Human immune therapies using a cd27 agonist in combination with another immune agonist to treat cancer

Abstract

Methods of inducing T cell proliferation and expansion in vivo for treating conditions wherein antigen-specific T cell immune response are therapeutically desirable such as cancer, infection, inflammation, allergy and autoimmunity and for enhancing the efficacy of vaccines are provided. These methods comprise the administration of at least one CD27 agonist, preferably an agonistic CD27 antibody, alone or in association with another moiety such as immune stimulant or immune modulator such as an anti-CD40, OX-40, 4-1BB, or CTLA-4 antibody or an agent that depletes regulatory cells, or a cytokine. These mono and combination therapies may also optionally include the administration of a desired antigen such as a tumor antigen, an allergen, an autoantigen, or an antigen specific to an infectious agent or pathogen against which a T cell response (often CD8+) is desirably elicited.

1 . An agonistic anti-human CD27 antibody or an antigen binding fragment thereof. 
     
     
         2 . The agonistic antibody of  claim 1  which comprises one of more of the following:
 (i) it recognizes an extracellular portion of human CD70; 
 (ii) the binding of said antibody is not appreciably affected by human CD70 or CD70-related ligands; 
 (iii) it is selected from a human antibody, a chimeric antibody, a humanized antibody, bispecific antibody, primatized antibody and a single chain antibody; 
 (iv) it is attached to an effector moiety; 
 (v) it contains at least one human constant domain selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE constant domains; 
 (vi) is engineered to modify (enhance or diminish) at least one antibody effector function; 
 (vii) it is engineered to modify at least one of Fc glycosylation, binding to FcR, binding to FeRn, or complement binding; 
 (viii) it promotes T cell immune responses; or (ix) it promotes Th1 immune responses. 
 
     
     
         3 - 10 . (canceled) 
     
     
         11 . A method of promoting immunity in a subject in need thereof comprising administering at least one CD27 agonistic antibody according to  claim 1  to a subject with a condition or treatment wherein enhanced immunity is therapeutically desirable in an amount effective to promote immunity. 
     
