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WO2025088308A1 - Produits et méthodes de traitement de maladies auto-immunes - Google Patents

Produits et méthodes de traitement de maladies auto-immunes Download PDF

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Publication number
WO2025088308A1
WO2025088308A1 PCT/GB2024/052698 GB2024052698W WO2025088308A1 WO 2025088308 A1 WO2025088308 A1 WO 2025088308A1 GB 2024052698 W GB2024052698 W GB 2024052698W WO 2025088308 A1 WO2025088308 A1 WO 2025088308A1
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Prior art keywords
car
cells
cell
seq
sle
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Inventor
Wolfram Brugger
Gianfranco PITTARI
Michelle Davies
Gianluca ROSSATO
Yiyun Zhang
Martin PULÉ
Helen WHITROW
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Autolus Ltd
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Autolus Ltd
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Priority claimed from GBGB2316183.9A external-priority patent/GB202316183D0/en
Priority claimed from GBGB2404412.5A external-priority patent/GB202404412D0/en
Priority claimed from GBGB2412689.8A external-priority patent/GB202412689D0/en
Priority claimed from GBGB2414148.3A external-priority patent/GB202414148D0/en
Application filed by Autolus Ltd filed Critical Autolus Ltd
Publication of WO2025088308A1 publication Critical patent/WO2025088308A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/421—Immunoglobulin superfamily
    • A61K40/4211—CD19 or B4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31—Chimeric antigen receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/416—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)

Definitions

  • the present invention relates to a chimeric antigen receptor (CAR) which binds the B- lymphocyte antigen CD19 (Cluster of Differentiation 19) and to use of cytolytic cells expressing the CAR for the treatment of autoimmune diseases such as systemic lupus erythromatosus (SLE).
  • CAR chimeric antigen receptor
  • B cells along with T cells, form the core of the adaptive arm of the immune system and play a key role in regulating immune response in both normal physiological and pathological conditions.
  • B cells are identified pharmacological targets in B cell malignancies and autoimmune diseases.
  • autoimmune mechanisms Numerous diseases are believed to result from autoimmune mechanisms. Common among these are rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, Type I diabetes, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, psoriasis, Graves’ disease, Hashimoto’s thyroiditis, myasthenia gravis, scleroderma, vasculitis and pemphigus vulgaris. Autoimmune diseases affect millions of individuals world-wide and the cost of these diseases, in terms of actual treatment expenditures and lost productivity, is measured in billions of dollars annually.
  • Systemic lupus erythematosus is an autoimmune disease characterised by the formation of autoantibodies and immune complex mediated inflammation and organ damage, including the skin, joints, central nervous system, heart, lung, and kidneys (Tsokos GC. (2011). Systemic lupus erythematosus. N Engl J Med 365(22):2110-21 ; Kaul A, Gordon C, Crow M, et al. (2016). Systemic lupus erythematosus. Nature Reviews 2:1-21 ; Mackensen A, Muller F, Mouglakakos D, et al. (2022). Anti-CD19 CAR T cell therapy for refractory lupus erythematosus.
  • Anifrolumab a type I interferon (IFN) receptor antagonist, has also been approved in the US and EU and is indicated as an add-on for the treatment of adult patients with moderate to severe SLE who are receiving standard therapy (Saphnelo (anifrolumab- fnia) IISPI. 2022.
  • IFN interferon
  • voclosporin (Lupkynis USPI, 2021) was approved for lupus nephritis based on the AURORA1 trial (Rovin et al., Lancet 2021) (www.doi.org/10.1016/S0140-6736(21)00578-X). Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. Despite these approvals, some patients have insufficient response, lack of response, or lack of sustained response and are at risk for further organ damage despite standard therapy. Hence, challenges remain with treatmentresistant disease.
  • CD19-targeting chimeric antigen receptor (CAR) T cells Cappell KM, Kochenderfer JN. (2023) Longterm outcomes following CAR T cell therapy: what we know so far. Nat Review 20:359- 371).
  • CD19-targeted CAR T cells are now approved for relapsed and/or refractory B cell lymphoma and B cell acute lymphoblastic leukemia (B-ALL) (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel and brexucabtagene autoleucel).
  • CD19-targeted CAR T cells are likely to be curative for a subset of patients with B cell lymphomas and possibly B-ALL (Cappell and Kochenderfer, supra; Westin J, Davis RE, Feng L, Hagemeister F, et al. (2023). Smart start: rituximab, lenalidomide, and ibrutinib in patients with newly diagnosed large B-cell lymphoma. J Clin Oncol 41 (4): 745-55).
  • CD8 + T cells expressing CD19-targeted CARs [1 D3 CAR (Kochenderfer JN, Yu Z, Frasheri D, et al. (2010), Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells.
  • Transferred anti-CD19 CAR T cells to MRL-lpr mice at onset of disease was assessed to determine their role in SLE prevention.
  • the adoptive transfer of the constructed anti-CD 19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice.
  • the transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression.
  • CAR-T cells with the 4-1 BB costimulatory motif showed better therapeutic efficiency, without cell enrichment, compared to CAR-T cells with CD28 costimulatory motif.
  • belimumab an anti-B cell activating factor (BAFF)/B lymphocyte stimulator (BlyS) monoclonal antibody
  • BAFF anti-B cell activating factor
  • BlyS B lymphocyte stimulator
  • Tolerability and efficacy were initially tested in a single SLE patient treated with a CD19 CAR (FMC63 CAR) (Mougiakakos D, Krdnke G, Volkl S, Kretschmann S, et al. (2021). CD-19-targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med 385(6): 567-9).
  • CD19 CAR T cell treatment in another autoimmune disease has recently been shown in patients with refractory idiopathic inflammatory myopathy associated with antisynthetase syndrome (Muller F, Boeltz S, Knitza J, Aigner M, et al. (2023).
  • CD19-targeted CAR T cells in refractory antisynthetase syndrome Lancet 401(10379):815-8; Percher AC, Hensen L, Klein R, et al. (2023).
  • CAR Chimeric Antigen Receptor
  • scFv single-chain variable fragments
  • monoclonal antibodies which recognise a target antigen, fused via a spacer and a transmembrane domain to a signalling endodomain.
  • Such molecules result in activation of the T cell in response to recognition by the scFv of its cognate target.
  • T cells express such a CAR, they recognize and kill target cells that express the target antigen.
  • CARs have been developed against tumour associated antigens, and adoptive transfer approaches using such CAR-expressing T cells are currently in clinical trial for the treatment of various cancers. To-date however, the main clinical exploration and potential application of CAR therapy is as treatment for B-cell malignancies.
  • CD19 is a B-cell antigen which is expressed very early in B-cell differentiation and is only lost at terminal B-cell differentiation into plasma cells. Hence, CD19 is expressed on all B-cell malignancies apart from multiple myeloma. It is not expressed on other haematopoietic populations or non-haematopoietic cells and therefore targeting this antigen should not lead to toxicity to the bone marrow or non-haematopoietic organs. Loss of the normal B-cell compartment is considered an acceptable toxicity when treating lymphoid malignancies, because although effective CD 19 CAR T cell therapy will result in B cell aplasia, the consequent hypogammaglobulinaemia can be treated with pooled immunoglobulin.
