ArticleThe Journal of biological chemistry2013
Engineered protease-resistant antibodies with selectable cell-killing functions.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 42 citations in OpenAlex.
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- Discovery and Phase 1 study of a novel monoclonal antibody against human IL-1β for the treatment of IL-1β-mediated diseases.Clinical and experimental immunology · 2025Article
- Determining key residues of engineered scFv antibody variants with improved MMP-9 binding using deep sequencing and machine learning.Computational and structural biotechnology journal · 2024Article
- Outsmarting Pathogens with Antibody Engineering.Annual review of chemical and biomolecular engineering · 2023Review
- Impairment of IgG Fc functions promotes tumor progression and suppresses NK cell antitumor actions.Communications biology · 2022Article
- Therapeutic antibodies - natural and pathological barriers and strategies to overcome them.Pharmacology & therapeutics · 2022Review
- Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer.Frontiers in immunology · 2022Review
- Considerations for the Design of Antibody-Based Therapeutics.Journal of pharmaceutical sciences · 2020Review
- The Proteolytic Cleavage of Therapeutic Monoclonal Antibody Hinge Region: More Than a Matter of Subclass.Frontiers in immunology · 2020Article
- Antibody Structure and Function: The Basis for Engineering Therapeutics.Antibodies (Basel, Switzerland) · 2019Review
- Proteolytic single hinge cleavage of pertuzumab impairs its Fc effector function and antitumor activity in vitro and in vivo.Breast cancer research : BCR · 2018Article
- Current progress in innovative engineered antibodies.Protein & cell · 2018Review
- Tumor evasion of humoral immunity mediated by proteolytic impairment of antibody triggered immune effector function.Oncoimmunology · 2016Article
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Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Molecularly engineered antibodies with fit-for-purpose properties will differentiate next generation antibody therapeutics from traditional IgG1 scaffolds. One requirement for engineering the most appropriate properties for a particular therapeutic area is an understanding of the intricacies of the target microenvironment in which the antibody is expected to function. Our group and others have demonstrated that proteases secreted by invasive tumors and pathological microorganisms are capable of cleaving human IgG1, the most commonly adopted isotype among monoclonal antibody therapeutics. Specific cleavage in the lower hinge of IgG1 results in a loss of Fc-mediated cell-killing functions without a concomitant loss of antigen binding capability or circulating antibody half-life. Proteolytic cleavage in the hinge region by tumor-associated or microbial proteases is postulated as a means of evading host immune responses, and antibodies engineered with potent cell-killing functions that are also resistant to hinge proteolysis are of interest. Mutation of the lower hinge region of an IgG1 resulted in protease resistance but also resulted in a profound loss of Fc-mediated cell-killing functions. In the present study, we demonstrate that specific mutations of the CH2 domain in conjunction with lower hinge mutations can restore and sometimes enhance cell-killing functions while still retaining protease resistance. By identifying mutations that can restore either complement- or Fcγ receptor-mediated functions on a protease-resistant scaffold, we were able to generate a novel protease-resistant platform with selective cell-killing functionality.
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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.