WO2024251978A1 - Conjugué de médicament ciblant ctla4, produits le comprenant et leurs utilisations thérapeutiques - Google Patents

Conjugué de médicament ciblant ctla4, produits le comprenant et leurs utilisations thérapeutiques Download PDF

Info

Publication number
WO2024251978A1
WO2024251978A1 PCT/EP2024/065790 EP2024065790W WO2024251978A1 WO 2024251978 A1 WO2024251978 A1 WO 2024251978A1 EP 2024065790 W EP2024065790 W EP 2024065790W WO 2024251978 A1 WO2024251978 A1 WO 2024251978A1
Authority
WO
WIPO (PCT)
Prior art keywords
ctla4
drug conjugate
agent
cancer
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/065790
Other languages
English (en)
Inventor
Sandrine SUSINI
Lambros TSELIKAS
Aurélien MARABELLE
Romane MARTINEAU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut Gustave Roussy (IGR)
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Saclay
Original Assignee
Institut Gustave Roussy (IGR)
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Saclay
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institut Gustave Roussy (IGR), Institut National de la Sante et de la Recherche Medicale INSERM, Universite Paris Saclay filed Critical Institut Gustave Roussy (IGR)
Priority to IL324808A priority Critical patent/IL324808A/en
Priority to AU2024284619A priority patent/AU2024284619A1/en
Priority to KR1020257043784A priority patent/KR20260021654A/ko
Priority to CN202480037748.0A priority patent/CN121511099A/zh
Publication of WO2024251978A1 publication Critical patent/WO2024251978A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], 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 [IG], 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • 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
    • C07K2317/77—Internalization into the cell

