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 cytokine release syndrome (CRS) severity induced by using a bispecific antibody or chimeric antigen receptor T cell (CAR-T) during treatment of a malignant disease and enhancement of tumor cytolysis comprising administering to a patient in need thereof
(a) an amount of a composition comprising a dual cytokine fusion protein of Formula II
NH 2 -(Y)-(X 1 )-(Z n )-(X 2 )-(Y)-COOH (Formula II)
wherein
“Y” is a monomer of IL10 comprising a sequence of SEQ ID No.: 5, or a variant thereof;
“X 1 ” is a VL or VH region from a first monoclonal antibody;
“X 2 ” is a VH or VL region from the first monoclonal antibody;
wherein when X 1 is a VL, X 2 is a VH or when X 1 is a VH, X 2 is a VL,
wherein the first monoclonal antibody is an anti-ebola antibody;
wherein the VL and VH from the anti-ebola antibody include 3 light chain CDRs and 3 heavy chain CDRs that are engrafted with 3 light chain CDRs and 3 heavy chain CDRs from an anti-EGFR monoclonal antibody;
“Z” is an IL-2; and
“n” is an integer of 1; and
(b) an amount of a bispecific antibody or CAR-T, wherein the bispecific antibody comprises specificity for a CD3 and a tumor associated antigen,
wherein the administering reduces induction of pro-inflammatory cytokines IL-1β, IL-6, TNFα, IL-12, IFNα, IFNγ, IL-23, or any combination thereof.
2 . The method according to claim 1 , wherein the dual cytokine fusion protein further comprises a scFv targeting domain that targets a receptor different from the bispecific antibody or CAR-T.
3 . The method according to claim 1 , wherein the bispecific antibody or CAR-T therapy targets a hematological or solid tumor.
4 . The method according to claim 1 , wherein the bispecific antibody or CAR-T targets an antigenic determinant 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 (CEA), MET, EGFR, EGFRvIII, ENPP1, DLL3, CLDN18, BCAM, PSMA, MUC17, HER2, HER3, FGFR4, EPCAM, EPHA2, ERBB2, GPC3, MSLN, Muc1, PDCD1, KDR, IL13RA2, FOLH1, FAP, CA9, FOLR1, L1CAM, ROR1, SLAMF7, GD2, 5T4, PSCA, GPNMB, CSPG4, PDGFR, PDL1, PD1 or TEM1.
5 . The method according to claim 1 , wherein the CAR-T therapy is idecabtagene vicleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, tisagenlecleucel, or axicabtagene ciloleucel.