WO2024088987A1 - Polythérapie pour le traitement du cancer - Google Patents

Polythérapie pour le traitement du cancer Download PDF

Info

Publication number
WO2024088987A1
WO2024088987A1 PCT/EP2023/079524 EP2023079524W WO2024088987A1 WO 2024088987 A1 WO2024088987 A1 WO 2024088987A1 EP 2023079524 W EP2023079524 W EP 2023079524W WO 2024088987 A1 WO2024088987 A1 WO 2024088987A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
tcb
seq
cancer
combination
Prior art date
Application number
PCT/EP2023/079524
Other languages
English (en)
Inventor
Maria AMANN
Christophe BOETSCH
Jan ECKMANN
Cristiano Ferlini
Vaios KARANIKAS
Theresa KOLBEN
Estelle MARRER-BERGER
Maria Valeria Gonzalez Nicolini
Gabriel SCHNETZLER
Roger Paulus Maria SUTMULLER
Pablo Umaña
Original Assignee
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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 F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2024088987A1 publication Critical patent/WO2024088987A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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 [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3007—Carcino-embryonic Antigens
    • 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
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]

Definitions

  • the present invention is directed to the combination of a T cell bispecific antibody (TCB) and a Treg cell depletion therapy for use in the treatment of cancer.
  • TB T cell bispecific antibody
  • Treg cell depletion therapy for use in the treatment of cancer.
  • Regulatory T cells with antibodies against CD25 has shown to be effective in various cancer mouse models, see for example as described in WO2017/174331 , W02018/167104, WO2019/175222 and Solomon I et al, Nature Cancer, vol 1 , p1153-1166 (2020).
  • response rates have been found to be lower in some poorly immunogenic mouse models, with only a partial response in the reduction of tumour (or tumor) growth shown to be achieved in some cases.
  • T cell bispecifics are engineered antibodies comprised of two binding moieties with an affinity for CD3e, a part of the T cell receptor, and a tumor surface antigen, differentially expressed on tumor cells over healthy tissue.
  • TCBs redirect T lymphocytes polyclonally and independent of the antigen specificity to lyse tumor cells positive for the respective tumor antigen.
  • CD4+ regulatory T cells are major players in immune homeostasis, and defects in their number and/or function are associated with a broad range of immunological disorders Tregs impair productive tumor immune surveillance and represent an obstacle for cancer immunotherapy.
  • TCB-engaged Tregs substantially inhibit interferon-y, tumor necrosis factor and IL-2 cytokine release of autologous TCB engaged T effector cells, as well as inhibiting their expansion and proliferation.
  • TCB-engaged Tregs substantially inhibit interferon-y, tumor necrosis factor and IL-2 cytokine release of autologous TCB engaged T effector cells, as well as inhibiting their expansion and proliferation.
  • T reg cells within the tumor microenvironment, and thus remove this barrier to a TCB redirected immune response are promising assets to increase the success of TCB immunotherapy.
  • Therapeutic antibodies that are specific for cell surface antigens of T reg cells (CTLA-4, CCR-4, 0x40, CCR8) have been developed to deplete Treg cells via ADCC and ADCP.
  • the present invention relates to the combination of a Treg cell depletion therapy and a TCB for use in treating cancer.
  • a Treg cell depletion therapy such as an anti-CD25 antibody provides an improved treatment regimen for patients with cancer.
  • a Treg cell depleting therapy such as an anti-CD25 antibody
  • a Treg cell depletion therapy and a TCB for use in the treatment of cancer.
  • the Treg cell depletion therapy and the TCB are for separate, simultaneous or sequential administration.
  • Treg cell depletion is achieved by an anti-CD25 antibody. Accordingly, in one aspect of the invention there is provided the combination of an anti-CD25 antibody and a TCB for use in the treatment of cancer.
  • the anti-CD25 antibody and the TCB are for separate, simultaneous or sequential administration.
  • a further aspect of the invention provides T reg cell depletion therapy (e.g. an anti-CD25 antibody) for use in the treatment of cancer, wherein the Treg cell depletion therapy is for use in combination with a TCB.
  • T reg cell depletion therapy e.g. an anti-CD25 antibody
  • the Treg cell depletion therapy is for use in combination with a TCB.
  • a further aspect of the invention provides a method for treating cancer in a subject comprising administering a therapeutically effective amount of each of Treg cell depletion therapy and a TCB to the subject.
  • a further aspect of the invention provides a Treg cell depletion therapy for use in treating or preventing relapse of cancer in a subject, wherein the Treg cell depletion therapy is for use in combination with at least one dose of a TCB, wherein the TCB is for administration to the subject after the Treg cell depletion therapy.
  • a further aspect of the invention provides a method of treating or preventing relapse of cancer in a subject, wherein the subject has undergone Treg cell depletion therapy for the treatment of cancer wherein the method comprises administering at least one dose of a TCB to the subject after the Treg cell depletion therapy.
  • FIGURE 1 Intratumoral T cell count by FACS analysis 72 hrs after administration of RG6292, MOXRO0916 or Ipilimumab. All antibodies were able to decrease the intratumoral Treg counts compared to vehicle treated control animals, but an increase of intratumoral activated CD8 T cell count was only evident after administration of RG6292.
  • Stem cell humanized NOG mice were s.c. injected with BxPC-3 prostate adenocarcinoma cells in matrigel. Mice were randomized for tumor size and human T-cell count on day 14. Six days after randomization mice were injected i.p.
  • TCB treated mice received weekly i.v. CEACAM-5 CD3 TCB [2.5 mg/kg] (day 15 and 22).
  • Tested were monotherapies and a combination of CEACAM-5 CD3 TCB with RG6292 (designated here as “aCD25 Mab GlyMAXX”). 10 days after randomization (72 hrs after monotherapy injection), tumor infiltrating lymphocytes were isolated and evaluated for the presence of T cells by flowcytometry.