Definitions

  • the present invention relates to a new drug conjugate comprising a Cytotoxic-T-Lymphocyte- Antigen 4 protein (CTLA4) targeting molecule, preferably an anti-CTLA4 monoclonal antibody, at least one cytotoxic agent, and a linker connecting the CTLA4 targeting molecule and the cytotoxic agent, as well as combinations, compositions and kits comprising such a drug conjugate, and to uses thereof in particular for treating cancer and/or for preventing a cancer relapse in a subject in need thereof.
  • CTL4 Cytotoxic-T-Lymphocyte- Antigen 4 protein
  • anti-PD(L)l and anti-CTLA4 immunotherapies are currently being developed for primary (localized) tumors in neo-adjuvant and adjuvant settings, as well as in metastatic settings for most cancers.
  • gains in relapse-free survival and overall survival for localized and metastatic cancers are achieved at the cost of severe adverse autoimmune or inflammatory toxic events of grade 3 to 5 according to Common Terminology Criteria for Adverse events (CTCAE), events also known as immune related adverse events (or irAEs). This toxicity is observed in a higher proportion of patients suffering of a localized cancerous tumor than in metastatic patients (>30%).
  • CTLA4 immune checkpoint blockade antagonistic to CD80 and CD86
  • ADCC Antibody Derived Cell Cytotoxicity
  • ADCP Antibody Derived Cell Phagocytosis
  • Intravenous anti-CTLA4 immunotherapy is currently approved for the treatment of localized melanoma and metastatic Melanoma (“MM”), Renal Cell Carcinoma (RCC), MSI-H/MMRd (Micro Satellite Instable High / Mismatch Repair Deficient) colorectal Cancer, Hepatocellular Carcinoma, Non-Small Cell Lung Cancer (“NSCLC”) and Malignant Pleural Mesothelioma, but at the cost of significant irAEs.
  • MM localized melanoma and metastatic Melanoma
  • RRCC Renal Cell Carcinoma
  • MSI-H/MMRd Micro Satellite Instable High / Mismatch Repair Deficient
  • NSCLC Non-Small Cell Lung Cancer
  • Malignant Pleural Mesothelioma but at the cost of significant irAEs.
  • an insufficient antitumor effect of those products is typically related to the limitation of the dose that can be administered systemically because of on-target off-t
  • the approved doses and regimens of these products is typically determined in Phase I clinical trials with a dose escalation part that stop at the maximum tolerated doses when treated patients faced dose limiting toxicities.
  • the combination of immunotherapies are limited by their additional and sometime synergistic effects on systemic toxicities.
  • the treatment of local cancers (Stages I-II, +/- III) with systemic immunotherapies is limited by the level of irreversible and sometime fatal effects of immunotherapies administered intravenously where the benefit/risk ratio is not comparable to the one observed for patients suffering of advanced relapsing/refractory cancers.
  • Inventors herein provide new therapeutic tools advantageously usable in the context of cancer treatment.
  • This drug conjugate comprises i) a Cytotoxic-T-Lymphocyte- Antigen 4 protein (CTLA4) targeting molecule, preferably an anti-CTLA4 monoclonal antibody, ii) at least one cytotoxic agent, and iii) a linker connecting the CTLA4 targeting molecule and the cytotoxic agent.
  • CTLA4 Cytotoxic-T-Lymphocyte- Antigen 4 protein
  • ADC anti-CTLA4 Antibody-Drug Conjugate
  • the anti-CTLA4 ADC comprises i) ipilimumab or tremelimumab as the anti-CTLA4 monoclonal antibody, ii) any cytotoxic agent as herein described, and iii) any linker as herein described connecting the anti-CTLA4 monoclonal antibody and the cytotoxic agent.
  • Patent application W02020/092155 describes a particular polypeptide having a heavy chain variable region and/or light chain variable region that specifically binds to CTLA4 protein as well as antibodies and fragments containing the same.
  • CTLA-4- targeted engineered toxin body (“ETB)” (“MT-8421”) which may be used alone or after a treatment with a aPD-1 monoclonal antibody.
  • ETB CTLA-4- targeted engineered toxin body
  • MT-8421 a drug conjugate according to the present invention comprising an anti-CTLA4 monoclonal antibody (mAh) such as ipilimumab or tremelimumab.
  • mAh anti-CTLA4 monoclonal antibody
  • CTLA4 targeting drug conjugate allows an advantageously superior therapeutic effect compared to the effect observed with a treatment involving the (intravenous or intra-tumoral) administration of the sole anti-CTLA4 agent, with much reduced toxicity.
  • the cancerous subject to be treated is a subject whose tumor or tumor Micro Environment (TME) comprises CTLA4+ cells, preferably CTLA4+ tumor cells and/or CTLA4+ immune cells.
  • TEE tumor or tumor Micro Environment
  • the cancerous subject is a subject having (primary or secondary) resistance to (naked, i.e., unmodified, uncoupled or unlinked to any other agent) anti-CTLA4 and/or anti-PD(L)l agent(s), in particular a subject whose tumor and/or TME displays no, low level of, or dysfunctional myeloid cells, such as macrophages, said myeloid cells expressing no or low levels of the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”).
  • CD64 Fey receptor I
  • CD16a Fey receptor Illa
  • CD16b Fey receptor Illb
  • the subject to be treated is a subject whose tumor or TME does not comprise myeloid cells, in particular macrophages, positive for the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”), or a subject who comprises a proportion of myeloid cells, in particular macrophages, positive for the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”) inferior to the proportion detected in a cancerous patient, or population of cancerous patients, suffering from the same cancer identified as exhibiting a durable clinical benefit (DCB) for an anti-cancer treatment, preferably an anticancer treatment, involving in particular an anti-CTEA-4 monoclonal antibody such as for example ipilimumab or tremelimumab [used alone or in combination with an additional conventional anti-cancer therapeutic agent such as an anti-PDl (for example nivolumab)].
  • Inventors also herein describe a pharmaceutical combination involving, or pharmaceutical composition comprising, at least one drug conjugate of the invention, for example at least two distinct drug conjugates, a first conjugate comprising a first cytotoxic agent and a second conjugate comprising a distinct cytotoxic agent, the composition comprising in addition a pharmaceutically acceptable support, excipient, carrier, or diluent.
  • a pharmaceutical combination involving, or pharmaceutical composition comprising, at least one drug conjugate of the invention, and distinct therapeutic agent(s) for example selected from an immune checkpoint targeting agent, an anti-angiogenic agent, a cytotoxic agent, an hormonal agent and any combination thereof, the composition comprising in addition a pharmaceutically acceptable support, excipient, carrier, or diluent.
  • kits comprises at least two drug conjugates of the invention, or at least one drug conjugate of the invention, and distinct therapeutic agent(s) for example selected from an immune checkpoint targeting agent, an anti-angiogenic agent, a cytotoxic agent, an hormonal agent and any combination thereof.
  • distinct therapeutic agent(s) for example selected from an immune checkpoint targeting agent, an anti-angiogenic agent, a cytotoxic agent, an hormonal agent and any combination thereof.
  • the drug conjugate, combination, composition and kit herein disclosed for the first time for use for treating a cancer or for preventing a cancer relapse in a subject in need thereof, as well as any method for preventing or treating cancer comprising a step of administering the drug conjugate, combination or composition comprising the same to the subject in need thereof.
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • tumor cancer
  • tumor tumor growth
  • tumor tumor growth
  • tumor tumor growth
  • tumor tumor growth
  • tumor tumor growth
  • tumor growth tumor growth
  • tumor growth tumor growth
  • tumor growth tumor growth
  • tumor growth tumor growth and/or systemic dissemination of proliferating cells
  • cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cell proliferation.
  • cancer refers to solid tumors named for the type of cells that form them, as well as cancer of blood, bone marrow, or the lymphatic system.
  • cancers of the blood include but are not limited to leukemias, lymphomas and myeloma.
  • cancer includes but is not limited to a primary cancer that originates at a specific site in the body.
  • the term cancer also includes a cancer that has metastasized, i.e., that has spread from the place in which it started to other parts of the body, for example to the brain, bone, lung, or liver; a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from latter one.
  • the cancer is characterized by malignant tumor and/or metastasis present in the brain, bone, lung, or liver.
  • a “tumor cell” or a “cancer cell” is a cell obtained from a tumor or tissue of a subject suffering from a cancer or at risk of developing a cancer, in particular from at least one of the herein identified cancers, for example melanoma, sarcoma or carcinoma, and exhibiting well-known hallmarks of cancer cells, e.g. sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis.
  • tumor cells used to identify cells obtained from a tumor of a subject, is also used, in the present description, to identify circulating tumor cells, cells obtained from a liquid tumor biopsy, cells obtained from a tumor bed, or cells obtained from a metastasis.
  • tumor cell designates, in addition to cancerous cells, any cell present in the tumor such as for example a stromal cell (for example a fibroblast or a vessel cell) or an immune cell.
  • the tumor is a malignant (cancerous) tumor. In another particular aspect, the tumor is a “pre-malignant” (precancerous) tumor.
  • a “conventional treatment of cancer” refers to the therapy routinely applied or, if not routinely applied, appropriate and at least recommended by health authorities.
  • the “conventional” treatment is chosen by the oncologist depending on the specific cancer to be prevented or treated.
  • the conventional cancer treatment may involve for example a cytotoxic agent, an anti-angiogenic agent, an anti-hormone agent (hormonotherapy), an immunotherapeutic agent (immunotherapy), and/or the exposition of the tumor to radiations (radiotherapy).
  • adjuvant therapy refers to additional treatment given after a main mode of therapy, notably after the surgical resection of a primary tumor.
  • Neoadjuvant and “neoadjuvant setting” refer to a treatment performed before surgery.
  • scientific and clinical advances have improved the understanding of the role and phenotype of T-regulatory lymphocytes (Tregs) in the context of cancer immune tolerance.
  • Tregs T-regulatory lymphocytes
  • Inventors identified the phenotype of tumor antigen-specific Tregs among other tumorinfiltrating lymphocytes. They showed that their presence within the tumor microenvironment (“TME”) is critical to the efficacy of immunotherapies targeting the CTLA4 and PD-1 immune checkpoints. Inventors in particular identified that membrane CTLA-4 is highly expressed by these tumour antigen-specific Tregs, and showed that, upon fixation to an anti-CTLA-4 agent such as ipilimumab, CTLA-4 is internalized into the cytoplasm of CTLA-4+ cells together with said anti-CTLA-4 agent.
  • TEE tumor microenvironment
  • Inventors herein provide novel therapeutic compounds, combinations of compounds, and pharmaceutical compositions comprising such compounds, and describe uses thereof in oncology. They more particularly developed and herein describe for the first time a CTLA4 targeting drug conjugate (also herein identified simply as “the drug conjugate”) which is significantly more cytotoxic towards CTLA-4 expressing cells than the sole anti-CTLA-4 and far less toxic for the patient since the effective concentrations are for example more than 6 times lower than the standard concentration used for ipilimumab.
  • the conjugate of the invention allows an advantageously superior remedie over risk therapeutic effect - if compared to the effect observed with a treatment involving the (systemic or intra-tumoral) administration of the sole anti-CTLA4 agent.
  • a CTLA4 targeting drug conjugate is advantageously capable of inducing the selective destruction of particular CTLA4+ population of cells, thereby allowing a more efficient treatment of cancer while simultaneously decreasing the toxicity of said treatment for the subject.
  • a drug conjugate comprising i) a Cytotoxic-T- Lymphocyte-Antigen 4 protein (CTLA4) targeting molecule, preferably an anti-CTLA-4 monoclonal antibody, ii) at least one anti-cancer agent, preferably at least one cytotoxic agent, and iii) a linker connecting the CTLA4 targeting molecule and the cytotoxic agent, is herein described.
  • CTLA4 targeting molecule preferably an anti-CTLA-4 monoclonal antibody
  • at least one anti-cancer agent preferably at least one cytotoxic agent
  • a linker connecting the CTLA4 targeting molecule and the cytotoxic agent is herein described.
  • CTLA-4 is a member of the immunoglobulin superfamily that is expressed by activated T cells and transmits an inhibitory signal to T cells.
  • the CTLA-4 receptor downregulates the immune system.
  • CTLA-4 is homologous to the T-cell co-stimulatory protein, CD28, and both molecules bind to CD80 and CD86, also called B7-1 and B7-2 respectively, on antigen-presenting cells.
  • CD80 and CD86 also called B7-1 and B7-2 respectively, on antigen-presenting cells.
  • CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands.
  • CTLA-4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4.
  • CTLA-4 is found in particular as a receptor expressed at the membrane level by regulatory T cells (Tregs) after engagement of their TCR receptor (Rowshanravan et al., 2018), and contributes to their inhibitory function.
  • Tregs regulatory T cells
  • the mechanism by which CTLA-4 acts in T cells remains somewhat controversial.
  • the CTLA4 protein contains an extracellular domain, a transmembrane domain, and a cytoplasmic tail. Alternate splice variants, encoding different isoforms, have been characterized.
  • the membrane-bound isoform functions as a homodimer interconnected by a disulfide, while the soluble isoform functions as a monomer.
  • the intracellular domain is similar to that of CD28, in that it has no intrinsic catalytic activity and contains one YVKM motif able to bind PI3K, PP2A and SHP-2 and one proline -rich motif able to bind SH3 containing proteins.
  • CTLA-4 The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signaling proteins such as CD3 and LAT. CTLA-4 can also affect signaling indirectly via competing with CD28 for CD80/86 binding. CTLA-4 can also bind PI3K, although the importance and results of this interaction are uncertain.
  • the CTLA4 targeting molecule is a molecule capable of recognizing and binding CTLA4 at the surface of a cell before being internalized by the CTLA4+ cell into the cytoplasm, for example of recognizing the CTLA4 extracellular domain.
  • the CTLA4+ cell is for example a tumor cell or a lymphocyte, in particular an activated T lymphocyte, even more particularly a regulatory T cell (Treg).
  • the CTLA4 targeting molecule is preferably an anti-CTLA-4 monoclonal antibody such as for example ipilimumab or tremelimumab.
  • CTLA4 targeting molecule is a molecule that can target and bind to, or in other words, that is directed against CTLA4.
  • the CTLA4 targeting molecule can be selected for example from a molecule capable of modulating, preferably capable of inhibiting or reducing, either directly or indirectly, the function of T cells, in particular the transmission of the herein above described inhibitory signal to T cells.
  • a particular CTLA4 targeting molecule is capable of selectively destroying CTLA4+ cells, in particular CTLA4+ cancer cells or CTLA4+ lymphocytes, preferably CTLA4+ Tregs, even more preferably CTLA4+ tumor-antigen specific Tregs (“tumor Tregs”).
  • CTLA4 targeting molecule is capable of mimicking or amplifying the biological function that CTLA4 exerts on Tregs.
  • a particular and preferred CTLA4 targeting molecule is an anti-CTLA4 molecule inducing the depletion of Tregs in a subject, preferably the depletion of tumor-antigen specific Tregs (“tumor Tregs”), even more preferably the specific depletion of tumor Tregs and of Tregs present in the tumor microenvironment (TME) to the exclusion of other tumor infiltrating lymphocytes or of any other lymphocytes present in the subject.
  • TEE tumor microenvironment
  • the CTLA4 targeting molecule is an anti-CTLA4 antibody (immunoglobulin), any (functional) fragment thereof (including a single chain antibody) or any (functional) variant thereof which would be considered as equivalent by the skilled person.
  • anti-CTLA4 antibody immunoglobulin
  • any (functional) fragment thereof including a single chain antibody
  • any (functional) variant thereof which would be considered as equivalent by the skilled person.
  • antibody designates any kind of antibody such as a monoclonal antibody, a multispecific antibody (i.e. an antibody comprising a first antigen binding site and at least one second different antigen binding site; e.g. a bispecific antibody) or a single chain antibody.
  • a multispecific antibody i.e. an antibody comprising a first antigen binding site and at least one second different antigen binding site; e.g. a bispecific antibody
  • a typical antibody consists of a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (or domain) (abbreviated herein as VH) and a heavy chain constant region (hereafter CH).
  • VH heavy chain variable region
  • CH heavy chain constant region
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the antibody's isotype as IgG, IgM, IgA, IgD, and IgE, respectively.
  • the heavy chain constant region of the immunoglobulin IgG, IgD, and IgA (y, 5 and a chains respectively) comprises three domains (CHI, CH2, and CH3) and a hinge region for added flexibility, and the heavy chain constant region of the immunoglobulin IgM and IgE contains 4 domains (CHI, CH2, CH3, and CH4).
  • the antibody of the invention can be of the IgG, IgM, IgA, IgD, and IgE isotype, depending on the structure of its heavy chain. However, in a preferred embodiment, the antibody of the invention is of the IgG isotype, i.e., its heavy chain is of the gamma (y) type.
  • IgG antibodies are classified in four distinct subtypes, namely IgGl, IgG2, IgG3 and IgG4 in the order of their abundance in serum (IgGl being the most abundant).
  • the structure of the hinge regions in the y chain gives each of these subtypes its unique biological profile (even though there is about 95% similarity between their Fc regions, the structure of the hinge regions is relatively different).
  • the antibody of the invention can be of the IgGl, IgG2, IgG3 or IgG4 subtype. However, in a preferred embodiment, the antibody of the invention is of the IgGl or IgG2 subtype.
  • Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region comprising only one domain, CL.
  • VL light chain variable region
  • CL light chain constant region
  • the antibody of the invention has a Kappa light chain.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed “Complementarity Determining Regions” (CDR), which are primarily responsible for binding an epitope of an antigen, and which are interspersed with regions that are more conserved, termed “Framework Regions” (FR).
  • CDR Complementarity Determining Regions
  • FR Framework Regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the functional ability of the antibody to bind a particular antigen depends on the variable regions of each light/heavy chain pair, and is largely determined by the CDRs.
  • variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone (or hybridome).
  • the constant regions of the antibodies mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g. effector cells) and the first component (Clq) of the classical complement system.
  • antibody fragments intends to designate Fab, Fab', F(ab')2, scFv, dsFv, ds-scFv, single chain antibody, dimers, minibodies, nanobodies, diabodies, and multimers thereof and bispecific antibody fragments.
  • Antibodies can be fragmented using conventional techniques. Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments. Fab, Fab' and F(ab')2, scFv, dsFv, ds-scFv, dimers, minibodies, nanobodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques.
  • the antibody fragment of the invention is a functional fragment, i.e. an antibody fragment capable of binding and preferably inhibiting or neutralizing the activity of a molecule of interest as does the antibody it is deriving from.
  • the antibody of the invention is a monoclonal antibody.
  • a “monoclonal antibody”, as used herein, designates an antibody arising from a nearly homogeneous population of antibodies. More particularly, the antibodies of a given subject are identical except for a few possible naturally-occurring mutations which can be found in minimal proportions.
  • a monoclonal antibody consists of a homogeneous antibody arising from the growth of a single cell clone (for example a hybridoma, a eukaryotic host cell transfected with a DNA molecule coding for the homogeneous antibody, a prokaryotic host cell transfected with a DNA molecule coding for the homogeneous antibody, etc.) and is generally characterized by heavy chains of one and only one isotype and subtype, and light chains of only one type.
  • each monoclonal antibody is directed to a single epitope of an antigen.
  • antibody producing cells can be harvested from an immunized animal as described above and fused with myeloma cells by standard somatic cell fusion procedures thereby immortalizing these cells and yielding hybridoma cells.
  • Such techniques are well known in the art (e.g. the hybridoma technique originally developed by Kohler and Milstein (1975)) as well as other techniques such as the human B-cell hybridoma technique, the EBV-hybridoma technique to produce human monoclonal antibodies, and screening of combinatorial antibody libraries.
  • Hybridoma cells can be screened immunochemically for production of antibodies specifically reactive with the target polypeptide(s) so that only monoclonal antibodies binding to said polypeptide(s) are isolated.
  • the antibody or a fragment thereof of the invention may be a human, chimeric, humanized, murine, CDR-grafted, phage-displayed, bacteria- displayed, yeast-displayed, transgenic-mouse produced, mutagenized, or randomized antibody or fragment.
  • a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody (mAh) and a human immunoglobulin constant region.
  • mAh murine monoclonal antibody
  • Humanized forms of antibodies of the invention are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity.
  • donor antibody such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity.
  • framework region (FR) residues of the human immunoglobulin (recipient antibody) are replaced by corresponding non-human residues of the donor antibody.
  • humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody.
  • the humanized antibody may comprise substantially all of at least one, typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin (donor antibody having the desired specificity, affinity, and capacity) and all or substantially all of the FRs are those of a human immunoglobulin sequence.
  • a humanized antibody has one or more amino acid residues introduced into it from a source, which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain.
  • Humanization may be essentially performed by substituting hypervariable region sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
  • humanized antibodies are typically human antibodies in which some hypervariable region residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • Other methods generally involve conferring donor CDR binding affinity onto an antibody acceptor variable region framework. One method involves simultaneously grafting and optimizing the binding affinity of a variable region binding fragment. Another method relates to optimizing the binding affinity of an antibody variable region.
  • the antibody or fragment thereof of the invention may have other agents conjugated to them, such as drug, toxin or radioactive atom.
  • the CTLA4 targeting molecule is a DARPIN (designed ankyrin repeat protein), such as the MP0250 DARPin® drug, MP0317 DARPin® drug, or MP0533 DARPin® drug.
  • the CTLA4 targeting molecule is an aptamer, in particular an oligonucleotide DNA or RNA sequence binding specifically CTLA4, such as pegaptanib.
  • the CTLA4 targeting molecule is preferably an anti-CTLA4 antibody, even more preferably an anti-CTLA4 monoclonal antibody, for example quavonlimab, ipilimumab or tremelimumab, preferably ipilimumab or tremelimumab, even more preferably ipilimumab.
  • Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4. Cytotoxic lymphocytes (CTLs) can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and boosts the body's immune response against cancer cells (i.e., allows the lymphocytes to continue to destroy cancer cells). Ipilimumab was approved by the US Food and Drug Administration (FDA) in March 2011, for the treatment of melanoma.
  • FDA US Food and Drug Administration
  • Nivolumab for the treatment of advanced renal cell carcinoma, microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma.
  • MSI-H microsatellite instability
  • dMMR mismatch repair deficient metastatic colorectal cancer
  • hepatocellular carcinoma hepatocellular carcinoma
  • NSCLC non-small cell lung cancer
  • malignant pleural mesothelioma malignant pleural mesothelioma
  • ipilimumab therapy A major drawback of ipilimumab therapy is its association with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation, occurring in ten to twenty percent of patients. Serious adverse effects include stomach pain, bloating, constipation, diarrhea, fever, trouble breathing, and urinating problems. Between 5.7 and 9.1% of individuals treated with ipilimumab develop checkpoint inhibitor induced colitis. Individual cases of severe neurologic disorders following ipilimumab have been observed, including acute inflammatory demyelination polyneuropathy and an ascending motor paralysis, as well as myasthenia gravis.
  • Tremelimumab is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma (a type of liver cancer), designed to attach to and block CTLA-4.
  • the most common side effects when used in combination with durvalumab include rash, pruritus (itching), diarrhea, abdominal (belly) pain, increased levels of liver enzymes, fever, hypothyroidism (an underactive thyroid gland), cough, peripheral edema (swelling especially of the ankles and feet) and increased level of lipase (an enzyme that helps digest fat, mainly made in the pancreas).
  • Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated downregulation of T cell activation. Subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition. Unlike ipilimumab, which is an IgGl isotype, tremelimumab is an IgG2 isotype.
  • ADC antibody-drug conjugate
  • ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells.
  • ADCs are complex molecules composed of an antibody linked to a biologically active payload, typically a cytotoxic (anti-cancer) agent or drug.
  • the ADC comprises preferably a monoclonal anti- CTLA4 antibody such as ipilimumab or tremelimumab, preferably ipilimumab.
  • the payloads for oncology drug conjugate are natural product based.
  • the payload is an antineoplastic agent, in particular a chemotherapeutic agent, for example a small molecule.
  • Payloads include for example the microtubule inhibitors such as for example monomethyl auristatin (MMAE), monomethyl auristatin F (MMAF) or a maytansinoid (such as DM1 or DM4); the DNA damaging agents such as for example a calicheamicin; the topoisomerase 1 inhibitors such as for example SN38 (active metabolite of irinotecan), or exatecan.
  • MMAE monomethyl auristatin
  • MMAF monomethyl auristatin F
  • a maytansinoid such as DM1 or DM4
  • the DNA damaging agents such as for example a calicheamicin
  • the topoisomerase 1 inhibitors such as for example SN38 (active metabolite of irinotecan), or exatecan.
  • SN38 active metabolite of irinotecan
  • the payload is an anticancer agent, preferably a cytotoxic agent, typically a small molecule.
  • the cytotoxic agent can be selected for example from a microtubule inhibitor (MTI), a DNA damaging agent such as an alkylating agent or a platinum complex; a cytotoxic antibiotic; an antimetabolite; a topoisomerase I inhibitor; a RNA Polymerase Inhibitor; an antimitotic agent, and any combination thereof.
  • MMI microtubule inhibitor
  • DNA damaging agent such as an alkylating agent or a platinum complex
  • cytotoxic antibiotic such as an alkylating agent or a platinum complex
  • an antimetabolite such as an alkylating agent or a platinum complex
  • a cytotoxic antibiotic such as an alkylating agent or a platinum complex
  • an antimetabolite such as an alkylating agent or a platinum complex
  • a cytotoxic antibiotic such as an alkylating agent or a platinum complex
  • an antimetabolite such as an alkylating agent or a platinum complex
  • a cytotoxic antibiotic such as an alkylating agent or
  • the microtubule inhibitor can be for example a taxane (such as for example paclitaxel or docetaxel); a vinca alkaloid (such as for example vinblastine (VBL), vinorelbine (VRL), vincristine (VCR) or vindesine (YDS)); or an epothilone (such as for example epotilone A, epothilone B, Ixabepilone, or a semi synthetic analog of epothilone B, epothilone C, epothilone D, epothilone E or epothilone F).
  • a taxane such as for example paclitaxel or docetaxel
  • a vinca alkaloid such as for example vinblastine (VBL), vinorelbine (VRL), vincristine (VCR) or vindesine (YDS)
  • epothilone such as for example epotilone A, epothilone B, Ix
  • the microtubule inhibitor is selected from a Maytansinoid (such as DM1 or DM4), auristatin and a derivative thereof such as monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).
  • a Maytansinoid such as DM1 or DM4
  • auristatin and a derivative thereof such as monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).
  • MMAE monomethyl auristatin E
  • MMAF monomethyl auristatin F
  • MMAE and MMAF are synthetic antineoplastic agents inhibiting cell division by blocking the polymerization of tubulin. Because of their high toxicity MMAE and MMAF cannot be used as a single-agent chemotherapeutic drug.
  • the auristatin derivative is preferably MMAF.
  • a particular conjugate comprises i) ipilimumab, ii) a microtubulin inhibitor as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular conjugate comprises i) tremelimumab, ii) a microtubulin inhibitor as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalaninelysine dipeptide.
  • a particular conjugate comprises i) ipilimumab, ii) a maytansinoid as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular conjugate comprises i) tremelimumab, ii) a maytansinoid as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) DM1 as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine- lysine dipeptide.
  • a particular and preferred conjugate comprises i) tremelimumab, ii) DM1 as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) DM4 as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) tremelimumab, ii) DM4 as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular conjugate comprises i) ipilimumab, ii) auristatin or a derivative of auristatin as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular conjugate comprises i) tremelimumab, ii) auristatin or a derivative or auristatin as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular conjugate comprises i) ipilimumab, ii) DNA damaging agent as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular conjugate comprises i) tremelimumab, ii) DNA damaging agent as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine- lysine dipeptide.
  • a particular conjugate comprises i) ipilimumab, ii) calicheamicin as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular conjugate comprises i) tremelimumab, ii) calicheamicin as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) a topoisomerase 1 inhibitor as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) tremelimumab, ii) a topoisomerase 1 inhibitor as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) SN38 as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) tremelimumab, ii) SN38 as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine- lysine dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) exatecan as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) tremelimumab, ii) exatecan as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine- lysine dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) a cytotoxic agent, preferably MMAF, and iii) a cleavable linker, preferably a linker comprising a valine-citrulline dipeptide such as the “Vc” dipeptide described herein below, or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) tremelimumab, ii) MMAF as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalaninelysine dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) MMAE as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) tremelimumab, ii) MMAE as a cytotoxic agent, and iii) a cleavable linker comprising a valine-citrullindipeptide or a phenylalanine-lysine dipeptide.
  • the cytotoxic agent is a DNA damaging agent such as an alkylating agent or a platinum complex.
  • alkylating agents include in particular Nitrogen mustards (e.g., bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan); Nitrosoureas (e.g., carmustine, lomustine, streptozocin); Alkyl sulfonates (e.g., busulfan); Triazines (e.g., dacarbazine, temozolomide); and Ethylenimines (e.g., altretamine, thiotepa).
  • Nitrogen mustards e.g., bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan
  • Nitrosoureas e.g., carmustine, lomustine, streptozocin
  • Alkyl sulfonates e.g., busulfan
  • Triazines
  • platinum complexes examples include cisplatin, carboplatin and oxaliplatin.
  • the cytotoxic agent is a cytotoxic antibiotic such as for example bleomycin, a calicheamicin, daunorubicin, doxorubicin, dactinomycin, epirubicin, idarubicin, mitoxantrone, and mitomycin.
  • a cytotoxic antibiotic such as for example bleomycin, a calicheamicin, daunorubicin, doxorubicin, dactinomycin, epirubicin, idarubicin, mitoxantrone, and mitomycin.
  • the cytotoxic agent is an antimetabolite such as for example 6- mercaptopurine, fludarabine, 5 -fluorouracil, gemcitabine, cytarabine, pemetrexed, methotrexate).
  • an antimetabolite such as for example 6- mercaptopurine, fludarabine, 5 -fluorouracil, gemcitabine, cytarabine, pemetrexed, methotrexate).
  • the cytotoxic agent is a topoisomerase inhibitor such as for example Irinotecan (CPT-11) and Topotecan.
  • the cytotoxic agent is a RNA Polymerase Inhibitor such as for example Lurbinectedin and CX-5461.
  • the cytotoxic agent is an antimitotic agent, in particular a non-taxoid site microtubule-stabilizing agent such as for example Peloruside A (PLA) or laulimalide.
  • the pay load may combine several distinct cytotoxic agents, for example any combination of the herein above described anticancer agents, in particular any combination of the herein above described cytotoxic agents.
  • the drug-to-antibody ratio i.e., the number of molecules of payload per antibody
  • the CTLA4 targeting molecule for example the CTLA4 antibody, preferably the CTLA-4 monoclonal antibody, and the cytotoxic (anti-cancer) agent are linked together by a linker ensuring that less of the cytotoxic payload falls off before reaching a tumor cell, thereby improving safety and limiting dosages.
  • the stability of the linker is critical in particular when the drug conjugate is administered to the subject in need thereof via the systemic route, typically by intravenous administration
  • Linkers are based on chemical motifs including disulfides, hydrazones or peptides (cleavable), or thioethers (non-cleavable). Cleavable and non-cleavable linkers were proved to be safe in preclinical and clinical trials [see for example brentuximab vedotin which includes an enzyme (cathepsin)-sensitive cleavable linker that delivers the antimicrotubule agent MMAE to humanspecific CD30+ malignant cells, and trastuzumab emtansine which is a combination of a microtubule-formation inhibitor and of the trastuzumab antibody and which employs a stable, non-cleavable linker] .
  • brentuximab vedotin which includes an enzyme (cathepsin)-sensitive cleavable linker that delivers the antimicrotubule agent MMAE to humanspecific CD30+ malignant cells
  • linker cleavable or non-cleavable
  • cleavable linker lends specific properties to the (cytotoxic) payload.
  • a non-cleavable linker keeps the drug within the cell.
  • the entire CTLA4 targeting molecule for example the CTLA4 antibody including a CTLA4 monoclonal antibody
  • linker and payload enter the targeted CTLA4+ cell, in particular the intratumoral Treg cell, where the CTLA4 targeting molecule is degraded.
  • the resulting complex - CTLA4 targeting molecule, linker and cytotoxic agent - is considered to be the active drug.
  • cleavable linkers are detached by enzymes in the cell.
  • the (cytotoxic) payload can then escape from the targeted cell and, in a process called “bystander killing”, attack neighboring cells.
  • a particular and preferred linker of the invention is a cleavable linker such as for example an acid-labile linker, an enzyme-cleavable linker, a lysosomal protease-sensitive linker, a disulfide linker or a P-glucuronide linker.
  • a preferred acid-labile linker is cleavable at the acidic pH existing within cellular endosomes.
  • a particular and preferred enzyme-cleavable linker comprises a valine-citrulline dipeptide (also identified in the experimental part as the “Vc” dipeptide) or a phenylalanine-lysine dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) a cytotoxic agent as herein described, and iii) a cleavable linker comprising a valine-citrulline dipeptide.
  • a particular and preferred conjugate comprises i) ipilimumab, ii) a cytotoxic agent as herein described, and iii) a cleavable linker comprising a phenylalanine-lysine dipeptide.
  • Another particular conjugate comprises i) tremelimumab, ii) a cytotoxic agent as herein described, and iii) a cleavable linker comprising a valine-citrulline dipeptide.
  • a further particular conjugate comprises i) tremelimumab, ii) a cytotoxic agent as herein described, and iii) a cleavable linker comprising a phenylalanine-lysine dipeptide.
  • a particular pharmaceutical composition of the invention comprises at least one drug conjugate according to the invention, for example at least two, three or four distinct drug conjugates, a first conjugate comprising a first payload (or cytotoxic agent), and a second or other (additional) conjugate comprising a distinct pay load (or cytotoxic agent), and a pharmaceutically acceptable support, excipient, carrier, or diluent.
  • a “pharmaceutical composition” refers to a mixture of one or more of the therapeutic agents described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable support, excipient, carrier and/or diluent.
