US2021269518A1PendingUtilityA1

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

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Assignee: HUMANIGEN INCPriority: Oct 2, 2017Filed: Jan 16, 2021Published: Sep 2, 2021
Est. expiryOct 2, 2037(~11.2 yrs left)· nominal 20-yr term from priority
Inventors:Cameron DurrantDale Chappell
A61K 2039/5158A61K 35/17C07K 2317/569A61P 31/00A61K 39/395C07K 2317/55A61P 35/00C07K 2317/76C07K 16/243C07K 2317/92A61K 2039/505C07K 14/7051
58
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Claims

Abstract

Methods for reducing relapse rate or preventing occurrence of tumor relapse in a subject treated with immunotherapy, in an absence of an incidence of immunotherapy-related toxicity or in a presence of immunotherapy-related toxicity. Methods for reducing a level of a cytokine or chemokine other than GM-CSF in a subject having an incidence of immunotherapy-related toxicity, the methods comprising administering a recombinant GM-CSF antagonist to the subject. Methods for treating or preventing immunotherapy-related toxicity in a subject, the methods comprising administering to the subject chimeric antigen receptor-expressing T-cells (CAR-T cells), the CAR-T cells having a GM-CSF gene knockout (GM-CSF k/o CAR-T cells), and a recombinant hGM-CSF antagonist.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method for reducing a level of a cytokine or chemokine other than GM-CSF in a subject having an incidence of immunotherapy-related toxicity, the method comprising administering to the subject a recombinant anti-hGM-CSF antibody, wherein the level of the cytokine or chemokine is reduced compared to the level thereof in a subject during the incidence of immunotherapy-related toxicity. 
     
     
         2 . The method of  claim 1 , wherein said immunotherapy comprises adoptive cell transfer, administration of monoclonal antibodies, administration of a cancer vaccine, T cell engaging therapies, or any combination thereof. 
     
     
         3 . The method of  claim 2 , 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. 
     
     
         4 . The method of  claim 3 , wherein the CAR-T cells are CD19 CAR-T cells. 
     
     
         5 . The method of  claim 1 , wherein the anti-hGM-CSF antibody binds a human GM-CSF. 
     
     
         6 . The method of  claim 1 , wherein the anti-hGM-CSF antibody binds a primate GM-CSF. 
     
     
         7 . The method of  claim 1 , wherein the anti-hGM-CSF antibody binds a mammalian GM-CSF. 
     
     
         8 . The method of  claim 1 , wherein the anti-hGM-CSF antibody is a monoclonal antibody. 
     
     
         9 . The method of  claim 1 , 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. 
     
     
         10 . The method of  claim 1 , wherein the anti-hGM-CSF antibody is a human GM-CSF neutralizing antibody. 
     
     
         11 . The method of  claim 1 , wherein the anti-hGM-CSF antibody is a recombinant or chimeric antibody. 
     
     
         12 . The method of  claim 1 , wherein the anti-hGM-CSF antibody is a human antibody. 
     
     
         13 . The method of  claim 1 , wherein the anti-hGM-CSF antibody comprises the VH region CDR3 and VL region CDR3 of chimeric 19/2. 
     
     
         14 . The method of  claim 1 , wherein the anti-hGM-CSF antibody comprises the VH region and VL region CDR1, CDR2, and CDR3 of chimeric 19/2. 
     
     
         15 . The method of  claim 1 , wherein the anti-hGM-CSF antibody binds to the same epitope as chimeric 19/2. 
     
     
         16 . The method of  claim 1 , wherein cytokine or chemokine is a human cytokine or chemokine selected from the group consisting of IP-10, IL-2, IL-3, IL-5, IL-1Ra, VEGF, TNF-a, FGF-2, IFN-γ, IL-12p40, IL-12p70, sCD40L, MDC, MCP-1, MIP-1a, MIP-1b or a combination thereof. 
     
     
         17 . The method of  claim 1 , wherein cytokine or chemokine is selected from the group consisting of IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-9, IL-10, IP-10, KC, MCP-1, MIP or a combination thereof. 
     
     
         18 . The method of  claim 1 , wherein the subject has acute lymphoblastic leukemia. 
     
