Cytomx Therapeutics, Inc. · NASDAQ:CTMX
Cytomx Therapeutics — American Association of Immunologists Annual Meeting 2023 - ICIS Symposium
22 slides from Cytomx Therapeutics's conference presentation, May 13, 2023
Slide 1: Designing Conditionally Activated Probody Cytokines to Localize Antitumor Activity to Cancers
Designing Conditionally Activated Probody® Cytokines to Localize Antitumor Activity to Cancers International Cytokine and Interferon Society (ICIS) Symposium: Understanding and Modulating Cytokine Activity through Structural Knowledge American Association of Immunologists Annual Meeting Dylan Daniel
Slide 2: Disclosures
Disclosures • Dylan Daniel is an employee and stockholder at CytomX Therapeutics, Inc. 2
Slide 3: The Promise of Conditionally Active, Localized Biologic Therapies
The Promise of Conditionally Active, Localized Biologic Therapies Addressing Major Challenges in Today’s Cancer R&D Landscape Probody® Therapeutics Designed to localize anti-cancer efficacy and decrease systemic toxicities R&D Challenge • Next Generation Biologic Therapies have evolved Tumor to high
Slide 4: The Probody Therapeutic Platform – Exploiting Cancer's Achilles' Heel
The Probody® Therapeutic Platform – Exploiting Cancer’s Achilles’ Heel Upregulated protease activity is a hallmark of cancer Adapted from Santi et al., Proteomics 2018 Protease Less Substrate Protease linker More Binding in Binding Normal in Tumors Tissues Mask Target “Masking” limits ability of Pro
Slide 5: Unmasked Cytokine Therapeutics Are Potent, But Associated With Safety Issues
Unmasked Cytokine Therapeutics Are Potent, But Associated With Safety Issues • Major regulators of innate and adaptive Probody® Cytokines immune system Cytokines and Cytokine • Antitumor activity demonstrated clinically by Therapeutics IFNa and IL-2 in melanoma and RCC • Clinical successes to date l
Slide 6: Conditionally Activated IFNa-2b: CX-801
Conditionally Activated IFNa-2b: CX-801 6
Slide 7: IFNα-2b is a Powerful Mediator of Immune Activation for Cancer Immunotherapy
IFNα-2b is a Powerful Mediator of Immune Activation with Ideal Properties for Cancer Immunotherapy Why IFNa-2b? Mechanism of Action • IFNa-2b provides an orthogonal activity to IL-12, IL-2 and IL-15 in the cancer immunity cycle − IFNa-2b can kill cancer cells directly leading to immunogenic cell dea
Slide 8: CX-801 is a Highly Masked, Conditionally Active IFNa-2b
CX-801 is a Highly Masked, Conditionally Active IFNa-2b Interferon pathway activation CX-801 (HEK-blueISRE reporter assay) • Multiplicative masking from two masking 1.5 approaches IFN signal (OD650) Affinity 1.0 mask • Leads to >1,000x masking in IFNa reporter Substrate assay 0.5 Steric mask • Prote
Slide 9: Activation of CX-801 by Tumor Proteases Fully Restores IFNa-2b Activity
Activation of CX-801 by Tumor Proteases Fully Restores IFNa-2b Activity Activation by tumor tissues Antiproliferative effect Intact Peptide 0h mask 2h Fluorescence removed 16h Fc mask removed Size • Exposure to tumor tissues removes masks • Unmasked CX-801 is as potent as recombinant IFN 9
Slide 10: What is the Structural Basis for Steric and Peptide Masking of IFNa-2b?
