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Building IP: BMY Patent Appl " METHODS OF TREATING CYTOKINE-RELATED ADVERSE EVENTS"METHODS OF TREATING CYTOKINE-RELATED ADVERSE EVENTSDOCUMENT IDUS 20230172923 A1 DATE PUBLISHED2023-06-08 INVENTOR INFORMATION NAMECITYSTATEZIP CODECOUNTRYJEYARAJU; Danny Vijey Hillsborough NJ N/A US AMATANGELO; Michael Madison NJ N/A US LA MOTTE-MOHS; Ross Randolph NJ N/A US PIERCEALL; William Madison NJ N/A US THAKURTA; Anjan G. Basking Ridge NJ N/A US APPLICANT INFORMATION NAME BRISTOL-MYERS SQUIBB COMPANY CITY Princeton STATE NJ ZIP CODE N/A COUNTRY US AUTHORITY N/A TYPE assignee APPLICATION NO17/921893 DATE FILED2021-04-29 FOREIGN APPLICATION PRIORITY DATA COUNTRYAPPLICATION NOAPPLICATION DATEEP 20172322.8 2020-04-30 AbstractThe disclosure relates to agents for use in the treatment or prevention of a cytokine-related adverse event or disease, such as cytokine release syndrome (CRS). Background/SummaryFIELD OF THE INVENTION [0001] The present invention relates to agents for use in the treatment or prevention of a cytokine-related adverse event or disease, such as cytokine release syndrome (CRS). BACKGROUND [0002] Cytokine release syndrome (CRS) is a potentially severe and life-threatening adverse event that is characterised by elevated levels of pro-inflammatory cytokines, in severe cases resulting in a systemic inflammatory response. Without being bound by theory, CRS may result from a large and/or rapid secretion of cytokines, for example because of activation and/or proliferation of immune effector cells. For example, CRS occurs when large numbers of white blood cells are activated and release inflammatory cytokines. [0003] CRS represents one of the most frequent serious adverse effects of T cell-engaging immunotherapies, including bispecific T-cell engaging antibodies and CAR T-cells (Teachey et al. (2013) Blood. 121(26): 5154-5157; Hay et al. (2017) Blood. 130(21): 2295-2306). CRS has also been described after infusion of several antibody-based therapies (Chatenoud et al. (1990) Transplantation. 49(4): 697-702; Freeman et al. (2015) Blood. 126(24): 2646-2649; Suntharalingam et al. (2006) N. Engl. J. Med. 355(10): 1018-1028; Winkler et al. (1999) Blood. 94(7): 2217-2224). The adverse event can also be triggered by other cell therapies and immunotherapies, as well as infection. [0004] Although treatments to mitigate the symptoms of the cytokine release exist, such as Tocilizumab and corticosteroids, understanding and eliminating the source of the cytokine release could potentially increase the therapeutic index of these cell therapies and immunotherapies. Many cytokines show elevated levels in serum of patients with CRS including interleukin-6 (IL-6). interleukin-10 (IL-10), and IL1-beta (Norelli et al. (2018) Nat. Med. 24(6): 739-748; Wang and Han (2018) Biomark. Res. 6: 4). IL-6 has been suggested as a central mediator of CRS toxicity (Tanaka et al. (2016) Immunotherapy. 8(8): 959-70) further supported by the effectiveness of Tocilizumab in treating severe CRS patients by blocking IL-6 signaling (Grupp et al. (2013) N. Engl. J. Med. 368: 1509-1518). Alternatively, IL1-beta signalling may be targeted by Anakinra (IL1-beta) to mitigate CRS. Typically, the agent will be used to target a single cytokine and prevent downstream signalling, and the initial secretion of IL-6 or IL1-beta is not prevented by the current treatments. In addition, existing treatments for CRS are not always effective and/or can have undesirable side effects. There is therefore a need for further therapies for the treatment or prevention of CRS. SUMMARY [0005] The present invention relates to methods of treating or preventing a cytokine-related adverse event or disease such as cytokine release syndrome (CRS) in a subject using a cytokine inhibitor (e.g. IL-6 inhibitor), preferably wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1 (4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3 -fluorobenzonitrile or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof). [0006] In one aspect, the present invention provides a cytokine inhibitor (e.g. IL-6 inhibitor) for use in a method of treating or preventing a cytokine-related adverse event or disease such as cytokine release syndrome (CRS) in a subject, wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1, and wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof. [0007] In another aspect, the present invention provides a method for treating or preventing a cytokine-related adverse event or disease such as cytokine release syndrome (CRS) in a subject, the method comprising administering to the subject a therapeutically effective dose of a cytokine inhibitor (e.g. IL-6 inhibitor), wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1, wherein the therapeutically effective dose is a dose sufficient to reduce or prevent the development of CRS in the subject, and wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-l-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof. [0008] In preferred embodiments, the cytokine-related adverse event or disease is cytokine release syndrome (CRS). In preferred embodiments, the subject has received or will receive a therapeutic agent that has caused or is likely to cause CRS. In particularly preferred embodiments, the therapeutic agent that has caused or is likely to cause CRS is a T cell engager. [0009] In alternative embodiments, the cytokine-related adverse event or disease is Coronavirus disease 19 (COVID-19). [0010] In yet further alternative embodiments, the cytokine-related adverse event or disease is cytokine-mediated neurotoxicity. In preferred embodiments, the subject has received or will receive a therapeutic agent that has caused or is likely to cause cytokine-mediated neurotoxicity. In particularly preferred embodiments, the therapeutic agent that has caused or is likely to cause cytokine-mediated neurotoxicity is a T cell engager. [0011] In another aspect, the present invention provides a BCMA therapeutic agent for use in a method of treating a disorder associated with BCMA expression in a subject, wherein the method comprises: [0012] a) administering to the subject the BCMA therapeutic agent, wherein the administering is likely to cause or has caused CRS in the subject; and [0013] b) administering to the subject a cytokine inhibitor (e.g. IL-6 inhibitor) at a dose sufficient to prevent or reduce the development of CRS in the subject, wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1, and wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-l-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof. [0014] In yet another aspect, the present invention provides a method for treating a disorder associated with BCMA expression in a subject, wherein the method comprises: [0015] a) administering to the subject a BCMA therapeutic agent, and [0016] b) administering to the subject a cytokine inhibitor (e.g. IL-6 inhibitor), wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1, and wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-l-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof. [0017] In another aspect, the present invention provides a BCMA therapeutic agent for use in a method of treating a disorder associated with BCMA expression in a subject, wherein the method comprises: [0018] a) administering to the subject a cytokine inhibitor (e.g. IL-6 inhibitor), wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1, and wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-y1)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-y1)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof; and [0019] b) following administration of the cytokine inhibitor, administering to the