Journal of nanobiotechnology, 2022-01, Vol.20 (1), p.58-11, Article 58
2022
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Details
- Autor(en) / Beteiligte
- Titel
- A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies
- Ist Teil von
- Journal of nanobiotechnology, 2022-01, Vol.20 (1), p.58-11, Article 58
- Ort / Verlag
- England: BioMed Central
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Humanization of mouse monoclonal antibodies (mAbs) is crucial for reducing their immunogenicity in humans. However, humanized mAbs often lose their binding affinities. Therefore, an in silico humanization method that can prevent the loss of the binding affinity of mAbs is needed. We developed an in silico V(D)J recombination platform in which we used V(D)J human germline gene sequences to design five humanized candidates of anti-tumor necrosis factor (TNF)-α mAbs (C1-C5) by using different human germline templates. The candidates were subjected to molecular dynamics simulation. In addition, the structural similarities of their complementarity-determining regions (CDRs) to those of original mouse mAbs were estimated to derive the weighted interatomic root mean squared deviation (wRMSD ) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (K ) of the humanized anti-TNF-α candidates was examined. To confirm whether our in silico estimation method can be used for other humanized mAbs, we tested our method using the anti-epidermal growth factor receptor (EGFR) a4.6.1, anti-glypican-3 (GPC3) YP9.1 and anti-α4β1 integrin HP1/2L mAbs. The R value for the correlation between the wRMSD and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R value for the correlation between wRMSD and log(K ) was 0.9921. The results indicated that our in silico V(D)J recombination platform could predict the binding affinity of humanized candidates and successfully identify the high-affinity humanized anti-TNF-α antibody (Ab) C1 with a binding affinity similar to that of the parental chimeric mAb (5.13 × 10 ). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4β1 integrin HP1/2L mAbs, the wRMSD and log(EC50) exhibited strong correlations (R = 0.9908, 0.9999, and 0.8907, respectively). Our in silico V(D)J recombination platform can facilitate the development of humanized mAbs with low immunogenicity and high binding affinities. This platform can directly transform numerous mAbs with therapeutic potential to humanized or even human therapeutic Abs for clinical use.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1477-3155eISSN: 1477-3155DOI: 10.1186/s12951-022-01259-2Titel-ID: cdi_doaj_primary_oai_doaj_org_article_682be9e061ff404fb8b92628dae0d0c1
- Format
- –
- Schlagworte
- Affinity, Animals, Antibodies, Monoclonal - chemistry, Antibodies, Monoclonal, Humanized, Antibody, Binding, Complementarity, Correlation, Epidermal growth factor, Epidermal growth factor receptors, Gene sequencing, Growth factors, Heparan sulfate proteoglycans, Humanized antibody, Immunogenicity, Methodology, Mice, Molecular dynamics, Monoclonal antibodies, Mutation, Root mean squared deviation (RMSD), Simulation, TNF-α, Tumor Necrosis Factor Inhibitors, Tumor Necrosis Factor-alpha, Tumor necrosis factor-TNF, Tumor necrosis factor-α, V(D)J Recombination