Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applications
The engineering of pH-sensitive therapeutic antibodies, particularly for improving effectiveness and specificity in acidic solid-tumor microenvironments, has recently gained traction. While there is a justified need for pH-dependent immunotherapies, current engineering techniques are tedious and lab...
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2404064 |
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| author | Wanlei Wei Traian Sulea |
| author_facet | Wanlei Wei Traian Sulea |
| author_sort | Wanlei Wei |
| collection | DOAJ |
| description | The engineering of pH-sensitive therapeutic antibodies, particularly for improving effectiveness and specificity in acidic solid-tumor microenvironments, has recently gained traction. While there is a justified need for pH-dependent immunotherapies, current engineering techniques are tedious and laborious, requiring repeated rounds of experiments under different pH conditions. Inexpensive computational techniques to predict the effectiveness of His pH-switches require antibody-antigen complex structures, but these are lacking in most cases. To circumvent these requirements, we introduce a sequence-based in silico method for predicting His mutations in the variable region of antibodies, which could lead to pH-biased antigen binding. This method, called Sequence-based Identification of pH-sensitive Antibody Binding (SIpHAB), was trained on 3D-structure-based calculations of 3,490 antibody-antigen complexes with solved experimental structures. SIpHAB was parametrized to enhance preferential binding either toward or against the acidic pH, for selective targeting of solid tumors or for antigen release in the endosome, respectively. Applications to nine antibody-antigen systems with previously reported binding preferences at different pHs demonstrated the utility and enrichment capabilities of this high-throughput computational tool. SIpHAB, which only requires knowledge of the antibody primary amino-acid sequence, could enable a more efficient triage of pH-sensitive antibody candidates than could be achieved conventionally. An online webserver for running SipHAB is available freely at https://mm.nrc-cnrc.gc.ca/software/siphab/runner/. |
| format | Article |
| id | doaj-art-bd1f5d5978474d8ab00891f2829d0515 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
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| series | mAbs |
| spelling | doaj-art-bd1f5d5978474d8ab00891f2829d05152025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2404064Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applicationsWanlei Wei0Traian Sulea1Human Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, Quebec, CanadaThe engineering of pH-sensitive therapeutic antibodies, particularly for improving effectiveness and specificity in acidic solid-tumor microenvironments, has recently gained traction. While there is a justified need for pH-dependent immunotherapies, current engineering techniques are tedious and laborious, requiring repeated rounds of experiments under different pH conditions. Inexpensive computational techniques to predict the effectiveness of His pH-switches require antibody-antigen complex structures, but these are lacking in most cases. To circumvent these requirements, we introduce a sequence-based in silico method for predicting His mutations in the variable region of antibodies, which could lead to pH-biased antigen binding. This method, called Sequence-based Identification of pH-sensitive Antibody Binding (SIpHAB), was trained on 3D-structure-based calculations of 3,490 antibody-antigen complexes with solved experimental structures. SIpHAB was parametrized to enhance preferential binding either toward or against the acidic pH, for selective targeting of solid tumors or for antigen release in the endosome, respectively. Applications to nine antibody-antigen systems with previously reported binding preferences at different pHs demonstrated the utility and enrichment capabilities of this high-throughput computational tool. SIpHAB, which only requires knowledge of the antibody primary amino-acid sequence, could enable a more efficient triage of pH-sensitive antibody candidates than could be achieved conventionally. An online webserver for running SipHAB is available freely at https://mm.nrc-cnrc.gc.ca/software/siphab/runner/.https://www.tandfonline.com/doi/10.1080/19420862.2024.2404064Histidine mutagenesisparatope engineeringPH-selective bindingrecycling/sweeping antibodiestumor selective antibodiesvirtual histidine scanning |
| spellingShingle | Wanlei Wei Traian Sulea Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applications mAbs Histidine mutagenesis paratope engineering PH-selective binding recycling/sweeping antibodies tumor selective antibodies virtual histidine scanning |
| title | Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applications |
| title_full | Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applications |
| title_fullStr | Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applications |
| title_full_unstemmed | Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applications |
| title_short | Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applications |
| title_sort | sequence based engineering of ph sensitive antibodies for tumor targeting or endosomal recycling applications |
| topic | Histidine mutagenesis paratope engineering PH-selective binding recycling/sweeping antibodies tumor selective antibodies virtual histidine scanning |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2404064 |
| work_keys_str_mv | AT wanleiwei sequencebasedengineeringofphsensitiveantibodiesfortumortargetingorendosomalrecyclingapplications AT traiansulea sequencebasedengineeringofphsensitiveantibodiesfortumortargetingorendosomalrecyclingapplications |