METHODS OF TREATING IMMUNOTHERAPY-RELATED TOXICITY USING A GM-CSF ANTAGONIST

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.