7S4G

Fab fragment bound to the Cter peptide of Ly6G6D

Summary for 7S4G

• Entry DOI: 10.2210/pdb7s4g/pdb
• Descriptor: heavy chain Fab 1G4, light chain Fab 1G4, Lymphocyte antigen 6 complex locus protein G6d, ... (6 entities in total)
• Functional Keywords: leukocyte antigen-6, signaling protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 12
• Total formula weight: 197392.36

Authors

Rouge, L.,Lupardus, P. (deposition date: 2021-09-08, release date: 2022-04-13, Last modification date: 2023-10-18)

Primary citation

Wang, P.,Sun, L.L.,Clark, R.,Hristopoulos, M.,Chiu, C.P.C.,Dillon, M.,Lin, W.,Lo, A.A.,Chalsani, S.,Das Thakur, M.,Zimmerman Savill, K.M.,Rouge, L.,Lupardus, P.,Piskol, R.,Husain, B.,Ellerman, D.,Shivva, V.,Leong, S.R.,Ovacik, M.,Totpal, K.,Wu, Y.,Spiess, C.,Lee, G.,Leipold, D.D.,Polson, A.G.
Novel Anti-LY6G6D/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Colorectal Cancer.
Mol.Cancer Ther., 21:974-985, 2022

PubMed Abstract: New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair-deficient or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell-dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB-mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.

PubMed: 35364611
DOI: 10.1158/1535-7163.MCT-21-0599

Experimental method

X-RAY DIFFRACTION (2.2 Å)