John Langowski, Ph.D. Nektar Therapeutics San Francisco, CA USA
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1 NKTR-38: a selective, first-in-class IL-2 pathway agonist which increases number and suppressive function of regulatory T cells for the treatment of immune inflammatory disorders John Langowski, Ph.D. Nektar Therapeutics San Francisco, CA USA
2 Introduction A progressive imbalance of regulatory T cells (Tregs) relative to conventional T cells (Tcon) is shared by many autoimmune diseases Enhanced sensitivity of Tregs to IL-2 supports use of low-dose IL-2 therapy Low-dose IL-2 therapy hampered by poor pharmacokinetics, AEs, short-lived effects Magnitude of Treg mobilization ultimately limited by elicitation of Tcon Clinical benefit demonstrated in GVHD, SLE and other indications
3 NKTR-38 Potential first-in-class therapeutic for direct manipulation of Tregs Biotherapeutic born from Nektar s extensive development experience with IL-2 and polymer conjugation Preferential increase in number and activity of Tregs, minimal action on non-tregs Utilizes the FDA-approved aldesleukin sequence Monthly or twice monthly self-administered subcutaneous product In development for autoimmune and allergy indications
4 NKTR-38 was identified by an in vivo screen IL-2 qdx s.c. C7Bl/6 Assess immune cell populations in blood using flow cytometry Conjugate Single dose s.c. Fold change in Treg NKTR-38 NKTR-38,.3 NKTR-38,.1 NKTR-38, Time (Days) Fold change in Treg (mean ± SEM) IL-2 IL-2,.1 qdx IL-2,.3 qdx IL-2, 1 qdx dosing Time (Days)
5 NKTR-38 promotes Treg proliferation and activation CD4 Treg, CD2 MFI 1 K i67 + Treg Mean Fluorescence Intensity K i67 + Treg (percent) 7 2 Single subcutaneous NKTR-38 administration in mice Induction of proliferation and activation markers Days post dose CD4 Treg, FoxP3 MFI Days post dose IC O S.3 m g/kg.1 m g/kg.3 V e h icle Helios, GITR, CTLA-4, CD39, CD73, OX4, and PD-1 (not shown) Similar effect in blood and spleen Mean Fluorescence Intensity ICO S + Treg (percent) Days post dose Days post dose
6 Preferential Treg expansion in non-human primates Cell number fold change (mean ± SEM) Dosing: Treg, CD8 in blood Days NKTR-38, Treg NKTR-38, CD8 Cell number fold change (mean ± SEM) Dosing: Days IL-2, Treg IL-2, CD8 %Ki67+ of Treg (mean ± SEM) Dosing: Treg proliferation (Ki67) Days Treg activation NKTR-38 IL-2 Fold-change in MFI (mean ± SEM) Dosing: Treg activation (CD2) NKTR Days IL-2 Cynomolgus monkey : 1M + 1F 2µg/kg : NKTR-38 single dose vs. qdx for IL-2
7 NKTR-38 suppresses antigen-driven inflammation Sensitization KLH, flank Elicitation KLH, ear Sensitization OVA, flank Elicitation OVA or KLH Measure ear Measure ear Day Day 3 4 weeks, no treatment Day Day NKTR-38 s.c. q3d; CsA qd Primary efficacy Rechallenge : Antigen-specific Treg memory 16 2 OVA Vehicle 2 KLH Vehicle 14 Vehicle.1 m g/kg.1 m g/kg ear thickness (m m x 1-2, m ean ± SEM) m g/kg.3 m g/kg Cyclosporin A, 1 ear thickness (m m x 1-2, m ean ± SEM) Time post KLH challenge (h) Time post OVA challenge (h) Time post KLH challenge (h)
8 NKTR-38 suppresses antigen-driven inflammation in a primate model of cutaneous hypersensitivity TT Sensitization Week -6 TT Sensitization Week -4 TT Sensitization Week -2 TT Elicitation Week Measure CHS CHS: Cutaneous Hypersensitivity TT: Tetanus Toxoid Arrows: NKTR-38 s.c.,.3 &. q2w *: p <. vs CHS, ANOVA Skin Spot Area Erythem a Edem a Skin Spot Area (m m 2 ) * * * C lin ic a l S c o re 2 1 * * C lin ic a l S c o re * * Naive CHS.3. Naive CHS.3. Naive CHS.3.
9 NKTR-38 is efficacious in a mouse model of SLE Anti-dsDNA lgg (week 2) Blood Urea Nitrogen (week 2) Blood Treg (week 2) 4 Protein Level (g/l) Urine Protein Level Vehicle (C7BL/6) Vehicle (MRL/MpJ-Faslpr).3 (MRL/MpJ-Faslpr).3 (MRL/MpJ-Faslpr) Concentration (ku/ml) Vehicle (C7Bl/6) Vehicle (lpr).3.3 BUN (mg/dl) Vehicle Vehicle (C7Bl/6) (lpr).3.3 Vehicle Vehicle (C7Bl/6) (lpr) NKTR-38 demonstrated dose-dependent efficacy on multiple parameters in mouse SLE % CD4+8-CD2+FoxP Week.3 (q3d, week 8-2) reduces urine protein and blood urea nitrogen to naïve mouse parameters Efficacy is consistent with Treg elevation
10 Summary Nektar s immune-regulatory cytokine drug NKTR-38 induces profound Treg effects Greater magnitude of total Treg cell increase than IL-2 Highly selective for Tregs with limited effects on non-treg cells Increased Treg suppressive capacity Prolonged activation and proliferation of Treg in higher species Phase I Single Ascending Dose trial initiated March 217 Primary readouts are Treg mobilization, functional activity, PK and safety Goal is to establish a range of dose levels to be advanced into a Multiple Ascending Dose trial in patients with SLE
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