  • CD19 is therefore an attractive CAR target.
  • the main clinical focus of the CAR field has been studies targeting CD19 on refractory B-cell cancers, as summarised in Table 1.
  • Cytokine release syndrome encompasses a range of inflammatory symptoms ranging from mild to multi-organ failure with hypotension and respiratory failure.
  • Some degree of CRS occurs commonly in patients treated with CD19 CAR T cells. Approximately 30% (21/73) patients treated in recent cohorts showed some degree of CRS (Davila et al ((2014). Sci. Transl. Med. 6, 224ra25; Lee et al (2014) Lancet. doi:10.1016/S0140-6736(14)61403-3; Kochenderfer et al. (2014) J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol., doi:10.1200/JCO.2014.56.2025).
  • CRS has also been seen in patients treated with blinatumomab, a bi-specific recombinant single-chain antibody recognising both CD19 and CD3.
  • CRS typically occurs 5-21 days after CAR T cell infusion.
  • CRS can be life threatening and requires treatment in an intensive care setting.
  • CRS is associated with elevated serum cytokine levels.
  • the cytokines most significantly elevated are IL-6, IL-10 and interferon gamma (IFNy).
  • IL-6 IL-6
  • IFNy interferon gamma
  • Clinical manifestations of severe CRS fever, hepatosplenomegaly, coagulopathy and hyperferritinaemia
  • MAS macrophage activation syndrome
  • MAS macrophage activation syndrome
  • MAS macrophage activation syndrome
  • a key initiating factor in MAS is release of copious Interferongamma (Lopez-Alvarez et al. (2009). Clin. Vaccine Immunol. CVI 16, 142-145).
  • Durable responses appeared to correlate with higher peak levels of circulating CAR transduced T cells, as well as with the duration of B cell aplasia. With exception of patients relapsing with CD19- disease, relapse was generally associated with loss of circulating CAR T cells and recovery of normal B cells.
  • T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged with expression of inhibitory receptor programmed death 1 (PD-1 ; also known as PDCD1), a negative regulator of activated T cells, being a key feature (Day et al. (2006) Nature 443, 350-354).
  • PD-1 inhibitory receptor programmed death 1
  • the present disclosure provides methods of treatment of autoimmune diseases with CD19 CAR T cells.
  • Treatment with CD19 CAR T cells is contemplated to more completely the B cell compartment than Rituximab, more effectively eliminating autoreactive B cells.
  • CD19 as a target in autoimmune diseases is advantageous over CD20-directed therapies as CD19 is expressed more broadly on B cells, including very early B-progenitor cells as well as immature plasmablasts.
  • the present invention provides methods of treating an autoimmune disease in a patient, where the patient is administered a cell comprising a chimeric antigen receptor (CAR) comprising a CD19-binding domain which comprises a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • CAR chimeric antigen receptor
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • the autoimmune disease may be systemic lupus erythrematosus (SLE).
  • SLE systemic lupus erythrematosus
  • the autoimmune disease may be severe SLE or refractory SLE.
  • the cell may be a T cell or NK cell.
  • the cell may an autologous peripheral blood T cells transduced ex vivo to express the CAR.
  • the cell may have been isolated from a peripheral blood mononuclear cell (PBMC) sample from the patient.
  • PBMC peripheral blood mononuclear cell
  • a dose of 50 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells may be administered to the patient.
  • the dose may be 100 x 10 6 ( ⁇ 20%) CD 19 CAR-positive viable T cells or 30 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells.
  • the administration may be an intravenous injection through a Hickman line or peripherally inserted central catheter.
  • the CD19 binding domain may comprise the six CDRs (SEQ ID Nos. 1-6) grafted on to a human antibody framework.
  • the CD19 binding domain may comprise a VH domain having the sequence shown as SEQ ID No. 7 and/or or a VL domain having the sequence shown as SEQ Id No. 8, or a variant of either having at least 95% sequence identity.
  • the CD19 binding domain may comprise an scFv in the orientation VH-VL.
  • the CD19 binding domain may comprise the sequence shown as SEQ ID No.. 9 or a variant thereof having at least 90% sequence identity.
  • the CAR may comprise a spacer that is a CD8 stalk.
  • the CAR may comprise an intracellular T cell signaling domain comprising the 41 BB endodomain and the CD3-Zeta endodomain.
  • the invention provides a method of treating an autoimmune disease in a patient comprising administering to the patient a dose of 50 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells.
  • the patient may be administered a dose of 30 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells.
  • the patient may be administered a dose of 100 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells.
  • the autoimmune disease according to the second aspect may be SLE.
  • the autoimmune disease may be severe SLE or refractory SLE.
  • the CAR may comprise the sequence shown as any of SEQ ID No. 10 to 15 or a variant thereof which has at least 80% sequence identity but retains the capacity to i) bind CD19 and ii) induce T cell signalling.
  • the CAR may have advantageous properties compared to the fmc63-based CAR used in the UPENN studies.
  • the CD19 (CAT) CAR herein has a lower affinity CD19 binder with a faster off-rate which mirrors more closely a physiological interaction and therefore, a more physiological T cell activation.
  • the CAR when expressed by a T cell and used to target a CD19 expressing cell, may cause lower IFNy release by the CD19-expressing target cell than that caused by a T cell expressing a CAR comprising a CD19-binding domain which comprises: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:CDR1 - GVSLPDY (SEQ ID No. 16); CDR2 - WGSET (SEQ ID No.
  • CDR3 - HYYYGGSYAMDY SEQ ID No. 18
  • VL light chain variable region
  • CDR1 - RASQDISKYLN SEQ ID No. 19
  • CDR2 - HTSRLHS SEQ ID No. 20
  • CDR3 - QQGNTLPYT SEQ ID No. 21.
  • the CDRs provided herein may be grafted on to a human or humanised framework. DESCRIPTION OF THE FIGURES
  • FIG. 1 CAR-T cell expansion in first SLE patient treated with obe-cel.
  • A) Flow cytometry of CD3+CAT19+ cells.
  • Chimeric antigen receptors also known as chimeric T cell receptors, artificial T cell receptors and chimeric immunoreceptors, are engineered receptors, which graft an arbitrary specificity onto an immune effector cell.
  • CARs also known as chimeric T cell receptors, artificial T cell receptors and chimeric immunoreceptors
  • CAR-encoding nucleic acids may be transferred to T cells using, for example, retroviral vectors. In this way, a large number of CD19-specific T cells can be generated for adoptive cell transfer. Phase I clinical studies of this approach show efficacy.
  • the target-antigen binding domain of a CAR is commonly fused via a spacer and transmembrane domain to an endodomain.
  • the endodomain may comprise or associate with an intracellular T cell signaling domain.
  • the human CD19 antigen is a 95 kd transmembrane glycoprotein belonging to the immunoglobulin superfamily.
