Work

7 Mice humanized for the immune system as validated tool for therapeutic antibody development

Year: 2026

Type: conference-abstract

Abstract: Background Preclinical evaluation of immunotherapies is often limited by the poor translational relevance of conventional animal models. Hence, there is a critical need for models that better recapitulate human immune response and relevant interactions between immune and cancer cells. Humanized mouse models have therefore emerged as powerful tools to bridge the gap between preclinical research and clinical outcomes.Methods Such humanized mice are developed by reconstituting the whole or a part of the immune system of immunodeficient animals with human immune cells from 2 possible origins: CD34 + hematopoietic stem cells (huCD34+ mice) isolated from cord blood, or mature peripheral blood mononuclear cells prepared from buffy coats (huPBMC mice). According to the compound to be tested and the goal of the research, one model may be preferred over the other.Results HuCD34 + mice exhibited multilineage reconstitution, including T, B, NK, and myeloid cells. We evaluated an efficient cytokine boosting strategy that significantly improved myeloid cell proportion, overcoming a key limitation of this model. Functional immune activation was confirmed in vivo through cytokine production and expression of Tcell activation markers. In a A375 melanoma model we evaluated the combination strategy of relatlimab (anti-LAG-3 antibody) and nivolumab (anti-PD-1 antibody) approved at the beginning of 2024 as a first-line treatment for specific melanoma indications. The combination strategy induced a significant decrease in tumor growth compared to single agents in line with the data observed in the RELATIVITY-047 clinical trial.1HuPBMC mice demonstrated efficient and dose-dependent engraftment of T-cells exclusively, with CD4 and CD8 proportions comparable to human circulation and effective tumor infiltration. Importantly, these models showed limited graftversushost disease over relevant study durations, enabling extended therapeutic windows. They proved particularly suitable for evaluating Tcell engagers (TCE). In a BT474-Clone5 breast cancer model, we showed dose-dependent efficacy of the CD3 x EpCAM bispecific antibody solitomab. However, T-cell engagers are limited by toxicity from sustained T-cell activation. Combining solitomab with a proprietary HER2 x CD2 bispecific antibody improved efficacy while reducing toxicity by lowering the required TCE dose.2Conclusions Humanized mouse models provide a powerful platform for evaluating therapeutic efficacy in a human immune context. HuPBMC models are optimal for rapid assessment of T-cell–driven mechanisms, whereas HuCD34 + models enable comprehensive immune system interrogation. Despite inherent limitations, ongoing refinements continue to enhance their translational relevance. Careful model selection is essential to align with the therapeutic modality and biological question, ultimately improving prediction of clinical outcomes.References Tawbi HA, et al. RELATIVITY-047 investigators. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. doi: 10.1056/NEJMoa2109970. PMID: 34986285; PMCID: PMC9844513.Danquah W, et al. Combination therapy with a novel CD2-targeted costimulatory bispecific antibody overcomes limitations of CD3 T cell engager treatment for solid tumors. MAbsss 2026 Dec 31;18(1):2684378. doi: 10.1080/19420862.2026.2684378. Epub 2026 Jun 10. PMID: 42271190; PMCID: PMC13271273.Ethics Approval All procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the European Council Directive (2010/63/UE) and were approved by the French Animal Ethical Committee (APAFIS#47793-2024022716325549 v2).

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0007