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703 Favorable pre-clinical safety profile of the novel not-alpha IL-2 agonist ANV419 supports first in human clinical development
  1. Christoph Huber1,
  2. Guzman Alonso2,
  3. Elena Gerralda2,
  4. Christoph Bucher1,
  5. Philippe Jacqmin3,
  6. Andreas Katopodis1 and
  7. Jennifer Sims4
  1. 1Anaveon AG, Basel, Switzerland
  2. 2Vall d' Hebron Institute of Oncology, Barcelona, Spain
  3. 3MnS, Dinant, Belgium
  4. 4Integrated Biologix, Basel, Switzerland


Background ANV419 is a novel interleukin-2 (IL-2)/anti-IL-2 fusion protein with preferential signaling through the IL-2 beta/gamma receptor that induces selective proliferation of CD8 T cells and NK cells in vivo for the treatment of cancer. The safety and pharmacodynamic effects of ANV419 were studied in a 4-week cynomolgus monkey GLP study to support the ongoing PhI dose escalation clinical trial.

Methods ANV419 was administered by i.v. injection over 1 min at doses of 0.03, 0.1, 0.3 mg/kg, or vehicle control on days 1 and 15 of the 29-day study. Assessments included body weight, blood pressure, hematology, clinical pathology, serum cytokines, immunophenotyping, histopathology, and pharmacokinetics.

Results The pharmacokinetics of ANV419 were characterized by target mediated disposition, with a half-life of approximately 24h at concentrations not affected by target mediated clearance. Dose-dependent increases in WBC were observed after each injection, driven by preferential expansion of CD8 T cells and NK cells over Tregs. NK cells were more sensitive to ANV419 than CD8 T cells reaching maximal proliferation in blood at 0.03 mg/kg vs. 0.3 mg/kg for CD8 T cells. Hematological changes included: transient dose-dependent increase in basophils; elevation in eosinophils, up to 2.2-fold above control animals at > 0.03 mg/kg, remaining within the normal range for cynomolgus monkeys (<1.94 G/L); minor decrease in platelets at day 4 after each injection. There were no relevant treatment-related changes in inflammatory serum cytokines (IL-1b, IL-5, IL-6, IL-8, IFNg, TNFa, GM-CSF). A mild systemic inflammatory response was observed at 0.3 mg/kg evidenced by a transient increase of CRP on days 4 and 19, preceded after the first injection by a slight dose dependent increase in IL-1RA at 4h post injection, and an increase in IL-10 at 24h post treatment at 0.3mg/kg. No significant changes in body weights or blood pressure and no signs of capillary leak were observed during the entire study.A multi-part PhI dose-escalation study of ANV419 has been initiated in cancer patients. In the part A single patient escalation cohort, two patients have been dosed Q2W multiple times with 0.003mg/kg and 0.006mg/kg respectively with the expected PD profile and no DLT observed.

Conclusions Consistent findings, relating to expected effects of ANV419 as a not-alpha IL-2 agonist, demonstrated a favorable tolerability and safety profile at pharmacodynamically relevant doses that strongly support its translational development in cancer patients to identify clinical benefits.

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