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. 2024 Nov 4;15:1452537. doi: 10.3389/fimmu.2024.1452537

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Copyright © 2024 Gardell, Maurer, Childs, Pham, Meengs, Julien, Tan, Boster, Quach, Therriault, Hermansky, Patton, Bowser, Chen, Morgan, Gilbertson, Bogatzki, Encarnacion, McMahan, Crane and Swiderek

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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MTX-101 binding, efficacy, mechanism of action, and dose titration in acute graft-versus-host disease (GvHD) human PBMC-engrafted NSG mouse model. (A) Survival study experimental design. NSG mice were irradiated (0.75 Gy) and injected intravenously with 1 × 10⁷ human PBMC healthy donor 3578 (haplotype HLA-DQ2.5). MTX-101 (2 mg/kg) or saline was injected every 7 days until day 28. Low-dose IL-2 (25,000 IU) was injected every other day from study day (SD) 0 to 10, n = 20/cohort. (B) MTX-101 binding to CD4, CD8, and CD8 regulatory T-cell (Treg) populations as detected by mean fluorescence intensity (MFI) of anti-human Fc antibody in the blood on SD20, and spleens were collected on SD15 (MTX-101 and saline, n = 3 mice; IL-2, n = 2 mice) and at study termination (MTX-101 and saline, n = 6 mice). SD20 timepoint is representative of mice remaining in the MTX-101 (n = 8) and IL-2 treatments (n = 6). (C) CD25 and ICOS-positive CD8 non-Tregs and CD8 Tregs in peripheral blood as detected on SD9 and 15 (n = 10/cohort). CD8 Tregs and CD8 non-Treg Granzyme B MFI on SD20. nd: not determined. (D) Absolute counts of CD25+CD4 T cells/μL of blood on SD15 (MTX-101 and saline, n = 3 mice; IL-2, n = 2 mice). Ki67 MFI in CD4 T cells in peripheral blood on SD15. (A–D) p-Values were determined with an unpaired t-test. ns: p > 0.05, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. (E) Survival curve in the acute GvHD model (saline, MTX-101, and low-dose IL-2, n = 18/cohort). Survival curves were compared using the log-rank (Mantel–Cox) test. p=0.0043. (F–H) Human NSG mice engrafted with 1 × 10⁷ human peripheral blood mononuclear cells (PBMCs) following irradiation (0.5 Gy) from donor LZ0007 and dosed with increasing concentrations of MTX-101 intravenously every 7 days on SD0–SD21. (F) Binding of MTX-101 to CD4, CD8, and CD8 Tregs (KLRG1+ CD8 T cells) in the blood on SD14. Granzyme B (MFI and percentage) on non-Treg CD8 and CD8 Treg populations in the blood and spleens from mice that were terminated on study day 11 (n = 3 mice). (G) CD25-positive CD8 Tregs and Helios-positive CD8 T cells in peripheral blood on SD14 (n = 8) and all surviving mice on SD42. (H) Percentage of CD25+ and Annexin V+ CD4 T cells on SD42 in peripheral blood and splenocytes. (F–H) p-Values were determined by an unpaired t-test. ns: p > 0.05, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.