WO2020183147A1 - Immunothérapie combinée à un anticorps anti-cd38 - Google Patents

Immunothérapie combinée à un anticorps anti-cd38 Download PDF

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WO2020183147A1
WO2020183147A1 PCT/GB2020/050567 GB2020050567W WO2020183147A1 WO 2020183147 A1 WO2020183147 A1 WO 2020183147A1 GB 2020050567 W GB2020050567 W GB 2020050567W WO 2020183147 A1 WO2020183147 A1 WO 2020183147A1
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antibody
days
immunotherapy
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Vijay PEDDAREDDIGARI
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Autolus Limited
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    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464411—Immunoglobulin superfamily
    • A61K39/464412—CD19 or B4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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 A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
    • 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 A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Definitions

  • the present invention relates to a CD38 inhibitor (e.g. an anti-CD38 antibody) for use in the prevention and/or treatment of cytokine release syndrome (CRS) in a subject undergoing immunotherapy.
  • a CD38 inhibitor e.g. an anti-CD38 antibody
  • CRS cytokine release syndrome
  • Immunotherapy is a powerful therapeutic tool that stimulates the host immune response to prevent and/or treat disorders.
  • Immunotherapy uses therapeutic factors such as drugs, agents or engineered cells to stimulate the host immune response against target disorder cells, such as for example, cancer cells.
  • Immunotherapy factors include, but are not limited to, antibody therapies or chimeric antigen receptor-modified (CAR) T cell therapies. These therapies are typically administered systemically and have shown significant promise in treating disorders, for example many cancers.
  • CAR chimeric antigen receptor-modified
  • T-cell mediated therapies such as CAR T cell therapies
  • TME hostile tumour micro environments
  • TME hostile tumour micro environments
  • solid tumours there is a strong metabolic and physical barrier in the TME, able to inhibit proliferation, activity and infiltration of the immunotherapy.
  • the TME is known to provide essential signals for survival, growth and immune resistance of the tumour cells (for example, cell-adhesion mediated immune resistance). For this reason, the TME is immunosuppressive, which prevents effective anti-tumour immune responses.
  • the TME contains multiple components and factors that can stop CAR T-cell function including physical barriers (e.g. dense extracellular matrix); dysfunctional epithelial cells; metabolic checkpoints (e.g. hypoxia and immunological barriers) and immunosuppressive molecules (Watanabe et ai, 2018, Front Immunol., 9(2486): 1 -12). Therefore, to target such tumours effectively, these multiple factors impacting efficacy must be simultaneously addressed. Accordingly, there remains a need for approaches to increase recruitment and activation of immune cells in the tumour site.
  • immunotherapies in the clinic has also raised safety and efficacy concerns in connection with the treatment of some disorders. While immunotherapy harnesses the power of the host immune response, it is known that an uncontrolled inflammatory immune response can result in Cytokine Release Syndrome (CRS) which can result in a range of symptoms that lead to further illness and death, if left unchecked. For example, anti-leukaemia efficacy by CD19-specific CAR T cells in humans has been associated with CRS. It is also known that immunotherapy associated conditions correlate with the activity of several cell types, such as macrophages and monocytes, and the release of a variety of factors including cytokines.
  • CRS Cytokine Release Syndrome
  • Cytokines are known to play a key role in the inflammatory immune response and notably, the cytokine IL-6, is known to have pleiotropic roles in regulating immune cell function and inflammatory immune responses.
  • a known therapeutic approach for the treatment of CRS involves a systemic approach that uses anti-IL-6 receptor antibodies or such antibodies with steroids.
  • the anti-IL6 receptor antibody tocilizumab has been used to treat CRS.
  • tocilizumab may control symptoms of CRS, it has low permeability of the blood brain barrier and fails to enhance the efficacy of the immunotherapy (Sciacca et ai, 2013, J Neuroinflammation, 10:29).
  • CD38 inhibitors such as an anti-CD38 antibody
  • immunotherapy regimens are advantageous two-fold 1) enhancing the tumour microenvironment by promoting T cell expansion and 2) preventing and/or treating cytokine release syndrome (CRS) resulting from said immunotherapy.
  • CRS cytokine release syndrome
  • the CD38 inhibitor may be an antibody or antigen-binding fragment thereof, a peptide or a small molecule.
  • the present invention provides an anti-CD38 antibody for use in the prevention and/or treatment of cytokine release syndrome in a subject undergoing immunotherapy, wherein the anti-CD38 antibody is administered before and/or after immunotherapy administration.
  • the anti-CD38 antibody may be administered more than once.
