Patent Publication Number: US-2018036424-A1

Title: Immune system enhancing immunotherapy for the treatment of cancer

Description:
FIELD OF THE INVENTION 
     Embodiments of the present disclosure are related to antibodies against a particular target (such as cancer associated antigen or cancer specific antigen) that are conjugated with an immune enhancer, recruiter or solicitor and compositions and methods thereof. 
     BACKGROUND OF THE DISCLOSURE 
     The treatment of cancer has progressed significantly with the development of pharmaceuticals that more efficiently target and kill cancer cells. To this end, researchers have taken advantage of cell-surface receptors and antigens selectively expressed by cancer cells to develop drugs based on antibodies that bind the tumor-specific or tumor-associated antigens. Cytotoxic molecules such as bacteria and plant toxins, radionuclides, and certain chemotherapeutic drugs have been chemically linked to monoclonal antibodies that bind tumor-specific or tumor-associated cell surface antigens. Such compounds are typically referred to as toxin, radionuclide, and drug “conjugates,” respectively. Often they also are referred to as immunoconjugates, radioimmunoconjugates and immunotoxins. 
     Despite the tumor selectivity afforded by drug conjugates, the use of toxins, radionuclides, and chemotherapeutic drugs continues to present several disadvantages in the clinical context. First, the manufacture of the drug conjugates are often hindered by stability issues such that the drug conjugate composition may be less stable than compositions containing the tumor-specific antibody alone. Second, the size of the drug conjugates may interfere with the binding affinity/specificity of the antibody component. 
     Thus, there remains a need for development of pharmaceuticals that more efficiently target and kill cancer cells and that seek to minimize the issues that exist with currently available drug conjugate compositions. There also remains a need for methods of using such specifically targeted pharmaceuticals to treat human diseases associated with cell proliferation, such as cancer. 
     SUMMARY OF THE INVENTION 
     Disclosed herein is a novel immune system enhancing immunotherapy involving an antibody against a tumor-associated antigen (TAA) or tumor-specific antigen (TSA) that is conjugated to an immune enhancer analogous to potent toxins. In this system, target cells are eliminated by natural cytotoxic processes of the immune system rather than being killed by toxins. The immune enhancer may be one of an antigenic protein, glycoprotein or polysaccharide derived from a virus, bacteria, or other microorganism. 
     Embodiments of the present invention contemplate immunoconjugates comprising an antibody and one or more immune enhancers, wherein the antibody is specific for a tumor antigen, and wherein the immune enhancer is an antigen derived from a viral entity or bacteria. 
     The present invention further contemplates immunoconjugates comprising one or more immune enhancers derived from a viral entity or bacteria, wherein the viral entity is a non-infectious, non-replicating virus, viral particle, virus-like particle (VLP), or antigenic component thereof. 
     According to some embodiments, an antibody to the tumor antigen aspartyl (asparaginyl) beta-hydroxylase (HAAH) polypeptide is conjugated with one or more immune enhancers. The immune enhancer may be a non-infectious, non-replicating virus or viral particle, for example, a bacteriophage or bacteriophage particle (e.g., lambda phage or lambda phage particle). In some embodiments, the immune enhancer may be a mycobacterial antigen such a tuberculosis (TB) antigen. 
     According to some embodiments, an antibody to the tumor antigen aspartyl (asparaginyl) beta-hydroxylase (HAAH) polypeptide is conjugated to both a non-replicating Lambda virus and TB antigens, as follows: 
       (Anti-HAAH)-(Non-Replicating Lambda Virus)-(TB Antigens). 
     This entity will bind to cancer cells expressing HAAH on their surface and subsequently recruit immune system components resulting in the cancer cell elimination without the negative effects associated with toxin. 
     The antibody and/or TB antigen may be chemically conjugated to the virus (e.g., Lambda virus) or, alternatively, the virus may be engineered to express the antibody (e.g., single chain fragment) and/or TB antigen on its surface. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     This application discloses immune system enhancing immunotherapy compositions and methods related to immunoconjugates that target or bind to tumor-associated antigens (TAA) or tumor-specific antigens (TSA) (“collectively, “tumor antigens”). Antibodies targeting tumor antigens (“anti-tumor antibody”) are conjugated with very strong immune enhancer(s), recruiter(s) or solicitor(s) (hereinafter “immune enhancer”) analogous to potent toxins. The immune enhancer may be protein nano-particles, microbial antigens, viral particles or antigenic fragments thereof, or a combination of these. The immunoconjugates of the present embodiments are thus capable of specifically targeting cancer cells expressing tumor antigen and subsequently recruiting immune system components resulting in the cancer cell elimination. 
     Immune Enhancers 
     The inventive composition contains a conjugate which comprises one or more immune enhancers. The immune enhancer is preferably an antigenic protein, glycoprotein or polysaccharide derived from a virus, bacteria, or other microorganism. In some embodiments, the immune enhancer is a viral antigen or an antigenic fragment/portion thereof or a bacterial antigen or a fragment thereof. In some embodiments, the immune enhancer is a viral antigen or an antigenic fragment/portion thereof or a bacterial antigen or a fragment thereof that can be recognized by autologous cytolytic T lymphocytes. 
     In some embodiments, the immune enhancer is a non-infectious, non-replicating virus or viral entity such as a viral particle or virus-like particle (VLP), or antigenic component thereof. Examples of viral entities include lentivirus, lambda virus and other bacteriophages. 
     The immune enhancer may be an antigenic protein (e.g., envelope protein or coat protein) or antigenic fragment thereof which contains at least one epitope. In some embodiments, the immune enhancer is a viral envelope glycoprotein. Examples of envelope glycoprotein include glycoprotein gp41, glycoprotein gp36, glycoprotein gp120, and fusogenic membrane glycoproteins. 
     In some embodiments, the immune enhancer is a tuberculosis (TB) antigen. The TB antigen may be selected from one or more of the following: ESAT-6, Ag85A, AG85B, MPT51, MPT64, CFP10, TB10.4, Mtb8.4, hspX, CFP6, Mtb12, Mtb9.9 antigens, Mtb32A, PstS-1, PstS-2, PstS-3, MPT 63, Mtb39, Mtb41, MPT83, 71-kDa, PPE 68, LppX, and antigenic portions thereof. 
     In some embodiments, the immune enhancer is viral hemagglutinin or antigenic fragment thereof. Viral hemagglutinin includes an influenza viral hemagglutinin protein such as influenza A viral hemagglutinin protein, influenza B viral hemagglutinin protein, or influenza C viral hemagglutinin protein. Influenza A is at least one member selected from the group consisting of H1, H2, H3, H5, H7 and H9. 
     In some embodiments, the immune enhancer is a viral particle or antigenic fragment thereof. The viral particle may be a lambda phage. The viral particle may be an adenovirus, adeno-associated virus (AAV), or lentivirus particle. 