  • “Pharmaceutical composition” typically means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions of the present invention encompass any composition made by admixing a compound, of the present invention, typically in a therapeutically effective amount, preferably at least one drug conjugate and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients, such as one or more additional therapeutic, preferably anti-cancer, compounds of the present invention, or a prodrug compound or other known active substance, preferably active against cancer.
  • an “effective dosage” or “effective amount” of a compound, for example of a drug conjugate, combination or composition is an amount sufficient to affect any one or more beneficial or desired outcomes, including biochemical, histological and/or behavioral symptoms, of the disease, typically cancer, and of its complications.
  • a “therapeutically effective amount” refers to that amount of a compound, for example of a drug conjugate, combination or composition being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • a therapeutically effective amount refers to that amount which has the effect of reducing the size of the tumor, inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer, or associated to the treatment of cancer itself, decreasing the dose of other medications required to treat the disease or the secondary adverse (toxic) effects of the cancer treatment.
  • an effective dosage can be administered in one or more administrations.
  • an effective dosage of drug, compound, (pharmaceutical) combination or (pharmaceutical) composition is an amount sufficient to accomplish prophylactic (in the context of the prevention of cancer relapse) or therapeutic treatment either directly or indirectly.
  • an effective dosage of a drug, compound, combination or composition may or may not be achieved in conjunction with another drug, compound, combination or composition.
  • a “pharmaceutically acceptable support, excipient, carrier, or diluent” refers to a support, excipient, carrier, or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the active compound(s) or therapeutic agent(s).
  • the pharmaceutical acceptable support, excipient, carrier, or diluent may comprise any conventional pharmaceutical support, excipient, carrier, or diluent.
  • the choice of support, excipient, carrier or diluent will to a large extent depend on factors such as the particular mode of administration, the effect of the support, excipient, carrier or diluent on solubility and stability, and the nature of the dosage form.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents (such as hydrates and solvates).
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, and the like.
  • compositions of the invention comprises a drug conjugate, distinct therapeutic agent(s), and a pharmaceutically acceptable support, excipient, carrier, or diluent.
  • the combination, composition, or herein below described kit comprises, in addition to the CTLA4 targeting drug conjugate, at least one (i.e., one or more additional) distinct therapeutic agent, preferably anti-cancer agent(s).
  • the distinct therapeutic agent(s) is (are) typically anti-cancer agent(s).
  • the anti-cancer agent(s) may be selected for example from an immune checkpoint targeting agent, an anti-angiogenic agent, a cytotoxic agent, an hormonal agent, an aromatase inhibitor, a glucocorticoid, and any combination thereof, wherein the amounts are preferably together effective in treating the cancer.
  • the immune checkpoint targeting agent can be an anti-PDl agent [i.e., an agent targeting the Programmed Cell Death- 1 receptor (PD1)] such as for example nivolumab, pembrolizumab, cemiplimab, retifanlimab, toripalimab or dostarlimab; an anti-PDLl (Programmed Cell Death- 1 receptor ligand) agent such as for example atezolizumab, durvalumab or avelumab; an anti- LAG3 (Lymphocyte-activation gene 3) agent such as relatlimab or eftilagimod; or an anti- TIGIT (T cell immunoreceptor with Ig and ITIM domains) agent such as tiragolumab or domvanalimab.
  • PD1 Programmed Cell Death- 1 receptor
  • the anti-angiogenic agent may be a tyrosine kinase inhibitor such as for example sorafenib, sunitinib, vendetanib, lenvatinib, axitinib or cabozantinib.
  • the anti-angiogenic agent may be a monoclonal antibody directed against the vascular endothelial growth factor (VEGF) pathway (ligands or receptors), such as for example bevacizumab or aflibercept.
  • VEGF vascular endothelial growth factor
  • the cytotoxic agent may be an anti-cancer cytotoxic chemotherapeutic agent, for example an alkylating agent such as Nitrogen mustards (e.g., bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine and melphalan); Nitrosoureas (e.g., carmustine, lomustine, streptozocin); Alkyl sulfonates (e.g., busulfan); Triazines (e.g, dacarbazine, temozolomide); Ethylenimines (e.g., altretamine, thiotepa); an antimetabolite such as 6-mercaptopurine, fludarabine, 5-fluorouracil, gemcitabine, cytarabine, pemetrexed, methotrexate; a topoisomerase inhibitor such as Irinotecan (CPT-11) or Topotecan; an antibiotic such as ble
  • the hormonal agent is an agent inhibiting the estrogen or progesterone pathway such as tamoxifen.
  • the anti-cancer agent may be an aromatase inhibitor such as anastrozole (Arimidex) or exemestane (aromasin).
  • anastrozole Arimidex
  • exemestane aromasin
  • the anti-cancer agent may be a glucocorticoid pathway targeting agent such as prednisone, prednisolone, triamcinolone, methylprednisolone or dexamethasone.
  • the additional anti-cancer agent is selected from the group consisting of an oncolytic virus (e.g., T-VEC), an oncolytic peptide (e.g., LTX315) and a protein kinase C agonist (e.g., tigilanol tiglate).
  • an oncolytic virus e.g., T-VEC
  • an oncolytic peptide e.g., LTX315
  • a protein kinase C agonist e.g., tigilanol tiglate
  • the at least one distinct therapeutic agent is selected from an immune checkpoint targeting agent, a cytotoxic agent, in particular an anti-cancer cytotoxic chemotherapeutic agent, an anti-angiogenic agent, an hormonal agent and any mixture or combination thereof.
  • the (pharmaceutical) combinations or (pharmaceutical) compositions of the invention include combinations and compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient(s). Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of an active compound of the present invention.
  • active compounds are preferably administered intravenously and/or intra-tumorally.
  • a preferred route of administration for the herein described drug conjugate is the intra-tumoral route.
  • the active ingredients may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. Dosage forms include for example tablets, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • the (pharmaceutical) combination or pharmaceutical composition may be in a form for example suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, suitable for parenteral injection as a sterile solution, suspension or emulsion, suitable for topical administration as an ointment or cream, or suitable for intratumoral administration as a sterile solution, suspension, emulsion, or slow release chemical formulation allowing for an augmented stay and a slow release of the drug conjugate, in particular of the CTLA4 ADC, in the tumor micro-environment.
  • the combination or pharmaceutical composition may be in unit dosage forms suitable for single administration of precise amounts.
  • compositions suitable for the delivery of the therapeutic agents of the combination therapies of the present invention and methods for their preparation will be readily apparent to those skilled in the art.
  • Such compositions and methods for their preparation may be found, for example, in ‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.
  • Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles may be found in Verma et al. , Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The disclosures of these references are incorporated herein by reference in their entireties.
  • the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical support, excipient, carrier and/or diluent according to conventional pharmaceutical compounding techniques.
  • a pharmaceutical support, excipient, carrier and/or diluent may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous or intratumoral).
  • the daily dosage of the anti-CTLA4 or CTLA4 targeting drug conjugate administered to the subject is for example of about 0,01 mg/kg to about 10 mg/kg, preferably of about 0,1 mg/kg to about 1 or 3 mg/kg, and even more preferably of about 0, 1 mg/kg to about 1 mg/kg.
  • An effective dosage of a CTLA4 targeting drug conjugate of the invention is typically in the range of from about 0,01 mg to about 5 or to about 10 mg per kg body weight, preferably from about 0,01 to about 1 mg/kg body weight, in single or divided doses.
  • This dosage may be administered to the subject in need thereof per day or per week or every 2 weeks or every 3 weeks.
  • This dosage regimen may be adjusted by the oncologist to provide the optimal therapeutic response to the patient.
  • drug conjugate dosage levels at the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the dosage may be administered as a single dose, or optionally may be subdivided into smaller doses, suitable for a twice-daily, three times-daily or four times-daily administration.
  • an effective amount of a CTLA4 targeting drug conjugate according to the invention is generally in the range from 0,01 to 5 or to 10 mg/kg of body weight of the recipient (mammal subject) per day and particularly typically in the range from 0,01 to 1 mg/kg of body weight per day.
  • the actual amount per day for an adult human weighing 70 kg is usually between 0,7 and 70 mg, where this amount can be administered as a single dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same.
  • any active ingredient herein described may vary depending on the particular compound employed, the mode of administration, the condition of treatment and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art, typically by an oncologist.
  • the drug conjugate comprises i) ipilimumab or tremelimumab, ii) a cytotoxic agent, such as for example a microtubulin inhibitor, a maytansinoid, a DNA binding agent or a toposisomerase inhibitor, in particular for example MMAE, MMAF, DM1, DM4, calicheamicin, SN38 or exatecan, preferably anyone of DM1, DM4, MMAE or MMAF, even more preferably MMAF, and iii) a cleavable linker, preferably a linker comprising a valine - citrulline dipeptide or a phenylalanine-lysine dipeptide, and said drug conjugate is present in the combination or composition at a dose of about 0,01 mg to about 10 mg, preferably about 0,1 mg to about 1 mg, for example 0,2 mg, 0,3 mg, 0,4 mg, 0,5 mg, 0,6 mg, 0,7 mg, 0,8 mg or
  • An effective dosage of a ipilimumab is typically in the range of from about 1 to about 10 mg per kg body weight, preferably about 3 to about 10 mg/kg, for example 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg or 9 mg/kg, in single or divided doses, typically per day.
  • the drug conjugate comprises i) ipilimumab or tremelimumab, ii) a cytotoxic agent, such as for example a microtubulin inhibitor, a maytansinoid, a DNA binding agent or a toposisomerase inhibitor, in particular for example MMAE, MMAF, DM1, DM4, calicheamicin, SN38 or exatecan, preferably anyone of DM1, DM4, MMAE or MMAF, and iii) a cleavable linker, preferably a linker comprising a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide, and said drug conjugate is present in the combination or composition at a dose of about 0,01 mg to about 10 mg, preferably about 0,1 mg to about 1 mg, for example 0,2 mg, 0,3 mg, 0,4 mg, 0,5 mg, 0,6 mg, 0,7 mg, 0,8 mg or 0,9 mg, and more preferably
  • An effective dosage of a ipilimumab is typically in the range of from about 1 to about 10 mg per kg body weight, preferably about 3 to about 10 mg/kg, for example 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg or 9 mg/kg, in single or divided doses, typically per day.
  • kits described herein may be particularly suitable for administering different dosage forms, for example, oral and parenteral (typically intravenous or intra-tumoral, preferably intratumor al), for administering the separate active (in particular therapeutic) agents of the combinations or compositions at different dosage intervals, or for titrating the active (in particular therapeutic) agents of the combination or compositions against one another.
  • the kit typically includes instructions for administration.
  • the kit may further comprise other materials that may be useful in administering the medicaments, such as diluents, filters, IV bags and lines, needles and syringes, and the like.
  • the kit of the invention comprises at least two drug conjugates as herein described, or at least one drug conjugate as herein described and distinct therapeutic agent(s) as herein described, for example selected from an immune checkpoint targeting agent, an anti-angiogenic agent, a cytotoxic agent, an hormonal agent and any combination thereof.
  • a particular kit comprises a) at least a drug conjugate comprising a CTLA4 targeting molecule as herein described, in particular a drug conjugate, in particular an anti-CTLA4 ADC, comprising i) a CTLA4 targeting molecule, preferably an anti-CTLA-4 monoclonal antibody, ii) at least one cytotoxic agent, and iii) a linker connecting the CTLA4 targeting molecule and the cytotoxic agent, and b) distinct therapeutic agent(s) as herein described, for example selected from an immune checkpoint targeting agent, an anti-angiogenic agent, a cytotoxic agent, an hormonal agent and a combination thereof.
  • kits comprises a pickering emulsion of a CTLA4 targeting molecule, in particular an anti-CTLA4 ADC, formulated in poly-lactic-co-glycolic acid (PLGA) nanoparticles, with or without radiopaque ethiodized oil, in order to allow a prolonged stay and slow release of the drug conjugate in the injected tumors.
  • a CTLA4 targeting molecule in particular an anti-CTLA4 ADC
  • PLGA poly-lactic-co-glycolic acid
  • the combination or composition of the invention comprises at least a CTLA4 targeting molecule as herein described, preferably a drug conjugate comprising i) a CTLA4 targeting molecule, preferably an anti-CTLA-4 monoclonal antibody, ii) at least one cytotoxic agent such as for example a microtubulin inhibitor, a maytansinoid, a DNA binding agent or a toposisomerase inhibitor, in particular for example MMAE, MMAF, DM1, DM4, calicheamicin, SN38 or exatecan, and iii) a linker, preferably a cleavable linker as herein described such as a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide, connecting the CTLA4 targeting molecule and the cytotoxic agent.
  • the combination or composition of the invention typically comprises additional (distinct) therapeutic agent(s).
  • the several distinct (active) therapeutic agent(s) preferably an anti-CTLA-4 monoclon
  • the terms “combination” or “combination therapy” refer to the administration of each therapeutic agent(s) of the combination therapy of the invention, either alone or in the form of a pharmaceutical composition or medicament, either sequentially, concurrently, or simultaneously.
  • sequential refers to the administration of each therapeutic agent(s) of the combination therapy of the invention, either alone or in a medicament, one after the other, wherein each therapeutic agent can be administered in any order. Sequential administration may be particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and/or the agents are administered according to different dosing schedules, for example, one agent is administered daily, and the second agent is administered less frequently such as weekly.
  • the term “concurrently” refers to the administration of each therapeutic agent in the combination therapy of the invention, either alone or in separate medicaments, the second therapeutic agent being administered immediately after the first therapeutic agent, and the therapeutic agents being administered in any order.
  • the therapeutic agents are administered concurrently.
  • the term “simultaneous” refers to the administration of each therapeutic agent of the combination therapy of the invention in the same medicament.
  • the combination therapy may be usefully administered to a subject during different stages of the treatment.
  • the drug conjugate, composition or kit of the invention is for use for treating (or used in the context of the treatment of) cancer, or is for use for preventing (or used in the context of the prevention of) a cancer relapse in a subject in need thereof.
  • the term “patient” and “subject” are synonyms and refer to any single subject for which therapy is desired or that is participating in a clinical trial, epidemiological study or used as a control, including humans and mammalian veterinary patients.
  • the “subject” or “patient” is typically a mammal.
  • the subject can be a human or a non-human mammal such as a rodent, for example a mouse or a rat; a rabbit; a primate such as a monkey; a dog, a cat, a bovid, an equine, for example a horse; or transgenic species thereof.
  • the mammal is a human being, whatever its age or sex.
  • the subject is an adult human subject.
  • the subject is a human child between the ages of birth and 18 years old.
  • the drug conjugate of the invention is administered to a subject, in particular to a subject diagnosed as suffering of cancer, who is previously untreated (for cancer), i.e. who is cancer treatment naive.
  • the drug conjugate of the invention is administered to a subject suffering of cancer who has been exposed to at least one prior therapy with an anti-cancer agent, in particular to a prior therapy comprising an anti-CTLA-4 monoclonal antibody such as any monoclonal antibody herein described, in particular ipilimumab or tremelimumab [used alone or in combination with an additional conventional anti-cancer agent such as an anti-PDl (for example nivolumab)], or whose tumor(s) has (have) been surgically resected, i.e., who is a treatment experienced-subject.
  • an anti-CTLA-4 monoclonal antibody such as any monoclonal antibody herein described, in particular ipilimumab or tremelimumab [used alone or in combination with an additional conventional anti-cancer agent such as an anti-PDl (for example nivolumab)]
  • an anti-PDl for example nivolumab
  • the drug conjugate of the invention is administered to a subject, in particular to a subject diagnosed as suffering of cancer, preferably in a neoadjuvant setting (i.e. before any surgery).
  • a subject diagnosed as suffering of cancer preferably in a neoadjuvant setting (i.e. before any surgery).
  • the malignant tumor in particular primary malignant tumor and/or draining lymph nodes, has (have) not been surgically resected.
  • the subject has been exposed for example to part of a complete conventional treatment protocol, for example to at least one cycle of the total planned treatment protocol.
  • the subject has been exposed to a complete conventional protocol.
  • Patients are preferably treated with the combination or composition of the invention when disease progression and/or an unacceptable therapy induced-toxicity are observed or are expected.
  • the subject’s cancer is a cancer as herein above defined, in particular a solid cancer selected from melanoma, renal cell carcinoma (RCC), colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC), mesothelioma (MM) in particular pleural mesothelioma, or a hematological malignancy selected from a lymphoma and a leukemia.
  • a cancer as herein above defined, in particular a solid cancer selected from melanoma, renal cell carcinoma (RCC), colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC), mesothelioma (MM) in particular pleural mesothelioma, or a hematological malignancy selected from a lymphoma and a leukemia.