  • the anti- CD38 antibody may be administered at least four times.
  • the anti-CD38 antibody may be administered before administration of the immunotherapy.
  • Administration of an anti-CD38 antibody before immunotherapy may be for the prevention of CRS resulting from immunotherapy.
  • the anti-CD38 antibody may be administered up to about 60 days before immunotherapy administration.
  • the anti-CD38 antibody may be administered 60 days or less, 50 days or less, 40 days or less, 30 days or less, 20 days or less, 10 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day before immunotherapy administration.
  • the anti-CD38 antibody may be further administered during immunotherapy administration and/or after immunotherapy administration.
  • the anti-CD38 antibody may be administered only after immunotherapy for use in the treatment of CRS resulting from immunotherapy.
  • the anti-CD38 antibody may be administered from about 60 days or less, 50 days or less, 40 days or less, 30 days or less, 20 days or less, 10 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day after immunotherapy administration.
  • the anti-CD38 antibody may be administered to the subject subcutaneously or intravenously.
  • the anti-CD38 antibody may be daratumumab or an antigen binding fragment thereof.
  • the anti-CD38 antibody may deplete CD38 positive expressing cells involved in immune suppression.
  • the anti-CD38 antibody depletes CD38 positive myeloid cells, such as monocytes.
  • the anti-CD38 antibody may be administered at a dose of from 2 to 32 mg/kg of weight of the subject.
  • the dose of the anti-CD38 antibody administered to the subject may be from 8 to 24 mg/kg.
  • the dose of the anti-CD38 antibody administered to the subject may be 16 mg/kg.
  • the subject may be undergoing immunotherapy for cancer.
  • the anti-CD38 antibody may be used for the prevention and/or treatment of CRS in a human subject undergoing immunotherapy, wherein the CRS results directly and/or indirectly from the immunotherapy.
  • the anti-CD38 antibody may be for use in a subject undergoing immunotherapy where the immunotherapy may be an engineered T cell therapy.
  • the engineered T cell therapy may be selected from CAR T cell therapy, transgenic TCR T cell therapy, BiTE therapy, an anti-CD3 antibody therapy or any other T cell agonist therapy.
  • the immunotherapy may be CAR T cell therapy.
  • the subject may be an adult or a paediatric subject.
  • the present invention provides a method of prevention and/or treatment of cytokine release syndrome in a human subject undergoing immunotherapy, the method comprising administering to a human subject in need thereof an anti-CD38 antibody before and/or after administration of immunotherapy.
  • the present invention provides for the use of an anti-CD38 antibody for the manufacture of a medicament for the prevention and/or treatment of cytokine release syndrome in a human subject undergoing immunotherapy, wherein the medicament is administered before and/or immunotherapy.
  • the invention provides an anti-CD38 antibody for use in the prevention and/or treatment of immunotherapy-associated neurotoxicity in a subject undergoing immunotherapy, wherein the anti-CD38 antibody is administered before and/or after immunotherapy administration.
  • CD38 inhibitor e.g. an anti-CD38 antibody
  • a CD38 inhibitor can be used to prevent and / or treat CRS-associated immunotherapy, as well as prepare the TME for effective immunotherapy.
  • CD38 positive immune regulatory cells e.g., such as macrophages, monocytes and / or myeloid-derived suppressor cell (MDSCs)
  • MDSCs myeloid-derived suppressor cell
  • FIG. 1 The adenosine pathway and model of activity of Cytokine-Induced Killer (CIK) cells.
  • CD38 is a receptor and a component of a pathway leading to the production of adenosine in the TME.
  • ADA adenosine deaminase
  • ATP adenosine triphosphate
  • TReg regulatory T
  • NAD + Oxidised nicotinamide adenine dinucleotide
  • MDSC myeloid derived suppressor cells.
  • Figure 2 Schematic of Suppression of CD38+ immune regulatory cells. This schematic shows suppression of CD38+ immune regulatory cells may result in the enhancement of T cell responses and promotion of clonal T cell expansion.
  • FIG. 3 Schematic of cytokine pattern associated with CAR T Cells. This schematic shows CAR T cells binding to antigens on cancer cells stimulating a cytotoxic response and proliferation. Among cytokines / chemokines elevated during CRS are several associated with activated T cells (IFN-g, IL-6), macrophage activation and recruitment (I L10, MCP-1), and inflammation (IL-6, IL-8).