What is the Structural Basis for Steric and Peptide Masking of IFNa-2b? • Type 1 IFN receptor is a heterodimer composed of: – IFNaR1 – Low affinity receptor – IFNaR2 – High affinity receptor • Both receptors must be engaged for IFNa signaling to occur • Monomeric test molecules used to probe masking
Slide 11: Modes of Masking Differentially Affect IFNa-2b Interaction with R1 and R2
Modes of Masking Differentially Affect IFNa-2b Interaction with R1 and R2 ELISA measurements of binding to Type I interferon receptors Binding to IFNaR2 (high affinity) Fc Binding to IFNaR1 (low affinity) Fc 2.5 1.0 2.0 Unmasked Unmasked OD450 OD450 1.5 Affinity mask Affinity mask 0.5 1.0 Bn Steric
Slide 12: CX-801 Induces Dose Dependent Tumor Regression in Human Xenograft Model
CX-801 Induces Dose Dependent Tumor Regression in Human Xenograft Model CX-801 Efficacy in Daudi Tumor Model CX-801 vs. Unmasked Controls 4000 Day 12 Tumor Volume (mm3) 3000 0.02 mg/kg 0.1 mg/kg Daudi Tumor Volume, mm3 PBS 2500 3000 0.02 mg/kg 2000 0.1 mg/kg 2000 1500 0.5 mg/kg 1000 1000 500 0 N l a
Slide 13: CX-801 Surrogate Shows Potent Single Agent Tumor Growth Inhibition
CX-801 Surrogate* Shows Potent Single Agent Tumor Growth Inhibition Combination with immune checkpoint inhibitor shows enhanced efficacy MC38 Tumor Mouse Model 1500 Tumor Volume (mm3) PBS Mean +/- SEM 1000 Pro-IFNa-A/D-Fc*, 50 ug Anti-PD-L1 200 ug Anti-PD-1 200 ug 500 Anti-PD-L1 Combination Anti-PD-
Slide 14: CX-801 Surrogate Activity is Protease-Dependent
CX-801 Surrogate Activity is Protease-Dependent Activates T cells in tumors, but not in periphery Protease-dependent activity Tumor-specific immune activation 3000 100 Tumor Volume (mm3) GzB+ cells, % CD8 2500 80 PBS Control 2000 NSUB 200 ug 60 1500 Pb-IFN-A/D-Fc 200 ug 40 1000 500 20 0 0 0 5 10 15
Slide 15: CX-801 Displays Linear Pharmacokinetics and High Stability in Cynomolgus Monkey
CX-801 Displays Linear Pharmacokinetics and High Stability in Circulation in Cynomolgus Monkey Dose Linear LC-MSPharmacokinetics Cyno PK High Stability in Circulation 10000 60 mpk IV Concentration (g/mL) 30 mpk SC 1000 30 mpk IV 15 mpk IV 100 7.5 mpk IV 10 1 0 100 200 300 400 15
Slide 16: CX-801 has Significantly Improved Tolerability
CX-801 has Significantly Improved Tolerability Compared to unmasked interferon in non-human primates Protection in multi-dose tolerability study is ≥ 30x Historical Peginterferon Data Probody® IFNα-2b Tolerability Study Dosing Dosing Peginterferon (SQ) (mpk/w) CX-801 (IV) (mpk/w) (3 x QW) 0.35 Toler
Slide 17: CX-801: Expanding the Reach of I/O Therapy
CX-801: Expanding the Reach of I/O Therapy CX-801 Potential Best in Class Best-in-Class Profile • Differentiated molecule with attractive preclinical efficacy and tolerability profile • Well tolerated in multi-dose pilot NHP tox study up to 60 mg/kg • Estimate predicted therapeutic index of ~3-7 Bro
Slide 18: Applying Probody Platform Across Cytokines
Applying Probody® Platform Across Cytokines Expanding Masking to IL-15 IL-15 IFNα-2b IL-15 • Activate antigen presenting cells • Strong agonist of immune • Promote pro-inflammatory TME effector cells – CD8+ T cells • Complementary biology to PD-1 IL-15 and NK cells • Broad combination potential IFNa
Slide 19: Designing an IL-15 Cytokine Probody Therapeutic
Designing an IL-15 Cytokine Probody® Therapeutic TARGET Target BACKGROUND Background Key PDC OPPORTUNITY Challenges/Opportunity • IL-15 is essential for NK, NKT, Challenges CD8+ T cell development and function • Clinical activity is limited by short half-life and Cmax related toxicity (e.g. fevers,
Slide 20: Exploring Probody Tx Technology for Steric Masking of IL-15
Exploring Probody® Tx Technology for Steric Masking of IL-15 IgG Fc Provides Steric Masking of IL-15 HEK-Blue IL15 Reporter Assay Steric Masked IL-15 1.0 0.8 IL-15 IL-15 rhIL-15 0.6 Steric Masking A620 Substrate ~50x Steric Masking + protease 0.4 Next Generation Masking Next Gen. Masking + protease
Slide 21: Probody Cytokines Summary
Probody® Cytokines Summary • Affinity peptide masking and steric masking act multiplicatively to increase the masking of conditionally activated IFNα-2b • Dual masked IFNα-2b CX-801 surrogate demonstrates protease-dependent, tumor localized CD8+ T cells activating activity • CX-801 shows a significa
Slide 22: Thank you!
Thank you! 22