Retraction of “Mutational Analysis of 48G7 Reveals that Somatic Hypermutation Affects Both Antibody Stability and Binding Affinity”

Sun, Sophie; Sen, Shiladitya; Kim, Nam Jung; Magliery, Thomas J.; Schultz, Peter G.; Wang, Rui

doi:10.1021/jacs.7b08106

Cited by 12 publications

(1 citation statement)

References 15 publications

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“…However, not all somatic mutations contribute to antibody affinity. Previous reports have suggested that antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations [9–12]. These studies raise the intriguing possibility that the natural process of reshaping the antigen-binding site during antibody affinity maturation involves chemical and structural changes that are destabilizing to the antibody framework, and compensatory mutations are required to maintain thermodynamic stability.…”

Section: Antibody Affinity/stability Trade-offsmentioning

confidence: 99%

Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility

Rabia

Desai

Jhajj

et al. 2018

Biochemical Engineering Journal

113

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The widespread use of monoclonal antibodies for therapeutic applications has led to intense interest in optimizing several of their natural properties (affinity, specificity, stability, solubility and effector functions) as well as introducing non-natural activities (bispecificity and cytotoxicity mediated by conjugated drugs). A common challenge during antibody optimization is that improvements in one property (e.g., affinity) can lead to deficits in other properties (e.g., stability). Here we review recent advances in understanding trade-offs between different antibody properties, including affinity, specificity, stability and solubility. We also review new approaches for co-optimizing multiple antibody properties and discuss how these methods can be used to rapidly and systematically generate antibodies for a wide range of applications.

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Section: Antibody Affinity/stability Trade-offsmentioning

confidence: 99%

Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility

Rabia

Desai

Jhajj

et al. 2018

Biochemical Engineering Journal

113

View full text Add to dashboard Cite

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Development of an inhibiting antibody against equine interleukin 5 to treat insect bite hypersensitivity of horses

Langreder

Schäckermann

Meier

et al. 2023

Sci Rep

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Insect bite hypersensitivity (IBH) is the most common allergic skin disease of horses. It is caused by insect bites of the Culicoides spp. which mediate a type I/IVb allergy with strong involvement of eosinophil cells. No specific treatment option is available so far. One concept could be the use of a therapeutic antibody targeting equine interleukin 5, the main activator and regulator of eosinophils. Therefore, antibodies were selected by phage display using the naïve human antibody gene libraries HAL9/10, tested in a cellular in vitro inhibition assay and subjected to an in vitro affinity maturation. In total, 28 antibodies were selected by phage display out of which eleven have been found to be inhibiting in the final format as chimeric immunoglobulin G with equine constant domains. The two most promising candidates were further improved by in vitro affinity maturation up to factor 2.5 regarding their binding activity and up to factor 2.0 regarding their inhibition effect. The final antibody named NOL226-2-D10 showed a strong inhibition of the interleukin 5 binding to its receptor (IC50 = 4 nM). Furthermore, a nanomolar binding activity (EC50 = 8.8 nM), stable behavior and satisfactory producibility were demonstrated. This antibody is an excellent candidate for in vivo studies for the treatment of equine IBH.

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Efficient affinity maturation of antibody variable domains requires co-selection of compensatory mutations to maintain thermodynamic stability

Julian

Garde

et al. 2017

Sci Rep

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The ability of antibodies to accumulate affinity-enhancing mutations in their complementarity-determining regions (CDRs) without compromising thermodynamic stability is critical to their natural function. However, it is unclear if affinity mutations in the hypervariable CDRs generally impact antibody stability and to what extent additional compensatory mutations are required to maintain stability during affinity maturation. Here we have experimentally and computationally evaluated the functional contributions of mutations acquired by a human variable (VH) domain that was evolved using strong selections for enhanced stability and affinity for the Alzheimer’s Aβ42 peptide. Interestingly, half of the key affinity mutations in the CDRs were destabilizing. Moreover, the destabilizing effects of these mutations were compensated for by a subset of the affinity mutations that were also stabilizing. Our findings demonstrate that the accumulation of both affinity and stability mutations is necessary to maintain thermodynamic stability during extensive mutagenesis and affinity maturation in vitro, which is similar to findings for natural antibodies that are subjected to somatic hypermutation in vivo. These findings for diverse antibodies and antibody fragments specific for unrelated antigens suggest that the formation of the antigen-binding site is generally a destabilizing process and that co-enrichment for compensatory mutations is critical for maintaining thermodynamic stability.

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Retraction of “Mutational Analysis of 48G7 Reveals that Somatic Hypermutation Affects Both Antibody Stability and Binding Affinity”

Cited by 12 publications

References 15 publications

Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility

Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility

Development of an inhibiting antibody against equine interleukin 5 to treat insect bite hypersensitivity of horses

Efficient affinity maturation of antibody variable domains requires co-selection of compensatory mutations to maintain thermodynamic stability

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