EO-3021: An antibody drug conjugate targeting CLDN18.2 expressing cancers David Dornan, PhD Elevation Oncology, Inc. Institution Logo, if desired |
Disclosure Information David Dornan I have the following relevant financial relationships to disclose: Employee of: Elevation Oncology, Inc. Consultant for: ReviR Therapeutics, Inc., Teon Therapeutics, Inc. Stockholder in: Elevation Oncology, Inc. 2 I will discuss investigational use in my presentation: EO-3021/SYSA1801/CPO102 in the Treatment of CLDN18.2 Positive Advanced Malignant Solid Tumors |
Claudin 18.2 Expression Profile Confers Selectivity for Therapeutic Intervention 3 • Claudin 18.2 is part of a family of tight junction membrane proteins • Claudin 18.2 expression in normal tissues is restricted to the gastric mucosa with basolateral localization • During malignant transformation, changes in cell polarity may result in exposure of Claudin 18.2 • Claudin 18.2 is overexpressed in several types of cancers including gastric, pancreatic, esophageal, ovarian, and lung • Claudin 18.2 expression has minimal overlap (<20%) with HER2 or PD-L1 expression in gastric cancer • No approved therapies targeting Claudin 18.2 Adenocarcinoma of the Esophagus CLDN18.2 Immunohistochemistry Gastric Cancer Normal Stomach Mucinous Ovarian CLDN18.1 CLDN18.2 Tissue Distribution RT-PCR Turechi et al. (2011) Sahin et al. (2008) Claudin 18.2 |
Estimated Incidence of Claudin 18.2 in Solid Tumors Estimated New Cancer Cases Claudin 18.2 expression per disease type (IHC) Cancer Type US Incidence1 Global Incidence2 Gastric 26,500 1,090,000 77%3 (adenocarcinoma) Esophageal 21,500 604,000 78%3 (adenocarcinoma) Pancreatic 64,000 496,000 59-80%3-5 (PDAC) Ovarian 20,000 314,000 24%3 (mucinous) Lung 238,000 2,207,000 6%6 (adenocarcinoma) 1Siegel RL, et al. CA: A Cancer Journal for Clinicians. 2023; 73:1. 2Sung H. et al. CA: A Cancer Journal for Clinicians. 2020; 71:3. 3Sahin, et al. Clin Cancer Res. 2008 1;14(23):7624-34. 4Wöll et al. Int J Cancer. 2014; 134(3). 5Tanaka, et al. J Histochem Cytochem. 2011; 59(10): 942–952. 6Micke, et al. Int J Cancer. 2014;135(9):2206-14. *Any level of expression (e.g., ≥1% cells with any staining intensity of CLDN18.2) Abbreviations: US, United States; IHC, Immunohistochemistry; PDAC, Pancreatic ductal adenocarcinoma 4 |
Examples of CLDN18.2 Targeted Therapy Modalities Monoclonal mAbs Bispecific mAbs CAR T-cell Antibody Drug Conjugates zolbetuximab FL-301 AMG-910 (CD3) FL-302 (CD137) PT886 (CD47) Q-1802 (PD-L1) TJ033721 (4-1BB) CT041 LCAR-C18S LY011 EO-3021/SYSA1801/CPO102 CMG901 RC118 LM302 SOT102 SKB315 TORL-2-307 JS107 IBI343 5 Not an exhaustive list of all publicly disclosed programs Abbreviations: mAb, monoclonal antibody |
Mechanism of Action for Antibody Drug Conjugates Modified from Tong et al. (2021) https://doi.org/10.3390/molecules26195847 6 |
EO-3021 Molecular Structure ▪ EO-3021 mAb Heavy Chain EVQLSESGGALVQPGESLRLSCAASGFTFSSYAMTWVRQAPGKGLEWVSSLSGSGRSTYYAASIKGRFTISRDNSKNTLYLQMSSLRAE DTAIYYCAKSLSYYHYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK ▪ EO-3021 mAb Light Chain DIQLTQSPSFLSASVGDRVPITCRASQDISNYLAWYQQKPGKAPKLLIYSASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYHCQQVK TYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC DO NOT POST 7 |
EO-3021 mAb is Specific for CLDN18.2 over CLDN18.1 Cell Binding Activity EO-3021 mAb: • Fully Human mAb • IgG1 Isotype • Kd = 0.6 nM for CLDN18.2 • No binding to CLDN18.1 10 -1 10 0 10 1 10 2 10 3 10 4 10 5 0 5000 10000 15000 20000 25000 HEK293-CLDN18.1 HEK293-CLDN18.2 Test article concentration (ng/ml) Binding activity (MFI) Test Article Concentration (ng/ml) EO-3021 Binding (MFI) CLDN18.2 ECL1 CLDN18.1 ECL1 8 HEK293-CLDN18.2 HEK293-CLDN18.1 Abbreviations: ECL1, Extracellular Loop 1; ECL2, Extracellular Loop 2; IgG1, immunoglobulin G1; TM, Transmembrane |
