NHS-IL12, a Tumor-Targeting Immunocytokine

Abstract

NHS-IL12 is a novel immunocytokine designed for delivery of IL-12 to the tumor microenvironment (TME). NHS-IL12 consists of two molecules of IL-12 fused to a human IgG1 (NHS76) recognizing DNA/histone complexes, which are often exposed in the necrotic portions of tumors. Preclinical studies demonstrated the tumor-targeting ability and longer plasma half-life for NHS-IL12 when compared with recombinant IL-12 (rIL-12). NHS-IL12 outperformed rIL-12 in enhancing the proliferation and activation of immune as well as antigen-presenting cells, resulting in a more robust primary immune response. NHS-IL12 also reduced the number and function of suppressive myeloid cells (myeloid derived suppressor cells/macrophages) within the TME. In a murine bladder tumor model, NHS-IL12 administration led to a coordinated increase in host immunity with a reduction of immunosuppressive myeloid cells in the TME resulting in substantial reduction in tumor growth. Several preclinical studies have demonstrated increased overall anti-tumor efficacy when NHS-IL12 was combined with either immune-based therapeutics or chemotherapeutic approaches.

Keywords:

• interleukin-12
• NHS-IL12
• immunotherapy
• cancer
• immuno-oncology
• review

Abbreviations

BMDC, bone marrow-derived dendritic cell; CTL; cytotoxic T lymphocyte; DC, dendritic cell; i.v., intravenous; LLC, Lewis lung carcinoma; MAb, monoclonal antibody; MDSC, myeloid derived suppressor cell; MTD, maximum tolerated dose; mu, murine; NK, natural killer; NKT, natural killer T cells; PBMC, peripheral blood mononuclear cell; s.c., subcutaneous; TCM, central memory T cell; TCR, T-cell receptor; TEM, effector memory T cell; Tg, transgenic; TIL, tumor-infiltrating lymphocyte; TME, tumor microenvironment; Treg, regulatory T cells.

Ethics Statement

Animal care was in compliance with the recommendations of The Guide for Care and Use of Laboratory Animals (National Research Council).

Acknowledgments

The authors thank Debra Weingarten for her editorial assistance in the preparation of this manuscript.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.