  • IFN-g activated T cells
  • I L10 macrophage activation and recruitment
  • IL-6, IL-8 inflammation
  • FIG. 4 Schematic of cytokine release syndrome. This schematic shows macrophages will interact with activated CAR T cells either via direct contact or T cell- derived cytokines, resulting in activation of macrophages that will secrete cytokines, which further activate the CAR T cells and recruit additional innate immune effectors exacerbating the inflammatory signals inducing CRS and neurotoxicity. CRS and neurotoxicity can be prevented by inhibiting CD38 to deplete macrophages expressing CD38.
  • FIG. 5 Inhibition of CRS with CD38 inhibitor.
  • CRS can be prevented by inhibiting CD38 to deplete macrophages, monocytes and/or myeloid suppressor cells (MDSC) which express CD38.
  • MDSC myeloid suppressor cells
  • CD38 (Uniprot ID: P28907) is a 46-kDa type II transmembrane glycoprotein with a short N-terminal cytoplasmic tail (20-aa) and a long extracellular domain (256-aa), which is identified on the surface of several cells of the immune system.
  • CD38 is also a signal transducing surface receptor and a component of a pathway leading to the production of adenosine in the tumour microenvironment, thus inducing local anergy.
  • the natural ligands for CD38 are nicotinamide adenine dinucleotide (NAD)+, the substrate for its ecto-enzyme activity (ADP-ribosyl cyclase), and CD31/PECAM. Binding of CD31/PECAM and CD38 induces tyrosine phosphorylation and downstream signaling events regulating proliferation and cytokine release in lymphocytes.
  • the adenosine pathway participates in the creation of an immune-tolerant tumour microenvironment by regulating the functions of a diverse set of immune and inflammatory cells, such as macrophages, myeloid-derived suppressor cells, T cells and natural killer (NK) cells, which are CD38 positive.
  • the adenosine pathway also regulates cancer growth and dissemination by interfering with cancer cell proliferation, apoptosis and angiogenesis via adenosine receptors that are expressed on cancer cells and endothelial cells, respectively (Figure 1).
  • CD38 may provide a functional block leading to decreased levels of adenosine in the tumour microenvironment which appear to contribute to general improvement in cancer immunotherapy and outcomes.
  • the present invention therefore concerns exploitation of the complex biology of CD38 to therapeutically regulate the immune system in preparation for immunotherapy, as well as prevent, reduce and /or treat CRS associated with immunotherapy administration.
  • CD38 function is associated with a wide range of metabolic disorders including for example, impaired immune response and ameliorating age-associated metabolic decline (Tarrago et al 2018., Cell Metab., 27(5): 1081 -1095).
  • Therapeutic CD38 inhibitors currently available include small molecules, biologies and antibodies.
  • two known CD38 inhibitors are Quercetin and Apigenin (a flavonoid apigenin) which both inhibit CD38 and promote an increase in intracellular NAD + levels (Escande et ai, 2013, Diabetes, 64(4): 1084-1093).
  • CD38 inhibitor is the anti-CD38 antibody, daratumumab, which is currently a first-in-class treatment for relapsed / refractory (RR) multiple myeloma (MM).
  • RR relapsed / refractory
  • MM multiple myeloma
  • Daratumumab (Darzalex), a human lgG1 -kappa monoclonal antibody, was the first naked CD38 monoclonal antibody (mAb) to be developed for clinical use following demonstration of promising anti-myeloma activity in preclinical studies with cell lines and animal models. It has been approved to treat RR MM for patients who have received at least three prior lines of therapy (e.g. including a proteasome inhibitor and an immunomodulatory agent) as an effective monotherapy (phase 2 SIRIUS trial).
  • mAb CD38 monoclonal antibody
  • Daratumumab targets CD38 expressing myeloma cells through complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and direct apoptosis with cross-linking of receptors. These mechanisms also target non-plasma cells that express CD38.
  • daratumumab may exert indirectly on cells by allowing an increase in T helper cells, cytotoxic T-lymphocytes, T cell function response and T-cell clonality ( Figure 2).
  • the researchers identified a subpopulation of T cells (Tregs) that express CD38 at high levels, which showed a significant and immediate decline following a dose of daratumumab.
  • daratumumab induces expansion of cytotoxic T cells, skewing the T cell repertoire, increasing the clonality of T cell receptors, and fostering improvement in the patient’s adaptive immune response (Figure 2).
  • Isa formerly SAR650984, is also a humanised lgG1 -kappa anti-CD38 mAb and can preferentially block immunosuppressive Tregs and restore immune effector function against RR MM.