  • Living human activated CD8 T cells huCD45+, huCD3+, huCD8+ huCTLA-4+
  • Tregs huCD45+, huCD3+, huCD4+, huCD25+ huFoxP3+
  • the box and whisker plot is shown for 5 animals per group.
  • Black 6 albino female mice were injected i.v. with B16-FAP-Fluc cells clone 106 (metastatic melanoma).
  • mice received i.p. a single injection of anti-mouse CD25 NIB (mouse lgG2a) [10 mg/kg] (CD25 monotherapy and combination treated mice).
  • Each group was comprised of 6 to 9 animals.
  • FIGURE 3 Plasma concentration of stem cell humanized mice bearing a subcutaneous multiple myeoloma NCI-H929 human cancer model treated with GPRC5D CD3 TCB with or without the CD25 Mab (RG6292).
  • FIGURE 4 Tumour growth of stem cell humanized mice bearing a subcutaneous multiple myeoloma NCI-H929 human cancer model treated with GPRC5D CD3 TCB with or without the CD25 Mab (RG6292).
  • the Fold Change of Tumor Growth was calculated as ratio of the tumour volume on the given day of experiment and the volume on day 8 before treatment start. Shown is the mean value of 10 animals per group and the respective SEM (Figure 4A). Spider plots show the tumour volume over time for each respective animal ( Figure 4B-D).
  • the present invention provides the combination of Treg cell depletion therapy and a TCB for use in the treatment of cancer in a subject.
  • the invention provides Treg cell depletion therapy, such as an anti-CD25 antibody as a first component, and a TCB as a second component, for use in the simultaneous or sequential treatment of cancer in a subject.
  • the invention also provides methods of treating cancer in a subject comprising administering a Treg cell depletion therapy, such as an anti-CD25 antibody, and administering a TCB.
  • Tregs are known to contribute to an immune suppressive tumor microenvironment (TME).
  • TEM immune suppressive tumor microenvironment
  • TME tumor microenvironment
  • TCB as defined herein
  • Treg cell depletion therapy for example by the administration of anti-CD25 antibody
  • TEE immunogenic tumor microenvironment
  • the treatment regimen of the invention produces an enhanced therapeutic effect as compared to the anti-CD25 or TCB administered alone.
  • the enhanced therapeutic effect means an improved therapeutic effect of the TCB by combining it with Treg cell depletion therapy.
  • the TCB is more effective in re-directing cytotoxic activity of a T-cell to a target cell, such as a cancer cell.
  • the TCB is more effective in lysis of the target cell, such as a cancer cell.
  • the enhanced therapeutic effect is more than additive.
  • a combination therapy comprising a Treg cell depletion therapy and a TCB for use in the treatment of cancer.
  • the Treg cell depletion therapy and the TCB-based therapy are for separate, simultaneous or sequential administration.
  • the combination comprises a) a first component which comprises a therapeutically effective amount of a Treg cell depletion therapy and b) a second component which comprises a therapeutically effective amount of a TCB for the simultaneous, separate or sequential use in the treatment of cancer.
  • the treatment regimen can involve administering multiple doses of the Treg cell depletion therapy and/or the TCB.
  • the Treg cell depletion therapy comprises administering an anti-CD25 antibody.
  • a combination comprising a) a first component which comprises an anti-CD25 antibody, b) a second component which comprises a TCB for simultaneous, separate or sequential use in the treatment of cancer.
  • a pharmaceutical product for use in the treatment of a patient with cancer comprising a) as a first component a therapeutically effective amount of an anti-CD25 antibody; and b) as a second component a therapeutically effective amount of a TCB, wherein both components are for combined, simultaneous or sequential administration.
  • each of the components are administered multiple times over the treatment cycle.
  • the dosing regimen may comprise a first dose of a component in a first dose amount, followed by the one or more additional doses in a second dose amount the same as the first dose amount.
  • different doses of each component within a dosing regimen are of different amounts.
  • a dosing regimen comprises a first dose in a first dose amount, followed by the one or more additional doses in a second dose amount different from the first dose amount.
  • the different antibodies may be administered in different dose amounts.
  • the different antibodies are administered in substantially the same dose amounts.
  • the same anti-CD25 antibody and TCB are used for each dose.
  • different anti-CD25 antibodies and/or TCB may be used as part of the treatment regimen.
  • the TCB is administered after the administration of the anti-CD25 antibody.
  • administered after it is meant that the TCB is preferably administered at a time period sufficiently after the administration of the anti-CD25 antibody for it to achieve its desired effect.
  • the TCB is administered after there is a depletion of Treg cells in the subject achieved by the administration of the anti-CD25 antibody.
  • the depletion of such Treg cells can be measured by any method known to the person of skill in the art, for example by flow cytometry or fluorescence activated cell sorting (FACS).
  • the treatment regimen involves administering an anti-CD25 antibody to the subject, followed by administering a TCB.
  • the treatment regimen can involve administering multiple doses of the anti-CD25 antibody and/or the TCB.
  • the treatment regimen involves administering multiple doses of the TCB.
  • the TCB is for administration in combination with a further dose of the anti-CD25 antibody, wherein the further dose of the anti-CD25 antibody is for administration before the TCB.
  • the treatment regimen involves administering the first dose of the TCB after at least two doses of the anti-CD25 antibody have been administered. Multiple doses of the anti-CD25 antibody may be administered to maintain Treg depletion in the subject.
  • said Treg cell depletion is achieved prior to administering said TCB.
  • the administration of said TCB, or at least the first dosing of said TCB may also be carried out prior to Treg cell depletion, or the first dose of a Treg cell depletion therapy.
  • the present invention provides a combination therapy for use in the treatment of a patient with cancer wherein the TCB is administered prior to the Treg depletion therapy.
  • Multiple doses, for example at least 2 doses, of the TCB may be administered before the first dose of the Treg cell depletion therapy.
