WO2022148781A1 - Combination of mcoln activators and immune checkpoint inhibitors - Google Patents
Combination of mcoln activators and immune checkpoint inhibitors Download PDFInfo
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- WO2022148781A1 WO2022148781A1 PCT/EP2022/050154 EP2022050154W WO2022148781A1 WO 2022148781 A1 WO2022148781 A1 WO 2022148781A1 EP 2022050154 W EP2022050154 W EP 2022050154W WO 2022148781 A1 WO2022148781 A1 WO 2022148781A1
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- cancer
- combination
- mcoln
- composition
- inhibitor
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- 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
- C07K16/2818—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 against CD28 or CD152
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- 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
- C07K16/2827—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 against B7 molecules, e.g. CD80, CD86
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- the present invention relates to the field of medicine, in particular to the field of oncology.
- DCs Dendritic cells initiate adaptive immune responses by carrying information from peripheral tissues -which are often exposed to external threats- to lymph nodes, through which T lymphocytes circulate. At the immature stage, DCs sample the interstitial space of tissues by internalizing important amounts of extracellular material. Upon encountering danger signals, they enter into a "maturation program" that down-regulates antigen internalization and promotes fast DC migration to lymph nodes for antigen presentation to T lymphocytes. This process is strictly needed for the establishment of adaptive immune responses.
- podosomes or invadosomes are cylindrical, actin-rich structures displaying a polarized pattern of distribution in migrating cells. Their primary purpose is related to cellular motility and invasion. Many different specialized cells exhibit these dynamic structures such as invasive cancer cells, and certain immune cells such as DCs (Gimona et al, Current opinion in cell biology 20 (2): 235-41).
- Cancer immunotherapy aims at eliciting an immune response directed against tumor antigens.
- One approach is through vaccination by the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo.
- DCs have been used in this context due to their high antigen presenting property, which makes them the natural agents for tumor-associated antigen delivery.
- ex vivo generated DCs can be loaded with antigens and re-infused to the patient.
- antigens can be targeted to DCs in vivo without need for ex vivo cell manipulations.
- the DCs injected to patients migrate inefficiently to lymphoid organs, a process required to trigger antitumoral immunity.
- the inventors discovered that the activation of the lysosomal calcium channel TRPML also called Mcoln might help the cold-to-hot transition of tumors, and thereby enhance the efficiency of anti-tumor immune responses and anti-checkpoint therapy.
- the inventors were able to show that activation of Mcoln leads to decreased tumor growth in the presence of an anti-checkpoint inhibitor in vivo.
- the present invention relates to a composition or combination comprising an activator of mucolipin (Mcoln) and an immune checkpoint inhibitor for use in the treatment of a cancer in a subject.
- Mcoln mucolipin
- the activator of Mcoln is selected from the group consisting of i) a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83, phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2) and a derivative or analog thereof, and ii) an agonist antibody directed against Mcoln.
- a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83, phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2) and a derivative or analog thereof, and ii) an agonist antibody directed against Mcoln.
- the activator of Mcoln is selected from the group consisting of ML-SA1, ML-SA5, SF-21, SF- 22, SF-51, SF-81, SN-2, MK6-83, Ptdlns(3,5)P2 and a derivative or analog thereof, preferably is ML-SA1 or a derivative or analog thereof. Even more preferably, the activator of Mcoln is ML-SA1 or ML-SA5 or a derivative or analog thereof activating Mcoln. Most preferably, the activator of Mcoln is ML-SA1 or a derivative or analog thereof activating Mcoln.
- the immune checkpoint inhibitor is an inhibitor of an immune checkpoint selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, 0X40 L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) and Butyrophilin-like2 (BTNL2) or any combination thereof.
- an immune checkpoint selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, 0X40 L, GI
- the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-1/PD-L1 inhibitor.
- the PD-1 inhibitor is i) a peptide or peptidomimetic inhibiting PD-1/PD-L1 interaction such as AUNP-12, (D)-PPA 1, BMS202, hPRDX5 and a derivative, variant or analog thereof ii) a small molecule inhibiting PD-1/PD-L1 interaction such as molecules containing a sulfamonomethoxine or sulfamethizole scaffold and iii) an anti-PD-1 or anti-PDLl antibody.
- a peptide or peptidomimetic inhibiting PD-1/PD-L1 interaction such as AUNP-12, (D)-PPA 1, BMS202, hPRDX5 and a derivative, variant or analog thereof
- a small molecule inhibiting PD-1/PD-L1 interaction such as molecules containing a sulfamonomethoxine or sulfamethizole scaffold and iii) an anti-PD-1 or anti-PDL
- the PD-1 or PD-L1 inhibitor is selected from the group consisting of atezolizumab, durvalumab, avelumab nivolumab, pembrolizumab, pidilizumab, cemiplimab, camrelizumab, sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), BMS 936559, MPDL3280A, MSB0010718C, MEDI4736 and any combination thereof.
- the Mcoln activator is ML-SA1 and the immune checkpoint inhibitor is a PD- 1 inhibitor, preferably an anti-PD-1 antibody.
- the immune checkpoint inhibitor is a PD-1 inhibitor.
- the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of atezolizumab, durvalumab, avelumab nivolumab, pembrolizumab, pidilizumab, cemiplimab, camrelizumab, sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR- 042, WBP-285), BMS 936559, MPDL3280A, MSB0010718C, MEDI4736 and any combination thereof.
- the cancer is a solid tumor such as sarcoma, carcinoma, and lymphoma.
- the cancer is selected from the group consisting of prostate cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, kidney cancer, ovarian cancer, hepatocellular cancer, osteosarcoma, melanoma, hypopharynx cancer, esophageal cancer, endometrial cancer, cervical cancer, pancreatic cancer, liver cancer, colon cancer, colorectal cancer, brain cancer, renal cancer, neuroendocrine tumors, muscle cancer, adrenal cancer, thyroid cancer, uterine cancer, skin cancer and bladder cancer, preferably colon cancer.
- the subject has already received a line of treatment with an immune checkpoint inhibitor, preferably a PD-1 inhibitor.
- an immune checkpoint inhibitor preferably a PD-1 inhibitor.
- the subject does not respond to a treatment with a PD-1 inhibitor alone.
- composition according to the invention is a combined preparation for simultaneous, separate or sequential use.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a molecule activating Mcoln and an immune checkpoint inhibitor, as disclosed herein.
- the invention finally concerns a combination comprising a molecule activating Mcoln and an immune checkpoint inhibitor such as disclosed herein.
- immune checkpoint or “immune checkpoint protein” has its general meaning in the art and refers to a molecule that is expressed by immune or cancer cells in that either turn up a signal (stimulatory checkpoint molecules) or turn down a signal (inhibitory checkpoint molecules). Many of the immune checkpoints are regulated by interactions between specific receptor and ligand pairs. Immune checkpoint molecules are recognized in the art to constitute immune checkpoint pathways, such as the well-known CTLA-4 and PD-1 dependent pathways (see e.g. Pardoll, 2012. Nature Rev Cancer 12:252-264; Mellman et al., 201 1. Nature 480:480- 489). Overexpression of inhibitory checkpoint molecules by cancer cells have often been associated with inhibition of anti tumor immune response as immune cell express their ligand or receptor counterparts.
- immune checkpoint inhibitor As used herein, the expressions "immune checkpoint inhibitor”, “checkpoint inhibitor” or “checkpoint blockade cancer immunotherapy agent” are used interchangeably and have its general meaning in the art and refers to any compound inhibiting the function of an immune checkpoint protein. Inhibition includes reduction of function and full blockade.
- the immune checkpoint inhibitors include peptides, proteins, antibodies, nucleic acid molecules and small molecules.
- Preferred immune checkpoint inhibitors are antibodies that specifically recognize immune checkpoint proteins. Examples of immune checkpoint inhibitors are provided here below under the associated paragraph.
- the term "immunotherapy” or “immunotherapy treatment” refers to a cancer therapeutic treatment using the immune system to reject cancer.
- the therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells. It includes immunization of the patient with tumor antigens (e.g. by administering a cancer vaccine), in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or administration of molecules stimulating the immune system such as cytokines, or administration of therapeutic antibodies such as drugs, in which case the patient's immune system is recruited by the therapeutic antibodies to destroy tumor cells.
- tumor antigens e.g. by administering a cancer vaccine
- molecules stimulating the immune system such as cytokines
- therapeutic antibodies such as drugs
- the patient's immune system is recruited by the therapeutic antibodies to destroy tumor cells.
- antibodies are directed against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.
- an important feature of the immune system is its ability to discriminate between normal cells in the body and those it sees as “foreign", in particular cancer cells. This allows the immune system to attack the cancer cells while leaving the normal cells alone. To do this, the immune system uses checkpoints, these checkpoints are molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Cancer cells sometimes exploit these checkpoints to avoid being attacked by the immune system.
- immune checkpoint immunotherapy refers to an immunotherapy that targets these checkpoints in order to allow or facilitate the attack of cancer cells by the immune system.
- cancer refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as the ones leading to uncontrolled proliferation, and/or immortality, and/or metastatic potential, and/or rapid growth and/or higher proliferation rate, and/or certain characteristic morphological features.
- This term refers to any type of malignancy (primary or metastases) in any type of subject. It may refer to solid tumor as well as hematopoietic tumor.
- immune response refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by these cells or the liver (including antibodies, cytokines, and complements) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
- the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human.
- the term “subject” can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.
- treatment refers to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of the disease.
- such term refers to the amelioration or eradication of a disease or symptoms associated with a disease.
- this term refers to minimizing the spread or worsening of the disease resulting from the administration of one or more therapeutic agents to a subject with such a disease.
- compositions refers to a preparation of one or more of the active agents, with optional other chemical components such as physiologically suitable carriers and excipients.
- the purpose of a pharmaceutical composition is to facilitate administration of the active agent to an organism.
- Compositions of the present invention can be in a form suitable for any conventional route of administration or use.
- a "composition” typically intends a combination of the active agent, e.g., compound or composition, and a naturally-occurring or non- naturally-occurring carrier, inert (for example, a detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers.
- a naturally-occurring or non- naturally-occurring carrier for example, a detectable agent or label
- active such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers.
- active principle As used herein, the terms "active principle”, “active ingredient” “active pharmaceutical ingredient”, “therapeutic agent”, “antitumor compound”, and “antitumor agent” are equivalent and refer to a component having a therapeutic effect.
- the term "therapeutic effect” refers to an effect induced by an active ingredient or by a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or the development of a cancer, or to cure or to attenuate the effects of a cancer.
- an effective amount or a “therapeutic effective amount” as used herein refers to the amount or quantity of active agent required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents, e.g. the amount of active agent that is needed to treat the targeted disease or disorder, or to produce the desired effect.
- the “effective amount” will vary depending on the agent(s), the disease and its severity, the characteristics of the subject to be treated including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation.
- a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment.
- effective amount it is particularly meant the quantity of the combination or pharmaceutical composition of the invention that prevents, removes or reduces the deleterious effects of cancer in mammals, including humans. More particularly, by “therapeutically efficient amount of a composition” is intended the amount that is sufficient to decrease the size of a tumor or the occurrence of metastasis.
- combination as used herein is meant either, simultaneous administration of two Compounds A and B as defined in the present application or of a composition comprising such, or any manner of separate or sequential administration of a Compound A, or a composition comprising such, and Compound B or a composition comprising such.
- the combination can be administered by the same route or by different routes, e.g. one compound may be administered intravenously and the other compound may be administered orally.
- kit defines especially a "kit of parts” in the sense that the combination partners (a) and (b), as defined in the present application can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e. simultaneously or at different time points.
- the parts of the kit of parts can then be administered simultaneously or chronologically staggered, that is at different time points for any part of the kit of parts.
- the ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can varied.
- the combination partners (a) and (b) can be administered by the same route or by different routes.
- the term "simultaneous” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered simultaneously, i.e. at the same time.
- the active ingredients may or may not be part of the same composition.
- the term "sequential" refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered sequentially, i.e. one after the other.
- the active ingredients are used or administered sequentially, i.e. one after the other.
- all the active ingredients are administered in less than about an hour, preferably less than about 10 minutes, even more preferably in less than about a minute.
- the term "separate” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered at distinct time of the day.
- the active ingredients are administered with an interval of about 1 hour to about 24 hours, preferably with an interval of about 1 hour and 15 hours, more preferably with an interval of about 1 hour and 8 hours, even more preferably with an interval of about 1 hour and 4 hours.
- responder refers to a patient who responds to a treatment of cancer, i.e. the volume of the tumor is decreased, at least one of his symptoms is alleviated, or the development of the cancer is stopped, or slowed down.
- a subject who responds to a cancer treatment is a subject who will be completely treated (cured), i.e., a subject who will survive to the cancer.
- a subject who responds to a cancer treatment is also, in the sense of the present invention, a subject who has an overall survival higher than the mean overall survival known for the particular cancer.
- good responder or “susceptible to have a therapeutic benefit” is intended a patient who shows a good therapeutic benefit of the treatment, that is to say a longer disease-free survival, a longer overall survival, a decreased metastasis occurrence, a decreased tumor growth and/or a tumor regression in comparison to a population of patients suffering from the same cancer and having the same treatment.
- non-responder refers to a subject who does not respond to a treatment of cancer, i.e. the volume of the tumor does not substantially decrease, or the symptoms of the cancer in the subject are not alleviated, or the cancer progresses, for example the volume of the tumor increases and/or the tumor generates local or distant metastasis.
- non-responder also refer to a subject who will die from the cancer, or will have an overall survival lower than the mean overall survival known for the particular cancer.
- “poor responder” or “non-responder” is intended a patient who shows a weak therapeutic benefit of the treatment, that is to say a shorter disease-free survival, a shorter overall survival, an increased metastasis occurrence and/or an increased tumor growth in comparison to a population of patients suffering from the same cancer and having the same treatment.
- Mucolipin Activator Mucolipin channel is also currently named Transcient Receptor Potential Cation Channel Mucolipin subfamily (TRPML). It is a small family of the TRPML channels that includes 3 members, (Mcoln-1, Mcoln-2 and Mcoln-3) which is a subgroup of the large protein family of TRP ion channels. It is a Ca 2+ channel localized in late endosomes and lysosomes. Unless specified otherwise, the term "Mcoln” refers to any of the Mcoln-1, Mcoln-2 and/or Mcoln-3 channels.
- TRPML1 was identified as the protein mutated in the lysosomal storage disease mucolipidosis type IV (Bargal et al., 2000).
- TRPML2 was found by database searches and TRPML3 was identified as the protein mutated in mice with the varitint-waddler phenotype (Di Palma et al., 2002).
- Mcoln-1 Human Mcoln-1 is described in several databases, namely under the references UniProt ID No Q9GZU1 and GenelD No 57192. Reference sequences are disclosed in Genbank under NM_020533 for mRNA and NP_065394 for protein. Because Mcoln-1 localizes to lysosomes, its luminal domains are directly accessible to extracellular compounds. Accordingly, there is no absolute need for Mcoln-1 activators to be cell-permeable.
- Human Mcoln-2 is for example described under the references UniProt ID No Q8IZK6 and Gen ID No 255231. Reference sequences are disclosed in Genbank under NP_001317576.1, NM_001330647.1, NP_694991.2 and NM_153259.3.
- Human Mcoln-3 is for example described under the references UniProt ID No Q8TDD5 and Gen ID No 55283. Reference sequences are disclosed in Genbank under NP_001240622.1, NM_001253693.1, NP_060768.8 and NM_018298.10.
- the Mcoln activator used in the combination according to the invention can be any molecule capable of increasing Mcoln activity, particularly Mcoln-1, Mcoln-2 and/or Mcoln-3 activity.
- the Mcoln activator can be any molecule capable of increasing Mcoln-1 activity.
- a Mcoln activator is a molecule capable of increasing the activity of Mcoln by at least 10, 20, 30, 40 or 50 % when compared to the activity in absence of the molecule.
- Mcoln activity can be determined by any method known by the person skilled in art and for instance in such as disclosed in Shen et al., 2012, Nat. Comm., 3:731.
- the activity of Mcoln channel can for example be assessed by measuring its calcium permeability.
- the Mcoln activator can be selected from the group consisting of i) a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83, phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2) and a derivative or analog thereof, and ii) an agonist antibody directed against Mcoln.
- a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83, phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2) and a derivative or analog thereof, and ii) an agonist antibody directed against Mcoln.
- a small molecule or peptide activating Mcoln such as ML
- Small molecules and other drug candidates can readily be obtained, for example, from combinatorial and natural product libraries and using methods known to the art, or screening methods for their Mcoln agonizing activity.
- Synthetic compound libraries are commercially available from a number of companies including Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, N. J.), Brandon Associates (Merrimack, N.H.), and Microsource (New Milford, Conn.). Combinatorial libraries are available or can be prepared according to known synthetic techniques.
- libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available from e.g., Pan Laboratories (Bothell, Wash.) and MycoSearch (NC), or are readily producible by methods well known in the art.
- random peptide libraries consisting of all possible combinations of amino acids, attached to a solid phase or in solution, may also be used to identify peptides that act as agonists.
- the activator of Mcoln is a small molecule having a molecular weight inferior to 500 Daltons, preferably inferior to 400 Daltons.
- the activator of Mcoln is a small molecule selected from the group consisting of ML-SA1 (2-[2-(3,4-Dihydro-2,2,4-trimethyl-l(2H)-quinolinyl)-2-oxoethyl]-lH-isoindole-l,3(2H)-dione, CAS number 332382-54-4, Sigma-Aldrich Cat # SML0627; Tocris Bioscience Cat # 4746), SF-21 (4- chloro-N-(2-morpholin-4-ylcyclohexyl)benzenesulfonamide), SF-22 (5-chloro-N-(2-piperidin-l- ylphenyl)thiophene-2-sulfonamide), SF-51 (2-[2-oxo-2-(2,2,4-trimethylquinolin-l-yl)ethyl]isoindole- 1,3-dione), SF-81 (4,6-
- the activator of Mcoln is ML-SA1 or ML-SA5 or a derivative or analog thereof activating Mcoln. More preferably, the activator of Mcoln is ML-SA1 or a derivative or analog thereof activating Mcoln.
- the Mcoln activator is a chemical compound having an activating activity on Mcoln such as phosphatidylinositol-3,5-bisphosphate (Ptdlns(3,5)P2).
- Ptdlns(3,5)P2 is one of the seven phosphoinositides found in eukaryotic cell membranes. This compound is commercially available for example by Echelon Bioscience Product Number: P-3508 and comprising for example the formula such as provided below:
- the Mcoln activator is ML-SA1, ML-SA5 or a derivative or analog thereof, for example such as described below.
- the Mcoln activator is ML-SA1 or a derivative or analog thereof.
- ML-SA1 is for example described under CAS registry No. : 332382-54-4.
- the Mcoln activator is ML-SA1, preferably of formula : In another aspect, the Mcoln activator is ML-SA5 or a derivative or analog thereof. . ML-SA1 is for example described under CAS registry No. : 2418670-70-7.
- the Mcoln activator is ML-SA5, preferably of formula :
- the activator of Mcoln is an agonist antibody.
- antibody refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen- binding site that immunospecifically bind an antigen, e.g. Mcoln-1, Mcoln-2 and/or Mcoln-3.
- Antibodies include any kind of antibodies, preferably monoclonal. They can be for instance IgG (immunoglobulin G) or VHH (heavy chain variable domain antibody from camelids).
- antibody encompasses fragments or derivatives thereof and include Fab, Fab', F(ab')2, scFv, (scFv)2, dAb, complementarity determining region (CDR) fragments, linear antibodies, single-chain antibody molecules, minibodies, diabodies, and multispecific antibodies formed from antibody fragments.
- An "agonist antibody” is an antibody that binds to a receptor and activates the receptor to produce a biological response.
- the Mcoln activator is an antibody directed against Mcoln-1, Mcoln-2 and/or Mcoln-3 and having an agonist activity.
- Such antibody can be for instance prepared by the following method comprising immunizing a non-human mammal with a composition comprising human Mcoln-1, Mcoln- 2 and/or Mcoln-3 or an immunogenic fragment thereof; optionally selecting an antibody that binds to Mcoln-1, Mcoln-2 and/or Mcoln-3 or the immunogenic fragment thereof, and selecting an antibody that increases the activity of Mcoln-1, Mcoln-2 and/or Mcoln-3.
- phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)).
- the Mcoln activator is selective in respect to Mcoln-1. That means that the Mcoln-1 activator has a greater efficacy on TRPML-1 in comparison to TRPML-2 and/or TRPML-3 (for instance by a factor of at least 10, 100 or 1000).
- immune checkpoint inhibitors include peptides, peptidomimetics, antibodies, nucleic acid molecules, small molecules and chemical compounds.
- a checkpoint inhibitor is an agent which blocks an immunosuppressive receptor expressed by activated T lymphocytes, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PD-1), or by NK cells, like various members of the killer cell immunoglobulin- like receptor (KIR) family, or an agent which blocks the principal ligands of these receptors, such as PD- 1 ligand CD274 (also known as PD-L1 or B7-H1).
- CTL4 cytotoxic T lymphocyte-associated protein 4
- PD-1 programmed cell death 1
- NK cells like various members of the killer cell immunoglobulin- like receptor (KIR) family, or an agent which blocks the principal ligands of these receptors, such as PD- 1 ligand CD274 (also known as PD-L1 or B7-H1).
- the immune checkpoint is selected from the group consisting of PD-1, PD-L1, PD-L2, CT LA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) and Butyrophilin-like2 (BTNL2).
- the immune checkpoint is PD-1.
- the terms “Programmed Death 1”, “Programmed Cell Death 1”, “PD1”, “PD-1”, “PDCD1”, “PD-1 antigen”, “human PD-1”, “hPD-1” and “hPDl” are used interchangeably and refer to the Programmed Death-1 receptor, also known as CD279, and include variants and isoforms of PD-1, and analogs having at least one common epitope with PD-1.
- PD-1 is a key regulator of the threshold of immune response and peripheral immune tolerance. It is expressed on activated T cells, B cells, monocytes, and dendritic cells and binds to its ligands PD-L1 and PD-L2.
- Human PD-1 is encoded by the PDCD1 gene.
- the amino acid sequence of a human PD-1 is disclosed under GenBank accession number NP_005009.
- PD1 has four splice variants expressed on human Peripheral blood mononuclear cells (PBMC).
- PBMC Peripheral blood mononuclear cells
- PD-1 proteins include full-length PD-1, as well as alternative splice variants of PD- 1, such as PD-lAex2, PD- lAex3, PD-lAex2,3 and PD-lAex2,3,4.
- the checkpoint inhibitor is an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2).
- the immune checkpoint inhibitor therapy is an immunotherapy, wherein the immune checkpoint is selected from the group consisting of an antibody directed against cytotoxic T lymphocyte associated protein (CTLA-4), programmed cell death protein 1 (PD-1), programmed cell death ligand (PD-L1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), B- and T-lymphocyte attenuator (BLTA), IDOl inhibitor, or any combination thereof, preferably selected from the group consisting of an antibody directed against PD-1, PD-L1 and CTLA-4 or any combination thereof, more preferably an antibody directed against PD-1 or PD-L1 and the combination thereof.
- CTLA-4 cytotoxic T lymphocyte associated protein
- PD-1 programmed cell death protein 1
- PD-L1 programmed cell death ligand
- TAGIT T cell immunoreceptor with Ig and ITIM domains
- the checkpoint inhibitor is an anti-PDl antibody.
- PD-1 antibody As used herein "PD-1 antibody,” “anti-PD- 1 antibody,” “PD-1 Ab,” “PD-l-specific antibody” or “anti-PD-1” are used interchangeably and refer to an antibody, as described herein, which specifically binds to PD-1, preferably human PD-1. In some embodiments, the antibody binds to the extracellular domain of PD-1.
- an anti-PD-1 antibody is an antibody capable of binding to a PD-1 antigen and inhibits the PD-l-mediated signaling pathway, and/or the interaction between PD-1 and PD-L1.
- the anti-PDl antibody can be selected from the group consisting of Pembrolizumab (also known as Keytruda lambrolizumab, MK-3475), Nivolumab (Opdivo, MDX-1106, BMS-936558, ONO-4538), Pidilizumab (CT-011), Cemiplimab (Libtayo), Camrelizumab, AUNP12, AMP- 224, AGEN-2034, BGB-A317 (Tisleizumab), PDR001 (spartalizumab), MK-3477, SCH-900475, PF- 06801591, JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, SHR-1201, BAT-1306, AK-103 (FIX-008), MEDI-0680 (also known as AMP-514)
- Pembrolizumab also known as Keytruda lambrolizumab, M
- BI-754091 CBT-501, INCSHR1210 (also known as SHR-1210), TSR-042 (also known as ANB011), GLS-010 (also known as WBP3055), AM-0001 (Armo), STI-1110 (see WO 2014/194302), AGEN2034 (see WO 2017/040790), MGA012 (see WO 2017/19846), or IBI308 (see WO 2017/024465, WO 2017/025016, WO 2017/132825, and WO 2017/133540), monoclonal antibodies 5C4, 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, described in WO 2006/121168.
- Bifunctional or bispecific molecules targeting PD-1 are also known such as RG7769 (Roche), XmAb20717 (Xencor), MEDI5752 (AstraZeneca), FS118 (F-star), SL-279252 (Takeda) and XmAb23104 (Xencor).
- the PD-1 inhibitor is selected from the group consisting of atezolizumab, durvalumab, avelumab nivolumab, pembrolizumab, pidilizumab, cemiplimab, camrelizumab, sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), BMS 936559, MPDL3280A, MSB0010718C, MEDI4736 and any combination thereof.
- the checkpoint inhibitor is an anti-PD-Ll antibody.
- Antibodies directed against PD-L1 are well-kwon in the art, such as Atezolizumab (Roche), Avelumab (Merck/Pfizer) and Durvalumab (AstraZeneca).
- the immune checkpoint inhibitor is an antibody directed against CTLA-4.
- Antibodies directed against CTLA-4 are also known such as ipilimumab, tremelimumab, MK-1308, AGEN-1884, XmAb20717 (Xencor), MEDI5752 (AstraZeneca).
- the immune checkpoint inhibitor is an antibody directed against TIGIT.
- Antibodies directed against TIGIT are also known in the art, such as BMS-986207 or AB154, BMS- 986207 CPA.9.086, CHA.9.547.18, CPA.9.018, CPA.9.027, CPA.9.049, CPA.9.057, CPA.9.059, CPA.9.083, CPA.9.089, CPA.9.093, CPA.9.101, CPA.9.103, CHA.9.536.1, CHA.9.536.3, CHA.9.536.4, CHA.9.536.5, CHA.9.536.6, CHA.9.536.7, CHA.9.536.8, CHA.9.560.1, CHA.9.560.3, CHA.9.560.4, CHA.9.560.5, CHA.9.560.6, CHA.9.560.7, CHA.9.560.8, CHA.9.546.1, CHA.9.547.1, CHA.9.547.2, CHA.9.547.
- Anti-TIGIT antibodies are also disclosed in WO16028656, W016106302, W016191643, W017030823, W017037707, WO17053748, WO17152088, WO18033798, WO18102536,
- the immune checkpoint inhibitor is an antibody directed against TIM3.
- Antibodies directed against TIM3 are also known such as Sym023, TSR-022, MBG453, LY3321367, INCAGN02390, BGTB-A425, LY3321367, RG7769 (Roche).
- a TFM-3 antibody is as disclosed in International Patent Application Publication Nos. W02013006490, W02016/161270, WO 2018/085469, or WO 2018/129553, WO 2011/155607, U.S. 8,552,156, EP 2581113 and U.S 2014/044728.
- the immune checkpoint inhibitor is an antibody directed against LAG-3.
- Antibodies directed against LAG-3 are also known such as BMS- 986016, IMP701, MGD012 or MGD013 (bispecific PD-1 and LAG-3 antibody).
- Anti-LAG-3 antibodies are also disclosed in W02008132601, EP2320940 and W019152574.
- the immune checkpoint inhibitor is an antibody directed against B7-H3.
- B7- H3 also known as CD276 was originally understood to be a co-stimulatory molecule but is now regarded as co-inhibitory.
- a preferred checkpoint inhibitor of B7-H3 is the Fc- optimized monoclonal antibody Enoblituzumab (MGA271; MacroGenics; cf. US 201 2/0294796 A1 ).
- the immune checkpoint inhibitor is an antibody directed against 0X40.
- Checkpoint inhibitor of 0X40 include MEDI6469 (Medlmmune/AstraZeneca), MEDI6383 (Medlmmune/AstraZeneca), MEDI0562 (Medlmmune/AstraZeneca), MOXR091 6 (RG7888;
- the checkpoint inhibitor is a PD-1 inhibitor or an inhibitor that inhibits the interaction between PD-1 and PD-L1.
- such PD-1/PD-L1 inhibitor is selected from the group consisting of i) a peptide or peptidomimetic inhibiting PD-1/PD-L1 interaction such as AUNP-12, (D)-PPA 1, BMS202, hPRDX5 and a derivative, variant or analog thereof ii) a small molecule inhibiting PD-1/PD-L1 interaction such as molecules containing a sulfamonomethoxine or sulfamethizole scaffold and iii) an antibody anti-PD-1 or anti-PD-Ll such as disclosed above.
- a peptide or peptidomimetic inhibiting PD-1/PD-L1 interaction such as AUNP-12, (D)-PPA 1, BMS202, hPRDX5 and a derivative, variant or analog thereof
- a small molecule inhibiting PD-1/PD-L1 interaction such as molecules containing a sulfamonomethoxine or sulfamethizole
- PD-1/PD-L1 peptide-based and small molecule inhibitors are particularly provided in Tingkai Chen, et al, European Journal of Medicinal Chemistry (2016), in Sasikumar, P.G. and Ramachandra, M. BioDrugs 32, 481-497 (2016) and in Guzik K, Tomala M, Muszak D, et al. Molecules. 2019;24(11):2071, the teachings of which being incorporated by reference.
- the checkpoint inhibitor is AUNP-12 (also known as AUR-012, Aurigene-012, Aurigene NP-12) or a derivative, variant or analog thereof, for example such as described under CAS No. 1353563-85-5, and commercially available by Selleckchem under the reference Catalog No. S8549.
- AUNP-12 also known as AUR-012, Aurigene-012, Aurigene NP-12
- a derivative, variant or analog thereof for example such as described under CAS No. 1353563-85-5, and commercially available by Selleckchem under the reference Catalog No. S8549.
- the checkpoint inhibitor is (D)-PPA 1 or a derivative, variant or analog thereof, for example such as described under CAS No. 1620813-53-7 and commercially available by RnDSystems under the reference Catalog No. 6515/1.
- the checkpoint inhibitor is BMS202 or a derivative, variant or analog thereof, for example such as described under CAS No. 1675203-84-5 and commercially available by Selleckchem under the reference Catalog No. S791201.
- the checkpoint inhibitor is hPRDX5 and a derivative, variant or analog thereof, such as described in Sen Zou et al., Cancer Chemother Pharmacol. 2020 Jan;85(l):185-193.
- the checkpoint inhibitor is a small molecule inhibiting PD-1/PD-L1 interaction such as molecules containing a sulfamonomethoxine or suifamethizoie scaffold, for example such as provided below:
- the present invention relates to a combination comprising a Mcoln activator and a checkpoint inhibitor, to a pharmaceutical composition comprising a Mcoln activator and a checkpoint inhibitor and to a kit comprising a Mcoln activator and a checkpoint inhibitor.
- the Mcoln activators and immune checkpoint inhibitors described herein are all referred to as "active compounds” or “active ingredients” and are more particularly described here above under the respective paragraph.
- the combination or composition comprising a Mcoln activator and a checkpoint inhibitor may further comprise one or more pharmaceutically or physiologically acceptable carriers, diluents, excipients, salt, and anti-oxidant as described hereafter. It should be understood that when referring to a combination or composition, these terms are either directed to a single composition comprising both of the Mcoln activator and checkpoint inhibitor, or two compositions comprising the Mcoln activator or checkpoint inhibitor that are to be administered simultaneously, sequentially or separately.
- the present invention relates to a Mcoln activator or a pharmaceutical comprising it for use as a drug or to the use of a Mcoln activator or a pharmaceutical comprising it for the manufacture of a drug, or a pharmaceutical composition comprising a Mcoln activator.
- the Mcoln activator can be used in combination with an additional drug, pharmaceutically or physiologically acceptable carrier, diluent, excipient, salt, and anti-oxidant as described hereafter.
- the Mcoln activator is used in combination with an immune checkpoint inhibitor.
- the present invention also relates to an immune checkpoint inhibitor or a pharmaceutical comprising it for use as a drug or to the use of an immune checkpoint inhibitor or a pharmaceutical comprising it for the manufacture of a drug, or a pharmaceutical composition comprising an immune checkpoint inhibitor.
- the immune checkpoint inhibitor can be used in combination with an additional drug, pharmaceutically or physiologically acceptable carrier, diluent, excipient, salt, and anti-oxidant as described hereafter.
- the immune checkpoint inhibitor is used in combination with a Mcoln activator.
- the combination or the pharmaceutical composition comprises 30%, 40%, 50%, 60%, 70%, 80%, 90% of a Mcoln activator for 100% by weight of the total combination or composition, or for 100% by weight of the sum of the Mcoln activator and the immune checkpoint inhibitor.
- the combination or the pharmaceutical composition comprises 30%, 40%, 50%, 60%, 70%, 80%, 90% of an immune checkpoint inhibitor for 100% by weight of the total combination or composition, or for 100% by weight of the sum of the Mcoln activator and the immune checkpoint inhibitor.
- the combination or the pharmaceutical composition comprises 50% of an immune checkpoint inhibitor and 50% of a Mcoln activator for 100% by weight of the sum of the Mcoln activator and the immune checkpoint inhibitor.
- the combination or the pharmaceutical composition comprises 50% of a PD-1/PD-L1 inhibitor, preferably an anti-PD-1 antibody, and 50% of a Mcoln activator, preferably ML-SA1, for 100% by weight of the sum of the Mcoln activator and the immune checkpoint inhibitor.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect.
- the pharmaceutical composition comprising the Mcoln activator and the checkpoint inhibitor may be formulated in accordance with standard pharmaceutical practice known by a person skilled in the art. For example, such as disclosed in Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York.
- the combination or pharmaceutical composition of the invention may further comprise one or more pharmaceutically acceptable carriers and excipients which do not deleteriously interact with the Mcoln activator and the immune checkpoint inhibitor "pharmaceutically acceptable" as referred to herein, is any known compound or combination of compounds that are known to those skilled in the art to be useful and suitable in formulating pharmaceutical compositions.
- the combination or pharmaceutical composition of the invention may further comprise one or more pharmaceutically acceptable salts.
- a "pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts.
- Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
- nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
- nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
- Base addition salts include those derived from alkaline metals or alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N- methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
- the combination pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant.
- pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetra-acetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxy
- the Mcoln activator and the checkpoint inhibitor according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle or carrier such as water, an organic solvent, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like a mixture of both or pharmaceutically acceptable oils or fats and suitable mixtures thereof.
- a pharmaceutically acceptable liquid vehicle or carrier such as water, an organic solvent, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like a mixture of both or pharmaceutically acceptable oils or fats and suitable mixtures thereof.
- the liquid vehicle can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, wetting agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- the pharmaceutical composition according to the invention can be formulated for any conventional route of administration including a topical, enteral, oral, parenteral, intranasal, intravenous, intra arterial, intramuscular, intra-tumoral, subcutaneous or intraocular administration and the like.
- a topical, enteral, oral, parenteral, intranasal, intravenous, intra arterial, intramuscular, intra-tumoral, subcutaneous or intraocular administration and the like The man of the art knows how to select the most appropriate vehicles and excipients for the preparation of a given type of formulation.
- the composition can be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules and liquid preparations such as syrups, elixirs, and concentrated drops.
- Nontoxic solid carriers or diluents may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
- binders which are agents which impart cohesive qualities to powdered materials, are also necessary.
- starch, gelatin, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders.
- Disintegrants are also necessary in the tablets to facilitate break-up of the tablet.
- Disintegrants include starches, clays, celluloses, algins, gums and crosslinked polymers.
- lubricants and glidants are also included in the tablets to prevent adhesion to the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material during manufacture.
- Colloidal silicon dioxide is most commonly used as a glidant and compounds such as talc or stearic acids are most commonly used as lubricants.
- composition can be formulated into ointment, cream or gel form and appropriate penetrants or detergents could be used to facilitate permeation, such as dimethyl sulfoxide, dimethyl acetamide and dimethylformamide.
- nasal sprays for transmucosal administration, nasal sprays, rectal or vaginal suppositories can be used.
- the active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or dissolution rate.
- water combination or composition can be administered by the drip method, whereby a Mcoln activator and a checkpoint inhibitor and a physiologically acceptable excipients are infused.
- Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients.
- Intramuscular preparations e.g., a sterile formulation of a suitable soluble salt form of the antibody, can be dissolved and administered in a pharmaceutical excipient such as Water-for-lnjection, 0.9% saline, or 5% glucose solution.
- the combination or pharmaceutical composition according to the invention is preferably administered by intravenous route of administration.
- the combination or pharmaceutical composition according to the invention is preferably administered by oral route of administration. This composition can also be administered locally.
- Combination and pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.
- the combination or pharmaceutical composition in some aspects can employ time-released, delayed release, and sustained release delivery systems such that the delivery of the composition occurs prior to, and with sufficient time to cause, sensitization of the site to be treated. Means known in the art can be used to prevent or minimize release and absorption of the composition until it reaches the target tissue or organ, or to ensure timed-release of the composition. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician.
- compositions according to the invention can comprise one or more molecule of the present invention associated with pharmaceutically acceptable excipients and/or carriers. These excipients and/or carriers are chosen according to the form of administration as described above.
- Combination and pharmaceutical composition according to the invention typically must be sterile and stable under the conditions of manufacture and storage.
- Sterile injectable solutions can be prepared by incorporating the active ingredients in the required amount in an appropriate solvent with one or a combination of additional ingredients enumerated above, as required, followed by sterilization microfiltration.
- the present invention further relates to a method for selecting or identifying a combination of molecules suitable for the treatment of cancer, in particular for reducing tumor growth and/or size.
- Such method particularly comprises determining the effect of a molecule on the activity of Mcoln and selecting the molecule if it increases the activity of Mcoln.
- the method further comprises the combination of such molecule with a checkpoint inhibitor, and a step of determining the effect of the selected combination on tumor size and/or growth, and selecting the combination if it decreases tumor growth and/or size.
- Such a screening method is disclosed for Mcoln-1 in US2003/064363.