     
         12 . The method of  claim 11  which comprises one or more of the following:
 (i) it enhances Th1 immunity; 
 (ii) it promotes the proliferation or survival of antigen-specific T cells; 
 (iii) it promotes the proliferation or survival of antigen-specific CD8 +  T cells; 
 (iv) it promotes the proliferation or survival of antigen-specific CD8 +  effector cells, or memory cells; 
 (v) it results in the generation of antigen-specific memory T cells; 
 (vi) it includes the administration of antigen; 
 (vii) the administered anti-CD27 antibody or antigen binding fragment promotes the expansion of T cells in an antigen-dependent manner; 
 (viii) the administered anti-CD27 antibody or antigen binding fragment is selected from a human antibody, primate antibody, chimeric antibody, humanized antibody, primatized antibody and single chain antibody; 
 (ix) the administered anti-CD27 antibody or antigen binding fragment is engineered to modify (enhance or diminish) at least one antibody effector function; 
 (x) the administered anti-CD27 antibody or antigen binding fragment (1) lacks glycosylation, 
 (xi) the administered anti-CD27 antibody or antigen binding fragment is modified to alter Fc glycosylation, (3) it comprises one or more Fc residue modifications, (4) it is modified to enhance or diminish binding to a specific FcR or (5) it comprises a combination of the foregoing modifications; 
 (xii) the administered anti-CD27 antibody or antigen binding fragment is modified to enhance or inhibit FcRn binding; 
 (xiii) the administered anti-CD27 antibody or antigen binding fragment comprises modifications that are selected from (1) modifications that reduce or enhance interaction with proteins of the complement system, or (2) modifications which reduce undesirable toxicity; 
 (xiv) the administered anti-CD27 antibody or antigen binding fragment is modified to inhibit toxicity elicited by release of cytokines; 
 (xv) the administered anti-CD27 antibody or antigen binding fragment contains at least one of human IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE constant domains; 
 (xvi) the administered anti-CD27 antibody or antigen binding fragment is an intact antibody selected from a group consisting of an intact IgG1 antibody, an intact IgG2 antibody, an intact IgG3 antibody, an intact IgG4 antibody, and intact IgM antibody, an intact IgA1 antibody, an intact IgA2 antibody, an intact secretory IgA antibody, an intact IgD antibody, or an intact IgE antibody; 
 (xvii) the administered anti-CD27 antibody or antigen binding fragment is used to treat a condition selected from cancer, infectious disease, inflammatory condition, autoimmune disease, and allergic condition; 
 (xviii) the administered anti-CD27 antibody or antigen binding fragment is used to treat an infectious disease caused by a bacterium, virus, mycobacterium, fungus, yeast or a parasite. 
 (xix) the administered anti-CD27 antibody or antigen binding fragment is used to treat an infectious disease caused by a parasite selected from  Babesia  sp.,  Entomoeba  sp,  Giarda  sp,  Plasmodium  sp,  Leishmania  sp,  Trypanosome  sp,  Toxoplasma  sp, flatworm and round worm parasites; or a bacterium is selected from  Escherichia, Staphylococcus, Pseudomonas, Streptococcus, Campylobacter, Listeria, Clostridium, Pasteurella, Pseudomonas, Neisseria, Enterococcus, Klebsiella, Heliobacter, Listeria, Salmonella, Corynebacterium, Haemophilus, Pasteurella, Bacteroides, Fusobacterium, Streptobacillus, Treponema, Leptospira, Rickettsia , and  Actinomyces  or a virus is selected from a retrovirus, picornavirus, enterovirus, hepatitis, poliovirus, Coxsackie's virus, rhinovirus, echovirus, Calciviridae, Togaviridae, Flaviviridae, Rhabdoviridae, Coronaviridae, Paramyxoviridae, Orthomyxoviridae, Filoviridae, Bungaviridae, Reoviridae, Adenoviridae, Bimaviridae, Papovaviridae, Herpeviridae, Iridoviridae, and unclassified viruses; or a fungus selected from  Aspergillus, Coccidoides, Blastomyces, Histoplasma, Chlamydia, Nocardia , and  Pneumocytis;    
 (xx) the administered anti-CD27 antibody or antigen binding fragment is used to treat a cancer selected from lymphoma, leukemia, chronic lymphocytic leukemia, breast cancer, prostate cancer, colon cancer, bone cancer, pancreatic cancer, stomach cancer, liver cancer, cervical cancer, bladder cancer, testicular cancer, kidney cancer, lung cancer (small and large cell), brain cancer, retinoblastoma, esophageal cancer, eye cancer, head and neck cancer, endometrial cancer, larynx cancer, melanoma, neuroblastoma, neuroblastoma, thyroid cancer, rhabdosarcoma, oral cavity cancer, uterine cancer, ovarian cancer, sarcoma, connective tissue cancer and skin cancer; 