  • the present invention provides a combination therapy for use in the treatment of a patient with cancer wherein the TCB is administered after the Treg depletion therapy.
  • Multiple doses, for example at least 2 doses, of the Treg cell depletion therapy may be administered before the first dose of the TCB.
  • the invention relates to the treatment of cancer.
  • the cancer can be a haematological cancer or a solid cancer.
  • the cancer is any human cancer for which the B16 cell line may represent preclinical models for validating compounds as being useful for their therapeutic management.
  • the cancer involves a solid tumour (e.g. a solid tumour cancer) and the treatment is for treating cancer or preventing the relapse of a solid tumour.
  • solid tumours are an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas, in particular, tumours and/or metastasis (wherever located) other than leukaemia or non-solid lymphatic cancers. Solid tumours may be benign or malignant.
  • solid tumours are named for the type of cells that form them and/or the tissue or organ in which they are located.
  • solid tumours are sarcomas (including cancers arising from transformed cells of mesenchymal origin in tissues such as cancellous bone, cartilage, fat, muscle, vascular, hematopoietic, or fibrous connective tissues), carcinomas (including tumours arising from epithelial cells), mesothelioma, neuroblastoma, retinoblastoma, etc.
  • a solid tumour is selected from breast cancer, lung cancer, colon cancer, ovarian cancer, melanoma cancer, bladder cancer, renal cancer, kidney cancer, liver cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric carcinoma cancer, esophageal cancer, mesothelioma or prostate cancer.
  • the cancer is selected from acute myeloid leukaemia, diffuse large cell B- Cell lymphoma, multiple myeloma, melanoma, non-small cell lung cancer, renal cancer, ovarian cancer, bladder cancer, pancreatic cancer, sarcoma and/or colorectal cancer.
  • the cancer is multiple myeloma.
  • treating or preventing relapse of cancer means to avoid the reoccurrence, return or reappearance of the cancer, after an initial response or partial response to a prior cancer therapy.
  • a relapse of the cancer may involve an increase in tumor volume.
  • Reference to “treatment”, “treat” or “treating” a cancer as used herein defines the achievement of at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumour size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumour metastasis or tumour growth.
  • Positive therapeutic effects in cancer can be measured in a number of ways (e.g. Weber (2009) J Nucl Med 50, 1S-10S).
  • a T/C % ratio of 42% is the minimum level of anti-tumour activity.
  • a “therapeutically effective amount” is the amount of the respective compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • a therapeutically effective amount is one that reduces the incidence and/or severity of, stabilizes, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition in accordance with the treatment regimen.
  • a “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular subject.
  • the treatment achieved by a therapeutically effective amount is any of progression free survival (PFS), disease free survival (DFS) or overall survival (OS).
  • PFS also referred to as "Time to Tumour Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
  • DFS refers to the length of time during and after treatment that the patient remains free of disease.
  • OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients.
  • a therapeutically effective amount is the dose or dose range as already approved or validated in such clinical trials. This also includes any approved or clinically tested dosage regimen (or dose schedule). Information about such doses and dosage regimen can for example be obtained from corresponding package inserts, in case of an already approved TCB, and/or clinical trial reports.
  • one condition of such effective treatment is the depletion of Treg cells in said patient.
  • Another condition of such effective treatment is the improved cytotoxic activity of a T-cell to a target cell, such as a cancer cell, by the combination treatment as disclosed herein.
  • Another condition of such effective treatment is that the TCB is more effective in lysis of the target cell when combined with a Treg depletion therapy as disclosed herein.
  • prevention refers to delaying or preventing the onset of the symptoms of the cancer. Prevention may be absolute (such that no disease occurs) or may be effective only in some individuals or for a limited amount of time.
  • Treg cell depletion therapy or “Treg depletion therapy” means a treatment regimen that results in the reduction of Tregs in the subject as compared to the level of Tregs in the subject before the therapy.
  • Compounds that deplete Treg cells are known in the art.
  • the depletion of Tregs can be measured by techniques known in the art for example as disclosed in W02018/167104 and Simpson et al (2013) J Exp Med 210, 1695- 710. The contents of which are incorporated herein by reference.
  • the “Treg cell depletion therapy” or “Treg depletion therapy” consists of the use of an anti-CD25 antibody as defined herein.
  • Treg regulatory T cells
  • Treg cells refer to a lineage of CD4+ T lymphocytes specialized in controlling autoimmunity, allergy and infection. Typically, they regulate the activities of T cell populations, but they can also influence certain innate immune system cell types. Tregs are usually identified by the expression of the biomarkers CD4, CD25 and Foxp3. Naturally occurring Treg cells normally constitute about 5-10% of the peripheral CD4+ T lymphocytes. However, within a tumour microenvironment (i.e. tumourinfiltrating Treg cells), they can make up as much as 20-30% of the total CD4+ T lymphocyte population.
  • CD25 is the alpha chain of the IL-2 receptor, and is found on activated T cells, regulatory T cells, activated B cells, some NK T cells, some thymocytes, myeloid precursors and oligodendrocytes. CD25 associates with CD122 and CD132 to form a heterotrimeric complex that acts as the high-affinity receptor for IL-2.
  • the consensus sequence of human CD25 is shown below and identified as SEQ ID NO:1 (Uniprot accession number P01589; the extracellular domain of mature human CD25, corresponding to amino acids 22-240 is underlined).
  • an “anti-CD25 antibody” or an “an antibody that binds CD25” refers to an antibody that is capable of binding to the CD25 subunit of the IL-2 receptor. This subunit is also known as the alpha subunit of the IL-2 receptor.
  • an anti-CD25 antibody is an antibody capable of specific binding to the CD25 subunit (antigen) of the IL-2 receptor.
  • Specific binding “Specific binding”, “bind specifically”, and “specifically bind” are understood to mean that the antibody has a dissociation constant (Kd) for the antigen of interest of less than about 10’ 6 M, 10’ 7 M, 10’ 8 M, 10’ 9 M, 1O’ 10 M, 10’ 11 M, 10’ 12 M or 10’ 13 M.