     In some embodiments, the immune enhancer is a virus-like particle (VLP). In some embodiments, the immune enhancer is a virus-like particle of a bacteriophage. Examples of VLPs include, but are not limited to, the capsid proteins of Hepatitis B virus, measles virus, Sindbis virus, rotavirus, foot-and-mouth-disease virus, Norwalk virus the retroviral GAG protein, the retrotransposon Ty protein p1, the surface protein of Hepatitis B virus, human papilloma virus, RNA phages, Ty, fr-phage, GA-phage and Qβ-phage. 
     As will be readily apparent to those skilled in the art, the VLP of the present embodiments is not limited to any specific form. The particle can be synthesized chemically or through a biological process, which can be natural or non-natural. By way of example, this type of embodiment includes a virus-like particle or a recombinant form thereof. In some embodiments, the immune enhancer is a microbial antigen. The microbial antigen may be selected from the group consisting of a bacterial antigen, a mycobacterial antigen, a viral antigen, a fungal antigen, and a parasitic antigen. Preferred microbial antigens are lipopolysaccharides, hemagglutinins, Streptococcal antigens (e.g.,  Streptococcus pneumoniae  polysaccharide type 4) and influenza antigens (e.g., influenza virus hemagglutinin). 
     In some embodiments, the immune enhancer is a bacterial antigen, which may be derived from a bacterial species selected from the group consisting of  E. coli, Staphylococcus, Streptococcus, Pseudomonas, Clostridium difficile, Legionella, Pneumococcus, Haemophilus, Klebsiella, Enterobacter, Citrobacter, Neisseria, Shigella, Salmonella, Listeria, Pasteurella, Streptobacillus, Spirillum, Treponema, Actinomyces, Borrelia, Corynebacterium, Nocardia, Gardnerella, Campylobacter, Spirochaeta, Proteus, Bacteriodes, H. pylori,  and  Bacillus anthracis.  The mycobacterial antigen may be derived from a mycobacterial species such as  M. tuberculosis  and  M. leprae,  but is not so limited. The bacterial antigen may be selected from Panton-Valentine Leukocidin (PVL) antigen of  S. aureus, S. aureus  Type 5,  S. aureus  Type 8,  S. aureus  336,  S. epidermidis PS 1,  S. epidermidis  GP1, α-toxin, lipoteichoic acid (LTA) and microbial surface components recognizing adhesive matrix molecule (MSCRAMM) proteins. See U.S. Publication No. 20090074755, incorporated herein by reference in its entirety. 
     In some embodiments, the immune enhancer is a viral antigen, which may be derived from a viral species selected from the group consisting of HIV, Herpes simplex virus I, Herpes simplex virus 2, cytomegalovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, human papilloma virus, Epstein Barr virus, rotavirus, adenovirus, influenza A virus, respiratory syncytial virus, varicella-zoster virus, small pox, monkey pox and SARS. 
     In some embodiments, the immune enhancer is a fungal antigen, which may be derived from a fungal species that causes an infection selected from the group consisting of candidiasis, ringworm, histoplasmosis, blastomycosis, paracoccidioidomycosis, crytococcosis, aspergillosis, chromomycosis, mycetoma infections, pseudallescheriasis, and tinea versicolor infection. 
     In some embodiments, the immune enhancer is a parasitic antigen, which may be derived from a parasite species selected from the group consisting of  Entamoeba, Trypanosoma cruzi, Fascioliasis, Leishmaniasis, Plasmodium, Onchocerciasis, Paragonimus, Trypanosoma brucei, Pneumocystis, Trichomonas vaginalis, Taenia, Hymenolepsis, Echinococcus, Schistosoma, Necator americanus,  and  Trichuris trichuria.    
     Antibodies 
     The inventive compositions relate to immunoconjugates comprising an antibody. According to some embodiments, the antibody is an anti-tumor antibody. For example, immunoconjugates of the present embodiments contain antibodies to known cancer associated/specific antigen, or any target associated with undesirable or proliferating cells (e.g., prostate-specific antigen (PSA) for cancer and benign prostatic hypertrophy). 
     The antibody molecules can be of the various isotypes, including: IgG (e.g., IgG1, IgG2 (e.g., IgG2a, IgG2b), IgG3, IgG4), IgM, i.e., IgM/λ, IgA1, IgA2, IgD, or IgE. A preferred antibody molecule is an IgG isotype (e.g., IgG2). The antibody molecules can be full-length (e.g., an IgG1 or IgG4 antibody) or can include only an antigen-binding fragment (e.g., a Fab, F(ab′) 2 , Fv or a single chain Fv fragment). In some embodiments, the antibody is an engineered antibody molecule, e.g., a fully human or a humanized antibody. 
     Any suitable antibody can be used in the inventive composition. In some embodiments, the immunoconjugates comprise an antibody (e.g., monoclonal antibody) to aspartyl (asparaginyl) beta-hydroxylase (HAAH) polypeptide. See e.g., U.S. Pat. No. 6,835,370, U.S. Pat. No. 6,783,758, U.S. Pat. No. 6,797,696, U.S. Pat. No. 6,812,206, U.S. Pat. No. 6,815,415, U.S. Pat. No. 6,835,370, U.S. Pat. No. 7,094,556, each of which is incorporated herein by reference in their entireties. 
     The antibody may have known therapeutic effects as a “naked” antibody or as an immunoconjugate such as an antibody conjugated to a radionuclide, toxin or other drug. In the case of the latter, the immune enhancers may serve as an additional conjugate to the known therapeutic immunoconjugate or may serve as a substitute for the conjugated radionuclide, toxin or other drug. That is, the antibody backbone of the immunoconjugate may be used to form the immunoconjugates with the immune enhancers disclosed herein. Examples of antibodies suitable for use in the present embodiments include, but are not limited to, the following: efalizumab, alefacept, infliximab, etanercept, basiliximab, daclizumab, muromonab, trastuzumab, ibritumomab, bevacizumab, cetuximab, rituximab, omalizumab, alemtuzumab, edrecolomab, panitumumab, and adalimumab. 
     The antibodies used in the present embodiments react immunologically with a tumor antigen and are thus anti-tumor antigen antibodies. Examples of tumor antigens include HER2, (EGFR) HER1, HER3, HER4, VEGFR, CD20, EpCAM, KIAA1815, LOC157378, FU20421, DSCD75, GPR160, GPCR41, SLC1A5, CEA, TRAIL, TRAIL-receptor 1, TRAIL-receptor 2, lymphotoxin-beta receptor, CCR4, CD19, CD22, CD28, CD33, CD40, CD80, CSF-1R, CTLA-4, fibroblast activation protein (FAP), hepsin, melanoma-associated chondroitin sulfate proteoglycan (MCSP), prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), VEGF receptor 1, VEGF receptor 2, IGF1-R, TSLP-R, TIE-1, TIE-2, TNF-alpha, TNF like weak inducer of apoptosis (TWEAK), IL-1R, CEA, and IGF1-R. Among the most widely studied tumor antigens are melanoma associated antigens, prostate specific antigen (PSA), E6 and E7, carcinoembryonic antigen (CEA), p53, and gangliosides (e.g., GM2). Melanoma antigens including other MAGEs, MART-1, glycoprotein 100 (gp100), tyrosinase, BAGE, and GAGE. NY-ESO-1 may be targeted in the treatment of liver cancer. GD2 is expressed on the surfaces of a wide range of tumor cells including neuroblastoma, medulloblastomas, astrocytomas, melanomas, small-cell lung cancer, osteosarcomas and other soft tissue sarcomas. GD2 is thus a convenient tumor-specific target for immunotherapies. In some embodiments, the tumor antigen is a breast cancer tumor antigen. 
     Tumor antigens that may be targeted with the antibody have been recited throughout the specification and include but are not limited to HER 2 (p185), CD20, CD33, GD3 ganglioside, GD2 ganglioside, carcinoembryonic antigen (CEA), CD22, milk mucin core protein, TAG-72, Lewis A antigen, ovarian associated antigens such as OV-TL3 and MOv18, high molecular weight melanoma associated antigens recognized by antibody 9.2.27, HMFG-2, SM-3, B72.3, PR5C5, PR4D2, and the like. Other tumor antigens are described in U.S. Pat. No. 5,776,427, incorporated by reference herein in its entirety. 
