Bispecific binding agent-ligand fusions for the degradation of target proteins
AssigneeThe Regents of the University of California
InventorsJames A. WELLS, Katarina PANCE, Josef A. GRAMESPACHER, Kaan Kumru
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Abstract
The present disclosure relates to targeted degradation platform technology. For example, the present disclosure relates to bispecific binding agents for degrading endogenous proteins, whether membrane-associated or soluble, using the lysosome pathway. The disclosure also provides methods useful for producing such agents, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating an activity of a cell and/or for the treatment of various disorders.
Claims79
A bispecific binding agent comprising:
- a) a first binding domain comprising a cytokine selected from the group consisting of CXCL12, CCL1, CCL2, CCL3, CCL3L1, CCL4, CC4L1, CCL5, CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCL11, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL13, CXCL14, CXCL16, CXCL17, CX3CL1, XCL1, XCL2, vMIPII, vCXC1 that specifically binds to at least one endogenous cell surface receptor, and
- b) a second binding domain that specifically binds to a target protein, wherein the endogenous cell surface receptor is membrane associated, and wherein the binding of the first binding domain to the at least one endogenous cell surface receptor results in the internalization of the target protein bound to the bispecific binding agent.
A bispecific binding agent comprising:
- a) a first binding domain that specifically binds to at least one endogenous cell surface receptor, and
- b) a second binding domain that specifically binds to a target protein,
- wherein the endogenous cell surface receptor is membrane associated, and wherein the binding of the first binding domain to the at least one endogenous cell surface receptor results in the internalization of the target protein bound to the bispecific binding agent.
The bispecific binding agent of any preceding claim, wherein the first binding domain specifically binds to one endogenous cell surface receptor.
The bispecific binding agent of any preceding claim wherein the first binding domain specifically binds to no more than two endogenous cell surface receptors.
The bispecific binding agent of any preceding claim, wherein the at least one endogenous cell surface receptor comprises targeting receptors and recycling receptors.
The bispecific binding agent of any one of the preceding claims, wherein the at least one endogenous cell surface receptor comprises single-pass and multi-pass membrane proteins.
The bispecific binding agent of any one of the preceding claims, wherein the at least one endogenous cell surface receptor comprises at least one cytokine receptor.
The bispecific binding agent of any one of the preceding claims, wherein the binding of the first binding domain to the at least one endogenous cell surface receptor results in the degradation of the target protein bound to the bispecific binding agent.
The bispecific binding agent of any one of the preceding claims, wherein the target protein comprises a soluble target protein and a membrane-associated target protein.
The bispecific binding agent of any one of the preceding claims, wherein the target protein is a membrane-associated target protein, and wherein the second binding domain binds to an extracellular epitope of a membrane-associated target protein.
The bispecific binding agent of any one of the preceding claims, wherein the target cell comprises a neoplastic cell.
The bispecific binding agent of any one of the preceding claims, wherein the target cell is a cancer cell selected from the group consisting of breast cancer, B cell lymphoma, pancreatic cancer, Hodgkin's lymphoma, ovarian cancer, prostate cancer, mesothelioma, lung cancer, non-Hodgkin's B-cell (B-NHL), melanoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, neuroblastoma, glioma, glioblastoma, bladder cancer, and colorectal cancer.
The bispecific binding agent of any one of the preceding claims, wherein the target cell comprises an immune cell.
The bispecific binding agent of any one of the preceding claims, wherein the target protein is an immune checkpoint protein.
The bispecific binding agent of any one of the preceding claims, wherein the target protein comprises a cancer antigen.
The bispecific binding agent of any one of the preceding claims, wherein the cancer antigen comprises HER2, EGFR, CDCP1, CD38, IGF-1R, MMP14, and TROP2.
The bispecific binding agent of any one of the preceding claims, wherein the target protein comprises an immunomodulatory protein.
The bispecific binding agent of any one of the preceding claims, wherein the immunomodulatory protein comprises PD-L1, PD-1, CTLA-4, B7-H3, B7-H4, LAG3, NKG2D, TIM-3, VISTA, CD39, CD73 (NT5E), A2AR, SIGLEC7, and SIGLEC15.
The bispecific binding agent of any one of the preceding claims, wherein the target protein comprises a B cell antigen.
The bispecific binding agent of any one of the preceding claims, wherein the B cell antigen comprises CD19 and CD20.
The bispecific binding agent of any one of the preceding claims, wherein the target protein comprises a soluble target protein.
The bispecific binding agent of any one of the preceding claims, wherein the soluble target protein comprises an inflammatory cytokine, a growth factor (GF), a toxic enzyme, an autoantibody, a target associated with metabolic diseases, or a neuronal aggregate.
The bispecific binding agent of any one of the preceding claims, wherein the inflammatory cytokine comprises lymphotoxin, interleukin-1 (IL-1), IL-2, IL-5, IL-6, IL-12, IL-13, IL-17, IL-18, IL-23, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF).
The bispecific binding agent of any one of the preceding claims, wherein the growth factor comprises EGF, FGF, NGF, PDGF, VEGF, IGF, GMCSF, GCSF, TGF, RANK-L, erythropieitn, TPO, BMP, HGF, GDF, neurotrophins, MSF, SGF, GDF, and an isoform thereof.
The bispecific binding agent of any one of the preceding claims, wherein the toxic enzyme comprises a protein arginine deiminase 1 (PAD1), PAD2, PAD3, PAD4, and PAD6, leucocidin, hemolysin, coagulase, treptokinase, hyaluronidase.
The bispecific binding agent of any one of the preceding claims, wherein the neuronal aggregate comprises Aβ, TTR, α-synuclein, TAO, and prion.
The bispecific binding agent of any one of the preceding claims, wherein the first binding domain and the second binding domain are each independently selected from the group consisting of natural ligands or a fragment, derivative, or small molecule mimetic thereof, IgG, half antibodies, single-domain antibodies, nanobodies, Fabs, monospecific Fab2, Fc, scFv, minibodies, IgNAR, V-NAR, hcIgG, VHH domains, camelid antibodies, and peptibodies.
The bispecific binding agent of any one of the preceding claims, wherein the first binding domain and the second binding domain together form a bispecific antibody, a bispecific diabody, a bispecific Fab2, a bispecific camelid antibody, a bispecific peptibody, scFv-Fc, a bispecific IgG, and a knob and hole bispecific IgG, a Fc-Fab, a knob and hole bispecific Fc-Fab, a cytokine-IgG fusion, a cytokine-Fab fusion, a cytokine-Fc-scFc fusion.
The bispecific binding agent of any one of the preceding claims, wherein the first binding domain comprises an Fc-fusion, and the second binding domain comprises a Fc-Fab.
The bispecific binding agent of any one of the preceding claims, comprising one or more sequences selected from Table 2.
A nucleic acid that encodes the bispecific binding agent of any one of the preceding claims.
An immunoconjugate comprising:
- i) a bispecific binding agent of any one of the preceding claims,
- ii) a small molecule, and
- iii) a linker.
A pharmaceutical composition, comprising the bispecific binding agent, the nucleic acid, the vector, the engineered cell, or the immunoconjugate of any one of the preceding claims, and a pharmaceutically acceptable excipient.
A method of treating a disorder in a subject, the method comprising administering to a subject in need thereof, a therapeutically effective amount of the bispecific binding agent, the nucleic acid, the vector, the engineered cell, the immunoconjugate, or the pharmaceutical composition of any one of the preceding claims.
Dependencies are inferred from the claim text.