A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies
Abstract Background 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....
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-01-01
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| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-022-01259-2 |
| _version_ | 1797999546797654016 |
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| author | Yuan-Chin Hsieh Jun-min Liao Kuo-Hsiang Chuang Kai-Wen Ho Shih-Ting Hong Hui-Ju Liu Bo-Cheng Huang I-Ju Chen Yen-Ling Liu Jaw-Yuan Wang Hsiang-Lin Tsai Yu-Cheng Su Yen-Tseng Wang Tian-Lu Cheng |
| author_facet | Yuan-Chin Hsieh Jun-min Liao Kuo-Hsiang Chuang Kai-Wen Ho Shih-Ting Hong Hui-Ju Liu Bo-Cheng Huang I-Ju Chen Yen-Ling Liu Jaw-Yuan Wang Hsiang-Lin Tsai Yu-Cheng Su Yen-Tseng Wang Tian-Lu Cheng |
| author_sort | Yuan-Chin Hsieh |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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 (wRMSDi) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (KD) 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. Results The R2 value for the correlation between the wRMSDi and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R2 value for the correlation between wRMSDi and log(KD) 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 × 10−10). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4β1 integrin HP1/2L mAbs, the wRMSDi and log(EC50) exhibited strong correlations (R2 = 0.9908, 0.9999, and 0.8907, respectively). Conclusions 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. Graphical Abstract |
| first_indexed | 2024-04-11T11:05:09Z |
| format | Article |
| id | doaj.art-682be9e061ff404fb8b92628dae0d0c1 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-11T11:05:09Z |
| publishDate | 2022-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-682be9e061ff404fb8b92628dae0d0c12022-12-22T04:28:21ZengBMCJournal of Nanobiotechnology1477-31552022-01-0120111110.1186/s12951-022-01259-2A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodiesYuan-Chin Hsieh0Jun-min Liao1Kuo-Hsiang Chuang2Kai-Wen Ho3Shih-Ting Hong4Hui-Ju Liu5Bo-Cheng Huang6I-Ju Chen7Yen-Ling Liu8Jaw-Yuan Wang9Hsiang-Lin Tsai10Yu-Cheng Su11Yen-Tseng Wang12Tian-Lu Cheng13Center for Biomarkers and Biotech Drugs, Kaohsiung Medical UniversityCenter for Biomarkers and Biotech Drugs, Kaohsiung Medical UniversityGraduate Institute of Pharmacognosy, Taipei Medical UniversityGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical UniversityGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical UniversityGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical UniversityInstitute of Biomedical Sciences, National Sun Yat-Sen UniversitySchool of Medicine, I-Shou UniversityDepartment of Biomedical Science and Environmental Biology, Kaohsiung Medical UniversityCenter for Biomarkers and Biotech Drugs, Kaohsiung Medical UniversityDivision of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical UniversityDepartment of Biological Science and Technology, National Yang Ming Chiao Tung UniversityCenter for Biomarkers and Biotech Drugs, Kaohsiung Medical UniversityCenter for Biomarkers and Biotech Drugs, Kaohsiung Medical UniversityAbstract Background 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. Methods 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 (wRMSDi) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (KD) 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. Results The R2 value for the correlation between the wRMSDi and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R2 value for the correlation between wRMSDi and log(KD) 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 × 10−10). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4β1 integrin HP1/2L mAbs, the wRMSDi and log(EC50) exhibited strong correlations (R2 = 0.9908, 0.9999, and 0.8907, respectively). Conclusions 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. Graphical Abstracthttps://doi.org/10.1186/s12951-022-01259-2AntibodyHumanized antibodyTNF-αRoot mean squared deviation (RMSD)Molecular dynamics |
| spellingShingle | Yuan-Chin Hsieh Jun-min Liao Kuo-Hsiang Chuang Kai-Wen Ho Shih-Ting Hong Hui-Ju Liu Bo-Cheng Huang I-Ju Chen Yen-Ling Liu Jaw-Yuan Wang Hsiang-Lin Tsai Yu-Cheng Su Yen-Tseng Wang Tian-Lu Cheng A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies Journal of Nanobiotechnology Antibody Humanized antibody TNF-α Root mean squared deviation (RMSD) Molecular dynamics |
| title | A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies |
| title_full | A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies |
| title_fullStr | A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies |
| title_full_unstemmed | A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies |
| title_short | A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies |
| title_sort | universal in silico v d j recombination strategy for developing humanized monoclonal antibodies |
| topic | Antibody Humanized antibody TNF-α Root mean squared deviation (RMSD) Molecular dynamics |
| url | https://doi.org/10.1186/s12951-022-01259-2 |
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