- the invention relates to a method of selecting a suitable combination of a Mcoln activator and a checkpoint inhibitor, for use in a subject suffering from cancer, comprising or consisting of at least one of the following steps:
- the most suitable immune checkpoint inhibitor treatment in particular an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2), such agent being preferably an antibody;
- step 4) optionally assessing the effect of the combination of step 3) on tumor size and/or growth, and
- the invention relates to a method of selecting a suitable combination of a Mcoln activator and a checkpoint inhibitor, for use in a subject suffering from cancer, comprising or consisting of at least one of the following steps:
- an immune checkpoint such as PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40
- Mcoln activator from the group consisting of i) a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83 and a derivative or analog thereof, ii) an agonist antibody directed against Mcoln and iii) a chemical compound having an activating activity on Mcoln such as phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2);
- step 4) optionally assessing the effect of the combination of step 3) on tumor size and/or growth,
- the invention relates to a method of preparing a combination of a Mcoln activator and a checkpoint inhibitor, comprising or consisting of at least one of the following steps:
- Mcoln activator from the group consisting of i) a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83 and a derivative or analog thereof, ii) an agonist antibody directed against Mcoln and iii) a chemical compound having an activating activity on Mcoln such as phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2).
- step 3) combining the molecule selected in lb) and 2), in particular with pharmaceutical acceptable excipients and/or carriers, 4) optionally assessing the effect of the combination of step 3) on tumor size and/or growth,
- the tumor sample of the patient may be obtained by biopsy or resection.
- the biopsy technique applied will depend on the tissue type to be evaluated, the size and type of the tumor, among other factors.
- Representative biopsy techniques include, but are not limited to, excisional biopsy, incisional biopsy, needle biopsy, surgical biopsy, and bone marrow biopsy.
- An "excisional biopsy” refers to the removal of an entire tumor mass with a small margin of normal tissue surrounding it.
- An “incisional biopsy” refers to the removal of a wedge of tissue that includes a cross-sectional diameter of the tumor.
- cancer sample or "tumor sample”, as used herein, means any sample containing tumor cells and cancer stromal cells derived from a subject suffering from cancer.
- Cancer tissues are particularly composed of cancer cells and the surrounding cancer stromal cells, including vascular endothelial cells, and immune cells, in addition to the extracellular matrix.
- the cancer sample contains nucleic acids and/or proteins. The sample may be treated prior to its use.
- the gene expression profile of a patient suffering from cancer is assed and compared between a cancer sample and a histologically matched normal sample from the same patient.
- the subject has previously been diagnosed as suffering from cancer.
- diagnosis refers to the determination as to whether a subject is likely to be affected by a cancer.
- diagnosis markers the presence, absence, or amount of which is indicative of the presence or absence of the cancer.
- Methods for determining the expression profile of a patient suffering from cancer and measuring expression level of immune checkpoint are known in the art.
- the methods based on the assessment of quantity of mRNA are well known in the art and include, but are not limited to, quantitative or semi-quantitative RT-PCR, real time quantitative or semi-quantitative RT-PCR.
- Other methods include, but are not limited to, ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA) and nucleic acid sequence-based amplification (NASBA).
- LCR ligase chain reaction
- TMA transcription-mediated amplification
- SDA strand displacement amplification
- NASBA nucleic acid sequence-based amplification
- the quantity of mRNA may be measured using the Nanostring's NCOUNTERTM Digital Gene Expression System (Geiss et al. 2008 Nat. Biotechnol. 26:317-325) which captures and counts individual mRNA transcripts by a molecular bar-coding technology and is commercialized by Nanostring Technologies, or the QuantiGene ® Plex 2.0 Assay (Affymetrix).
- the quantity of mRNA may alternatively be determined using approaches based on high-throughput sequencing technology such as RNA-Seq (Wang et al. Nat Rev Genet. 2009 January; 10(1): 57-63) or sequencing technologies using microfluidic systems or transcriptome approaches. Next Generation Sequencing methods (NGS) may also be used.
- NGS Next Generation Sequencing methods
- compositions comprising both of the Mcoln activator and checkpoint inhibitor or two compositions comprising the Mcoln activator or checkpoint inhibitor that are to be administered simultaneously, sequentially or separately, such as described above.
- the present invention particularly relates to a composition or combination comprising an activator of mucolipin (Mcoln or TRPML) and an immune checkpoint inhibitor for use in the treatment of a cancer in a subject.
- an activator of mucolipin Mcoln or TRPML
- an immune checkpoint inhibitor for use in the treatment of a cancer in a subject.
- the invention also relates to the use of a combination or a pharmaceutical composition comprising a Mcoln activator and a checkpoint inhibitor in the manufacture of a medicament for treating a disease and/or disorder in a subject, in particular cancer.
- the invention also provides a method of treating a cancer, for instance of inhibiting growth of tumor cells, in a subject, in particular a subject having a cancer, comprising administering to the subject a therapeutically effective amount of the combination or pharmaceutical composition according to the invention.
- the present invention relates to the treatment of a subject using the combination or pharmaceutical composition according to the invention such that growth of cancerous cells is inhibited.
- a patient suffering from cancer comprising: (a) identifying a patient in need of treatment; and (b) administering to the patient a therapeutically effective amount of the combination or pharmaceutical composition described herein.
- the invention relates to a method of treatment of a pathology, disease and/or disorder, in particular such as cancer that could be prevented or treated by the inhibition of the binding of PD- L1 and/or PD-L2 to PD-1.
- the invention relates to a method of treatment of a pathology, disease and/or disorder, in particular such as cancer, in which the subject has a mutated or deficient TFEB (Transcription factor EB, UniProtKB - P19484) or a mutated or deficient Mcoln, e.g. Mcoln-1.
- TFEB Transcription factor EB, UniProtKB - P19484
- Mcoln e.g. Mcoln-1.
- the subject in need of a treatment may be a human having, at risk for, or suspected of having a disease associated with the signaling pathway mediated by PD-1/PD-L1.
- a patient can be identified by routine medical examination.
- a subject suitable for the treatment can be identified by examining whether such subject carries PD-1, PD-L1 and/or PD-L2 positive cells.
- a subject who needs a treatment is a patient having, suspected of having, or at risk for a disease, preferably a PD-1, PDL1 and/or PDL2 positive disease, even more preferably a disease where PD-1 and/or at least one ligand of PD-1 is overexpressed.
- the combination or pharmaceutical composition described herein can be used for treating PD-1 positive cells.
- the invention relates to a method of treatment of a pathology, disease and/or disorder, in particular such as cancer that could be prevented or treated by the inhibition of the binding of CTLA- 4 to CD80 or CD86.
- the subject in need of a treatment may be a human having, at risk for, or suspected of having a disease associated with the signaling pathway mediated by CTLA-4.
- a patient can be identified by routine medical examination.
- a subject suitable for the treatment can be identified by examining whether such subject carries CTLA-4, CD80 and/or CD86 positive cells.
- a subject who needs a treatment is a patient having, suspected of having, or at risk for a disease, preferably a CTLA-4, CD80 and/or CD86 positive disease, even more preferably a disease where CTLA-4 is overexpressed.
- the combination or pharmaceutical composition described herein can be used for treating CTLA-4 positive cells.
- the invention particularly provides a method of reducing the growth and/or the size of a tumor in a subject, comprising administering to the subject a therapeutic effective amount of a combination or composition such described herein, such that the tumor in the subject is reduced or its growth limited or decreased.
- the amount of the combination or composition according to the invention is effective in inhibiting or reducing the tumor size or growth, in particular by at least 10%, 20%, 30%, 40%, 50%, 80% or 100% as compared to a control.
- the combination or composition according to the invention is effective in inhibiting or reducing the tumor size or growth by 40 % as compared to a control.
- the control can be a tumor that have not been treated, a tumor that has been treated by a Mcoln activator only, or with a checkpoint inhibitor only.
- the combination or pharmaceutical composition described herein can be administered to a subject, e.g., in vivo, to enhance immunity, preferably in order to treat a disorder and/or disease such as cancer.
- a subject e.g., in vivo
- the immune response is enhanced, increased, stimulated or up-regulated.
- the immune response enhancement can result in the inhibition of the binding of the immune checkpoint inhibitor to its receptor or ligand, thereby reducing the immunosuppressive environment around the tumor. Additional Therapy
- the combination or composition according to the invention can be used in further combination with another therapeutic agent, especially another anticancer treatment.
- the anticancer treatment can be surgery, radiotherapy, chemotherapy, immunotherapy or hormone therapy.
- Such anticancer treatment may be administered simultaneously or chronologically staggered, that is at different time points, from the combination or composition according to the invention.
- chemotherapy refers to a cancer therapeutic treatment using chemical or biochemical substances, in particular using one or several antineoplastic agents.
- immunotherapy refers to a cancer therapeutic treatment including with therapeutic antibodies.
- antibodies are directed against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.
- specific antigens such as the unusual antigens that are presented on the surfaces of tumors.
- therapeutic antibodies functions to deplete tumor cells in a patient.
- therapeutic antibodies specifically bind to antigens present on the surface of the tumor cells, e.g. tumor specific antigens present predominantly or exclusively on tumor cells.
- therapeutic antibodies may also prevent tumor growth by blocking specific cell receptors.
- hormone therapy refers to a cancer treatment having for purpose to block, add or remove hormones.
- estrogen and progesterone can promote the growth of some breast cancer cells. So, in these patients, hormone therapy is given to block estrogen and a non-exhaustive list commonly used drugs includes: Tamoxifen, Fareston, Arimidex, Aromasin, Femara, Zoladex/Lupron, Megace, and Flalotestin.
- the additional therapeutic agent can be selected in the non-exhaustive list comprising alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-2 family inhibitors), activators of death receptor pathway, antibody drug conjugates, biologic response modifiers, Bruton's tyrosine kinase (BTK) inhibitors, cyclin-dependent kinase inhibitors, cell cycle inhibitors, growth factor inhibitors, heat shock protein inhibitors, histone deacetylase (FIDAC) inhibitors, hormonal therapies, inhibitors of inhibitors of apoptosis proteins (lAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, microRNAs, non-steroidal anti-inflammatory drugs (NSAIDs), platinum chemotherapeutics, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor
- the additional therapeutic agent is an additional checkpoint inhibitor, for example an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, 0X40 L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIG IT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2), or any combination thereof.
- an additional checkpoint inhibitor for example an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, 0X40 L, GITR, HVE
- the additional therapeutic agent can be selected from the group consisting of an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim 3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIG IT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2) and any combination thereof.
- composition or combination according to the invention may be administered as part of the anticancer treatment.
- the composition or combination according to the invention may be administered to the patient before and/or after radiation or surgery to reduce the size of a tumor.
- the present invention relates to a combination of a Mcoln activator and an immune checkpoint inhibitor, a pharmaceutical composition comprising such, for use as a medicament, particularly for use in the prevention or treatment of a disease such as cancer. It also relates to the use of combination or a pharmaceutical composition of the present invention in the manufacture of a medicament for treating a cancer in a subject. Finally, it relates to a method for treating a cancer in a subject comprising administering a therapeutically effective amount of a combination or pharmaceutical composition according to the invention to the subject. Examples of treatments are more particularly described hereafter under the section "Methods and Uses".
- the subject under consideration may be a mammal, in particular any animal subject such as a laboratory animal (e.g. non-human primate, rat, mouse, hamster, guinea pig), livestock (e.g. cow, sheep, goat, pig, turkey and chicken) or a domestic species (e.g. dog, cat and rodent), in particular a human.
- a laboratory animal e.g. non-human primate, rat, mouse, hamster, guinea pig
- livestock e.g. cow, sheep, goat, pig, turkey and chicken
- a domestic species e.g. dog, cat and rodent
- the subject to treat may be a human, particularly a human at the prenatal stage, a new-born, a child, an infant, an adolescent or an adult, in particular an adult of at least 30 years old, 40 years old, preferably an adult of at least 50 years old, still more preferably an adult of at least 60 years old, even more preferably an adult of at least 70 years old.
- the patient has already received at least one line of treatment, in particular one line of treatment, two lines of treatment or three lines of treatment or more, preferably several lines of treatment.
- the patient has not received any treatment.
- the subject was heavily pre-treated and even more preferably the subject exhausted therapeutic options.
- the patient has already received at least one line of treatment, in particular a checkpoint inhibitor, and is a poor responder to such treatment.
- a subject who needs a treatment or is treated is a patient having a cancer, suspected of having a cancer, or at risk of having a cancer.
- the subject is affected with a cancer that may involve the PD-l/PDL-1 pathway, particularly wherein, at least one of the ligands of PD-1 (e.g. PDL-1 and/or PDL-2) or PD-1 is/are expressed, especially overexpressed.
- PD-1 e.g. PDL-1 and/or PDL-2
- the subject is suffering from cancer, even more preferably from a PD1, PD-L1 and/or PD-L2 positive cancer or a PD-1 positive cancer.
- the subject is affected with a cancer that may involve the CTLA-4 pathway, particularly wherein, CTLA-4 is expressed, especially overexpressed.
- the subject is suffering from cancer, even more preferably from a CTLA-4 positive cancer.
- compositions of the present invention can be adjusted by the man skilled in the art according to the type and severity of the infection, and to the patient, in particular its age, weight, sex, and general physical condition.
- compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired.
- the Mcoln activator preferably ML-SA1 is administered at a dose of between 1 and 20 mg/kg, 1 and 15 mg/kg, 1 and 10 mg/kg, preferably between 5 and 10 mg/kg, even more preferably about 10 mg/kg.
- the checkpoint inhibitor preferably a PD-1/PD-L1 inhibitor, even more preferably an anti-PD-1 antibody is administered at a dose of between 1 and 20 mg/kg, 1 and 15 mg/kg, 1 and 10 mg/kg, preferably between 5 and 10 mg/kg, even more preferably about 10 mg/kg.
- the checkpoint inhibitor preferably CTLA-4 inhibitor, even more preferably an anti- CTLA-4 antibody is administered at a dose of between 1 and 20 mg/kg, 1 and 15 mg/kg, 1 and 10 mg/kg, preferably between 5 and 10 mg/kg, even more preferably about 10 mg/kg.
- combination or composition according to the invention may be administered as a single dose or in multiple doses.
- combination or composition according to the invention is to be administered in separate doses, that is to say that the Mcoln activator is comprised in a dose and the checkpoint inhibitor in a separate dose.
- the treatment starts no longer than a month, preferably no longer than a week, after the determination of the expression profile of the patient suffering from cancer, to determine the most suitable checkpoint inhibitor to use, in particular using a method such as disclosed herein.
- the treatment with the combination or composition according to the invention is administered regularly, preferably between every day, every week or every month, more preferably between every day and every one, two, three or four weeks.
- the treatment with the combination or composition according to the invention is administered every two days.
- the treatment is administered several times a day, preferably 2 or 3 times a day.
- the Mcoln activator preferably ML-SA1
- the checkpoint inhibitor preferably a PD-1/PD-L1 inhibitor or a CTLA-4 inhibitor, even more preferably an anti-PD-1, anti-PD-Ll or anti-CTLA-4 antibody is administered every four days.
- the duration of treatment is preferably comprised between 1 day and 20 weeks, more preferably between 1 day and 10 weeks, still more preferably between 1 day and 4 weeks, even more preferably between 1 day and 3 weeks. In a very particular embodiment, the treatment lasts three weeks. Alternatively, the treatment may last as long as the disease persists.
- the invention provides a combination or a pharmaceutical composition comprising a Mcoln activator and a checkpoint inhibitor for use in the treatment of a subject having a cancer, comprising administering to the individual an effective amount of the combination or pharmaceutical composition.
- the invention provides a combination or a pharmaceutical composition comprising a Mcoln activator and a checkpoint inhibitor for use in the treatment of a subject having a disease or disorder associated with an altered TFEB or Mcoln pathway, in particular a mutated or deficient TFEB (Transcription factor EB, UniProtKB - P19484) or a mutated or deficient Mcoln, e.g. Mcoln-1, and/or a disease or disorder that can be improved by increasing the migration of immune cells.
- a mutated or deficient TFEB Transcription factor EB, UniProtKB - P19484
- Mcoln-1 mutated or deficient Mcoln
- the cancer is a solid tumor such as sarcoma, carcinoma, and lymphoma.
- the cancer is selected among a carcinoma, a sarcoma, a leukemia, a lymphoma, a blastoma and a melanoma, preferably a sarcoma, carcinoma and melanoma.
- the cancer is preferably a solid tumor or a hematopoietic malignancy.
- the cancer may be selected from the non-exhaustive list comprising chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), or chronic lymphocytic leukemia.
- chronic myeloid leukemia acute lymphoblastic leukemia
- Philadelphia chromosome positive acute lymphoblastic leukemia Ph
- the cancer is selected from the list consisting of lung cancer, breast cancer, melanoma, colon and/or rectum cancer, renal cancer, prostate cancer, pancreas cancer and cervix/ovary cancer.
- the cancer is colon cancer.
- the invention provides a combination or a pharmaceutical composition comprising a Mcoln activator and a PD-1/PD-L1 inhibitor for use in the treatment of a subject having a cancer, comprising administering to the individual an effective amount of the Mcoln activator and the PD-1/PD-L1 inhibitor.
- a subject who needs a treatment or is treated is a patient having cancer, suspected of having cancer, or at risk of having cancer, in particular a PD-1 or PD-L1 positive cancer, even more preferably a cancer where PD-1 or PD-L1 is expressed or overexpressed.
- a patient suitable for the treatment can be identified by examining the gene expression profile of the patient and/or whether such a patient carries PD-L1 positive tumor cells.
- PD-L1 positive tumor cells or "PD-L2 positive tumor cells” is intended to refer to a population of tumor cells in which PD-L1 or PD-L2, respectively, are expressed in at least 10% of tumor cells, preferable at least 20, 30, 40 or 50 % of tumor cells.
- the subject suitable for the treatment is a subject having tumor infiltrating T cells that express or overexpress PD-1.
- the present invention is also useful for treatment of metastatic cancers, especially metastatic cancers that express PD-L1 (Iwai et al. (2005) Int. Immunol. 17: 133-144).
- the cancer is a CTLA-4 positive cancer.
- a subject who needs a treatment or is treated is a patient having cancer, suspected of having cancer, or at risk of having cancer, in particular a CTLA-4 positive cancer, even more preferably a cancer where CTLA-4 is expressed or overexpressed.
- a patient suitable for the treatment can be identified by examining the gene expression profile of the patient and/or whether such a patient carries CTLA-4 cells, in particular having tumor infiltrating T cells that express or overexpress CTLA-4.
- the cancer is a cancer with high probability or risk of metastasis. In particular, it could be a primary cancer associated with lymph node invasion by tumor cells.
- kits comprising the combination or composition according to the invention, in particular such as described here above.
- kits comprising the combination or composition according to the invention, for use in the treatment of cancer, particularly for reducing tumor growth and/or size.
- the invention thus also has as its object a kit comprising the combination of a Mcoln activator and a checkpoint inhibitor, said kit being adapted to subjects suffering from cancer.
- the kit(s) may be tailored to a particular cancer for an individual, the Mcoln activator and the checkpoint inhibitor being chosen for example by the method provided herein.
- said kit comprises i) a composition comprising a Mcoln activator and a checkpoint inhibitor or ii) a composition comprising a Mcoln activator, and a composition comprising a checkpoint inhibitor.
- said kit comprises 1) a composition comprising the Mcoln activator, and 2) a composition comprising a PD-1 checkpoint inhibitor, preferably an anti-PDl antibody.
