US2022025034A1PendingUtilityA1

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

58
Assignee: HUMANIGEN INCPriority: Oct 2, 2017Filed: Jul 16, 2021Published: Jan 27, 2022
Est. expiryOct 2, 2037(~11.2 yrs left)· nominal 20-yr term from priority
Inventors:Cameron DurrantDale Chappell
A61P 25/00A61K 39/3955C07K 2317/622C07K 2317/56A61K 2039/505C07K 2317/21C07K 2317/565C07K 2317/569C07K 2319/33C07K 2317/55C07K 16/243C07K 2317/54A61K 2039/545C07K 2317/41C07K 2317/92C07K 2317/24C07K 2317/567C07K 2319/03C07K 2317/34C07K 2317/76C07K 16/2803C07K 2317/33
58
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Claims

Abstract

Methods for reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering a recombinant GM-CSF antagonist to the subject. Methods for preserving blood-brain barrier integrity in a subject treated with immunotherapy, the method comprising administering a recombinant hGM-CSF antagonist to the subject. Methods for decreasing or preventing CAR-T cell therapy-induced neuroinflammation in a subject in need thereof, the method comprising administering a recombinant GM-CSF antagonist to the subject. Methods for preventing or reducing blood-brain barrier in a subject treated with immunotherapy, the method comprising administering CAR-T cells having a GM-CSF gene knockout (GM-CSFk/o CAR-T cells) to the subject.

Claims

exact text as granted — not AI-modified
1 . A method for reducing blood-brain-barrier disruption in a subject treated with immunotherapy, the method comprising administering a recombinant GM-CSF antagonist to the subject. 
     
     
         2 . The method of  claim 1 , wherein the subject has an incidence of immunotherapy-related toxicity. 
     
     
         3 . The method of  claim 1 , wherein the 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. 
     
     
         4 . The method of  claim 3 , wherein the 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. 
     
     
         5 . The method of  claim 4 , wherein the CAR T-cells are CD19 CAR-T cells. 
     
     
         6 . The method of  claim 1 , wherein the recombinant GM-CSF antagonist is an hGM-CSF antagonist. 
     
     
         7 . The method of  claim 1 , wherein the recombinant GM-CSF antagonist is an anti-GM-CSF antibody. 
     
     
         8 . The method of  claim 7 , wherein the anti-GM-CSF antibody binds mammalian GM-CSF or binds primate GM-CSF. 
     
     
         9 . The method of  claim 8 , wherein the primate is a monkey, a baboon, a macaque, a chimpanzee, a gorilla, a lemur, a lorise, a tarsier, a galago, a potto, a sifaka, an indri, an aye-ayes an ape or a human. 
     
     
         10 . The method of  claim 7 , wherein the anti-GM-CSF antibody is an anti-hGM-CSF antibody. 
     
     
         11 . The method of  claim 10 , wherein the anti-hGM-CSF antibody is administered prior to, concurrent with, following immunotherapy or a combination thereof. 
     
     
         12 . The method of  claim 10 , wherein the anti-hGM-CSF antibody binds human GM-CSF. 
     
     
         13 . The method of  claim 10 , wherein the anti-hGM-CSF antibody is a monoclonal antibody. 
     
     
         14 . The method of  claim 10 , 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. 
     
     
         15 . The method of  claim 10 , wherein the anti-hGM-CSF antibody is a human GM-CSF neutralizing antibody. 
     
     
         16 . The method of  claim 10 , wherein the anti-hGM-CSF antibody is a recombinant or chimeric antibody. 
     
     
         17 . The method of  claim 10 , wherein the anti-hGM-CSF antibody is a human antibody. 
     
     
         18 . The method of  claim 10 , wherein the anti-hGM-CSF antibody binds to the same epitope as chimeric 19/2 antibody. 
     
     
         19 . The method of  claim 10 , wherein the anti-hGM-CSF antibody comprises the VH region CDR3 and VL region CDR3 of chimeric 19/2 antibody. 
     
     
         20 . The method of  claim 10 , wherein the anti-hGM-CSF antibody comprises the VH region and VL region CDR1, CDR2, and CDR3 of chimeric 19/2 antibody. 
     
     
         21 . The method of  claim 10 , wherein the anti-hGM-CSF antibody comprises a VH region that comprises a CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) or RDRFPY (SEQ ID NO: 13), 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 (SEQ ID NO: 12). 
     
