde Maarten、Orlando Gabriele、Vizarraga David、Garcia Teresa、Volkov Alexander N.、Pubul Luis Serrano
Switch Laboratory, VIB Center for Brain and Disease Research||Switch Laboratory, Department of Cellular and Molecular Medicine||Switch Laboratory, VIB Center for AI & ComputaRonal BiologySwitch Laboratory, VIB Center for Brain and Disease Research||Switch Laboratory, Department of Cellular and Molecular Medicine||Switch Laboratory, VIB Center for AI & ComputaRonal BiologySwitch Laboratory, VIB Center for Brain and Disease Research||Switch Laboratory, Department of Cellular and Molecular Medicine||Switch Laboratory, VIB Center for AI & ComputaRonal Biology||Laboratory for TherapeuRc and DiagnosRc AnRbodies, Department of PharmaceuRcal and Pharmacological SciencesUnit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University||Unit for Structural Biology, VIB-UGent Center for InflammaRon ResearchSwitch Laboratory, VIB Center for Brain and Disease Research||Switch Laboratory, Department of Cellular and Molecular Medicine||Switch Laboratory, VIB Center for AI & ComputaRonal BiologyCentre for Genomic RegulaRon (CRG), The Barcelona InsRtute of Science and TechnologyCentre for Genomic RegulaRon (CRG), The Barcelona InsRtute of Science and TechnologyCentre for Genomic RegulaRon (CRG), The Barcelona InsRtute of Science and TechnologySwitch Laboratory, VIB Center for Brain and Disease Research||Switch Laboratory, Department of Cellular and Molecular Medicine||Switch Laboratory, VIB Center for AI & ComputaRonal BiologyUnit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University||Unit for Structural Biology, VIB-UGent Center for InflammaRon ResearchLaboratory for TherapeuRc and DiagnosRc AnRbodies, Department of PharmaceuRcal and Pharmacological Sciences||PharmAbs, the KU Leuven AnRbody CenterSwitch Laboratory, VIB Center for Brain and Disease Research||Switch Laboratory, Department of Cellular and Molecular Medicine||Switch Laboratory, VIB Center for AI & ComputaRonal BiologyCentre for Genomic RegulaRon (CRG), The Barcelona InsRtute of Science and TechnologySwitch Laboratory, VIB Center for Brain and Disease Research||Switch Laboratory, Department of Cellular and Molecular Medicine||Switch Laboratory, VIB Center for AI & ComputaRonal BiologyVIB-VUB Center for Structural Biology||Jean Jeener NMR Centre, Vrije Universiteit Brussel (VUB)Centre for Genomic RegulaRon (CRG), The Barcelona InsRtute of Science and Technology||Universitat Pompeu Fabra (UPF)||ICREA
医学研究方法生物科学研究方法、生物科学研究技术生物化学
Rousseau Frederic,van der Kant Rob,Zhang Zhongyao,Markovi? Iva,Maragkou Katerina,Blanco Javier Delgado,Cianferoni Damiano,Carolis Carlo,Schymkowitz Joost,Savvides Savvas N.,Dewilde Maarten,Orlando Gabriele,Vizarraga David,Garcia Teresa,Volkov Alexander N.,Pubul Luis Serrano.De novo design of high-affinity single-domain antibodies[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2024.04.22.589762.点此复制
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