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-γ 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:

• anti-tumor therapy
• Interleukin 12
• large established immunogenic tumors
• Immunoglobulin heterodimeric Fc
• Inflammation and cancer
• Models of immunostimulation
• monovalent binding format
• memory CD8⁺ T cells
• Therapeutic antibodies

Disclosure of potential conflicts of interests

Y.S.K., J.H.H., and K.J. are listed as inventors on pending patent applications related to the technology described in this work. J.A.K., Y.J.K., and C.H.K. declare no competing financial interests.

Acknowledgments

We thank Chan-Yuil Kang for providing the CT26-HER2/neu colon cancer cells. This work was supported by grants from the Pioneer Research Center Program (2014M3C1A3051470) and the Global Frontier Project (2013M3A6A4043874) from the National Research Foundation (NRF), and the Korea Health Technology R&D Project (HI16C0992) through the Korea Health Industry Development Institute (KHIDI), funded by the Republic of Korea.

Additional information

Funding

This work was supported by the Global Frontier Project from the National Research Foundation (2013M3A6A4043874). This work was supported by the Pioneer Research Center Program (2014M3C1A3051470). This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI16C0992).