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Regular and Young Investigator Award Abstracts
Biomarkers, Immune Monitoring and Novel Technologies
6 A novel IL12Rβ1 and IL12Rβ2 humanized mouse model for preclinical efficacy and toxicity evaluation of human IL-12 analogs
  1. Linlin Wang1,
  2. Jing Guo1,
  3. Meiqing Zhang1,
  4. Saina Ma1,
  5. Jiansu Zhang1,
  6. Xiaofei Zhou1 and
  7. Jianing Li2
  1. 1Biocytogen Pharmaceuticals, Beijing, China
  2. 2Biocytogen Boston Corp, Waltham, MA, USA

  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

Background Interleukin 12 (IL12), a heterodimer cytokine composed of IL12A (p35) and IL12B (p40), is mainly produced by dendritic cells and macrophages in response to antigenic stimulation. The receptor of IL-12 is a protein complex encoded by interleukin 12 receptor beta 1 (IL12Rβ1) and beta 2 (IL12Rβ2) genes. IL12 is a major regulator of both innate and adaptive immunity. It induces the proliferation and activation of cytotoxic lymphocytes and natural killer (NK) cells, stimulates the production of interferon (IFN)-γ, and promotes the differentiation and production of Th1-associated immunoglobulins. IL12 is a promising anti-tumor drug capable of transforming the tumor microenvironment from ‘cold’ to ‘hot’. However, unmodified IL12 may be ineffective and can cause severe immune-related adverse effects. Modified IL12 or its combination with other therapeutic agents may enhance efficacy and overcome safety challenges.

Methods A novel mouse model with knock-in (KI) of human IL12RB1 and IL12RB2 genes, named B-hIL12RB1/hIL12RB2 mice ad, was generated by crossing independently developed IL12RB1 and IL12RB2 single KI mice. To validate the functionality of the humanized IL12Rβ1 and IL12Rβ2 receptor complex, CD4+ T cells sorted from splenocytes of C57BL/6 and homozygous B-hIL12RB1/hIL12RB2 mice ad were stimulated with human IL-12 in vitro, and IFN-γ production was detected by ELISA. To evaluate the in-vivo toxicity of human IL-12 analogs, B-hIL12RB1/hIL12RB2 mice ad were treated with human IL12 daily for 3 days. Body weight was measured daily during treatment. Liver and spleen weights were measured at the endpoint of the experiment. Alanine transaminase (ALT) and aspartate transaminase (AST) levels in mouse serum were measured by ELISA 6-hour and 24-hour post last treatment.

Results Human IL12 induced the IFN-γ production by CD4+ T cells from homozygous B-hIL12RB1/hIL12RB2 mice ad, but not C57BL/6 mice. In the in-vivo toxicity study, human IL12 treatment increased the ratios of liver weight to body weight and spleen weight to body weight, as well as exhibited a tendency towards increased AST activity in B-hIL12RB1/hIL12RB2 mice ad.

Conclusions The humanization of the IL12RB1 and IL12RB2 genes was successful in B-hIL12RB1/hIL12RB2 mice ad, enabling evaluation of the efficacy and toxicity of human IL12 analogs.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2024-SITC2024.0006

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