Background IL-2 binds two forms of IL-2 receptor: a high affinity trimeric receptor composed of CD25, CD122, and CD132, and a low affinity dimeric receptor composed of CD122 and CD132. Binding to the dimeric receptors, expressed on effector cells, causes expansion of the effector arm of the immune system including CD8 T-cells, NK-cells and NKT-cells. Binding to the trimeric receptor, expressed on Tregs as well as on pulmonary and vascular epithelium, results in expansion of Treg cells and Vascular Leak Syndrome, both are undesired outcomes of high-dose recombinant IL-2 (Aldesleukin), approved for treatment of Melanoma and Renal-Cell-Carcinoma.
Methods Flow-cytometry analysis of immune-cell populations of C57BL/6 mice and hPBMCs. Tumor-Growth-Index of murine cancer models.
Results AU-007, is a computationally designed human antibody that bind the CD25-binding portion on IL-2, preventing binding of IL-2 to the trimeric receptor, but not the dimeric receptor. This leads to immune effector activation while also preventing the Treg expansion via the autoinhibitory loop caused by endogenous IL-2 secreted from activated T effector cells (figure 1). AU-007 binds human IL-2 with picomolar affinity and has excellent biophysical properties with low potential for anti-drug immunogenicity (figure 2). Administration of an AU-007/low dose hIL-2 complex to non-tumor bearing C57BL/6 mice promoted proliferation of effector cells with no effect on Tregs (figure 3). Additionally, an AU-007/low dose hIL-2 complex was highly effective in inhibiting tumor progression in a syngeneic B16F10 melanoma model (figure 4). pSTAT5 analysis of hPBMCs incubated with AU-007 and hIL-2 demonstrated activation of the effector cells and inhibition of Tregs expansion (figure 5). hPBMCs activated with anti-CD3/anti-CD28 and treated with either AU-007 or an isotype control antibody but without exogenous IL-2, showed expansion of effector cells. However, while the isotype control antibody expanded also Tregs , AU-007 inhibited Tregs proliferation, indicating that AU-007 captures endogenous IL-2 and prevents the Treg expansion autoinhibitory loop caused by endogenous IL-2 secreted from activated T effector cells (figure 6).Additionally, following establishment of the IL-2 auto-secretion feedback loop in mice genetically engineered to express hIL-2 instead of murine IL-2, AU-007 treatment significantly inhibited MC38 colorectal-tumor growth for twelve days, in a manner comparable to treatment with anti-PD1 (figure 7).
Conclusions AU-007 is a human antibody that blocks the CD25-binding epitope on IL-2. It redirects endogenous IL-2 to promote effector cell expansion while simultaneously blocking the Treg expansion autoinhibitory loop, indicating its unique therapeutic profile and high potential as a novel cancer treatment. AU-007 is expected to enter clinical testing in 2021.
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