EO-3021 is ADCC and CDC Competent: Modest Differences Relative to Unconjugated mAb ADCC CDC EC50 = 113 ng/ml EC50 = 39 ng/ml 10 -1 10 0 10 1 10 2 10 3 10 4 10 5 0 1 2 3 4 5 EO-3021 mAb EO-3021 Test Article Concentration (ng/ml) CDC Activity (OD490) Test Article Concentration (ng/ml) 10 Relative CDC Activity (OD490) -2 10 0 10 2 10 4 10 6 0 1500 3000 4500 6000 7500 9000 Test Article Concentration (ng/ml) ADCC Activity (RLU) EO-3021 mAb EO-3021 EC50 = 168 ng/ml EC50 = 99.7 ng/ml Test Article Concentration (ng/ml) Relative ADCC Activity (RLU) HEK293-CLDN18.2 + Jurkat/FCGR3A-NFAT CHO-K1-CLDN18.2 + human serum complement 9 EO-3021 mAb EO-3021 EO-3021 mAb EO-3021 Abbreviations: ADCC, antibody dependent cellular cytotoxicity; CDC, complement dependent cytotoxicity |
EO-3021-Mediated Endocytosis and Reduction of Cell Viability is Dependent on CLDN18.2 Expression Endocytosis of Fluorescent Labeled EO-3021 EO-3021 Impact on Cell Viability IC50 = 100 ng/ml HEK293 HEK293-CLDN18.1 HEK293-CLDN18.2 HEK293-CLDN18.1 HEK293-CLDN18.2 HEK293 Cell Viability (RFU) EO-3021 Tx (2 mg/ml) labeled with Zenon pHrodo iFL, 24-hour incubation EO-3021 Tx (varying concentration), 72-hour incubation, resazurin assay Test article (ng/ml) 10 |
EO-3021 EO-3021 mAb 10 -1 10 0 10 1 10 2 10 3 10 4 0 10000 20000 30000 40000 50000 SYSA1801 SYSA1801 mAb Test Article Concentration (ng/ml) Relative Fluorescence Unit (RFU) EO-3021 in vitro Activity More Notable in Cell Lines with Medium or High Levels of CLDN18.2 Expression Pancreatic Cancer BxPC3-18.2 CLDN18.2 High Gastric Cancer NCI-N87-18.2 CLDN18.2 Medium HER2 Amplified Test article (ng/ml) Test article (ng/ml) EC50 = 28 ng/ml Pancreatic Cancer PATU8988S CLDN18.2 Low Cell Viability (RFU) Cell Viability (RFU) Approximately 15% of CLDN18.2 expressing gastric cancers co-express HER27 Test article (ng/ml) EC50 = 132,725 ng/ml Cell Viability (RFU) 10 -5 10 0 10 5 10 10 0 10000 20000 30000 40000 50000 EO-3021 EO-3021 mAb Test Article Concentration (ng/ml) Relative Fluorescence Unit (RFU) EC50 = 7 ng/ml 11 7Schuler MH et al. J Clin Oncol. 2017. 35:15_suppl 4038-4038. |
EO-3021 Promotes G2/M Cell Cycle Arrest and Activates Caspase 3/7 Cell Cycle Distribution Post-Tx Caspase 3/7 Activity Post-Tx BxPC3-CLDN18.2, 600 ng/ml Tx, 66+3 hours BxPC3-CLDN18.2, 24+3 hours Vehicle EO-3021 mAb EO-3021 mAb EO-3021 G1 Test article (ng/ml) Caspase 3/7 Activity (RLU) Cell Cycle Distribution 12 EO-3021 S G2/M |
EO-3021 Demonstrates Bystander Effect on CLDN18.2 Negative Cells HEK-293-Luc cells co-cultured with either BxPC3-CLDN18.2 (Ag positive) or BxPC3 (Ag negative) cells and Tx for 96 hours 13 Abbreviations: Ag, antigen 200 1000 5000 0 5×10 5 1×10 6 1.5×10 6 2×10 6 EO-3021 (ng/ml) HEK293-Luc Cell Viability (RLU) HEK293-Luc cells + BxPC3-CLDN18.2 cells HEK293-Luc cells + BxPC3 cells |
Single Dose of EO-3021 Confers Tumor Regressions in CLDN18.2 High Expressing Xenograft Model BxPC3-CLDN18.2 Pancreatic Xenograft Model CLDN18.2 High Nu/nu mice were administered single dose of Tx, unless otherwise indicated. Dosing initiated on Day 0. 14 0 5 10 15 20 25 30 0 300 600 900 1200 1500 Vehicle EO-3021 2 mg/kg EO-3021 4 mg/kg EO-3021 8 mg/kg EO-3021 mAb 8 mg/kg Gemcitabine 50 mg/kg biw x8 Time (days) Tumor Volume (mm 3 ) |
