TY - JOUR
T1 - A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy
AU - Quijano-Rubio, Alfredo
AU - Bhuiyan, Aladdin M.
AU - Yang, Huilin
AU - Leung, Isabel
AU - Bello, Elisa
AU - Ali, Lestat R.
AU - Zhangxu, Kevin
AU - Perkins, Jilliane
AU - Chun, Jung Ho
AU - Wang, Wentao
AU - Lajoie, Marc J.
AU - Ravichandran, Rashmi
AU - Kuo, Yun Huai
AU - Dougan, Stephanie K.
AU - Riddell, Stanley R.
AU - Spangler, Jamie B.
AU - Dougan, Michael
AU - Silva, Daniel Adriano
AU - Baker, David
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2023/4
Y1 - 2023/4
N2 - The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration. We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers. We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15—Neoleukin-2/15 (Neo-2/15)—both for trans-activating immune cells surrounding targeted tumor cells and for cis-activating directly targeted immune cells. In trans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models. In cis-activation mode, immune cell targeting of the two components selectively expanded CD8+ T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.
AB - The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration. We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers. We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15—Neoleukin-2/15 (Neo-2/15)—both for trans-activating immune cells surrounding targeted tumor cells and for cis-activating directly targeted immune cells. In trans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models. In cis-activation mode, immune cell targeting of the two components selectively expanded CD8+ T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.
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U2 - 10.1038/s41587-022-01510-z
DO - 10.1038/s41587-022-01510-z
M3 - Article
C2 - 36316485
AN - SCOPUS:85141001640
SN - 1087-0156
VL - 41
SP - 532
EP - 540
JO - Nature biotechnology
JF - Nature biotechnology
IS - 4
ER -