     
         22 . The method of  claim 21 , wherein the J segment comprises YFDYWGQGTLVTVSS (SEQ ID NO: 14). 
     
     
         23 . The method of  claim 21 , wherein the CDR3 comprises RQRFPYYFDY (SEQ ID NO: 15) or RDRFPYYFDY (SEQ ID NO: 16). 
     
     
         24 . The method of  claim 21 , 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. 
     
     
         25 . The method of  claim 21 , 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 . 
     
     
         26 . The method of  claim 21 , wherein the V-segment sequence has a VH V segment sequence shown in  FIG. 1 . 
     
     
         27 . The method of  claim 21 , wherein the VH has the sequence of VH #1, VH #2, VH #3, VH #4, or VH #5 set forth in  FIG. 1 . 
     
     
         28 . The method of  claim 10 , wherein the anti-hGM-CSF antibody comprises a VL-region that comprises a CDR3 comprising the amino acid sequence FNK or FNR. 
     
     
         29 . The method of  claim 28 , wherein the anti-hGM-CSF antibody comprises a human germline JK4 region. 
     
     
         30 . The method of  claim 28 , wherein the VL region CDR3 comprises QQFN(K/R)SPL. 
     
     
         31 . The method of  claim 30 , wherein the anti-hGM-CSF antibody comprises a VL region that comprises a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18). 
     
     
         32 . The method of  claim 28 , where the VL region comprises a CDR1, or a CDR2, or both a CDR1 and CDR2 of a VL region shown in  FIG. 1 . 
     
     
         33 . The method of  claim 28 , 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 . 
     
     
         34 . The method of  claim 28 , wherein the VL region has the sequence of VK #1, VK #2, VK #3, or VK #4 set forth in  FIG. 1 . 
     
     
         35 . The method of  claim 10 , wherein the anti-hGM-CSF antibody has a VH region CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) or RDRFPY (SEQ ID NO: 13) and a VL region that has a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18). 
     
     
         36 . The method of  claim 35 , 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 . 
     
     
         37 . The method of  claim 35 , 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. 
     
     
         38 . The method of  claim 6 , wherein the hGM-CSF antagonist is selected from the group comprising of an anti-hGM-CSF receptor antibody or a soluble hGM-CSF receptor or receptor sub-unit, 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. 
     
     
         39 . The method of  claim 2 , wherein the immunotherapy-related toxicity is CAR-T related toxicity. 
     
     
         40 . The method of  claim 2 , wherein the CAR-T related toxicity is cytokine release syndrome, neurotoxicity, neuro-inflammation or a combination thereof. 
     
     
         41 . A method for preserving blood-brain barrier integrity in a subject treated with immunotherapy, the method comprising administering a recombinant hGM-CSF antagonist to the subject. 
     
     
         42 . The method of  claim 41 , wherein the recombinant hGM-CSF antagonist is an anti-GM-CSF antibody. 
     
     
         43 . The method of  claim 42 , wherein the anti-GM-CSF antibody binds mammalian GM-CSF or binds primate GM-CSF. 
     
     
         44 . The method of  claim 43 , wherein the primate is a monkey, a baboon, a macaque, a chimpanzee, a gorilla, a lemur, a lorise, a tarsier, a galago, a potto, a sifaka, an indri, an aye-ayes an ape or a human. 
     
     
         45 . The method of  claim 42 , wherein the anti-GM-CSF antibody is an anti-hGM-CSF antibody. 
     
     
         46 . The method of  claim 45 , wherein the anti-hGM-CSF antibody is administered prior to, concurrent with, following immunotherapy or a combination thereof. 
     
     
         47 . The method of  claim 45 , wherein the anti-hGM-CSF antibody binds human GM-CSF. 
     
     
         48 . The method of  claim 45 , wherein the anti-hGM-CSF antibody is a monoclonal antibody. 
     
     
         49 . The method of  claim 45 , 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. 
     
     
         50 . The method of  claim 45 , wherein the anti-hGM-CSF antibody is a human GM-CSF neutralizing antibody. 
     
     
         51 . The method of  claim 45 , wherein the anti-hGM-CSF antibody is a recombinant or chimeric antibody. 
     
     
         52 . The method of  claim 45 , wherein the anti-hGM-CSF antibody is a human antibody. 
     
     
         53 . The method of  claim 45 , wherein the anti-hGM-CSF antibody binds to the same epitope as chimeric 19/2 antibody. 
     