     
         19 . The method of  claim 1 , 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 YFDYWGQGTLVTVSS (SEQ ID NO: 14) and the V-segment comprises at least 90% identity to a human germ line VH1 1-03 sequence or VH1 1-02 sequence. 
     
     
         20 . The method of  claim 19 , wherein the J segment comprises YFDYWGQGTLVTVSS (SEQ ID NO: 14). 
     
     
         21 . The method of  claim 19 , wherein the CDR3 comprises RQRFPYYFDY (SEQ ID NO: 15) or RDRFPYYFDY (SEQ ID NO: 16). 
     
     
         22 . The method of  claim 19 , 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. 
     
     
         23 . The method of  claim 19 , wherein the anti-hGM-CSF antibody comprises a VH CDR1, a VH CDR2, or both a VH CDR1 and a VH CDR2 as shown in a VH region set forth in  FIG. 1 . 
     
     
         24 . The method of  claim 19 , wherein the V-segment sequence has a VH V segment sequence shown in  FIG. 1 . 
     
     
         25 . The method of  claim 19 , wherein the VH region has the sequence of VH #1, VH #2, VH #3, VH #4, or VH #5 set forth in  FIG. 1 . 
     
     
         26 . The method of  claim 19 , wherein the anti-hGM-CSF antibody comprises a VL-region that comprises a CDR3 comprising the amino acid sequence FNK or FNR. 
     
     
         27 . The method of  claim 26 , wherein the anti-hGM-CSF antibody comprises a human germline JK4 region. 
     
     
         28 . The method of  claim 26 , wherein the VL region CDR3 comprises QQFN(K/R)SPLT (SEQ ID NO: 17). 
     
     
         29 . The method of  claim 28 , wherein the anti-hGM-CSF antibody comprises a VL region that comprises a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18). 
     
     
         30 . The method of  claim 28 , wherein the anti-hGM-CSF antibody comprises a VL region that comprises a CDR3 comprising QQFNRSPLT (SEQ ID NO: 28). 
     
     
         31 . The method of  claim 26 , where the VL region comprises a CDR1, a CDR2, or both a CDR1 and CDR2 of a VL region shown in  FIG. 1 . 
     
     
         32 . The method of  claim 26 , 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 . 
     
     
         33 . The method of  claim 26 , wherein the VL region has the sequence of VK #1, VK #2, VK #3, or VK #4 set forth in  FIG. 1 . 
     
     
         34 . The method of  claim 1 , 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) or QQFNRSPLT (SEQ ID NO: 28). 
     
     
         35 . The method of  claim 1 , 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 . 
     
     
         36 . 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. 
     
     
         37 . The method of  claim 33 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #1 set forth in  FIG. 1  and the VL region having the sequence of VK #3 set forth in  FIG. 1 . 
     
     
         38 . The method of  claim 33 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #2 set forth in  FIG. 1  and the VL region having the sequence of VK #3 set forth in  FIG. 1 . 
     
     
         39 . The method of  claim 33 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #3 set forth in  FIG. 1  and the VL region having the sequence of. VK #1 set forth in  FIG. 1 . 
     
     
         40 . The method of  claim 33 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #4 set forth in  FIG. 1  and the VL region having the sequence of. VK #4 set forth in  FIG. 1 . 
     
     
         41 . The method of  claim 33 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #4 set forth in  FIG. 1  and the VL region having the sequence of. VK #2 set forth in  FIG. 1 . 
     
     
         42 . The method of  claim 33 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #5 set forth in  FIG. 1  and the VL region having the sequence of VK #1 set forth in  FIG. 1 . 
     
     
         43 . The method of  claim 33 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #5 set forth in  FIG. 1  and a VL region having sequence VK #2 set forth in  FIG. 1 . 
     
     
         44 . The method of  claim 1 , wherein the anti-hGM-CSF antibody has a VH region CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) and a VL region that has a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18). 
     
     
         45 . The method of  claim 1 , wherein the immunotherapy-related toxicity is CAR-T related toxicity. 
     
     
         46 . The method of  claim 43 , wherein the CAR-T related toxicity is cytokine release syndrome, neurotoxicity or neuro-inflammation.

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