subject the BCMA therapeutic agent, wherein the administering is likely to cause CRS in the subject. [0020] In a related aspect, the present invention provides a method for treating a disorder associated with BCMA expression in a subject, wherein the method comprises: [0021] a) administering to the subject a cytokine inhibitor (e.g. IL-6 inhibitor), wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1, and wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperi din-3 -yl)-1-oxoisoindolin-4-yl)oxy)methyl)b enzyl)pip erazin-1-yl)-3 -fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof; and [0022] b) following administration of the cytokine inhibitor, administering to the subject a BCMA therapeutic agent, wherein the administering is likely to cause CRS in the subject. [0023] In some embodiments, the cytokine inhibitor (e.g. IL-6 inhibitor) is administered as a first dose at least 1 day before the BCMA therapeutic agent, preferably at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days before the BCMA therapeutic agent. [0024] In another aspect, the present invention provides a BCMA therapeutic agent for use in a method of treating a disorder associated with BCMA expression in a subject, wherein the method comprises: [0025] a) administering to the subject the BCMA therapeutic agent, wherein the administering is likely to cause or has caused CRS in the subject; and [0026] b) following administration of the BCMA therapeutic agent, administering to the subject a cytokine inhibitor (e.g. IL-6 inhibitor), wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1, and wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof. [0027] In a related aspect, the present invention provides a method for treating a disorder associated with BCMA expression in a subject, wherein the method comprises: [0028] a) administering to the subject a BCMA therapeutic agent, wherein the administering is likely to cause or has caused CRS in the subject; and [0029] b) following administration of the BCMA therapeutic agent, administering to the subject a cytokine inhibitor (e.g. IL-6 inhibitor), wherein the cytokine inhibitor (e.g. IL-6 inhibitor) is pomalidomide, iberdomide, lenalidomide, avadomide or Compound 1, and wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof. [0030] In some embodiments, the BCMA therapeutic agent is administered as a first dose at least 1 day before the cytokine inhibitor, preferably at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days before the cytokine inhibitor. [0031] In a further aspect, the present invention provides a BCMA therapeutic agent (e.g. a multispecific antibody which specifically binds to BCMA and to an antigen that promotes activation of one or more T cells) for use in a method of treating a disorder associated with BCMA expression in a subject, wherein the method comprises: [0032] a) administering to the subject the BCMA therapeutic agent, wherein the administering is likely to cause or has caused CRS in the subject; and [0033] b) administering to the subject Compound 1, wherein Compound 1 is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-l-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog or a pharmaceutically acceptable salt thereof. [0034] In certain embodiments of any aspect of the invention, the “subject” or “patient” is a human. [0035] In particularly preferred embodiments, the BCMA therapeutic agent is a T cell engager. [0036] In embodiments of any aspect of the invention, the T cell engager is a multispecific antibody that specifically binds to a target antigen (e.g. cancer antigen such as BCMA) and to an antigen that promotes activation of one or more T cells. In some embodiments, the antigen that promotes activation of one or more T cells is selected from the group consisting of CD3, TCRα, TCRβ, TCRγ, TCRζ, ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226. In