TransCon IL-2 β/γ, a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog, demonstrates improved pharmacokinetics and profound expansion of cytotoxic immune cells in non-human primates.

Medientyp: E-Artikel
Titel: TransCon IL-2 β/γ, a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog, demonstrates improved pharmacokinetics and profound expansion of cytotoxic immune cells in non-human primates
Beteiligte: Rosen, David; Månsson Kvarnhammar, Anne; Olling, Janne Damm; Laufer, Burkhardt; Knappe, Thomas; Karlsson, Jens Jakob; Kurpiers, Thomas; Zettler, Joachim; Runz, Josefine; Faltinger, Frank; Viet, Laura; Krusch, Mathias; Schnabel, Meike; Reich, Diana; Glock, Philipp; Singel, Stina Mui; Sprogøe, Kennett; Abel, Kristin Laura; Breinholt, Vibeke Miller; Punnonen, Juha
Erschienen: American Society of Clinical Oncology (ASCO), 2022
Erschienen in: Journal of Clinical Oncology
Sprache: Englisch
DOI: 10.1200/jco.2022.40.16_suppl.2563
ISSN: 0732-183X; 1527-7755
Schlagwörter: Cancer Research ; Oncology
Entstehung:
Anmerkungen:
Beschreibung: <jats:p> 2563 </jats:p><jats:p> Background: Recombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe side effects including cytokine release syndrome (CRS) and vascular leak syndrome (VLS). This is believed to be due to activation of IL-2Rα<jats:sup>+</jats:sup> endothelial cells and inflammatory eosinophils as well as high C<jats:sub>max</jats:sub> due to the short half-life requiring frequent high dose administrations. Also, potent activation of immunosuppressive IL-2Rα<jats:sup>+</jats:sup> regulatory T cells (Tregs) may limit IL-2’s efficacy. TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog designed to optimally address these shortcomings. Methods: Naïve male and female cynomolgus monkeys received 2-3 doses of TransCon IL-2 β/γ intravenously Q2W. Blood samples were taken to assess plasma concentrations of IL-2 β/γ (active drug), serum cytokines, hematology and immunophenotyping. Histopathology was also performed. Results: Administration of TransCon IL-2 β/γ induced robust increases in absolute lymphocyte counts (ALC), with no/minor increases in eosinophil counts. The increase in ALC was primarily driven by potent activation and expansion of CD8<jats:sup>+</jats:sup> T cells, NK cells and γδ T cells, relative to CD4<jats:sup>+</jats:sup> T cells and Tregs. At doses with maximum pharmacodynamic (PD) responses, TransCon IL-2 β/γ induced on average > 20-fold ALC increases, > 19-fold CD8<jats:sup>+</jats:sup> T cell increases, > 50-fold Effector Memory CD8<jats:sup>+</jats:sup> T cell increases, > 18-fold NK cell increases and > 400-fold γδ T cell increases compared to pre-dose levels. These changes corresponded with a low C<jats:sub>max</jats:sub> and a long effective half-life ( > 30 hours) for IL-2 β/γ. A clear induction of soluble CD25 and chemokine MCP-1 was seen after dosing, while levels of IL-5, IL-6, IFN-γ and TNF-α remained low. Further, histopathology showed no signs of vascular damage, tissue necrosis, pulmonary edema or eosinophilia. Conclusions: In cynomolgus monkeys, TransCon IL-2 β/γ demonstrated remarkable PD responses in CD8<jats:sup>+</jats:sup> T cells, NK cells and γδ T cells over Tregs and eosinophils. No signs of VLS or CRS were observed. These results are likely due to the selective IL-2Rβ/γ bias along with the slow and sustained release of IL-2 β/γ resulting in low C<jats:sub>max</jats:sub> and long circulatory half-life enabled by the TransCon prodrug technology. The massive expansion of γδ T cells, which are known to possess considerable anti-tumor activity, is to our knowledge a unique finding for TransCon IL-2 β/γ among IL-2 variants in clinical development. Altogether, the responses seen in monkeys are suggestive of a potentially substantial improvement in the therapeutic index beyond what has been achieved by aldesleukin or new IL-2 variants to date. TransCon IL-2 β/γ is currently being evaluated in a clinical Phase 1/2 trial as monotherapy and in combination with pembrolizumab (NCT05081609). </jats:p>
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