- a combination kit comprising i) the Mcoln activator, preferably in association with a pharmaceutically acceptable carrier; and ii) the checkpoint inhibitor, preferably in association with a pharmaceutically acceptable carrier.
- the kit comprises i) MLS-A1 preferably in association with a pharmaceutically acceptable carrier; and ii) an anti PD-1 antibody, an anti-PD-Ll antibody or a CTLA-4 antibody, preferably in association with a pharmaceutically acceptable carrier.
- the combination kit comprises: a first container comprising a Mcoln activator such as disclosed herein, preferably in association with a pharmaceutically acceptable carrier; and a second container comprising a checkpoint inhibitor such as disclosed herein, preferably in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
- the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
- the invention relates to a kit as defined above for a single-dose administration unit.
- the kit of the invention may also contain a first recipient comprising a dried/lyophilized Mcoln activator and/or immune checkpoint inhibitor and a second recipient comprising an aqueous formulation.
- kits containing single-chambered and multi-chambered pre filled syringes e.g., liquid syringes and lyosyringes are provided.
- compositions comprised in the kit according to the invention may also be formulated into a syringe compatible composition.
- the container means may itself be a syringe, pipette, or the like.
- kits of this invention are in suitable packaging.
- suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like.
- the components of the kit are provided in a form which is suitable for sequential, separate and/or simultaneous administration.
- the kit can also be provided by instruction, such as dosage and administration instructions.
- dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
- the kit further includes an additional agent for treating cancer, and the additional agent may be combined with the combination or composition according to the invention, or other components of the kit of the present invention or may be provided separately in the kit.
- the kits described herein may include one or more additional therapeutic agents such as those described in the "Additional Therapy" described here above.
- compositions present in the kit are similar to those of the composition according to the invention, particularly in terms of the mass ratio of Mcoln activator and the checkpoint inhibitor to each other.
- composition present in the kit may comprise one or more additional ingredients selected from the additional pharmaceutically acceptable carrier, additives, excipients and active ingredients as described above.
- Figure 1 Lack of ML-SA1 toxicity in vivo (no mouse weight fluctuation).
- Figure 2 Impact of ML-SA1 alone (10 mg/Kg) or in combination with anti-PDl antibody (10 mg/Kg) on MC38 tumor growth in C57BL/6 mice.
- Figure 3 Impact of ML-SA1 (10 mg/Kg) with/without anti-PDl antibody (10 mg/Kg) on MC38 tumor growth in irradiated C57BL/6 mice reconstituted with WT or TRPMLl KO bone marrows.
- Figure 4 Impact of MLSA1 (10 mg/Kg) and MLSA5(5 or 10 mg/Kg) on B16-OVA tumor growth in CBL/6 mice.
- ML-SA1 and MLSA5 were dissolved in DMSO at 20 mg/ml and stored at -80°C.
- the solutions were prepared by diluting ML-SA1/MLSA5 in 1 mg/ml PBS.
- the solutions contained 30% propylene glycol, 30% polyethylene glycol 300, 35% PBS and 5% ML-SA1/MLSA5 at 20 mg/ml.
- mice are injected with MC38 or B16-OVA cancer cells subcutaneously, in the flank (5x10 s cells in a volume of IOOmI of PBS). As soon as the tumors were palpable (typically 6 days for MC38 or 7 days for B16-OVA upon tumor cell injection), mice are injected four times a week over 15/16 days with ML- SA1/MLSA5 at 5mg/Kg or 10 mg/kg. In MC38 model, mice also received two injections per week of anti-PDl antibody (Mouse anti-PDl (clone RMP1-14, BioXcell)) at 10 mg/kg. ML-SA1 and anti-PDl injections are done intraperitoneally.
- anti-PDl antibody Mae anti-PDl (clone RMP1-14, BioXcell)
- Tumors are measured every two days starting from day 6 for MC38 and day 7 for B16+OVA. Mice were sacrificed 15/20 days after tumor cell injection, tumors and tumor-draining lymph nodes were dissected, digested and analyzed by flow cytometry for immune cell infiltration.
- the inventors were able to show that activation of TRPML1 by the small molecule ML-SA1 leads to decreased tumor growth in the presence of the anti-checkpoint inhibitor anti-PDl in vivo. This observation was made using the MC38 tumor model, which originates from a murine colon carcinoma. This model was chosen because anti-PDl antibody had limited effect in this model, allowing to have a window of improvement with ML-SA1.
- mice were randomized and divided in 4 groups of 8 mice, and treaded as follows:
- mice were injected with PBS.
- mice were injected every 2 days with ML-SA1 (lOmg/kg, intraperitoneally).
- mice were injected with anti-PDl antibody every 4 days (at lOmg/kg, intraperitoneally in all experiments throughout the project).
- mice were injected with both ML-SA1 and anti-PDl antibody at the same dose and frequency than in Groups 2 & 3.
- Anti-PDl antibody had very little effect on tumor growth in these settings, as expected for this tumor cell line.
- ML-SA1 showed no effect when injected alone.
- combination of anti-PDl antibody and ML-SA1 decreased tumor growth by approximately 40%.
- mice that had been irradiated and repopulated with bone marrow from TRPML1WT or TRPML1KO animals (for 2.5 months). These animals therefore have or not a TRPML1 deficiency restricted to their bone-marrow-derived immune cells, including DCs, T cells, B cells, NK cells and monocyte-derived cells. Reconstitution with both types of bone marrow was equally efficient, as shown by flow cytometry on lymph node-resident immune cells. 6 groups of 8 mice were treated in the following conditions:
- Group 1 TRPML1WT injected with PBS.
- Group 2 TRPML1WT injected with anti-PDl antibody.
- TRPML1WT mice perfectly reproduce the results described above in 2): while anti-PDl antibody has little effect on MC38 tumor growth, combining this antibody with ML-SA1 reduced tumor growth by approximately 40%.
- the second conclusion is that ML-SA1 decreases tumor growth by targeting TRPML1 in immune cells rather than in other cells, as there is no effect of this small molecule in mice exhibiting a TRPML1KO immune system. This further demonstrates the specificity of ML-SA1 for TRPML1.
- TRPML1 helps immune cells limiting tumor growth and 2) stimulation of TRPML1 activity in vivo enhances the efficiency of anti-PDl immunotherapy.
- B16-OVA cells melanoma
- 10 s B16-OVA cells were injected subcutaneously in 2-month old female C57BL/6 mice and after 7 days (when tumors were visible), mice were randomized and divided in 4 groups of 10 mice, and treaded as follows
- mice were treated on day 7 upon tumor injection (time at which the inventors start palpating tumors). Injections were made on days 7, 8, 10, 11, 13 and 14). Injections were made intra-peritoneally.
- ML-SA5 at 10 mg/Kg clearly inhibited B16-OVA tumor growth and showed a stronger effect on the tumor size than ML-SA1 lOmg/Kg, more precisely with a 2 fold increase.
- MLSA1 lOmg/kg showed similar results to MLSA5 5mg/kg, suggesting that MLSA5 is more potent than MLSA1 in inhibiting tumor growth.
- Task 1.1 Optimizing the dose of ML-SA1 in the MC38 model
- mice have injected mice with the ML-SA1 dose of lOmg/kg every 2 days, starting on day 5 upon tumor injection (time at which the inventors start palpating tumors).
- This dose was chosen based on the solubility of ML-SA1 and the toxicity analysis (see figure 1). However, lower doses are to be tested. Indeed, this is important to envision transposition to the clinic, for which the minimal active dose of ML-SA1 must be known. This one will also be more suited to decipher the molecular mechanism of ML-SA1.
- mice transplanting 10 s MC38 tumor cells in female C57BL/6 mice, and measuring tumors every 2 days. All injections are made intra-peritoneally.
- ML-SA1 dose 0.5, 1 or 5 mg/kg
- the 3 following conditions are tested, preferably with 8 mice per group:
- the inventors also test whether enhancing the amount of ML-SA1 administered to mice can increase its synergistic effect with anti-PDl antibodies or even show an effect of the drug on its own. Indeed, preliminary results indicating that tumors grow faster in TRPML1KO mice suggest that ML-SA1 could maybe have an effect alone if administered at higher dose. However, the solubility of this compound prevents from using higher concentrations. The inventors therefore address this question by enhancing the frequency of injections, adding the two following groups of mice:
- mice from groups 1 & 2 are sacrificed 3 weeks after tumor injection.
- mice treated with ML- SA1 plus anti-PDl antibody, which should decrease tumor growth, are maintained further to evaluate how long-lasting can be the effect of these combined therapies.
- ML-SA1 optimized on the MC38 model
- these models include the colon adenocarcinoma MCA205, which responds to anti-checkpoint therapy and the B16-F10 melanoma cell line, which is resistant to anti- PDl.
- Experiments are performed using the four groups of mice described in Task 1.1. All tumors are implanted in female C57BL/6 mice (10 s cells/mouse, already optimized), and tumor size are measured every two days. Mice are sacrificed between 2 and 3 weeks after tumor injection, depending on the size of the tumor in respect with the animal ethical rules.
- Task 1.3 Evaluating the impact of ML-SA1 on tumor growth in combination with other anticheckpoint inhibitors than anti-PDl
- anti-PD-Ll and anti-CTLA4 inhibitors The inventors perform similar experiments but comparing the combination of ML-SA1 with two other anti-checkpoint inhibitors having different mode of actions than anti-PDl inhibitors: anti-PD-Ll and anti-CTLA4 inhibitors.
- anti-PD-Ll antibodies have been described to have an effect on tumor growth by a mechanism involving glucose metabolism, independently from its interaction with PD-1.
- Anti-CTLA4 antibodies have been proposed to act on tumor growth by targeting regulatory lymphocytes (Tregs). The inventors therefore evaluate if these two additional anti-checkpoint antibodies can synergize with ML-SA1 in different ways as compared to anti-PDl antibodies.
- these experiments may be informative on the mechanism by which TRPML1 activation by ML-SA1 can decrease tumor growth.
- the optimal dose of ML-SA1 defined above is used (Task 1.1) and the tumor cell lines whose growth is the most inhibited by this dose of ML-SA1 in combination with anti- PDl (Task 1.2).
- mice 4 groups of 8 mice are treated in the following conditions:
- - Group 2 Mice injected with ML-SA1.
- - Group 3 Mice are injected with anti-PDLl antibody or anti-CTLA4 antibody (1 intra-peritoneal injection every 4 days at lOmg/kg, as for anti-PDl).
- Task 1.4 Evaluating the impact of ML-SA5 on tumor growth in combination with anti-PDl inhibitors or in combination with other anti-checkpoint inhibitors than anti-PDl
- the inventors perform similar experiments but comparing the combination of ML-SA5 with an anti- PDl inhibitors, anti-PD-Ll and/or anti-CTLA4 inhibitors on different tumor models (for example such as B16-OVA and MC38).
- the inventors define the optimal dose of ML-SA5 in combination with an anti-PDl inhibitors, anti-PD- Ll and/or anti-CTLA4 inhibitors.
- mice 4 groups of 8 mice are treated in the following conditions:
- Group 3 Mice are injected with anti-PDl antibody, anti-PDLl antibody or anti-CTLA4 antibody (1 intra-peritoneal injection every 4 days at lOmg/kg, as for anti-PDl).
- ML-SA5 is more effective than ML-SA1, it is believed that the combination with the immune checkpoint inhibitor is also more effective on the reduction of the tumor.
- the inventors have injected mice with the ML-SA5 dose of 5 or lOmg/kg. However, lower doses are to be tested. Indeed, this is important to envision transposition to the clinic, for which the minimal active dose of ML-SA5 must be known. Tests are to be performed in a similar manner as described in Task 1.1 for ML-SA1.
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Abstract
The present invention relates to a composition or combination comprising an activator of mucolipin channel (Mcoln) and an immune checkpoint inhibitor and uses thereof, in particular for treating cancer.
Description
Combination of Mcoln activators and immune checkpoint inhibitors
Field of the Invention
The present invention relates to the field of medicine, in particular to the field of oncology.
Background of the Invention
Dendritic cells (DCs) initiate adaptive immune responses by carrying information from peripheral tissues -which are often exposed to external threats- to lymph nodes, through which T lymphocytes circulate. At the immature stage, DCs sample the interstitial space of tissues by internalizing important amounts of extracellular material. Upon encountering danger signals, they enter into a "maturation program" that down-regulates antigen internalization and promotes fast DC migration to lymph nodes for antigen presentation to T lymphocytes. This process is strictly needed for the establishment of adaptive immune responses.
Recent findings have highlighted the essential role of DCs in anti-tumor immunity. Beyond their capacity to transport tumor neo-antigens to lymph nodes and prime the naive T cells able to recognize them, it appears that tumor infiltration with specific DC sub-populations can impact on the efficiency of anti-tumor immune responses. Promoting efficient DC recruitment to tumors might therefore be of first importance to not only trigger but also maintain anti-tumor immune responses. This equally applies to NK cells and cytotoxic T cells, whose recruitment to the tumor bed helps tumor clearance. Efficient tumor recruitment of cytotoxic T cells has further been identified as essential for the success of anti-checkpoint therapies. Therefore, designing novel strategies to promote tumor infiltration by immune cells exhibiting anti-tumor activities is essential.
Interestingly, cancer cells share migration properties with DCs. More particularly, podosomes or invadosomes are cylindrical, actin-rich structures displaying a polarized pattern of distribution in migrating cells. Their primary purpose is related to cellular motility and invasion. Many different specialized cells exhibit these dynamic structures such as invasive cancer cells, and certain immune cells such as DCs (Gimona et al, Current opinion in cell biology 20 (2): 235-41).
An understanding of the mechanism by which cells migrate may lead to the development of novel therapeutic strategies for controlling, for example, invasive tumoral cells. For instance, invasion into the lymphatic system allows the transport of tumor cells to regional and distant lymph nodes and, ultimately, to other parts of the body. Cancer cells may spread to lymph nodes near the primary tumor and then disseminate. This is the most common route of metastasis for carcinomas. Therefore, it might
be advantageous to decrease or prevent cancer cell migration in order to avoid metastasis. However, attempts to prevent cancer spreading by inhibiting cell migration have not succeeded so far.
Cancer immunotherapy aims at eliciting an immune response directed against tumor antigens. One approach is through vaccination by the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. DCs have been used in this context due to their high antigen presenting property, which makes them the natural agents for tumor-associated antigen delivery. In particular, ex vivo generated DCs can be loaded with antigens and re-infused to the patient. Alternatively, antigens can be targeted to DCs in vivo without need for ex vivo cell manipulations. (Palucka & Bachereau, Nat Rev Cancer, 2012, 12, 265; Tacken et al, Nat Rev Immunol, 2007, 7, 790). However, one limitation is that the DCs injected to patients migrate inefficiently to lymphoid organs, a process required to trigger antitumoral immunity.
The approach of targeting T cell inhibition checkpoints for dis-inhibition with therapeutic antibodies is an area of intense investigation (for a review, see Pardoll, Nat Rev Cancer. 2012; 12:253-264). Targeting immune checkpoints of the adaptive immunity has shown great therapeutic efficacy to fight numerous cancers, but in a limited proportion of patients. Immune checkpoint on innate myeloid cells (macrophages, dendritic cells, MDSC, PMN) remain poorly studied while these cells represent the most abundant immune cell type in many solid tumors and are often associated with a poor outcome. Combining immune checkpoint therapies targeting both innate (mediated by myeloid cells) and adaptive (mediated by T cells) immune responses has demonstrated great efficiency in preclinical models but remains a challenge in the clinic. A critical point was shown to be the infiltration of immune cells, in particular CD8+ T cells, within the tumor. This stresses the urgent need to transform "cold tumors", i.e. tumors devoid of immune cells exhibiting anti-tumoral activity, into "hot tumors", i.e. tumors infiltrated with such cells.
Summary of the Present Invention
The inventors discovered that the activation of the lysosomal calcium channel TRPML also called Mcoln might help the cold-to-hot transition of tumors, and thereby enhance the efficiency of anti-tumor immune responses and anti-checkpoint therapy.
The inventors were able to show that activation of Mcoln leads to decreased tumor growth in the presence of an anti-checkpoint inhibitor in vivo.
The present invention relates to a composition or combination comprising an activator of mucolipin (Mcoln) and an immune checkpoint inhibitor for use in the treatment of a cancer in a subject.
In particular, the activator of Mcoln is selected from the group consisting of i) a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83,
phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2) and a derivative or analog thereof, and ii) an agonist antibody directed against Mcoln.
Preferably, the activator of Mcoln is selected from the group consisting of ML-SA1, ML-SA5, SF-21, SF- 22, SF-51, SF-81, SN-2, MK6-83, Ptdlns(3,5)P2 and a derivative or analog thereof, preferably is ML-SA1 or a derivative or analog thereof. Even more preferably, the activator of Mcoln is ML-SA1 or ML-SA5 or a derivative or analog thereof activating Mcoln. Most preferably, the activator of Mcoln is ML-SA1 or a derivative or analog thereof activating Mcoln.
In particular, the immune checkpoint inhibitor is an inhibitor of an immune checkpoint selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, 0X40 L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) and Butyrophilin-like2 (BTNL2) or any combination thereof.
Preferably, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-1/PD-L1 inhibitor.
Preferably, the PD-1 inhibitor is i) a peptide or peptidomimetic inhibiting PD-1/PD-L1 interaction such as AUNP-12, (D)-PPA 1, BMS202, hPRDX5 and a derivative, variant or analog thereof ii) a small molecule inhibiting PD-1/PD-L1 interaction such as molecules containing a sulfamonomethoxine or sulfamethizole scaffold and iii) an anti-PD-1 or anti-PDLl antibody.
Particularly, the PD-1 or PD-L1 inhibitor is selected from the group consisting of atezolizumab, durvalumab, avelumab nivolumab, pembrolizumab, pidilizumab, cemiplimab, camrelizumab, sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), BMS 936559, MPDL3280A, MSB0010718C, MEDI4736 and any combination thereof.
In a very particular aspect, the Mcoln activator is ML-SA1 and the immune checkpoint inhibitor is a PD- 1 inhibitor, preferably an anti-PD-1 antibody. Preferably, the immune checkpoint inhibitor is a PD-1 inhibitor. Particularly, the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of atezolizumab, durvalumab, avelumab nivolumab, pembrolizumab, pidilizumab, cemiplimab, camrelizumab, sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR- 042, WBP-285), BMS 936559, MPDL3280A, MSB0010718C, MEDI4736 and any combination thereof.
In particular, the cancer is a solid tumor such as sarcoma, carcinoma, and lymphoma.
Preferably the cancer is selected from the group consisting of prostate cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, kidney cancer, ovarian cancer, hepatocellular cancer, osteosarcoma, melanoma, hypopharynx cancer, esophageal cancer, endometrial cancer, cervical cancer, pancreatic cancer, liver cancer, colon cancer, colorectal cancer, brain cancer, renal cancer,
neuroendocrine tumors, muscle cancer, adrenal cancer, thyroid cancer, uterine cancer, skin cancer and bladder cancer, preferably colon cancer.
In a particular aspect, the subject has already received a line of treatment with an immune checkpoint inhibitor, preferably a PD-1 inhibitor.
In another aspect, the subject does not respond to a treatment with a PD-1 inhibitor alone.
Particularly the composition according to the invention is a combined preparation for simultaneous, separate or sequential use.
The invention also relates to a pharmaceutical composition comprising a molecule activating Mcoln and an immune checkpoint inhibitor, as disclosed herein.
