Abstract 1643: B-hIL12A/hIL12B/hIL12RB1/hIL12RB2: A novel animal model for generation of IL12 therapies

Abstract

Abstract The pro-inflammatory cytokine, interleukin 12 (IL12), is primarily responsible for cell-mediated immunity and is chiefly produced by antigen presenting cells. Prior preclinical studies elucidated a promising role for IL12 mediating anti-tumor effects, however, clinical studies using cancer patients showed disappointing efficacy results, as well as severe adverse effects, with administration of systemic IL12 therapies. Intriguingly, progress in targeted delivery to the tumor microenvironment renewed high expectations on IL12 as a promising anti-tumor drug either alone or in combination due to its ability to inhibit and/or reprogram immunosuppressive cell subsets. Therefore, to evaluate the efficacy of IL12 and IL12 analogs in preclinical studies, Biocytogen has successfully generated a novel hIL12A/hIL12B/hIL12RB1/hIL12RB2 knock-in mouse strain. In this mouse model, the full coding sequences (CDS) of the mouse Il12a or Il12b gene were replaced by their human counterpart IL12A or IL12B gene sequences respectively. In addition, chimeric CDS, composed of human IL12RB1 or IL12RB2 extracellular region plus mouse Il12rb1 or Il12rb2 cytoplasmic region, was inserted into the mouse endogenous gene locus in in these animals, to express an IL12 receptor (IL12R) capable of recognizing human IL12 signaling. Expression analysis by RT-PCR detected human IL12A/IL12B/IL12RB1/IL12RB2 mRNA in humanized mice but not in wild-type mice. Additionally, human IL12 p70 was successfully detected in the serum of humanized mice by ELISA. The immune cell subpopulations in spleen, blood, and lymph node did not differ between humanized mice and wild-type mice suggesting no impact on cell differentiation and maturation. Anti-tumor activity of a modified human IL12 was assessed in humanized mice bearing colon cancer MC38 cells and showed tumor inhibitory effects. Moreover, the tumor growth recovered when the administration of the drug was stopped. Altogether, B-hIL12A/hIL12B/hIL12RB1/hIL12RB2 humanized mice provide a promising preclinical efficacy model for human IL12 therapy alone or in combination. Keywords: IL12, humanized mice, antibody efficacy Citation Format: Linlin Wang, Chang Liu, Veronika Chromikova, Ruili Lyu, Tianquan Jin, Mari Kuraguchi. B-hIL12A/hIL12B/hIL12RB1/hIL12RB2: A novel animal model for generation of IL12 therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1643.