     Tumor antigens can be classified in a variety of ways. Tumor antigens include antigens encoded by genes that have undergone chromosomal alteration. Many of these antigens are found in lymphoma and leukemia. Even within this classification, antigens can be characterized as those that involve activation of quiescent genes. These include BCL-1 and IgH (Mantel cell lymphoma), BCL-2 and IgH (Follicular lymphoma), BCL-6 (Diffuse large B-cell lymphoma), TAL-1 and TCR.delta. or SIL (I-cell acute lymphoblastic leukemia), c-MYC and IgH or IgL (Burkitt lymphoma), MUN/IRF4 and IgH (Myeloma), PAX-5 (BSAP) (Immunocytoma). 
     Other tumor antigens that involve chromosomal alteration and thereby create a novel fusion gene and/or protein include RARoa, PML, PLZF, NPM or NuM4 (Acute promyelocytic leukemia), BCR and ABL (Chronic myeloid/acute lymphoblastic leukemia), MLL (HRX) (Acute leukemia), E2A and PBX or HLF (B-cell acute lymphoblastic leukemia), NPM, ALK (Anaplastic large cell leukemia), and NPM, MLF-1 (Myelodysplastic syndrome/acute myeloid leukemia). 
     Other tumor antigens are specific to a tissue or cell lineage. These include cell surface proteins such as CD20, CD22 (Non-Hodgkin&#39;s lymphoma, B-cell lymphoma, Chronic lymphocytic leukemia (CLL)), CD52 (B-cell CLL), CD33 (Acute myelogenous leukemia (AML)), CD 10(gp100) (Common (pre-B) acute lymphocytic leukemia and malignant melanoma), CD3/T-cell receptor (TCR) (T-cell lymphoma and leukemia), CD79/B-cell receptor (BCR) (B-cell lymphoma and leukemia), CD26 (Epithelial and lymphoid malignancies), Human leukocyte antigen (HLA)-DR, HLA-DP, and HLA-DQ (Lymphoid malignancies), RCAS1 (Gynecological carcinomas, bilary adenocarcinomas and ductal adenocarcinomas of the pancreas), and Prostate specific membrane antigen (Prostate cancer). 
     Tissue- or lineage-specific tumor antigens also include epidermal growth factor receptors (high expression) such as EGFR (HER1 or erbB1) and EGFRvIII (Brain, lung, breast, prostate and stomach cancer), erbB2 (HER2 or HER2/neu) (Breast cancer and gastric cancer), erbB3 (HER3) (Adenocarcinoma), and erbB4 (HER4) (Breast cancer). 
     Tissue- or lineage-specific tumor antigens also include cell-associated proteins such as Tyrosinase, Melan-A/MART-1, tyrosinase related protein (TRP)-1/gp75 (Malignant melanoma), Polymorphic epithelial mucin (PEM) (Breast tumors), and Human epithelial mucin (MUC1) (Breast, ovarian, colon and lung cancers). 
     Tissue- or lineage-specific tumor antigens also include secreted proteins such as Monoclonal immunoglobulin (Multiple myeloma and plasmacytoma), Immunoglobulin light chains (Multiple Myeloma), alpha.-fetoprotein (Liver carcinoma), Kallikreins 6 and 10 (Ovarian cancer), Gastrin-releasing peptide/bombesin (Lung carcinoma), and Prostate specific antigen (Prostate cancer). 
     Still other tumor antigens are cancer testis (CT) antigens that are expressed in some normal tissues such as testis and in some cases placenta. Their expression is common in tumors of diverse lineages and as a group the antigens form targets for immunotherapy. Examples of tumor expression of CT antigens include MAGE-A1, -A3, -A6, -A12, BAGE, GAGE, HAGE, LAGE-1, NY-ESO-1, RAGE, SSX-1, -2, -3, -4, -5, -6, -7, -8, -9, HOM-TES-14/SCP-1, HOM-TES-85 and PRAME. Still other examples of CT antigens and the cancers in which they are expressed include SSX-2, and -4 (Neuroblastoma), SSX-2 (HOM-MEL-40), MAGE, GAGE, BAGE and PRAME (Malignant melanoma), HOM-TES-14/SCP-1 (Meningioma), SSX-4 (Oligodendrioglioma), HOM-TES-14/SCP-1, MAGE-3 and SSX-4 (Astrocytoma), SSX member (Head and neck cancer, ovarian cancer, lymphoid tumors, colorectal cancer and breast cancer), RAGE-1, -2, -4, GAGE-1-2, -3, -4, -5, -6, -7 and -8 (Head and neck squamous cell carcinoma (HNSCC)), HOM-TES14/SCP-1, PRAME, SSX-1 and CT-7 (Non-Hodgkin&#39;s lymphoma), and PRAME (Acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL)). 
     Other tumor antigens are not specific to a particular tissue or cell lineage. These include members of the carcinoembryonic antigen (CEA) CD66a, CD66b, CD66c, CD66d and CD66e. These antigens can be expressed in many different malignant tumors and can be targeted by immunotherapy. 
     Still other tumor antigens are viral proteins and these include Human papilloma virus protein (cervical cancer), and EBV-encoded nuclear antigen (EBNA)-1 (lymphomas of the neck and oral cancer). 
     Still other tumor antigens are mutated or aberrantly expressed molecules such as but not limited to CDK4 and beta-catenin (melanoma). 
     In some embodiments, the antigen is a tumor antigen. The tumor antigen may be selected from the group consisting of MART-1/Melan-A, gp100, adenosine deaminase-binding protein (ADAbp), FAP, cyclophilin b, colorectal associated antigen (CRC)-C017-1A/GA733, carcinoembryonic antigen (CEA), CAP-1, CAP-2, etv6, AML1, prostate specific antigen (PSA), PSA-1, PSA-2, PSA-3, prostate-specific membrane antigen (PSMA), T-cell receptor/CD3-zeta chain, and CD20. The tumor antigen may also be selected from the group consisting of MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE A11, MAGE-A12, MAGE-Xp2 (MAGE B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1, MAGE-C2, MAGE-C3, MAGE-C4, MAGE-C5). In still another embodiment, the tumor antigen is selected from the group consisting of GAGE -1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, GAGE-9. And in yet a further embodiment, the tumor antigen is selected from the group consisting of BAGE, RAGE, LAGE-1, NAG, GnT-V, MUM-1, CDK4, tyrosinase, p53, MUC family, HER2/neu, p21 ras, RCAS 1, α-fetoprotein, E-cadherin, α-catenin, β-catenin, .gamma.-catenin, p120ctn, gp100Pmel117, PRAME, NY-ESO-1, cdc27, adenomatous polyposis coli protein (APC), fodrin, Connexin 37, Ig-idiotype, p15, gp75, GM2 ganglioside, GD2 ganglioside, human papilloma virus proteins, Smad family of tumor antigens, Imp-1, P1A, EBV-encoded nuclear antigen (EBNA)-1, brain glycogen phosphorylase, SSX-1, SSX-2 (HOM-MEL-40), SSX-1, SSX-4, SSX-5, SCP-1 and CT-7, and c-erbB-2. 
     Cancer or tumor antigens can also be classified according to the cancer or tumor they are associated with (i.e., expressed by). Cancers or tumors associated with tumor antigens include acute lymphoblastic leukemia (etv6; am11; cyclophilin b), B cell lymphoma (Ig-idiotype); Burkitt&#39;s (Non-Hodgkin&#39;s) lymphoma (CD20); glioma (E-cadherin; α-catenin; β-catenin; .gamma.-catenin; p120ctn), bladder cancer (p21ras), biliary cancer (p21ras), breast cancer (MUC family; HER2/neu; c-erbB-2), cervical carcinoma (p53; p21ras), colon carcinoma (p21ras; HER2/neu; c-erbB-2; MUC family), colorectal cancer (Colorectal associated antigen (CRC)-C017-1A/GA733; APC), choriocarcinoma (CEA), epithelial cell-cancer (cyclophilin b), gastric cancer (HER2/neu; c-erbB-2; ga733 glycoprotein), hepatocellular cancer (α-fetoprotein), Hodgkin&#39;s lymphoma (Imp-1; EBNA-1), lung cancer (CEA; MAGE-3; NY-ESO-1), lymphoid cell-derived leukemia (cyclophilin b), melanoma (p15 protein, gp75, oncofetal antigen, GM2 and GD2 gangliosides), myeloma (MUC family; p21 ras), non-small cell lung carcinoma (HER2/neu; c-erbB-2), nasopharyngeal cancer (Imp-1; EBNA-1), ovarian cancer (MUC family; HER2/neu; c-erbB-2), prostate cancer (Prostate Specific Antigen (PSA) and its immunogenic epitopes PSA-1, PSA-2, and PSA-3; PSMA; HER2/neu; c-erbB-2), pancreatic cancer (p21ras; MUC family; HER2/neu; c-erbB-2; ga733 glycoprotein), renal (HER2/neu; c-erbB-2), squamous cell cancers of cervix and esophagus (viral products such as human papilloma virus proteins and non-infectious particles), testicular cancer (NY-ESO-1), T cell leukemia (HTLV-1 epitopes), and melanoma (Melan-A/MART-1; cdc27; MAGE-3; p21ras; gp100 Pmc117 ). 
     Still other cancer antigens are listed in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Tumor-specific antigens 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Lymphocyte 
                   