  • the dissociation constant is less than 10' 8 M, for instance in the range of 10' 9 M, 10' 1 ° M, 10' 11 M, 10’ 12 M or 10’ 13 M.
  • An anti-CD25 antibody suitable for use in the invention are antibodies that are capable of depleting or reducing Treg cells.
  • references to “depleted” or “depleting” (with respect to the depletion of regulatory T cells by an anti-CD25 antibody agent) it is meant that the number, ratio or percentage of Tregs is decreased relative to when the antibody is not administered. In particular embodiments of the invention as described herein, over about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99% of the regulatory T cells are depleted.
  • Anti-CD25 antibodies that can deplete Treg cells and are suitable for use in the invention include for example those described in WO2017/174331 , W02018/167104, WO20 19/008386, WO2019/175215, WO2019/175216, WO2019/175217, WO2019/175220, WO2019/17522. WO2019/175223, WO2019/175224, WO2019/175226, the contents of which are incorporated herein by reference.
  • the anti-CD25 antibody binds FcyR with high affinity, preferably an activating receptor with high affinity.
  • the antibody binds FcyRI and/or FcyRlla and/or FcyRllla with high affinity.
  • the antibody binds to at least one activatory Fey receptor with a dissociation constant of less than about 10' 6 M, 10' 7 M, 10- 8 M, 10' 9 M or 10- 10 M.
  • the antibody is an lgG1 antibody, preferably a human lgG1 antibody, which is capable of binding to at least one Fc activating receptor.
  • the antibody may bind to one or more receptor selected from FcyRI, FcyRlla, FcyRllc, FcyRllla and FcyRlllb.
  • the antibody is capable of binding to FcyRllla.
  • the antibody is capable of binding to FcyRllla and FcyRlla and optionally FcyRI.
  • the antibody is capable of binding to these receptors with high affinity, for example with a dissociation constant of less than about 10' 7 M, 10' 8 M, 10' 9 M or 10' 1 °M.
  • the antibody binds an inhibitory receptor, FcyRllb, with low affinity. In some embodiments, the antibody binds FcyRllb with a dissociation constant higher than about 10 -7 M, higher than about 10' 6 M or higher than about 10' 5 M.
  • the anti-CD25 antibody may be afucosylated.
  • the Fc region of the antibody can be modified to change the glycosylation profile using known techniques in the art. Available techniques to produce antibodies with absent or reduced fucosylation profiles, include commercially available technologies such as GlyMAXX (ProBiogen) and methods such as those disclosed in WO2011/035884.
  • the anti-CD25 antibody induces ADCC activity.
  • the anti-CD25 antibody exhibits ADCC activity against CD25+ target cells.
  • ADCC antibody-dependent cell- mediated cytotoxicity
  • FcRs Fc receptors
  • NK Natural Killer
  • macrophages e.g., neutrophils, neutrophils, and macrophages
  • ADCP Antibodydependent cell-mediated phagocytosis
  • phagocytes such as macrophages
  • FcRs Fc receptors
  • the anti-CD25 antibody used in the invention many function through ADCC and ADCP activity.
  • ADCC and ADCP can be measured using assays that are known and available in the art.
  • the anti-CD25 antibody does not inhibit the binding of lnterleukin-2 (IL-2) to CD25.
  • References herein to “does not inhibit the binding of lnterleukin-2 to CD25” may alternatively be expressed as the anti-CD25 antibody is a non-IL- 2 blocking antibody or a “non-blocking” antibody (with respect to the non-blocking of IL-2 binding to CD25 in the presence of the anti-CD25 antibody), i.e. the antibody does not block the binding of lnterleukin-2 to CD25 and in particular does not inhibit lnterleukin-2 signalling in CD25-expressing cells.
  • References to “non-blocking” “non-IL-2 blocking”, “does not block”, or “without blocking” and the like include embodiments wherein the anti-CD25 antibody of the invention does not block the signalling of IL-2 via CD25.
  • the anti-CD25 antibody inhibits less than 50% of IL-2 signalling compared to IL-2 signalling in the absence of the antibodies.
  • the anti-CD25 antibody inhibits less than about 50%, 40%, 35%, 30%, preferably less than about 25% of IL- 2 signalling compared to IL-2 signalling in the absence of the antibodies.
  • Some anti-CD25 antibodies may allow binding of IL-2 to CD25, but still block signalling via the CD25 receptor.
  • the non-IL-2 blocking anti-CD25 antibodies allow binding of IL-2 to CD25 to facilitate at least 50% of the level of signalling via the CD25 receptor compared to the signalling in the absence of the anti-CD25 antibody.
  • IL-2 signalling via CD25 may be measured by methods as discussed for example in W02018/167104 and as known in the art. Comparison of IL-2 signalling in the presence and absence of the anti-CD25 antibody agent can occur under the same or substantially the same conditions. In some embodiments, IL-2 signalling can be determined by measuring by the levels of phosphorylated STAT5 protein in cells, using a standard Stat-5 phosphorylation assay.
  • a Stat-5 phosphorylation assay to measure IL-2 signalling may involve culturing PMBC cells in the presence of the anti-CD25 antibody at a concentration of 10ug/ml for 30 mins and then adding varying concentrations of IL-2 (for example 10U/ml or vary concentrations of 0.25U/ml, 0.74U/ml, 2.22U/ml, 6.66U/ml or 20U/ml) for 10 mins. Cells may then be permeabilized and levels of STAT5 protein can then be measured with a fluorescent labelled antibody to a phosphorylated STAT5 peptide analysed by flow cytometry.
  • non-blocking anti-CD25 antibodies are described in W02018/167104, WO2019/175215, WO2019/175216, WO2019/175217, WO2019/175220, WO2019/17522. WO2019/175223, WO2019/17524, WO2019/17526 the contents of which are incorporated herein by reference in their entirety.
