Fate Therapeutics Inc (FATE)

[jondoeuk]

(OT) Artec Biotech is built upon methods for differentiating iPSCs into NK cells, as well as proprietary modifications. One example is the alteration of checkpoint receptors, such as PD-1 KO, which will be used for ART-002. The lead is ART-001, an unmodified NK product.

Although iPSC-NKs and PB-NKs of the same donor exhibited similar gene expression profiles, analysis revealed notable differences in genes that are important for NK cell function. Some of these genes were highlighted. Given the success of checkpoint inhibition in treating certain types of cancer, they evaluated checkpoint receptor expression in iPSC-NKs compared to PB-NKs. As demonstrated by a recent study, the expression of multiple checkpoint inhibitors was significantly higher in CD73+ cells, and the frequency of CD73+ cells correlated with larger tumour size in breast cancer patients https://www.jci.org/articles/view/128895

In their differentiation system, they produced NKs with down-regulated CD73 expression.

The next gene of interest was PTGER4, which encodes prostaglandin E2 receptor 4 (EP4). In NK cells, the binding of prostaglandin E2 to the receptor can initiate immunosuppression. In contrast, EP4 inhibition has been shown to enhance NK antitumour activity https://www.tandfonline.com/doi/full/10.1080/2162402X.2021.1896643

EP4 was down-regulated.

TIGIT was another gene of focus. Although not expressed in iPSC-NKs, it was highly expressed in PB-NK control. Overall, TIGIT is variably expressed in human NKs. Notably, NKs with lower TIGIT expression have exhibited higher cytokine secretion capability, degranulation activity, and cytotoxic potential https://onlinelibrary.wiley.com/doi/10.1002/eji.201545480

Furthermore, blocking TIGIT expression via monoclonal antibodies alleviated NK exhaustion https://www.nature.com/articles/s41590-018-0132-0

Similar to TIGIT, cytokine-inducible Src homology 2–containing protein (CIS), encoded by the CISH gene, is also involved in cytokine secretion. CIS is a member of the suppressor-of-cytokine signaling family of proteins. CISH deletion in either iPSC-NKs or PB-NKs increases their sensitivity to IL-15 and enhances JAK/STAT and mTORC1 signaling. This leads to increased NK metabolic fitness that contributes to an improved antitumour response https://ashpublications.org/blood/article/137/5/624/463715/Targeting-a-cytokine-checkpoint-enhances-the

Their iPSC-NKs have significantly down-regulated CISH expression compared to PB-NKs.

Aside from direct mechanisms that tumours employ to down-regulate NK function, the tumour microenvironment also impairs NK function by negatively affecting NK metabolism https://www.frontiersin.org/articles/10.3389/fimmu.2019.02278/full

Enhancing NK metabolic functionality is currently being pursued as one of the avenues for increasing NK cell activity against tumours https://www.pnas.org/doi/10.1073/pnas.2107507118

Considering this, they further evaluated the metabolic profile of iPSC-NKs and PB-NKs. The assessment focused on significantly expressed genes, which impact NK metabolic function. The following genes showed up-regulation in iPSC-NKs: Slc2a1 (involved in glucose transport), Slc7a5 (an amino acid transporter), Slc3a2/CD98 (an amino acid transporter), and TFRC/CD71 (involved in receptor-mediated iron uptake). These data yield insight into the efficacy of iPSC-NKs because nutrient transport is essential and increased expression of nutrient transporters promotes an increased metabolic rate, as well as elevated NK activity https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02377-8