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-11980652-B2
Publication Date
2024-05-14
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 by periodically subcutaneously administering a fusion protein of SEQ ID NO: 1, including a circularly permuted IL-2/IL-2Rα fusion protein (cpIL-2:IL-2Rα). The fusion protein selectively targets an intermediate-affinity IL-2 receptor (IL-2Rβγ) and is used to enhance CD8+ T-cell and NK-cell activation while minimizing regulatory T-cell (Treg) expansion.
The approach is described as mitigating T-cell exhaustion/inactivation while promoting immune activation relevant to cancer treatment. Periodic subcutaneous administration is positioned to improve immune outcomes and tolerability compared with other administration approaches described in the document, including effects on cytokines and specific tolerability risks such as capillary leak syndrome (CLS), cytokine release syndrome (CRS), tumor lysis syndrome (TLS), and neurotoxicity.
The document further supports periodic dosing once every about 3 days to once every about 60 days, including embodiments that narrow the dosing interval and that administer a dose of the specified fusion protein or a fusion protein with sequence identity at least 80% over a contiguous sequence of at least about 20 amino acids up to the full length of SEQ ID NO: 1. It additionally describes optional combination therapy, including co-administration with an immune checkpoint inhibitor that targets PD-1/PD-L1.
Claims Coverage
The partial claim set contains three independent claims: one covering a general method of treating cancer, one directed specifically to small cell lung cancer (SCLC), and one directed specifically to ovarian cancer. Across these independent claims, the core inventive elements are the specific IL-2/IL-2Rα fusion protein sequence (SEQ ID NO: 1, including defined sequence-identity variants) and subcutaneous periodic administration within a defined dosing interval range.
Periodically subcutaneously administering a defined cpIL-2:IL-2Rα fusion protein variant
Periodically subcutaneously administering to a patient a dose of a fusion protein of SEQ ID NO: 1, or a fusion protein having a sequence identity of at least 80% over a contiguous sequence of at least about 20 amino acids up to the full length of SEQ ID NO: 1, wherein the periodic dosing is once every about 3 days to once every about 60 days.
Subcutaneously administering the defined fusion protein for small cell lung cancer
Subcutaneously administering to a 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 at least about 20 amino acids up to the full length of SEQ ID NO: 1 to treat small cell lung cancer (SCLC) in a patient.
Subcutaneously administering the defined fusion protein for ovarian cancer
Subcutaneously administering to a 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 at least about 20 amino acids up to the full length of SEQ ID NO: 1 to treat ovarian cancer in a patient.
Overall, the independent claims cover cancer treatment using subcutaneous administration of SEQ ID NO: 1 (or a sequence-identity variant defined relative to SEQ ID NO: 1). The general cancer claim further requires periodic dosing once every about 3 days to once every about 60 days, while the SCLC and ovarian cancer claims are directed to those specific cancer types using the defined fusion protein.
Stated Advantages
Enhances CD8+ T-cell and NK-cell activation.
Minimizes regulatory T-cell (Treg) expansion.
Mitigates T-cell exhaustion/inactivation.
Provides PK advantages with lower Cmax and prolonged exposure versus IV/daily SC in the described comparison.
Provides cytokine-related advantages with higher IFNγ fold-change and lower IL-6 fold-change as described.
Improves anti-tumor efficacy with reduced tolerability risks, including mitigation of capillary leak syndrome (CLS), cytokine release syndrome (CRS), tumor lysis syndrome (TLS), and neurotoxicity.
Documented Applications
Treating cancer in a patient using periodically subcutaneous administration of the specified fusion protein variant.
Treating small cell lung cancer (SCLC) in a patient using subcutaneous administration of the specified fusion protein variant.
Treating ovarian cancer in a patient using subcutaneous administration of the specified fusion protein variant.
Combination therapy with an immune checkpoint inhibitor targeting PD-1/PD-L1 (including pembrolizumab) as described in the document.
A Phase 1/2 clinical study with described endpoints and biomarker assessments (circulating immune subsets; IFNγ and IL-6; PK; anti-drug antibodies) as described in the partial content.
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