TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity
IL-2 is a pleiotropic cytokine that plays an essential role in the survival, expansion, and function of CD8 T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Previous studies showed that binding IL-2 with an anti-IL-2 monoclonal antibody (mAb) with a particular specificity could bl...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2019.1681869 |
| _version_ | 1818740411531788288 |
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| author | Jun-Young Lee Eunjin Lee Sung-Wook Hong Daeun Kim O. Eunju Jonathan Sprent Sin-Hyeog Im You Jeong Lee Charles D. Surh |
| author_facet | Jun-Young Lee Eunjin Lee Sung-Wook Hong Daeun Kim O. Eunju Jonathan Sprent Sin-Hyeog Im You Jeong Lee Charles D. Surh |
| author_sort | Jun-Young Lee |
| collection | DOAJ |
| description | IL-2 is a pleiotropic cytokine that plays an essential role in the survival, expansion, and function of CD8 T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Previous studies showed that binding IL-2 with an anti-IL-2 monoclonal antibody (mAb) with a particular specificity could block its interaction with IL-2Rα, which is mainly expressed on Tregs. This selectivity can enhance the anti-tumor effects of IL-2 by activating CD8 T and NK cells, while disfavoring Treg stimulation. Based on this, we newly developed a series of anti-human IL-2 (hIL-2) mAbs (TCB1-3) that selectively stimulate CD8 T and NK cells without overtly activating Tregs. Among them, the hIL-2/TCB2 complex (hIL-2/TCB2c) exerted the best efficacy by inducing a prodigious expansion of host memory phenotype (MP) CD8 T (60-fold) and NK cells (18-fold) with less efficient Treg proliferation (5-fold). As a result, there was an average eightfold increase in the ratio of MP CD8 to Tregs. Accordingly, hIL-2/TCB2c strongly inhibited the growth of B16F10, MC38, and CT26 tumors. More remarkably, hIL-2/TCB2c showed synergy with checkpoint inhibitors such as anti-CTLA-4 or PD1 antibodies, and resulted in almost complete regression of implanted tumors and resistance to secondary tumor challenge. For direct clinical use, we generated a humanized form of TCB2 that had equal immunostimulatory and anti-tumor efficacy as a murine one. Collectively, these results show that TCB2 can provide a potent immunotherapeutic modality either alone or together with checkpoint inhibitors in cancer patients. |
| first_indexed | 2024-12-18T01:40:18Z |
| format | Article |
| id | doaj.art-a2316550117245cb9f178b1827b25430 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-18T01:40:18Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-a2316550117245cb9f178b1827b254302022-12-21T21:25:21ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2019.16818691681869TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunityJun-Young Lee0Eunjin Lee1Sung-Wook Hong2Daeun Kim3O. Eunju4Jonathan Sprent5Sin-Hyeog Im6You Jeong Lee7Charles D. Surh8Institute for Basic Science (IBS)Pohang University of Science and Technology (POSTECH)Institute for Basic Science (IBS)Institute for Basic Science (IBS)Institute for Basic Science (IBS)Garvan Institute of Medical ResearchInstitute for Basic Science (IBS)Institute for Basic Science (IBS)Institute for Basic Science (IBS)IL-2 is a pleiotropic cytokine that plays an essential role in the survival, expansion, and function of CD8 T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Previous studies showed that binding IL-2 with an anti-IL-2 monoclonal antibody (mAb) with a particular specificity could block its interaction with IL-2Rα, which is mainly expressed on Tregs. This selectivity can enhance the anti-tumor effects of IL-2 by activating CD8 T and NK cells, while disfavoring Treg stimulation. Based on this, we newly developed a series of anti-human IL-2 (hIL-2) mAbs (TCB1-3) that selectively stimulate CD8 T and NK cells without overtly activating Tregs. Among them, the hIL-2/TCB2 complex (hIL-2/TCB2c) exerted the best efficacy by inducing a prodigious expansion of host memory phenotype (MP) CD8 T (60-fold) and NK cells (18-fold) with less efficient Treg proliferation (5-fold). As a result, there was an average eightfold increase in the ratio of MP CD8 to Tregs. Accordingly, hIL-2/TCB2c strongly inhibited the growth of B16F10, MC38, and CT26 tumors. More remarkably, hIL-2/TCB2c showed synergy with checkpoint inhibitors such as anti-CTLA-4 or PD1 antibodies, and resulted in almost complete regression of implanted tumors and resistance to secondary tumor challenge. For direct clinical use, we generated a humanized form of TCB2 that had equal immunostimulatory and anti-tumor efficacy as a murine one. Collectively, these results show that TCB2 can provide a potent immunotherapeutic modality either alone or together with checkpoint inhibitors in cancer patients.http://dx.doi.org/10.1080/2162402X.2019.1681869il-2tcb2cytokine-antibody compleximmunotherapy |
| spellingShingle | Jun-Young Lee Eunjin Lee Sung-Wook Hong Daeun Kim O. Eunju Jonathan Sprent Sin-Hyeog Im You Jeong Lee Charles D. Surh TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity OncoImmunology il-2 tcb2 cytokine-antibody complex immunotherapy |
| title | TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity |
| title_full | TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity |
| title_fullStr | TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity |
| title_full_unstemmed | TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity |
| title_short | TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity |
| title_sort | tcb2 a new anti human interleukin 2 antibody facilitates heterodimeric il 2 receptor signaling and improves anti tumor immunity |
| topic | il-2 tcb2 cytokine-antibody complex immunotherapy |
| url | http://dx.doi.org/10.1080/2162402X.2019.1681869 |
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