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Compositions and methods for cancer immunotherapy

A cancer, course of treatment technology, applied in the field of compositions and methods for cancer immunotherapy, which can solve problems such as toxicity

Pending Publication Date: 2022-04-29
ALKERMES PHARMA IRELAND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, it was hypothesized that a direct interaction between rhIL-2 and the high-affinity IL-2R expressed on vascular and pulmonary endothelial cells leads to rhIL-2-mediated toxicity through capillary leak syndrome
Despite poor tolerability, immunotherapy with rhIL-2 remains one of the few treatment options for metastatic melanoma and RCC that elicits complete and durable responses in a subset of patients

Method used

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  • Compositions and methods for cancer immunotherapy
  • Compositions and methods for cancer immunotherapy
  • Compositions and methods for cancer immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] The first human clinical data described in Example 1 show that the fusion protein of SEQ ID NO: 1 activates the expansion of CD8+ cells and NK cells in a dose-dependent manner, but there is no dose-dependent activation of Treg. Thus, a fusion protein of SEQ ID NO: 1 can be administered in a human patient at a concentration that causes equal or greater expansion of NK cells and CD8+ cells compared to high-dose rhIL-2, but has Much lower (at least two-fold lower) relative expansion of immunosuppressive Tregs (Table 2). This result was unexpected.

[0094] Dosing regimen

[0095] Preferably, the fusion protein of SEQ ID NO: 1 is administered to cancer patients according to the methods and dosage regimens of the present invention. Preferred routes of administration are intravenous, eg, intravenous injection, and intravenous infusion, eg, via central venous access. Additional routes of administration include subcutaneous, intramuscular, oral, nasal and pulmonary adminis...

Embodiment

[0246] Example 1 - Intravenous as monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors The SEQ ID administered within Phase 1 study of NO:1 fusion protein.

[0247] The fusion protein of SEQ ID NO: 1 is designed to selectively activate medium affinity IL-2R consisting of IL-2R beta and gamma to activate cytotoxic CD8 + The circular sequences of T cells and NK cells reconstitute a fusion of IL-2 and IL-2 receptor alpha (IL-2Rα). Intermediate-affinity IL-2R is predominantly expressed on effector lymphocytes, which play an important role in driving antitumor immune responses. Wild-type IL-2 is activated by IL-2Rα, β and γ c Constitutes high-affinity IL-2R, thereby driving immunosuppressive CD4 at lower concentrations than activating effector cells carrying intermediate-affinity IL-2R + Adjust T(T reg ) cell expansion. Selective activation of intermediate-affinity IL-2R has the potential to enhance tumor killing and exhibits enhanced a...

Embodiment 2

[0279] Example 2 - Peripheral blood lymphocyte responses in renal cell carcinoma (RCC) patients treated with high dose IL-2.

[0280] background

[0281] Recombinant human interleukin-2 (rhIL-2, aldesleukin) is approved for the treatment of metastatic melanoma and renal cell carcinoma 1-8 . However, due to the associated capillary leak syndrome and resulting hypotension, the use of rhIL-2 is limited to patients with normal cardiac and pulmonary function 9-12 .

[0282] Despite the poor tolerability associated with rhIL-2 therapy, it remains one of the few treatment options for metastatic melanoma and renal cell carcinoma that elicits complete and durable responses in subpopulations of patients, with up to 12%, up to 7% in renal cell carcinoma 7,8 . It has been hypothesized that rhIL-2 preferentially activates and induces expansion of immunosuppressive CD4+ Tregs 13 , and high doses of IL-2 are required to induce signaling on receptor complexes expressed on potentiall...

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Abstract

The present invention provides compositions and improved methods for treating cancer using IL-2 immunotherapy. The methods of the invention comprise administering to a patient a fusion protein of SEQ ID NO: 1 at a dose of about 6 [mu] g / kg / day to about 70 [mu] g / kg / day, and preferably at a dose of at least about 6 [mu] g / kg / day to about 15 [mu] g / kg / day, or based on, for example, an adult of about 60 to about 70 kg on average, or based on, for example, a child of about 12 to about 50 kg or heavier, a corresponding fixed daily dose, wherein the administration results in a dose-dependent increase in circulating NK cells and CD8 + cells in the patient without a dose-dependent increase in circulating immunosuppressive T-regulated (Treg) cells, and preferably wherein the increase in circulating NK cells and CD8 + cells is more than the increase in circulating Treg cells.

Description

[0001] Related applications [0002] This application claims the benefit of U.S. Provisional Application Nos. 62 / 860,182, filed June 11, 2019, 62 / 932,160, filed November 7, 2019, and 62 / 924,356, filed October 22, 2019. The entire teaching of the foregoing application is hereby incorporated by reference. Background technique [0003] Interleukin-2 (IL-2) is a cytokine that induces the proliferation of antigen-activated T cells and stimulates natural killer (NK) cells. The biological activity of IL-2 is mediated through the multisubunit IL-2 receptor complex (IL-2R) of three polypeptide subunits spanning the cell membrane: p55 (IL-2Rα, α subunit, also known as CD25 in humans ), p75 (IL-2R13, beta subunit, also known as CD122 in humans) and p64 ​​(IL-2Rγ, γ subunit, also known as CD132 in humans). The T cell response to IL-2 depends on several factors, including: (1) the concentration of IL-2; (2) the number of IL-2R molecules on the cell surface; and (3) the amount of IL-2 oc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/20A61K38/17A61K39/395A61P35/00A61P35/02
CPCA61K38/2013A61K38/1793A61K9/0019A61K39/3955A61P35/00A61P35/02A61K47/6425A61K45/06A61K9/19A61K2300/00C07K14/55C12N5/0636C12N2501/2302C12N5/0646C07K14/7155C07K2319/00A61K38/16C07K16/2818C07K14/155
Inventor H·C·洛西孙蕾
Owner ALKERMES PHARMA IRELAND LTD