  • Isa induced cell death in myeloma cell lines by ADCC, CDC, and ADCP as well as the induction of tumor cell death in a CD38- dependent manner. It is the latter activity which differentiates Isa from other therapeutic CD38 monoclonal antibodies because tumour cell death is directly induced by Isa in the absence of immune effector cells. It has similar half maximal effective concentrations (EC50 ⁇ 0.1 pg/mL) and maximal binding as daratumumab.
  • phase III trials were launched in 2017. The first trial assessed the benefit of Isa in combination with bortezomib, Len and Dex versus bortezomib, Len and Dex in patients with newly diagnosed MM not eligible for transplant (IMROZ trial). The second trial assessed the benefit of Isa combined with carfilzomib and Dex versus carfilzomib with Dex in patients with RR MM previously treated with 1 to 3 prior lines (IKEMA). A Phase III trial to evaluate isatuximab plus pomalidomide/dexamethasone is planned.
  • Mor202 is another example of a human anti-CD38 antibody. It has been reported to efficiently trigger ADCC and ADCP -mediated killing of CD38 positive multiple myeloma cell lines e.g., U266, as well as in vitro in a xenograft mouse model (Stevenson et al. , 2006). The antibody does not involve CDC, an additional immune mechanism involved in tumour cell killing. In addition, pre-clinical data point to low NK- cell depletion.
  • CD38 monocloncal antibodies are equally potent at inducing ADCC against CD38-expressing tumor cells.
  • Daratumumab has demonstrated superior induction of CDC in Daudi lymphoma cells as determined by flow cytometry, when compared with other CD38 antibodies in current clinical development.
  • Isa more potently than daratumumab, inhibits ecto-enzyme function of CD38.
  • Isa produced the largest inhibition of cyclic GDP-ribose (cGDPR) production, indicating a higher modulation of CD38 cyclase activity.
  • cGDPR cyclic GDP-ribose
  • the three anti-CD38 antibodies described above are non-limiting examples of CD38 inhibitors of the present invention.
  • immunotherapy is defined herein as any therapeutic approach that prevents or treats a disorder by stimulating or modifying the immune response.
  • the immunotherapy may result in neurotoxicity and/or CRS.
  • immunotherapy can relate to modifying any part of the immune system.
  • immunotherapy relates to the induction of the inflammatory response.
  • the immunotherapy may be used to prevent and/or treat any appropriate disorder. Examples of disorders that may be prevented and/or treated by immunotherapy include but are not limited to, cancer, Crohn’s disease or rheumatoid arthritis.
  • CAR T cell therapy is known to be highly effective in preventing and/or treating acute lymphoblastic leukaemia (ALL).
  • ALL acute lymphoblastic leukaemia
  • the subject may be undergoing immunotherapy for any disorder associated with the immune system either directly or indirectly.
  • the disorder that is being prevented and/or treated by immunotherapy is cancer.
  • cancer include but are not limited to leukaemia, lymphoma, solid tumours that metastasize to brain, for example, breast, renal and brain cancers.
  • the cancer may be a solid tumour.
  • the cancer may be a cancer such as neuroblastoma, prostate cancer, bladder cancer, breast cancer, colon cancer, endometrial cancer, kidney cancer (renal cell), leukaemia, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, and thyroid cancer.
  • TAA tumour associated antigens
  • the immunotherapy may be a CAR therapy, in particular a CAR T cell therapy, which is targeted against a TAA as indicated in Table 1.
  • CAR T cell therapy in particular a CAR T cell therapy, which is targeted against a TAA as indicated in Table 1.
  • the immunotherapy may be an antibody therapy, preferably a monoclonal antibody therapy.
  • the antibody therapy may comprise use of antibody fragments.
  • the antibody therapy may target CD3 and a target antigen.
  • the immunotherapy may be an anti-CD3 antibody therapy.
  • the immunotherapy may be a non-specific therapy, preferably an interferon, interleukin, cytokine or chemokine therapy.
  • the immunotherapy may be a vaccine therapy or virus therapy, preferably an oncolytic virus therapy.
  • the immunotherapy may be a cell therapy or engineered cell therapy.
  • the immunotherapy may be a T-cell therapy, preferably a CAR T cell therapy or a transgenic TCR T cell therapy.
  • the immunotherapy may be a BiTE therapy.
  • Immunotherapies comprising cell therapies are well known in the art.
  • CAR T cell therapy is known to obtain T cells from a patient and modify the cells to express a chimeric antigen receptor. Said cells are cultured and infused back into the patient for immunotherapy.
  • Many variations and alternative approaches are also well known in the art.
  • the method of cell-mediated immunotherapy may involve the steps of:
  • nucleic acid construct, vector(s) or nucleic acids may be introduced by transduction.
