Slide 1: ZW1528: A Dual-Targeting Bispecific Antibody to Broadly Suppress Airway Inflammation
ZW1528: A Dual-Targeting Bispecific Antibody to Broadly Suppress Airway Inflammation by Inhibiting IL-4Ra and IL-33 Pathways Alexey Berezhnoy Director of Immunology Blair Hardman, Purva Bhojane, Robert Nechanitzky, Omar Kassas, Veronica Luu, Janessa Li, Yunfan Lyu, Tristan Philip, Kesha Patel, Andre
Slide 2: Azymetric – Adaptable to Different Formats and Applications
Azymetric – Adaptable to Different Formats and Applications Engineering Set of transferable mutations supporting pure and stable Fc heterodimer formation with exclusive chain pairing during Simultaneous Pathway 1 + 1 Formats co-expression Blockade Libraries of constant domain Fab mutations available
Slide 3: Differentiated Development of Multifunctional Therapeutics
Differentiated Development of Multifunctional Therapeutics Program Technology Target Indication Discovery Preclinical Phase 1 Phase 2 Phase 3 Solid Tumor Oncology: Antibody-Drug Conjugates (ADC) ZW191 Gynecolog ical Topo1i ADC | DAR 8 | Fc WT ZD0 6519 Payload FRα Thoracic NCT06555744 ZW220 Gynecolog
Slide 4: Bispecific Antibody Therapeutics as the Answer to Complex Biology of Autoimmune and Inflammatory Diseases
Bispecific Antibody Therapeutics as the Answer to Complex Biology of Autoimmune and Inflammatory Diseases Patients Clinical science Technology − Serious, difficult to treat diseases ＋ Clinically validated targets ＋ Clinically validated platform − Large patient population ＋ Benefits of combination ＋
Slide 5: Rationale for anti-IL-4Rα as an Anchor Arm
Rationale for anti-IL-4Rα as an Anchor Arm • Dupixent®/dupilumab is a highly successful mAb targeting IL-4Rα ▪ Approved for multiple atopic and inflammatory diseases • Blocking IL-4Rα inhibits both IL-4 and IL-13 signaling ▪ Two key cytokines responsible for driving Type II inflammation Anti-IL-4Rα
Slide 6: IL-33 as a Bispecific Arm in COPD and other Respiratory Diseases
IL-33 as a Bispecific Arm in COPD and other Respiratory Diseases • IL-33 is a tissue alarmin released in response to epithelial damage ▪ Acts on a range of cells e.g., neutrophils, Th2 cells, eosinophils, and mast cells • Initiates and amplifies inflammatory response / perpetuates chronic immune res
Slide 7: IL-4Rα x IL-33 Bispecific Provides Opportunity to Treat Broader Set of COPD Patients
IL-4Rα x IL-33 Bispecific Provides Opportunity to Treat Broader Set of COPD Patients with Single Molecule Anti-IL4Rα and anti-IL-33 therapeutics are being developed IL-4Rα x IL-33 bispecific provides opportunity to treat to treat different COPD populations broader set of COPD patients with single mo
Slide 8: ZW1528 IL-4Rα x IL-33 Bispecific
Design • Native IgG-like geometry; highly Anti-IL4Rα Anti-IL-33 manufacturable, compatible with half-life extending Fc modifications • Clinically-validated targets • Core arm mediates complete, prolonged IL-4Rα blockade. Second arm adds inhibition of IL-33, an upstream cytokine involved in perpetuat
Slide 9: ZW1528 Design and Proposed Mechanism of Action
ZW1528 Design and Proposed Mechanism of Action Dupilumab blocks IL-4Ra Itepekimab/tozorakimab block IL-33 Dual blockade by ZW1528 Type 2 inflammation suppression Type 2 and non-T2 inflammation suppression. • Aim at complete, prolonged blockade of IL-4Rα Improved tissue remodelling. Approved in asthm
Slide 10: ZW1528 Effectively Blocks both IL-4/13 and IL-33 Signaling
ZW1528 Effectively Blocks both IL-4/13 and IL-33 Signaling IL-33 blockade, OD620nm 1.5 IL-33 blockade, OD620nm 1.5 1.0 Blockade of IL-4/13 Blockade of IL-33 1.0 0.5 1.0 1.5 0.5 0.0 Anti-IL4Rα Anti-IL-33 IL-33 blockade, OD620nm IL-4 blockade, OD620nm 1.0 10-2 0 100 102 0.8 IL-4 blockade, OD620nm 0.0
Slide 11: ZW1528 Blocks Two Complementary Pathways of Airway Inflammation in Primary Cells of COPD Patients
ZW1528 Blocks Two Complementary Pathways of Airway Inflammation in Primary Cells of COPD Patients Blockade of IL-4 Blockade of IL-33 Anti-IL4Rα Anti-IL-33 • ZW1528 effectively blocks IL-4Ra and IL-33 in PBMC of _COPD patients_ in vitro • Enhanced blockade of IL-33 axis Making a Meaningful Difference