 (xxi) the administered anti-CD27 antibody or antigen binding fragment is used to treat an autoimmune disease selected from multiple sclerosis, diabetes, psoriasis, Crohn's disease, inflammatory bowel disease, SLE, myasthenia gravis, Goodpasture's syndrome, ITP, Graves disease, hemolytic anemia, rheumatoid arthritis, Hashimoto's thyroiditis, scleroderma, and Addison's disease; 
 (xxii) the administered anti-CD27 antibody or antigen binding fragment is administered in a subject that is further administered a vaccine and the anti-CD27 antibody or antigen binding fragment enhances the immune response elicited by said vaccine; 
 (xxiii) the administered anti-CD27 antibody or antigen binding fragment is administered in a subject that is further administered an antitumor vaccine and the anti-CD27 antibody or antigen binding fragment enhances the antitumor immune response elicited by said vaccine; 
 (xxiv) the administered anti-CD27 antibody or antigen binding fragment is administered to a subject that is further administered a vaccine for affording immunity against an infectious agent and the anti-CD27 antibody or antigen binding fragment enhances the immune response elicited by said vaccine against the infectious agent optionally selected from a bacterium, a virus, a yeast, a fungus, a mycobacteria, or a parasite; 
 (xxv) the administered anti-CD27 antibody or antigen binding fragment is administered in conjunction with at least one antigen or allergen; 
 (xxvi) the administered anti-CD27 antibody or antigen binding fragment is administered before, after or in conjunction with a vaccine composition or is combined with the vaccine as a combined composition, optionally wherein the vaccine is a viral vaccine that confers immunity to a virus selected from a hepatitis, HIV, picornavirus, poliovirus, enterovirus, human Coxsackie virus, influenza virus, rhinovirus, echovirus, rubella virus, encephalitis virus, rabies virus, herpes virus, papillomavirus, polyoma virus, RSV, adenovirus, yellow fever virus, dengue virus, parainfluenza virus, hemorrhagic virus, pox virus, varicella zoster virus, parainfluenza virus, reovirus, orbivirus, rotavirus, parvovirus, African swine fever virus, measles, mumps, and Norwalk virus or the vaccine is a bacterial vaccine that confers immunity to a bacterium selected from  Pasteurella, Escherichia, Staphylococcus, Streptococcus, Salmonella, Heliobacter, Mycobacteria, Campylobacter, Enterococcus, Clostridium, Corynebacterium, Treponema, Bacteroides, Fusobacterium, Fusobacterium, Neisseria, Bacillus, Enterobacter, Streptobacillus, Leptospira, Haemophilus, Borrelia, Legionella, Erysipelothrix , and  Listeria  or the vaccine is specific to a parasite elected from  Babesia, Entomoeba, Giarda, Leishmania, Plasmodium, Toxoplasma, Trypanosome , round worm and flat worm; 
 (xxvii) the administered administered anti-CD27 antibody or antigen binding fragment elicits enhanced CD8 +  T cell proliferation, survival and/or cytotoxic lymphocyte lytic (CTL) response in a subject in need thereof; 
 (xxviii) the administered anti-CD27 antibody or antigen binding fragment is administered in combination with another therapeutic moiety, optionally wherein said other moiety is selected from the group consisting of another immune agonist, antibody, cytokine, chemotherapeutic, immunomodulator and immunostimulant; 
 (xxix) the administered anti-CD27 antibody or antigen binding fragment is administered together with a second immune agonist and an antigen specific to a desired target, optionally a tumor; 
 (xxx) the administered anti-CD27 antibody or antigen binding fragment is administered together with a second immune agonist and an antigen specific to a desired target, selected from the group consisting of a tumor associated peptide (TAA), tumor lysate, apoptotic tumor cells, and tumor-antigen carrying dendritic cells; 
 (xxxi) the administered anti-CD27 antibody or antigen binding fragment is administered together with a second immune agonist and an antigen specific to a melanoma and the combination enhances (boosts) the immune response elicited against the tumor cells which express the target melanoma antigen; 
 (xxxii) the administered anti-CD27 antibody or antigen binding fragment is administered together with another moiety selected from the group consisting of an immune stimulatory antibody or protein (positive costimulant), an immune antibody or protein that acts as a negative costimulant, an antibody or other moiety that blocks inhibitory signals to T cells and an antibody that binds to tumor cells or vasculature or stoma; or 
 (xxxiii) the administered anti-CD27 antibody or antigen binding fragment is administered together with another moiety selected from the group consisting of an anti-CD40 antibody, an anti-OX40 antibody, an anti-4-1BB antibody, an anti-CD70 antibody, an anti-B7.1 antibody, an anti-B7.2 antibody, an anti-CTLA-4 antibody, an anti-CD28 antibody, a moiety that depletes or blocks regulatory T cells, and a cytokine. 
 