  • nucleic acid construct, vector(s) or nucleic acids may be introduced by transfection.
  • the cell may be autologous.
  • the cell may be allogenic.
  • the engineered immune effector cell may be administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition may additionally comprise a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition may optionally comprise one or more further pharmaceutically active polypeptides and/or compounds.
  • Such a formulation may, for example, be in a form suitable for intravenous infusion.
  • the present the disorder may be targeted by immunotherapy directly and/or indirectly.
  • CRS Cytokine Release Syndrome
  • the present invention is directed to preventing and/or treating CRS, preferably wherein the CRS arises due to immunotherapy.
  • CRS are well known to be associated with immunotherapies.
  • CRS is known to develop in response to monoclonal antibody therapies (such as with OKT-3 and Rituximab) or T-cell therapies, such as CAR T cell therapy targeted against CD19 to treat ALL.
  • monoclonal antibody therapies such as with OKT-3 and Rituximab
  • T-cell therapies such as CAR T cell therapy targeted against CD19 to treat ALL.
  • the CRS may be the result of administered engineered cells inducing host immune cell activation. In a further embodiment, the CRS may be the result of administered cells inducing tumour microenvironment cell activation. Alternatively, the CRS may be the result of tumour microenvironment cells.
  • CRS CRS is known to occur as a result of hyper activation of the immune system and is well characterised in the art. CRS is known to clinically manifest when large numbers of lymphocytes and/or myeloid cells release inflammatory cytokines upon activation.
  • CRS symptom onset may arise within hours or days of immunotherapy, for example with respect to when a patient undergoes immune cell infusion. Symptom onset depends on the degree of immune cell activation. CRS symptoms include but are not limited to, fever, rigors, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, headache, rash, diarrhoea, tachypnea, hypoxemia, tachycardia, hypotension, widened pulse pressure, early increased cardiac output, late diminished cardiac output, hallucinations, tremor, altered gait, seizures and death.
  • the present invention is directed to preventing and/or treating CRS.
  • CRS CRS
  • the symptoms of CRS place a significant burden on hospitals and carers for monitoring and treatment.
  • CRS is associated with a very high fever which itself can result in significant complications and lead to death.
  • CRS is associated with rapid onset cardiac dysfunction even though with timely treatment this can be reversible.
  • the present invention provides for the treatment and/or prevention of complex conditions that result from CRS, for example by reducing or eliminating very high fever, improving patient health and the time and resources of hospitals and carers.
  • an anti-CD38 antibody which may reduce or eliminate one or more of the known neurotoxicity symptoms or side-effects of the subject.
  • Neurotoxicity may include cerebellar syndrome - acute (confusion), cerebral edema (swelling of the brain), cerebral hemorrhage (bleeding of the brain), cerebral herniation, cerebral infarction (stroke), cerebral ischemia (stroke), cerebrovascular accident (stroke) and/or cerebrospinal fluid leak (from the brain or spinal cord), meningeal inflammation and neurodegeneration.
  • Neurotoxicity may result in a broad range of symptoms. In the case of immunotherapy induced neurotoxicity, the symptoms depend on the response of the subject to immunotherapy. Measurements for the severity of neurotoxicity symptoms are well known in the art. For example, the Common Terminology Criteria for Adverse Events (CTCAE) scale for cancer treatment patients measure the severity of symptoms (including neurotoxicity symptoms) as: 1 , mild; 2, moderate; 3, severe; 4, life-threatening or disabling; 5, fatal.
  • CCAE Common Terminology Criteria for Adverse Events
  • use of the bispecific antibody blinatumomab which targets CD3/CD19 to treat Acute Lymphoblastic Leukemia (ALL) is known to be associated with neurotoxicity including convulsions.
  • CAR T cell therapy targeted against CD19 to treat ALL is known to be associated with tremor, encelopathy, cerebellar alteration, or seizures.
  • a close relationship for neurotoxicity with the inflammatory cytokines associated with CRS is also known in the art.
  • the symptoms of neurotoxicity place a significant burden on hospitals and carers for monitoring and treatment. Neurotoxicity can result in long term damage to the central nervous system requiring long term care. Neurotoxicity can also lead to death.
  • the present invention advantageously provides a means for the treatment and/or prevention of complex symptoms and conditions that result from neurotoxicity, improving patient health and the time and resources of hospitals and carers.
  • neurotoxicity is immune induced neurotoxicity with the administration of immunotherapy.
  • the neurotoxicity may be the result of immunotherapy and/or a disorder.
