Compounds for targeted immunotherapy

Abstract

Compounds for targeted immunotherapy, compositions comprising the compounds and use of the compounds in the treatment of diseases such as cancer are disclosed. The compounds having the structure of formula TM-Ln-AM, wherein TM is a targeting moiety, AM is an activating moiety that is capable of activating a human dendritic cell, NK cell, or tumor cell, or a combination thereof, Ln is a linker, and n is an integer selected from 0 and 1.

What is claimed is: 
     
         1 . A compound having the structure of Formula (I):
   TM-L-AM   (I),
   wherein TM is a targeting moiety comprising an immunoglobulin, or functional fragment thereof, that specifically binds to a tumor antigen on a tumor cell, wherein the tumor antigen is selected from the group consisting of CD2, CD22, CD37, CD44, CD47, CD52, CD56, CD79, 5T4, AGS-5, AGS-16, BT-062, BTLA, CAIX, Cripto, EGFL7, EpCAM, EFAP, Folate Receptor, Ganglioside GM3, GD2, gpA33, ICOS, KIR, LAG-3, Lewis Y, Mesothelin, c-MET, MN Carbonic anhydrase IX, MUC16, Nectin-4, NKGD2, NOTCH, OX40L, PD-1, PD-L1, PSCA, RANKL, SLC44A4, Syndecan-1, TACI, TAG-72, Tenascin, and TIM3; AM is an activating moiety that is capable of binding specifically to human TLR7 or TLR8 and is capable of activating a human dendritic cell, NK cell, or tumor cell, or a combination thereof; and L is a linker.   
     
     
         2 . The compound of  claim 1 , wherein said human dendritic cell is a plasmacytoid dendritic cell. 
     
     
         3 . The compound of  claim 1 , wherein said human dendritic cell is a myeloid dendritic cell. 
     
     
         4 . The compound of  claim 1 , wherein the activating moiety is capable of binding specifically to human TLR7. 
     
     
         5 . The compound of  claim 4 , wherein the activating moiety is CL264, CL307, Gardiquimod, Loxoribine, or Imiquimod. 
     
     
         6 . The compound of  claim 1 , wherein the activating moiety is capable of binding specifically to human TLR8. 
     
     
         7 . The compound of  claims 1 , wherein said targeting moiety is capable of binding to a tumor cell specifically or preferably in comparison to a non-tumor cell. 
     
     
         8 . The compound of  claim 7 , wherein said the tumor cell is of a carcinoma, a sarcoma, a lymphoma, a myeloma, or a central nervous system cancer. 
     
     
         9 . The compound of  claim 1 , the antibody is selected from the group consisting of: Nivolumab, MPDL3280A, and Lambrolizumab. 
     
     
         10 . The compound of  claim 1 , wherein said targeting moiety comprises a functional fragment of said imunnogloblulin. 
     
     
         11 . The compound of  claim 10 , wherein said targeting moiety comprises a Fab, Fab′, F(ab′)2, single domain antibody, T and Abs dimer, Fv, scFv, dsFv, ds-scFv, Fd, linear antibody, minibody, diabody, bispecific antibody fragment, bibody, tribody, sc-diabody, kappa (lamda) body, BiTE, OVO-Ig, SIP, SMIP, DART, or an antibody analogue comprising one or more CDRs. 
     
     
         12 . The compound of  claim 1 , wherein said linker is a polypeptide. 
     
     
         13 . The compound of  claim 1 , wherein said linker is enzymatically cleavable. 
     
     
         14 . The compound of  claims 1 , wherein said linker is not enzymatically cleavable. 
     
     
         15 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         16 . The pharmaceutical composition of  claim 15 , further comprising a chemotherapeutic agent. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein said chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, imatanib, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, cytarabine, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristine, vinblastine, nocodazole, teniposide etoposide, gemcitabine, epothilone, vinorelbine, camptothecin, daunorubicin, actinomycin D, mitoxantrone, acridine, doxorubicin, epirubicin, or idarubicin. 
     
     
         18 . A method for treating a disease condition in a subject that is in need of such treatment, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         19 . The method of  claim 18 , wherein said disease condition is a tumor. 
     
     
         20 . The method of  claim 18 , wherein said disease condition comprises abnormal cell proliferation. 
     
     
         21 . The method of  claim 20 , wherein said abnormal cell proliferation comprises a pre-cancerous lesion. 
     
     
         22 . The method of  claim 20 , wherein, wherein said abnormal proliferation is of cancer cells. 
     
     
         23 . The method of  claim 22 , wherein said cancer is selected from the group consisting of: breast cancer, colorectal cancer, diffuse large B-cell lymphoma, endometrial cancer, follicular lymphoma, gastric cancer, glioblastoma, head and neck cancer, hepatocellular cancer, lung cancer, melanoma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma.