DUAL ACTING CD1D IMMUNOGLOBULIN
The present invention relates to the field of immunology, more in particular to the field of binding moieties and/or immunoglobulins which bind to human CD1d, including antibodies and fragments thereof that modify CD1d-mediated biological functions such as enhanced activation and reduced activation of CD1d-restricted T cells, including the natural killer T-cells and gamma-delta T-cells, and modulation of the function of cells expressing CD1d. The invention also relates to bi-, tri- or multi-specific immunoglobulins that bind to CD1d and a gamma-delta TCR and/or a tumor target. The invention further relates to pharmaceutical preparations and use of such mono-, bi-, and tri- or multi-specific binding moieties and/or immunoglobulins in the treatment of diseases or disorders.
1 . A method for the treatment of disorders caused, maintained and/or propagated by CD1d-restricted Vδ1+ T-cell activation comprising administering to a subject a binding molecule comprising a binding moiety that is able to compete with the single domain antibody set forth in SEQ ID NO:4 in binding to a CD1d molecule.
2 . A binding molecule comprising a first binding moiety that is able to compete with the antibody set forth in SEQ ID NO:4 in binding to a CD1d molecule and comprising a second binding moiety that is able to specifically bind to a Vγ9Vδ2-TCR, wherein the binding molecule is able to activate Vγ9Vδ2 T cells.
3 . (canceled)
4 . A method for the treatment of a tumor comprising administering to a subject the binding molecule according to claim 2 .
5 . The binding molecule according to claim 2 , wherein the binding molecule is able to reduce Vδ1 T cell activation.
6 . The binding molecule according to claim 2 , wherein the binding molecule is able to activate iNKT cells.
7 . The binding molecule according to claim 2 , wherein the binding molecule binds to the same epitope on CD1d as the antibody set forth in SEQ ID NO:4.
8 . The binding molecule according to claim 2 , wherein the second binding moiety is able to compete with a single domain antibody having a sequence according to any one of SEQ ID NOs: 59-76 in binding to a Vγ9Vδ2-TCR.
9 . The binding molecule according to claim 2 , wherein the first and/or second-binding moiety is a binding moiety of an antibody.
10 . The binding molecule according to claim 2 , wherein the binding molecule binds to the same epitope on CD1d as the antibody set forth in SEQ ID NO:4, wherein the binding molecule is able to activate iNKT cells and wherein the first and second binding moieties are binding moieties of an antibody.
11 . The binding molecule according to claim 2 , wherein the first and/or second binding moiety is a single domain antibody.
12 . The binding molecule according to claim 2 , wherein the first binding moiety comprises a CDR1 sequence according to SEQ ID NO: 1, a CDR2 sequence according to SEQ ID NO: 2, and/or a CDR3 sequence according to SEQ ID NO: 3, or any of those sequences wherein, independently, any of the amino acids has been conservatively substituted, according to table 3.
13 . The binding molecule according to claim 2 , wherein the first binding moiety comprises the sequence set forth in SEQ ID NO: 85.
