Compositions and Methods for Targeted Immunomodulatory Antibodies and Fusion Proteins
First Claim
1. A molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein:
- (a) the targeting moiety specifically binds a target molecule, and(b) the immunomodulatory moiety specifically binds to a molecule selected from;
(i) Transforming growth factor-beta (TGF-β
);
Transforming growth factor-beta receptor (TGF-β
R);
Programmed death-1 ligand 1 (PD-L1;
B7-H1) or Programmed death-1 ligand 2 (PD-L2;
B7-DC);
Programmed death-1 (PD-1);
Receptor activator of nuclear factor-κ
B ligand (RANKL);
or Receptor activator of nuclear factor-κ
B (RANK); and
(ii) 4-1BB (CD137);
4-1BB ligand (4-1BBL;
CD137L);
OX40 (CD134;
TNR4);
OX40 ligand (OX40L);
glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR;
AITR);
GITR ligand (GITRL);
HVEM;
LIGHT;
CD27;
or CD70.
2 Assignments
0 Petitions
Accused Products
Abstract
The present invention is based on the seminal discovery that targeted immunomodulatory antobodies and fusion proteins can counter act or reverse immune tolerance of cancer cells. Cancer cells are able to escape elimination by chemotherapeutic agents or tumor-targeted antobodies via specific immunosuppressive mechanisms in the tumor microenvironment and such ability of cancer cells is recognized as immune tolerance. Such immuno-suppressive mechanisms include immunosuppressive cytokines (for example, Transforming growth factor beta (TGF-β)) and regulatory T cells and/or immunosuppressive myeloid dendritic cells (DCs). By conteracting tumor-induced immune tolerance, the present invention provides effective compositions and methods for cancer treatment, optional in combination with another existing cancer treatment. The present invention provides strategies to counteract tumor-induced immune tolerance and enhance the antitumor efficacy of chemotherapy by activating and leveraging T cell-mediated adaptive antitumor immunity against resistant or disseminated cancer cells.
103 Citations
63 Claims
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1. A molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein:
-
(a) the targeting moiety specifically binds a target molecule, and (b) the immunomodulatory moiety specifically binds to a molecule selected from; (i) Transforming growth factor-beta (TGF-β
);
Transforming growth factor-beta receptor (TGF-β
R);
Programmed death-1 ligand 1 (PD-L1;
B7-H1) or Programmed death-1 ligand 2 (PD-L2;
B7-DC);
Programmed death-1 (PD-1);
Receptor activator of nuclear factor-κ
B ligand (RANKL);
or Receptor activator of nuclear factor-κ
B (RANK); and(ii) 4-1BB (CD137);
4-1BB ligand (4-1BBL;
CD137L);
OX40 (CD134;
TNR4);
OX40 ligand (OX40L);
glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR;
AITR);
GITR ligand (GITRL);
HVEM;
LIGHT;
CD27;
or CD70. - View Dependent Claims (2, 4, 5, 6, 7, 8, 10, 11, 12, 14, 15, 16, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 55, 56, 57, 58, 59)
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3. (canceled)
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9. (canceled)
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13. (canceled)
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17. (canceled)
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21. (canceled)
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53-54. -54. (canceled)
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60-61. -61. (canceled)
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62. A method of treatment of a neoplastic disease comprising:
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administering to a subject in need thereof an antibody or Fc-containing fusion protein that targets CD4 in combination with another therapy, wherein the neoplastic disease is not a T cell malignancy, and the therapy comprises one or more of the following; (i) an immunostimulatory molecule; (ii) a tumor-targeted antibody;
or(iii) a cytotoxic anticancer agent.
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63-67. -67. (canceled)
Specification