骨髄系細胞および樹状細胞は、ヒト化genO-BRGSF-HIS前臨床モデルにおいて、治療薬誘発性サイトカイン放出症候群の症状を増強する

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Predicting the potential toxicity of therapeutics, including the systemic inflammatory response known as cytokine release syndrome (CRS), is of utmost importance in drug discovery.  

Immunodeficient mice reconstituted with a human immune system (HIS) have proved useful for the study and prediction of CRS in preclinical settings. HIS mice can be obtained from reconstitution of immunodeficient mice with adult peripheral blood mononuclear cells (PBMC) or human umbilical cord blood CD34⁺ cells. PBMC-HIS mice were previously shown to be responsive to CRS-inducing OKT3 treatment, whereas CBC-reconstituted NSG-HIS mice were described as unresponsive.⁽¹⁾ However, the PBMC-HIS mice immune system is composed of mature adult immune cells specific to the donor’s immune history, which can greatly impact, and bias, immune responses. It was previously shown that BRGSF mice reconstituted withCD34⁺ cells show systematic and persistent presence of plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), monocytes/macrophages, and neutrophils, and that their myeloid compartment can be boosted by hFlt3L treatment.⁽²⁾ In this boosted model, the absolute and relative numbers of monocytes/macrophages, pDCs, and cDCs are increased not just in the bone marrow and spleen but also systemically.

In a brand-new paper recently accepted for publication in Frontiers of Immunology (resulting from our collaboration with Sensei Biotherapeutics, and CrownBioscience), we used genO-BRGSF-HIS mice to investigate CRS-like traits triggered by different classes of biologics, and assess the potential contribution of myeloid cells in this process.

Upon injection with anti-CD3 antibody (OKT3), CD34⁺-reconstituted genO-BRGSF-HIS mice displayed hallmark features of CRS, specifically inflammatory cytokines release, modifications of immune cell distribution and activation, body weight loss, and temperature drop. Interestingly, myeloid-boosted mice displayed enhanced CRS features, revealing a significant role of myeloid cells in this process. Moreover, OKT3-induced CRS could be attenuated by anti-TNF-α (infliximab) treatment. Comparison of OKT3 treatment’s effect on CD34⁺- and PBMC-reconstituted genO-BRGSF-HIS mice showed broadened CRS features, namely a wider spectrum of myeloid-associated cytokines and depletion of cDCs, in CD34⁺-reconstituted mice. Finally, we further determined that CD34⁺-reconstituted genO-BRGSF-HIS mice developed CRS-like traits upon injection of blinatumomab, a bispecific T-cell engager targeting CD3 and CD19⁽³⁾, or myeloid-targeting anti-hVISTA (V-domain Ig suppressor of T-cell activation) antibody JNJ⁽⁴⁾, both known to induce CRS in patients.^{(5, 6)}

Taken together, these data show that myeloid cells enhance CRS-features in genO-BRGSF-HIS mice, confirming a significant role of these cells in CRS development. They also demonstrate that these mice, reconstituted with human umbilical cord blood CD34⁺ cells, represent a valuable tool for CRS assessment of a variety of compounds targeting the lymphoid and/or myeloid compartment, exhibiting the versatility of the genO-BRGSF-HIS model for therapeutics-induced safety assessment.

The genO-BRGSF-HIS model is available at genOway, designer and provider of multiple preclinical models in several research areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.

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References:‍

1. Matas-Cespedes A, BrownL, Mahbubani KT, Bareham B, Higgins J, Curran M, et al. Use of human splenocytes in an innovative humanised mouse model for prediction of immunotherapy-induced cytokine release syndrome. Clin Transl Immunology.2020;9(11):e1202.
2. Lopez-Lastra S, Masse-Ranson G, Fiquet O, Darche S, Serafini N, Li Y, et al. A functional DC cross talk promotes human ILC homeostasis in humanized mice. Blood Adv. 2017;1(10):601-14.
3. Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science.2008;321(5891):974-7.
4. Yuan L, Tatineni J, Mahoney KM, Freeman GJ. VISTA: A Mediator of Quiescence and aPromising Target in Cancer Immunotherapy. Trends Immunol. 2021;42(3):209-27.
5. Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154-7.
6. Research J, Development L. A Study of Safety, Pharmacokinetics, Pharmacodynamics of JNJ-61610588 in Participants With Advanced Cancer. https://classic.clinicaltrials.gov/show/NCT02671955.