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- 조회115
J. Immunother. Cancer, Mar 13 2025, 13 (3) e008594 | https://doi.org/10.1136/jitc-2023-008594
Novel anti-CD73-IL-2v bispecific fusion protein augments antitumor immunity by alleviating immunosuppressive adenosine pathways in CD8+ T cells
Kayoung Shin,1 Min Park,1 Seoho Kim,1 Haejong Lee,1 Yuseong Lee,1 Jongil Kim,1 Suyoun Park,1 Jisoo Kim,1 Kyungwha Lee,1 Chong Woo Park,1 Ji-Hyun Kim,1 Eun-Jin Lee,1 Hyuckjun Mok,1 Sung-Man Oh,1 Sanghee Lee,1 Young Min Oh,1 Wonjae Lee,1 Yaein Amy Shim,1 Young-Gyu Cho,1 Junsik Park,2 Jung-Yun Lee,2 Young Jun Koh,1 Kook Hwan Kim,1 Myoung Ho Jang1,3
1Research Institute, GI Innovation Inc, Songpa-gu, Korea (the Republic of)
2Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seodaemun-gu, Korea (the Republic of)
3World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan
KS and MP contributed equally.
Correspondence to Dr Young Jun Koh; Dr Kook Hwan Kim; Dr Myoung Ho Jang
1Research Institute, GI Innovation Inc, Songpa-gu, Korea (the Republic of)
2Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seodaemun-gu, Korea (the Republic of)
3World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan
KS and MP contributed equally.
Correspondence to Dr Young Jun Koh; Dr Kook Hwan Kim; Dr Myoung Ho Jang
Abstract
Background Adenosine accumulated in the tumor microenvironment functions as an immune-modulating factor, exerting immunosuppressive actions via adenosine A2A/A2B receptor (A2AR/A2BR) in various immune cell types. CD73, a key enzymatic regulator responsible for adenosine production, is frequently overexpressed in diverse cancers, and its overexpression is associated with reduced responsiveness to conventional anti-cancer drug treatments such as chemotherapy, radiation therapy, targeted therapy, or immunotherapy. Despite numerous therapeutic applications of IL-2 in cancer immunotherapy, the relationship between the CD73-adenosine axis and IL-2-based immunotherapy remains largely unexplored.
Methods To evaluate the effect of CD73 blockade on IL-2 signaling of CD8+ T cells, we screened novel CD73 antibodies using human single-chain variable fragment phage library and immunized Alpaca phage library. To optimize targeting to CD73-expressing cells and reinvigorate the antitumor effect of IL-2 in adenosine-rich microenvironment, we engineered a novel bifunctional GI-αCD73/IL-2v fusion protein. Functionality of GI-αCD73/IL-2v fusion protein was assessed in the in vitro cell-based assays and the in vivo tumor-bearing mouse model or cynomolgus monkey.
Results IL-2-induced increase in proliferation of CD8+ T cells was not observed under adenosine-rich microenvironment. We demonstrated that the functional impairment of IL-2 signaling in CD8+ T cells in these conditions can be reversed by our anti-CD73 antibody (GI-αCD73). Furthermore, GI-αCD73/IL-2v fusion protein significantly restored the impaired proliferation of CD8+ T cells and consequently enhanced tumor cell killing under adenosine-mediated immunosuppression, surpassing the combined treatment of GI-αCD73 and Fc-IL-2v. These synergistic effects were attributed to the enhanced delivery of the IL-2v component of GI-αCD73/IL-2v to IL-2Rβγ on CD73-expressing CD8+ T cells through a cis-binding mechanism. GI-αCD73/IL-2v elicited a potent antitumor effect in both the human CD73 knock-in (hCD73 KI) mouse model and the humanized mouse model. In non-human primates, GI-αCD73/IL-2v exhibited excellent tolerability while inducing robust and durable expansions of cytotoxic lymphocytes.
Conclusions GI-αCD73/IL-2v bispecific protein is a novel and potent immunocytokine with significant antitumor immunity through cis-binding on CD8+ T cells.
Methods To evaluate the effect of CD73 blockade on IL-2 signaling of CD8+ T cells, we screened novel CD73 antibodies using human single-chain variable fragment phage library and immunized Alpaca phage library. To optimize targeting to CD73-expressing cells and reinvigorate the antitumor effect of IL-2 in adenosine-rich microenvironment, we engineered a novel bifunctional GI-αCD73/IL-2v fusion protein. Functionality of GI-αCD73/IL-2v fusion protein was assessed in the in vitro cell-based assays and the in vivo tumor-bearing mouse model or cynomolgus monkey.
Results IL-2-induced increase in proliferation of CD8+ T cells was not observed under adenosine-rich microenvironment. We demonstrated that the functional impairment of IL-2 signaling in CD8+ T cells in these conditions can be reversed by our anti-CD73 antibody (GI-αCD73). Furthermore, GI-αCD73/IL-2v fusion protein significantly restored the impaired proliferation of CD8+ T cells and consequently enhanced tumor cell killing under adenosine-mediated immunosuppression, surpassing the combined treatment of GI-αCD73 and Fc-IL-2v. These synergistic effects were attributed to the enhanced delivery of the IL-2v component of GI-αCD73/IL-2v to IL-2Rβγ on CD73-expressing CD8+ T cells through a cis-binding mechanism. GI-αCD73/IL-2v elicited a potent antitumor effect in both the human CD73 knock-in (hCD73 KI) mouse model and the humanized mouse model. In non-human primates, GI-αCD73/IL-2v exhibited excellent tolerability while inducing robust and durable expansions of cytotoxic lymphocytes.
Conclusions GI-αCD73/IL-2v bispecific protein is a novel and potent immunocytokine with significant antitumor immunity through cis-binding on CD8+ T cells.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-17)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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