ArticleScience immunology2022
Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility.
Article in Science immunology, 2022. 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, 45 citations in OpenAlex.
- Realizing the potential of agonistic antibody immunotherapy.Nature reviews. Drug discovery · 2026Review
- SynNotch Receptors for Visualizing Immunoreceptor Force Transmission and Downstream Signaling In Vivo.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- SynNotch receptors for visualizing immunoreceptor force transmission and downstream signaling in vivo.bioRxiv : the preprint server for biology · 2026Article
- Gas-phase unfolding assay rapidly predicts structure-function relationships in engineered antibodies with tuned flexibilities.Nature communications · 2026Article
- A simple and broadly applicable nanobody-based approach to generate potent TNFR agonists.Cell death & disease · 2026Article
- Increased soluble CD200 in serum of SLE patients does not reflect disease activity or affect CD200R1 function in T cells.Arthritis research & therapy · 2026Article
- Structural mechanism of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity.Communications biology · 2026Article
- Harnessing multivalency and FcγRIIB engagement to augment anti-CD27 immunotherapy.Nature communications · 2025Article
- Review
- Antigenic peptide delivery to antigen-presenting cells using a CD40-coiled coil affinity-based platform.Drug delivery · 2025Article
- Structural mechanism of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity.Research square · 2025Article
- Diffusion, search and attack motions of antibodies.Communications biology · 2025Article
- Solution structure and synaptic analyses reveal determinants of bispecific T cell engager potency.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structure-guided disulfide engineering restricts antibody conformation to elicit TNFR agonism.Nature communications · 2025Article
- Genetically engineered IgG1 and nanobody oligomers acquire strong intrinsic CD40 agonism.Bioengineered · 2024Article
- Targeting TNFRSF25 by agonistic antibodies and multimeric TL1A proteins co-stimulated CD8Journal for immunotherapy of cancer · 2024Article
- Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations.Journal for immunotherapy of cancer · 2024Article
- Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities.Signal transduction and targeted therapy · 2024Review
- Agonist Antibodies for Cancer Immunotherapy: History, Hopes, and Challenges.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Review
- Fcγ-Receptor-Independent Controlled Activation of CD40 Canonical Signaling by Novel Therapeutic Antibodies for Cancer Therapy.Antibodies (Basel, Switzerland) · 2024Article
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Authors and funding
18 authors at 4 institutions in 3 countries.
Funding
Abstract
Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural "switch" affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.
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Registered trials
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.