The invention finally concerns a combination comprising a molecule activating Mcoln and an immune checkpoint inhibitor such as disclosed herein.
Detailed Description of the invention
Definitions
As used herein, the term "immune checkpoint" or "immune checkpoint protein" has its general meaning in the art and refers to a molecule that is expressed by immune or cancer cells in that either turn up a signal (stimulatory checkpoint molecules) or turn down a signal (inhibitory checkpoint molecules). Many of the immune checkpoints are regulated by interactions between specific receptor and ligand pairs. Immune checkpoint molecules are recognized in the art to constitute immune checkpoint pathways, such as the well-known CTLA-4 and PD-1 dependent pathways (see e.g. Pardoll, 2012. Nature Rev Cancer 12:252-264; Mellman et al., 201 1. Nature 480:480- 489). Overexpression of inhibitory checkpoint molecules by cancer cells have often been associated with inhibition of anti tumor immune response as immune cell express their ligand or receptor counterparts.
As used herein, the expressions "immune checkpoint inhibitor", "checkpoint inhibitor" or "checkpoint blockade cancer immunotherapy agent" are used interchangeably and have its general meaning in the art and refers to any compound inhibiting the function of an immune checkpoint protein. Inhibition includes reduction of function and full blockade. The immune checkpoint inhibitors include peptides, proteins, antibodies, nucleic acid molecules and small molecules. Preferred immune checkpoint inhibitors are antibodies that specifically recognize immune checkpoint proteins. Examples of immune checkpoint inhibitors are provided here below under the associated paragraph.
As used herein, the term "immunotherapy" or "immunotherapy treatment" refers to a cancer therapeutic treatment using the immune system to reject cancer. The therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells. It includes immunization
of the patient with tumor antigens (e.g. by administering a cancer vaccine), in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or administration of molecules stimulating the immune system such as cytokines, or administration of therapeutic antibodies such as drugs, in which case the patient's immune system is recruited by the therapeutic antibodies to destroy tumor cells. In particular, antibodies are directed against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.
An important feature of the immune system is its ability to discriminate between normal cells in the body and those it sees as "foreign", in particular cancer cells. This allows the immune system to attack the cancer cells while leaving the normal cells alone. To do this, the immune system uses checkpoints, these checkpoints are molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Cancer cells sometimes exploit these checkpoints to avoid being attacked by the immune system. As used herein, the term "immune checkpoint immunotherapy" refers to an immunotherapy that targets these checkpoints in order to allow or facilitate the attack of cancer cells by the immune system.
The term "cancer" or "tumor", as used herein, refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as the ones leading to uncontrolled proliferation, and/or immortality, and/or metastatic potential, and/or rapid growth and/or higher proliferation rate, and/or certain characteristic morphological features. This term refers to any type of malignancy (primary or metastases) in any type of subject. It may refer to solid tumor as well as hematopoietic tumor.
The term "immune response" refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by these cells or the liver (including antibodies, cytokines, and complements) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
As used herein, the terms "subject", "individual" or "patient" are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.
As used herein, the term "treatment", "treat" or "treating" refers to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of the disease. In certain embodiments, such term refers to the amelioration or eradication of a disease or symptoms associated with a disease. In other embodiments, this term refers to minimizing the spread or
worsening of the disease resulting from the administration of one or more therapeutic agents to a subject with such a disease.
As used herein, a "pharmaceutical composition" refers to a preparation of one or more of the active agents, with optional other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active agent to an organism. Compositions of the present invention can be in a form suitable for any conventional route of administration or use. In one embodiment, a "composition" typically intends a combination of the active agent, e.g., compound or composition, and a naturally-occurring or non- naturally-occurring carrier, inert (for example, a detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers.
As used herein, the terms "active principle", "active ingredient" "active pharmaceutical ingredient", "therapeutic agent", "antitumor compound", and "antitumor agent" are equivalent and refer to a component having a therapeutic effect.
As used herein, the term "therapeutic effect" refers to an effect induced by an active ingredient or by a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or the development of a cancer, or to cure or to attenuate the effects of a cancer.
"An effective amount" or a "therapeutic effective amount" as used herein refers to the amount or quantity of active agent required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents, e.g. the amount of active agent that is needed to treat the targeted disease or disorder, or to produce the desired effect. The "effective amount" will vary depending on the agent(s), the disease and its severity, the characteristics of the subject to be treated including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. By "effective amount" it is particularly meant the quantity of the combination or pharmaceutical composition of the invention that prevents, removes or reduces the deleterious effects of cancer in mammals, including humans. More particularly, by "therapeutically efficient amount of a composition" is intended the amount that is sufficient to decrease the size of a tumor or the occurrence of metastasis.
By the term "combination" as used herein is meant either, simultaneous administration of two Compounds A and B as defined in the present application or of a composition comprising such, or any manner of separate or sequential administration of a Compound A, or a composition comprising such, and Compound B or a composition comprising such. The combination can be administered by the same route or by different routes, e.g. one compound may be administered intravenously and the other compound may be administered orally.
The terms "kit", "product" or "combined preparation", as used herein, defines especially a "kit of parts" in the sense that the combination partners (a) and (b), as defined in the present application can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e. simultaneously or at different time points. The parts of the kit of parts can then be administered simultaneously or chronologically staggered, that is at different time points for any part of the kit of parts. The ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can varied. The combination partners (a) and (b) can be administered by the same route or by different routes.
As used herein, the term "simultaneous" refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered simultaneously, i.e. at the same time. The active ingredients may or may not be part of the same composition.
As used herein, the term "sequential" refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered sequentially, i.e. one after the other. Preferably, when the administration is sequential, all the active ingredients are administered in less than about an hour, preferably less than about 10 minutes, even more preferably in less than about a minute.
As used herein, the term "separate" refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered at distinct time of the day. Preferably, when the administration is separate, the active ingredients are administered with an interval of about 1 hour to about 24 hours, preferably with an interval of about 1 hour and 15 hours, more preferably with an interval of about 1 hour and 8 hours, even more preferably with an interval of about 1 hour and 4 hours.
The term "and/or" as used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, "A and/or B" is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually.
The term "a" or "an" can refer to one of or a plurality of the elements it modifies (e.g., "a reagent" can mean one or more reagents) unless it is contextually clear either one of the elements or more than one of the elements is described.
The term "about" as used herein in connection with any and all values (including lower and upper ends of numerical ranges) means any value having an acceptable range of deviation of up to +/- 10% (e.g., +/- 0.5%, +/-1 %, +/-1 -5%, +/- 2%, +/- 2.5%, +/- 3%, +/- 3.5%, +/- 4%, +/- 4.5%, +/- 5%, +/- 5.5%, +/- 6%, +/- 6.5%, +/- 7%, +/- 7.5%, +/- 8%, +/- 8.5%, +/- 9%, +/-9.5%). The use of the term "about" at the beginning of a string of values modifies each of the values (i.e. "about 1, 2 and 3" refers to about 1, about 2 and about 3). Further, when a listing of values is described herein (e.g. about 50%, 60%, 70%, 80%, 85% or 86%) the listing includes all intermediate and fractional values thereof (e.g., 54%, 85.4%).
Within the context of this invention, "responder", "responsive" or "have a therapeutic benefit" refers to a patient who responds to a treatment of cancer, i.e. the volume of the tumor is decreased, at least one of his symptoms is alleviated, or the development of the cancer is stopped, or slowed down. Typically, a subject who responds to a cancer treatment is a subject who will be completely treated (cured), i.e., a subject who will survive to the cancer. A subject who responds to a cancer treatment is also, in the sense of the present invention, a subject who has an overall survival higher than the mean overall survival known for the particular cancer. By "good responder" or "susceptible to have a therapeutic benefit" is intended a patient who shows a good therapeutic benefit of the treatment, that is to say a longer disease-free survival, a longer overall survival, a decreased metastasis occurrence, a decreased tumor growth and/or a tumor regression in comparison to a population of patients suffering from the same cancer and having the same treatment.
Within the context of this invention, "non-responder" refers to a subject who does not respond to a treatment of cancer, i.e. the volume of the tumor does not substantially decrease, or the symptoms of the cancer in the subject are not alleviated, or the cancer progresses, for example the volume of the tumor increases and/or the tumor generates local or distant metastasis. The terms "non-responder" also refer to a subject who will die from the cancer, or will have an overall survival lower than the mean overall survival known for the particular cancer. By "poor responder" or "non-responder" is intended a patient who shows a weak therapeutic benefit of the treatment, that is to say a shorter disease-free survival, a shorter overall survival, an increased metastasis occurrence and/or an increased tumor growth in comparison to a population of patients suffering from the same cancer and having the same treatment.
Mucolipin Activator
Mucolipin channel (Mcoln) is also currently named Transcient Receptor Potential Cation Channel Mucolipin subfamily (TRPML). It is a small family of the TRPML channels that includes 3 members, (Mcoln-1, Mcoln-2 and Mcoln-3) which is a subgroup of the large protein family of TRP ion channels. It is a Ca2+ channel localized in late endosomes and lysosomes. Unless specified otherwise, the term "Mcoln" refers to any of the Mcoln-1, Mcoln-2 and/or Mcoln-3 channels.
TRPML1 was identified as the protein mutated in the lysosomal storage disease mucolipidosis type IV (Bargal et al., 2000). TRPML2 was found by database searches and TRPML3 was identified as the protein mutated in mice with the varitint-waddler phenotype (Di Palma et al., 2002).
Human Mcoln-1 is described in several databases, namely under the references UniProt ID No Q9GZU1 and GenelD No 57192. Reference sequences are disclosed in Genbank under NM_020533 for mRNA and NP_065394 for protein. Because Mcoln-1 localizes to lysosomes, its luminal domains are directly accessible to extracellular compounds. Accordingly, there is no absolute need for Mcoln-1 activators to be cell-permeable.
Human Mcoln-2 is for example described under the references UniProt ID No Q8IZK6 and Gen ID No 255231. Reference sequences are disclosed in Genbank under NP_001317576.1, NM_001330647.1, NP_694991.2 and NM_153259.3.
Human Mcoln-3 is for example described under the references UniProt ID No Q8TDD5 and Gen ID No 55283. Reference sequences are disclosed in Genbank under NP_001240622.1, NM_001253693.1, NP_060768.8 and NM_018298.10.
The Mcoln activator used in the combination according to the invention can be any molecule capable of increasing Mcoln activity, particularly Mcoln-1, Mcoln-2 and/or Mcoln-3 activity. In a particular aspect, the Mcoln activator can be any molecule capable of increasing Mcoln-1 activity.
The terms "activator" and "agonist" can be used interchangeably. Preferably, a Mcoln activator is a molecule capable of increasing the activity of Mcoln by at least 10, 20, 30, 40 or 50 % when compared to the activity in absence of the molecule. Mcoln activity can be determined by any method known by the person skilled in art and for instance in such as disclosed in Shen et al., 2012, Nat. Comm., 3:731. The activity of Mcoln channel can for example be assessed by measuring its calcium permeability.
The Mcoln activator can be selected from the group consisting of i) a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83, phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2) and a derivative or analog thereof, and ii) an agonist antibody directed against Mcoln.
"Small molecules" as used herein are a class of molecules that is well known in the art and refer in particular to small organic molecules with a molecular mass <1000 Da and with a size on the order of 1 nm. Small molecules particularly bind specific biological molecules and act as an effector, modifying the activity or function of their target.
Small molecules and other drug candidates can readily be obtained, for example, from combinatorial and natural product libraries and using methods known to the art, or screening methods for their Mcoln agonizing activity. Synthetic compound libraries are commercially available from a number of companies including Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, N. J.), Brandon Associates (Merrimack, N.H.), and Microsource (New Milford, Conn.). Combinatorial libraries are available or can be prepared according to known synthetic techniques. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available from e.g., Pan Laboratories (Bothell, Wash.) and MycoSearch (NC), or are readily producible by methods well known in the art. Furthermore, random peptide libraries, consisting of all possible combinations of amino acids, attached to a solid phase or in solution, may also be used to identify peptides that act as agonists.
In one embodiment, the activator of Mcoln is a small molecule having a molecular weight inferior to 500 Daltons, preferably inferior to 400 Daltons.
In one embodiment, the activator of Mcoln is a small molecule selected from the group consisting of ML-SA1 (2-[2-(3,4-Dihydro-2,2,4-trimethyl-l(2H)-quinolinyl)-2-oxoethyl]-lH-isoindole-l,3(2H)-dione, CAS number 332382-54-4, Sigma-Aldrich Cat # SML0627; Tocris Bioscience Cat # 4746), SF-21 (4- chloro-N-(2-morpholin-4-ylcyclohexyl)benzenesulfonamide), SF-22 (5-chloro-N-(2-piperidin-l- ylphenyl)thiophene-2-sulfonamide), SF-51 (2-[2-oxo-2-(2,2,4-trimethylquinolin-l-yl)ethyl]isoindole- 1,3-dione), SF-81 (4,6-dimethyl-3-(2-methylphenyl)sulfonyl-l-propan-2ylpyridin-2-one), MK6-83 (5- Methyl-N-[2-(l-piperidinyl)phenyl]-2-thiophenesulfonamide, CAS number 1062271-24-2), SN-2 (3a,4,5,6,7,7a-Flexahydro-3-(2,4,6-trimethylphenyl)-4,7-methano-l,2-benzisoxazole, CAS number 823218-99-1) and a derivative or analog thereof.
Preferably, the activator of Mcoln is ML-SA1 or ML-SA5 or a derivative or analog thereof activating Mcoln. More preferably, the activator of Mcoln is ML-SA1 or a derivative or analog thereof activating Mcoln.
In another aspect, the Mcoln activator is a chemical compound having an activating activity on Mcoln such as phosphatidylinositol-3,5-bisphosphate (Ptdlns(3,5)P2). Ptdlns(3,5)P2 is one of the seven phosphoinositides found in eukaryotic cell membranes. This compound is commercially available for
example by Echelon Bioscience Product Number: P-3508 and comprising for example the formula such as provided below:
Preferably, the Mcoln activator is ML-SA1, ML-SA5 or a derivative or analog thereof, for example such as described below.
Preferably, the Mcoln activator is ML-SA1 or a derivative or analog thereof. ML-SA1 is for example described under CAS registry No. : 332382-54-4.
In one embodiment, the Mcoln activator is ML-SA1, preferably of formula :
In another aspect, the Mcoln activator is ML-SA5 or a derivative or analog thereof. . ML-SA1 is for example described under CAS registry No. : 2418670-70-7.
In another embodiment, the activator of Mcoln is an agonist antibody. As used herein, the terms "antibody" and "immunoglobulin" have the same meaning and are used indifferently in the present invention. The term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen-
binding site that immunospecifically bind an antigen, e.g. Mcoln-1, Mcoln-2 and/or Mcoln-3. Antibodies include any kind of antibodies, preferably monoclonal. They can be for instance IgG (immunoglobulin G) or VHH (heavy chain variable domain antibody from camelids). The term "antibody" encompasses fragments or derivatives thereof and include Fab, Fab', F(ab')2, scFv, (scFv)2, dAb, complementarity determining region (CDR) fragments, linear antibodies, single-chain antibody molecules, minibodies, diabodies, and multispecific antibodies formed from antibody fragments. An "agonist antibody" is an antibody that binds to a receptor and activates the receptor to produce a biological response.
In particular, the Mcoln activator is an antibody directed against Mcoln-1, Mcoln-2 and/or Mcoln-3 and having an agonist activity. Such antibody can be for instance prepared by the following method comprising immunizing a non-human mammal with a composition comprising human Mcoln-1, Mcoln- 2 and/or Mcoln-3 or an immunogenic fragment thereof; optionally selecting an antibody that binds to Mcoln-1, Mcoln-2 and/or Mcoln-3 or the immunogenic fragment thereof, and selecting an antibody that increases the activity of Mcoln-1, Mcoln-2 and/or Mcoln-3. The preparation of monoclonal or polyclonal antibodies is well known in the art, and any of a large number of available techniques can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy (1985)). Techniques for the production of single chain antibodies (for example such as disclosed in U.S. Pat. No. 4,946,778) can be adapted to produce antibodies to desired polypeptides. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized, chimeric, or similarly modified antibodies. Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)).
In one aspect, the Mcoln activator is selective in respect to Mcoln-1. That means that the Mcoln-1 activator has a greater efficacy on TRPML-1 in comparison to TRPML-2 and/or TRPML-3 (for instance by a factor of at least 10, 100 or 1000).
Immune checkpoint inhibitor
A number of immune checkpoints are known and in analogy are known immune checkpoint inhibitors. The immune checkpoint inhibitors include peptides, peptidomimetics, antibodies, nucleic acid molecules, small molecules and chemical compounds.
Typically, a checkpoint inhibitor is an agent which blocks an immunosuppressive receptor expressed by activated T lymphocytes, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PD-1), or by NK cells, like various members of the killer cell immunoglobulin-
like receptor (KIR) family, or an agent which blocks the principal ligands of these receptors, such as PD- 1 ligand CD274 (also known as PD-L1 or B7-H1).
In one aspect, the immune checkpoint is selected from the group consisting of PD-1, PD-L1, PD-L2, CT LA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) and Butyrophilin-like2 (BTNL2).
Preferably, the immune checkpoint is PD-1. As used herein, the terms "Programmed Death 1", "Programmed Cell Death 1", "PD1", "PD-1", "PDCD1", "PD-1 antigen", "human PD-1", "hPD-1" and "hPDl" are used interchangeably and refer to the Programmed Death-1 receptor, also known as CD279, and include variants and isoforms of PD-1, and analogs having at least one common epitope with PD-1. PD-1 is a key regulator of the threshold of immune response and peripheral immune tolerance. It is expressed on activated T cells, B cells, monocytes, and dendritic cells and binds to its ligands PD-L1 and PD-L2. Human PD-1 is encoded by the PDCD1 gene. As an example, the amino acid sequence of a human PD-1 is disclosed under GenBank accession number NP_005009. PD1 has four splice variants expressed on human Peripheral blood mononuclear cells (PBMC). Accordingly, PD-1 proteins include full-length PD-1, as well as alternative splice variants of PD- 1, such as PD-lAex2, PD- lAex3, PD-lAex2,3 and PD-lAex2,3,4.
In one embodiment, the checkpoint inhibitor is an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2).
Preferably, the immune checkpoint inhibitor therapy is an immunotherapy, wherein the immune checkpoint is selected from the group consisting of an antibody directed against cytotoxic T lymphocyte associated protein (CTLA-4), programmed cell death protein 1 (PD-1), programmed cell death ligand (PD-L1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), B- and T-lymphocyte attenuator (BLTA), IDOl inhibitor, or any combination thereof, preferably selected from the group consisting of an antibody directed against PD-1, PD-L1 and CTLA-4 or any combination thereof, more preferably an antibody directed against PD-1 or PD-L1 and the combination thereof.
Preferably, the checkpoint inhibitor is an anti-PDl antibody. As used herein "PD-1 antibody," "anti-PD- 1 antibody," "PD-1 Ab," "PD-l-specific antibody" or "anti-PD-1" are used interchangeably and refer to an antibody, as described herein, which specifically binds to PD-1, preferably human PD-1. In some embodiments, the antibody binds to the extracellular domain of PD-1. Particularly, an anti-PD-1
antibody is an antibody capable of binding to a PD-1 antigen and inhibits the PD-l-mediated signaling pathway, and/or the interaction between PD-1 and PD-L1.