Slide 12: ZW1528 Demonstrates IgG-like PK and Blocks IL-4Rα in vivo
ZW1528 Demonstrates IgG-like PK and Blocks IL-4Rα in vivo Half-life extension (Tg32 mice PK) Suppression of IgE after inhaled allergen challenge Serum Concentration (ug/mL) 1000 subcutaneous inhaled 300 Serum IgE concentration, ug/mL 100 ZW1528 HDM treatment challenge 10 200 1 hIL-4/hIL-4Rα mice 0.1
Slide 13: ZW1528 Demonstrates Biomarkers of IL-4Rα/IL-33 Blockade in NHP
ZW1528 Demonstrates Biomarkers of IL-4Rα/IL-33 Blockade in NHP Pharmacokinetics IL-4Rα Receptor Occupancy Reduction of Serum IgE 1000000 1.0 NHP Serum IgE, Log2 Fold Change ZW1528 Iso type Pre-dose 48 hours Concentration (ng/mL) 100000 10000 0.5 1000 CD2 0 100 0.0 10 LLQ -0.5 0.1 0 50 100 150 200 an
Slide 14: ZW1528-mediated Blockade of Primary Cell Activation is Superior to Dupilumab and Itepekimab
ZW1528-mediated Blockade of Primary Cell Activation is Superior to Dupilumab and Itepekimab IL-33 and IL-13 activate human epithelial cells ZW1528 blocks activation HEKa IL-13/33 stim 4 Fold change of CCL2 (relative expression) 3 IL-13+IL-31 stim 2 1 0 IL-13 ted- -1+ 3 33- 3+3 3 3 3 3 a L L - 3/ 3/3
Slide 15: Summary: ZW1528, an IL-4Rα x IL-33 Bispecific Antibody
Summary: ZW1528, an IL-4Rα x IL-33 Bispecific Antibody has the Potential to be a Significant New Treatment Option for Patients with COPD ZW1528 potently blocks two complementary pathways of respiratory inflammation • dual blockade of IL-4Ra and IL-33, preliminary evidence of bispecific advantage ZW1
Slide 16: Multiple Therapeutic Programs Using Validated IL-4Rα Blocker
Multiple Therapeutic Programs Using Validated IL-4Rα Blocker Program Target Pair Target Validation 20 Japan Patients with Moderate-Severe Disease, 2024 (mln) ZW1528 Anti-IL4Rα approved in COPD 18 EU4+UK IL4Rα x IL-33 (2026 IND/CTA) Anti-IL33 in pivotal COPD phase 3 studies USA 16 0.7 ZW1572 Anti-IL4
Slide 17: ZW1572 IL-4Rα x IL-31 Bispecific
Design • Native IgG-like geometry; highly Anti-IL4Rα Anti-IL-31 manufacturable, compatible with half-life extending Fc modifications • Clinically-validated targets • Core arm mediates complete, prolonged IL-4Rα blockade. Second arm adds inhibition of IL-31, a main driver of itch in atopic dermatitis
Slide 18: IL-4, IL-13 and IL-31 Act Synergistically in Atopic Dermatitis
IL-4, IL-13 and IL-31 Act Synergistically in Atopic Dermatitis to Drive Inflammation, Pruritis and Skin Barrier Defects • IL-4 promotes differentiation of naïve T cells to Th2 cells • IL-4 and IL-13 maintain the Th2 response ▪ Drive recruitment of eosinophils and mast cells ▪ Stimulate B cells to ma
Slide 19: ZW1572: Bispecific Inhibitor of IL-4Ra and IL-31 for Atopic Dermatitis
ZW1572: Bispecific Inhibitor of IL-4Ra and IL-31 for Atopic Dermatitis Enhanced blockade of IL-31 Suppression of CCL2 induction in keratinocytes Anti-IL-4Ra Anti-IL-31 5 4 IL-13+IL-31 stim CCL2 expression, log2 fold change 3 ZW1572 NM026 2 1 0 -1 d 1 3 1 Ab a b 7 2 te L-3 L-1 + 3 a m lum 15 ul I I 3
Slide 20: Optimized Fc Portion Enhances IL-4Ra Pathway Blockade and Pharmacokinetics of ZW1572
Optimized Fc Portion Enhances IL-4Ra Pathway Blockade and Pharmacokinetics of ZW1572 Blockade of IL-4-driven activation Extended half-life in humanized in vitro FcRn (Tg32) mice CD2 3 e xpr ession by mo nocytes, Ser um concentration, ug/mL MFI Concentration, pM Time a fter i.v. administration, d ays
Slide 21: ZW1572 Demonstrates Antibody-like PK and RO in NHP
ZW1572 Demonstrates Antibody-like PK and RO in NHP Pharmacokinetics IL-4Rα Receptor Occupancy 1000 Pre-dose 48 hours 10 mg/kg Concentration (ng/mL) 100 10 1 mg/kg 1 CD20 0.1 0.01 0.001 0.0001 0 50 100 150 200 ant i-hIgG4 ant i-hIgG4 Time (hours) • IgG-like pharmacokinetics and biomarkers of IL-4Rα b
Slide 22: Benefits of Bispecific Therapeutics for AIID Patients
Benefits of Bispecific Therapeutics for AIID Patients: Blockade of Multiple Cytokines by a Single Molecule for Patients Convenience and Better Outcomes Opportunity to benefit patients with autoimmune and inflammatory diseases • Blockade of complementary pathways of autoimmunity could enhance therape