  • the subject’s cancer is either an early stage cancer such as a localized primary tumor, or an advanced cancer or cancer with poor prognosis such as a locally advanced cancer, a (surgically) inoperable cancer, a metastatic cancer, a recurrent cancer, or a cancer resistant to a conventional therapeutic treatment.
  • the drug conjugate, composition, combination or kit is for use (used) in combination with a radiation therapy (radiotherapy), i.e., is combined with the exposition of the subject’s tumor(s) to radiations.
  • a radiation therapy i.e., is combined with the exposition of the subject’s tumor(s) to radiations.
  • the radiation therapy can be for example external-beam radiation therapy, brachytherapy, systemic radiation therapy, notably radio-ligand based radiation therapy, or proton therapy.
  • the invention beneficiates in particular to the subjects suffering of a cancer whose tumor(s) or cancer tumor microenvironment (TME) comprise(s) CTLA4+ cells (i.e., CTLA4 expressing cells), in particular CTLA4+ tumor cells and/or CTLA4+ immune cells, preferably CTLA4+ Tregs.
  • CTLA4+ cells i.e., CTLA4 expressing cells
  • CTLA4+ tumor cells and/or CTLA4+ immune cells preferably CTLA4+ Tregs.
  • Such tumors are herein considered as being in an “immuno-editing stage”, i.e., as tumors particularly sensitive to (/ able to beneficiate from) an anti-CTLA4 drug conjugate of the invention.
  • the invention also beneficiates in particular to the subjects who, in addition of suffering of a cancer whose tumor(s) or cancer tumor microenvironment (TME) comprise(s) CTLA4+ cells (in particular CTLA4+ tumor cells and/or CTLA4+ immune cells, preferably CTLA4+ Tregs), do not or will not exhibit a “Durable Clinical Benefit” upon (naked) anti-CTLA4 and/or anti- PD(L)1 therapy (“DCB” meaning being in complete response or partial response or stable disease according to RECIST 1.1 criteria at 6 months post treatment initiation). These patients are also herein identified as “no Durable Clinical Benefit” (or “no DCB”) patients.
  • DCB “Durable Clinical Benefit” upon (naked) anti-CTLA4 and/or anti- PD(L)1 therapy
  • these subjects or patients are either patients naive to anti-cancer treatment or patients who have been exposed to anti-cancer treatment but exhibit resistance (primary or secondary resistance, preferably primary resistance) to said treatment, in particular to (naked) anti-CTLA4 and/or anti-PD(L) 1.
  • the subject naive to (anti-cancer) treatment is a subject predicted to be resistant to (naked) anti-CTLA4 and/or anti-PD(L)l agent(s).
  • a particular predicted “no DCB” subject or patient is a subject whose tumor comprises no, low level of, or dysfunctional myeloid cells, in particular macrophages, said myeloid cells expressing no or low level of the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”).
  • a low level of the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”) expressed by myeloid cells is a level insufficient to allow an ADCC or ADCP activity.
  • a dysfunctional myeloid cell is herein defined as a cell which is not able to perform an antibody derived cell cytotoxicity (ADCC) or antibody derived cell phagocytosis (ADCP).
  • ADCC antibody derived cell cytotoxicity
  • ADCP antibody derived cell phagocytosis
  • In vitro ADCC / ADCP tests may be performed by the skilled person in the art according to know methods (cf. Yamashita, M., Kitano, S., Aikawa, H. et al. A novel method for evaluating antibody-dependent cell-mediated cytotoxicity by flowcytometry using cryopreserved human peripheral blood mononuclear cells. Sci Rep 6, 19772 (2016)).
  • Another particular predicted “no DCB” subject or patient is a subject whose tumor comprises a proportion of myeloid cells, in particular macrophages, positive for Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”) inferior to the proportion detected in a cancerous patient, or population of cancerous patients, suffering from the same cancer identified, or predicted, as exhibiting a durable clinical benefit for an anti-cancer treatment, preferably an anti-cancer treatment involving in particular an anti-CTLA-4 monoclonal antibody such as for example ipilimumab or tremelimumab [used alone or in combination with an additional conventional anti-cancer therapeutic agent such as an anti-PDl (for example nivolumab)] .
  • an anti-CTLA-4 monoclonal antibody such as for example ipilimumab or tremelimumab [used alone or in combination with an additional conventional anti-cancer therapeutic agent such as an anti-PDl (
  • the “no DCB” subjects are preferred subjects in the context of the present invention. Indeed, these no DCB patients are particularly likely to benefit from the ADC of the present invention since said ADC is capable of generating a clinical benefit in said patients, or in other words is capable of turning a “no DCB” subject or patient into “DCB” subject or patient. In these DCB patients, a stabilization, or a partial or total regression, of the disease will be advantageously observed thanks to the present invention.
  • CTLA4 expressing cells sensitive to the herein described anti-CTLA4 drug conjugate are regulatory T-cells, preferably CD4+FOXP3+CTLA4-I- T cells and/or CD4+CD25+CD39+ T cells. These Treg cells are clonally expanding Treg cells specific for the tumor antigen(s).
  • Preferred subjects are subjects suffering from a cancer whose tumor(s) and/or TME comprise(s) such CTLA4 expressing cells. Those subjects are the more likely to benefit of the administration of a drug conjugate or composition comprising such a drug conjugate of the present invention, in particular a drug conjugate comprising i) a Cytotoxic-T-Lymphocyte- Antigen 4 protein (CTLA4) targeting molecule, preferably an anti-CTLA-4 monoclonal antibody, ii) at least one cytotoxic agent, and iii) a linker connecting the CTLA4 targeting molecule and the cytotoxic agent.
  • CTLA4 Cytotoxic-T-Lymphocyte- Antigen 4 protein
  • tumour antigen-specific Tregs allow the development of advantageous specific anti-tumour immune response(s) to cancer while preserving (i.e., being less toxic) to the healthy tissue, typically to the healthy tissue surrounding the tumor(s), in particular if the anti-CTLA4 drug conjugate or composition comprising said drug conjugate is intra-tumorally administered.
  • the cancerous subject to be treated is a subject whose tumor or Tumor Micro Environment (TME) comprises CTLA4+ cells, preferably CTLA4+ tumor cells and/or CTLA4+ immune cells, notably CTLA4+ Tregs.
  • TEE Tumor Micro Environment
  • the subject is a subject having resistance to (naked) anti-CTLA4 and/or anti- PD(L)1 agent(s).
  • the cancerous subject to be treated is a subject whose tumor and/or TME display(s) no, low level of, or dysfunctional myeloid cells, said myeloid cells expressing no or low levels of the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”), in particular a subject whose tumor or TME does not comprise myeloid cells, in particular macrophage, expressing no or low levels of the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”).
  • CD64 Fey receptor I
  • CD16a Fey receptor Illa
  • CD16b Fey receptor Illb
  • the subject to be treated is a subject who comprises a proportion of myeloid cells, in particular macrophages, positive for the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”) inferior to the proportion detected in a cancerous patient, or population of cancerous patients, suffering from the same cancer identified, or predicted, as exhibiting a durable clinical benefit (DCB) for an anti-cancer treatment, preferably an anti-cancer treatment, involving in particular an anti-CTEA-4 monoclonal antibody such as for example ipilimumab or tremelimumab [used alone or in combination with an additional conventional anti-cancer therapeutic agent such as an anti-PDl (for example nivolumab)].
  • DCB durable clinical benefit
  • herein described is also a method to select/ identify the subjects, typically patients, most likely to be sensitive, or more responsive, to the herein described cancer treatments, in particular to be rendered sensitive again, or more responsive, to a treatment of cancer, for example after having shown resistance to anti-cancer treatment, or having been identified or predicted as “no DCB” subjects.
  • Said method preferably comprises a step i) of determining the presence or absence of CTLA4+ cells in the tumor or in the TME (said cells being also identified as “intratumoral CTLA4+ cells”), and also possibly the presence or absence of myeloid cells in the tumor or in the TME (said cells being also identified as “intratumoral myeloid cells”), notably macrophages, and/or the expression level by said myeloid cells of the Fey receptor I (“CD64”), Fey receptor Illa (“CD16a”) and/or Fey receptor Illb (“CD16b”), and a step ii) of identifying said subject as a subject who will particularly beneficiate of a treatment as herein described comprising the administration of a drug conjugate of the invention.
  • CTEA4+ cells may be easily performed in vitro, ex vivo or in vivo, by the person of ordinary skill in the art with any commercially available anti-CTEA4 staining antibody, such as Biolegend ref 369612 (BD Biosciences ref 557301).
  • the detection and quantification of myeloid cells may be easily performed on fixed or frozen baseline tumor biopsies from cancerous patients in vitro, by the person of ordinary skill in the art with a transcriptomic assessment method such as RNAseq or qRT-PCR used to detect or quantify expression levels of anyone of the following genes: CD68, CD163, CSF1R, CD16a, CD16b and CD64, or any combination thereof, in particular CD64, CD 16a and/or CD 16b.
  • the drug conjugate or composition of the invention may be administered to the subject as a neoadjuvant therapeutic agent, preferably before any partial or total tumor surgical resection or focal destruction by any cytoreductive strategy, in monotherapy or in combination with distinct anti-cancer therapeutic agent(s), and preferably by local delivery including intra-tumoral (IT) route, intra-vascular (IV) route or topical route, via a single administration or via repeated administrations.
  • a neoadjuvant therapeutic agent preferably before any partial or total tumor surgical resection or focal destruction by any cytoreductive strategy, in monotherapy or in combination with distinct anti-cancer therapeutic agent(s), and preferably by local delivery including intra-tumoral (IT) route, intra-vascular (IV) route or topical route, via a single administration or via repeated administrations.
  • the drug conjugate of the invention can be advantageously administered intratumorally to cancer patients, in particular to patients having localized solid cancers, preferably before any cancer treatment, in particular prior surgery.
  • the intra-tumorally administered anti-CTEA4 drug conjugate in particular anti-CTEA4 ADC, herein described, maximizes the bioavailability and therefore the local efficacy of the treatment of cancer, in particular of the anti-cancer payload, by inducing the depletion of CTEA4+ immune cells in the tumor and/or tumor microenvironment while avoiding any anti-cancer treatment systemic toxicity (by considerably lowering the systemic exposure).
  • the drug conjugate of the invention can be also advantageously administered to cancer patients having metastatic malignant tumors.
  • a drug conjugate for use as a medicament, preferably for treating cancer is advantageously herein above described by inventors.
  • the corresponding therapeutic uses in particular the corresponding methods for treating cancer or preventing cancer relapse in a subject in need thereof. These methods comprise a step of administering the drug conjugate or composition of the invention comprising said drug conjugate to the subject in need thereof, alone or in combination with one or several distinct therapeutic compounds such as those herein described.
  • a preferred drug conjugate comprises i) a CTLA4 targeting molecule, in particular an anti-CTLA4 monoclonal antibody such as ipilimumab or tremelimumab, ii) at least one cytotoxic agent such as for example a microtubulin inhibitor, a maytansinoid, a DNA binding agent or a toposisomerase inhibitor, in particular for example MMAE, MMAF, DM1, DM4, calicheamicin, SN38 or exatecan, and iii) a linker, preferably a cleavable linker as herein described such as a valine-citrulline dipeptide or a phenylalanine-lysine dipeptide, connecting the CTLA4 targeting molecule and the cytotoxic agent.
  • a CTLA4 targeting molecule in particular an anti-CTLA4 monoclonal antibody such as ipilimumab or tremelimumab
  • at least one cytotoxic agent such as for example
  • Ipilimumab is internalized and localized in sub-membrane intracellular vesicles within 1 hour on CTLA4 expressing cells. Diffused Ipilimumab intracellular staining is observed upon 24hours.
  • FIG. 4 Intracytoplasmic FoxP3 and Membrane CTLA4 labeling by flow cytometry among CD4+ CD25+ CD39+ populations (double positive, single positive, or double negative) of freshly dissociated melanoma tumors.
  • CD4+CD25+CD39+ intratumoral Tregs significantly diminish in proportion upon intratumoral ipilimumab treatment.
  • Figure 6 Single cell sequencing of enriched CD45+ cells from five freshly resected tumors, (a) clonality among the 4 main subsets of T cells; (b) specific T cells clustering; (c) subset of specific T cells.
  • Intratumoral ipilimumab generates less toxicity in patients than intravenous ipilimumab while maintaining the same anti-tumor efficacy.
  • Figure 8 Generation of 3 Ipilimumab antibody-drug conjugates.
  • Lanes left to right are 1 : DM1, 2: DMl+Ipilimumab, 3: DMl+Rituximab, 4: VcMMAE, 5: VcMMAE+Ipilimumab, 6:VcMMAE+Rituximab, 7: VcMMAF, 8: VcMMAF+Ipilimumab, 8 VcMMAF+Rituximab, 10: Ladder, 11: Ipilimumab, 12: Rituximab
  • Figure 9 Phenotype of Raji hCTLA4 and Raji cell lines.
  • Figure 10 Cytotoxicity induced by in vitro ipilimumab ADC treatments on a cell line overexpressing hCTLA-4 (a, b, c) and on a control cell line which does not express CTLA4 (d).
  • Figure 11 Structural side scatter representation of RajihCTLA4 cells treated with increasing concentrations of Ipilimumab- VcMMAF, Rituximab- VcMMAF, Ipilimumab, Rituximab and VcMMAF.
  • Figure 12 The tumor microenvironment of patients resistant to ipilimumab are devoid of adequate macrophages.
  • the tumor microenvironment of patients resistant to ipilimumab are devoid of adequate macrophages (CD68 and/or CD163 and/or CSF1R) and FcgRI (CD64) and/or FcgRIIIa (CD16a) and/or FcgRIIIb (CD16b).
  • TPM transcripts per million
  • DCB clinical benefits
  • noDCB non clinical benefits
  • Ipilimumab and Rituximab were labeled to three different cytotoxic drug pay loads (DM1, VcMMAE, VcMMAF) following the manufacturer (oYoLink®’s Alpha thera) protocols. Each different payload is linked via the lysosomally cleavable dipeptide, valine-citrulline (“vc” or “Vc”).
  • Raji hCTLA-4 cell line has been grown with Iscove’s Modified Dulbecco’s Medium (Sigma Life Sciences, ref : I3390-500mL) supplemented with 10% decomplemented SVF Hyclone (Research Grade, ref : SV30160.03), 1% L-Glutamine (Gibco, ref : 25030-024), 25nM Hepes (Gibco, ref : 15630-056), 1% Penicillin/Streptomycin (Gibco, ref : 15140-122), 10 pg/ml of Blasticidin (Invivogen, ref : ant-bl-1).
  • Raji cell line has been grown with IMDM (Sigma Life Sciences, ref : I3390-500mL) supplemented with 10% decomplemented SVF Hyclone (Research Grade, ref : SV30160.03), 1% L-Glutamine (Gibco, ref : 25030-024), 1% Penicillin/Streptomycin (Gibco, ref : 15140-122).
  • the proportion of dead cells was estimated by flow cytometry using Zombie Aqua (Biolegend) staining of dead cells and expressed as the percentage of dead cells in all events excluding cell debris.
  • the cells are incubated at room temperature during 20 minutes and then washed with 2 ml of PBS.
  • inventors compared the percentage of dead cells induced by concentrations between 0 and IpM of Ipilimumab-Drug conjugates to the Rituximab-Drug conjugates, to Ipilimumab, to Rituximab and to the payloads alone at different time points: 48 hours, 72 hours and 96 hours.
  • CD4+FOXP3+ T cells called regulatory T cells or “Tregs” are a subgroup of lymphocytes with a key role in generating immune system tolerance (Lucca and Dominguez-Villar, 2020; Plitas and Rudensky, 2020). Their presence or function in excess or deficiency has been associated with autoimmune diseases or cancers respectively (Tay et al., 2023).
  • CTLA4 is a co-inhibitory (“checkpoint”) receptor expressed at the membrane level by Tregs after engagement of their TCR receptor (Rowshanravan et al., 2018). Consensus on the mechanism of action of anti- CTLA4 molecules in mice points to a specific depletion of tumour Tregs (Marabelle et al.
  • Inventors also showed by single cell sequencing (single cell RNAseq) of dissociated human tumors that the cell populations expressing high CTLA4 and in clonal expansion are represented at 79.5% by the cluster 2 population (turquoise blue) composed of Tregs (CD4+FOXP3+CD25-I-CD39-I-). This clonality of tumour-infiltrating Tregs suggests the Tregs’ proliferation after recognition of antigens from the tumour microenvironment ( Figure 6).
  • NIVIPIT clinical trial (NCT02857569)
  • inventors also demonstrated that intra-tumoral injection of small doses of the anti-CTLA4 drug ipilimumab (0.3 mg/kg) significantly reduced the toxicity of the drug while advantageously maintaining a level of efficacy comparable to that obtained at FDA and EMA approved doses in the treatment of metastatic melanoma (Figure 7).
  • a drug conjugate comprising a CTLA4 targeting molecule, in particular an intra-tumoral anti-CTLA4 antibody drug conjugate (ADC), offering a very advantageous superior efficacy to IT and IV administered anti-CTLA4 with greatly reduced toxicity, this conjugate being particularly favorable to patients suffering of cancers whose tumors are still in the immuno-editing stage involving CTLA4+ Tregs.
  • ADC intra-tumoral anti-CTLA4 antibody drug conjugate
  • inventors generated 3 ipilimumab antibody drug conjugates with the anti- CTLA4 antibody being conjugated to three different payloads: DM1 (Emtansine), VcMMAE (monomethyl auristatin E) and VcMMAF (monomethyl auristatin F) by using the Alpha Thera’s oYoLink® technology.
  • Ipilimumab following the CTLA4 intracellular trafficking (Khailaie et al., 2018), they chose a lysosomally cleavable dipeptide valine-citrulline linker (Alpha Thera’s oYoLink® Technology) ( Figure 3).
  • the anti-CD20 Rituximab antibody was coupled to these same drugs as a positive control since the CTLA4+ transgenic cell line was derived from the CD20+ Raji lymphoma cell line.
  • Ipilimumab-ADC concentrations were tested between 0 nM and 1 pM.
  • they compared the percentage of dead cells induced by the Ipilimumab-Drug conjugates to the Rituximab-Drug conjugates, to Ipilimumab, to Rituximab and to each of the three payloads alone at different time points: 48 hours ( Figure 10a), 72 hours ( Figure 10b) and 96 hours ( Figure 10c).
  • Ipilimumab-MMAF target selectively cells expressing CTLA4
  • the drug conjugate of the invention offers a new and very advantageous therapeutic option, allowing both increased therapeutic efficacy and reduced toxicity for the patient.
  • Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double -blind, phase 3 trial. Lancet. Oncol. 16, 522-530.
  • CTLA-4 A moving target in immunotherapy. Blood 131, 58-67.
  • Anti-CTLA-4 immunotherapy does not deplete Foxp3 [r regulatory T cells (Tregs) in human cancers. Clin. Cancer Res. 25, 1233-1238.

