897 Pre-clinical characterization of PEC3001, a PD-1 targeted IL-2Rα-active IL-2 immunocytokine with potent anti-tumor activity and a favorable safety profile
Year: 2026
Type: conference-abstract
Abstract: Background Interleukin-2 (IL-2) immunotherapy can induce durable clinical responses in patients with advanced cancer, but its broader use has been limited by a short serum half-life, systemic toxicity, and a narrow therapeutic index. Second-generation ‘non-α’ IL-2 variants designed to eliminate IL-2 receptor alpha (IL-2Rα) binding have demonstrated only modest clinical efficacy, highlighting the challenge of achieving selective, tumor-restricted immune activation. To overcome these limitations, we developed PEC3001, a PD-1–targeted IL-2 immunocytokine retaining IL-2Rα binding, designed to preferentially activate tumor-specific PD-1 + T cells while minimizing peripheral immune activation associated with conventional IL-2 therapies.Methods PEC3001 was generated by fusing a high-affinity PD-1-blocking antibody to an IL-2 mutein engineered to have reduced affinity for the trimeric IL-2Rαβγ receptor. Signaling potency was evaluated in vitro using phospho-STAT5 assays in activated versus resting immune cell populations. In vivo efficacy was assessed using a surrogate molecule (mPEC3001) in MC38 and B16F10 syngeneic tumor models by monitoring tumor growth inhibition and tolerability. Pharmacology and mechanisms associated with response were analyzed on peripheral blood and tumor tissues using flow cytometry, cytokine multiplex assays, transcriptomics, high-plex immunofluorescence, and immunoassays.Results PEC3001 induced potent STAT5 phosphorylation in CD3/CD28-stimulated T cells with minimal activation of naïve T cells and NK cells, demonstrating enhanced functional selectivity relative to benchmark molecules. In vivo, mPEC3001 was well tolerated following repeated dosing and demonstrated superior anti-tumor efficacy compared with anti–PD-1, an untargeted IL-2 mutein, and combination therapy, inducing durable tumor regression and immune memory. Mechanistically, mPEC3001 selectively expanded tumor-specific T cells and enhanced effector molecule production within the tumor microenvironment, with minimal systemic immune activation, suggesting spatially restricted pharmacology. In ex vivo patient-derived tumors spanning multiple tumor types, PEC3001 induced greater pro-inflammatory cytokine production than anti–PD-1, untargeted IL-2, their combination, or an α-biased PD-1–IL-2 competitor molecule. Transcriptomic profiling revealed robust upregulation of cytotoxic and effector cytokine-related genes, and broad transcriptional remodeling with minimal induction of Treg-associated signatures.Conclusions PEC3001 leverages PD-1-directed targeting and preserved IL-2Rα engagement to selectively amplify anti-tumor T-cell responses while minimizing systemic immune activation. The strong biological rationale and favorable pre-clinical profile of PEC3001 supports its clinical development as a differentiated next-generation PD-1-targeted IL-2 immunocytokine. A first-in-human clinical trial evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of PEC3001 in patients with relapsed/refractory advanced or metastatic solid tumors is expected to begin in late 2026.Ethics Approval Mouse in vivo work was performed in accordance with current regulations and standards of the U.S Department of Health and Human Services, Public Health Service (PHS), and the NIH Office of Laboratory Animal Welfare (OLAW). Animal studies were conducted at two AAALAC-accredited facilities, PharmaEssentia Innovation Research Center (Bedford, MA) and Charles River Laboratories (Shrewsbury, MA), with approval of their respective Institutional Animal Care and Use Committees (IACUC).
Authors: Jack D Huck, Celesztina Nagy-Domonkos, Menqrong Wu, Luke Lin, Yite Yo, Ali Sepahi, Pratiksha Ramteke, Molly Foster, Kelsey Joyce, Josephine Orrick, Henry S Cheng, Robert Wheeler, Prasanna Baskar, Mei-Ling Yang, Tom Lin, Kuan-Chun Huang, Erik R Sampson, Shihlong Yan, Ming-Tang Chen, Lih-Ling Lin
Institution: PharmaEssentia Corporation (Taiwan)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225203751