Cytokine-based therapies and methods
The disclosure relates to methods for redirecting an active form of an endogenous cytokine to a target cell or target tissue of interest in a biological system or subject in need thereof by administering a multi-specific binding molecule comprising (a) a binding domain that specifically binds to an active form of a cytokine and (b) a binding domain that specifically binds to an epitope on a molecule that is a marker on a target cell or tissue, wherein the multi-specific binding molecule, when bound to the cytokine, does not block or only partially blocks, the ability of the cytokine to bind to and agonize a cognate receptor for the cytokine.
1 . A method of redirecting an endogenous interleukin 15 (IL-15) to a tumor microenvironment in a subject suffering from cancer, the method comprising:
administering to the subject a composition that comprises a multispecific binding molecule that comprises:
(a) a first region that binds to the endogenous IL-15; and
(b) a second region that binds to a marker expressed in the tumor microenvironment in the subject,
wherein the administering redirects the endogenous IL-15 to the tumor microenvironment, thereby treating the cancer, wherein the endogenous IL-15 when complexed with the multispecific binding molecule retains its ability to bind to its cognate receptor, and wherein the composition does not comprise an exogenous IL-15.
2 . A method of redirecting an endogenous interleukin 2 (IL-2) to a tumor microenvironment in a subject suffering from cancer, the method comprising:
administering to the subject a composition that comprises a multispecific binding molecule that comprises:
(a) a first region that binds to the endogenous IL-2; and
(b) a second region that binds to a marker expressed in the tumor microenvironment in the subject,
wherein the administering redirects the endogenous IL-2 to the tumor microenvironment, thereby treating the cancer, wherein the endogenous IL-2 when complexed with the multispecific binding molecule retains its ability to bind its cognate receptor, and wherein the composition does not comprise an exogenous IL-2.
3 . The method of claim 1 , wherein the subject is a human.
4 . The method of claim 1 , wherein the administering results in activation of an immune cell subtype, wherein the immune cell subtype is a T cell subtype, a macrophage subtype, or a natural killer (NK)-cell subtype.
5 . The method of claim 4 , wherein the immune cell subtype is a T cell subtype.
6 . The method of claim 5 , wherein the T cell subtype is a CD4+ T cell or a CD8+ T cell.
7 . The method of claim 5 , wherein the T cell subtype is a CD8+ T cell.
8 . The method of claim 4 , wherein the immune cell subtype is an NK cell.
9 . The method of claim 8 , wherein the NK cell subtype is a CD56++ NK cell, or a CD56+ CD16+ NK cell.
10 . The method of claim 1 , wherein the administering results in a level of CD4+ T cells, CD4+ Treg cells, and B cells in a blood sample obtained from the subject that is substantially the same level of CD4+ T cells, CD4+ Treg cells, and B cells in the blood of the subject prior to the administering.
11 . The method of claim 1 , wherein the first region that binds to the endogenous IL-15 comprises a binding molecule selected from the group consisting of: a divalent antibody fragment, a fragment antigen-binding region, a minibody, a monovalent antibody, a single-chain variable fragment (scFv), a reduced immunoglobulin, a disulfide-stabilized variable fragment, a Fab fragment, a nanobody, an immunoglobulin domain antibody, a fynomer, and a darpin.
12 . The method of claim 11 , wherein the first region that binds to the endogenous IL-15 comprises an scFv.
13 . The method of claim 11 , wherein the first region that binds to the endogenous IL-15 comprises a Fab.
14 . The method of claim 1 , wherein the second region that binds to the marker expressed in the tumor microenvironment comprises a binding molecule selected from the group consisting of: a divalent antibody fragment, a fragment antigen-binding region, a minibody, a monovalent antibody, a single-chain variable fragment (scFv), a reduced immunoglobulin, a disulfide-stabilized variable fragment, a Fab fragment, a nanobody, an immunoglobulin domain antibody, a fynomer, and a darpin.
15 . The method of claim 14 , wherein the second region that binds to the marker expressed in the tumor microenvironment comprises an scFv.
16 . The method of claim 14 , wherein the second region that binds to the marker expressed in the tumor microenvironment comprises a Fab.
17 . The method of claim 1 , wherein the cell is an effector cell.
18 . The method of claim 2 , wherein the cell is an effector cell.
19 . A method comprising administering to a non-human subject a composition that comprises a multispecific binding molecule that comprises:
(a) a first region that binds to endogenous IL-2 or endogenous IL-15; and
(b) a second region that binds to a marker expressed by a cell in the non-human subject,
wherein the administering redirects the endogenous IL-2 or the endogenous IL-15 to the cell, wherein the endogenous IL-2 or the endogenous IL-15, when complexed with the multispecific binding molecule retains its ability to bind to a cognate receptor, and wherein the composition does not comprise an exogenous IL-2 or exogenous IL-15.
20 . A method comprising contacting a tissue with a composition in vitro, wherein the composition comprises a multispecific binding molecule that comprises:
(a) a first region that binds to IL-2 or IL-15; and
(b) a second region that binds to a marker expressed by a cell of the tissue,
wherein the upon binding to the IL-2 or IL-15, the multispecific binding molecule redirects the IL-2 or IL-15 to the cell of the tissue, wherein the IL-2 or IL-15 when complexed with the multispecific binding molecule retains its ability to bind to a cognate receptor, and wherein the composition does not comprise an exogenous IL-2 or exogenous IL-15.