Methods of treating immunotherapy-related toxicity using a gm-csf antagonist

Abstract

Methods of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity in a subject, the method comprising a step of administering a recombinant hGM-CSF antagonist to the subject, wherein said administering inhibits or reduces the incidence or the severity of immunotherapy-related toxicity in said subject, are provided. An hGM-CSF antagonist for use in methods of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity in a subject also are provided.

1 - 59 . (canceled) 
     
     
         60 . A hGM-CSF antagonist for use in a method of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity in a subject, the method comprising a step of administering a recombinant hGM-CSF antagonist to the subject, wherein said administering inhibits or reduces the incidence of immunotherapy-related toxicity in said subject. 
     
     
         61 . The hGM-CSF antagonist of  claim 60 , wherein said immunotherapy comprises adoptive cell transfer, administration of monoclonal antibodies, administration of cytokines, administration of a cancer vaccine, T cell engaging therapies, or any combination thereof. 
     
     
         62 . The hGM-CSF antagonist of  claim 61 , wherein said adoptive cell transfer comprises administering chimeric antigen receptor-expressing T-cells (CAR T-cells), T-cell receptor (TCR) modified T-cells, tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR)-modified natural killer cells, or dendritic cells, or any combination thereof. 
     
     
         63 . The hGM-CSF antagonist of  claim 61 , wherein said monoclonal antibody is selected from a group comprising: anti-CD3, anti-CD52, anti-PD1, anti-PD-L1, anti-CTLA4, anti-CD20, anti-BCMA antibodies, bi-specific antibodies, or bispecific T-cell engager (BiTE) antibodies, or any combination thereof. 
     
     
         64 . The hGM-CSF antagonist of  claim 61 , wherein said cytokines are selected from a group comprising: IFNα, IFNβ, IFNγ, IFNλ, IL-2, IL-7, IL-15, IL-21, IL-11, IL-12, IL-18, hGM-CSF, TNFα, or any combination thereof. 
     
     
         65 . The hGM-CSF antagonist of any of  claims 60 - 64 , wherein said inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity comprises reducing the concentration of at least one inflammation-associated factor in the serum or in the CSF of said subject is decreased. 
     
     
         66 . The hGM-CSF antagonist of  claim 65 , wherein said inflammation-associated factor is selected from a group comprising: C-reactive protein, GM-CSF, IL-2, sIL2R□, IL-5, IL-6, IL-8, IL-10, IP10, IL-15, MCP-1, MIG, MIP1□, IFNγ, CX3CR1, or TNFα, or any combination thereof. 
     
     
         67 . The hGM-CSF antagonist of any of  claims 60 - 66 , wherein administration of said recombinant GM-CSF antagonist does not reduce the efficacy of said immunotherapy. 
     
     
         68 . The hGM-CSF antagonist of any of  claims 60 - 67 , wherein said immunotherapy is administered at higher doses that it would be administered without the administration of said hGM-CSF antagonists. 
     
     
         69 . The hGM-CSF antagonist of any of  claims 60 - 68 , wherein administration of said recombinant hGM-CSF antagonist occurs prior to, concurrent with, or following said immunotherapy. 
     
     
         70 . The hGM-CSF antagonist of any of  claims 60 - 69 , wherein said recombinant hGM-CSF antagonist is co-administered with corticosteroids, anti-IL6 antibodies, tocilizumab, cyclosporine, antiepileptics, benzodiazepines, acetazolamide, hyperventilation therapy, or hyperosmolar therapy, or any combination thereof. 
     
     
         71 . The hGM-CSF antagonist of any of  claims 60 - 70 , wherein said immunotherapy-related toxicity comprises a brain disease, damage or malfunction. 
     
     
         72 . The hGM-CSF antagonist of  claim 71 , wherein said brain disease, damage or malfunction comprises CAR-T cell related neurotoxicity or CAR-T cell related encephalopathy syndrome (CRES). 
     
     
         73 . The hGM-CSF antagonist of  claim 72 , wherein the CAR-T cell related neurotoxicity is reduced by about 90% compared to a reduction in neurotoxicity in a subject treated with CAR-T cells and a control antibody. 
     
     
         74 . The hGM-CSF antagonist of any of  claims 71 - 73 , wherein said inhibiting or reducing incidence of a brain disease, damage or malfunction comprises reducing headaches, delirium, anxiety, tremor, seizure activity, confusion, alterations in wakefulness, hallucinations, dysphasia, ataxia, apraxia, facial nerve palsy, motor weakness, seizures, nonconvulsive EEG seizures, coma, endothelial activation, vascular leak, intravascular coagulation, or any combination thereof in said subject. 
     
     
         75 . The hGM-CSF antagonist of any of  claims 71 - 74 , wherein the serum concentration of ANG2 or VWF, or the serum ANG2:ANG1 ratio of said subject is reduced. 
     