preferred embodiments, the antigen that promotes activation of one or more T cells is CD3. [0037] In alternative embodiments of any aspect of the invention, the T cell engager is a chimeric antigen receptor (CAR) directed to a target antigen (e.g. cancer antigen such as BCMA), or a T cell expressing at least one CAR directed to a target antigen (e.g. cancer antigen such as BCMA). [0038] In embodiments of any aspect of the invention, the therapeutic agent that has caused or is likely to cause CRS or the BCMA therapeutic agent comprises an anti-BCMA antibody or antigen-binding fragment thereof comprising a CDR1H, CDR2H, CDR3H, CDR1L, CDR2L, and CDR3L region combination selected from: [0039] a) CDR1H region of SEQ ID NO:21, CDR2H region of SEQ ID NO:22, CDR3H region of SEQ ID NO: 17, CDR1L region of SEQ ID NO:23, CDR2L region of SEQ ID NO:24, and CDR3L region of SEQ ID NO:20; [0040] b) CDR1H region of SEQ ID NO:21, CDR2H region of SEQ ID NO:22, CDR3H region of SEQ ID NO: 17, CDR1L region of SEQ ID NO:25, CDR2L region of SEQ ID NO:26, and CDR3L region of SEQ ID NO:20; [0041] c) CDR1H region of SEQ ID NO:21, CDR2H region of SEQ ID NO:22, CDR3H region of SEQ ID NO: 17, CDR1L region of SEQ ID NO:27, CDR2L region of SEQ ID NO:28, and CDR3L region of SEQ ID NO:20; [0042] d) CDR1H region of SEQ ID NO:29, CDR2H region of SEQ ID NO:30, CDR3H region of SEQ ID NO: 17, CDR1L region of SEQ ID NO:31, CDR2L region of SEQ ID NO:32, and CDR3L region of SEQ ID NO:33; [0043] e) CDR1H region of SEQ ID NO:34, CDR2H region of SEQ ID NO:35, CDR3H region of SEQ ID NO: 17, CDR1L region of SEQ ID NO:31, CDR2L region of SEQ ID NO:32, and CDR3L region of SEQ ID NO:33; [0044] f) CDR1H region of SEQ ID NO:36, CDR2H region of SEQ ID NO:37, CDR3H region of SEQ ID NO: 17, CDR1L region of SEQ ID NO:31, CDR2L region of SEQ ID NO:32, and CDR3L region of SEQ ID NO:33; or [0045] g) CDR1H region of SEQ ID NO: 15, CDR2H region of SEQ ID NO: 16, CDR3H region of SEQ ID NO: 17, CDR1L region of SEQ ID NO: 18, CDR2L region of SEQ ID NO: 19, and CDR3L region of SEQ ID NO:20. [0046] In some embodiments of any aspect of the invention, the therapeutic agent that has caused or is likely to cause CRS or the BCMA therapeutic agent comprises an anti-BCMA antibody or antigen-binding fragment thereof comprising a VH and a VL selected from the group consisting of: [0047] a) a VH region of SEQ ID NO: 10 and a VL region of SEQ ID NO: 12; [0048] b) a VH region of SEQ ID NO: 10 and a VL region of SEQ ID NO: 13; [0049] c) a VH region of SEQ ID NO: 10 and a VL region of SEQ ID NO: 14; [0050] d) a VH region of SEQ ID NO:38 and a VL region of SEQ ID NO: 12; [0051] e) a VH region of SEQ ID NO:39 and a VL region of SEQ ID NO: 12; [0052] f) a VH region of SEQ ID NO: 40 and a VL region of SEQ ID NO: 12; or [0053] g) a VH region of SEQ ID NO: 9 and a VL region of SEQ ID NO: 11. [0054] In preferred embodiments of any aspect of the invention, the therapeutic agent that has caused or is likely to cause CRS or the BCMA therapeutic agent comprises an anti-BCMA antibody or antigen-binding fragment thereof comprising a VH region of SEQ ID NO: 10 and a VL region of SEQ ID NO: 14. [0055] In alternative embodiments of any aspect of the invention, the therapeutic agent that has caused or is likely to cause CRS or the BCMA therapeutic agent comprises an anti-BCMA antibody antigen-binding fragment thereof comprises a VH comprising a CDR1H of SEQ ID NO:64, a CDR2H of SEQ ID NO: 65 and a CDR3H of SEQ ID NO: 66, and a VL comprising a CDR1L, a CDR2L and a CDR3L set of sequences selected from: [0056] a) CDR1L of SEQ ID NO:67, CDR2L of SEQ ID NO:68, and CDR3L of SEQ ID NO:69, optionally wherein the BCMA therapeutic agent comprises a VH of SEQ ID NO: 76 and a VL of SEQ ID NO: 77; [0057] b) CDR1L of SEQ ID NO:70, CDR2L of SEQ ID NO:71, and CDR3L of SEQ ID NO:72, optionally