               
               
                 Gene 
                 Peptide 
                 Position 
                 Stimulation Method 
                 References 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 BAGE-1 
                 AARAVFLAL 
                  2-10 
                 autologous tumor cells 
                 Boel, 1995 
               
               
                   
               
               
                 GAGE-1, 2, 8 
                 YRPRPRRY 
                  9-16 
                 autologous tumor cells 
                 Van den Eynde, 1995 
               
               
                   
               
               
                 GAGE-3, 4, 5, 
                 YYWPRPRRY 
                 10-18 
                 autologous tumor cells 
                 De Backer, 1999 
               
               
                 6, 7 
                   
                   
                   
                   
               
               
                   
               
               
                 GnTV f   
                 VLPDVFIRC(V) 
                 intron 
                 autologous tumor cells 
                 Guilloux, 1996 
               
               
                   
               
               
                 HERV-K-MEL 
                 MLAVISCAV 
                 1-9 
                 autologous tumor cells 
                 Schiavetti, 2002 
               
               
                   
               
               
                 KK-LC-1 
                 RQKRILVNL 
                 76-84 
                 autologous tumor cells 
                 Fukuyama, 2006 
               
               
                   
                 EYSKECLKEF 
                 499-508 
                 peptide 
                 Monji, 2004 
               
               
                   
                 EYLSLSDKI 
                 770-778 
                 peptide 
                 Monji, 2004 
               
               
                   
               
               
                 LAGE-1 
                 MLMAQEALAFL 
                 ORF2 
                 autologous tumor cells 
                 Aarnoudse, 1999 
               
               
                   
                   
                  (1-11) 
                   
                   
               
               
                   
                 SLLMWITQC 
                 157-165 
                 peptide 
                 Rimoldi, 2000 
               
               
                   
                 LAAQERRVPR 
                 ORF2 
                 autologous tumor cells 
                 Wang, 1998 
               
               
                   
                   
                 (18-27) 
                   
                   
               
               
                   
                 ELVRRILSR 
                 103-111 
                 adenovirus-dendritic 
                 Sun, 2006 
               
               
                   
                   
                   
                 cells 
                   
               
               
                   
                 APRGVRMAV 
                 ORF2 
                 adenovirus-APC 
                 Slager, 2004b 
               
               
                   
                   
                 (46-54) 
                   
                   
               
               
                   
                 SLLMWITQCFLPVF 
                 157-170 
                 peptide 
                 Zeng, 2001 
               
               
                   
                 QGAMLAAQERRVPRAAE 
                 ORF2 
                 protein 
                 Slager, 2004a 
               
               
                   
                 VPR 
                 (14-33) 
                   
                   
               
               
                   
                 AADHRQLQLSISSCLQQ 
                 139-156 
                 protein 
                 Jager, 2000 
               
               
                   
                 L 
                   
                   
                   
               
               
                   
                 CLSRRPWKRSWSAGSCP 
                 ORF2 
                 peptide 
                 Slager, 2003 
               
               
                   
                 GMPHL 
                  (81-102) 
                   
                   
               
               
                   
                 CLSRRPWKRSWSAGSCP 
                 ORF2 
                 peptide 
                 Slager, 2003 
               
               
                   
                 GMPHL 
                  (81-102) 
                   
                   
               
               
                   
                 ILSRDAAPLPRPG 
                 108-120 
                 autologous tumor cells 
                 Wang, 2004 
               
               
                   
                 AGATGGRGPRGAGA 
                 37-50 
                 protein 
                 Hasegawa, 2006 
               
               
                   
               
               
                 MAGE-A1 
                 EADPTGHSY 
                 161-169 
                 autologous tumor cells 
                 Traversari, 1992 
               
               
                   
                 KVLEYVIKV 
                 278-286 
                 peptide 
                 Ottaviani, 2005 
               
               
                   
                   
                   
                   
                 Pascolo, 2001 
               
               
                   
                 SLFRAVITK 
                  96-104 
                 poxvirus-dendritic cells c   
                 Chaux, 1999a 
               
               
                   
                 EVYDGREHSA 
                 222-231 
                 poxvirus-dendritic cells 
                 Chaux, 1999a 
               
               
                   
                 RVRFFFPSL 
                 289-298 
                 poxvirus-dendritic cells 
                 Luiten, 2000a 
               
               
                   
                 EADPTGHSY 
                 161-169 
                 poxvirus-dendritic cells 
                 Luiten, 2000b 
               
               
                   
                 REPVTKAEML 
                 120-129 
                 autologous tumor cells 
                 Tanzarella, 1999 
               
               
                   
                 DPARYEFLW 
                 258-266 
                 poxvirus-dendritic cells 
                 Chaux, 1999a 
               
               
                   
                 ITKKVADLVGF 
                 102-112 
                 ALVAC-dendritic cells 
                 Corbière, 2004 
               
               
                   
                 SAFPTTINF 
                 62-70 
                 poxvirus-dendritic cells 
                 Chaux, 1999a 
               
               
                   
                 SAYGEPRKL 
                 230-238 
                 poxvirus-dendritic cells 
                 Chaux, 1999a 
               
               
                   
                 SAYGEPRKL 
                 230-238 
                 autologous tumor cells 
                 van der Bruggen, 1994a 
               
               
                   
                 TSCILESLFRAVITK 
                  90-104 
                 peptide 
                 Wang, 2007 
               
               
                   
                 PRALAETSYVKVLEY 
                 268-282 
                 peptide 
                 Wang, 2007 
               
               
                   
                 FLLLKYRAREPVTKAE 
                 112-127 
                 protein 
                 Chaux, 1999b 
               
               
                   
                 EYVIKVSARVRF 
                 281-292 
                 protein 
                 Chaux, 2001 
               
               
                   
               
               
                 MAGE-A2 
                 YLQLVFGIEV 
                 157-166 
                 peptide 
                 Kawashima, 1998 
               
               
                   
                 EYLQLVFGI 
                 156-164 
                 peptide 
                 Tahara, 1999 
               
               
                   
                 REPVTKAEML 
                 127-136 
                 autologous tumor cells 
                 Tanzarella, 1999 
               
               
                   
                 EGDCAPEEK 
                 212-220 
                 lentivirus-dendritic cells 
                 Breckpot, 2004 
               
               
                   
                 LLKYRAREPVTKAE 
                 121-134 
                 protein 
                 Chaux, 1999b 
               
               
                   
               
               
                 MAGE-A3 
                 EVDPIGHLY 
                 168-176 
                 autologous tumor cells 
                 Gaugler, 1994 
               
               
                   
                 FLWGPRALV d   
                 271-279 
                 peptide 
                 van der Bruggen, 1994b 
               
               
                   
                 KVAELVHFL 
                 112-120 
                 peptide 
                 Kawashima, 1998 
               
               
                   
                 TFPDLESEF 
                  97-105 
                 peptide 
                 Oiso, 1999 
               
               
                   
                 VAELVHFLL 
                 113-121 
                 peptide 
                 Miyagawa, 2006 
               
               
                   
                 MEVDPIGHLY 
                 167-176 
                 adeno-dendritic cells 
                 Bilsborouh, 2002 
               
               
                   
                 EVDPIGHLY 
                 168-176 
                 poxvirus-dendritic cells 
                 Schultz, 2001 
               
               
                   
                 REPVTKAEML 
                 127-136 
                 autologous tumor cells 
                 Tanzarella, 1999 
               
               
                   
                 AELVHFLLL i   
                 114-122 
                 adeno-dendritic cells 
                 Schultz, 2002 
               
               
                   
                 MEVDPIGHLY 
                 167-176 
                 peptide 
                 Herman, 1996 
               
               
                   
                 WQYFFPVIF 
                 143-151 
                 retrovirus-dendritic cells h   
                 Russo, 2000 
               
               
                   
                 EGDCAPEEK 
                 212-220 
                 lentivirus-dendritic cells 
                 Breckpot, 2004 
               
               
                   
                 KKLLTQHFVQENYLEY 
                 243-258 
                 protein 
                 Schultz, 2000 
               
               
                   
                 KKLLTQHFVQENYLEY 
                 243-258 
                 peptide 
                 Schultz, 2000 
               
               
                   
                 ACYEFLWGPRALVETS 
                 267-282 
                 protein 
                 Zhang, 2003 
               
               
                   
                 RKVAELVHFLLLKYR 
                 111-125 
                 peptide 
                 Cesson, 2010 
               
               
                   
                 VIFSKASSSLQL 
                 149-160 
                 peptide 
                 Kobayashi, 2001 
               
               
                   
                 VIFSKASSSLQL 
                 149-160 
                 peptide 
                 Kobayashi, 2001 
               
               
                   
                 VFGIELMEVDPIGHL 
                 161-175 
                 peptide 
                 Cesson, 2010 
               
               
                   
                 GDNQIMPKAGLLIIV 
                 191-205 
                 peptide 
                 Consogno, 2003 
               
               
                   
                 TSYVKVLHHMVKISG 
                 281-295 
                 protein 
                 Manici, 1999 
               
               
                   
                 RKVAELVHFLLLKYRA 
                 111-126 
                 protein 
                 Chaux, 1999b 
               
               
                   
                 FLLLKYRAREPVTKAE 
                 119-234 
                 protein 
                 Chaux, 1999b 
               
               
                   
               
               
                 MAGE-A4 
                 EVDPASNTY j   
                 169-177 
                 peptide after tetramer 
                 Kobayashi, 2003 
               