  • Neurotoxicity and CRS are known to occur independently with distinct timing and kinetics in response to immunotherapy. However, the underlying mechanisms of neurotoxicity and CRS appear interlinked. For example, it is known that up to 50% of patients treated with CD19 CAR-T immunotherapy have at least Grade 3 neurotoxicity or CRS symptoms.
  • Described herein is an advantageous means to prevent and/or treat neurotoxicity and/or CRS where additional steroid treatment may not be required.
  • Prolonged use of steroids as part of a therapy is known in the art to have many negative side-effects.
  • side-effects can include increased appetite, mood changes and difficulty sleeping.
  • prevention in connection with CRS (and/or neurotoxicity) refers to reducing or eliminating symptoms and/or pathology before they occur.
  • treatment in connection with CRS (and/or neurotoxicity) refers to reducing or eliminating symptoms and/or pathology after symptom onset.
  • treatment may further include prevention (prophylaxis) of neurotoxicity and/or CRS, or amelioration or elimination of the disorder once it has been established.
  • the term“subject” refers to a human. It is not intended that the term “subject” be limited to a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are encompassed by the term.
  • the subject is an adult subject.
  • the term“adult” refers to a subject that has reached biological maturity.
  • the subject is a pediatric subject.
  • the term“pediatric” refers to an infant, child or adolescent.
  • the present invention is directed to preventing and/or treating CRS, wherein an CD38 inhibitor, such as an anti-CD38 antibody, is administered to a subject before and/or after administration of an immunotherapy treatment.
  • an CD38 inhibitor such as an anti-CD38 antibody
  • undergoing immunotherapy is defined as encompassing a subject who has been selected to undergo immunotherapy in the future but is yet to begin immunotherapy, and/or a subject concurrently undergoing immunotherapy and/or a subject who has undergone immunotherapy. It is understood that immunotherapy encompasses the administration of the therapeutic to the patient, either directly or indirectly.
  • the anti-CD38 antibody administered before immunotherapy.
  • the anti-CD38 antibody is further administered during or concurrently with immunotherapy.
  • the anti-CD38 antibody is administered after immunotherapy.
  • the term“before immunotherapy” may refer to any point in time after a subject has been selected to undergo immunotherapy but prior to the commencement of administration of the immunotherapy treatment.
  • the anti-CD38 antibody may be administered about 30 days or less before immunotherapy administration.
  • the anti-CD38 antibody may be administered 1 to 60 days, 5 to 60 days, 10 to 60 days, 20 to 60 days, 30 to 60 days, or 40 to 60 days, 50 to 60 days before immunotherapy administration.
  • the anti-CD38 antibody may be administered 1 to 5 days, 5 to 10 days, 10 to 20 days, 20 to 30 days, 30 to 40 days, 40 to 50 and /or 50 to 60 days before immunotherapy administration
  • the CD38 inhibitor may be administered 60 days or less, 50 days or less, 40 days or less, 30 days or less, 20 days or less, 10 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day before immunotherapy administration.
  • the term “during immunotherapy” may refer to any point in time while the immunotherapy is being administered through an individual treatment or treatment programme over time, or concurrently as the immunotherapy is administered.
  • the CD38 inhibitor such as an anti-CD38 antibody
  • immunotherapy may be administered concurrently.
  • “concurrent” is used to mean administration of the CD38 inhibitor and immunotherapy by simultaneous, sequential or separate means.
  • “simultaneous” is used to mean that the CD38 inhibitor and immunotherapy are administered at an overlapping or the same time.
  • “sequential” is used to mean that the CD38 inhibitor and immunotherapy are not administered concurrently, but one after the other.
  • “separately” is used herein to mean that the gap between administering one agent and the other is significant i.e. the first administered agent may no longer be present in the bloodstream in a therapeutically effective amount when the second agent is administered.
  • administration“sequentially” may permit the CD38 inhibitor to be administered within 5 minutes, 10 minutes or a matter of hours before or after the immunotherapy administration provided the circulatory half-life of the first administered agent is such that they are both concurrently present in therapeutically effective amounts.
  • the time delay between administration of the CD38 inhibitor and immunotherapy will vary depending on the exact nature of the CD38 inhibitor and immunotherapy, the interaction there between, and their respective half-lives.
  • after immunotherapy may refer to any point in time after the administration of any individual immunotherapy treatment or treatment programme has completed.
  • the CD38 inhibitor such as an anti-CD38 antibody
  • the CD38 inhibitor may be administered between 1 to 60 days after immunotherapy administration.
