Slide 1: CNTY-813: Scalable Production of Allo-Evasion 5.0-Engineered iPSC Islets
CNTY-813: Scalable Production of Allo-EvasionTM 5.0-Engineered iPSC Islets for Off-the-Shelf Cell Therapies G. Grant Welstead, PhD SVP, Head of Research
Slide 2: Disclosures
Disclosures Relevant Financial Relationship • Employee, Century Therapeutics Presentation Information Presenter • This presentation describes preclinical research related to G. Grant CNTY-813, an investigational iPSC-derived islet cell therapy for T1D Welstead, PhD • The content is intended for scie
Slide 3: Forward-looking statements
Forward-looking statements This presentation contains forward-looking statements within the meaning of, and made pursuant to the safe harbor provisions of, The Private Securities Litigation Reform Act of 1995. All statements contained in this presentation, other than statements of historical facts o
Slide 4: Islet cell transplantation provides potential for curative therapy in T1D
Islet cell transplantation provides potential for curative therapy in T1D In T1D, islet cells are destroyed Islet transplantation provides a potentially curative therapy for T1D Insulin independence following pancreatic islet transplantation Insulin independence Healthy islet achieved for one cells
Slide 5: CNTY-813 design integrates key capabilities for off-the-shelf T1D cell therapy
CNTY-813 design integrates key capabilities for off-the-shelf T1D cell therapy Differentiation Functional ALLO-EVASION 5.0 platform islets • Scalable iPSC-derived islet • Glucose-responsive insulin • T cell protection manufacturing secretion • NK cell protection • Reproducible islet • In vivo glucos
Slide 6: Generation of islets with a 29-day defined process
Generation of islets with a 29-day defined process High purity and reproducible across batches Definitive Primitive Pancreatic Pancreatic Endocrine β Cell Endoderm Gut Tube Progenitor I Progenitor II iPSC Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Stage 6 Stage 1 Stage 4 Stage 6 Stage 6 Definitive Endo
Slide 7: CNTY-813 islets contain defined, terminally differentiated endocrine cell populations
CNTY-813 islets contain defined, terminally differentiated endocrine cell populations scRNAseq Cell Type Annotations scRNAseq Cell Cycle Annotations Diff. Stage: iPSC 1 2 3 4 5 6 Population (30,151 total) Frequency β cells 66.3% FEV+ Islet Cells 26.4% ⍺ cells 5.5% δ cells 0.8% Exocrine/Ductal 1.0% •
Slide 8: CNTY-813 islet cells demonstrate robust glucose-responsive function
CNTY-813 islet cells demonstrate robust glucose-responsive function Nonclinical Potency Glucose Stimulated Insulin Secretion Stimulation Index Total Insulin Content 15 Index (20mM glucose/ 2mM glucose) Stimulation Index Glucose Stimualtion 2mM Glucose 40000 10 uIU Insulin/ 1E6 Cells 20mM Glucose 300
Slide 9: CNTY-813 islets rapidly restored normoglycemia in STZ-induced diabetic mice
CNTY-813 islets rapidly restored normoglycemia in STZ-induced diabetic mice Nonclinical Potency Non-Fasted Blood Glucose Glucose Tolerance Test Diabetic Control CNTY-813 600 CNTY-813 (SRC) resected (5M) - 12 weeks 500 Blood Glucose (mg/dL) CNTY-813 (SRC) (5M) - 49 weeks 400 300 200 Glucose 100 Contr
Slide 10: CNTY-813 grafts maintain endocrine identity with no evidence of tumorigenesis in mouse models
CNTY-813 grafts maintain endocrine identity with no evidence of tumorigenesis in mouse models Endocrine graft identity over time 2 weeks 4 weeks 8 weeks 24 weeks INS+ (green) CHGA+ (orange) Merged (yellow) Ki67+ ✓ Endocrine graft morphology maintained (pink) ✓ Stable Insulin and low Ki67 staining po
Slide 11: CNTY-813 is engineered to evade T cell, NK cell, and humoral responses
CNTY-813 is engineered to evade T cell, NK cell, and humoral responses ALLO-EVASION 5.0 IgG Cleavage CD8+ Reduces Fc binding Protection from T Cell and humoral activity Fc Deletion of HLA-I T cells No HLA-I Deletion of HLA-II Prevents recognition by CD8+ cells T cells NK cell NK cells Inse
Slide 12: CNTY-813 demonstrated protection from multiple immune effector mechanisms
CNTY-813 demonstrated protection from multiple immune effector mechanisms 01 NK-CELL Protection 02 IgG Cleavage 03 Protected from phagocytosis Reduced NK Cell Activation Rapid IgG Cleavage Reduced Antibody-Dependent 40 Phagocytosis (ADCP) WT **** **** **** DKO **** CD107a+ (%) 30 CTNY-813 NK 20 Acti
Slide 13: Employing a humanized mouse model to study allogeneic graft rejection
Employing a humanized mouse model to study allogeneic graft rejection Humanized Mouse Engrafted with Healthy Donor PBMCs NSG-MHC I/II DKO+/+ NSG-Tg(Hu-IL15)+/+ • Functional human T cells without GvHD (MHC DKO) – Supports longer study durations X • Supports engraftment and survival of human NK cells
Slide 14: Allo-Evasion 5.0 protected CNTY-813 from rejection in a humanized mouse model
Allo-EvasionTM 5.0 protected CNTY-813 from rejection in a humanized mouse model Glucose Stimulation Index Glucose Tolerance Test (GTT) (11 weeks post-islet infusion) (C-peptide induction over baseline) 600 15 Glucose-Stimulated Insulin Blood Glucose (mg/dL) Unedited Islets Unedited Islets Secretion
Slide 15: Phase 1 clinical manufacturing process established and executed from MCB across multiple batches
Phase 1 clinical manufacturing process established and executed from MCB across multiple independent batches MCB Thaw iPSC Expansion Bioreactor Differentiation Cryopreserved Intermediate Post-Thaw Maturation Final Fresh Product CHGA+ INS+NKX6.1+ Ki67+ Consistent final product flow cytometry profiles
Slide 16: Successful CNTY-813 engraftment in rat livers via portal vein injection
Successful CNTY-813 engraftment in rat livers via portal vein injection Vehicle Control CNTY-813 – H&E CNTY-813 – IF DAPI Chromogranin A HA HA BD Insulin BD BD HA HA HA BD BD BD BD PV CNTY-813 CNTY-813 CNTY-813 CNTY-813 aggregates are identified in Islets stain positive for chromogranin A the liver
Slide 17: Clinical-scale islets restored durable normoglycemia after 96-hours in cold storage
Clinical-scale islets restored durable normoglycemia after 96-hours in cold storage Clinical-scale product with 96-hour cold storage stability Islets manufactured at clinical scale retained full functionality after 96-hours in cold storage solution Rapid restoration of glycemic control Transplanted
Slide 18: CNTY-813 demonstrated reproducible differentiation, durable glucose control, and immune-evasive function
CNTY-813 demonstrated reproducible differentiation, durable glucose control, and immune-evasive function in preclinical models Differentiation Functional ALLO-EVASION 5.0 platform islets • Reproducible, bioreactor- • GSIS potency similar to • Engineered to reduce T-cell, enabled differentiation from
Slide 19: Acknowledgements
Acknowledgements Entire Century Team Mike Brehm & Lab – UMASS Chan School of Medicine and Diabetes Center of Excellence 19