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

Abstract

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 and activates Tregs leading to clinical response in several autoimmune diseases. However, the narrow therapeutic window of IL-2 results in loss of selectivity for Tregs and concurrent activation of conventional T cells (Tconv) and NK cells, limiting its clinical utility. This loss of selectivity may negate the clinical benefit of Treg activation and lead to dose-limiting side effects. PT101 is a novel engineered variant of IL-2 fused to an Fc protein backbone which in preclinical studies selectively activates Tregs without expanding Tconv or NK cells. PT101 is in clinical development for the treatment of patients with autoimmune diseases.Objectives:To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PT101 after a single dose in healthy human volunteers.Methods:We conducted a randomized, double-blind, single-ascending dose trial of PT101 or placebo (3:1 allocation). Five dose levels from 1 mg to 10 mg were administered by subcutaneous injection. Adverse events, physical examination findings, and clinical laboratory results were assessed for 29 days. Serum PT101 levels and antidrug antibody were assessed. Changes in mononuclear cell populations were measured in peripheral blood by flow cytometry.Results:56 subjects were administered PT101 or placebo. All subjects completed the study. There were no deaths, serious adverse events, dose limiting toxicities, or clinically significant changes in vital sign, ECG, or laboratory results. All adverse events were Grade 1 or 2 and self-limited. Injection site reactions were the most common adverse event. Transient increases in eosinophil counts were observed in some subjects, consistent with the known class effect of IL-2. Peak levels of PT101 occurred 11.0 to 14.6 hours after administration, and declined with a mean half-life of 20.4 to 28.3 hours, demonstrating linear exposure through the dose range. No anti-drug antibodies were induced. PT101 caused dose-related expansion of Tregs that plateaued at doses between 3.5 and 10 mg. Mean maximum expansion above baseline was 3.6-fold for total Tregs and 72.5-fold for the CD25bright subset of Tregs. Maximal expansion was observed by Day 8-10 with a return toward baseline by Day 29. Over 80% of subjects achieved a 2-fold or greater expansion of total Tregs (Table 1). No significant expansion of Tconv or NK cells was observed at any dose level.Table 1.Percent Total Treg RespondersFold Change Total TregsPlacebo(n=14)1 mg(n=6)3.5 mg(n=12)5 mg(n=12)7.5 mg(n=6)10 mg(n=6)≥ 2X7%33%83%83%100%100%≥ 3X0%0%58%75%33%50%≥ 4X0%0%24%42%33%17%Conclusion:PT101 was safe and well tolerated after a single dose in healthy volunteers. Marked expansion of both total Treg and CD25bright Treg cells was observed. High selectivity for Tregs was observed with no significant expansion of pro-inflammatory Tconv and NK cells even at the highest dose studied. These results support the therapeutic potential of PT101 in planned multiple dose studies in systemic lupus erythematosus, ulcerative colitis, and other autoimmune diseases.References:[1]Klatzmann, D., Abbas, A. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15, 283–294 (2015)Acknowledgements:Pandion Therapeutics acknowledges the participants and research staff who contributed to this clinical trialDisclosure of Interests:John S Sundy Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Kevin L. Otipoby Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Nathan Higginson-Scott Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Jyothsna Visweswaraiah Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Erik Sampson Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Katalin Kis-Toth Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Adrianne Monsef Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Parika Petaipimol Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, David Essayan Consultant of: Pandion Therapeutics, Mary Ellen Cosenza Consultant of: Pandion Therapeutics, Rahul Kakkar Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Jo Viney Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics

IL-2 immunotherapy for targeting regulatory T cells in autoimmunity

“… SLE MAD: five dosing cohorts; every 2 weeks; treatment for 12 weeks; subcutaneously; 2nd line Phase 1; NCT03451422, completed (Oct 2021) Peak T reg expansion at day 8 post dose sustained for up to 42 days after the last dose; Mean peak increases in T reg 1.1-17.4-fold above the baseline depending on the dose; Increased Helios, PD-1, ICOS, CD39, GITR in expanded T reg ; No significant changes in CD4 and CD8 T cells nor NK cells; No changes in pro-inflammatory cytokines. AE: mild-to-moderate injection site reactions, No dose-limiting toxicities; PK: linear and dose-dependent, half-life 18 −30 h. RA MAD: multiple dosing schedules, follow-up for 12 weeks; 2nd line Phase 1/2; NCT03410056, terminated (May 2020) N/A N/A GvHD (chronic) MAD: weekly or every 2 weeks; 2nd line Phase 1/2; NCT03422627, terminated (Feb 2022) N/A N/A SLE Dose-ranging; 2nd line Phase 2b; NCT04680637, terminated (Jun 2023) N/A N/A Ulcerative colitis Dose-finding; 2nd line Phase 2; NCT04987307, recruiting (Jun 2024) N/A N/A RG7835 (RO7049665) [ 115 ] IL-2Rα-biased IL-2m (T3A, N88D, C125A) IgG1-fusion protein Healthy volunteers SAD; subcutaneous Phase 1; NCT03221179, completed (Jul 2019) N/A N/A Ulcerative colitis MAS; subcutaneous; 1st line Phase 1; NCT03943550, terminated based on the lack of robust clinical improvement in the underlying condition after 8 weeks of treatment (Jul 2021) N/A N/A Autoimmune hepatitis Every 2 weeks; subcutaneous administration; 2nd line Phase 2; NCT04790916, terminated based on a lack of efficacy seen with RO7049665 in a study of ulcerative colitis (Nov 2021) N/A N/A PT101/ MK-6194 [ 144 ] IL-2Rα-biased IL-2m (L118I, N88D, V69A, Q74P, C125S) Fc-fusion protein Healthy volunteers SAD: five dose levels from 1 mg to 10 mg, subcut...…”

“…These expanded T reg had increased expression of FOXP3 and CD25, suggesting enhanced function and stability. In a phase 1a single ascending dose clinical trial in healthy volunteers, PT101 was safe and well-tolerated, and a dose-dependent expansion of CD25 bright T reg cells was observed with a mean maximum increase of 72.5-fold for CD25 bright T reg by day 8-10 (and an overall 3.6-fold increase in total T reg ) [ 144 ]. T conv and NK cells were not increased while increases in eosinophil counts were transient.…”

Challenges and opportunities in achieving effective regulatory T cell therapy in autoimmune liver disease

“…The engineered IL-2 mutein-IgG complex supported selective Treg expansion over a wide dose range and resolved non-obese diabetes (NOD) in mice [ 66 ]. The promise of IL-2 mutein in human disease is now being realised after safety and dose finding studies supported the progression to a pioneering clinical trial of PT101 IL-2 mutein complex in patients with active ulcerative colitis [ 67 , 68 ] (ClinicalTrials.gov NCT04924114).…”