ArticleThe Journal of biological chemistry2015
Deep Sequencing-guided Design of a High Affinity Dual Specificity Antibody to Target Two Angiogenic Factors in Neovascular Age-related Macular Degeneration.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 63 citations in OpenAlex.
- The Evolution of Artificial Intelligence in Antibody Design: From Structure-Based Engineering to Generative Models.Antibodies (Basel, Switzerland) · 2026Review
- CD98hc-targeted antibody shuttles for central nervous system delivery with broad cross-species reactivity.Nature biomedical engineering · 2026Article
- AbAgym: a well-curated dataset for the mutational analysis of antibody-antigen complexes.mAbs · 2025Article
- ALLM-Ab: Active Learning-Driven Antibody Optimization Using Fine-Tuned Protein Language Models.Journal of chemical information and modeling · 2025Article
- Deep Mutational Scanning in Immunology: Techniques and Applications.Pathogens (Basel, Switzerland) · 2025Review
- Disulfide-constrained Fabs overcome target size limitation for high-resolution single particle cryoEM.Nature communications · 2025Article
- Leveraging neonatal Fc receptor (FcRn) to enhance antibody transport across the blood brain barrier.Nature communications · 2025Article
- Epitope mapping via in vitro deep mutational scanning methods and its applications.The Journal of biological chemistry · 2025Review
- Position-Specific Enrichment Ratio Matrix scores predict antibody variant properties from deep sequencing data.Bioinformatics (Oxford, England) · 2023Article
- Protein engineering via sequence-performance mapping.Cell systems · 2023Review
- Accurate profiling of full-length Fv in highly homologous antibody libraries using UMI tagged short reads.Nucleic acids research · 2023Article
- An optimized thermodynamics integration protocol for identifying beneficial mutations in antibody design.Frontiers in immunology · 2023Article
- Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology.Antibodies (Basel, Switzerland) · 2022Review
- A Generic Strategy to Generate Bifunctional Two-in-One Antibodies by Chicken Immunization.Frontiers in immunology · 2022Article
- Antibody design using LSTM based deep generative model from phage display library for affinity maturation.Scientific reports · 2021Article
- Learning the heterogeneous hypermutation landscape of immunoglobulins from high-throughput repertoire data.Nucleic acids research · 2020Article
- In vitro evolution of antibody affinity via insertional scanning mutagenesis of an entire antibody variable region.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Quantitative mapping of binding specificity landscapes for homologous targets by using a high-throughput method.The Biochemical journal · 2020Article
- A bispecific IgG format containing four independent antigen binding sites.Scientific reports · 2020Article
- Adaption of human antibody λ and κ light chain architectures to CDR repertoires.Protein engineering, design & selection : PEDS · 2019Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The development of dual targeting antibodies promises therapies with improved efficacy over mono-specific antibodies. Here, we engineered a Two-in-One VEGF/angiopoietin 2 antibody with dual action Fab (DAF) as a potential therapeutic for neovascular age-related macular degeneration. Crystal structures of the VEGF/angiopoietin 2 DAF in complex with its two antigens showed highly overlapping binding sites. To achieve sufficient affinity of the DAF to block both angiogenic factors, we turned to deep mutational scanning in the complementarity determining regions (CDRs). By mutating all three CDRs of each antibody chain simultaneously, we were able not only to identify affinity improving single mutations but also mutation pairs from different CDRs that synergistically improve both binding functions. Furthermore, insights into the cooperativity between mutations allowed us to identify fold-stabilizing mutations in the CDRs. The data obtained from deep mutational scanning reveal that the majority of the 52 CDR residues are utilized differently for the two antigen binding function and permit, for the first time, the engineering of several DAF variants with sub-nanomolar affinity against two structurally unrelated antigens. The improved variants show similar blocking activity of receptor binding as the high affinity mono-specific antibodies against these two proteins, demonstrating the feasibility of generating a dual specificity binding surface with comparable properties to individual high affinity mono-specific antibodies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.