JP-2022513888-A5 -

Dates

Publication Date

20221206

Application Date

20191213

Description

While embodiments of the present invention have been described with reference to the accompanying drawings, it should be understood that the present invention is not limited to specific embodiments and that various modifications and alterations can be made thereto by those skilled in the art without departing from the scope or spirit of the invention as defined in the accompanying claims. The present invention provides, for example, the following items: (Item 1) An activatable proprotein comprising a first polypeptide and a second polypeptide, wherein each of the first and second polypeptides comprises a masking portion operably linked to IL-15 or a variant via a first C-terminal linker, the IL-15 or a variant linked to IL-15Rα or a variant via a second C-terminal linker, and the masking portion masks the active portion of the proprotein. (Item 2) The activatable proprotein according to item 1, wherein the first linker on the first or second polypeptide, or on both the first and second polypeptides, is a cleavable linker. (Item 3) An activatable proprotein according to any one of items 1 to 2, wherein the second linker on the first or second polypeptide, or on both the first and second polypeptides, is a cleavable linker. (Item 4) An activatable proprotein according to any one of items 1 to 3, wherein the IL-15 or a variant thereof and the IL-15Rα or a variant thereof in the first polypeptide and the IL-15 or a variant thereof and the IL-15Rα or a variant thereof in the second polypeptide contain one or more Cys substitution mutations. (Item 5) The activatable proprotein according to item 4, wherein IL-15 or a variant in the first polypeptide containing one or more Cys substitution mutations forms a disulfide bond with IL-15Rα or a variant in the second polypeptide containing one or more Cys substitution mutations, or IL-15 or a variant in the second polypeptide containing one or more Cys substitution mutations forms a disulfide bond with IL-15Rα or a variant in the first polypeptide containing one or more Cys substitution mutations. (Item 6) A dimeric proprotein, an activatable proprotein as described in any one of items 1 to 5. (Item 7) The activatable proprotein according to item 6, wherein the dimeric proprotein comprises a first polypeptide and a second polypeptide, each having a masking portion linked from the N-terminus to the C-terminus via the first linker to the IL-15 or a variant thereof, wherein the IL-15 or a variant thereof is linked to the IL-15Rα or a variant thereof via the second linker, and the masking portion of the first polypeptide forms one or more covalent disulfide bonds or one or more non-covalent bonds with the masking portion of the second polypeptide. (Item 8) The activatable proprotein according to any one of items 1 to 7, wherein the masking portion in the first polypeptide comprises one or more protein domains. (Item 9) The activatable proprotein according to any one of items 1 to 8, wherein the masking portion in the second polypeptide comprises one or more protein domains. (Item 10) The activatable proprotein according to any one of items 1 to 9, wherein the masking portion in the first polypeptide does not bind to the antigen. (Item 11) The masking portion in the first polypeptide is an activatable proprotein according to any one of items 1 to 9, wherein the masking portion binds to an antigen. (Item 12) The activatable proprotein according to any one of items 1 to 9, wherein the masking portion in the second polypeptide does not bind to the antigen. (Item 13) An activatable proprotein according to any one of items 1 to 9, wherein the masking portion in the second polypeptide binds to an antigen. (Item 14) The activatable proprotein according to any one of items 1 to 13, wherein the masking portion in the first polypeptide comprises a CH1, CH2, CH3, CH2CH3, or CH1CH2CH3 domain in the antibody constant (Fc) region. (Item 15) The activatable proprotein according to any one of items 1 to 14, wherein the masking portion in the first polypeptide comprises one or more heterodimers of at least two different CH3 variant domains of the antibody constant (Fc) region. (Item 16) The activatable proprotein according to any one of items 1 to 9 and 11, wherein the masking portion in the first polypeptide comprises a fusion of the antigen-binding domain with the CH1, CH2, CH3, CH2CH3, or CH1CH2CH3 domain of the antibody constant (Fc) region. (Item 17) The activatable proprotein according to any one of items 1 to 13, wherein the masking portion in the second polypeptide comprises a CH1, CH2, CH3, CH2CH3, or CH1CH2CH3 domain in the antibody constant (Fc) region. (Item 18) The activatable proprotein according to any one of items 1 to 13 or 17, wherein the masking portion in the second polypeptide comprises one or more heterodimers of at least two different CH3 variant domains of the antibody constant (Fc) region. (Item 19) The activatable proprotein according to any one of items 1 to 9 and 1