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• W4308394969 abstract "<h3>Background</h3> The PD-1/PD-L1 molecular pathway is one of the primary mechanisms of immune evasion deployed by cancer cells and several anti-PD-L1 monoclonal antibodies (mAbs) have been approved for the treatment of multiple cancers, including cancers of the GI tract and liver. In such cancers, one of the issues observed is broad-spectrum autoimmune toxicities, including pneumonitis, and others. primarily owing to their long systemic half-life. Therefore, small molecule inhibitors of PD-L1 with gut restricted exposure should potentially be able overcome these toxicities. JBI-1527 is a small molecule PD-L1 inhibitor with similar binding and mechanism of action as anti-PD-L1 antibodies that shows much higher exposure in gastrointestinal tract and liver as compared to plasma. It shows comparable efficacy as approved mAbs in preclinical studies. <h3>Methods</h3> Structure based drug design was used to design PD-L1 inhibitors; potency of these inhibitors was assessed in an in-vitro TR-FRET assay. Reporter assays and ex-vivo co-culture assays were used to assess T-cell proliferation and function. Pharmacokinetics studies were performed in multiple pre-clinical species to assess tissue distribution. In vivo efficacy was assessed in partially humanized mice efficacy models. <h3>Results</h3> JBI-1527 showed strong in vitro IC₅₀ of 2.9 nM in TR-FRET assay that measures interaction between PD-1 and PD-L1 and led to stabilization of PD-L1 protein as measured by thermal shift assay. This molecule also augmented T-cell co-inhibitory signalling as observed by Jurkat cell/SHP-1 assay. Competition study between anti-PD-L1 blocking antibody suggested that JBI-1527 finger-printing on PD-L1 is similar to mAbs. X-ray crystal structure studies clearly demonstrated that JBI-1527 caused dimerization of PD-L1. More importantly, JBI-1527 showed favourable gastrointestine localised pharmacokinetic profile with high exposure in colon, jejunum, duodenum, ileum (11 to >280 fold vs. plasma) as compared to plasma in preclinical species when dosed orally. JBI-1527 showed comparable efficacy to the anti-PD-L1 antibody Atezolizumab in hPD-L1/MC38 syngeneic and orthotopic models by oral administration and is well tolerated at efficacious doses. <h3>Conclusions</h3> Gastrointestine localised pharmacokinetic profile of JBI-1527 provides an attractive option to be used in the treatment of colon cancer, HCC and other GI-related cancers with minimal systemic toxicity as compared to mAbs." @default.
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• W4308394969 date "2022-11-01" @default.
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• W4308394969 title "1386 Novel gut-restricted small molecule inhibitor of PD-L1 for targeting GI cancers" @default.
• W4308394969 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1386" @default.
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