  • the anti-CD25 antibody may specifically bind to an epitope within the extracellular region of human CD25. In some embodiments the antibody binds to an epitope that is distinct from the IL-2 binding site and and does not block the binding of IL-2 to CD25.
  • epitopes refers to a portion of an antigen that is bound by an antibody or antigen-binding fragment.
  • epitopes can be formed both from contiguous amino acids (linear epitope) or non-contiguous amino acids juxtaposed by tertiary folding of a protein (conformational epitopes). Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents.
  • An epitope is conformational in that it is comprised of portions of an antigen that are not covalently contiguous in the antigen but that are near to one another in three-dimensional space when the antigen is in a relevant conformation.
  • conformational epitopes are those comprised of amino acid residues that are not contiguous in CD25 extracellular domain
  • linear epitopes are those comprised of amino acid residues that are contiguous in CD25 extracellular domain.
  • Means for determining the exact sequence and/or particularly amino acid residues of the epitope for the anti-CD25 antibody are known in the literature, including competition with peptides, from antigen sequences, binding to CD25 sequences from different species, truncated, and/or mutagenized (e.g. by alanine scanning or other site-directed mutagenesis), phage display-based screening, yeast presentation technologies, or (co-) crystallography techniques.
  • Methods of determining spatial conformation of epitopes are also well known in the art and include, for example, x-ray crystallography and 2-D nuclear magnetic resonance. See, for example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed (1996). Therefore, in some embodiments the anti-CD25 antibody may recognise a conformational epitope.
  • the anti-CD25 antibody binds to an epitope wherein the epitope comprises one or more amino acid residues comprised in one or more of the amino acid stretches selected from amino acids 150-163 of SEQ ID NO:1 (YQCVQGYRALHRGP; SEQ ID NO: 52, herein), amino acids 166-186 of SEQ ID NO: 1 (SVCKMTHGKTRWTQPQLICTG; SEQ ID NO: 53 herein), amino acids 42-56 of SEQ ID NO: 1 (KEGTMLNCECKRGFR; SEQ ID NO: 54, herein) and amino acids 70-88 of SEQ ID NO: 1 (NSSHSSWDNQCQCTSSATR; SEQ ID NO: 55, herein).
  • the epitope comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen or more amino acid residues comprised in one of more the amino acid stretches selected from amino acids 150-163 of SEQ ID NO: 1 (YQCVQGYRALHRGP), amino acids 166-186 of SEQ ID NO: 1 (SVCKMTHGKTRWTQPQLICTG), amino acids 42-56 of SEQ ID NO: 1 (KEGTMLNCECKRGFR) and/or amino acids 70-88 of SEQ ID NO: 1 (NSSHSSWDNQCQCQCTSSATR).
  • amino acids 150-163 of SEQ ID NO: 1 YQCVQGYRALHRGP
  • amino acids 166-186 of SEQ ID NO: 1 SVCKMTHGKTRWTQPQLICTG
  • the anti-CD25 antibody binds to an epitope of human CD25 wherein the epitope comprises at least one sequence selected from amino acids 150-158 of SEQ ID NO: 1 (YQCVQGYRA; SEQ ID NO: 56, herein), amino acids 176-180 of SEQ ID NO: 1 (RWTQP; SEQ ID NO: 57, herein), amino acids 42-56 of SEQ ID NO: 1 (KEGTMLNCECKRGFR) and amino acids 74-84 of SEQ ID NO: 1 (SSWDNQCQCTS; SEQ ID NO: 58, herein).
  • Such antibodies do not inhibit the binding of IL-2 to CD25.
  • the anti-CD25 antibody binds to an epitope comprising the sequence of amino acids 70-84 of SEQ ID NO: 1 (NSSHSSWDNQCQCTS; SEQ ID NO: 59, herein).
  • Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each heavy chain has at the amino terminus a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at the amino terminus (VL) and a constant domain at the carboxy terminus.
  • variable regions are capable of interacting with a structurally complementary antigenic target and are characterized by differences in amino acid sequence from antibodies of different antigenic specificity.
  • the variable regions of either heavy or light chains contain the amino acid sequences capable of specifically binding to antigenic targets. Within these sequences are smaller sequences dubbed “hypervariable” because of their extreme variability between antibodies of differing specificity. Such hypervariable regions are also referred to as “complementarity determining regions” or “CDR” regions.
  • CDR regions account for the basic specificity of the antibody for a particular antigenic determinant structure.
  • the CDRs represent non-contiguous stretches of amino acids within the variable regions but, regardless of species, the positional locations of these critical amino acid sequences within the variable heavy and light chain regions have been found to have similar locations within the amino acid sequences of the variable chains.
  • the variable heavy and light chains of all antibodies each have 3 CDR regions, each non-contiguous with the others (termed as H1 , H2, H3, L1 , L2, L3) for the respective heavy (H) and light (L) chains.
  • the CDR regions specified herein are defined according to Kabat (Kabat et al., 1977. J Biol Chem 252, 6609-6616).
  • the anti-CD25 antibody is selected from the group consisting of:
  • an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 2-5, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 6-11 and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 12, and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 13, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 15;
  • an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 23, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 25, and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28; and (c) an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 31-33, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 34-38, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39, and
  • the anti-CD25 antibody is selected from the group consisting of:
  • an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 15;
  • an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 7 and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 15;
  • an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8 and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 15;
  • an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 9 and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 15;
  • an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:
  • an antibody or antigen binding fragment thereof comprising: a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:
  • the anti-CD25 antibody is selected from the group consisting of:
  • an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 29 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30;
  • an antibody comprising a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NO: 43-48 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 49.
  • the anti-CD25 antibody is selected from the group consisting of:
  • an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22;
  • an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 18 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22;
  • an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light variable region comprising the amino acid sequence of SEQ ID NO: 22;
  • an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 20 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22;
  • an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22;
  • an antibody comprising a heavy chain variable region comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NO: 16-21 and a light chain variable region comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 22.