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Cell Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un nouveau conjugué de médicament comprenant une molécule de ciblage de CTLA4, au moins un agent cytotoxique, et un agent de liaison reliant la molécule de ciblage de CTLA4 et l'agent cytotoxique, ainsi que des compositions et des kits comprenant un tel conjugué de médicament, et leurs utilisations en particulier pour le traitement du cancer et/ou pour la prévention d'une rechute de cancer chez un sujet en ayant besoin.
PCT/EP2024/065790 2023-06-09 2024-06-07 Conjugué de médicament ciblant ctla4, produits le comprenant et leurs utilisations thérapeutiques Pending WO2024251978A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
IL324808A IL324808A (en) 2023-06-09 2024-06-07 CTLA4-targeting conjugate drug, products containing the same and their therapeutic uses
AU2024284619A AU2024284619A1 (en) 2023-06-09 2024-06-07 Drug conjugate targeting ctla4, products comprising the same and therapeutic uses thereof
KR1020257043784A KR20260021654A (ko) 2023-06-09 2024-06-07 Ctla4를 표적화하는 약물 접합체, 이를 포함하는 제품, 및 이의 치료적 용도
CN202480037748.0A CN121511099A (zh) 2023-06-09 2024-06-07 靶向ctla4的药物缀合物、包含其的产品及其治疗用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23305926 2023-06-09
EP23305926.0 2023-06-09

