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Heterodimeric Fc-fused IL12 shows potent antitumor activity by generating memory CD8(+) T cells

Authors
Jung, K | Ha, JH | Kim, JE | Kim, JA | Kim, YJ | Kim, CH  | Kim, YS
Citation
Oncoimmunology, 7(7). : e1438800-e1438800, 2018
Journal Title
Oncoimmunology
ISSN
2162-40112162-402X
Abstract
Interleukin-12 (IL12) (p35/p40 complex) is a heterodimeric cytokine with potent anti-tumor activity. However, its short serum half-life and high dose-related toxicities limit its clinical efficacy. Here, we constructed heterodimeric immunoglobulin Fc-fused mouse IL12 (mIL12) in a monovalent binding format (mono-mIL12-Fc) to generate long-acting mIL12 in the naturally occurring heterodimeric form. Mono-mIL12-Fc exhibited a much longer plasma half-life than recombinant mIL12, enabling twice-weekly systemic injections to remove established tumors in syngeneic mouse models. Mono-mIL12-Fc was more potent than wild-type Fc-based bivalent-binding IL12-Fc (bi-mIL12-Fc) for eradicating large established immunogenic tumors without noticeable toxicities by enhancing interferon-gamma production and the proliferation of immune effector cells in tumors. More importantly, mono-mIL12-Fc triggered weaker IL12 signaling than bi-mIL12-Fc, favoring the generation of functional and protective memory CD8(+) T cells. Our results demonstrate that heterodimeric-Fc-fused IL12 is a suitable format for augmenting adaptive CD8(+) T cell immune responses, providing a practical alternative to the systemic administration of IL12 for antitumor therapy.
Keywords

DOI
10.1080/2162402X.2018.1438800
PMID
29900039
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Otolaryngology
Ajou Authors
김, 철호
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