# US 12,599,675 B2 · Conjugate of immune-stimulating il-2 analog and preparation method thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,599,675 B2 - Document ID: US12599675B2 - Status: Granted - Kind: B2 - Application number: 18/000,096 - Filed: 2022-03-31 - Published: 2024-01-11 - Granted: 2026-04-14 - Earliest claimed: 2021-03-31 - Assignees: Hanmi Pharm. Co., Ltd. - Applicants: Hanmi Pharm. Co., Ltd. - Inventors: Yong Ho Heo; Euh Lim Oh; Da Hyeon Park; Jin Young Kim; Jun Sub Park; Yu Yon Kim; A Ram Lee; Sang Yun Kim - Web page: https://patentgrep.com/patent/US12599675B2 ## CPC - A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - A61K 38/20: Interleukins [IL] - A61K 38/2013: {IL-2} - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/6813: {the drug being a peptidic cytokine, e.g. an interleukin or interferon} - A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment} - A61P 35/00: Antineoplastic agents - C07K 14/55: IL-2 - C07K 16/46: Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00) - C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} - C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract The present invention relates to a long-acting conjugate of an interleukin-2 analog with altered binding affinity for interleukin-2 receptors. ## Claims ### Claim 1 A method for treating cancer, comprising administering to a human cancer patient in need thereof a pharmaceutical composition comprising a pharmaceutically effective amount of a long-acting conjugate and a pharmaceutically acceptable excipient, wherein the long-acting conjugate comprises an interleukin-2 analog, and is represented by Chemical Formula 1 below: X—La—F [Chemical Formula 1] wherein, X is an interleukin-2 analog having an increased binding affinity for interleukin-2 beta receptors compared to aldesleukin under a same condition; L is a polyethylene glycol linker; a is 0 or a natural number, with the proviso that when a is 2 or more, each L is independent of each other; F is an immunoglobulin Fc region in the form of a dimer; and — indicates a covalent linkage between X and L and between L and F; wherein the interleukin-2 analog comprises the amino acid sequence of SEQ ID NO: 87, wherein the cancer is selected from the group consisting of metastatic renal cell cancer, metastatic melanoma, colorectal cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, and breast cancer. ### Claim 2 (depends on 1) The method of claim 1, wherein the pharmaceutical composition exhibits one or more of the following properties: (i) high blood exposure relative to aldesleukin; (ii) high tumor growth inhibitory activity compared to aldesleukin, (iii) high memory T cell-generating response compared to aldesleukin; wherein the pharmaceutical composition is administered via an intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, or intrarectal route; or wherein the pharmaceutical composition is administered at a time interval ranging from 1 week to 1 month. ### Claim 3 (depends on 1) The method of claim 1, wherein the polyethylene glycol linker has a molecular weight of 2 kDa to 30 kDa. ### Claim 4 (depends on 1) The method of claim 1, wherein the immunoglobulin Fc region is those derived from IgG, IgA, IgD, IgE, IgM, or a combination thereof, or a hybrid thereof; wherein the immunoglobulin Fc region is an IgG4 Fc region; wherein the immunoglobulin Fc region is non-glycosylated; wherein the L contains ethylene glycol repeating units, and the formula weight of the ethylene glycol repeating unit moiety is in the range of 1 kDa to 100 kDa; or wherein the long-acting conjugate is a long-acting conjugate in which one molecule of X is covalently linked to one of the Fc regions of the dimeric immunoglobulin Fc region via the polyethylene glycol linker. ### Claim 5 (depends on 3) The method of claim 3, wherein the immunoglobulin Fc region is an immunoglobulin Fc region of IgG, IgA, IgD, IgE, IgM, or a combination thereof, or a hybrid thereof; or wherein the immunoglobulin Fc region is non-glycosylated. ### Claim 6 (depends on 5) The method of claim 5, wherein the immunoglobulin Fc region is an IgG4 Fc region. ### Claim 7 A method for treating cancer, comprising administering to a human cancer patient in need thereof a pharmaceutical composition comprising a pharmaceutically effective amount of a long-acting conjugate and a pharmaceutically acceptable excipient, wherein the long-acting conjugate comprises an interleukin-2 analog, and is represented by Chemical Formula 1 below: X—La—F [Chemical Formula 1] wherein, X is an interleukin-2 analog having an increased binding affinity for interleukin-2 beta receptors compared to aldesleukin under a same condition; L is a polyethylene glycol linker; a is 0 or a natural number, with the proviso that when a is 2 or more, each L is independent of each other; F is an immunoglobulin Fc region in the form of a dimer; and — indicates a covalent linkage between X and L and between L and F; wherein the interleukin-2 analog comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 22, 42, and 53, wherein the cancer is selected from the group consisting of metastatic renal cell cancer, metastatic melanoma, and colorectal cancer. ### Claim 8 (depends on 7) The method of claim 7, wherein the pharmaceutical composition exhibits one or more of the following properties: (i) high blood exposure relative to aldesleukin; (ii) high tumor growth inhibitory activity compared to aldesleukin, (iii) high memory T cell-generating response compared to aldesleukin; wherein the pharmaceutical composition is administered via an intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, or intrarectal route; or wherein the pharmaceutical composition is administered at a time interval ranging from 1 week to 1 month. ### Claim 9 (depends on 7) The method of claim 7, wherein the polyethylene glycol linker has a molecular weight of 2 kDa to 30 kDa. ### Claim 10 (depends on 7) The method of claim 7, wherein the immunoglobulin Fc region is those derived from IgG, IgA, IgD, IgE, IgM, or a combination thereof, or a hybrid thereof; wherein the immunoglobulin Fc region is an IgG4 Fc region; wherein the immunoglobulin Fc region is non-glycosylated; wherein the L contains ethylene glycol repeating units, and the formula weight of the ethylene glycol repeating unit moiety is in the range of 1 kDa to 100 kDa; or wherein the long-acting conjugate is a long-acting conjugate in which one molecule of X is covalently linked to one of the Fc regions of the dimeric immunoglobulin Fc region via the polyethylene glycol linker. ### Claim 11 (depends on 10) The method of claim 10, wherein the immunoglobulin Fc region is an immunoglobulin Fc region of IgG, IgA, IgD, IgE, IgM, or a combination thereof, or a hybrid thereof; or wherein the immunoglobulin Fc region is non-glycosylated. ### Claim 12 (depends on 11) The method of claim 11, wherein the immunoglobulin Fc region is an IgG4 Fc region.