ArticleThe Journal of biological chemistry2022
An antibody Fc engineered for conditional antibody-dependent cellular cytotoxicity at the low tumor microenvironment pH.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 16 citations in OpenAlex.
- Mouse Fc-FcγRIV structure guides Fc engineering for cross-species FcγR recognition.bioRxiv : the preprint server for biology · 2026Article
- Unveiling the molecular and immunological drivers of antibody-drug conjugates in cancer treatment.Nature reviews. Cancer · 2025Review
- Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures.mAbs · 2025Article
- Generation Using Phage-Display of pH-Dependent Antibodies Against the Tumor-Associated Antigen AXL.Antibodies (Basel, Switzerland) · 2025Article
- Bispecific immunotherapy based on antibodies, T-cell receptors, and aptamers: mechanisms of action, adverse effects, and future perspectives.Frontiers in immunology · 2025Review
- Epigenetic and metabolic reprogramming via nanotechnology: a synergistic approach to cancer vaccination in lung tumors.Frontiers in genetics · 2025Review
- The interplay between the tumor microenvironment and tumor-derived small extracellular vesicles in cancer development and therapeutic response.Cancer biology & therapy · 2024Review
- Fc engineering by monoclonal mammalian cell display for improved affinity and selectivity towards FcγRs.Antibody therapeutics · 2024Article
- High-fidelity large-diversity monoclonal mammalian cell libraries by cell cycle arrested recombinase-mediated cassette exchange.Nucleic acids research · 2023Article
- Comparative Performance of High-Throughput Methods for Protein pJournal of chemical information and modeling · 2023Article
- Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite the exquisite specificity and high affinity of antibody-based cancer therapies, treatment side effects can occur since the tumor-associated antigens targeted are also present on healthy cells. However, the low pH of the tumor microenvironment provides an opportunity to develop conditionally active antibodies with enhanced tumor specificity. Here, we engineered the human IgG1 Fc domain to enhance pH-selective binding to the receptor FcγRIIIa and subsequent antibody-dependent cellular cytotoxicity (ADCC). We displayed the Fc domain on the surface of mammalian cells and generated a site-directed library by altering Fc residues at the Fc-FcγRIIIa interface to support interactions with positively charged histidine residues. We then used a competitive staining and flow cytometric selection strategy to isolate Fc variants exhibiting reduced FcγRIIIa affinities at neutral pH, but physiological affinities at the tumor-typical pH 6.5. We demonstrate that antibodies composed of Fab arms binding the breast cell epithelial marker Her2 and the lead Fc variant, termed acid-Fc, exhibited an ∼2-fold pH-selectivity for FcγRIIIa binding based on the ratio of equilibrium dissociation constants K
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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.