| RRC ID |
69580
|
| 著者 |
Kobayashi M, Kojima K, Murayama K, Amano Y, Koyama T, Ogama N, Takeshita T, Fukuhara T, Tanaka N.
|
| タイトル |
MK-6, a novel not-α IL-2, elicits a potent antitumor activity by improving the effector to regulatory T cell balance.
|
| ジャーナル |
Cancer Sci
|
| Abstract |
IL-2 is a pleiotropic cytokine that regulates immune cell homeostasis. Its immunomodulatory function has been used clinically as an active immunotherapy agent for metastatic cancers. However, severe adverse effects, including the vascular leak syndrome and the preferential stimulation of anti-immunogenic Treg rather than effector T cells, have been obstacles. We newly designed a mutein IL-2, Mutakine-6 (MK-6), with reduced IL-2Rα-binding capability. MK-6 induced comparable cell growth potential toward IL-2Rβγ-positive T cells but was far less efficient in in vitro Treg proliferation and STAT5 activation. Unlike IL-2, in vivo administration of MK-6 produced minimal adverse effects. Using CT26 and B16F10-syngeneic tumor models, we found MK-6 was highly efficacious on tumor regression. Serum albumin conjugation to MK-6 prolonged in vivo half-life and accumulated in CT26 tumors, showing enhanced antitumor effect. Tumor-infiltrating leukocytes analysis revealed that albumin-fused MK-6 increased the ratio of effector CD8+ T cells to CD4+ Treg cells. These results demonstrated that MK-6 is an efficient immunomodulator potentially used for improved immunotherapy with decreased adverse effects and attenuated Treg stimulation.
|
| 巻・号 |
112(11)
|
| ページ |
4478-4489
|
| 公開日 |
2021-11-1
|
| DOI |
10.1111/cas.15127
|
| PMID |
34545658
|
| PMC |
PMC8586658
|
| MeSH |
Animals
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects*
Disease Models, Animal
Female
Half-Life
Immunity, Cellular
Immunologic Factors / pharmacology*
Interleukin Receptor Common gamma Subunit / metabolism
Interleukin-2 / adverse effects
Interleukin-2 / metabolism
Interleukin-2 / therapeutic use
Interleukin-2 Receptor alpha Subunit / metabolism
Interleukin-2 Receptor beta Subunit / metabolism
Lymphocytes, Tumor-Infiltrating / cytology
Lymphocytes, Tumor-Infiltrating / drug effects*
Lymphocytes, Tumor-Infiltrating / physiology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Phosphorylation
STAT5 Transcription Factor / metabolism
Serum Albumin / metabolism
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / drug effects*
T-Lymphocytes, Regulatory / physiology
Tumor Suppressor Proteins / metabolism
|
| IF |
4.966
|
| リソース情報 |
| ヒト・動物細胞 |
B16F10(RCB2630)
CTLL-2(RCB0637) |
