1124 Strong preclinical evidence for treatment efficacy of a novel immune checkpoint inhibitor (ICI) in melanoma that targets a rare heparan sulfate

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