  • CD19 is classified as a type I transmembrane protein, with a single transmembrane domain, a cytoplasmic C-terminus, and extracellular N- terminus.
  • CD19 is expressed very early in B-cell differentiation and is only lost at terminal B-cell differentiation into plasma cells.
  • CD19 is a biomarker for normal B cells as well as follicular dendritic cells.
  • CD19 primarily acts as a B cell co-receptor in conjunction with CD21 and CD81 . Upon activation, the cytoplasmic tail of CD19 becomes phosphorylated, which leads to binding by Src-family kinases and recruitment of PI-3 kinase.
  • CD19 is also expressed on all B-cell malignancies but not multiple myeloma cells. It is not expressed on other haematopoietic populations or non-haematopoietic cells and therefore targeting this antigen should not lead to toxicity to the bone marrow or non-haematopoietic organs. Loss of the normal B-cell compartment is considered an acceptable toxicity when treating lymphoid malignancies, because although effective CD19 CAR T cell therapy will result in B cell aplasia, the consequent hypogammaglobulinaemia can be treated with pooled immunoglobulin.
  • the antigen-binding domain of a CAR which binds to CD19 may be any domain which is capable of binding CD19.
  • the antigen-binding domain may comprise a CD19 antigen-binding domain as described in Table 3.
  • the gene encoding CD19 comprises ten exons: exons 1 to 4 encode the extracellular domain; exon 5 encodes the transmembrane domain; and exons 6 to 10 encode the cytoplasmic domain.
  • the antigen-binding domain of a CD19 CAR herein may bind an epitope of CD19 encoded by exon 1 of the CD19 gene.
  • the antigen-binding domain of a CD19 CAR herein may bind an epitope of CD19 encoded by exon 2 of the CD19 gene.
  • the antigen-binding domain of a CD19 CAR herein may bind an epitope of CD19 encoded by exon 3 of the CD19 gene.
  • the antigen-binding domain of a CD19 CAR herein may bind an epitope of CD19 encoded by exon 4 of the CD19 gene.
  • a CD19-binding domain exemplified herein comprises variable regions with complementarity determining regions (CDRs) from an antibody referred to as CAT19, a) a heavy chain variable region (VH) having CAT19 CDRs with the following sequences:
  • the CAT19 antibody is described in WO 2016/139487.
  • Each CDR may, for example, have one, two or three amino acid mutations.
  • the CDRs may be in the format of a single-chain variable fragment (scFv), which is a fusion protein of the heavy variable region (VH) and light chain variable region (VL) of an antibody, connected with a short linker peptide of ten to about 25 amino acids.
  • scFv single-chain variable fragment
  • VH heavy variable region
  • VL light chain variable region
  • the scFv may be in the orientation VH-VL, /.e., the VH is at the amino-terminus of the CAR molecule and the VL domain is linked to the spacer and, in turn the transmembrane domain and endodomain.
  • the CDRs may be grafted on to the framework of a human antibody or scFv.
  • the CAR may comprise a CD19-binding domain consisting or comprising one of the following sequences.
  • the CD19 CAR may comprise the following VH sequence. SEQ ID No. 7 - VH sequence from CAT19 murine monoclonal antibody
  • the CD19 CAR may comprise the following VL sequence.
  • the CD19 CAR may comprise the following scFv sequence.
  • the CAR may consist of or comprise one of the following sequences.
  • “Campana” architecture refers to a CAR with a CD8a spacer and transmembrane domain, 4-1 BB endodomain and TCR CD3z endodomain.
  • the CAR provided herein may comprise a variant of the polypeptide of SEQ ID Nos. 1-15 having at least 80, 85, 90, 95, 98 or 99% sequence identity, provided that the variant sequence retains the capacity to bind CD19 (when in conjunction with a complementary VL or VH domain, if appropriate).
  • the percentage identity between two polypeptide sequences may be readily determined by programs such as BLAST which is freely available at blast.ncbi.nlm.nih.gov.
  • the CD19 CAR exemplified herein (/.e., the CAT19CAR using “Campana” architecture, SEQ ID No. 10) has properties contemplated by the disclosure to result in lower toxicity and better efficacy in treated patients.
  • the CAT19CAR exemplified herein effected killing of target cells expressing CD19 and proliferated in response to CD19 expressing targets, but Interferon-gamma release was less.
  • a small animal model of an aggressive B-cell lymphoma showed equal efficacy and equal engraftment between the fmc63- and CAT 19-based CAR-T cells, but surprisingly, less of the CAT 19 CAR T cells were exhausted than fmc63 CAR T cells. See, Examples 2 and 3 of US Publication No.: 2018-0044417.
  • the CAT19CAR provided herein may cause 25, 50, 70 or 90% lower IFNy release in a comparative assay involving bringing CAR T cells into contact with target cells.
  • the CAT19CAR provided herein may result in a smaller proportion of CAR T cells becoming exhausted than fmc63 CAR T cells. T cell exhaustion may be assessed using methods known in the art, such as analysis of PD-1 expression.
  • the CAR may cause 20, 30, 40, 50, 60 of 70% fewer CAR T cells to express PD-1 that fmc63 CAR T cells in a comparative assay involving bringing CAR T cells into contact with target cells.
  • CD19 antigen-binding domain contemplated by the disclosure is based on the CD19 antigen-binding domain CD19ALAb (described in WO20 16/102965) and comprises: a) a heavy chain variable region (VH) having CDRs with the following sequences:
  • Each CDR may, for example, have one, two or three amino acid mutations.
  • the CAR may comprise one of the following amino acid sequences.
  • SEQ ID No. 22 Murine CD19ALAb scFv sequence QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPG DGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYA MDYWGQGTTVTVSSDIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQ QIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDP
  • the scFv may be in a VH-VL orientation (as shown in SEQ ID NO:s 9, 22, 23 and 24) or a VL-VH orientation.
  • the CAR may comprise one of the following VH sequences:
  • the CAR may comprise one of the following VL sequences:
  • the CAR provided herein may comprise a variant of the sequence shown as any of SEQ ID Nos. 16-29 having at least 80, 85, 90, 95, 98 or 99% sequence identity, provided that the variant sequence retains the capacity to bind CD19 (when in conjunction with a complementary VL or VH domain, if appropriate).
  • the CAR provided herein may comprise a variant of the sequence shown as any of SEQ ID Nos. 22-29 or 44-49 having at least 80, 85, 90, 95, 98 or 99% sequence identity, provided that the variant sequence retains the capacity to bind CD19 (when in conjunction with a complementary VL or VH domain, if appropriate).
  • the percentage identity between two polypeptide sequences may be readily determined by programs such as BLAST which is freely available at blast.ncbi.nlm.nih.gov.
  • the transmembrane domain is the domain of the CAR that spans the membrane.
  • a transmembrane domain may be any protein structure which is thermodynamically stable in a membrane. This is typically an alpha helix comprising of several hydrophobic residues.
  • the transmembrane domain of any transmembrane protein can be used to supply the transmembrane portion provided herein.