Publications (1)

Publication Number Publication Date
WO2024251978A1 true WO2024251978A1 (fr) 2024-12-12

Family

ID=87158476

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/065790 Pending WO2024251978A1 (fr) 2023-06-09 2024-06-07 Conjugué de médicament ciblant ctla4, produits le comprenant et leurs utilisations thérapeutiques

Country Status (5)

Country Link
KR (1) KR20260021654A (fr)
CN (1) CN121511099A (fr)
AU (1) AU2024284619A1 (fr)
IL (1) IL324808A (fr)
WO (1) WO2024251978A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2001054732A1 (fr) * 2000-01-27 2001-08-02 Genetics Institute, Llc. Anticorps contre ctla4 (cd152), conjugues comprenant lesdits anticorps, et leurs utilisations
WO2020092155A1 (fr) 2018-10-31 2020-05-07 Bioatla, Llc Anticorps anti-ctla4, fragments d'anticorps, leurs immunoconjugués et utilisations associées
WO2023172983A1 (fr) * 2022-03-08 2023-09-14 Molecular Templates, Inc. Molécules de liaison à ctla-4 comprenant des échafaudages de sous-unité de toxine de shiga a et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2001054732A1 (fr) * 2000-01-27 2001-08-02 Genetics Institute, Llc. Anticorps contre ctla4 (cd152), conjugues comprenant lesdits anticorps, et leurs utilisations
WO2020092155A1 (fr) 2018-10-31 2020-05-07 Bioatla, Llc Anticorps anti-ctla4, fragments d'anticorps, leurs immunoconjugués et utilisations associées
WO2023172983A1 (fr) * 2022-03-08 2023-09-14 Molecular Templates, Inc. Molécules de liaison à ctla-4 comprenant des échafaudages de sous-unité de toxine de shiga a et leurs utilisations