  • SEQ ID NOs for the complementarity determining regions (HCDR1-3 and LCDR1- 3), and heavy and light chain variable region of exemplified antibodies are provided in the below table 1 :
  • aCD25-a-686 or “aCD25 Mab GlyMAXX” (see e.g. Fig. 1) may also be referred to as RG6292.
  • the anti-CD25 antibody is RG6292.
  • the anti-CD25 antibody referred to as “RG6292”, is an afucosylated human lgG1 monoclonal antibody.
  • RG6292 has a heavy chain sequence having the sequence of SEQ ID NO: 50 and a light chain sequence having the sequence of SEQ ID NO: 51.
  • Such antibodies are known to be “non-IL-2 blocking” antibodies and do not inhibit the binding of IL-2 to CD25.
  • Variants of the above defined antibodies can also be used.
  • Variants of the antibodies include antibodies wherein the sequence for each CDR sequence comprises an amino acid sequence with:
  • variants of the antibodies also include antibodies wherein the sequence for each of the light chain and heavy chains comprise an amino acid sequence with:
  • an anti-CD25 antibody for use in the treatment of cancer selected from the group comprising: a) antibody or antigen binding fragment thereof comprising:
  • a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 2-5, a CDR-H2 comprising the amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 6-11 and a CDR-H3 comprising the amino acid sequence having at least 85% sequence identity to SEQ ID NO: 12, and
  • a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence having one, two, or three, amino acid substitutions relative to any one of SEQ ID NOs: 2-5, a CDR-H2 comprising the amino acid sequence having one, two, or three amino acid substitutions relative to any one of SEQ ID NOs: 6-11 and a CDR- H3 comprising the amino acid sequence having one, two, or three, amino acid substitutions relative to SEQ ID NO: 12, and
  • a light chain variable region comprising a CDR-L1 comprising the amino acid sequence having one, two, or three, amino acid substitutions relative to SEQ ID NO: 13, CDR-L2 comprising the amino acid sequence having one, two, or three, amino acid substitutions relative to SEQ ID NO: 14, and a CDR-L3 comprising the amino acid sequence having one, two, or three, amino acid substitutions relative to SEQ ID NO: 15; and c) antibody or antigen binding fragment thereof comprising:
  • a heavy chain variable region comprising: i) an amino acid sequence having at least 80% sequence identity to any one of SEQ ID NOs: 16-21 ; or ii) an amino acid sequence having one, two, three, four or five amino acid substitutions compared to SEQ ID NOs: 16-21 ; and
  • a light chain variable region comprising: i) an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 22; or ii) an amino acid sequence having one, two, three, four or five amino acid substitutions compared to SEQ ID NO: 22.
  • Percent (%) identity is the relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as the case may be, as determined by the match between strings of such sequences. While there exist a number of methods to measure identity between two polypeptides or two polynucleotide sequences, methods commonly employed to determine identity are codified in computer programs.
  • Preferred computer programs to determine identity between two sequences include, but are not limited to, GCG program package (Devereux, et al., Nucleic Acids Research, 12, 387 (1984), BLASTP, BLASTN, and FASTA (Atschul et al., J. Molec. Biol. 215, 403 (1990)).
  • the percent identity of two amino acid sequences or of two nucleic acid sequences is determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the first sequence for best alignment with the sequence) and comparing the amino acid residues or nucleotides at corresponding positions.
  • the “best alignment” is an alignment of two sequences which results in the highest percent identity.
  • % identity number of identical positions/total number of positions x 100.
  • references to % identity herein refer to % identity along the entire length of the molecule, unless the context specifies or implies otherwise.
  • antibody refers to both intact immunoglobulin molecules as well as fragments thereof that include the antigen-binding site, and includes polyclonal, monoclonal, genetically engineered and otherwise modified forms of antibodies, including but not limited to chimeric antibodies, humanised antibodies, heteroconjugate and/or multispecific antibodies (e.g., bispecific antibodies, diabodies, tribodies, and tetrabodies), and antigen binding fragments of antibodies, including e.g.
  • an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally.
  • an antibody may contain a covalent modification (e.g., attachment of a glycan, a detectable moiety, a therapeutic moiety, a catalytic moiety, or other chemical group providing improved stability or administration of the antibody, such as poly-ethylene glycol).
  • the antibody may be in the form of a masked antibody (e.g. Probodies ®).
  • a masked antibody can comprise a blocking or “mask” peptide that specifically binds to the antigen binding surface of the antibody and interferes with the antibody’s antigen binding.
  • the mask peptide is linked to the antibody by a cleavable linker (e.g. by a protease).
  • an antibody may also refer to camelid antibodies (heavy-chain only antibodies) and antibody-like molecules such as anticalins (Skerra (2008) FEBS J 275, 2677-83).
  • an antibody is polyclonal or oligoclonal, that is generated as a panel of antibodies, each associated to a single antibody sequence and binding more or less distinct epitopes within an antigen (such as different epitopes within human CD25 extracellular domain that are associated to different reference anti-human CD25 antibodies.
  • Polyclonal or oligoclonal antibodies can be provided in a single preparation for medical uses as described in the literature (Kearns JD et al., 2015. Mol Cancer Ther. 14:1625-36).
  • the antibodies used in the present invention may be monospecific, bispecific, or multispecific. “Multispecific antibodies” may be specific for different epitopes of one target antigen or polypeptide, or may contain antigen-binding domains specific for more than one target antigen or polypeptide. In some embodiments of the invention the antibody is monospecific. In some embodiments the antibody binds CD25 in a monovalent manner. In some embodiments the antibody is a TCB as further defined herein.
  • the antibody is monoclonal.
  • the antibody may additionally or alternatively be humanised or human.
  • the antibody is human, or in any case an antibody that has a format and features allowing its use and administration in human subjects.