  • the presence and span of a transmembrane domain of a protein can be determined by those skilled in the art using the TMHMM algorithm (http://www.cbs. dtu.dk/services/TMHMM-2.0/).
  • transmembrane domain of a protein is a relatively simple structure, i.e, a polypeptide predicted to form a hydrophobic alpha helix of sufficient length to span the membrane
  • an artificially designed transmembrane domain may also be used (US 7052906 B1 describes synthetic transmembrane components).
  • the transmembrane domain may be derived from CD28, which gives good receptor stability.
  • the CD28 transmembrane domain is shown as SEQ ID No. 50. SEQ ID No. 50
  • the transmembrane domain may be derived from human Tyrp-1 .
  • the tyrp-1 transmembrane domain sequence is shown as SEQ ID No. 51.
  • the transmembrane domain may be derived from CD8A.
  • the CD8A transmembrane domain sequence is shown as SEQ ID NO: 52.
  • the endodomain is the signal-transmission portion of the CAR. After antigen recognition, receptors cluster and a signal is transmitted to the cell.
  • the most commonly used endodomain component is that of CD3-zeta which contains 3 ITAMs. This transmits an activation signal to the T cell after antigen is bound.
  • CD3-zeta may not provide a fully competent activation signal and additional co-stimulatory signaling may be needed.
  • endodomains from CD28, or 0X40 or 41 BB can be used with CD3-Zeta to transmit a proliferative I survival signal, or all three can be used together.
  • the endodomain of the CAR of the present invention may comprise combinations of one or more of the CD3-Zeta endodomain, the 41 BB endodomain, the 0X40 endodomain or the CD28 endodomain.
  • the intracellular T cell signalling domain (endodomain) of the CAR of the present invention may comprise the sequence shown as SEQ ID Nos. 53, 54, 55, 56, 57, 30, 31 or 32 or a variant thereof having at least 80% sequence identity.
  • Examples of combinations of such endodomains include 41 BB-Z, QX40-Z, CD28-Z and CD28-QX40-Zeta.
  • a variant sequence may have at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID Nos. 25, 26, 27, 28, 29, 30, 31 or 32 provided that the sequence provides an effective transmembrane domain/intracellular T cell signaling domain.
  • the CAR of the present invention may comprise a signal peptide so that when the CAR is expressed inside a cell, such as a T cell, the nascent protein is directed to the endoplasmic reticulum and subsequently to the cell surface, where it is expressed.
  • the core of the signal peptide may contain a long stretch of hydrophobic amino acids that has a tendency to form a single alpha-helix.
  • the signal peptide may begin with a short positively charged stretch of amino acids, which helps to enforce proper topology of the polypeptide during translocation.
  • At the end of the signal peptide there is typically a stretch of amino acids that is recognized and cleaved by signal peptidase.
  • Signal peptidase may cleave either during or after completion of translocation to generate a free signal peptide and a mature protein.
  • the free signal peptides are then digested by specific proteases.
  • the signal peptide may be at the amino terminus of the molecule.
  • the CAR of the invention may have the general formula:
  • Signal peptide - CD19-binding domain - spacer domain - transmembrane domain/intracellular T cell signaling domain may comprise a variant having 5, 4, 3, 2 or 1 amino acid mutations (insertions, substitutions, or additions) provided that the signal peptide still functions to cause cell surface expression of the CAR.
  • the signal peptide of SEQ ID No. 33 is compact and highly efficient. It is predicted to give about 95% cleavage after the terminal glycine, giving efficient removal by signal peptidase.
  • the signal peptide of SEQ ID No. 34 is compact and highly efficient. It is predicted to give about 95% cleavage after the terminal glycine, giving efficient removal by signal peptidase.
  • the signal peptide of SEQ ID NO: 35 is derived from lgG1.
  • the signal peptide of SEQ ID NO: 36 is derived from CD8.
  • the CAR of the present invention may comprise a spacer sequence to connect the CD19-binding domain with the transmembrane domain and spatially separate the CD19-binding domain from the endodomain.
  • a flexible spacer allows to the CD19- binding domain to orient in different directions to enable CD19 binding.
  • the spacer sequence may, for example, comprise an lgG1 Fc region, an lgG1 hinge or a CD8 stalk, or a combination thereof.
  • the spacer may alternatively comprise an alternative sequence which has similar length and/or domain spacing properties as an IgG 1 Fc region, an lgG1 hinge or a CD8 stalk.
  • a human I gG 1 spacer may be altered to remove Fc binding motifs. Examples of amino acid sequences for these spacers are given below:
  • SEQ ID No. 39 (human lgG1 hinge):
  • SEQ ID No. 41 (lgG1 Hinge - Fc modified to remove Fc receptor recognition motifs)
  • Modified residues are underlined; * denotes a deletion.
  • SEQ ID NO: 42 (CD2 ectodomain)
  • SEQ ID NO: 43 (CD34 ectodomain) SLDNNGTATPELPTQGTFSNVSTNVSYQETTTPSTLGSTSLHPVSQHGNEATTNITE TTVKFTSTSVITSVYGNTNSSVQSQTSVISTVFTTPANVSTPETTLKPSLSPGNVSDL STTSTSLATSPTKPYTSSSPILSDIKAEIKCSGIREVKLTQGICLEQNKTSSCAEFKKD RGEGLARVLCGEEQADADAGAQVCSLLLAQSEVRPQCLLLVLANRTEISSKLQLMK KHQSDLKKLGI LDFTEQDVASHQSYSQKT
  • CD19 CAR based on the CAT19 scFv has properties which may result in lower toxicity and better efficacy.
  • a small animal model of an aggressive B-cell lymphoma showed equal efficacy and equal engraftment between the fmc63 and CAT19 based CARs, but surprisingly, less of the CAT19 CAR T cells were exhausted than fmc63 CAR T cells.
  • the CAR of the invention may cause 25, 50, 70 or 90% lower IFNy release in a comparative assay involving bringing CAR T cells into contact with target cells.
  • the CAR of the invention may result in a smaller proportion of CAR T cells becoming exhausted than fmc63 CAR T cells. T cell exhaustion may be assessed using methods known in the art, such as analysis of PD-1 expression.
  • the CAR of the present invention may cause 20, 30, 40, 50, 60 of 70% fewer CAR T cells to express PD-1 that fmc63 CAR T cells in a comparative assay involving bringing CAR T cells into contact with target cells.
  • the second aspect of the invention relates to a nucleic acid sequence which codes for a CAR of the methods herein.
  • the nucleic acid sequence may be capable of encoding a CAR having the amino acid sequence shown as any of SEQ ID Nos. 10-15.
  • polynucleotide As used herein, the terms “polynucleotide”, “nucleotide”, and “nucleic acid” are intended to be synonymous with each other.
  • the nucleic acid may be, for example, an RNA, a DNA or a cDNA.
  • Nucleic acids may comprise DNA or RNA. They may be single-stranded or double-stranded. They may also be polynucleotides which include within them synthetic or modified nucleotides.
  • oligonucleotides A number of different types of modification to oligonucleotides are known in the art. These include methylphosphonate and phosphorothioate backbones, addition of acridine or polylysine chains at the 3' and/or 5' ends of the molecule.