Non-Patent Citations (36)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY
ANTONIA, S.J.VILLEGAS, A.DANIEL, D.VICENTE, D.MURAKAMI, S.HUI, R.YOKOI, T.CHIAPPORI, A.LEE, K.H.DE WIT, M. ET AL.: "Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer", N. ENGL. J. MED., vol. 377, 2017, pages 1919 - 1929, XP055831331, DOI: 10.1056/NEJMoa1709937
BLANK CHRISTIAN U ET AL: "Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma", NATURE MEDICINE, NATURE PUBLISHING GROUP US, NEW YORK, vol. 24, no. 11, 8 October 2018 (2018-10-08), pages 1655 - 1661, XP036901017, ISSN: 1078-8956, [retrieved on 20181008], DOI: 10.1038/S41591-018-0198-0 *
BRUNET JFDENIZOT FLUCIANI MFROUX-DOSSETO MSUZAN MMATTEI MGGOLSTEIN P: "A new member of the immunoglobulin superfamily-CTLA4", NATURE, vol. 328, no. 6127, 1987, pages 267 - 70, XP002915323, DOI: 10.1038/328267a0
BYRNE LAUREN ET AL: "Engineered toxin body targeting CTLA-4 (MT-8421) depletes Tregs in the tumor microenvironment and synergizes with [alpha]PD-1 to enhance T cell immunity", REGULAR AND YOUNG INVESTIGATOR AWARD ABSTRACTS, 7 November 2022 (2022-11-07), pages A852 - A852, XP093096779, DOI: 10.1136/jitc-2022-SITC2022.0817 *
CHAMPIAT, S. ET AL.: "Intratumoral Immunotherapy: From Trial Design to Clinical Practice", CLIN. CANCER RES., vol. 27, 2021, pages 665 - 679
DARIAVACH PMATTÉI MGGOLSTEIN PEFRANC MP: "Human Ig superfamily CTLA-4 gene: chromosomal localization and ientity of protein sequence between murine and human CTLA-4 cytoplasmic domains", EUROPEAN JOURNAL OF IMMUNOLOGY, vol. 18, no. 12, December 1988 (1988-12-01), pages 1901 - 5, XP000613323, DOI: 10.1002/eji.1830181206
EGGERMONT, A.M.M.BLANK, C.U.MANDALA, M.LONG, G. V.ATKINSON, V.DALLE, S.HAYDON, A.LICHINITSER, M.KHATTAK, ACARLINO, M.S. ET AL.: "Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma", N. ENGL. J. MED., vol. 378, 2018, pages 1789 - 1801, XP055919692, DOI: 10.1056/NEJMoa1802357
EGGERMONT, A.M.M.BLANK, C.U.MANDALA, M.LONG, G. V: "Longer Follow-Up Con fi rms Recurrence-Free Survival Bene fi t of Adjuvant Pembrolizumab", HIGH-RISK STAGE III MELANOMA : UPDATED RESULTS FROM THE EORTC 1325-MG / KEYNOTE-054 TRIAL ABSTRACT, 2020
EGGERMONT, A.M.M.CHIARION-SILENI, V.GROB, J.-J.DUMMER, R.WOLCHOK, J.D.SCHMIDT, H.HAMID, O.ROBERT, C.ASCIERTO, P.A.RICHARDS, J.M. E: "Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial", LANCET. ONCOL., vol. 16, 2015, pages 522 - 530, XP029586820, DOI: 10.1016/S1470-2045(15)70122-1
EGGERMONT, A.M.M.CHIARION-SILENI, V.GROB, J.-J.DUMMER, R.WOLCHOK, J.D.SCHMIDT, H.HAMID, O.ROBERT, C.ASCIERTO, P.A.RICHARDS, J.M. E: "Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy", N. ENGL. J. MED., vol. 375, 2016, pages 1845 - 1855
FERRARA, R.SUSINI, S.MARABELLE, A.: "Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3 + Regulatory T Cells (Tregs) in Human Cancers-Letter", CLIN. CANCER RES., vol. 25, 2019, pages 3468 - 3468
GAO, J.NAVAI, N.ALHALABI, O.SIEFKER-RADTKE, A.CAMPBELL, M.T.SLACK TIDWELL, R.GUO, C.C.KAMAT, A.M.MATIN, S.F.ARAUJO, J.C. ET AL.: "Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma", NAT. MED., 2020
KHAILAIE S.ROWSHANRAVAN, B.ROBERT, P. A.WATERS E.HALLIDAY, N.BADILLO HERRERA, J. D.WALKER L. S. K.SANSOM D. M.MEYER-HERMANN M., CHARACTERIZATION OF CTLA4 TRAFFICKING ANS IMPLICATIONS FOR ITS FUNCTION. B. J., vol. 115, 2018, pages 1330 - 1343
KHANNA SWATI: "Engineered toxin body targeting CTLA-4 (MT-8421) depletes Tregs in the tumor microenvironment and synergizes with [alpha]PD-1 to enhance T cell immunity", 7 November 2022 (2022-11-07), pages 1 - 1, XP093096785, Retrieved from the Internet <URL:https://d1io3yog0oux5.cloudfront.net/_1e4e4e30bdfb56d618c77b6cd9632896/mtem/db/846/7029/pdf/SITC_817%281%29.pdf> [retrieved on 20231031] *
L. APETOH ET AL: "Combining immunotherapy and anticancer agents: the right path to achieve cancer cure?", ANNALS OF ONCOLOGY, vol. 26, no. 9, 28 April 2015 (2015-04-28), pages 1813 - 1823, XP055567184, DOI: 10.1093/annonc/mdv209 *
LUCCA L. E.DOMINGUEZ-VILLAR, M.: "Modulation of regulatory T cell function and stability by co-inhibitory receptors", NAT. REV. IMMUNOL, 2020
LUKE, J.J., RUTKOWSKI, P., QUEIROLO, P., DEL VECCHIO, M., MACKIEWICZ, J., CHIARION-SILENI, V.,DE LA CRUZ MERINO, L., KHATTAK, M.A.: "Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.", LANCET, 2022, pages 1 - 12
MARABELLE, A. ET AL.: "Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT", ANN. ONCOL. OFF. J. EUR. SOC. MED. ONCOL., vol. 29, 2018, pages 2163 - 2174
MARABELLE, A.KOHRT, H.SAGIV-BARFI, I.AJAMI, B.AXTELL, R.C.ZHOU, G.RAJAPAKSA, R.GREEN, M.R.TORCHIA, J.BRODY, J. ET AL.: "Depleting tumor-specific Tregs at a single site eradicates disseminated tumors", J. CLIN. INVEST., vol. 123, 2013, pages 2447 - 2463, XP002759891, DOI: 10.1172/JCI64859
MARABELLE, A.TSELIKAS, L.DE BAERE, T.HOUOT, R.: "Intratumoral immunotherapy: using the tumor as the remedy", ANN. ONCOL., vol. 28, 2017, pages xii33 - xii43, XP055724506, DOI: 10.1093/annonc/mdx683
MUTHANA MUSLEH M ET AL: "CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment", ELIFE, vol. 12, 21 December 2023 (2023-12-21), GB, XP093191971, ISSN: 2050-084X, Retrieved from the Internet <URL:https://cdn.elifesciences.org/articles/87281/elife-87281-v1.xml> [retrieved on 20240802], DOI: 10.7554/eLife.87281 *
PLITAS, G.RUDENSKY, A.Y.: "Regulatory T Cells", CANCER. ANNU. REV. CANCER BIOL., vol. 4, 2020, pages 459 - 477
ROBERT, C. ET AL.: "1082MO 5 year characterization of complete responses in patients with advanced melanoma who received nivolumab plus ipilimumab (Nivo+lpi) or Nivo alone", ANN. ONCOL., vol. 31, 2020, pages S734 - S735
ROWSHANRAVAN, B.HALLIDAY, N.SANSOM, D.M.: "CTLA-4: A moving target in immunotherapy", BLOOD, vol. 131, 2018, pages 58 - 67, XP086691541, DOI: 10.1182/blood-2017-06-741033
SELBY, M.J.ENGELHARDT, J.J.QUIGLEY, M.HENNING, K.A.CHEN, T.SRINIVASAN, M.KORMAN, A.J.: "Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells", CANCER IMMUNOL. RES., vol. 1, 2013, pages 32 - 42, XP055100395, DOI: 10.1158/2326-6066.CIR-13-0013
SHARMA, A.SUBUDHI, S.K.BLANDO, J.SCUTTI, J.VENCE, L.WARGO, J.ALLISON, J.PRIBAS, A.SHARMA, P.: "Anti-CTLA-4 immunotherapy does not deplete Foxp3 p regulatory T cells (Tregs) in human cancers", CLIN. CANCER RES., vol. 25, 2019, pages 1233 - 1238, XP093124798, DOI: 10.1158/1078-0432.CCR-18-0762
SIMPSON, T.R., LI, F., MONTALVO-ORTIZ, W., SEPULVEDA, M.A., BERGERHOFF, K., ARCE, F., RODDIE,C., HENRY, J.Y., YAGITA, H., WOLCHOK,, J. EXP. MED., vol. 210, 2013, pages 1695 - 1710
TAY, C.TANAKA, A.SAKAGUCHI, S.: "Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy", CANCER CELL, vol. 41, 2023, pages 450 - 465
TAZZARI PIER-LUIGI ET AL: "Immunotoxins Containing Recombinant Anti-CTLA-4 Single-Chain Fragment Variable Antibodies and Saporin: In Vitro Results and In Vivo Effects in an Acute Rejection Model", THE JOURNAL OF IMMUNOLOGY, vol. 167, no. 8, 15 October 2001 (2001-10-15), US, pages 4222 - 4229, XP093191986, ISSN: 0022-1767, Retrieved from the Internet <URL:https://journals.aai.org/jimmunol/article-pdf/167/8/4222/1142624/4222.pdf> [retrieved on 20240802], DOI: 10.4049/jimmunol.167.8.4222 *
TSELIKAS LAMBROS ET AL: "Safety and efficacy of intratumoral ipilimumab with IV nivolumab in metastatic melanoma. The NIVIPIT trial", JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 9, no. Suppl 2, 10 November 2021 (2021-11-10), pages A300 - A300, XP093097038, DOI: 10.1136/jitc-2021-SITC2021.277 *
TSELIKAS, L. ET AL.: "Interventional radiology for local immunotherapy in oncology", CLIN. CANCER RES, 2021
TSELIKAS, L. ET AL.: "Interventional radiology for local immunotherapy in oncology", CLIN. CANCER RES., 2021
TSELIKAS, L. ET AL.: "Pickering emulsions with ethiodized oil and nanoparticles for slow release of intratumoral anti-CTLA4 immune checkpoint antibodies", J. IMMUNOTHER. CANCER, vol. 8, 2020, pages e000579
VERMA ET AL., PHARMACEUTICAL TECHNOLOGY ON-LINE, vol. 25, no. 2, 2001, pages 1 - 14
YAMASHITA, M.KITANO, S.AIKAWA, H. ET AL.: "A novel method for evaluating antibody-dependent cell-mediated cytotoxicity by flowcytometry using cryopreserved human peripheral blood mononuclear cells", SCI REP, vol. 6, 2016, pages 19772

Also Published As

Publication number Publication date
IL324808A (en) 2026-01-01
AU2024284619A1 (en) 2025-12-04
CN121511099A (zh) 2026-02-10
KR20260021654A (ko) 2026-02-13

Similar Documents

Publication Publication Date Title
CN106999594B (zh) 用于治疗瘤形成的治疗组合
KR20190137151A (ko) 병용 요법
EP3858858A1 (fr) Molécules de liaison liant pd-l1 et lag-3
CA3031168A1 (fr) Polytherapie contre le cancer
JP2020517640A5 (fr)
WO2018187613A2 (fr) Anticorps agonistes anti-icos et leurs utilisations
CN113286616A (zh) 分子佐剂
AU2020325981A1 (en) Combination therapy involving antibodies against Claudin 18.2 and immune checkpoint inhibitors for treatment of cancer
WO2022100590A1 (fr) Anticorps humanisé enrichi en adcc pour claudin 18a2 et application associée
KR20190137847A (ko) 항-cd25 항체-약물 접합체와의 병용 요법
KR20200074214A (ko) 암을 치료하는데 사용하기 위한 면역자극 효능작용 항체
JP2020517629A5 (fr)
JP2023548051A (ja) 肺がんのためのｌａｇ－３アンタゴニスト療法
CN114450028A (zh) Lag-3拮抗剂治疗的定量空间剖析
CA2969665A1 (fr) Combinaison d&#39;anticorps anti-cs1 et anti-pd1 pour traiter le cancer (myelome)
KR20240099362A (ko) 혈액암에 대한 lag-3 길항제 요법
KR20260020459A (ko) 항-ceacam5 항체-약물 접합체, 항-pd1/pd-l1 항체 및 항-ctla4 항체를 함유하는 항종양 조합물
US20250296966A1 (en) Combination of an antibody specific for a tumor antigen and a cd47 inhibitor
WO2024251978A1 (fr) Conjugué de médicament ciblant ctla4, produits le comprenant et leurs utilisations thérapeutiques
JP2024521667A (ja) 抗－ｃｄ２０５抗体及び免疫チェックポイント・インヒビターを含む組み合わせ医薬
EP4055052A1 (fr) Méthodes de traitement du cancer à l&#39;aide d&#39;anticorps anti-pd-1
TW202432585A (zh) 癌症新輔助治療的組合物及方法
TW202523359A (zh) 抗體-藥物結合物與抗pd-1/tim-3雙特異性結合蛋白質之組合
JP2025525011A (ja) がんの治療のための併用療法
WO2024204629A1 (fr) Anticorps anti-cd25 et conjugué anticorps-médicament anti-cd25

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24730392

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: AU2024284619

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2024284619

Country of ref document: AU

Date of ref document: 20240607

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2025/014785

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 202517125855

Country of ref document: IN

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112025027254

Country of ref document: BR

WWP Wipo information: published in national office

Ref document number: 202517125855

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 1020257043784

Country of ref document: KR

Free format text: ST27 STATUS EVENT CODE: A-0-1-A10-A15-NAP-PA0105 (AS PROVIDED BY THE NATIONAL OFFICE)

WWE Wipo information: entry into national phase

Ref document number: 2024730392

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024730392

Country of ref document: EP

Effective date: 20260109

WWE Wipo information: entry into national phase

Ref document number: 2025137528

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2024730392

Country of ref document: EP

Effective date: 20260109

ENP Entry into the national phase

Ref document number: 2024730392

Country of ref document: EP

Effective date: 20260109

ENP Entry into the national phase

Ref document number: 2024730392

Country of ref document: EP

Effective date: 20260109

ENP Entry into the national phase

Ref document number: 2024730392

Country of ref document: EP

Effective date: 20260109

WWP Wipo information: published in national office

Ref document number: 2025137528

Country of ref document: RU