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

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-? 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.

SUBMITTER: Jung K

PROVIDER: S-EPMC5993495 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Heterodimeric Fc-fused IL12 shows potent antitumor activity by generating memory CD8<sup>+</sup> T cells.

Jung Keunok K Ha Ji-Hee JH Kim Jung-Eun JE Kim Jeong-Ah JA Kim Ye-Jin YJ Kim Chul-Ho CH Kim Yong-Sung YS

Oncoimmunology 20180306 7

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 ...[more]

PMID: 29900039

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Project description:Tumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (K D) mainly varying in their dissociation rates (k off) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (K D = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (K D = 0.54 or 46 nM) due to the slow k off from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (K D = 130 nM) and a faster k off. The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4+ and CD8+ T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.

Dataset Information

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

Publications

Heterodimeric Fc-fused IL12 shows potent antitumor activity by generating memory CD8<sup>+</sup> T cells.

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Dataset Information

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

Publications

Heterodimeric Fc-fused IL12 shows potent antitumor activity by generating memory CD8<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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