Company: HURA
Filing Date: 2025-05-23
Form Type: 424B3
Source: 0001193125-25-125499
Chunk: 419

Company: TuHURA Biosciences, Inc./NV
Filing Date: 2025-05-23
Form: 424B3
Chunk 419
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to the microenvironment or inhibiting their production in the bone marrow. Another potential strategy is inhibiting MDSC-mediated immunosuppression by developing inhibitors to individual MDSC-related immune suppressing compounds such as IDO, iNOS or
COX2 inhibitors.

TuHURA’s Delta Opioid Receptor (DOR) inhibitors: bi-specific,bi-functional antibody peptide or drug conjugates (APC, ADCs)

The Delta Opioid Receptor, or DOR, is the first cloned G protein-coupled receptor. Many recent
studies on Delta Opioid Receptor functions have determined that the Delta Opioid Receptor is involved in the regulation of malignant transformation and tumor progression in multiple cancers. In hepatocellular carcinoma (HCC), higher expression of
Delta Opioid Receptor was observed in liver tumor tissue cells compared to normal liver tissue/cells. When DOR gene expression was silenced or inhibited, the proliferation of HCC ells was inhibited, and tumor cells underwent apoptosis, the cell
cycle was arrested and tumor cell invasion and migration.

While Delta Opioid Receptor overexpression and its role in tumor biology is
well established in the literature, the company believes that TuHURA, along with scientists at Moffitt Cancer Center, are the first to

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describe the high differential expression of the Delta Opioid Receptor on tumor associated MDSCs compared to bone marrow (BM) or spleen derived MDSCs either in tumor free or tumor bearing models.
(See Figures 1 and 2 below, courtesy of P Rodriguez, Moffitt Cancer Center).

As a previously unrecognized target to reprogram tumor
associated MDSCs immunosuppressive functions on the tumor microenvironment, developing small molecule or peptide antagonists of the Delta Opioid Receptor represents a novel approach to reprograming MDSC functionality to overcome acquired resistance
to checkpoint inhibitors and other cancer immunotherapies.

Inhibition of the Delta Opioid Receptor on tumor associated MDSCs is designed to block MDSC production of
multiple immunosuppressing factors through a single point of intervention. TuHURA’s bi-specific APCs consists of a patented peptidomimetic Delta Opioid Receptor specific inhibitor conjugated to a
checkpoint inhibitor like anti-PD-1 antibody. Moffitt Cancer Center scientists demonstrated that in Delta Opioid Receptor expressing,
PD-1 resistant murine lung cancer models treatment with its APC, accumulated in the tumor