     
         76 . The hGM-CSF antagonist of any of  claims 71 - 75 , wherein said subject has a body temperature above 38° C., IL6 serum concentration above 16 pg/ml, or MCP1 serum concentration above 1,300 pg/ml during the first 36 hours after infusion of said CAR-T cells. 
     
     
         77 . The hGM-CSF antagonist of any of  claims 70 - 76 , wherein said subject is predisposed to have said brain disease, damage or malfunction. 
     
     
         78 . The hGM-CSF antagonist of any of  claims 70 - 77 , wherein said subject has an ANG2:ANG1 ratio in serum above 1 prior to the infusion of said CAR-T cells. 
     
     
         79 . The hGM-CSF antagonist of any of  claims 60 - 70 , wherein said immunotherapy-related toxicity comprises hemophagocytic lymphohistiocytosis (HLH) or macrophage-activation syndrome (MAS). 
     
     
         80 . The hGM-CSF antagonist of  claim 79 , wherein said inhibiting or reducing incidence of HLH or MAS comprises increasing survival time and/or time to relapse, reducing macrophage activation, reducing T cell activation, reducing the concentration of circulating IFNγ, or reducing the concentration of circulating of hGM-CSF, or any combination thereof. 
     
     
         81 . The hGM-CSF antagonist of any of  claim 79  or  80 , wherein said subject presents with fever, splenomegaly, cytopenias involving two or more lines, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis, low or absent NK-cell activity, ferritin serum concentration above 500 U/ml, or soluble CD25 serum concentration above 2400 U/ml, or any combination thereof. 
     
     
         82 . The hGM-CSF antagonist of any of  claims 79 - 81 , wherein said subject is predisposed to acquiring HLH or MAS. 
     
     
         83 . The hGM-CSF antagonist of any of  claims 77 - 82 , wherein said subject carries a mutation in a gene selected from: PRF1, UNC13D, STX11, STXBP2, or RAB27A, or has reduced expression of perforin, or any combination thereof. 
     
     
         84 . The hGM-CSF antagonist of any one of  claims 60 - 83 , wherein the hGM-CSF antagonist is an anti-hGM-CSF antibody. 
     
     
         85 . The hGM-CSF antagonist of  claim 84 , wherein the anti-hGM-CSF antibody blocks binding of hGM-CSF to the alpha subunit of the hGM-CSF receptor. 
     
     
         86 . The hGM-CSF antagonist of any of  claim 84  or  85 , wherein the anti-hGM-CSF antibody is a polyclonal antibody. 
     
     
         87 . The hGM-CSF antagonist of any of  claim 84  or  85 , wherein the anti-hGM-CSF antibody is a monoclonal antibody. 
     
     
         88 . The hGM-CSF antagonist of any of  claims 84 - 87 , wherein the anti-hGM-CSF antibody is an antibody fragment that is a Fab, a Fab′, a F(ab′)2, a scFv, or a dAB. 
     
     
         89 . The hGM-CSF antagonist of  claim 88 , wherein the antibody fragment is conjugated to polyethylene glycol. 
     
     
         90 . The hGM-CSF antagonist of any of  claims 84 - 89 , wherein the anti-hGM-CSF antibody has an affinity ranging from about 5 pM to about 50 pM. 
     
     
         91 . The hGM-CSF antagonist of any of  claims 84 - 90 , wherein the anti-hGM-CSF antibody is a neutralizing antibody. 
     
     
         92 . The hGM-CSF antagonist of any of  claims 84 - 91 , wherein the anti-hGM-CSF antibody is a recombinant or chimeric antibody. 
     
     
         93 . The hGM-CSF antagonist of any of  claims 84 - 92 , wherein the anti-hGM-CSF antibody is a human antibody. 
     
     
         94 . The hGM-CSF antagonist of any of  claims 84 - 92 , wherein the anti-hGM-CSF antibody comprises a human variable region. 
     
     
         95 . The hGM-CSF antagonist of any of  claims 84 - 92 , wherein the anti-hGM-CSF antibody comprises a human light chain constant region. 
     
     
         96 . The hGM-CSF antagonist of any of  claims 84 - 95 , wherein the anti-hGM-CSF antibody comprises a human heavy chain constant region. 
     
     
         97 . The hGM-CSF antagonist of  claim 96 , wherein the human heavy chain constant region is a gamma chain. 
     
     
         98 . The hGM-CSF antagonist of any of  claims 84 - 97 , wherein the anti-hGM-CSF antibody binds to the same epitope as chimeric 19/2. 
     
     
         99 . The hGM-CSF antagonist of any of  claims 84 - 97 , wherein the anti-hGM-CSF antibody comprises the VH region CDR3 and VL region CDR3 of chimeric 19/2. 
     