               
                   
                   
                   
                 sorting 
                   
               
               
                   
                 GVYDGREHTV 
                 230-239 
                 adeno-dendritic cells 
                 Duffour, 1999 
               
               
                   
                 NYKRCFPVI 
                 143-151 
                 peptide 
                 Miyahara, 2005 
               
               
                   
                   
                   
                   
                 Ottaviani, 2006 
               
               
                   
                 SESLKMIF 
                 156-163 
                 poxvirus-dendritic cells 
                 Zhang, 2002 
               
               
                   
               
               
                 MAGE-A6 
                 MVKISGGPR 
                 290-298 
                 autologous tumor cells 
                 Zorn, 1999 
               
               
                   
                 EVDPIGHVY 
                 168-176 
                 autologous tumor cells 
                 Benlalam, 2003 
               
               
                   
                 REPVTKAEML 
                 127-136 
                 autologous tumor cells 
                 Tanzarella, 1999 
               
               
                   
                 EGDCAPEEK 
                 212-220 
                 lentivirus-dendritic cells 
                 Breckpot, 2004 
               
               
                   
                 ISGGPRISY 
                 293-301 
                 autologous tumor cells 
                 Vantomme, 2003 
               
               
                   
                 LLKYRAREPVTKAE 
                 121-134 
                 protein 
                 Chaux, 1999b 
               
               
                   
               
               
                 MAGE-A9 
                 ALSVMGVYV 
                 223-231 
                 peptide 
                 Oehlrich, 2005 
               
               
                   
               
               
                 MAGE-A10 
                 GLYDGMEHL l   
                 254-262 
                 autologous tumor cells 
                 Huang, 1999 
               
               
                   
                 DPARYEFLW 
                 290-298 
                 poxvirus-dendritic cells 
                 Chaux, 1999a 
               
               
                   
               
               
                 MAGE-A12 
                 FLWGPRALV e   
                 271-279 
                 peptide 
                 van der Bruggen, 19994b 
               
               
                   
                 VRIGHLYIL 
                 170-178 
                 autologous tumor cells 
                 Heidecker, 2000 
               
               
                   
                   
                   
                   
                 Panelli, 2000 
               
               
                   
                 EGDCAPEEK 
                 212-220 
                 lentivirus-dendritic cells 
                 Breckpot, 2004 
               
               
                   
                 REPFTKAEMLGSVIR 
                 127-141 
                 peptide 
                 Wang, 2007 
               
               
                   
                 AELVHFLLLKYRAR 
                 114-127 
                 protein 
                 Chaux, 1999b 
               
               
                   
               
               
                 MAGE-C1 
                 SSALLSIFQSSPE 
                 137-149 
                 peptide 
                 Nuber, 2010 
               
               
                   
                 SFSYTLLSL 
                 450-458 
                 peptide 
                 Nuber, 2010 
               
               
                   
                 VSSFFSYTL 
                 779-787 
                 peptide 
                 Nuber, 2010 
               
               
                   
               
               
                 MAGE-C2 
                 LLFGLALIEV 
                 191-200 
                 autologous tumor cells 
                 Ma, 2004 
               
               
                   
                 ALKDVEERV 
                 336-344 
                 autologous tumor cells 
                 Ma, 2004 
               
               
                   
                 SESIKKKVL 
                 307-315 
                 autologous tumor cells 
                 Godelaine, 2007 
               
               
                   
               
               
                 mucin k   
                 PDTRPAPGSTAPPAHGV 
                   
                 transfected B cells 
                 Jerome, 1993 
               
               
                   
                 TSA 
                   
                   
                   
               
               
                   
               
               
                 NA88-A 
                 QGQHFLQKV 
                   
                 tumor-infiltrating 
                 Moreau-Aubry, 2000 
               
               
                   
                   
                   
                 lymphocytes 
                   
               
               
                   
               
               
                 NY-ESO-1/ 
                 SLLMWITQC 
                 157-165 
                 autologous tumor cells 
                 Jager, 1998 
               
               
                 LAGE-2 
                   
                   
                   
                 Chen, 2000 
               
               
                   
                   
                   
                   
                 Valmori, 2000 
               
               
                   
                 MLMAQEALAFL 
                 ORF2 
                 autologous tumor cells 
                 Aarnoudse, 1999 
               
               
                   
                   
                  (1-11) 
                   
                   
               
               
                   
                 ASGPGGGAPR 
                 53-62 
                 autologous tumor cells 
                 Wang, 1998 
               
               
                   
                 LAAQERRVPR 
                 ORF2 
                 autologous tumor cells 
                 Wang, 1998 
               
               
                   
                   
                 (18-27) 
                   
                   
               
               
                   
                 TVSGNILTIR 
                 127-136 
                 mRNA-transfected cells 
                 Matsuzaki, 2008 
               
               
                   
                 APRGPHGGAASGL 
                 60-72 
                 peptide 
                 Ebert, 2009 
               
               
                   
                 MPFATPMEA 
                  94-102 
                 autologous tumor cells 
                 Benlalam, 2003 
               
               
                   
                 KEFTVSGNILTI 
                 124-135 
                 mRNA-transfected cells 
                 Knights, 2009 
               
               
                   
                 MPFATPMEA 
                  94-102 
                 adenovirus-APC 
                 Jäger, 2002 
               
               
                   
                 LAMPFATPM 
                  92-100 
                 adenovirus-PBMC 
                 Gnjatic, 2000 
               
               
                   
                 ARGPESRLL 
                 80-88 
                 adenovirus-PBMC d   
                 Gnjatic, 2000 
               
               
                   
                 SLLMWITQCFLPVF 
                 157-170 
                 peptide 
                 Zeng, 2001 
               
               
                   
                 LLEFYLAMPFATPMEAE 
                  87-111 
                 peptide 
                 Mandic, 2005 
               
               
                   
                 LARRSLAQ 
                   
                   
                   
               
               
                   
                 LLEFYLAMPFATPMEAE 
                  87-111 
                 peptide 
                 Mandic, 2005 
               
               
                   
                 LARRSLAQ 
                   
                   
                   
               
               
                   
                 EFYLAMPFATPM 
                  89-100 
                 protein 
                 Chen, 2004 
               
               
                   
                 PGVLLKEFTVSGNILTI 
                 119-143 
                 peptide 
                 Ayyoub, 2010 
               
               
                   
                 RLTAADHR 
                   
                   
                   
               
               
                   
                 RLLEFYLAMPFA 
                 86-97 
                 protein 
                 Chen, 2004 
               
               
                   
                 QGAMLAAQERRVPRAAE 
                 ORF2 
                 protein 
                 Slager, 2004a 
               
               
                   
                 VPR 
                 (14-33) 
                   
                   
               
               
                   
                 PFATPMEAELARR 
                  95-107 
                 peptide 
                 Mizote, 2010 
               
               
                   
                 PGVLLKEFTVSGNILTI 
                 119-138 
                 peptide and protein 
                 Jager, 2000 
               
               
                   
                 RLT 
                   
                   
                 Zarour, 2000 
               
               
                   
                 VLLKEFTVSG 
                 121-130 
                 peptide 
                 Zeng, 2000 
               
               
                   
                 AADHRQLQLSISSCLQQ 
                 139-156 
                 protein 
                 Jager, 2000 
               
               
                   
                 L 
                   
                   
                   
               
               
                   
                 LLEFYLAMPFATPMEAE 
                  87-111 
                 peptide 
                 Mandic, 2005 
               
               
                   
                 LARRSLAQ 
                   
                   
                   
               
               
                   
                 LKEFTVSGNILTIRL 
                 123-137 
                 protein 
                 Bioley, 2009 
               
               
                   
                 PGVLLKEFTVSGNILTI 
                 119-143 
                 peptide 
                 Zarour, 2002 
               
               
                   
                 RLTAADHR 
                   
                   
                   
               
               
                   
                 LLEFYLAMPFATPMEAE 
                  87-111 
                 peptide 
                 Mandic, 2005 
               
               
                   
                 LARRSLAQ 
                   
                   
                   
               
               
                   
                 KEFTVSGNILT 
                 123-134 
                 peptide 
                 Mizote, 2010 
               
               
                   
                 LLEFYLAMPFATPM 
                  87-100 
                 peptide 
                 Mizote, 2010 
               
               
                   
                 AGATGGRGPRGAGA 
                 37-50 
                 protein 
                 Hasegawa, 2006 
               
               
                   
               
               