Several anti-PD-1 antibodies are already clinically approved and others are still in clinical developments. For instance, the anti-PDl antibody can be selected from the group consisting of Pembrolizumab (also known as Keytruda lambrolizumab, MK-3475), Nivolumab (Opdivo, MDX-1106, BMS-936558, ONO-4538), Pidilizumab (CT-011), Cemiplimab (Libtayo), Camrelizumab, AUNP12, AMP- 224, AGEN-2034, BGB-A317 (Tisleizumab), PDR001 (spartalizumab), MK-3477, SCH-900475, PF- 06801591, JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, SHR-1201, BAT-1306, AK-103 (FIX-008), MEDI-0680 (also known as AMP-514) MEDI0608, JS001 (see Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), BI-754091, CBT-501, INCSHR1210 (also known as SHR-1210), TSR-042 (also known as ANB011), GLS-010 (also known as WBP3055), AM-0001 (Armo), STI-1110 (see WO 2014/194302), AGEN2034 (see WO 2017/040790), MGA012 (see WO 2017/19846), or IBI308 (see WO 2017/024465, WO 2017/025016, WO 2017/132825, and WO 2017/133540), monoclonal antibodies 5C4, 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, described in WO 2006/121168. Bifunctional or bispecific molecules targeting PD-1 are also known such as RG7769 (Roche), XmAb20717 (Xencor), MEDI5752 (AstraZeneca), FS118 (F-star), SL-279252 (Takeda) and XmAb23104 (Xencor). Particularly, the PD-1 inhibitor is selected from the group consisting of atezolizumab, durvalumab, avelumab nivolumab, pembrolizumab, pidilizumab, cemiplimab, camrelizumab, sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), BMS 936559, MPDL3280A, MSB0010718C, MEDI4736 and any combination thereof.
In one embodiment, the checkpoint inhibitor is an anti-PD-Ll antibody. Antibodies directed against PD-L1 are well-kwon in the art, such as Atezolizumab (Roche), Avelumab (Merck/Pfizer) and Durvalumab (AstraZeneca).
In another embodiment, the immune checkpoint inhibitor is an antibody directed against CTLA-4. Antibodies directed against CTLA-4 are also known such as ipilimumab, tremelimumab, MK-1308, AGEN-1884, XmAb20717 (Xencor), MEDI5752 (AstraZeneca).
In another embodiment, the immune checkpoint inhibitor is an antibody directed against TIGIT. Antibodies directed against TIGIT are also known in the art, such as BMS-986207 or AB154, BMS- 986207 CPA.9.086, CHA.9.547.18, CPA.9.018, CPA.9.027, CPA.9.049, CPA.9.057, CPA.9.059, CPA.9.083, CPA.9.089, CPA.9.093, CPA.9.101, CPA.9.103, CHA.9.536.1, CHA.9.536.3, CHA.9.536.4, CHA.9.536.5, CHA.9.536.6, CHA.9.536.7, CHA.9.536.8, CHA.9.560.1, CHA.9.560.3, CHA.9.560.4, CHA.9.560.5, CHA.9.560.6, CHA.9.560.7, CHA.9.560.8, CHA.9.546.1, CHA.9.547.1, CHA.9.547.2, CHA.9.547.3, CHA.9.547.4, CHA.9.547.6, CHA.9.547.7, CHA.9.547.8, CHA.9.547.9, CHA.9.547.13, CHA.9.541.1, CHA.9.541.3, CHA.9.541.4, CHA.9.541.5, CHA.9.541.6, CHA.9.541.7, and CHA.9.541.8 as disclosed in
W019232484. Anti-TIGIT antibodies are also disclosed in WO16028656, W016106302, W016191643, W017030823, W017037707, WO17053748, WO17152088, WO18033798, WO18102536,
WO18102746, W018160704, W018200430, WO18204363, W019023504, WO19062832,
W019129221, W019129261, W019137548, W019152574, W019154415, W019168382 and W019215728.
In another embodiment, the immune checkpoint inhibitor is an antibody directed against TIM3. Antibodies directed against TIM3 are also known such as Sym023, TSR-022, MBG453, LY3321367, INCAGN02390, BGTB-A425, LY3321367, RG7769 (Roche). In some embodiments, a TFM-3 antibody is as disclosed in International Patent Application Publication Nos. W02013006490, W02016/161270, WO 2018/085469, or WO 2018/129553, WO 2011/155607, U.S. 8,552,156, EP 2581113 and U.S 2014/044728.
In another embodiment, the immune checkpoint inhibitor is an antibody directed against LAG-3. Antibodies directed against LAG-3 are also known such as BMS- 986016, IMP701, MGD012 or MGD013 (bispecific PD-1 and LAG-3 antibody). Anti-LAG-3 antibodies are also disclosed in W02008132601, EP2320940 and W019152574.
In another embodiment, the immune checkpoint inhibitor is an antibody directed against B7-H3. B7- H3 (also known as CD276) was originally understood to be a co-stimulatory molecule but is now regarded as co-inhibitory. A preferred checkpoint inhibitor of B7-H3 is the Fc- optimized monoclonal antibody Enoblituzumab (MGA271; MacroGenics; cf. US 201 2/0294796 A1 ).
In another embodiment, the immune checkpoint inhibitor is an antibody directed against 0X40. Checkpoint inhibitor of 0X40 include MEDI6469 (Medlmmune/AstraZeneca), MEDI6383 (Medlmmune/AstraZeneca), MEDI0562 (Medlmmune/AstraZeneca), MOXR091 6 (RG7888;
Roche/Genentech) and GSK3174998 (GSK).
In a particular embodiment, the checkpoint inhibitor is a PD-1 inhibitor or an inhibitor that inhibits the interaction between PD-1 and PD-L1.
Preferably, such PD-1/PD-L1 inhibitor is selected from the group consisting of i) a peptide or peptidomimetic inhibiting PD-1/PD-L1 interaction such as AUNP-12, (D)-PPA 1, BMS202, hPRDX5 and a derivative, variant or analog thereof ii) a small molecule inhibiting PD-1/PD-L1 interaction such as molecules containing a sulfamonomethoxine or sulfamethizole scaffold and iii) an antibody anti-PD-1 or anti-PD-Ll such as disclosed above.
Examples of PD-1/PD-L1 peptide-based and small molecule inhibitors are particularly provided in Tingkai Chen, et al, European Journal of Medicinal Chemistry (2018), in Sasikumar, P.G. and
Ramachandra, M. BioDrugs 32, 481-497 (2018) and in Guzik K, Tomala M, Muszak D, et al. Molecules. 2019;24(11):2071, the teachings of which being incorporated by reference.
In one embodiment, the checkpoint inhibitor is AUNP-12 (also known as AUR-012, Aurigene-012, Aurigene NP-12) or a derivative, variant or analog thereof, for example such as described under CAS No. 1353563-85-5, and commercially available by Selleckchem under the reference Catalog No. S8549.
In one embodiment, the checkpoint inhibitor is (D)-PPA 1 or a derivative, variant or analog thereof, for example such as described under CAS No. 1620813-53-7 and commercially available by RnDSystems under the reference Catalog No. 6515/1.
In one embodiment, the checkpoint inhibitor is BMS202 or a derivative, variant or analog thereof, for example such as described under CAS No. 1675203-84-5 and commercially available by Selleckchem under the reference Catalog No. S791201.
In one embodiment, the checkpoint inhibitor is hPRDX5 and a derivative, variant or analog thereof, such as described in Sen Zou et al., Cancer Chemother Pharmacol. 2020 Jan;85(l):185-193.
In one embodiment, the checkpoint inhibitor is a small molecule inhibiting PD-1/PD-L1 interaction such as molecules containing a sulfamonomethoxine or suifamethizoie scaffold, for example such as provided below:
SulfamcHionnethoxine Suifamethizoie
Combination and Pharmaceutical Composition
The present invention relates to a combination comprising a Mcoln activator and a checkpoint inhibitor, to a pharmaceutical composition comprising a Mcoln activator and a checkpoint inhibitor and to a kit comprising a Mcoln activator and a checkpoint inhibitor. The Mcoln activators and immune checkpoint inhibitors described herein are all referred to as "active compounds" or "active ingredients" and are more particularly described here above under the respective paragraph.
Preferably, the combination or composition comprising a Mcoln activator and a checkpoint inhibitor may further comprise one or more pharmaceutically or physiologically acceptable carriers, diluents, excipients, salt, and anti-oxidant as described hereafter.
It should be understood that when referring to a combination or composition, these terms are either directed to a single composition comprising both of the Mcoln activator and checkpoint inhibitor, or two compositions comprising the Mcoln activator or checkpoint inhibitor that are to be administered simultaneously, sequentially or separately.
In a more general aspect, the present invention relates to a Mcoln activator or a pharmaceutical comprising it for use as a drug or to the use of a Mcoln activator or a pharmaceutical comprising it for the manufacture of a drug, or a pharmaceutical composition comprising a Mcoln activator. The Mcoln activator can be used in combination with an additional drug, pharmaceutically or physiologically acceptable carrier, diluent, excipient, salt, and anti-oxidant as described hereafter. In particular, the Mcoln activator is used in combination with an immune checkpoint inhibitor.
The present invention also relates to an immune checkpoint inhibitor or a pharmaceutical comprising it for use as a drug or to the use of an immune checkpoint inhibitor or a pharmaceutical comprising it for the manufacture of a drug, or a pharmaceutical composition comprising an immune checkpoint inhibitor. The immune checkpoint inhibitor can be used in combination with an additional drug, pharmaceutically or physiologically acceptable carrier, diluent, excipient, salt, and anti-oxidant as described hereafter. In particular, the immune checkpoint inhibitor is used in combination with a Mcoln activator.
In one embodiment, the combination or the pharmaceutical composition comprises 30%, 40%, 50%, 60%, 70%, 80%, 90% of a Mcoln activator for 100% by weight of the total combination or composition, or for 100% by weight of the sum of the Mcoln activator and the immune checkpoint inhibitor.
In one embodiment, the combination or the pharmaceutical composition comprises 30%, 40%, 50%, 60%, 70%, 80%, 90% of an immune checkpoint inhibitor for 100% by weight of the total combination or composition, or for 100% by weight of the sum of the Mcoln activator and the immune checkpoint inhibitor.
In one embodiment, the combination or the pharmaceutical composition comprises 50% of an immune checkpoint inhibitor and 50% of a Mcoln activator for 100% by weight of the sum of the Mcoln activator and the immune checkpoint inhibitor. Preferably, the combination or the pharmaceutical composition comprises 50% of a PD-1/PD-L1 inhibitor, preferably an anti-PD-1 antibody, and 50% of a Mcoln activator, preferably ML-SA1, for 100% by weight of the sum of the Mcoln activator and the immune checkpoint inhibitor.
The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to
produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect.
The pharmaceutical composition comprising the Mcoln activator and the checkpoint inhibitor may be formulated in accordance with standard pharmaceutical practice known by a person skilled in the art. For example, such as disclosed in Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York.
The combination or pharmaceutical composition of the invention may further comprise one or more pharmaceutically acceptable carriers and excipients which do not deleteriously interact with the Mcoln activator and the immune checkpoint inhibitor "pharmaceutically acceptable" as referred to herein, is any known compound or combination of compounds that are known to those skilled in the art to be useful and suitable in formulating pharmaceutical compositions.
The combination or pharmaceutical composition of the invention may further comprise one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline metals or alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N- methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
The combination pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetra-acetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
The Mcoln activator and the checkpoint inhibitor according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle or carrier such as water, an organic solvent, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like a mixture of both or pharmaceutically acceptable oils or fats and suitable mixtures thereof. The liquid
vehicle can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, wetting agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
The pharmaceutical composition according to the invention can be formulated for any conventional route of administration including a topical, enteral, oral, parenteral, intranasal, intravenous, intra arterial, intramuscular, intra-tumoral, subcutaneous or intraocular administration and the like. The man of the art knows how to select the most appropriate vehicles and excipients for the preparation of a given type of formulation.
For oral administration, the composition can be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules and liquid preparations such as syrups, elixirs, and concentrated drops. Nontoxic solid carriers or diluents may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. For compressed tablets, binders, which are agents which impart cohesive qualities to powdered materials, are also necessary. For example, starch, gelatin, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders. Disintegrants are also necessary in the tablets to facilitate break-up of the tablet. Disintegrants include starches, clays, celluloses, algins, gums and crosslinked polymers. Moreover, lubricants and glidants are also included in the tablets to prevent adhesion to the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material during manufacture. Colloidal silicon dioxide is most commonly used as a glidant and compounds such as talc or stearic acids are most commonly used as lubricants.
For transdermal administration, the composition can be formulated into ointment, cream or gel form and appropriate penetrants or detergents could be used to facilitate permeation, such as dimethyl sulfoxide, dimethyl acetamide and dimethylformamide.
For transmucosal administration, nasal sprays, rectal or vaginal suppositories can be used. The active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or dissolution rate.
For intravenous injection, water combination or composition can be administered by the drip method, whereby a Mcoln activator and a checkpoint inhibitor and a physiologically acceptable excipients are infused. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients. Intramuscular preparations, e.g., a sterile formulation of
a suitable soluble salt form of the antibody, can be dissolved and administered in a pharmaceutical excipient such as Water-for-lnjection, 0.9% saline, or 5% glucose solution.
When administered parentally, the combination or pharmaceutical composition according to the invention is preferably administered by intravenous route of administration. When administered enterally, the combination or pharmaceutical composition according to the invention is preferably administered by oral route of administration. This composition can also be administered locally.
Combination and pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration. The combination or pharmaceutical composition in some aspects can employ time-released, delayed release, and sustained release delivery systems such that the delivery of the composition occurs prior to, and with sufficient time to cause, sensitization of the site to be treated. Means known in the art can be used to prevent or minimize release and absorption of the composition until it reaches the target tissue or organ, or to ensure timed-release of the composition. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician.
Pharmaceutical compositions according to the invention can comprise one or more molecule of the present invention associated with pharmaceutically acceptable excipients and/or carriers. These excipients and/or carriers are chosen according to the form of administration as described above.
Combination and pharmaceutical composition according to the invention typically must be sterile and stable under the conditions of manufacture and storage. Sterile injectable solutions can be prepared by incorporating the active ingredients in the required amount in an appropriate solvent with one or a combination of additional ingredients enumerated above, as required, followed by sterilization microfiltration.
Method of selecting a suitable combination of Mcoln activator and checkpoint inhibitor
The present invention further relates to a method for selecting or identifying a combination of molecules suitable for the treatment of cancer, in particular for reducing tumor growth and/or size.
Such method particularly comprises determining the effect of a molecule on the activity of Mcoln and selecting the molecule if it increases the activity of Mcoln. The method further comprises the combination of such molecule with a checkpoint inhibitor, and a step of determining the effect of the selected combination on tumor size and/or growth, and selecting the combination if it decreases tumor growth and/or size. Such a screening method is disclosed for Mcoln-1 in US2003/064363. In addition, methods for screening modulators of cation channel have been disclosed and can be easily adapted by the person skilled in the art to Mcoln, especially for TRPM4b in WO 2004/039941; for
TRPM5 in WO 2004/076632; for TRPM7 in W02007/041687 and in WO2011/072275; for TRPM4 in W02007/140308; for TRPM8 in W02006/029142.
In an aspect, the invention relates to a method of selecting a suitable combination of a Mcoln activator and a checkpoint inhibitor, for use in a subject suffering from cancer, comprising or consisting of at least one of the following steps:
1) a. testing the ability of a molecule to bind to Mcoln, b. testing the ability of the molecule to activate Mcoln-1, 2 and/or 3; and c. selecting the Mcoln activator capable of binding and activating Mcoln;
2) a. testing a patient cancer sample, and determining the expression profile of the patient suffering from cancer, in particular identifying whether such cancer sample expresses or overexpresses an immune checkpoint such as PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, 0X40 L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG- 3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) and Butyrophilin-like2 (BTNL2), and b. selecting the most suitable immune checkpoint inhibitor treatment, in particular an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2), such agent being preferably an antibody;
3) combining the Mcoln activator selected in lc) and the checkpoint inhibitor selected in 2b), in particular with pharmaceutical acceptable excipients and/or carriers,
4) optionally assessing the effect of the combination of step 3) on tumor size and/or growth, and
5) optionally administering the combination to the subject suffering from cancer.
In another aspect, the invention relates to a method of selecting a suitable combination of a Mcoln activator and a checkpoint inhibitor, for use in a subject suffering from cancer, comprising or consisting of at least one of the following steps:
1) a. testing a patient cancer sample, and determining the expression profile of the patient suffering from cancer, in particular identifying whether such cancer sample expresses or overexpresses an immune checkpoint such as PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, 0X40 L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-
3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIG IT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) and Butyrophilin-like2 (BTNL2), and b. selecting the most suitable immune checkpoint inhibitor treatment according to the patient expression profile, in particular an immunotherapy against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim 3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIGIT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2);
2) selecting a Mcoln activator from the group consisting of i) a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83 and a derivative or analog thereof, ii) an agonist antibody directed against Mcoln and iii) a chemical compound having an activating activity on Mcoln such as phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2);
3) combining the molecule selected in lb) and 2), in particular with pharmaceutical acceptable excipients and/or carriers,
4) optionally assessing the effect of the combination of step 3) on tumor size and/or growth,
5) optionally administering the combination to the subject suffering from cancer.
In another aspect, the invention relates to a method of preparing a combination of a Mcoln activator and a checkpoint inhibitor, comprising or consisting of at least one of the following steps:
1) a. testing a patient cancer sample, and determining the expression profile of the patient suffering from cancer, in particular identifying whether such cancer sample expresses or overexpresses PD-1 and/or PD-L1, b. selecting a PD-1/PD-L1 immune checkpoint inhibitor treatment, preferably selected from the group consisting of i) a peptide or peptidomimetic inhibiting PD-1/PD-L1 interaction such as AUNP-12, (D)- PPA 1, BMS202, hPRDX5 and a derivative, variant or analog thereof ii) a small molecule inhibiting PD- 1/PD-Ll interaction such as molecules containing a sulfamonomethoxine or sulfamethizole scaffold and iii) an antibody anti-PD-1 or anti-PD-Ll such as describe above;
2) selecting a Mcoln activator from the group consisting of i) a small molecule or peptide activating Mcoln such as ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SF-81, SN-2, MK6-83 and a derivative or analog thereof, ii) an agonist antibody directed against Mcoln and iii) a chemical compound having an activating activity on Mcoln such as phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2).
3) combining the molecule selected in lb) and 2), in particular with pharmaceutical acceptable excipients and/or carriers,
4) optionally assessing the effect of the combination of step 3) on tumor size and/or growth,
5) optionally administering the combination to the subject suffering from cancer.
Typically, the tumor sample of the patient may be obtained by biopsy or resection. The biopsy technique applied will depend on the tissue type to be evaluated, the size and type of the tumor, among other factors. Representative biopsy techniques include, but are not limited to, excisional biopsy, incisional biopsy, needle biopsy, surgical biopsy, and bone marrow biopsy. An "excisional biopsy" refers to the removal of an entire tumor mass with a small margin of normal tissue surrounding it. An "incisional biopsy" refers to the removal of a wedge of tissue that includes a cross-sectional diameter of the tumor.