     
         54 . The method of  claim 45 , wherein the anti-hGM-CSF antibody comprises the VH region CDR3 and VL region CDR3 of chimeric 19/2 antibody. 
     
     
         55 . The method of  claim 45 , wherein the anti-hGM-CSF antibody comprises the VH region and VL region CDR1, CDR2, and CDR3 of chimeric 19/2 antibody. 
     
     
         56 . The method of  claim 45 , wherein the anti-hGM-CSF antibody comprises a VH region that comprises a CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) or RDRFPY (SEQ ID NO: 13), 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 (SEQ ID NO: 12). 
     
     
         57 . The method of  claim 55 , wherein the J segment comprises YFDYWGQGTLVTVSS (SEQ ID NO: 14). 
     
     
         58 . The method of  claim 55 , wherein the CDR3 comprises RQRFPYYFDY (SEQ ID NO: 15) or RDRFPYYFDY (SEQ ID NO: 16). 
     
     
         59 . The method of  claim 55 , 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. 
     
     
         60 . The method of  claim 55 , 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 . 
     
     
         61 . The method of  claim 55 , wherein the V-segment sequence has a VH V segment sequence shown in  FIG. 1 . 
     
     
         62 . The method of  claim 55 , wherein the VH has the sequence of VH #1, VH #2, VH #3, VH #4, or VH #5 set forth in  FIG. 1 . 
     
     
         63 . The method of  claim 45 , wherein the anti-hGM-CSF antibody comprises a VL-region that comprises a CDR3 comprising the amino acid sequence FNK or FNR. 
     
     
         64 . The method of  claim 63 , wherein the anti-hGM-CSF antibody comprises a human germline JK4 region. 
     
     
         65 . The method of  claim 63 , wherein the VL region CDR3 comprises QQFN(K/R)SPL. 
     
     
         66 . The method of  claim 65 , wherein the anti-hGM-CSF antibody comprises a VL region that comprises a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18). 
     
     
         67 . The method of  claim 63 , where the VL region comprises a CDR1, or a CDR2, or both a CDR1 and CDR2 of a VL region shown in  FIG. 1 . 
     
     
         68 . The method of  claim 63 , 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 . 
     
     
         69 . The method of  claim 63 , wherein the VL region has the sequence of VK #1, VK #2, VK #3, or VK #4 set forth in  FIG. 1 . 
     
     
         70 . The method of  claim 45 , wherein the anti-hGM-CSF antibody has a VH region CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) or RDRFPY (SEQ ID NO: 13) (SEQ ID NO: 13) and a VL region that has a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18). 
     
     
         71 . The method of  claim 70 , 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 . 
     
     
         72 . The method of  claim 70 , 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. 
     
     
         73 . The method of  claim 41 , wherein the hGM-CSF antagonist is selected from the group comprising of an anti-hGM-CSF receptor antibody or a soluble hGM-CSF receptor or receptor sub-unit, 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. 
     
     
         74 . The method of  claim 41 , wherein the subject has an immunotherapy-related toxicity. 
     
     
         75 . The method of  claim 74 , wherein the immunotherapy-related toxicity is CAR-T related toxicity. 
     
     
         76 . The method of  claim 75 , wherein the CAR-T related toxicity is cytokine release syndrome, neurotoxicity, neuro-inflammation or a combination thereof. 
     
     
         77 . A method for preventing or reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering CAR-T cells having a GM-CSF gene knockout (GM-CSF k/o  CAR-T cells) to the subject. 
     
     
         78 . The method of  claim 77 , further comprising administering a recombinant hGM-CSF antagonist to the subject. 
     
     
         79 . The method of  claim 78 , wherein the recombinant GM-CSF antagonist is an hGM-CSF antagonist. 
     
     
         80 . The method of  claim 79 , wherein the recombinant GM-CSF antagonist is an anti-GM-CSF antibody. 
     
     
         81 . The method of  claim 80 , 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. 
     
     
         82 . The method of  claim 80 , 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 . 
     
     
         83 . The method of  claim 80 , 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. 
     
     
         84 . The method of  claim 78 , wherein the hGM-CSF antagonist is selected from the group comprising of an anti-hGM-CSF receptor antibody or a soluble hGM-CSF receptor or receptor sub-unit, 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. 
     
     
         85 . The method of  claim 77 , wherein the subject further has a CAR-T related toxicity selected from cytokine release syndrome, neurotoxicity, or a combination thereof.

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