TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity
SCIE
SCOPUS
- Title
- TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity
- Authors
- Lee, Jun-Young; Lee, Eunjin; Hong, Sung Wook; Kim, Daeun; Eunju, O.; Sprent, Jonathan; Im, Sin-Hyeog; Lee, You Jeong; Surh, Charles D.
- Date Issued
- 2019-11
- Publisher
- TAYLOR & FRANCIS INC
- Abstract
- 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-2R alpha, 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.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/100895
- DOI
- 10.1080/2162402X.2019.1681869
- ISSN
- 2162-402X
- Article Type
- Article
- Citation
- ONCOIMMUNOLOGY, vol. 9, no. 1, 2019-11
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