     
         100 . The hGM-CSF antagonist of any of  claims 84 - 97 , wherein the anti-hGM-CSF antibody comprises the VH region and VL region CDR1, CDR2, and CDR3 of chimeric 19/2. 
     
     
         101 . The hGM-CSF antagonist of any of  claims 84 - 97 , wherein the anti-hGM-CSF antibody comprises a VH region that comprises a CDR3 binding specificity determinant RQRFPY or RDRFPY, a J segment, and a V-segment, wherein the J-segment comprises at least 95% identity to human JH4 (YFD YWGQGTL VTVSS) and the V-segment comprises at least 90% identity to a human germ line VH1 1-02 or VH1 1-03 sequence; or a VH region that comprises a CDR3 binding specificity determinant RQRFPY. 
     
     
         102 . The hGM-CSF antagonist of  claim 101 , wherein the J segment comprises YFDYWGQGTLVTVSS. 
     
     
         103 . The hGM-CSF antagonist of any of  claim 101  or  102 , wherein the CDR3 comprises RQRFPYYFDY or RDRFPYYFDY. 
     
     
         104 . The hGM-CSF antagonist of any of  claims 101 - 103 , wherein the VH region CDR1 is a human germline VH1 CDR1; the VH region CDR2 is a human germline VH1 CDR2; or both the CDR1 and CDR2 are from a human germline VH1 sequence. 
     
     
         105 . The hGM-CSF antagonist of any of  claims 101 - 103 , wherein the anti-hGM-CSF antibody comprises a VH CDR1, or a VH CDR2, or both a VH CDR1 and a VH CDR2 as shown in a VH region set forth in  FIG. 1 . 
     
     
         106 . The hGM-CSF antagonist of any of  claims 101 - 103 , wherein the V-segment sequence has a VH V segment sequence shown in  FIG. 1 . 
     
     
         107 . The hGM-CSF antagonist of any of  claims 101 - 103 , wherein the VH has the sequence of VH#1, VH#2, VH#3, VH#4, or VH#5 set forth in  FIG. 1 . 
     
     
         108 . The GM-CSF antagonist of any of  claims 84 - 107 , wherein the anti-hGM-CSF antibody comprises a VL-region that comprises a CDR3 comprising the amino acid sequence FNK or FNR. 
     
     
         109 . The hGM-CSF antagonist of  claim 108 , wherein the anti-hGM-CSF antibody comprises a human germline JK4 region. 
     
     
         110 . The hGM-CSF antagonist of any of  claim 108  or  109 , wherein the VL region CDR3 comprises QQFN(K/R)SPLT. 
     
     
         111 . The hGM-CSF antagonist of  claim 110 , wherein the anti-hGM-CSF antibody comprises a VL region that comprises a CDR3 comprising QQFNKSPLT. 
     
     
         112 . The hGM-CSF antagonist of any of  claims 108 - 111 , where the VL region comprises a CDR1, or a CDR2, or both a CDR1 and CDR2 of a VL region shown in  FIG. 1 . 
     
     
         113 . The hGM-CSF antagonist of any of  claims 108 - 112 , wherein the VL region comprises a V segment that has at least 95% identity to the VKIII A27 V-segment sequence as shown in  FIG. 1 . 
     
     
         114 . The GM-CSF antagonist of  claim 108 , wherein the VL region has the sequence of VK#1, VK#2, VK#3, or VK#4 set forth in  FIG. 1 . 
     
     
         115 . The hGM-CSF antagonist of any of  claims 84 - 97 , wherein the anti-hGM-CSF antibody has a VH region CDR3 binding specificity determinant RQRFPY or RDRFPY and a VL region that has a CDR3 comprising QQFNKSPLT. 
     
     
         116 . The hGM-CSF antagonist of any of  claims 84 - 97 , wherein the anti-hGM-CSF antibody has a VH region sequence set forth in  FIG. 1  and a VL region sequence set forth in  FIG. 1 . 
     
     
         117 . The hGM-CSF antagonist of any of  claims 84 - 116 , wherein the VH region or the VL region, or both the VH and VL region amino acid sequences comprise a methionine at the N-terminus. 
     
     
         118 . The hGM-CSF antagonist of any of  claims 60 - 83 , wherein the hGM-CSF antagonist is selected from the group comprising of an anti-hGM-CSF receptor antibody, a soluble hGM-CSF receptor, a cytochrome b562 antibody mimetic, a hGM-CSF peptide analog, an adnectin, a lipocalin scaffold antibody mimetic, a calixarene antibody mimetic, and an antibody like binding peptidomimetic. 
     
     
         119 - 137 . (canceled) 
     
     
         138 . A pharmaceutical composition comprising an anti-hGM-CSF antagonist of any one of  claims 60  to  118 .