                 SAGE 
                 LYATVIHDI 
                 715-723 
                 peptide 
                 Miyahara, 2005 
               
               
                   
               
               
                 Sp17 
                 ILDSSEEDK 
                 103-111 
                 protein 
                 Chiriva-Internati, 2003 
               
               
                   
               
               
                 SSX-2 
                 KASEKIFYV 
                 41-49 
                 autologous tumor cells 
                 Ayyoub, 2002 
               
               
                   
                 EKIQKAFDDIAKYFSK 
                 19-34 
                 peptide 
                 Ayyoub, 2004a 
               
               
                   
                 WEKMKASEKIFYVYMKR 
                 37-54 
                 peptide 
                 Ayyoub, 2005a 
               
               
                   
                 K 
                   
                   
                   
               
               
                   
                 KIFYVYMKRKYEAMT 
                 45-59 
                 peptide 
                 Neumann, 2004 
               
               
                   
                 KIFYVYMKRKYEAM 
                 45-58 
                 protein 
                 Ayyoub, 2004b 
               
               
                   
               
               
                 SSX-4 
                 INKTSGPKRGKHAWTHR 
                 151-170 
                 peptide 
                 Ayyoub, 2005b 
               
               
                   
                 LRE 
                   
                   
                   
               
               
                   
                 YFSKKEWEKMKSSEKIV 
                 31-50 
                 peptide 
                 Ayyoub, 2005b 
               
               
                   
                 YVY 
                   
                   
                   
               
               
                   
                 MKLNYEVMTKLGFKVTL 
                 51-70 
                 peptide 
                 Valmori, 2006 
               
               
                   
                 PPF 
                   
                   
                   
               
               
                   
                 KHAWTHRLRERKQLVVY 
                 161-180 
                 peptide 
                 Valmori, 2006 
               
               
                   
                 EEI 
                   
                   
                   
               
               
                   
                 LGFKVTLPPFMRSKRAA 
                 61-80 
                 peptide 
                 Ayyoub, 2005b 
               
               
                   
                 DFH 
                   
                   
                   
               
               
                   
                 KSSEKIVYVYMKLNYEV 
                 41-60 
                 peptide 
                 Ayyoub, 2005b 
               
               
                   
                 MTK 
                   
                   
                   
               
               
                   
                 KHAWTHRLRERKQLVVY 
                 161-180 
                 peptide 
                 Valmori, 2006 
               
               
                   
                 EEI 
                   
                   
                   
               
               
                   
               
               
                 TAG-1 
                 SLGWLFLLL 
                 78-86 
                 peptide 
                 Adair, 2008 
               
               
                   
                 LSRLSNRLL 
                 42-50 
                 peptide 
                 Adair, 2008 
               
               
                   
               
               
                 TAG-2 
                 LSRLSNRLL 
                 42-50 
                 peptide 
                 Adair, 2008 
               
               
                   
               
               
                 TRAG-3 
                 CEFHACWPAFTVLGE 
                 34-48 
                 peptide 
                 Janjic, 2006 
               
               
                   
                 CEFHACWPAFTVLGE 
                 34-48 
                 peptide 
                 Janjic, 2006 
               
               
                   
                 CEFHACWPAFTVLGE 
                 34-48 
                 peptide 
                 Janjic, 2006 
               
               
                   
               
               
                 TRP2-INT2 g   
                 EVISCKLIKR 
                 intron 2 
                 autologous tumor cells 
                 Lupetti, 1998 
               
               
                   
               
               
                 XAGE-1b 
                 CATWKVICKSCISQTPG 
                 33-49 
                 autologous tumor cells 
                 Shimono, 2007 
               
               
                   
               
            
           
         
       
     