  • polynucleotides may be modified by any method available in the art. Such modifications may be carried out in order to enhance the in vivo activity or life span of polynucleotides of interest.
  • Alternative codons may be used in regions of sequence encoding the same or similar amino acid sequences, in order to avoid homologous recombination when both CARs are encoded by the same vector.
  • codons “ccg” and “cca” both encode the amino acid proline, so using “ccg” may be exchanged for “cca” without affecting the amino acid in this position in the sequence of the translated protein.
  • RNA codons which may be used to encode each amino acid are summarized in Table 4.
  • Alternative codons may be used in the portions of nucleic acid which encode the spacer of the first CAR and the spacer of the second CAR, especially if the same or similar spacers are used in the first and second CARs.
  • Alternative codons may be used in the portions of nucleic acid which encode the transmembrane domain of the first CAR and the transmembrane of the second CAR, especially if the same or similar transmembrane domains are used in the first and second CARs.
  • Alternative codons may be used in one or more nucleic acids which encode costimulatory domains, such as the CD28 endodomain.
  • Alternative codons may be used in one or more domains which transmit survival signals, such as 0X40 and 41 BB endodomains.
  • Alternative codons may be used in the portions of nucleic acid encoding a CD3zeta endodomain and/or the portions of nucleic acid encoding one or more costimulatory domain(s) and/or the portions of nucleic acid encoding one or more domain(s) which transmit survival signals.
  • the present invention also provides a vector which comprises a nucleic acid sequence according to the present invention.
  • a vector may be used to introduce the nucleic acid sequence into a host cell so that it expresses and produces a molecule according to the first aspect of the invention.
  • the vector may, for example, be a plasmid or a viral vector, such as a retroviral vector or a lentiviral vector.
  • the vector may be capable of transfecting or transducing a cell, such as a T cell.
  • the invention also provides a cell which comprises a nucleic acid according to the invention.
  • the invention provides a cell which expresses a CAR provided herein at the cell surface.
  • the cell may be any eukaryotic cell capable of expressing a CAR at the cell surface, such as an immunological cell.
  • the cell may be an immune effector cell such as a T cell or a natural killer (NK) cell.
  • an immune effector cell such as a T cell or a natural killer (NK) cell.
  • T cells or T lymphocytes are a type of lymphocyte that play a central role in cell- mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of a T cell receptor (TCR) on the cell surface.
  • TCR T cell receptor
  • Helper T helper cells assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages.
  • TH cells express CD4 on their surface.
  • TH cells become activated when they are presented with peptide antigens by MHC class II molecules on the surface of antigen presenting cells (APCs).
  • APCs antigen presenting cells
  • TH1 , TH2, TH3, TH 17, Th9, or TFH which secrete different cytokines to facilitate different types of immune responses.
  • Cytotoxic T cells TC cells, or CTLs
  • CTLs destroy vi rally infected cells and tumor cells, and are also implicated in transplant rejection.
  • CTLs express the CD8 at their surface.
  • CD8+ cells recognize their targets by binding to antigen associated with MHC class I, which is present on the surface of all nucleated cells.
  • MHC class I MHC class I
  • IL-10 adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis.
  • Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections.
  • Memory T cells comprise three subtypes: central memory T cells (TCM cells) and two types of effector memory T cells (TEM cells and TEMRA cells). Memory cells may be either CD4+ or CD8+. Memory T cells typically express the cell surface protein CD45RO.
  • Treg cells Regulatory T cells
  • suppressor T cells are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell- mediated immunity toward the end of an immune reaction and to suppress auto- reactive T cells that escaped the process of negative selection in the thymus.
  • Treg cells Two major classes of CD4+ Treg cells have been described — naturally occurring Treg cells and adaptive Treg cells.
  • Naturally occurring Treg cells arise in the thymus and have been linked to interactions between developing T cells with both myeloid (CD11c+) and plasmacytoid (CD123+) dendritic cells that have been activated with TSLP.
  • Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.
  • Adaptive Treg cells may originate during a normal immune response.
  • the T cell provided herein may be any of the T cell types mentioned above, in particular a CTL.
  • Natural killer (NK) cells are a type of cytolytic cell which forms part of the innate immune system. NK cells provide rapid responses to innate signals from virally infected cells in an MHC independent manner.
  • NK cells (belonging to the group of innate lymphoid cells) are defined as large granular lymphocytes (LGL) and constitute the third kind of cells differentiated from the common lymphoid progenitor generating B and T lymphocytes. NK cells are known to differentiate and mature in the bone marrow, lymph node, spleen, tonsils and thymus where they then enter into the circulation.
  • LGL large granular lymphocytes
  • the CAR-expressing cells provided herein may be any of the cell types mentioned above.
  • T or NK cells provided herein may be derived from ex vivo differentiation of inducible progenitor cells or embryonic progenitor cells to T or NK cells.
  • an immortalized T cell line which retains its lytic function and could act as a therapeutic may be used.
  • Binding kinetics of the CAT scFv (used in obe-cel) and FMC63 scFv (used in axicabtagene ciloleucel and tisagenlecleucel) with recombinant CD19 were determined using surface plasmon resonance.
  • Equilibrium dissociation constants (KD) of 14.4 nM for CAT and 0.328 nM for FMC63 were determined, when the data were fitted to a 1 :1 Langmuir binding model.
  • CD19 (CAT) CAR T cell proliferation was greater than CD19 (FMC63) CAR T cells when co-cultured with Raji and NALM-6 cells.
  • the enhanced proliferation was not a result of increased IL-2 production indicating an IL-2 independent mechanism.
  • CAT CD19
  • FMC63 CD19
  • Raji cells a Burkitt’s lymphoma cell line that expresses CD19
  • pro-inflammatory cytokines were analysed in the supernatant at 48 hours.
  • T cells transduced to express CD19 (CAT) CAR or CD19 (FMC63) CAR were incubated with CD19-negative and CD19 expressing targets.
  • Cell killing was significantly greater for CD 19 (CAT) CAR T cells than for CD19 (FMC63) CAR T cells, particularly at low effectortarget ratios.
  • CD19 (CAT) CAR T cells and CD19 (FMC63) CAR T cells were assessed in a NALM-6 NSG-mouse xenograft model and compared. In control mice receiving non-transduced T cells, rapid, disseminated tumour infiltration was observed. CD19 (FMC63) CAR T cells slowed but did not prevent growth of the tumour. In contrast, equivalent numbers of CD19 (CAT) CAR T cells resulted in tumour regression.
  • the CAT scFv binding domain used in obe-cel has a > 40-fold lower affinity to recombinant CD19 in vitro than the FMC63 scFv binding domain used in other CAR T products.
  • CD19 (CAT) CAR enables transduced T cells to proliferate, secrete cytokines in response to CD19-positive targets and specifically lyse CD19-positive cell lines in vitro with greater cytotoxicity compared to CD19 (FMC63) CAR T cells.