14 . The binding molecule according to claim 2 , wherein the second binding moiety comprises a CDR 1 sequence according SEQ ID NO: 5, a CDR 2 sequence according to SEQ ID NO: 6 and/or a CDR 3 sequence according to SEQ ID NO: 7; or a CDR 1 sequence according SEQ ID NO: 8, a CDR 2 sequence according to SEQ ID NO: 9 and/or a CDR 3 sequence according to SEQ ID NO: 10; or a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 12 and/or a CDR 3 sequence according to SEQ ID NO: 13; or a CDR 1 sequence according SEQ ID NO: 14, a CDR 2 sequence according to SEQ ID NO: 15 and/or a CDR 3 sequence according to SEQ ID NO: 16; or a CDR 1 sequence according SEQ ID NO: 17, a CDR 2 sequence according to SEQ ID NO: 18 and/or a CDR 3 sequence according to SEQ ID NO: 19; or a CDR 1 sequence according SEQ ID NO: 20, a CDR 2 sequence according to SEQ ID NO: 21 and/or a CDR 3 sequence according to SEQ ID NO: 22; or a CDR 1 sequence according SEQ ID NO: 23, a CDR 2 sequence according to SEQ ID NO: 24 and/or a CDR 3 sequence according to SEQ ID NO: 25; or a CDR 1 sequence according SEQ ID NO: 26, a CDR 2 sequence according to SEQ ID NO: 27 and/or a CDR 3 sequence according to SEQ ID NO: 28; or a CDR 1 sequence according SEQ ID NO: 29, a CDR 2 sequence according to SEQ ID NO: 30 and/or a CDR 3 sequence according to SEQ ID NO: 31; or a CDR 1 sequence according SEQ ID NO: 32, a CDR 2 sequence according to SEQ ID NO: 33 and/or a CDR 3 sequence according to SEQ ID NO: 34; or a CDR 1 sequence according SEQ ID NO: 35, a CDR 2 sequence according to SEQ ID NO: 36 and/or a CDR 3 sequence according to SEQ ID NO: 37; or a CDR 1 sequence according SEQ ID NO: 38, a CDR 2 sequence according to SEQ ID NO: 39 and/or a CDR 3 sequence according to SEQ ID NO: 40; or a CDR 1 sequence according SEQ ID NO: 41, a CDR 2 sequence according to SEQ ID NO: 42 and/or a CDR 3 sequence according to SEQ ID NO: 43; or a CDR 1 sequence according SEQ ID NO: 44, a CDR 2 sequence according to SEQ ID NO: 45 and/or a CDR 3 sequence according to SEQ ID NO: 46; or a CDR 1 sequence according SEQ ID NO: 47, a CDR 2 sequence according to SEQ ID NO: 48 and/or a CDR 3 sequence according to SEQ ID NO: 49; or a CDR 1 sequence according SEQ ID NO: 50, a CDR 2 sequence according to SEQ ID NO: 51 and/or a CDR 3 sequence according to SEQ ID NO: 52; or a CDR 1 sequence according SEQ ID NO: 53, a CDR 2 sequence according to SEQ ID NO: 54 and/or a CDR 3 sequence according to SEQ ID NO: 55; or a CDR 1 sequence according SEQ ID NO: 56, a CDR 2 sequence according to SEQ ID NO: 57 and/or a CDR 3 sequence according to SEQ ID NO: 58, or any of those sequences wherein, independently, any of the amino acids has been conservatively substituted, according to table 3.
15 . The binding molecule according to claim 2 , wherein the second binding moiety comprises the sequence set forth in SEQ ID NO: 86 or SEQ ID NO: 88.
16 . The binding molecule according to claim 2 , wherein the binding molecule comprises the sequence set forth in SEQ ID NO: 87.
17 . The binding molecule according to claim 2 , further comprising a tumor targeting moiety.
18 . The method according to claim 4 , wherein the tumor is selected from hematological malignancies such as T cell lymphoma, multiple myeloma, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, B cell lymphoma, smoldering myeloma, Hodgkin lymphoma, myelomonocytic leukemias, lymphoplasmacytic lymphoma, hairy cell leukemia, and splenic marginal zone lymphoma, or solid tumors, such as renal cell carcinoma, melanoma, colorectal carcinoma, head and neck cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, gastro-esophageal cancer, small bowel carcinoma, central nervous system tumors, medulloblastomas, hepatocellular carcinoma, ovarian cancer, glioma, neuroblastoma, urothelial carcinomas, bladder cancer, sarcoma, penile cancer, basal cell carcinoma, merkel cell carcinoma, neuroendocrine carcinoma, neuroendocrine tumors, carcinoma of unknown primary (CUP), thymoma, vulvar cancer, cervical carcinoma, testicular cancer, cholangiocarcinoma, appendicular carcinoma, mesothelioma, ampullary carcinoma, anal cancer, and choriocarcinoma.
19 . A pharmaceutical composition comprising a binding molecule according to claim 2 and a pharmaceutically acceptable excipient.