     The antibody molecule may be a fully human, chimeric or humanized monoclonal antibody, examples of which include huN901, huMy9-6 (ATCC PTA-4786, deposited on Nov. 15, 2002, American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110-2209), huB4, huC242, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab. The antibody may be the huN901 humanized monoclonal antibody or the huMy9-6 humanized monoclonal antibody. Other humanized monoclonal antibodies are known in the art and can be used in connection with the inventive composition. 
     In some embodiments, the antibody molecule of the immunoconjugates of the present invention is an anti-vascular endothelial growth factor (VEGF) antibody. For example, the anti-VEGF antibody molecule may be the monoclonal antibody bevacizumab (Avastin®), which is approved to treat a number of cancers. An immunoconjugate comprising bevacizumab (Avastin®) may be used for the treatment of the following conditions: colon cancer; rectal cancer; non-squamous, non-small cell lung cancer; breast cancer; glioblastoma brain cancer; renal cell carcinoma (a type of kidney cancer). 
     In some embodiments, the antibody molecule of the immunoconjugates of the present invention is an anti-CD20 antibody. For example, the anti-CD20 antibody molecule may be tositumomab (Bexxar®), a murine IgG2a lambda monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B lymphocytes. Tositumomab is produced in an antibiotic-free culture of mammalian cells and is composed of two murine gamma 2a heavy chains of 451 amino acids each and two lambda light chains of 220 amino acids each. Ibritumomab (Zevalin®) and rituximab (Rituxan®) are other anti-CD20 antibodies suitable for the present embodiments. An immunoconjugate comprising an anti-CD20 antibody may be used for the treatment of the following conditions: B cell non-Hodgkin&#39;s lymphoma, a lymphoproliferative disorder and thus affects the lymphatic system. 
     In some embodiments, the antibody molecule of the immunoconjugates of the present invention is an anti-CD33 antibody. 
     In some embodiments, the antibody molecule of the immunoconjugates of the present invention is an anti-HER2 antibody. For example, the anti-HER2 antibody molecule may be trastuzumab (Herceptin®). An immunoconjugate comprising an anti-HER2 antibody may be used for the treatment of breast cancer. 
     In some embodiments, the antibody molecule of the immunoconjugates of the present invention is an anti-epidermal growth factor receptor (EGFR) antibody. For example, the anti-EGFR antibody molecule may be Erbitux® (cetuximab), an epidermal growth factor receptor (EGFR) antagonist. An immunoconjugate comprising Erbitux® (cetuximab) may be used for the treatment of of locally or regionally advanced squamous cell carcinoma of the head and neck. Thus, in some embodiments, the antibody molecule binds EGFR, preferably a monoclonal antibody selected from the group consisting of: cetuximab, panitumumab, zalutumumab, nimotuzumab, necitumumab and matuzumab. 
     In some embodiments, the antibody molecule of the immunoconjugates of the present invention is an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) antibody. For example, the anti-CTLA-4 antibody molecule may be YERVOY™ (ipilimumab). An immunoconjugate comprising an anti-CTLA-4 antibody may be used for the treatment of melanoma. 
     In some embodiments, the immunoconjugates of the present embodiments comprise one or more of the following antibody molecules: an Anti-CD137 antibody; an Anti-CS1 antibody (e.g., Elotuzumab); an Anti-PD-L1 antibody; an Anti-PD1 antibody; and Anti-CD19 antibody; and an Anti-CXCR4 antibody. 
     Immunoconjugates 
     In some embodiments, the immune enhancer is chemically conjugated to the antibody. In some embodiments, the antibody and a first immune enhancer (fIE) may be chemically conjugated to a second immune enhancer (sIE). Examples of such embodiments may are described by the following formulas: 
       (Antibody)-(fIE)-(sIE) and 
       (fIE)-(Antibody)-(sIE). 
     For example, an anti-HAAH antibody may be chemically conjugated to a non-replicating lambda virus (or fragment thereof), which is also conjugated to one or more TB antigens resulting in an immunoconjugate with the following formula: 
       (Anti-HAAH)-(Non-Replicating Lambda Virus)-(TB Antigens). 
     This entity is capable of binding cancer cells expressing HAAH on their surface and promoting the subsequent recruitment of immune system components and systemic immune response. Use of the immunoconjugates of the present embodiments thus allows for the benefits of cancer cell elimination, specifically, without any toxic effect common with the use of toxins. 
     In some embodiments, where the immune enhancer is a virus, the virus is engineered to express the antibody (e.g., single chain fragment) and/or another immune enhancer (e.g., TB antigen) on its surface. 
     Compositions 
     The compositions of the present embodiments comprises a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to an immune enhancer. A “therapeutically effective amount” means an amount sufficient to show a meaningful benefit in an individual, e.g., promoting at least one aspect of tumor cell cytotoxicity, or treatment, healing, prevention, or amelioration of other relevant medical condition(s) associated with a particular cancer. Therapeutically effective amounts may vary depending upon the biological effect desired in the individual, condition to be treated, and/or the specific characteristics of the conjugate, and the individual. Thus, in accordance with the methods described herein, the attending physician (or other medical professional responsible for administering the composition) will typically decide the amount of the composition with which to treat each individual patient. The concentration of the conjugate in the inventive composition desirably is about 0.1 mg/mL to about 5 mg/mL (e.g., about 0.5 mg/mL, about 2 mg/mL, or about 5 mg/mL). In a preferred embodiment, the concentration of the conjugate in the inventive composition is about 1 mg/mL or higher (e.g., about 2 mg/mL or higher, about 3 mg/mL or higher, or about 4 mg/mL or higher). Most preferably, the concentration of the conjugate in the inventive composition is about 5 mg/mL. While compositions comprising at least 1 mg/mL of the conjugate are particularly preferred, conjugate concentrations of less than 1 mg/mL (e.g., concentrations of about 0.1 mg/mL to about 0.9 mg/mL) also can be stably maintained in the inventive composition, and thus are within the scope of the invention. Compositions comprising greater than 1 mg/mL of the conjugate molecule are advantageous for clinical and commercial use, in that such concentrations enable single doses of the composition to be prepared in a more convenient (i.e., smaller) volume for administration, 
     The inventive composition desirably is formulated to be acceptable for pharmaceutical use, such as, for example, administration to a human host in need thereof. To this end, the conjugate molecule preferably is formulated into a composition comprising a physiologically acceptable carrier (e.g., excipient or diluent). Physiologically acceptable carriers are well known and are readily available, and include buffering agents, anti-oxidants, bacteriostats, salts, and solutes that render the formulation isotonic with the blood or other bodily fluid of the human patient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers (e.g., surfactants), and preservatives. The choice of carrier will be determined, at least in part, by the location of the target tissue and/or cells, and the particular method used to administer the composition. Examples of suitable carriers and excipients for use in drug conjugate formulations are known in the art. 
     Methods of Treatment 
     The invention provides methods that relate to a novel therapeutic strategy for the treatment of cancer. In particular, the method comprises administration of one or more immunoconjugates of the present embodiments or a pharmaceutical composition comprising such one or more immunoconjugates admixed with at least one pharmaceutically acceptable excipient. 
     The immunoconjugates of the present embodiments are useful to treat certain cancers. In some embodiments, the cancer is a hematopoietic cancer. In some embodiments, the hematopoietic cancer is selected from the group consisting of leukemia, lymphoma, and myeloma. 
     In some embodiments, the hematopoietic cancer is of lymphoid lineage. In some embodiments, the hematopoietic cancer is of lymphoid lineage is selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin&#39;s lymphoma, non-Hodgkin&#39;s lymphoma, hairy cell lymphoma and Burkett&#39;s lymphoma. 
     In some embodiments, the hematopoietic cancer is of myeloid lineage. In some embodiments, the hematopoietic cancer of myeloid lineage is selected from acute myelogenous leukemia, chronic myelogenous leukemia, multiple myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia. 
     In some embodiments, the cancer is a non-hematopoietic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; melanoma; neuroendocrine cancers; CNS cancers; brain tumors; bone cancer; and soft tissue sarcoma. In some embodiments it is lung cancer (non-small cell lung cancer, small-cell lung cancer), colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer or breast cancer. 
     According to some embodiments, methods are provided for killing a cell in a human comprising administering to the human a composition comprising a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to an immune enhancer. 
     The inventive method involves administering the inventive composition to a human. Ideally, the inventive method is used to target and kill cells affected by a disease, particularly a disease associated with elevated levels of cellular proliferation, such as cancer. Thus, in this regard, the inventive method preferably is used to kill tumor cells in a human, thereby resulting in the prevention, amelioration, and/or cure of the cancer. 
     While any suitable means of administering the composition to a human can be used within the context of the invention, typically and preferably the inventive composition is administered to a human via injection, and most preferably via infusion. By the term “injection,” it is meant that the composition is forcefully introduced into a target tissue of the human. By the term “infusion,” it is meant that the composition is introduced into a tissue, typically and preferably a vein, of the human. The composition can be administered to the human by any suitable route, but preferably is administered to the human intravenously or intraperitoneally. When the inventive method is employed to kill tumor cells, however, intratumoral administration of the inventive composition is particularly preferred. When the inventive composition is administered by injecting, any suitable injection device can be used to administer the composition directly to a tumor. For example, the common medical syringe can be used to directly inject the composition into a subcutaneous tumor. Alternatively, the composition can be topically applied to the tumor by bathing the tumor in the inventive liquid composition. Likewise, the tumor can be perfused with the inventive composition over a period of time using any suitable delivery device, e.g., a catheter. While less preferred, other routes of administration can be used to deliver the composition to the human. Indeed, although more than one route can be used to administer the inventive composition, a particular route can provide a more immediate and more effective reaction than another route. For example, while not particularly preferred, the inventive composition can be applied or instilled into body cavities, absorbed through the skin, inhaled, administered subcutaneously, intradermaly, intranasaly, or administered parenterally via, for instance, intramuscular or intraarterial administration. Preferably, the inventive composition parenterally administered to a human is specifically targeted to particular cells, e.g., cancer cells. 
     As described herein, the conjugate comprises an antibody, which may be a fully human, chimeric or humanized monoclonal antibody, such as an anti-tumor antibody. Suitable antibodies include, for example, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab. When compositions comprising such conjugates are employed in the inventive method, the antibody targets the conjugate to a desired cell (e.g., a tumor cell) through interactions with antigens (e.g., tumor-specific antigens) expressed at the surface of the cell (e.g., tumor cell). Tumor-specific antigens have been extensively described in the prior art for a variety of tumors, including, for example, epithelial cancers (e.g., MUC1), and breast and ovarian cancer (e.g., HER2/neu), and as described herein. 
     For the purposes of human administration, the inventive liquid composition described herein may be administered (e.g., infused) directly to a human, or diluted with a suitable diluent immediately prior to administration. Suitable diluents are known in the art and include D5W and normal saline (NS). Dilutions of 1:1, 1:2, 1:3, or more (e.g., 1:5, 1:10, or even 1:50) with suitable diluents are possible. Dilution of the inventive composition desirably does not reduce the concentration of the conjugate molecule in the composition below about 0.1 mg/mL. Upon diluting the inventive liquid composition, the previously described concentrations of each of the components (e.g., buffering agent, surfactant, and sodium chloride) of the composition are correspondingly reduced. 
