Compositions and methods for subcutaneous administration of cancer immunotherapy
Inventors
LOSEY, HEATHER C. • Lopes, Jared • Sun, Lei • Winquist, Raymond J.
Assignees
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Publication Number
US-11246906-B2
Publication Date
2022-02-15
Expiration Date
Abstract
The invention provides compositions, methods and treatment regimens for treating cancer comprising periodic subcutaneous administration of the fusion protein of SEQ ID NO:1 to a cancer patient resulting in enhanced activation of CD8+ T-cells with minimal effects on regulatory T cell (Treg) expansion and providing enhanced anti-tumor efficacy while also mitigating T cell inactivation/exhaustion.
Core Innovation
The invention relates to cancer immunotherapy using a fusion protein of SEQ ID NO:1, in which circularly permuted IL-2 is fused to IL-2Rα/CD25. The fusion protein is administered periodically by the subcutaneous route. The method is directed to selective intermediate-affinity IL-2 receptor (IL-2Rβγ) activation while limiting expansion of CD4+ regulatory T cells.
The method addresses treating cancer by modulating T-cell populations, specifically reducing CD4+ regulatory T cells and increasing CD8+ memory T cells. The periodic subcutaneous dosing interval is once every about 3 days to once every about 60 days, including embodiments such as q3d, q4d, q7d, q14d, q21d, and q60d. The documented immunologic outcomes include enhanced CD8+ T-cell and memory phenotype expansion with minimal CD4+ Treg expansion.
The described approach also addresses safety and tolerability concerns associated with cytokine effects. With equivalent dosing, subcutaneous administration is associated with reduced systemic pro-inflammatory cytokine effects, including lower IL-6 rise compared with intravenous administration. The method is further supported by comparative nonclinical and human evidence, and includes combination therapy with pembrolizumab to inhibit the PD-1/PD-L1 pathway.
Claims Coverage
The relevant claim set includes one independent claim covering a periodic subcutaneous dosing method using a SEQ ID NO:1 fusion protein (or a high-identity variant) for cancer treatment, with the key inventive features focused on T-cell population modulation, the defined fusion protein sequence scope, and the periodic dosing interval set to once every about 3 days to once every about 60 days.
Reducing CD4+ regulatory T cells and increasing CD8+ memory T cells for treating cancer
A method of reducing CD4+ regulatory T cells and increasing CD8+ memory T cells for treating cancer in a patient.
Periodically subcutaneously administering SEQ ID NO:1 IL-2 variant fusion protein
Periodically subcutaneously administering to the patient a dose of the fusion protein of SEQ ID NO:1, or a fusion protein having a sequence identity of at least 80% over a contiguous sequence of the full length of SEQ ID NO:1.
Periodic dosing once every about 3 days to about 60 days
The periodic dosing is once every about 3 days to once every about 60 days.
Subcutaneous formulation as stable aqueous solution or lyophilized formulation
Administering a pharmaceutical composition for subcutaneous administration, wherein the composition is either a stable aqueous solution or a lyophilized formulation.
Higher CD8+ T cell to CD4+ Treg ratio than daily subcutaneous dosing
Producing a higher CD8+ T cell to CD4+ Treg ratio in the patient than daily subcutaneous administration.
At least about 2-fold less IL-6 increase versus intravenous at equivalent dose
When an equivalent dose is given subcutaneously, the IL-6 increase in a patient’s peripheral blood, serum, or plasma is at least about 2-fold less than the increase caused by intravenous administration.
At least about 2-fold greater IFNγ increase versus intravenous at equivalent dose
Characterized by subcutaneous administration producing an at least about 2-fold greater increase in IFNγ levels in a patient's peripheral blood, serum, or plasma compared with intravenous administration of an equivalent dose.
Co-administration with pembrolizumab
Co-administering pembrolizumab before, together with, or after administration of a fusion protein defined as SEQ ID NO:1, including separate compositions and dosing options.
The claim coverage centers on periodically subcutaneous administration of a SEQ ID NO:1 (or ≥80% identity) circularly permuted IL-2 variant fusion protein to reduce CD4+ regulatory T cells and increase CD8+ memory T cells for treating cancer, with the periodic interval constrained to once every about 3 days to once every about 60 days. Dependent claims further define subcutaneous formulation options, comparative immunologic ratios versus daily dosing, quantified cytokine differences versus intravenous at equivalent dose, and co-administration with pembrolizumab.
Stated Advantages
Reduces CD4+ regulatory T cells while increasing CD8+ memory T cells.
Enhanced CD8+ T-cell and memory phenotype expansion with minimal CD4+ Treg expansion.
Reduced T-cell exhaustion/inactivation.
Improved anti-tumor efficacy.
Lower systemic pro-inflammatory cytokine effects, including a lower IL-6 rise versus intravenous at an equivalent dose.
Higher IFNγ induction versus intravenous at an equivalent dose.
Improved tolerability and reduced risks such as capillary leak syndrome (CLS) and cytokine release syndrome (CRS) compared with daily subcutaneous/intravenous or high-dose IL-2.
Documented Applications
Treating cancer in a patient using periodic subcutaneous dosing of the fusion protein of SEQ ID NO:1 (or ≥80% identity variant).
Combination cancer therapy with pembrolizumab as PD-1/PD-L1 pathway blockade alongside the periodic subcutaneous fusion protein regimen.
Examples and supporting evidence are described across tumor contexts and diseases including an MC38 tumor model and tumor types including renal cell carcinoma (RCC), melanoma, NSCLC, SCLC, SCCHN, and HCC.
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