Nektar Therapeutics Reveals Initial Preclinical Data on NKTR-0165, a TNFR2 Agonist for Inflammatory Diseases, at EULAR 2024

Nektar Therapeutics recently showcased promising preclinical data on their novel antibody, NKTR-0165, at the 2024 European Alliance of Associations for Rheumatology (EULAR) Congress. NKTR-0165 is a pioneering TNFR2 agonist designed as a bivalent antibody that selectively activates the TNFR2 receptor, without influencing TNFR1 signaling. The significance of TNFR2 signaling lies in its role as a key regulator of inflammation, with deficiencies linked to numerous autoimmune conditions. This receptor is prominently expressed on regulatory T cells (Tregs), neuronal cells, and endothelial cells, enhancing the immunosuppressive functions and overall effectiveness of Tregs.

Dr. Jonathan Zalevsky, Senior Vice President and Chief Research & Development Officer at Nektar, highlighted that the preclinical findings underline NKTR-0165's potential as a first-in-class treatment for autoimmune diseases such as ulcerative colitis and vitiligo. The antibody uniquely binds to TNFR2 on Tregs, boosting their immunosuppressive activities. This selective binding leads to the upregulation of critical proteins involved in Treg proliferation and functionality, which has been confirmed through various animal models. These models demonstrated that NKTR-0165 reduces inflammation by enhancing Treg cell functions through TNFR2 agonism.

Key insights from the presentation at EULAR included:

1. Selective TNFR2 Binding and Agonism: NKTR-0165 demonstrates exclusive binding to TNFR2 on human Tregs, with minimal interaction and signaling activity in other immune cells expressing TNFR2.
2. Enhanced Treg Function: The agonistic activity of NKTR-0165 promotes the stabilization of the Treg lineage and boosts expressions of proteins crucial for Treg proliferation and performance.
3. Therapeutic Efficacy in Animal Models: NKTR-0165 showed therapeutic potential in a KLH-induced delayed type hypersensitivity model in human TNFR2 knock-in mice.

Nektar Therapeutics is a clinical-stage biotech company focusing on treatments that address immunological dysfunctions in autoimmune and chronic inflammatory diseases. Their leading product candidate, rezpegaldesleukin (NKTR-358), is a novel Treg stimulator currently in Phase 2b clinical trials for atopic dermatitis and alopecia areata. Their pipeline also includes NKTR-0165, which is in preclinical stages, and NKTR-255, an IL-15 receptor agonist being tested in various cancer trials.

The company is progressing with IND-enabling studies for NKTR-0165, with plans to start first-in-human studies in the first half of 2025. These developments underline Nektar's commitment to innovative therapies that target the underlying mechanisms of autoimmune and inflammatory diseases, potentially leading to significant advancements in treatment options for these conditions.

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