AB0282 SAFETY, TOLERABILITY AND SELECTIVE EXPANSION OF REGULATORY T CELLS BY A SINGLE DOSE OF THE NOVEL IL-2 MUTEIN PT101 IN A PHASE 1 STUDY IN HEALTHY VOLUNTEERS

Background: Activation and expansion of regulatory T cells (Tregs) has been proposed as a strategy to treat autoimmunity. When administered in low doses, IL-2 expands activates Tregs leading clinical response several autoimmune diseases. However, the narrow therapeutic window results loss selectivity for concurrent activation conventional (Tconv) NK cells, limiting its utility. This may negate benefit Treg lead dose-limiting side effects. PT101 is novel engineered variant fused an Fc protein backbone which preclinical studies selectively without expanding Tconv or cells. development treatment patients with Objectives: To assess safety, tolerability, pharmacokinetics (PK) pharmacodynamics (PD) after single dose healthy human volunteers. Methods: We conducted randomized, double-blind, single-ascending trial placebo (3:1 allocation). Five levels from 1 mg 10 were by subcutaneous injection. Adverse events, physical examination findings, laboratory assessed 29 days. Serum antidrug antibody assessed. Changes mononuclear cell populations measured peripheral blood flow cytometry. Results: 56 subjects placebo. All completed study. There no deaths, serious adverse toxicities, clinically significant changes vital sign, ECG, results. events Grade 2 self-limited. Injection site reactions most common event. Transient increases eosinophil counts observed some subjects, consistent known class effect IL-2. Peak occurred 11.0 14.6 hours administration, declined mean half-life 20.4 28.3 hours, demonstrating linear exposure through range. No anti-drug antibodies induced. caused dose-related that plateaued at doses between 3.5 mg. Mean maximum above baseline was 3.6-fold total 72.5-fold CD25bright subset Tregs. Maximal Day 8-10 return toward 29. Over 80% achieved 2-fold greater (Table 1). any level. Table 1. Percent Total Responders Fold Change Placebo (n=14) (n=6) (n=12) 5 7.5 ≥ 2X 7% 33% 83% 100% 3X 0% 58% 75% 50% 4X 24% 42% 17% Conclusion: safe well tolerated Marked both observed. High pro-inflammatory even highest studied. These support potential planned multiple systemic lupus erythematosus, ulcerative colitis, other References: [1]Klatzmann, D., Abbas, A. The promise low-dose interleukin-2 therapy inflammatory Nat Rev Immunol 15, 283–294 (2015) Acknowledgements: Pandion Therapeutics acknowledges participants research staff who contributed this Disclosure Interests: John S Sundy Shareholder of: Therapeutics, Employee Kevin L. Otipoby Nathan Higginson-Scott Jyothsna Visweswaraiah Erik Sampson Katalin Kis-Toth Adrianne Monsef Parika Petaipimol David Essayan Consultant Mary Ellen Cosenza Rahul Kakkar Jo Viney