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- W4366184450 abstract "We discovered the precise T-cell ligand of DC-HIL/Gpnmb to be a rare heparan sulfate (rHS) conserved between mice and human. We created a single-domain anti-rHS Ab (1A7) that inhibited melanoma growth in mice much more than anti-DC-HIL Ab. We next compared 1A7 Ab to the current industry standard for ICI, anti-PD1 Ab (pembrolizumab), using in vitro T-cell assays. Crosslinking of rHS+ receptors on T cells by 1A7 Ab inhibited CD3-induced proliferation 30x better than anti-PD1 Ab (IC50 15 nM vs 501 nM, n=4). Moreover, 1A7 Ab enhanced IFNγ response of allogeneic T cells in mixed lymphocyte reaction more than anti-PD1 Ab (2.5x vs 2.1x to control, n=5, p<0.01). We next used 3 humanized mouse models with little-to-no HLA-matched allogeneicity: (1) Immunodeficient mice bearing human SK-MEL-5/28 tumor were infused i.v. with human PBMC (5 expts) and treated i.p. twice weekly with 1A7 (20 μg/mouse) or PD1 Ab (200 μg/mouse). Note 1A7 MW is 10x less. 2-3 wk later 1A7 reduced tumor growth by 80% vs 55% for anti-PD1 Ab (p<0.001). (2) Similar mice bearing melanoma patient xenografts were treated with the 2 Ab (3 expts). 2 wk later 1A7 was associated with 0.5 cm3 tumors vs 0.6 cm3 for anti-PD1 Ab (p=0.02) vs 1.4 cm3 for control (p<0.001). (3) Finally, we used NOG-exl-hGM-SCF/hIL-3 mice transplanted with hCD34 stem cells capable of generating immune cell lineages including hCD3, CD19, CD33 and CD56 cells detected in blood by FACS. These mice were engrafted with SK-MEL-5/28 and treated weekly with the 2 Ab as before (2 expts, 8 mice/group). 5 wk later 1A7 was more potent than anti-PD1 Ab in reducing tumor size (123 mm3 vs 250 mm3 (p=0.06) vs 820 mm3 for control (p=0.0001), and in increasing intra-tumoral CD8 cells (1,020 cells/mm2 vs 806/mm2, p=0.2) vs 210/mm2for control (p=0.04). Combining 1A7 and anti-PD1 Ab had no additive effects. Our data strongly support development of anti-rHS platforms for treating melanoma patients." @default.
- W4366184450 created "2023-04-19" @default.
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- W4366184450 date "2023-05-01" @default.
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- W4366184450 title "1124 Strong preclinical evidence for treatment efficacy of a novel immune checkpoint inhibitor (ICI) in melanoma that targets a rare heparan sulfate" @default.
- W4366184450 doi "https://doi.org/10.1016/j.jid.2023.03.1136" @default.
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