TY - JOUR
T1 - Immunoregulation by IL-7R-targeting antibody-drug conjugates
T2 - Overcoming steroid-resistance in cancer and autoimmune disease
AU - Yasunaga, Masahiro
AU - Manabe, Shino
AU - Matsumura, Yasuhiro
N1 - Funding Information:
The authors thank Dr. SI. Nishikawa and Mrs. S. Nishikawa for their helpful comments and for providing CYG82 cells, RAG−/− cells and the A7R34-producing hybridoma. The authors also thank Dr. S. Saijou and Dr. R. Tsumura for assistance with these studies and Mrs. M. Nakayama and Mrs. M. Shimada for secretarial support. This work was financially supported by grants from the National Cancer Center Research and Development Fund (23-B-21 and 27-S-5 for M.Y.), Japan Leukemia Research Fund (M.Y.) and Children's Cancer Association of Japan (M.Y.) and Kawano Masanori Memorial Foundation for Promotion of Pediatrics (M.Y.).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Steroid-resistance is a common complication in the treatment of malignancies and autoimmune diseases. IL-7/IL-7R signaling, which regulates lymphocyte growth and survival, has been implicated in the development of malignancies and autoimmune diseases. However, the biological significance of IL-7/IL-7R signaling in steroid treatment is poorly understood. Here, we identified a novel relationship between IL-7R signaling and steroid-resistance, and showed that an anti-IL-7R antibody conjugated with SN-38 (A7R-ADC-SN-38) has strong anti-tumor effects against both parental and steroid-resistant malignant cells. Furthermore, inflammation in the mouse autoimmune arthritis model was suppressed to greater extent by A7R-ADC conjugated to MMAE than by A7R-ADC-SN-38. Given that an increased proportion of IL-7R-positive cells is a common mechanism underlying the pathogenesis of autoimmunity, we found that specific depletion of this cell population abrogated the progression of disease. This suggests that the cytotoxicity and immunosuppressive capacity of A7R-ADC could be modulated to treat specific malignancies or autoimmune diseases through the introduction of different payloads, and represents a novel alternative to steroid therapy.
AB - Steroid-resistance is a common complication in the treatment of malignancies and autoimmune diseases. IL-7/IL-7R signaling, which regulates lymphocyte growth and survival, has been implicated in the development of malignancies and autoimmune diseases. However, the biological significance of IL-7/IL-7R signaling in steroid treatment is poorly understood. Here, we identified a novel relationship between IL-7R signaling and steroid-resistance, and showed that an anti-IL-7R antibody conjugated with SN-38 (A7R-ADC-SN-38) has strong anti-tumor effects against both parental and steroid-resistant malignant cells. Furthermore, inflammation in the mouse autoimmune arthritis model was suppressed to greater extent by A7R-ADC conjugated to MMAE than by A7R-ADC-SN-38. Given that an increased proportion of IL-7R-positive cells is a common mechanism underlying the pathogenesis of autoimmunity, we found that specific depletion of this cell population abrogated the progression of disease. This suggests that the cytotoxicity and immunosuppressive capacity of A7R-ADC could be modulated to treat specific malignancies or autoimmune diseases through the introduction of different payloads, and represents a novel alternative to steroid therapy.
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U2 - 10.1038/s41598-017-11255-4
DO - 10.1038/s41598-017-11255-4
M3 - Article
C2 - 28878234
AN - SCOPUS:85028912085
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 10735
ER -