     
     
         13 - 56 . (canceled) 
     
     
         57 . A method for synergistically eliciting an enhanced T-cell response comprising administering to a subject in need thereof:
 a synergistically effective amount (i) at least one CD27 agonist and (ii) at least one agonist selected from a CD40 agonist, a 4-1BB (CD137) antibody, an OX-40 antibody, a CD28 antibody, and a CTLA-4 antibody.   
     
     
         58 . The method of  claim 57  which comprises one or more of the following;
 (i) the immune response is a Th1 immune response; 
 (ii) the CD40 agonist is a CD40 agonistic antibody or a soluble CD40L fusion protein or soluble CD40 fragment or a conjugate thereof; 
 (iii) the CD40 agonist is a chimeric, human or humanized antibody that specifically binds human CD40; 
 (iv) the CD27 agonist is an anti-CD27 agonistic antibody or a soluble CD70 fusion protein or a soluble fragment or soluble conjugate thereof; 
 (v) the method further includes the administration of an antigen selected from a tumor antigen, bacterial antigen, viral antigen, parasite antigen, allergen, and autoantigen; 
 (vi) the agonistic anti-CD27 antibody is a chimeric, human or humanized antibody which is intact or modified; 
 (vii) the CD27 agonist or the other agonist is attached to an effector moiety; 
 (viii) the CD27 agonist or the other agonist is attached to an effector moiety selected from a toxin, drug and radionuclide; 
 (ix) the CD27 agonist and the CD40 agonist are administered together or separately; 
 (x) the CD27 agonist and the CD40 agonist are administered together and are contained in the same composition; 
 (xi) either or both the CD27 agonist and the CD40 agonist comprise agonistic antibodies; 
 (xii) the CD40 agonist is a soluble CD40L or soluble CD40 fusion protein; 
 (xiii) the CD40 agonist and the CD27 agonist are administered separately from one another and administration may be effected in either order; optionally within one day of each other, within 8 hours of each other, or within 1-4 hours of each other; 
 (xiv) the method further comprises the administration of a 4-1BB or 4-1BBL agonist, optionally an antibody; 
 (xv) the method potentiates antigen-specific CD8 +  T cell immunity; 
 (xvi) the method is used to treat human cancer, optionally a CD40 expressing cancer; 
 (xvii) the method is used to treat a solid tumor; 
 (xviii) the method is used to treat a cancer selected from the group consisting of: breast, liver, ovarian, colorectal, lung, stomach, kidney, melanoma, ovarian and lymphoma; 
 (xix) the method is used to treat non-Hodgkin's lymphoma; 
 (xx) the CD40 agonist is a chimeric, human or humanized anti-human CD40 antibody; 
 (xxi) the method is used to treat renal cancer; 
 (xxii) the method further includes administration of at least one chemotherapeutic; 
 (xxiii) the method further includes administration of at least one cytokine, optionally an interferon, interleukin, tumor necrosis factor or colony stimulating factor; or (xxiv) the method is used to treat a subject with an autoimmune disease, inflammatory condition, infectious or allergic condition. 
 
     
     
         59 - 99 . (canceled) 
     
     
         100 . A synergistic agonist combination adopted for use in enhancing CTL immune responses and CD8 +  T cell proliferation in vivo in humans which comprises synergistically effective amounts of (i) at least one CD27 agonist and (ii) at least one anti-CD40, OX-40, 4-1BB or CTLA-4 agonistic antibody. 
     
     
         101 . The synergistic agonist combination of  claim 100  wherein the CD40 agonist is an agonistic CD40 antibody or a soluble CD40L, fragment or fusion protein containing. 
     
     
         102 . The synergistic agonist combination of  claim 100  wherein the agonistic antibody is a chimeric, human, humanized or otherwise genetically engineered antibody. 
     
     
         103 . The synergistic agonist combination of  claim 100  wherein the CD27 agonist is an agonistic CD27 antibody. 
     
     
         104 . The synergistic agonist combination of  claim 103  wherein the CD27 antibody is a chimeric, human humanized or otherwise genetically engineered antibody.