wherein the BCMA therapeutic agent comprises a VH of SEQ ID NO:76 and a VL of SEQ ID NO: 78; or [0058] c) CDR1L of SEQ ID NO:73, CDR2L of SEQ ID NO:74, and CDR3L of SEQ ID NO:75 optionally wherein the BCMA therapeutic agent comprises a VH of SEQ ID NO: 76 and a VL of SEQ ID NO:79. [0059] In some embodiments, the multispecific antibody comprises an anti-CD3 antibody, or antigen binding fragment thereof. In some embodiments, the anti-CD3 antibody, or antigen binding fragment thereof comprises a variable domain VH comprising the heavy chain CDRs of SEQ ID NOs: 1, 2 and 3 as respectively heavy chain CDR1H, CDR2H and CDR3H and a variable domain VL comprising the light chain CDRs of SEQ ID NOs: 4, 5 and 6 as respectively light chain CDR1L, CDR2L and CDR3L. In preferred embodiments, the anti-CD3 antibody, or antigen binding fragment thereof, comprises a VH region of SEQ ID NO:7 and a VL region of SEQ ID NO: 8. [0060] In particularly preferred embodiments, the multispecific antibody comprises an anti-BCMA antibody, or antigen binding fragment thereof, comprising a VH region of SEQ ID NO: 10 and a VL region of SEQ ID NO: 14, and an anti-CD3 antibody, or antigen binding fragment thereof, comprising a VH region of SEQ ID NO:7 and a VL region of SEQ ID NO:8. [0061] In some embodiments, the multispecific antibody is a bispecific antibody. In some embodiments, the bispecific antibody is bivalent (e.g. 1+1 format). In alternative embodiments, the bispecific antibody is trivalent (e.g. 2+1 format). In some embodiments, the trivalent bispecific antibody has the format: CD3 Fab - BCMA Fab - BCMA Fab; or BCMA Fab – CD3 Fab – BCMA Fab (i.e. when no Fc is present). Alternatively, the trivalent bispecific antibody may have the format: BCMA Fab – Fc – CD3 Fab – BCMA Fab; BCMA Fab – Fc – BCMA Fab – CD3 Fab; or CD3 Fab – Fc – BCMA Fab – BCMA Fab (i.e. when an Fc is present). In preferred embodiments, the trivalent bispecific antibody has the format BCMA Fab – Fc – CD3 Fab – BCMA Fab. [0062] In some embodiments, the anti-CD3 Fab comprises a light chain and a heavy chain, wherein the light chain is a crossover light chain that comprises a variable domain VH and a constant domain CL, and wherein the heavy chain is a crossover heavy chain that comprises a variable domain VL and a constant domain CH1. [0063] In some embodiments, the CH1 domain of the anti-BCMA Fab fragment comprises the amino acid modifications K147E/D and K213E/D (numbered according to EU numbering) and a corresponding immunoglobulin light chain comprising a CL domain having amino acid modifications E123K/R/H and Q124K/R/H (numbered according to Kabat). [0064] In some embodiments, the multispecific (e.g. bispecific) antibody further comprises an Fc. In some embodiments, the Fc is an IgGl Fc. In some embodiments, the (e.g. IgGl) Fc comprises a first Fc chain comprising first constant domains CH2 and CH3, and a second Fc chain comprising second constant domains CH2 and CH3, and wherein: [0065] a) the first CH3 domain comprises the modifications T366S, L368A and Y407V, or conservative substitutions thereof (numbered according to EU numbering); and [0066] b) the second CH3 domain comprises the modification T366W, or conservative substitutions thereof (numbered according to EU numbering). [0067] In some embodiments, the (e.g. IgGl) Fc comprises: [0068] a) the modifications L234A, L235A and P329G (numbered according to EU numbering); and/or [0069] b) the modifications D356E, and L358M (numbered according to EU numbering). [0070] In further embodiments, the bispecific antibody according to the invention comprises a heavy and light chain set of the polypeptides set forth in the following SEQ ID NOs: [0071] 83A10-TCBcv: 48, 45, 46, 47 (x2); [0072] 22-TCBcv: 48, 52, 53, 54 (x2); or [0073] 42-TCBcv: 48, 55, 56, 57 (x2). [0074] In a preferred embodiment, the bispecific antibody