  • CD19 (CAT) CAR T cells also have better anti-tumour efficacy and engraftment versus CD19 (FMC63) CAR T cells in an NSG NALM-6 mouse model of leukaemia.
  • ALLCAR19 (EudraCT 2016-004027-22, NCT02935257 2017) (Roddie C, Dias J, O'Reiilly MA, et al (2021). Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B- Cell Acute Lymphoblastic Leukemia. J Clin Oncol; 39(30):3352-63; Roddie C, Dias J, O’Reilly M, Mitsikakou M, et al. (2022a).
  • the Phase II portion of the FELIX study is the pivotal study to achieve the marketing authorization of obe-cel (Roddie C, Sandhu KS, Tholouli E, Shaughnessy P, et al. (2023a).
  • Safety and effiacy of obecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r IB- ALL): top line result of the pivotal FELIX study.
  • r/r IB- ALL relapsed/refractory adult B-cell acute lymphoblastic leukemia
  • Severe neurotoxicity was limited with 1 patient in the CARPALL study (5%); 3 patients in the ALLCAR19 study (15%) and 9 patients in the FELIX study (7.1 %) reporting >grade 3 neurological AE/ICANS.
  • Preliminary results obtained in indolent B NHL look promising with all 10 patients treated with obe-cel achieving complete molecular response (data cut-off 18-Nov- 2021).
  • the safety profile remains favourable in this small sample size with four patients with grade 1 , two patients with grade 2 CRS and no ICANS of any grade reported.
  • Cells such as T cells or NK cells expressing a CAR molecule provided herein may be used for the treatment of an autoimmune disease, in particular an autoimmune disease mediated by CD19-positive B lymphocytes or B cells.
  • the present disclosure provides a method for treating an autoimmune disease mediated by CD19-positive B lymphocytes in a patient comprising administering to the patient an CD19 CAR T cell or a population of CD19 CAR T cells.
  • the present disclosure provides a CD19 CAR T cell or a population of CD19 CAR T cells for use in treating an autoimmune disease mediated by CD19-positive B lymphocytes.
  • the present disclosure provides the use of a CD19 CAR T cell or a population of CD19 CAR T cells in the manufacture of a medicament for treating an autoimmune disease mediated by CD19-positive B lymphocytes.
  • autoimmune diseases include, but are not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis, idiopathic inflammatory myopathy (IIM, myositis), systemic sclerosis, ANCA-associated vasculitis, inflammatory bowel disease (IBD), multiple sclerosis (MS), Type I diabetes, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Graves’ disease, Hashimoto’s thyroiditis or Hashimoto’s disease, myasthenia gravis, neuromyelitis optica, A/-methyl- D-aspartate receptor (NMDAR) encephalitis, Lambert-Eaton syndrome, scleroderma, vasculitis, pemphigus vulgaris, pemphigus foliaceus, epidermolysis bullosa acquisita, bullous pemphigoid, lupus nephritis, membranous l
  • the autoimmune disease may be SLE.
  • the autoimmune disease may be severe SLE.
  • the autoimmune disease may be refractory SLE.
  • the autoimmune disease may be severe, refractory SLE.
  • the Lupus Nephritis may be severe.
  • the Lupus Nephritis may be active.
  • the SLE may present with active, severe Lupus Nephritis.
  • Methods for treating autoimmune disease relate to the therapeutic use of a cell or population of cells provided herein.
  • the cells may be administered to a subject having an existing disease or condition in order to lessen, reduce or improve at least one symptom associated with the disease and/or to slow down, reduce or block the progression of the disease.
  • the method may cause or promote cell mediated killing of CD19-expressing cells, such as B cells.
  • CD19 CAR T cell product for example, obe-cel
  • infusion of a patient with a CD19 CAR T cell product will eliminate the malfunctioning autoreactive B cells and subsequently, normal, non-autoreactive B cells are produced.
  • Patients to be treated include, but are not limited to, patients with severe, refractory SLE who are predicted to have a poor outcome if treated with standard of care therapy due to disease severity, one or more areas of SLE-related organ system involvement, and prior exposure to multiple SLE treatment strategies.
  • Patients to be treated may have a diagnosis of SLE fulfilling the 2019 European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) Classification Criteria for Systemic Lupus Erythematosus; may be positive for at least one of the following autoantibodies: antinuclear antibodies (ANA) at a titer of >1 :80, or anti-dsDNA (>30 IIJ/mL) or anti-Sm (> ULN), anti-histone or anti-chromatin (> ULN); may have severe SLE defined as a) a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of > 8 points (of which 4 are non-laboratory items and with the exclusion of points associated with neurological findings [SLEDAI 2K items 1-7]) and b) at least one of the following significant SLE-related organ involvements: i) renal (ongoing active, biopsy-proven lupus nephritis), ii
  • Patients may be subject to a pre-conditioning chemotherapy such as lymphodepletion chemotherapy prior to CD19 CAR treatment.
  • the lymphodepletion chemotherapy may comprise treatment with fludarabine and cyclophosphamide.
  • the patients may receive three doses of fludarabine 25 mg/m 2 /d intravenous administration on Day -5, Day -4, and Day -3 relative to CD 19 CAR treatment and one dose of cyclophosphamide 1000 mg/m 2 intravenous administration on Day -3 relative to CD 19 CAR treatment.
  • the patients may be administered a single dose of 50 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells.
  • Alternative doses contemplated are an escalated (100 x 10 6 [ ⁇ 20%]) or a de-escalated (30 x 10 6 [ ⁇ 20%]) CAR-positive T cell dose.
  • the administration may be, for example, an intravenous injection through a Hickman line or peripherally inserted central catheter (PICC line).
  • the starting material leukapheresate
  • manufacturing of the CD19 CAR-positive T cells may lead to dose variability, i.e. variability in the amount of CD19 CARpositive T cells that is administered to the patient. It is contemplated herein that the dose may have a variability of ⁇ 5%, ⁇ 10%, ⁇ 15%, ⁇ 20%, ⁇ 25%, or ⁇ 30%.
  • LDAS Lupus Low Disease Activity State
  • improvements may include SLEDAI-2K ⁇ 4 (no activity in major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, fever and no hemolytic anemia or gastrointestinal activity), no new features of lupus disease activity compared to the previous assessment, PGA ⁇ 1 on a visual analog scale from 0-3, current prednisolone (or equivalent) dose ⁇ 7.5 mg daily, and/or well-tolerated standard maintenance doses of immunosuppressive drugs and approved biologic agents, excluding investigational drugs;
  • SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index-2000
  • Physician Physician’s global assessment (PGA);
  • HAQ-DI Health Assessment Questionnaire - Disability Index
  • Autoantibody panel anti-double stranded DNA [anti- dsDNA], anti-Smith, anti-RNA binding protein [anti-RBP]);
  • Antiphospholipid profile (lupus anticoagulant, anti-cardiolipin antibodies and beta-2 glycoprotein 1);
  • T and B cell phenotype Determination of T and B cell phenotype over time as assessed by flow cytometry in the peripheral blood;
  • Obe-cel obecabtagene autoleucel also referred to as ALITO1
  • CAR T cell-based therapies such as obe-cel provide further advantages over antibodies because CAR T cells require only a single administration, expand, and have the potential to persist in vivo, migrate to multiple lymphoid tissues and organs in the recipient and develop into both effector and memory cell population. Longer persistency of obe-cel with its CAT CD19 binder, when indirectly compared with the approved FMC63 CD19 CAR T cells, provides another advantage.