The term "cancer sample" or "tumor sample", as used herein, means any sample containing tumor cells and cancer stromal cells derived from a subject suffering from cancer. Cancer tissues are particularly composed of cancer cells and the surrounding cancer stromal cells, including vascular endothelial cells, and immune cells, in addition to the extracellular matrix. Preferably, the cancer sample contains nucleic acids and/or proteins. The sample may be treated prior to its use.
Preferably, the gene expression profile of a patient suffering from cancer is assed and compared between a cancer sample and a histologically matched normal sample from the same patient.
Particularly, the subject has previously been diagnosed as suffering from cancer. As used herein, the term "diagnosis" refers to the determination as to whether a subject is likely to be affected by a cancer. The skilled artisan often makes a diagnosis on the basis of one or more diagnosis markers, the presence, absence, or amount of which is indicative of the presence or absence of the cancer.
Methods for determining the expression profile of a patient suffering from cancer and measuring expression level of immune checkpoint are known in the art. For example, the methods based on the assessment of quantity of mRNA are well known in the art and include, but are not limited to, quantitative or semi-quantitative RT-PCR, real time quantitative or semi-quantitative RT-PCR. Other methods include, but are not limited to, ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA) and nucleic acid sequence-based amplification (NASBA). Probes targeting immune checkpoint inhibitors are well known in the art.
Particularly, the quantity of mRNA may be measured using the Nanostring's NCOUNTER™ Digital Gene Expression System (Geiss et al. 2008 Nat. Biotechnol. 26:317-325) which captures and counts individual mRNA transcripts by a molecular bar-coding technology and is commercialized by Nanostring Technologies, or the QuantiGene® Plex 2.0 Assay (Affymetrix). The quantity of mRNA may alternatively be determined using approaches based on high-throughput sequencing technology such as RNA-Seq
(Wang et al. Nat Rev Genet. 2009 January; 10(1): 57-63) or sequencing technologies using microfluidic systems or transcriptome approaches. Next Generation Sequencing methods (NGS) may also be used.
The formulation of the combination is more particularly described here below and encompass composition comprising both of the Mcoln activator and checkpoint inhibitor, or two compositions comprising the Mcoln activator or checkpoint inhibitor that are to be administered simultaneously, sequentially or separately, such as described above.
Methods and Uses
The combination, composition and method of the present invention have numerous in vitro and in vivo utilities and applications.
The present invention particularly relates to a composition or combination comprising an activator of mucolipin (Mcoln or TRPML) and an immune checkpoint inhibitor for use in the treatment of a cancer in a subject.
The invention also relates to the use of a combination or a pharmaceutical composition comprising a Mcoln activator and a checkpoint inhibitor in the manufacture of a medicament for treating a disease and/or disorder in a subject, in particular cancer.
Accordingly, in one embodiment, the invention also provides a method of treating a cancer, for instance of inhibiting growth of tumor cells, in a subject, in particular a subject having a cancer, comprising administering to the subject a therapeutically effective amount of the combination or pharmaceutical composition according to the invention. Particularly, the present invention relates to the treatment of a subject using the combination or pharmaceutical composition according to the invention such that growth of cancerous cells is inhibited.
Disclosed herein, are methods of treating a patient suffering from cancer, the method comprising: (a) identifying a patient in need of treatment; and (b) administering to the patient a therapeutically effective amount of the combination or pharmaceutical composition described herein.
In one aspect, the invention relates to a method of treatment of a pathology, disease and/or disorder, in particular such as cancer that could be prevented or treated by the inhibition of the binding of PD- L1 and/or PD-L2 to PD-1.
In another aspect, the invention relates to a method of treatment of a pathology, disease and/or disorder, in particular such as cancer, in which the subject has a mutated or deficient TFEB (Transcription factor EB, UniProtKB - P19484) or a mutated or deficient Mcoln, e.g. Mcoln-1.
Accordingly, the subject in need of a treatment may be a human having, at risk for, or suspected of having a disease associated with the signaling pathway mediated by PD-1/PD-L1. Such a patient can
be identified by routine medical examination. For example, a subject suitable for the treatment can be identified by examining whether such subject carries PD-1, PD-L1 and/or PD-L2 positive cells. In one embodiment, a subject who needs a treatment is a patient having, suspected of having, or at risk for a disease, preferably a PD-1, PDL1 and/or PDL2 positive disease, even more preferably a disease where PD-1 and/or at least one ligand of PD-1 is overexpressed. In some embodiments, the combination or pharmaceutical composition described herein can be used for treating PD-1 positive cells.
In one aspect, the invention relates to a method of treatment of a pathology, disease and/or disorder, in particular such as cancer that could be prevented or treated by the inhibition of the binding of CTLA- 4 to CD80 or CD86.
Accordingly, the subject in need of a treatment may be a human having, at risk for, or suspected of having a disease associated with the signaling pathway mediated by CTLA-4. Such a patient can be identified by routine medical examination. For example, a subject suitable for the treatment can be identified by examining whether such subject carries CTLA-4, CD80 and/or CD86 positive cells. In one embodiment, a subject who needs a treatment is a patient having, suspected of having, or at risk for a disease, preferably a CTLA-4, CD80 and/or CD86 positive disease, even more preferably a disease where CTLA-4 is overexpressed. In some embodiments, the combination or pharmaceutical composition described herein can be used for treating CTLA-4 positive cells.
The invention particularly provides a method of reducing the growth and/or the size of a tumor in a subject, comprising administering to the subject a therapeutic effective amount of a combination or composition such described herein, such that the tumor in the subject is reduced or its growth limited or decreased.
In some embodiments, the amount of the combination or composition according to the invention is effective in inhibiting or reducing the tumor size or growth, in particular by at least 10%, 20%, 30%, 40%, 50%, 80% or 100% as compared to a control. In particular, the combination or composition according to the invention is effective in inhibiting or reducing the tumor size or growth by 40 % as compared to a control. The control can be a tumor that have not been treated, a tumor that has been treated by a Mcoln activator only, or with a checkpoint inhibitor only.
In another aspect the combination or pharmaceutical composition described herein can be administered to a subject, e.g., in vivo, to enhance immunity, preferably in order to treat a disorder and/or disease such as cancer. Preferably, the immune response is enhanced, increased, stimulated or up-regulated. The immune response enhancement can result in the inhibition of the binding of the immune checkpoint inhibitor to its receptor or ligand, thereby reducing the immunosuppressive environment around the tumor.
Additional Therapy
The combination or composition according to the invention can be used in further combination with another therapeutic agent, especially another anticancer treatment. The anticancer treatment can be surgery, radiotherapy, chemotherapy, immunotherapy or hormone therapy. Such anticancer treatment may be administered simultaneously or chronologically staggered, that is at different time points, from the combination or composition according to the invention.
As used herein, the term "chemotherapy" refers to a cancer therapeutic treatment using chemical or biochemical substances, in particular using one or several antineoplastic agents.
The term "immunotherapy" refers to a cancer therapeutic treatment including with therapeutic antibodies. In particular, antibodies are directed against specific antigens such as the unusual antigens that are presented on the surfaces of tumors. As illustrating example, one can cite Trastuzumab or Herceptin antibody that is directed against HER2 and approved by FDA for treating breast cancer. Preferably, therapeutic antibodies functions to deplete tumor cells in a patient. In particular, therapeutic antibodies specifically bind to antigens present on the surface of the tumor cells, e.g. tumor specific antigens present predominantly or exclusively on tumor cells. Alternatively, therapeutic antibodies may also prevent tumor growth by blocking specific cell receptors. The term "hormone therapy" refers to a cancer treatment having for purpose to block, add or remove hormones. For instance, in breast cancer, the female hormones estrogen and progesterone can promote the growth of some breast cancer cells. So, in these patients, hormone therapy is given to block estrogen and a non-exhaustive list commonly used drugs includes: Tamoxifen, Fareston, Arimidex, Aromasin, Femara, Zoladex/Lupron, Megace, and Flalotestin.
In an aspect, the additional therapeutic agent can be selected in the non-exhaustive list comprising alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-2 family inhibitors), activators of death receptor pathway, antibody drug conjugates, biologic response modifiers, Bruton's tyrosine kinase (BTK) inhibitors, cyclin-dependent kinase inhibitors, cell cycle inhibitors, growth factor inhibitors, heat shock protein inhibitors, histone deacetylase (FIDAC) inhibitors, hormonal therapies, inhibitors of inhibitors of apoptosis proteins (lAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, microRNAs, non-steroidal anti-inflammatory drugs (NSAIDs), platinum chemotherapeutics, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids, alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, peptide, DNA or RNA vaccine, cell therapy and the like, as well as combinations of one or more of these agents.
In a particular embodiment, the additional therapeutic agent is an additional checkpoint inhibitor, for example an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, 0X40 L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIG IT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2), or any combination thereof.
For example, when the combination comprises a PD-1 inhibitor, the additional therapeutic agent can be selected from the group consisting of an agent against PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim 3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIG IT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) or Butyrophilin-like2 (BTNL2) and any combination thereof.
In some embodiments, the composition or combination according to the invention may be administered as part of the anticancer treatment. For example, in some embodiments, the composition or combination according to the invention may be administered to the patient before and/or after radiation or surgery to reduce the size of a tumor.
Subject, regimen and administration
The present invention relates to a combination of a Mcoln activator and an immune checkpoint inhibitor, a pharmaceutical composition comprising such, for use as a medicament, particularly for use in the prevention or treatment of a disease such as cancer. It also relates to the use of combination or a pharmaceutical composition of the present invention in the manufacture of a medicament for treating a cancer in a subject. Finally, it relates to a method for treating a cancer in a subject comprising administering a therapeutically effective amount of a combination or pharmaceutical composition according to the invention to the subject. Examples of treatments are more particularly described hereafter under the section "Methods and Uses".
The subject under consideration may be a mammal, in particular any animal subject such as a laboratory animal (e.g. non-human primate, rat, mouse, hamster, guinea pig), livestock (e.g. cow, sheep, goat, pig, turkey and chicken) or a domestic species (e.g. dog, cat and rodent), in particular a human.
The subject to treat may be a human, particularly a human at the prenatal stage, a new-born, a child, an infant, an adolescent or an adult, in particular an adult of at least 30 years old, 40 years old, preferably an adult of at least 50 years old, still more preferably an adult of at least 60 years old, even more preferably an adult of at least 70 years old.
In a particular embodiment, the patient has already received at least one line of treatment, in particular one line of treatment, two lines of treatment or three lines of treatment or more, preferably
several lines of treatment. Alternatively, the patient has not received any treatment. Preferably, the subject was heavily pre-treated and even more preferably the subject exhausted therapeutic options.
In one embodiment, the patient has already received at least one line of treatment, in particular a checkpoint inhibitor, and is a poor responder to such treatment.
In the context of the invention, a subject who needs a treatment or is treated is a patient having a cancer, suspected of having a cancer, or at risk of having a cancer.
Particularly, the subject is affected with a cancer that may involve the PD-l/PDL-1 pathway, particularly wherein, at least one of the ligands of PD-1 (e.g. PDL-1 and/or PDL-2) or PD-1 is/are expressed, especially overexpressed. Preferably, the subject is suffering from cancer, even more preferably from a PD1, PD-L1 and/or PD-L2 positive cancer or a PD-1 positive cancer.
Particularly, the subject is affected with a cancer that may involve the CTLA-4 pathway, particularly wherein, CTLA-4 is expressed, especially overexpressed. Preferably, the subject is suffering from cancer, even more preferably from a CTLA-4 positive cancer.
Examples of cancers are more particularly described hereafter.
The form of the pharmaceutical compositions, the route of administration and the dose of administration of the combination or pharmaceutical composition according to the invention can be adjusted by the man skilled in the art according to the type and severity of the infection, and to the patient, in particular its age, weight, sex, and general physical condition. The compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired.
In one embodiment, the Mcoln activator, preferably ML-SA1 is administered at a dose of between 1 and 20 mg/kg, 1 and 15 mg/kg, 1 and 10 mg/kg, preferably between 5 and 10 mg/kg, even more preferably about 10 mg/kg.
In one embodiment, the checkpoint inhibitor, preferably a PD-1/PD-L1 inhibitor, even more preferably an anti-PD-1 antibody is administered at a dose of between 1 and 20 mg/kg, 1 and 15 mg/kg, 1 and 10 mg/kg, preferably between 5 and 10 mg/kg, even more preferably about 10 mg/kg.
In another embodiment, the checkpoint inhibitor, preferably CTLA-4 inhibitor, even more preferably an anti- CTLA-4 antibody is administered at a dose of between 1 and 20 mg/kg, 1 and 15 mg/kg, 1 and 10 mg/kg, preferably between 5 and 10 mg/kg, even more preferably about 10 mg/kg.
The combination or composition according to the invention may be administered as a single dose or in multiple doses.
In one embodiment, combination or composition according to the invention is to be administered in separate doses, that is to say that the Mcoln activator is comprised in a dose and the checkpoint inhibitor in a separate dose.
Preferably, the treatment starts no longer than a month, preferably no longer than a week, after the determination of the expression profile of the patient suffering from cancer, to determine the most suitable checkpoint inhibitor to use, in particular using a method such as disclosed herein.
Preferably, the treatment with the combination or composition according to the invention is administered regularly, preferably between every day, every week or every month, more preferably between every day and every one, two, three or four weeks. Preferably, the treatment with the combination or composition according to the invention is administered every two days. In a particular embodiment, the treatment is administered several times a day, preferably 2 or 3 times a day.
In one particular embodiment, the Mcoln activator, preferably ML-SA1, is administered every two days and the checkpoint inhibitor, preferably a PD-1/PD-L1 inhibitor or a CTLA-4 inhibitor, even more preferably an anti-PD-1, anti-PD-Ll or anti-CTLA-4 antibody is administered every four days.
The duration of treatment is preferably comprised between 1 day and 20 weeks, more preferably between 1 day and 10 weeks, still more preferably between 1 day and 4 weeks, even more preferably between 1 day and 3 weeks. In a very particular embodiment, the treatment lasts three weeks. Alternatively, the treatment may last as long as the disease persists.
Cancer
The invention provides a combination or a pharmaceutical composition comprising a Mcoln activator and a checkpoint inhibitor for use in the treatment of a subject having a cancer, comprising administering to the individual an effective amount of the combination or pharmaceutical composition.
More generally, the invention provides a combination or a pharmaceutical composition comprising a Mcoln activator and a checkpoint inhibitor for use in the treatment of a subject having a disease or disorder associated with an altered TFEB or Mcoln pathway, in particular a mutated or deficient TFEB (Transcription factor EB, UniProtKB - P19484) or a mutated or deficient Mcoln, e.g. Mcoln-1, and/or a disease or disorder that can be improved by increasing the migration of immune cells.
In one embodiment, the cancer is a solid tumor such as sarcoma, carcinoma, and lymphoma.
In a particular embodiment, the cancer is selected among a carcinoma, a sarcoma, a leukemia, a lymphoma, a blastoma and a melanoma, preferably a sarcoma, carcinoma and melanoma. The cancer is preferably a solid tumor or a hematopoietic malignancy. For instance, the cancer may be selected
from the non-exhaustive list comprising chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), or chronic lymphocytic leukemia. More preferably, the cancer is selected from the list consisting of lung cancer, breast cancer, melanoma, colon and/or rectum cancer, renal cancer, prostate cancer, pancreas cancer and cervix/ovary cancer. Particularly, the cancer is colon cancer.
In one particular aspect, the invention provides a combination or a pharmaceutical composition comprising a Mcoln activator and a PD-1/PD-L1 inhibitor for use in the treatment of a subject having a cancer, comprising administering to the individual an effective amount of the Mcoln activator and the PD-1/PD-L1 inhibitor.
In such particular embodiment, a subject who needs a treatment or is treated is a patient having cancer, suspected of having cancer, or at risk of having cancer, in particular a PD-1 or PD-L1 positive cancer, even more preferably a cancer where PD-1 or PD-L1 is expressed or overexpressed. For example, a patient suitable for the treatment can be identified by examining the gene expression profile of the patient and/or whether such a patient carries PD-L1 positive tumor cells. Preferably, by "PD-L1 positive tumor cells" or "PD-L2 positive tumor cells" is intended to refer to a population of tumor cells in which PD-L1 or PD-L2, respectively, are expressed in at least 10% of tumor cells, preferable at least 20, 30, 40 or 50 % of tumor cells.
Additionally or alternatively, the subject suitable for the treatment is a subject having tumor infiltrating T cells that express or overexpress PD-1.
The present invention is also useful for treatment of metastatic cancers, especially metastatic cancers that express PD-L1 (Iwai et al. (2005) Int. Immunol. 17: 133-144).
In another embodiment, the cancer is a CTLA-4 positive cancer. Accordingly, a subject who needs a treatment or is treated is a patient having cancer, suspected of having cancer, or at risk of having cancer, in particular a CTLA-4 positive cancer, even more preferably a cancer where CTLA-4 is expressed or overexpressed. For example, a patient suitable for the treatment can be identified by examining the gene expression profile of the patient and/or whether such a patient carries CTLA-4 cells, in particular having tumor infiltrating T cells that express or overexpress CTLA-4.
In an embodiment, the cancer is a cancer with high probability or risk of metastasis. In particular, it could be a primary cancer associated with lymph node invasion by tumor cells.
Kit
An additional object according to the invention is a kit, an administration kit or a pharmaceutical kit comprising the combination or composition according to the invention, in particular such as described here above. The present disclosure also provides kits comprising the combination or composition according to the invention, for use in the treatment of cancer, particularly for reducing tumor growth and/or size.
The invention thus also has as its object a kit comprising the combination of a Mcoln activator and a checkpoint inhibitor, said kit being adapted to subjects suffering from cancer. The kit(s) may be tailored to a particular cancer for an individual, the Mcoln activator and the checkpoint inhibitor being chosen for example by the method provided herein.
Particularly, said kit comprises i) a composition comprising a Mcoln activator and a checkpoint inhibitor or ii) a composition comprising a Mcoln activator, and a composition comprising a checkpoint inhibitor.
In a particular embodiment, said kit comprises 1) a composition comprising the Mcoln activator, and 2) a composition comprising a PD-1 checkpoint inhibitor, preferably an anti-PDl antibody.
In one aspect there is provided a combination kit comprising i) the Mcoln activator, preferably in association with a pharmaceutically acceptable carrier; and ii) the checkpoint inhibitor, preferably in association with a pharmaceutically acceptable carrier.
Preferably the kit comprises i) MLS-A1 preferably in association with a pharmaceutically acceptable carrier; and ii) an anti PD-1 antibody, an anti-PD-Ll antibody or a CTLA-4 antibody, preferably in association with a pharmaceutically acceptable carrier.
In one embodiment the combination kit comprises: a first container comprising a Mcoln activator such as disclosed herein, preferably in association with a pharmaceutically acceptable carrier; and a second container comprising a checkpoint inhibitor such as disclosed herein, preferably in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. In an embodiment, the invention relates to a kit as defined above for a single-dose administration unit. The kit of the invention may also contain a first recipient comprising a dried/lyophilized Mcoln activator and/or immune checkpoint inhibitor and a second recipient comprising an aqueous formulation. In
certain embodiments of this invention, kits containing single-chambered and multi-chambered pre filled syringes (e.g., liquid syringes and lyosyringes) are provided.
The compositions comprised in the kit according to the invention may also be formulated into a syringe compatible composition. In this case, the container means may itself be a syringe, pipette, or the like.
The kits of this invention are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like.
Preferably the components of the kit are provided in a form which is suitable for sequential, separate and/or simultaneous administration.