Single Dose of EO-3021 Confers Tumor Regressions in CLDN18.2 Medium Expressing Xenograft Model NUGC4-CLDN18.2 Gastric Xenograft Model CLDN18.2 Medium, HER2 Amplified Nu/nu mice were administered single dose of Tx, unless otherwise indicated. Dosing initiated on Day 0. 15 0 5 10 15 20 0 250 500 750 1000 1250 1500 EO-3021 mAb 4 mg/kg Vehicle EO-3021 0.5 mg/kg EO-3021 1 mg/kg EO-3021 2 mg/kg EO-3021 4 mg/kg Cisplatin 6 mg/kg qw x3 Time (days) Tumor Volume (mm 3 ) |
Single Dose of EO-3021 Confers Tumor Regressions in CLDN18.2 Low Expressing Xenograft Model Nu/nu mice were administered single dose of Tx, unless otherwise indicated. Dosing initiated on day 0. 16 0 5 10 15 20 25 30 0 100 200 300 400 500 Time (days) EO-3021 20 mg/kg EO-3021 10 mg/kg EO-3021 9 mg/kg qw x3 EO-3021 6 mg/kg qw x3 EO-3021 3 mg/kg qw x3 EO-3021-mAb 9 mg/kg qw x3 Gemcitabine 50 mg/kg qw x3 Vehicle Tumor Volume (mm 3 ) PATU8988S Pancreatic Xenograft Model CLDN18.2 Low |
Nonclinical Toxicology and PK Summary of EO-3021 ▪ EO-3021 mAb is cross reactive with major toxicology species ▪ NHP PK is dose proportional with t1/2 ~7 days ▪ General toxicology profile across species (cyno and rat) is consistent with either MMAE payload or CLDN18.2 targeting in the stomach ▪ Pharmacology/toxicology integrated data suggest EO-3021 can achieve doses in humans that result in anti-tumor activity EO-3021 mAb Cross Reactivity Test article (ng/ml) EO-3021 Binding (MFI) 17 Mouse CLDN18.2 Cynomolgus CLDN18.2 Human CLDN18.2 Rat CLDN18.2 Abbreviations: MMAE, monomethyl auristatin E; NHP, non-human primates; PK, pharmacokinetics; t½ , half-life |
B A S E L I N E W E E K 2 4 EO-3021/SYSA1801 Activity in a Patient with Gastric Cancer ● Patient: 47-year-old female with gastric cancer ● Metastases: lymph nodes ● Prior therapy: XELOX (oxaliplatin + capecitabine) with immunotherapy ● EO-3021 treatment: 1.0 mg/kg IV Q3W x 12 cycles (ongoing) ● Target Lesion: Retroperitoneal lymph node ● RECIST v1.1: Best overall response of confirmed partial response (66.7% maximal tumor reduction) ● Duration of response: ~11 months (ongoing) ● Clinical Trial: Phase I (NCT05009966) -100 -80 -60 -40 -20 0 20 40 0 1 2 3 4 5 6 7 8 9 10 11 12 T A R G E T L E S I O N C H A N G E F R O M B A S E L I N E ( % ) T I M E F R O M S T A R T O F T R E A T M E N T ( M O N T H S ) P R P R P R P R ( o n g o i n g ) P R Progressive disease Partial response P R 18 EO-3021 is under investigation in a clinical trial and has not been approved for any indication by a regulatory administration Image courtesy of Peking University Cancer Hospital & Institute |
EO-3021 Summary ▪ Antibody drug conjugate composed of a fully human IgG1 CLDN18.2 selective mAb conjugated at Q295 with a vcMMAE linker payload to give DAR2 ▪ Promotes cell killing of cell lines expressing CLDN18.2 and a consequential bystander effect on CLDN18.2 negative cells ▪ Robust in vivo activity in xenografts with varying levels of CLDN18.2 • Single dose tumor regressions in models with varying levels of CLDN18.2 with a lower minimal efficacious dose in models with medium and high levels of CLDN18.2 relative to models with low CLDN18.2 ▪ Pharmacology/toxicology integrated data suggest EO-3021 can achieve doses in humans that results in anti-tumor activity ▪ Confirmed PR (66.7% reduction) with 11 months (and ongoing) duration of response in a patient living with metastatic gastric cancer in an ongoing Phase I clinical trial (NCT05009966) ▪ Elevation Oncology sponsored Phase I trial to initiate in US 2H 2023 19 |
Acknowledgements CSPC ▪ Mo Dan ▪ Xiwu Hui ▪ Yancui Wang ▪ Can Yuan ▪ Yang Zhang ▪ Xiaoyan Wang ▪ Charles Wang Elevation Oncology ▪ Thomas O’Hare ▪ Jaya Srivastava ▪ Valerie Jansen ▪ Shawn Leland ▪ Joe Ferra Peking University Cancer Hospital & Institute ▪ Yakun Wang ▪ Jifang Gong ▪ Lin Shen |