  • obe-cel is prepared from enriched autologous T cells that are transduced with a lentiviral vector to express a novel, second generation CAR targeting CD19 with a 4-1 BB and CD3- endodomain.
  • the CAR of the obe-cel CAR T cells comprises a single chain variable fragment (scFv) called CAT with a lower affinity for CD19 and a faster off rate compared with that of the FMC63 scFv used in other approved CD19 CAR T therapies.
  • This fast-off binding kinetics is contemplated to confer an opportunity for physiological T cell activation, reduced immune-toxicity and potential for improved persistence. See, WO20 16/139487.
  • Obe-cel is classified as an advanced therapy investigational medicinal product (ATIMP). It is an autologous cellular therapy product where the active component is the patient’s own T cells transduced with a lentiviral vector to express a novel second generation CAR targeting CD19 (sometimes referred to herein as “CD19 CAT CAR”). Obe-cel also contains non-transduced autologous T cells and non-T cells.
  • ATIMP advanced therapy investigational medicinal product
  • CAR T cells Once administered to patients, obe-cel CAR T cells circulate throughout the body.
  • the CAR T cells recognize CD19 surface antigens on all B cells and B-progenitor cells, resulting in activation and proliferation of the CAR T cells. Activated CAR T cells will then in turn cause destruction of these cells via several physiological effector mechanisms.
  • the patients treated are patients with severe, refractory SLE who are predicted to have a poor outcome if treated with standard of care therapy due to disease severity, one or more areas of SLE-related organ system involvement, and prior exposure to multiple SLE treatment strategies.
  • antinuclear antibodies at a titer of >1:80, or anti-dsDNA (>30 IIJ/mL) or antiSmith (> ULN), anti-histone or anti-chromatin (> ULN).
  • SLEDAI-2K A Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of > 8 points (of which 4 are non-laboratory items and with the exclusion of points associated with neurological findings [SLEDAI 2K items 1-7]) AND
  • Severe hematologic manifestation e.g., severe thrombocytopenia or severe autoimmune hemolytic anemia
  • Refractory SLE (defined as lack of response, insufficient response or lack of sustained response) or intolerance to: a. Hydroxychloroquine treatment in combination with corticosteroids AND b. s2 of the following treatment groups used for at least 3 months each or less if intolerant: i Immunosuppressive drugs (e.g., methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, tacrolimus, leflunomide, cyclosporine, voclosporin or cyclophosphamide) ii. B cell-targeting agents (e.g., belimumab, anti-CD20 mAb) iii Cytokine inhibitors (e.g., anifrolumab)
  • Immunosuppressive drugs e.g., methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, tacrolimus, leflunomide, cyclosporine,
  • non-SLE autoimmune disease e.g., dermatomyositis, polymyositis, scleroderma, rheumatoid arthritis
  • other non-SLE autoimmune disease or overlap syndrome e.g., dermatomyositis, polymyositis, scleroderma, rheumatoid arthritis
  • other non-SLE autoimmune disease or overlap syndrome e.g., dermatomyositis, polymyositis, scleroderma, rheumatoid arthritis
  • CNS pathology such as epilepsy, paresis, aphasia, or stroke
  • Prior treatment with anti-CD19 therapy including bispecifics, adoptive T cell therapy or any prior gene therapy product (e.g., CAR T cell therapy).
  • indwelling line or drain e.g., percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter.
  • indwelling line or drain e.g., percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter.
  • Central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted.
  • patients may receive bridging therapy with permitted standard of care (SOC) medications to treat SLE.
  • SOC standard of care
  • Lymphodepletion chemotherapy with fludarabine and cyclophosphamide is recognized as standard of care before CAR T cell infusion.
  • Clinical CAR T cell data collectively indicate that Fludarabine/Cyclophosphamide are required for CAR T cell engraftment, and CAR T cell engraftment is required for activity towards B cells
  • This lymphodepletion regimen matches the one published by Mackensen et al, 2022.
  • lymphodepletion therapy may be repeated.
  • the starting material for generation of obe-cel is mononuclear cells from a nonmobilized leukapheresis collection from the patient.
  • obe-cel is an autologous product and is therefore specific for each patient.
  • the autologous T cells are enriched and transduced ex vivo with a lentiviral vector to express a novel CD19-targeting (i.e., anti-CD19) CAR referred to as “CD19 (CAT) CAR.”
  • CD19 (CAT) CAR novel CD19-targeting CAR referred to as “CD19 (CAT) CAR.”
  • the “CAT” binding domain was chosen as a binding domain as it showed a substantially lower affinity to CD19 (>40 fold) than FMC63 scFv, a binder used in already marketed CAR T cell therapies
  • the CD19 (CAT) CAR construct is derived from a murine CAT13.1 E10 hybridoma, where the CAR comprises an anti-CD19 scFv, CD8-derived stalk and trans-membrane domain, and a compound endodomain fusion of 4-1 BB- CD3 endodomains.
  • Obe-cel is generated by ex vivo transduction of activated peripheral blood mononuclear cells using an engineered HIV derived lentiviral vector containing the CD19 CAR expression cassette.
  • the lentiviral vector is produced under Good Manufacturing Practice (GMP) conditions by four plasmid co transfection of HEK293T cells and subsequent harvest and purification of the culture supernatant.
  • GMP Good Manufacturing Practice
  • Cells from the leukapheresis starting material are enriched by positive selection for CD4+/CD8+ cells using magnetic beads on the Miltenyi CliniMACS® Prodigy bioreactor. Cells are then washed and stimulated with mitogenic ligands and cytokines. One day after activation, cells are transduced with the lentiviral vector. Posttransduction, cells are expanded (drug substance) to produce the desired dose. The cells are then washed and formulated with a phosphate-buffered saline (PBS)/ ethylenediaminetetraacetic acid (EDTA) I human serum albumin (HSA) I dimethyl sulfoxide (DMSO) buffer and filled into final packaging and cryopreserved (drug product). The obe-cel product comprises transduced and non-transduced T cells. The dose given to patients is expressed as the total number of CD19 CAR-positive T cells (the active substance).
  • PBS phosphate-buffered saline
  • Obe-cel is supplied as a cryopreserved cell suspension in a cryostorage-compatible infusion bag, to be thawed at 37°C.
  • the selection and justification for the obe-cel dose is based in part on the prior use of obe-cel in patients with B-ALL and other B cell malignancies.
  • a single dose of 50 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells is to be infused to patients on Day 1 after lymphodepletion chemotherapy.
  • Other doses contemplated are an escalated (100 x 10 6 [ ⁇ 20%]) or a de-escalated (30 x 10 6 [ ⁇ 20%]) CAR-positive T cell dose.