  • the CD38 inhibitor may be administered 1 to 60 days, 5 to 60 days, 10 to 60 days, 15 to 60 days, 20 to 60 days, or 30 to 60 days, 40 to 60 days, and/or 50 to 60 days after immunotherapy administration.
  • the CD38 inhibitor may be administered 1 to 5 days, 5 to 10 days, 10 to 20 days, 20 to 30 days, 30 to 40 days, 40 to 50 days and/or 50 to 60 days after immunotherapy administration.
  • the CD38 inhibitor may be administered 60 days or less, 50 days or less, 40 days or less, 30 days or less, 20 days or less, 10 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day after immunotherapy administration.
  • the anti-CD38 antibody according to the present invention may be administered once. In another embodiment the anti-CD38 antibody may be administered more than once. In another embodiment, the anti-CD38 may be administered four times or more, for example four, five, six, seven, eight, nine, ten or more times. The administration may be before, during and/or after immunotherapy.
  • administering or“administration” in relation to an anti-CD38 antibody refers to application or delivery of the CD38 inhibitor, such as an anti-CD38 antibody to the subject by any route of delivery.
  • the anti-CD38 antibody of the present invention is administered to the subject using means and methods that are known and standard practise in the art.
  • the anti-CD38 antibody may be administered to a subject by a subcutaneous or intravenous route.
  • the administration may be systemic or local.
  • parenteral refers to any route in the body other than the mouth and alimentary canal. Parenteral routes are well known in the art and include but are not limited to subcutaneous, intravenous and intramuscular routes.
  • enteral refers to any route that involves the gastrointestinal tract. Enteral routes are well known in the art and include but are not limited to oral, sublingual and rectal routes.
  • the mode of administration is chosen to be appropriate for the age and symptoms of the subject.
  • daratumumab is administered parenterally, preferably intravenously, more preferably subcutaneously.
  • daratumumab is administered in a liquid formulation.
  • the anti-CD38 antibody of the present invention is administered in a dose that prevents and/or treats CRS.
  • the dose will be sufficient to reduce or eliminate CD38 transduction.
  • a person of ordinary skill in the art can easily determine an appropriate dose of the CD38 inhibitor, such as an anti-CD38 antibody according to the present invention, to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the anti-CD38 antibody such as daratumumab
  • the anti-CD38 antibody is preferably administered in a dose of from about 2 to 32 mg/kg.
  • the dose administered will be adjusted according to the subject’s body weight.
  • daratumumab may be administered 60 days before or after immunotherapy administration.
  • the anti-CD38 antibody daratumumab is administered in a dose of from about 2 to 32 mg/kg per day, preferably 8 to 24 mg/kg per day, preferably 16 mg/kg per day.
  • the dose may be split over two, three, four, five or six consecutive days rather than administration by a single infusion.
  • compositions comprising anti-CD38 antibody for use in the prevention and/or treatment of CRS in a subject undergoing immunotherapy, wherein the anti-CD38 antibody is administered before and/ or after immunotherapy.
  • compositions comprising anti-CD38 antibody for use according to the invention encompass all embodiments as described herein.
  • compositions of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy.
  • a pharmaceutical carrier excipient or diluent
  • Such formulations, along with methods for their preparation, will be familiar to a person of ordinary skill in the art.
  • the CD38 inhibitor is administered to the subject as a composition, preferably a pharmaceutical composition.
  • a composition preferably a pharmaceutical composition.
  • said composition may contain pharmaceutically acceptable carriers or additives, depending on the route of administration.
  • the form of the pharmaceutical composition is well known in the art and readily determinable.
  • composition for use according to the invention may be in a lyophilized form.
  • the composition for use may be dissolved in an aqueous carrier.
  • the composition for use may further comprise any components that promote stability of the CD38 inhibitor in solution.
  • the present invention also includes solvate forms of the compositions comprising CD38 inhibitors.
  • the pharmaceutical composition may comprise buffering agents, tonicity agents, antioxidants, stabilizers, surfactants, bulking agents, chelating agents and preservatives.
  • the pharmaceutical composition for use according to the present invention comprises an CD38 inhibitor such as an anti-CD38 antibody and further comprises at least one further active pharmaceutical ingredient (API).
  • an CD38 inhibitor such as an anti-CD38 antibody
  • at least one further active pharmaceutical ingredient (API) at least one further active pharmaceutical ingredient
  • the invention provides a method of treating and/or preventing CRS in a human subject undergoing immunotherapy, the method comprising administering to a human subject in need thereof an CD38 inhibitor, such as an anti-CD38 antibody, before and/or after immunotherapy.