The kit can also be provided by instruction, such as dosage and administration instructions. Such dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
In some embodiments, the kit further includes an additional agent for treating cancer, and the additional agent may be combined with the combination or composition according to the invention, or other components of the kit of the present invention or may be provided separately in the kit. Particularly, the kits described herein may include one or more additional therapeutic agents such as those described in the "Additional Therapy" described here above.
The characteristics of the compositions present in the kit are similar to those of the composition according to the invention, particularly in terms of the mass ratio of Mcoln activator and the checkpoint inhibitor to each other.
Each composition present in the kit may comprise one or more additional ingredients selected from the additional pharmaceutically acceptable carrier, additives, excipients and active ingredients as described above.
Further aspects and advantages of this invention are disclosed in the following experimental section, which should be regarded as illustrative and not limiting the scope of this application.
Brief Description of the Drawings
Figure 1: Lack of ML-SA1 toxicity in vivo (no mouse weight fluctuation).
Figure 2: Impact of ML-SA1 alone (10 mg/Kg) or in combination with anti-PDl antibody (10 mg/Kg) on MC38 tumor growth in C57BL/6 mice.
Figure 3: Impact of ML-SA1 (10 mg/Kg) with/without anti-PDl antibody (10 mg/Kg) on MC38 tumor growth in irradiated C57BL/6 mice reconstituted with WT or TRPMLl KO bone marrows.
Figure 4: Impact of MLSA1 (10 mg/Kg) and MLSA5(5 or 10 mg/Kg) on B16-OVA tumor growth in CBL/6 mice.
Examples
Materials and Methods
ML-SA1 and MLSA5 were dissolved in DMSO at 20 mg/ml and stored at -80°C. The solutions were prepared by diluting ML-SA1/MLSA5 in 1 mg/ml PBS. The solutions contained 30% propylene glycol, 30% polyethylene glycol 300, 35% PBS and 5% ML-SA1/MLSA5 at 20 mg/ml.
Mice are injected with MC38 or B16-OVA cancer cells subcutaneously, in the flank (5x10s cells in a volume of IOOmI of PBS). As soon as the tumors were palpable (typically 6 days for MC38 or 7 days for B16-OVA upon tumor cell injection), mice are injected four times a week over 15/16 days with ML- SA1/MLSA5 at 5mg/Kg or 10 mg/kg. In MC38 model, mice also received two injections per week of anti-PDl antibody (Mouse anti-PDl (clone RMP1-14, BioXcell)) at 10 mg/kg. ML-SA1 and anti-PDl injections are done intraperitoneally.
Tumors are measured every two days starting from day 6 for MC38 and day 7 for B16+OVA. Mice were sacrificed 15/20 days after tumor cell injection, tumors and tumor-draining lymph nodes were dissected, digested and analyzed by flow cytometry for immune cell infiltration.
Results
The inventors were able to show that activation of TRPML1 by the small molecule ML-SA1 leads to decreased tumor growth in the presence of the anti-checkpoint inhibitor anti-PDl in vivo. This observation was made using the MC38 tumor model, which originates from a murine colon carcinoma. This model was chosen because anti-PDl antibody had limited effect in this model, allowing to have a window of improvement with ML-SA1.
Three sets of experiments were performed:
1. Lack of ML-SA1 toxicity in vivo (Figure 1)
The TRPML1 agonist ML-SA1 was tested at two doses for its toxicity in C57BL/6 mice at two concentrations (5 and lOmg/kg), according to the compound's solubility limitations. Intraperitoneal injections of the drug were done every 2 days during 3 weeks. Mice were weighted every day. After 3 weeks, they were sacrificed and the morphology of their organs was analyzed. No weight loss or any sign of toxicity was observed at both ML-SA1 doses. The inventors therefore decided to perform the next experiments using the lOmg/kg ML-SA1 dose.
2. Impact of ML-SA1 alone or in combination with anti-PDl antibody on tumor growth (Figure
2)
This experiment has been conducted with MC38 tumoral cells (colon adenocarcinoma cells). 10s MC38 cells were injected subcutaneously in 3-month old female C57BL/6 mice and after 5 days (when tumors were visible), mice were randomized and divided in 4 groups of 8 mice, and treaded as follows:
- Group 1: Control group, mice were injected with PBS.
- Group 2: Mice were injected every 2 days with ML-SA1 (lOmg/kg, intraperitoneally).
- Group 3: Mice were injected with anti-PDl antibody every 4 days (at lOmg/kg, intraperitoneally in all experiments throughout the project).
- Group 4: Mice were injected with both ML-SA1 and anti-PDl antibody at the same dose and frequency than in Groups 2 & 3.
Tumors were measured every two days until mouse sacrifice (3 weeks after tumor injection).
Anti-PDl antibody had very little effect on tumor growth in these settings, as expected for this tumor cell line. ML-SA1 showed no effect when injected alone. In sharp contrast, combination of anti-PDl antibody and ML-SA1 decreased tumor growth by approximately 40%. These results suggest that ML- SA1 enhances the efficacy of the anti-checkpoint therapy targeting PD-1.
3. Impact of ML-SA1 alone or in combination with anti-PDl antibody on tumor growth in irradiated mice (Figure 3)
The same experimental design was applied to C57BL/6 mice that had been irradiated and repopulated with bone marrow from TRPML1WT or TRPML1KO animals (for 2.5 months). These animals therefore have or not a TRPML1 deficiency restricted to their bone-marrow-derived immune cells, including DCs, T cells, B cells, NK cells and monocyte-derived cells. Reconstitution with both types of bone marrow was equally efficient, as shown by flow cytometry on lymph node-resident immune cells. 6 groups of 8 mice were treated in the following conditions:
- Group 1: TRPML1WT injected with PBS.
- Group 2: TRPML1WT injected with anti-PDl antibody.
- Group 3: TRPML1WT injected with both ML-SA1 and anti-PDl antibody.
- Group 4: TRPML1KO injected with PBS.
- Group 5: TRPML1KO injected with anti-PDl antibody.
- Group 6: TRPML1KO injected with both ML-SA1 and anti-PDl antibody.
The first conclusion is that TRPML1WT mice perfectly reproduce the results described above in 2): while anti-PDl antibody has little effect on MC38 tumor growth, combining this antibody with ML-SA1 reduced tumor growth by approximately 40%. The second conclusion is that ML-SA1 decreases tumor growth by targeting TRPML1 in immune cells rather than in other cells, as there is no effect of this small molecule in mice exhibiting a TRPML1KO immune system. This further demonstrates the specificity of ML-SA1 for TRPML1. Finally, the third conclusion that the inventors can draw from this experiment is that even in the absence of ML-SA1, TRPML1 expression in immune cells limits tumor growth as mice reconstituted with TRPML1KO bone marrow showed enhanced tumor growth as compared to their TRPML1WT counterpart.
Altogether, these results show that 1) TRPML1 helps immune cells limiting tumor growth and 2) stimulation of TRPML1 activity in vivo enhances the efficiency of anti-PDl immunotherapy.
4. Impact of ML-SA5 on tumor growth in mice (Figure 4)
This experiment has been conducted with another model of tumoral cells, i.e. B16-OVA cells (melanoma). 10s B16-OVA cells were injected subcutaneously in 2-month old female C57BL/6 mice and after 7 days (when tumors were visible), mice were randomized and divided in 4 groups of 10 mice, and treaded as follows
- Group 1: Mice injected with PBS + vehicle (Control)
- Group 2: Mice injected with ML-SA1 (10 mg/ml).
- Group 3: Mice injected with ML-SA5 (5 mg/ml).
- Group 4: Mice injected with ML-SA5 (10 mg/ml).
The mice were treated on day 7 upon tumor injection (time at which the inventors start palpating tumors). Injections were made on days 7, 8, 10, 11, 13 and 14). Injections were made intra-peritoneally.
Tumors were measured every two days until mouse sacrifice (2 weeks after tumor injection).
ML-SA5 at 10 mg/Kg clearly inhibited B16-OVA tumor growth and showed a stronger effect on the tumor size than ML-SA1 lOmg/Kg, more precisely with a 2 fold increase. In addition, MLSA1 lOmg/kg
showed similar results to MLSA5 5mg/kg, suggesting that MLSA5 is more potent than MLSA1 in inhibiting tumor growth.
Task 1.1. Optimizing the dose of ML-SA1 in the MC38 model
So far, the inventors have injected mice with the ML-SA1 dose of lOmg/kg every 2 days, starting on day 5 upon tumor injection (time at which the inventors start palpating tumors). This dose was chosen based on the solubility of ML-SA1 and the toxicity analysis (see figure 1). However, lower doses are to be tested. Indeed, this is important to envision transposition to the clinic, for which the minimal active dose of ML-SA1 must be known. This one will also be more suited to decipher the molecular mechanism of ML-SA1.
Experiments are performed as above: transplanting 10s MC38 tumor cells in female C57BL/6 mice, and measuring tumors every 2 days. All injections are made intra-peritoneally. For each ML-SA1 dose (0.5, 1 or 5 mg/kg), the 3 following conditions are tested, preferably with 8 mice per group:
- Group 1: Mice injected with PBS.
- Group 2: Mice injected with anti-PDl antibody.
- Group 3: Mice injected with both ML-SA1 and anti-PDl antibody.
The inventors also test whether enhancing the amount of ML-SA1 administered to mice can increase its synergistic effect with anti-PDl antibodies or even show an effect of the drug on its own. Indeed, preliminary results indicating that tumors grow faster in TRPML1KO mice suggest that ML-SA1 could maybe have an effect alone if administered at higher dose. However, the solubility of this compound prevents from using higher concentrations. The inventors therefore address this question by enhancing the frequency of injections, adding the two following groups of mice:
- Group 4: Mice injected with ML-SA1 (lOmg/kg) alone every day (instead of every 2 days).
- Group 5: Mice injected with ML-SA1 (lOmg/kg) every day and anti-PDl antibody (injected every 2 days)
Mice from groups 1 & 2 are sacrificed 3 weeks after tumor injection. In contrast, mice treated with ML- SA1 plus anti-PDl antibody, which should decrease tumor growth, are maintained further to evaluate how long-lasting can be the effect of these combined therapies.
These experiments allow finding the dose of ML-SA1 working in monotherapy and/or defining the optimal dose of ML-SA1 to be used to limit tumor growth in combination with anti-PDl therapy. They further highlight the duration of the anti-tumor growth effect of the MLSA1 plus anti-PDl combination.
Task 1.2: Evaluating the impact of ML-SA1 in combination with anti-PDl antibody on other tumor models
Once the dose of ML-SA1 optimized on the MC38 model, the impact of the drug on 2 additional tumor models available are assessed. These models include the colon adenocarcinoma MCA205, which responds to anti-checkpoint therapy and the B16-F10 melanoma cell line, which is resistant to anti- PDl. Experiments are performed using the four groups of mice described in Task 1.1. All tumors are implanted in female C57BL/6 mice (10s cells/mouse, already optimized), and tumor size are measured every two days. Mice are sacrificed between 2 and 3 weeks after tumor injection, depending on the size of the tumor in respect with the animal ethical rules.
These experiments highlight whether the combination of ML-SA1 plus anti-PDl antibody limits the growth of two additional tumor models described as differently sensitive to anti-checkpoint immunotherapy.
Confirmation of inhibition of tumor growth by MLSA1 alone has already been obtained in a melanoma cell model (Figure 4).
Task 1.3: Evaluating the impact of ML-SA1 on tumor growth in combination with other anticheckpoint inhibitors than anti-PDl
The inventors perform similar experiments but comparing the combination of ML-SA1 with two other anti-checkpoint inhibitors having different mode of actions than anti-PDl inhibitors: anti-PD-Ll and anti-CTLA4 inhibitors. Indeed, anti-PD-Ll antibodies have been described to have an effect on tumor growth by a mechanism involving glucose metabolism, independently from its interaction with PD-1. Anti-CTLA4 antibodies have been proposed to act on tumor growth by targeting regulatory lymphocytes (Tregs). The inventors therefore evaluate if these two additional anti-checkpoint antibodies can synergize with ML-SA1 in different ways as compared to anti-PDl antibodies. Flence, these experiments may be informative on the mechanism by which TRPML1 activation by ML-SA1 can decrease tumor growth.
For the experiments of Task 1.3, the optimal dose of ML-SA1 defined above is used (Task 1.1) and the tumor cell lines whose growth is the most inhibited by this dose of ML-SA1 in combination with anti- PDl (Task 1.2).
4 groups of 8 mice are treated in the following conditions:
- Group 1: Mice injected with PBS.
- Group 2: Mice injected with ML-SA1.
- Group 3: Mice are injected with anti-PDLl antibody or anti-CTLA4 antibody (1 intra-peritoneal injection every 4 days at lOmg/kg, as for anti-PDl).
- Group 4: Mice injected with both ML-SA1 and anti-PD-Ll antibody or anti-CTLA4 antibody as in Groups 2 & 3. Tumor size is assessed every two days.
These experiments highlight whether the combination of ML-SA1 plus anti-PD-Ll antibody or anti- CTLA4 antibody limits tumor growth (as so far observed for the ML-SA1 + anti-PDl combination). This allow optimizing the conditions for ML-SA1 to enhance the efficacy of anti-checkpoint inhibitor therapies. Task 1.4: Evaluating the impact of ML-SA5 on tumor growth in combination with anti-PDl inhibitors or in combination with other anti-checkpoint inhibitors than anti-PDl
The inventors perform similar experiments but comparing the combination of ML-SA5 with an anti- PDl inhibitors, anti-PD-Ll and/or anti-CTLA4 inhibitors on different tumor models (for example such as B16-OVA and MC38). The inventors define the optimal dose of ML-SA5 in combination with an anti-PDl inhibitors, anti-PD- Ll and/or anti-CTLA4 inhibitors.
4 groups of 8 mice are treated in the following conditions:
- Group 1: Mice injected with PBS.
- Group 2: Mice injected with ML-SA5. - Group 3: Mice are injected with anti-PDl antibody, anti-PDLl antibody or anti-CTLA4 antibody (1 intra-peritoneal injection every 4 days at lOmg/kg, as for anti-PDl).
- Group 4: Mice injected with both ML-SA5 and anti-PDl antibody, anti-PD-Ll antibody or anti-CTLA4 antibody as in Groups 2 & 3.
Tumor size is assessed every two days. These experiments highlight whether the combination of ML-SA5 and anti-PDl antibody, anti-PD-Ll antibody or anti-CTLA4 antibody limits tumor growth (as so far observed for the ML-SA1 + anti-PDl combination).
Since ML-SA5 is more effective than ML-SA1, it is believed that the combination with the immune checkpoint inhibitor is also more effective on the reduction of the tumor.
The inventors have injected mice with the ML-SA5 dose of 5 or lOmg/kg. However, lower doses are to be tested. Indeed, this is important to envision transposition to the clinic, for which the minimal active dose of ML-SA5 must be known. Tests are to be performed in a similar manner as described in Task 1.1 for ML-SA1.
Claims
1- A composition or combination comprising an activator of mucolipin (Mcoln) and an immune checkpoint inhibitor for use in the treatment of a cancer in a subject.
2- The composition or combination for use according to claim 1, wherein the activator of Mcoln is selected from the group consisting of i) a small molecule or peptide activating Mcoln such as ML- SA1, ML-SA5, SF-21, SF-22, SF-51, SN-2, MK6-83, phosphatidylinositol-3, 5-biphosphate (Ptdlns(3,5)P2) and a derivative or analog thereof, and ii) an agonist antibody directed against Mcoln.
3- The composition or combination for use according to claim 2, wherein the activator of Mcoln is selected from the group consisting of ML-SA1, ML-SA5, SF-21, SF-22, SF-51, SN-2, MK6-83, Ptdlns(3,5)P2 and a derivative or analog thereof, preferably is ML-SA1 or a derivative or analog thereof.
4- The composition or combination for use according to claim 2, wherein the activator of Mcoln is ML-SA1 or ML-SA5 or a derivative or analog thereof activating Mcoln.
5- The composition or combination for use according to claim 2, wherein the activator of Mcoln is ML-SA1 or a derivative or analog thereof activating Mcoln.
6- The composition or combination for use according to any one of claims 1 to 5, wherein the immune checkpoint inhibitor is an inhibitor of an immune checkpoint selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, CD86, CD80, CD28, CD40, CD40L, ICOS, ICOS-L, OX40L, GITR, HVEM, BTLA, CD160, LIGHT, TNFRSF25, 2B4, CD48, Timl, Tim3, Tim4, Gal9, LAG-3, CD40, CD40L, CD70, CD27, VISTA, B7H3, B7H4 (B7x), TIG IT, CD112, HHLA2 (B7-H7), TMIGD2 (CD28H) and Butyrophilin-like2 (BTNL2) or any combination thereof.
7- The composition or combination for use according to claim 6, wherein the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.
8- The composition or combination for use according to claim 7, wherein the PD-1 or a PD-L1 inhibitor is i) a peptide or peptidomimetic inhibiting PD-1/PD-L1 interaction such as AUNP-12, (D)-PPA 1, BMS202, hPRDX5 and a derivative, variant or analog thereof; ii) a small molecule inhibiting PD-l/PD- L1 interaction such as molecules containing a sulfamonomethoxine or sulfamethizole scaffold and iii) an anti-PDl or anti-PD-Ll antibody.
9- The composition or combination for use according to claim 7, wherein the PD-1 or a PD-L1 inhibitor is an anti-PDl or anti-PD-Ll antibody.
10- The composition or combination for use according to claim 7, wherein the PD-1 or PD-L1 inhibitor is selected from the group consisting of atezolizumab, durvalumab, avelumab nivolumab, pembrolizumab, pidilizumab, cemiplimab, camrelizumab, sintilimab (IBI308), tislelizumab (BGB-A317),
toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), BMS 936559, MPDL3280A, MSB0010718C, MEDI4736 and any combination thereof.
11- The composition or combination for use according to claim 6, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.
12- The composition or combination for use according to claim 11, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of atezolizumab, durvalumab, avelumab nivolumab, pembrolizumab, pidilizumab, cemiplimab, camrelizumab, sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), BMS 936559, MPDL3280A, MSB0010718C, MEDI4736 and any combination thereof
13- The composition or combination for use according to claim 6, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, preferably an anti-CTLA-4 antibody.
14- The composition or combination for use according to any one of claims 1 to 13, wherein the cancer is a solid tumor such as sarcoma, carcinoma, and lymphoma.
15- The composition or combination for use according to any one of claims 1 to 14, wherein the cancer is selected from the group consisting of prostate cancer, lung cancer, head and neck cancer, breast cancer, gastric cancer, kidney cancer, ovarian cancer, hepatocellular cancer, osteosarcoma, melanoma, hypopharynx cancer, esophageal cancer, endometrial cancer, cervical cancer, pancreatic cancer, liver cancer, colon cancer, colorectal cancer, brain cancer, renal cancer, neuroendocrine tumors, muscle cancer, adrenal cancer, thyroid cancer, uterine cancer, skin cancer and bladder cancer, preferably colon cancer.
16- The composition or combination for use according to any one of claims 1 to 15, wherein the subject does not respond to a treatment with a PD-1 inhibitor alone.
17- The combination for use according to any one of claims 1 to 16, as a combined preparation for simultaneous, separate or sequential use.
18- A pharmaceutical composition comprising a molecule activating Mcoln and an immune checkpoint inhibitor, in particular as defined according to any one of claims 2-13.
19- A combination comprising a molecule activating Mcoln and an immune checkpoint inhibitor according to anyone of claims 2-13.
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