  • monoclonal antibody is not limited to antibodies produced through hybridoma technology.
  • the term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.
  • human antibody refers to antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • Antibodies (Abs) and immunoglobulins (Igs) are glycoproteins having the same structural characteristics.
  • Immunoglobulins may be from any class such as IgA, IgD, IgG, IgE or IgM.
  • Immunoglobulins can be of any subclass such as lgG1 , lgG2, lgG3, or lgG4.
  • the anti-CD25 antibody is from the IgG class, preferably the lgG1 subclass.
  • the anti-CD25 antibody is from the human lgG1 subclass.
  • TCB T cell bispecific antibody
  • TCBs are known in the art and designated by several terms such as, for example, T cell-engaging BsAbs (T-BsAbs) or T cell engagers, T cell-dependent BsAbs, T cell-redirecting BsAbs, T cell-recruiting BsAbs, etc. These terms are all derived from the ability of a TCB to induce an antitumor immune response, via internal T cell cytotoxicity by binding to two different targets: a first target on a tumour cell and a second target on a T cell (see e.g. M.
  • TCBs according to the present invention can have different formats.
  • a TCB can have one binding domain, for example a Fab, to the target on the T cell and one binding domain to the target on the tumour cell; or a TCB can have 2 binding domains to the target on the tumour cell and one binding domain to the target on the T cell (2+1 - or 2:1 format).
  • the target on the T cell is CD3, or a CD3 subunit or epitope, particularly CD3E, most particularly human CD3 / CD3e.
  • the CD3 binder in a TCB according to the present invention is or can compete for binding with antibody H2C (PCT publication no. W02008/119567), antibody V9 (Rodrigues et al., Int J Cancer Suppl 7, 45-50 (1992) and US patent no.
  • the CD3 binder in a TCB according to the present invention may also be an antibody that specifically binds to CD3 as described in WO 2005/040220, WO 2005/118635, WO 2007/042261 , WO 2008/119567, WO 2008/119565, WO 2012/162067, WO 2013/158856, WO 2013/188693, WO 2013/186613, WO 2014/110601 , WO 2014/145806, WO 2014/191113, WO 2014/047231 , WO 2015/095392, WO 2015/181098, WO 2015/001085, WO 2015/104346, WO 2015/172800, WO 2016/071004, WO 2016/116626, WO 2016/166629, WO 2016/020444, WO 2016/014974, WO 2016/204966, WO 2017/009442, WO 2017/53469, WO 2017/0
  • Suitable target cell antigens include in particular antigens expressed on solid tumours, or targets being characteristic for haematological tumours.
  • targets may include, for example, carcinoembryonic antigen (CEA, CEACAM5), epithelial cell adhesion molecule (EpCAM), Her2, Her3, epidermal growth factor receptor (EGFR), EGFRvlll, ganglioside GD2, CD44v6, six-transmembrane epithelial antigen of prostate 1 (STEAP-1), mesothelin (MSLN), melanoma-associated chondroitin sulfate proteoglycan (MCSP), fibroblast activation protein (FAP), 5T4 oncofetal antigen, Trop2, cadherin 19 (CDH19), CDH3, P-cadherin, Fc receptor-like 5 (FcRH5), glypican 3 (GPC3), claudin (CLDN), B7-
  • CEACAM5 epithelial cell adhesion
  • the target is selected from CD19, CD20, CD38, CEA (CEACAM5), BCMA, TYRP1 , EGFRvlll, GPRC5D and/or FCRH5.
  • the TCB targets CD3, or a CD3 subunit or epitope, particularly CD3e, on a T cell and a tumour associated antigen selected from CD19, CD20, CD38, CEACAM5, TYRP1 , EG FRvI 11 , GPRC5D or FCRH5 on the tumour cell.
  • the TCB targets CD3, or a CD3 subunit or epitope, particularly CD3s, on a T cell and a tumour associated antigen selected from CD19, CD20, CD38, CEACAM5, TYRP1 , MAGEA4, WT1 , LY6G6D, HER2, EGFRvlll, GPRC5D or FCRH5 on the tumour cell.
  • a TCB directed to CD3 and CEA is as disclosed with specific sequence information in WO2014/131712, W02018/219901 or WO2017/055389.
  • the CEACAM5 CD3 TCB comprises a CD3 binding moiety comprising the heavy chain variable region sequence of SEQ ID NO: 7 and the light chain variable region sequence of SEQ ID NO: 8; and a CEACAM5 binding moiety comprising the heavy chain variable region sequence of SEQ ID NO: 23 and the light chain variable region sequence of SEQ ID NO: 24 as disclosed in WO2018/219901.
  • the bispecific CEACAM5 CD3 antibody comprises a polypeptide comprising the sequence of SEQ ID NO: 29, a polypeptide comprising the sequence of SEQ ID NO: 30, a polypeptide comprising the sequence of SEQ ID NO: 31 , and a polypeptide comprising the sequence of SEQ ID NO: 32 as disclosed in W02018/219901.
  • This antibody is used in the working examples of the present application. Therefore, the sequences and SEQ ID NOs of WO2018/219901 , referred to above, have the following SEQ ID NOs in the present application (see Table 2):
  • a TCB directed to CD3 and TYRP1 is as disclosed with specific sequence information in WO2020/127619 (see e.g. Example 4).
  • the TRP1 binder comprised in this TCB is generated by humanization of the TRP1 binder “TA99” (see GenBank entries AXQ57811 and AXQ57813 for the heavy and light chain, respectively).
  • the full length sequences of a TRP1 CD3 TCB are given by SEQ ID Nos 23, 24, 25 and 26 of WO2020/127619.
  • the full length sequences of a TRP1 CD3 TCB are given by SEQ ID Nos 23, 24, 25 and 27 of WO2020/127619.