  • an CD38 inhibitor such as an anti-CD38 antibody
  • the method of treatment and/or prevention of CRS comprises the administration of an CD38 inhibitor according to the embodiments as described herein.
  • the subject is undergoing immunotherapy according to the embodiments as described herein.
  • the method for preventing neurotoxicity and/or CRS relates to the prophylactic use of the CD38 inhibitor.
  • the CD38 inhibitor may be administered to a subject who has not yet contracted the disorder and/or who is not showing any symptoms of the disorder, and/or who has not yet undergone immunotherapy.
  • the subject may have a predisposition for or be thought to be at risk of developing a disorder and/or may be a candidate for immunotherapy.
  • the methods for preventing and/or treating a disorder provided by the present invention may involve monitoring the progression of the disorder and/or the progression of response to immunotherapy.
  • “Monitoring the progression of the disorder” means to assess the symptoms associated with the disorder and/or immunotherapy treatment over time to determine if they are reducing/improving or increasing/worsening.
  • the dose of the CD38 inhibitor administered to a subject, or the frequency of administration may be altered in order to provide an acceptable level of both disorder progression and immunotherapy treatment according to the methods of the invention.
  • the specific level of disorder progression and toxic activities determined to be ‘acceptable’ will vary according to the specific circumstances and should be assessed on such a basis.
  • the invention provides the use of an CD38 inhibitor, such as an anti- CD38 antibody, for the manufacture of a medicament for the treatment and/or prevention of neurotoxicity and/or CRS in a human subject undergoing immunotherapy, wherein the medicament is administered before immunotherapy.
  • an CD38 inhibitor such as an anti- CD38 antibody
  • the treatment and/or prevention of neurotoxicity and/or CRS comprises administering an CD38 inhibitor according to the embodiments as described herein.
  • the subject is undergoing immunotherapy according to the embodiments as described herein.
  • 3 x 10 L 6 Raji tumour cells from ATCC are injected intraperitoneally into a 6-8 week old female SCID-beige mouse (Taconic) and allow to grow for 20 days, until they eventually grow into vascularised solid tumour masses.
  • 30 x 10 L 6 CD19 CAR T cells are then injected into the mouse.
  • a panel of known CRS markers are monitored e.g. percentage weight change over 65 hours, serum cytokine profile including IL6 levels and/or IL15 levels and/or iNOS + cells.
  • CRS is confirmed in mice displaying, for example, more than 10% weight drop in 65 hours and/or raised IL6 levels.
  • mCD40L is constitutively expressed with the CD19 CAR T cells (CAR-mCD40L).
  • Example 2 CRS in immunotherapy following administration of anti-CD38 antibody before immunotherapy administration
  • the CRS markers are measured as described in Example 1 in tumour-bearing mice which receive daratumumab (16 mg/kg mouse weight per day) daily from 10 days to 1 day (day-10 to day-1 ) before CAR T cell infusion. CAR T cells are injected into mice 7 days after the first T cell activation.
  • the marker levels measured are compared CRS markers levels with tumour-bearing mice which receive daratumumab only during (day 0) or post-CAR T cell therapy (day+1 to day+4).
  • Control mice receive PBS supplemented with 2% human serum.
  • mice which received pre-administration of daratumumab showed significantly less weight loss over a 65-hour period following CAR T cell infusion compared with mice which did not receive daratumumab.
  • Example 3 CRS in immunotherapy following administration of anti-CD38 antibody
  • Example 2 The pre-administration protocol described in Example 2 is repeated (day-10 to day-1).
  • the administration of daratumumab (16 mg/kg mouse weight per day) is continued on day 0 and/or 1 day to 4 days post CAR T cell infusion (day-10 to dayO / or day-10 to day+4).
  • the marker levels are then measured and compared with levels in tumour bearing mice which receive daratumumab during (day 0) and/or only post CAR T cell therapy (day+1 to day+4).
  • Control mice receive PBS supplemented with 2% human serum.
  • mice which received pre-administration dosages of daratumumab showed significantly less weight loss over a 65-hour period following CAR T cell infusion compared with mice which received daratumumab only during or only after CAR T cell infusion.

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Abstract

La présente invention concerne l'utilisation d'un anticorps anti-CD38 chez un sujet subissant une immunothérapie, l'anticorps anti-CD38 étant administré avant et/ou après l'immunothérapie.
PCT/GB2020/050567 2019-03-11 2020-03-10 Immunothérapie combinée à un anticorps anti-cd38 WO2020183147A1 (fr)

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