Abstract 4189: BALB/c-hIL12RB1/hIL12RB2: A robust model for preclinical research in human IL-12 therapy

Abstract Interleukin-12 (IL-12) is a multifaceted cytokine primarily produced by antigen-activated dendritic cells, macrophages, and neutrophils. Its receptor is a composite of IL12RB1 and IL12RB2, and the union of these two subunits forms a high-affinity receptor complex proficient in mediating IL-12 signaling. As a pivotal regulator of innate and adaptive immunity, IL-12 plays a crucial role in steering the differentiation of naïve T cells into Th1 cells. It is renowned as a T cell stimulatory factor, fostering T cell proliferation. Furthermore, IL-12 has the capacity to augment the activation of cytotoxic lymphocytes and natural killer cells (NK), thereby enhancing interferon (IFN-γ) production. Empirical evidence consistently demonstrates that IL-12 synergistically exerts anti-tumor effects in conjunction with various immune cells, such as T cells and NK cells. Its effectiveness in preclinical studies has solidified IL-12 as an appealing drug target, leading to the development of activating antibodies, therapeutic IL-12 proteins, and tumor vaccines as potential treatments. To delve deeper into the functionality and therapeutic potential of IL-12, we have engineered a humanized mouse model, known as BALB/c-hIL12RB1/hIL12RB2. Notably, this model fully preserves the intracellular domains of mouse IL12RB1 and IL12RB2 proteins, ensuring the normal propagation of intracellular signaling. It also effectively expresses human IL12RB1 and IL12RB2. In vitro functional validation experiments have verified that BALB/c-hIL12RB1/hIL12RB2 mice can proficiently generate IFN-γ when induced by human IL-12. Furthermore, in vivo efficacy experiments have yielded compelling results. Intratumoral administration of human IL-12 mRNA in BALB/c-hIL12RB1/hIL12RB2 mice led to a significant suppression in the growth of CT26 tumors, culminating in complete tumor regression. Subsequent rechallenge experiments conducted after the discontinuation of treatment revealed no tumor recurrence, signifying the enduring inhibitory effect of hIL12 mRNA on mouse tumors. In conclusion, the development of BALB/c-hIL12RB1/hIL12RB2 mice stands as a robust model for advancing preclinical research in the realm of human IL-12 therapy. Citation Format: Yuan Fang, Huiyi Wang, Jun Xing, Lu Yang, Jing Zhao, Xiang Gao, Cunxiang Ju. BALB/c-hIL12RB1/hIL12RB2: A robust model for preclinical research in human IL-12 therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4189.