Abstract B014: Characterization of Nectin-4 protein expression in non-small cell lung cancer patients
Authors: Santos Sean M , Darlington Emma , Woodhouse Laura , Peters Niamh , Peat Erin , De Rienzo Assunta , Smale Rob , Watson Shawn , Blakemore Stephen , Carter Louise , Campbell Carly 
Published: December 2023

Nectin-4, a cell adhesion molecule from the Nectin-like family, is a validated tumor target overexpressed on the surface of cells in several cancers. Using Bicycles, a novel class of fully synthetic, short, constrained peptides, we are developing Bicycle Toxin Conjugates® (BTCs) and Bicycle Tumor-Targeted Immune Cell Agonists (Bicycle TICAs) that target Nectin-4 expressing tumors. BT8009 is a BTC™ which consists of a bicyclic peptide targeting Nectin-4 linked to the cytotoxin monomethyl auristatin E (MMAE) via a molecular spacer and cleavable linker. BT7480 is a Bicycle TICA™ that binds Nectin-4 on tumor cells and CD137 on immune cells to induce CD137 mediated immune agonism. Both BT8009 and BT7480 are currently under investigation in clinical trials, BT8009-100 (NCT04561362) and BT7480-100 (NCT05163041), respectively. To identify tumors expressing Nectin-4, we previously developed a proprietary Nectin-4 monoclonal antibody to measure its protein expression in an immunohistochemistry (IHC) assay. In collaboration with The Christie Hospital & The Manchester Cancer Research Centre Biobank (MCRC), we performed Nectin-4 IHC on tissue microarrays (TMAs) consisting of tumor biopsies from 59 non-small cell lung cancer (NSCLC) patients, including 4 longitudinal pairs, and 10 synchronous primaries with an average of 4 cores per tissue. A pathologist manually scored the TMAs for Nectin-4, evaluating both H-score and tumor proportion score (TPS) independently in the tumor cell membrane and tumor cytoplasm. Given the high degree of heterogeneity observed across multiple TMA cores from a single sample, Nectin-4 positivity was defined as a tumor proportion score (TPS) &gt; 1 in either the tumor membrane or tumor cytoplasm, in at least 1 core. In samples collected around diagnosis, 69.5% of patients were positive for Nectin-4. In the 4 longitudinal pairs, all samples were Nectin-4 positive at the later timepoint. No statistically significant differences were observed in Nectin-4 positivity when analyzed by grade (grade 1 66.6% (n=6), grade 2 88.9% (n=9), grade 3 69.7% (n=33)), stage (stage I 75% (n=24), stage II 75% (n=16), stage III 64.3% (n=14), stage IV 40% (n=5)) or morphology (adenocarcinoma 65.2% (n=23), squamous cell carcinoma 77.4% (n=31)) when compared using Fisher’s exact test. A similarly high percent of Nectin-4 positivity was observed when comparing samples across demographic and mutational data. The high percent of Nectin-4 positivity observed in NSCLC supports the inclusion of this indication in Bicycle's BT8009-100 and BT7480-100 studies.

Citation Format: Sean M Santos, Emma Darlington, Laura Woodhouse, Niamh Peters, Erin Peat, Assunta De Rienzo, Rob Smale, Shawn Watson, Stephen Blakemore, Louise Carter, Carly Campbell. Characterization of Nectin-4 protein expression in non-small cell lung cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B014.