     Definitions 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and claims. 
     The term “antibody,” as used herein, refers to any immunoglobulin, any antigen-binding portion, any immunoglobulin fragment, such as Fab, F(ab′) 2 , dsFv, sFv, diabodies, and triabodies, or immunoglobulin chimera, which can bind to an antigen on the surface of a cell (e.g., which contains a complementarity determining region (CDR)). Any suitable antibody can be used in the inventive composition. One of ordinary skill in the art will appreciate that the selection of an appropriate antibody will depend upon the cell population to be targeted. In this regard, the type and number of cell surface molecules (i.e., antigens) that are selectively expressed in a particular cell population (typically and preferably a diseased cell population) will govern the selection of an appropriate antibody for use in the inventive composition. Cell surface expression profiles are known for a wide variety of cell types, including tumor cell types, or, if unknown, can he determined using routine molecular biology and histochemistry techniques. 
     The antibody can be polyclonal or monoclonal, but is most preferably a monoclonal antibody. As used herein, “polyclonal” antibodies refer to heterogeneous populations of antibody, typically contained in the sera of immunized animals. “Monoclonal” antibodies refer to homogenous populations of antibody molecules that are specific to a particular antigen. Monoclonal antibodies are typically produced by a single clone of B lymphocytes (“B cells”). Monoclonal antibodies may be obtained using a variety of techniques known to those skilled in the art, including standard hybridoma technology. In brief, the hybridoma method of producing monoclonal antibodies typically involves injecting any suitable animal, typically and preferably a mouse, with an antigen (i.e., an “immunogen”). The animal is subsequently sacrificed, and B cells isolated from its spleen are fused with human myeloma cells. A hybrid cell is produced (i.e., a “hybridoma”), which proliferates indefinitely and continuously secretes high titers of an antibody with the desired specificity in vitro. Any appropriate method known in the art can be used to identify hybridoma cells that produce an antibody with the desired specificity. Such methods include, for example, enzyme-linked immunosorbent assay (ELISA), Western blot analysis, and radioimmunoassay. The population of hybridomas is screened to isolate individual clones, each of which secrete a single antibody species to the antigen. Because each hybridoma is a clone derived from fusion with a single B cell, all the antibody molecules it produces are identical in structure, including their antigen binding site and isotype. Monoclonal antibodies also may be generated using other suitable techniques including EBV-hybridoma technology or bacteriophage vector expression systems. To prepare monoclonal antibody fragments, recombinant methods typically are employed. 
     The monoclonal antibody can be isolated from or produced in any suitable animal, but is preferably produced in a mammal, more preferably a mouse, and most preferably a human. Methods for producing an antibody in mice are well known to those skilled in the art and are described herein. With respect to human antibodies, one of ordinary skill in the art will appreciate that polyclonal antibodies can be isolated from the sera of human subjects vaccinated or immunized with an appropriate antigen. Alternatively, human antibodies can be generated by adapting known techniques for producing human antibodies in non-human animals such as mice. 
     While being the ideal choice for therapeutic applications in humans, human antibodies, particularly human monoclonal antibodies, typically are more difficult to generate than mouse monoclonal antibodies. Mouse monoclonal antibodies, however, induce a rapid host antibody response when administered to humans, which can reduce the therapeutic or diagnostic potential of the antibody-drug conjugate. To circumvent these complications, a monoclonal antibody preferably is not recognized as “foreign” by the human immune system. To this end, phage display can be used to generate the antibody. In this regard, phage libraries encoding antigen-binding variable (V) domains of antibodies can be generated using standard molecular biology and recombinant DNA techniques. Phage encoding a variable region with the desired specificity are selected for specific binding to the desired antigen, and a complete human antibody is reconstituted comprising the selected variable domain. Nucleic acid sequences encoding the reconstituted antibody are introduced into a suitable cell line, such as a myeloma cell used for hybridoma production, such that human antibodies having the characteristics of monoclonal antibodies are secreted by the cell. Alternatively, monoclonal antibodies can be generated from mice that are transgenic for specific human heavy and light chain immunoglobulin genes. Such methods are known in the art. Most preferably the antibody is a humanized antibody. As used herein, a “humanized” antibody is one in which the complementarily-determining regions (CDR) of a mouse monoclonal antibody, which form the antigen binding loops of the antibody, are grafted onto the framework of a human antibody molecule. Owing to the similarity of the frameworks of mouse and human antibodies, it is generally accepted in the art that this approach produces a monoclonal antibody that is antigenically identical to a human antibody but binds the same antigen as the mouse monoclonal antibody from which the CDR sequences were derived. Methods for generating humanized antibodies are well known in the art. Humanized antibodies can also be generated using the antibody resurfacing technology. While the antibody employed in the conjugate of the inventive composition most preferably is a humanized monoclonal antibody, a human monoclonal antibody or a mouse monoclonal antibody, as described above, are also within the scope of the invention. 
     An antibody may be an antibody fragment. Antibody fragments that have at least one antigen binding site, and thus recognize and bind to at least one antigen or receptor present on the surface of a target cell, also are within the scope of the invention. In this respect, proteolytic cleavage of an intact antibody molecule can produce a variety of antibody fragments that retain the ability to recognize and bind antigens. For example, limited digestion of an antibody molecule with the protease papain typically produces three fragments, two of which are identical and are referred to as the Fab fragments, as they retain the antigen binding activity of the parent antibody molecule. Cleavage of an antibody molecule with the enzyme pepsin normally produces two antibody fragments, one of which retains both antigen-binding arms of the antibody molecule, and is thus referred to as the F(ab′) 2  fragment. A single-chain variable region fragment (sFv) antibody fragment, which consists of a truncated Fab fragment comprising the variable (V) domain of an antibody heavy chain linked to a V domain of a light antibody chain via a synthetic peptide, can be generated using routine recombinant DNA technology techniques. Similarly, disulfide-stabilized variable region fragments (dsFv) can be prepared by recombinant DNA technology. Antibody fragments of the present embodiments, however, are not limited to these exemplary types of antibody fragments. Any suitable antibody fragment that recognizes and binds to a desired cell surface receptor or antigen can be employed. Antibody-antigen binding can be assayed using any suitable method known in the art, such as, for example, radioimmunoassay (RIA), ELISA, Western blot, immunoprecipitation, and competitive inhibition assays. 
     In addition, the antibody can be a chimeric antibody. By “chimeric” is meant that the antibody comprises at least two immunoglobulins, or fragments thereof, obtained or derived from at least two different species (e.g., two different immunoglobulins, a human immunoglobulin constant region combined with a murine immunoglobulin variable region). 
     An “anti-tumor antibody” is an antibody that binds to a cancer or tumor antigen. The terms “cancer antigen” and “tumor antigen” are used interchangeably. 
     As used herein, the term “antigen” refers to a molecule capable of being bound by an antibody or a T cell receptor (TCR) if presented by MHC molecules. The term “antigen”, as used herein, also encompasses T-cell epitopes. At the molecular level, an antigen is characterized by its ability to be “bound” at the antigen-binding site of an antibody. An antigen is additionally capable of being recognized by the immune system. In some instances, an antigen is capable of inducing a humoral immune response. In some instances, an antigen is capable of inducing cellular immune response leading to the activation of B- and/or T-Iymphocytes. In some instance, an antigen may be antigenic and not immunogenic. For the purposes of the present embodiments, antigens are usually proteins or polysaccharides that includes parts (coats, capsules, cell walls, flagella, fimbrae, and toxins) of bacteria, viruses, and other microorganisms (e.g., a protein or polysaccharide derived from bacteria, virus, or other microorganism). 
     A “bacteriophage” is any one of a number of viruses that infect bacteria. 
     An “epitope”, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. 
     As used herein, “specific binding” refers to the property of the antibody, to: (1) to bind to the specific target antigen (e.g., a tumor antigen) with an affinity of at least 1×10 7  M −1 , and (2) preferentially bind to the target antigen (e.g., a tumor antigen) with an affinity that is at least two-fold, 50-fold, 100-fold, 1000-fold, or more greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) 
     A “virus particle” (also known as virions) consist of two or three parts: the genetic material made from either DNA or RNA; a protein coat that protects these genes; and in some cases an envelope of lipids that surrounds the protein coat when they are outside a cell. 
     As used herein, the term “virus-like particle” refers to a structure resembling a virus particle. Moreover, a virus-like particle in accordance with the invention is non-replicative and noninfectious since it lacks all or part of the viral genome, in particular the replicative and infectious components of the viral genome. Virus-like particles refer to structures resembling a virus particle but which are not pathogenic. In general, virus-like particles lack the viral genome and, therefore, are noninfectious. Also, virus-like particles can be produced in large quantities by heterologous expression and can be easily purified. 
     A virus-like particle may contain nucleic acid distinct from their genome. A virus-like particle may be a viral capsid such as the viral capsid of the corresponding virus, bacteriophage, or RNA-phage. The terms “viral capsid” or “capsid”, as interchangeably used herein, refer to a macromolecular assembly composed of viral protein subunits. Typically and preferably, the viral protein subunits assemble into a viral capsid and capsid, respectively, having a structure with an inherent repetitive organization, wherein said structure is, typically, spherical or tubular. For example, the capsids of RNA-phages or HBcAg&#39;s have a spherical form of icosahedral symmetry. The term “capsid-like structure” as used herein, refers to a macromolecular assembly composed of viral protein subunits resembling the capsid morphology in the above defined sense but deviating from the typical symmetrical assembly while maintaining a sufficient degree of order and repetitiveness. 
     As used herein, the term “virus-like particle of a bacteriophage” refers to a virus-like par structure of a bacteriophage, being non replicative and noninfectious, and lacking at least the gene or genes encoding for the replication machinery of the bacteriophage, and typically also lacking the gene or genes encoding the protein or proteins responsible for viral attachment to or entry into the host. This definition should, however, also encompass virus-like particles of bacteriophages, in which the aforementioned gene or genes are still present but inactive, and, therefore, also leading to non-replicative and noninfectious virus-like particles of a bacteriophage. 
     For the purposes of promoting an understanding of the embodiments described herein, reference will be made to preferred embodiments and specific language will be used to describe the same. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. As used throughout this disclosure, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a composition” includes a plurality of such compositions, as well as a single composition, and a reference to “a therapeutic agent” is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth. Thus, for example, a reference to “a hostcell” includes a plurality of such host cells, and a reference to “an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth. 
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