ArticleProtein science : a publication of the Protein Society2008
Critical contribution of VH-VL interaction to reshaping of an antibody: the case of humanization of anti-lysozyme antibody, HyHEL-10.
Article in Protein science : a publication of the Protein Society, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 50 citations in OpenAlex.
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- Modeling Immunity with Rosetta: Methods for Antibody and Antigen Design.Biochemistry · 2021Review
- Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Structural Basis of Antibody Conformation and Stability Modulation by Framework Somatic Hypermutation.Frontiers in immunology · 2021Article
- Shark Antibody Variable Domains Rigidify Upon Affinity Maturation-Understanding the Potential of Shark Immunoglobulins as Therapeutics.Frontiers in molecular biosciences · 2021Article
- Sagacity in antibody humanization for therapeutics, diagnostics and research purposes: considerations of antibody elements and their roles.Antibody therapeutics · 2020Review
- Ancient species offers contemporary therapeutics: an update on shark VAntibody therapeutics · 2020Review
- Antibody Structure and Function: The Basis for Engineering Therapeutics.Antibodies (Basel, Switzerland) · 2019Review
- Design and Production of Bispecific Antibodies.Antibodies (Basel, Switzerland) · 2019Review
- Inaugural Editorial: Searching for Magic Bullets.Antibody therapeutics · 2018Article
- Article
- Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition.Frontiers in immunology · 2018Review
- Determinants of the assembly and function of antibody variable domains.Scientific reports · 2017Article
- An insight into the thermodynamic characteristics of human thrombopoietin complexation with TN1 antibody.Protein science : a publication of the Protein Society · 2016Article
- Redistribution of flexibility in stabilizing antibody fragment mutants follows Le Châtelier's principle.PloS one · 2014Article
- The structural basis of antibody-antigen recognition.Frontiers in immunology · 2013Review
- Computational screening of the human TF-glycome provides a structural definition for the specificity of anti-tumor antibody JAA-F11.PloS one · 2013Article
- Specific fluorine labeling of the HyHEL10 antibody affects antigen binding and dynamics.Biochemistry · 2012Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
To clarify the effects of humanizing a murine antibody on its specificity and affinity for its target, we examined the interaction between hen egg white lysozyme (HEL) and its antibody, HyHEL-10 variable domain fragment (Fv). We selected a human antibody framework sequence with high homology, grafted sequences of six complementarity-determining regions of murine HyHEL-10 onto the framework, and investigated the interactions between the mutant Fvs and HEL. Isothermal titration calorimetry indicated that the humanization led to 10-fold reduced affinity of the antibody for its target, due to an unfavorable entropy change. Two mutations together into the interface of the variable domains, however, led to complete recovery of antibody affinity and specificity for the target, due to reduction of the unfavorable entropy change. X-ray crystallography of the complex of humanized antibodies, including two mutants, with HEL demonstrated that the complexes had almost identical structures and also paratope and epitope residues were almost conserved, except for complementary association of variable domains. We conclude that adjustment of the interfacial structures of variable domains can contribute to the reversal of losses of affinity or specificity caused by humanization of murine antibodies, suggesting that appropriate association of variable domains is critical for humanization of murine antibodies without loss of function.
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