AACR 2021: Improved LAG-3 humanized knock-in mouse model for assessment of mono- and combination therapy strategies for cancer treatment

AACR 2021: Improved LAG-3 humanized knock-in mouse model for assessment of mono- and combination therapy strategies for cancer treatment

Author: Huilin Li, Xiaofei Zhou, Dirui Li, Veronika Chromikova, Qingcong Lin

In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. One of the potential therapeutic targets that seems increasingly attractive is LAG-3 (Lymphocyte activation gene 3, CD223), a human protein encoded by the LAG3 gene. LAG-3 can be found on activated T cells, NK cells, B cells and plasmacytoid DCs and serves as a negative regulator of immunity. Inhibition of LAG-3 enhances the antitumor effect of specific CD8+ T cells, which is an observation pursued by several pharmaceutical companies with their products in pre-clinical or early clinical development. Therefore, it is clear there is a need for suitable preclinical models able to accurately reflect the relevant physiological processes to evaluate the safety and efficacy of LAG3-targeted therapeutics. Biocytogen has generated a humanized LAG-3 mouse model for both in vitro functional validation and in vivo efficacy evaluation of anti-hLAG-3 antibodies. Subsequently, we built on this model further to also generate PD-1/PD-L1/LAG3 multi-gene humanized mice, in which blood cell composition, morphology and the levels of ALT, AST and other indicators were comparable to wild-type mice. This model is ideal to assess an increased therapeutic benefit in cancer treatment provided by combination therapies. Indeed, in our hands using the MC38 tumor model, the combination of anti-LAG-3 antibodies with anti-PD-1 (or anti-PD-L1) antibodies shows synergistic inhibitory effects, demonstrating that the PD-1/PD-L1/LAG3 humanized mice represent a powerful tool for preclinical assessment of in vivo efficacy of future therapeutics

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