Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy.
During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin G1 (IgG1) hinge as an Ab lock...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-06-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3000286 |
| _version_ | 1818361563586756608 |
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| author | Yun-Chi Lu Chih-Hung Chuang Kuo-Hsiang Chuang I-Ju Chen Bo-Cheng Huang Wen-Han Lee Hsin-Ell Wang Jia-Je Li Yi-An Cheng Kai-Wen Cheng Jaw-Yuan Wang Yuan-Chin Hsieh Wen-Wei Lin Tian-Lu Cheng |
| author_facet | Yun-Chi Lu Chih-Hung Chuang Kuo-Hsiang Chuang I-Ju Chen Bo-Cheng Huang Wen-Han Lee Hsin-Ell Wang Jia-Je Li Yi-An Cheng Kai-Wen Cheng Jaw-Yuan Wang Yuan-Chin Hsieh Wen-Wei Lin Tian-Lu Cheng |
| author_sort | Yun-Chi Lu |
| collection | DOAJ |
| description | During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specifically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα downstream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Furthermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeutic efficiency, providing a novel strategy for RA therapy. |
| first_indexed | 2024-12-13T21:18:41Z |
| format | Article |
| id | doaj.art-39db0cdbd8aa45ea8f35056529c673f5 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-13T21:18:41Z |
| publishDate | 2019-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-39db0cdbd8aa45ea8f35056529c673f52022-12-21T23:31:11ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852019-06-01176e300028610.1371/journal.pbio.3000286Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy.Yun-Chi LuChih-Hung ChuangKuo-Hsiang ChuangI-Ju ChenBo-Cheng HuangWen-Han LeeHsin-Ell WangJia-Je LiYi-An ChengKai-Wen ChengJaw-Yuan WangYuan-Chin HsiehWen-Wei LinTian-Lu ChengDuring rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specifically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα downstream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Furthermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeutic efficiency, providing a novel strategy for RA therapy.https://doi.org/10.1371/journal.pbio.3000286 |
| spellingShingle | Yun-Chi Lu Chih-Hung Chuang Kuo-Hsiang Chuang I-Ju Chen Bo-Cheng Huang Wen-Han Lee Hsin-Ell Wang Jia-Je Li Yi-An Cheng Kai-Wen Cheng Jaw-Yuan Wang Yuan-Chin Hsieh Wen-Wei Lin Tian-Lu Cheng Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. PLoS Biology |
| title | Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. |
| title_full | Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. |
| title_fullStr | Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. |
| title_full_unstemmed | Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. |
| title_short | Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. |
| title_sort | specific activation of pro infliximab enhances selectivity and safety of rheumatoid arthritis therapy |
| url | https://doi.org/10.1371/journal.pbio.3000286 |
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