according to the invention is 42-TCBcv and comprises a heavy and light chain set of the polypeptides set forth in SEQ ID NO:48, SEQ ID NO:55, SEQ ID NO:56, and two copies of SEQ ID NO:57. [0075] In embodiments of any aspect of the invention, the BCMA therapeutic agent is AMG-420 [Amgen], BCMA tri-specific [Affirmed], AFM26 [Affirmed], Ab-957 [Janssen], BCMA/PD-L1 [Immune pharmaceuticals], AMG-701 [Amgen], PF-06863135 [Pfizer], REGN-5458 [Regeneron / Sanofi], or TNB-383B [TeneoBio]. [0076] In embodiments of any aspect of the invention, the BCMA therapeutic agent is a chimeric antigen receptor (CAR) directed to BCMA, or a T cell expressing at least one CAR directed to BCMA (“BCMA CAR T cell”). [0077] In some embodiments, the BCMA CAR T cell is idecabtagene-vicleucel (ide-cel), bb21217, JCARH125 (orva-cel), KITE-585 (Kite Pharmaceuticals), P-BCMA-101 (Poseida Therapeutics), CART-BCMA (Novartis), LCAR-B38M (Legend Biotech), JNJ-528 (Janssen Biotech), P-BCMA-101 (Poseida Therapeutics), CT053 (CARsgen Therapeutics), CTX120 (CRISPR Therapeutics), ET140 (Juno Therapeutics), UCART-BCMA (Cellectis), P-BCMA-101 (Poseida), JNJ-528ALCAR-B38M (Johnson & Johnson). In certain embodiments, the BCMA CAR T cell is MCARH171, FCARH143, CTX120, CT053 (First Affiliated Hospital of Wenzhou Medical University, CN), or BCMA-CART (Hrain Biotechnology, Shanghai CN). In preferred embodiments, the BCMA CAR T cell is idecabtagene-vicleucel, bb21217, or JCARH125. [0078] In embodiments of any aspect of the invention, the therapeutic agent that has caused or is likely to cause CRS or the BCMA therapeutic agentis an antibody-drug conjugate (ADC). [0079] In embodiments of any aspect of the invention, the cytokine inhibitor (e.g. IL-6 inhibitor) is administered before (e.g. within 12 or 24 hours before) administration of the therapeutic agent (e.g. BCMA therapeutic agent), on the same day as administration of the therapeutic agent (e.g. BCMA therapeutic agent) or after (e.g. within 12 or 24 hours after) administration of the therapeutic agent (e.g. BCMA therapeutic agent). [0080] In some embodiments of any aspect of the invention, the cytokine inhibitor (e.g. IL-6 inhibitor) is administered as a pre-treatment before administration of the therapeutic agent (e.g. BCMA therapeutic agent). In some embodiments, the cytokine inhibitor (e.g. IL-6 inhibitor) is administered as one or more doses before (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days before) administration of the therapeutic agent (e.g. BCMA therapeutic agent). In some embodiments, the cytokine inhibitor (e.g. IL-6 inhibitor) is administered on days 1, 2, 3, 4, 5, 6 and 7, before administration of the therapeutic agent (e.g. BCMA therapeutic agent) on day 8. [0081] In alternative embodiments, the therapeutic agent (e.g. BCMA therapeutic agent) is administered before administration of the cytokine inhibitor (e.g. IL-6 inhibitor). In some embodiments, the therapeutic agent (e.g. BCMA therapeutic agent) is administered as one or more doses before (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days before) administration of the cytokine inhibitor (e.g. IL-6 inhibitor). In some embodiments, the therapeutic agent (e.g. BCMA therapeutic agent) is administered on day 1 and optionally day 4, before administration of the cytokine inhibitor (e.g. IL-6 inhibitor) on day 8. [0082] In some embodiments of any aspect of the invention, the cytokine inhibitor (e.g. IL-6 inhibitor) is administered within 12 hours after diagnosis of CRS. [0083] Aspects and embodiments of the invention are set out in the appended claims. These and other aspects and embodiments of the invention are also described herein. |
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11291 | Re: Building IP: BMY Patent Appl " METHODS OF TREATING CYTOKINE-RELATED ADVERSE EVENTS" | grafzeppelin | 1 | 6/9/2023 8:35:36 AM |