METHOD OF REDUCING BISPECIFIC T CELL ENGAGER OR CHIMERIC ANTIGEN RECEPTOR T CELL MEDIATED CYTOKINE RELEASE SYNDROME USING INTERLEUKINS-4, -10, OR A FUSION PROTEIN THEREOF
The disclosure provides for various methods including a method of reducing the severity of bispecific T cell engager (BiTE) or chimeric antigen receptor T cell (CAR-T) induced cytokine release syndrome (CRS) comprising administering to a patient in need thereof an amount of a composition comprising an interleukin 10 (IL-10) or an IL-10 agent, an interleukin 4 (IL-4) or an IL-4 agent, or combinations thereof.
1 . A method of reducing the severity of bispecific T cell engager (BiTE) or chimeric antigen receptor T cell (CAR-T) induced cytokine release syndrome (CRS) comprising administering to a patient in need thereof an amount of a composition comprising an interleukin 10 (IL-10) or an IL-10 agent, an interleukin 4 (IL-4) or an IL-4 agent, or combinations thereof.
2 . The method according to claim 1 , wherein the composition comprises a human IL-10 or viral IL-10, mutein, variants, fusion protein, and fragments thereof.
3 . The method according to claim 2 , wherein the human IL-10 is a sequence of SEQ ID No: 1.
4 . The method according to claim 2 , wherein viral IL-10 is an Epstein Barr viral (EBV) IL-10 of SEQ ID No: 5.
5 . The method according to claim 1 , wherein the IL-10 agent is a fusion protein comprising IL-10.
6 . The method according to claim 1 , wherein the IL-4 agent is a fusion protein comprising IL-4.
7 . The method according to claim 6 , wherein the fusion protein is a diakine comprising IL-10.
8 . The method according to claim 7 , wherein the fusion protein is a diakine comprising IL-4.
9 . The method according to claim 7 , wherein the diakine further comprises a scFv targeting domain that targets a receptor different from the BiTE or CAR-T.
10 . The method according to claim 8 , wherein the diakine further comprises a scFv targeting domain that targets a receptor different from the BiTE or CAR-T.
11 . The method according to claim 10 , wherein the scFv targets a receptor selected from EGFR, CD3, CD4, CD5, CD7, CD14, CD19, CD20, CD22, CD25, CD30, CD33, CD34, CD38, CD40, CD47, CD52, CD56, CD70, CD79B, CD117, CD123, CD138, CD147, BCMA, C-type lectin-like molecule-1 (CLL01), PD-L1, PD-1, TIM3, BTLA, latent membrane protein 1 (LMP-1), signal lymphocytic activation molecule F7 (SLAMF7), NY-ESO-1, transmembrane activator and CAML interactor (TACI), CS-1, CXCR4, NKG2D, B7-H3, LAG3, CTLA4, GD-2, VEGFR1, VEGFR2, HER2, HER3, PDGFR, EpCAM, mesothelin (MSO), PSCA, PSA, MUC1, Lewis-Y, GPC3, AXL, Claudin 18.2, GD2, CEA, ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, VCAM, FAPα, 5T4, Trop2, EDB-FN; TGFβ, Trap, MAdCAM, β7 integrin subunit, α4β7 integrin, α4 integrin, SR-A1, SR-A3, SR-A4, SR-A5, SR-A6, SR-B, dSR-C1, SR-D1, SR-E1, SR-F1, SR-F2, SR-G, SR-H1, SR-H2, SR-l1, SR-J1, HIV, or Ebola.
12 . The method according to claim 11 , wherein the scFv targets a receptor selected from EGFR, CD3, CD4, CD5, CD7, CD14, CD19, CD20, CD22, CD25, CD30, CD33, CD34, CD38, CD40, CD47, CD52, CD56, CD70, CD79B, CD117, CD123, CD138, CD147, BCMA, C-type lectin-like molecule-1 (CLL01), PD-L1, PD-1, TIM3, BTLA, latent membrane protein 1 (LMP-1), signal lymphocytic activation molecule F7 (SLAMF7), NY-ESO-1, transmembrane activator and CAML interactor (TACI), CS-1, CXCR4, NKG2D, B7-H3, LAG3, CTLA4, GD-2, VEGFR1, VEGFR2, HER2, HER3, PDGFR, EpCAM, mesothelin (MSO), PSCA, PSA, MUC1, Lewis-Y, GPC3, AXL, Claudin 18.2, GD2, CEA, ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, VCAM, FAPα, 5T4, Trop2, EDB-FN; TGFβ, Trap, MAdCAM, β7 integrin subunit, α4β7 integrin, α4 integrin, SR-A1, SR-A3, SR-A4, SR-A5, SR-A6, SR-B, dSR-C1, SR-D1, SR-E1, SR-F1, SR-F2, SR-G, SR-H1, SR-H2, SR-l1, SR-J1, HIV, or Ebola.
13 . The method according to claim 9 , wherein the diakine comprising IL-10 further comprises a second cytokine selected from IFN-α, IL-2, IL-4, IL-7, IL-12, IL-15, IL-21, IL-27.
14 . The method according to claim 10 , wherein the diakine comprising IL-4 further comprises a second cytokine selected from IFN-α, IL-2, IL-7, IL-10, IL-12, IL-15, IL-21, IL-27.
15 . The method according to claim 1 , wherein the BiTE or CAR-T therapy targets hematological or solid tumors, selected from CD19, CD20, or CD22.
16 . The method according to claim 1 , wherein the CAR-T targets are selected from TNFRSF17, IL3RA, SDC1, CD5, CD19, CD20, CD22, CD23, CD33, CD38, CD44, CD70, CD133, CD174, CD274, CD276, CEACAM6, GFRA1, ITGB6, MS4A1, TNFRSF8, NCAM1, ULBP1, ULBP2, IL1RAP, CEACAM5, MET, EGFR, EGFRvIII, ENPP1, FGFR4, EPCAM, EPHA2, ERBB2, GPC3, MSLN, Muc1, PDCD1, KDR, IL13RA2, FOLH1, FAP, CA9, FOLR1, L1CAM, ROR1, SLAMF7, GD2, PSCA, GPNMB, CSPG4, or TEM1.
17 . The method according to claim 1 , wherein the CAR-T therapy is idecabtagene vicleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, tisagenlecleucel, or axicabtagene ciloleucel.
18 . A method of inhibiting cytokine release syndrome (CRS) in a patient undergoing a bispecific T cell engager (BiTE) or chimeric antigen receptor T cell (CAR-T) therapy comprising administering to the patient in need thereof a composition comprising an interleukin 10 (IL-10) or an IL-10 agent.
19 . A method of inhibiting cytokine release syndrome (CRS) in a patient undergoing a bispecific T cell engager (BiTE) or chimeric antigen receptor T cell (CAR-T) therapy comprising administering to the patient in need thereof a composition comprising an interleukin 4 (IL-4) or an IL-4 agent.
20 . A method of inhibiting the induction of proinflammatory cytokines in a patient undergoing BiTE or CAR-T therapy comprising administering to the patient undergoing said therapy a composition comprising an interleukin 10 (IL-10) or an IL-10 agent or an interleukin 4 (IL-4) or an IL-4 agent.