  • the starting dose of 50 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells is 8-fold lower than the total obe-cel target dose utilized in adult B-ALL patients, which have demonstrated a tolerable safety profile in the B-ALL patient population.
  • the mean (standard deviation) body weight in two large, randomized phase 3 belimumab studies in a total of 865 SLE patients was 61 ⁇ 13 kg, the lowest body weight in these studies was 35 kg (US Food & Drug Administration. Arthritis advisory committee meeting briefing document BLA 125370. October 2010) suggesting that indeed a flat dose of 50 x 10 6 [ ⁇ 20%]) CARpositive T cells is contemplated to be safe and effective.
  • Example 5 Obe-cel infusion and assessments of disease activity and response to treatment
  • IV intravenously
  • Obe-cel is infused on Day 1.
  • obe-cel is thawed in a 37°C water bath under sterile conditions.
  • Obe-cel is given as an IV infusion using a syringe or gravity-assisted infusion through a central or peripheral venous line through an 18-gauge blood set over a few minutes (maximum 30 minutes from obe-cel being thawed to preserve cell viability).
  • Example 6 A single-arm, open-label, Phase I study to determine the safety, tolerability and preliminary efficacy of obecabtagene autoleucel (obe-cel) in patients with severe, refractory systemic lupus erythematosus (SLE)
  • Participants are expected to receive a single infusion of obe-cel at a target dose of 50 x 10 6 ( ⁇ 25%) CD19 CAR-positive T cells.
  • the primary endpoint is the proportion of participants achieving a CRR at Month 12 after obe-cel infusion as adjudicated by an Independent Response Review Committee (IRRC).
  • IRRC Independent Response Review Committee
  • the study may be stopped due to insufficient response, or excessive treatment toxicity.
  • the study comprises 3 periods:
  • Screening Period From Day -30 to Day of Enrollment a. Screening: After informed consent is obtained, participants are to undergo screening procedures to confirm they are eligible for the study and are able to undergo leukapheresis. b. Leukapheresis: Eligible participants are to proceed to leukapheresis to collect mononuclear cells to be used for manufacturing obe-cel. c. Enrollment: A participant is to be enrolled into the study at the point they meet all eligibility criteria and the participant’s leukapheresis material has been accepted for manufacturing.
  • Treatment Period From Day of Enrollment to Day 1 to End of Treatment (EOT)/Day 1 a. Lymphodepletion (LD) Evaluation: Participants are to undergo an evaluation from Day -8 to Day -6 to confirm eligibility for start of LD. b. LD Chemotherapy: Participants are to receive intravenous (i.v.) fludarabine and cyclophosphamide for LD to enhance treatment efficacy and CD19 CAR T cell survival.
  • EOT End of Treatment
  • LD Lymphodepletion
  • Fludarabine 25 mg/m 2 /day i.v. on Day -5, Day -4, and Day -3
  • Cyclophosphamide 1 ,000 mg/m 2 i.v. on Day -3
  • Day -1 the next step is the infusion, defined as Day 1.
  • the EOT is defined as the day of infusion (Day 1) or the day of premature study discontinuation if prior to infusion.
  • Efficacy and Safety follow-up: a. After the infusion, all participants are to be closely monitored for safety and efficacy. The first efficacy assessment is to be performed at Day 28 post-infusion. b. Thereafter, participants are to be followed with monthly or 3-monthly assessments of safety, tolerability, and efficacy until the EOS. c. Following the Month 24 visit, participants are to be followed every 3 months until the last participant, last visit (LPLV) is completed for the study (i.e., when the last enrolled participant reaches Month 24). The last 3-monthly follow-up assessment occurring prior to LPLV is to determine the EOS date for each individual participant. d. The EOS is defined as completion of the LPLV for the study.
  • Severe, Active SLE defined as: o ASLEDAI-2K score of > 8 points (of which 4 are non-laboratory items and with the exclusion of points associated with neurological findings [SLEDAI-2K items 1-7]), and
  • Severe active LN defined as: o SLE-related renal organ involvement. A biopsy must be performed in the 6 months prior to the screening visit or during the screening period to confirm ongoing, active, class III, IV or V (V only in combination with class III or IV) active or active/chronic LN in accordance with kidney biopsy evidence of International Society of Nephrology/Renal Pathology Society 2019.
  • o UPGR > 1 mg/mg from a 24-hour urine collection, and eGFR of > 30 mL/min/1.73 m 2
  • Refractory SLE (defined as lack of response, insufficient response, or lack of sustained response or intolerance related to such drugs not allowing their further use): a. hydroxychloroquine in combination with corticosteroids AND b. to > 2 of the following treatment groups used for at least 6 months: i. Immunosuppressive drugs (e.g., methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, leflunomide, or cyclophosphamide). ii. Calcineurin inhibitors (e.g., cyclosporine, voclosporin, tacrolimus). iii. B cell-targeting agents (e.g., belimumab, anti-CD20 mAb) OR cytokine inhibitors (e.g., anifrolumab).
  • Immunosuppressive drugs e.g., methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid
  • LD lymphodepletion
  • SLE systemic lupus erythematosus
  • Example 7 A single-arm, open-label, Phase I study to determine the safety, tolerability and preliminary efficacy of obecabtagene autoleucel (obe-cel) in patients with severe, refractory systemic lupus erythematosus (SLE): Results of first treated patient
  • a 32-year-old female SLE patient was treated with obe-cel. This patient was black or African American, with a SLE diagnosis in 2021, showing renal (LN class IVA/), musculoskeletal, dermal, immunologic organ system involvement and a medical history of hypertension. She had ANA, anti-dsDNA, anti-Smith, anti-RBP, anti-chromatin autoantibodies and a SLEDAI-2K score of 24 at screening. Prior SLE treatments included hydroxychloroquine, corticosteroids, mycophenolate, rituximab, and Obinutuzumab.
  • this patient received a single dose of 50 x 10 6 ( ⁇ 20%) CD19 CAR-positive viable T cells on Day 1 after lymphodepletion chemotherapy. Methylprednisolone was used as bridging therapy.
  • anti-dsDNA decreased from >300 at screening to 40.6;
  • IgG levels decreased from 6.07 at screening to 2.39 at Day 28.
  • IgA decreased from 1.84 to 0.46 and IgM from 0.53 to 0.12, respectively;
  • SAE Grade 3 serious adverse effect
  • the CD19 CAR-T cells (obe-cel) showed a good expansion with a peak at Day 10 post CAR-T cell infusion by flow cytometry and ddPCR, as shown by Figure 2a and 2b, respectively.

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Abstract

La présente invention concerne un récepteur antigénique chimérique (CAR) qui se lie à l'antigène des lymphocytes B CD19 (groupe de différenciation 19) et l'utilisation de lymphocytes T exprimant un tel CAR pour le traitement de maladies auto-immunes, telles que le lupus érythémateux disséminé (LED).
PCT/GB2024/052698 2023-10-23 2024-10-22 Produits et méthodes de traitement de maladies auto-immunes Pending WO2025088308A1 (fr)

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