  • a mouse surrogate of this TCB was used in the present working examples. Therefore, the sequences and SEQ ID NOs of WO2020/127619, referred to above, have the following SEQ ID NOs in the present application (see Table 3):
  • a TCB directed to CD3 and GPRC5D (a “GPRC5D-CD3 TCB” ) is as disclosed with specific sequence information in WQ2019/154890 or WO2021/018859.
  • a GPRC5D-CD3 TCB is the antibody represented by the sequences of SEQ ID NOs 122-125 in WO2021/018859. This antibody is used in the working examples of the present application. Therefore, the sequences and SEQ ID NOs of WO2021/018859, referred to above, have the following SEQ ID NOs in the present application (see Table 4):
  • a TCB as used herein is independently selected from the antibodies with the INN blinatumomab, odronextamab, epcoritamab, mosunetuzumab, glofitamab, cevostamab or talquetamab.
  • the antibody with INN cevostamab has the full length sequence information as published by the WHO (see recommended INN List 84; WHO Drug Information, Vol. 34, No. 3, 2020, page 701-703).
  • the antibody with the INN cevostamab has the full lengths sequences represented by the following SEQ ID NOs herein (Table 5):
  • the TCB and Treg cell depletion therapy are each administered in a therapeutically effective amount.
  • the selection of an appropriate dosage of the antibodies will be within the capability of one skilled in the art. For example, 0.01 , 0.1 , 0.3, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50 mg/kg.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e. , with a therapeutic dosing regimen).
  • the dosage may also be varied for route of administration, the cycle of treatment, or consequently to dose escalation protocol that can be used to determine the maximum tolerated dose and dose limiting toxicity (if any) in connection to the administration of the antibody or TCB at increasing doses.
  • compositions which additionally comprises a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier, diluent or excipient.
  • compositions include, for example, liquid, semisolid and solid dosage formulations, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, or liposomes.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., dispersions or suspensions
  • tablets pills, or liposomes.
  • a preferred form may depend on the intended mode of administration and/or therapeutic application.
  • Pharmaceutical compositions containing the antibody can be administered by any appropriate method known in the art, including, without limitation, oral, mucosal, by-inhalation, topical, buccal, nasal, rectal, or parenteral (
  • a formulation may, for example, be in a form of an injectable or infusible solution that is suitable for intradermal, intratumoural or subcutaneous administration, or for intravenous infusion.
  • the administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.
  • the antibodies can be prepared with carriers that protect it against rapid release and/or degradation, such as a controlled release formulation, such as implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation such as implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used.
  • route of delivery e.g., oral vs intravenous vs subcutaneous vs intratumoural, etc
  • dose amount may impact route of delivery.
  • route of delivery e.g., oral vs intravenous vs subcutaneous vs intratumoural, etc
  • dose amount may impact route of delivery.
  • route of delivery e.g., oral vs intravenous vs subcutaneous vs intratumoural, etc
  • required dose amount may impact route of delivery.
  • route of delivery e.g., oral vs intravenous vs subcutaneous vs intratumoural, etc
  • focused delivery e.g., in this example, intratumoural delivery
  • Other factors to be considered when optimizing routes and/or dosing schedule for a given therapeutic regimen may include, for example, the particular cancer being treated (e.g., type, stage, location, etc.), the clinical condition of a subject (e.g., age, overall health, etc.), and other factors known to medical practitioners.
  • compositions for each component typically should be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating the antibody in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations as discussed herein.
  • Sterile injectable formulations may be prepared using a non-toxic parenterally acceptable diluent or solvent.
  • Each pharmaceutical composition for use in accordance with the present invention may include pharmaceutically acceptable dispersing agents, wetting agents, suspending agents, isotonic agents, coatings, antibacterial and antifungal agents, carriers, excipients, salts, or stabilizers are non-toxic to the subjects at the dosages and concentrations employed.
  • such a composition can further comprise a pharmaceutically acceptable carrier or excipient for use in the treatment of cancer that that is compatible with a given method and/or site of administration, for instance for parenteral (e.g. sub- cutaneous, intradermal, or intravenous injection), intratumoral, or peritumoral administration.
  • the invention provides the combined use of a Treg cell depletion therapy and a TCB in the manufacture of a medicament for the treatment of cancer.
  • the invention provides an anti-CD25 antibody for use in the treatment of cancer, wherein the anti-CD25 antibody is for use in combination with a TCB.
  • the invention provides the use of an anti-CD25 antibody in the manufacture of a medicament for the treatment of cancer, wherein the anti-CD25 antibody is for use in combination with a TCB.
  • the invention provides a TCB for use in the treatment of cancer, wherein the TCB is for use in combination with an anti-CD25 antibody.
  • the invention provides a TCB for the manufacture of a medicament for the treatment of cancer, wherein the TCB is for use in combination with an anti-CD25 antibody.
  • the invention provides a kit for use in treating a cancer.
  • the kit comprises at least two active ingredients wherein the kit comprises: a) a first composition comprising a Treg cell depletion therapy; and b) a second composition comprising a TCB, and optionally instructions for using the compositions in a combination therapy for the treatment of cancer.
  • the combination therapy can comprise administering the T reg cell depletion therapy; and the TCB in accordance with dosage regimens as described for the first and further aspects of the invention.
  • a further aspect of the invention provides a method of treating a patient, with cancer, comprising administering to said patient a combination product comprising a) a therapeutically effective amount of a TCB; and b) a therapeutically effective amount of a Treg cell depletion therapy, preferably an anti-CD25 antibody as defined herein.
  • the combination is for simultaneous or sequential administration.
  • a further aspect of the invention provides a method of treating or preventing relapse of a patient, with cancer, comprising administering to said patient a combination product comprising a) a therapeutically effective amount of a TCB; and b) a therapeutically effective amount of a Treg cell depletion therapy, preferably an anti-CD25 antibody as defined herein.
  • the combination is for simultaneous or sequential administration.
  • a further aspect of the invention provides a method of inducing or enhancing lysis of a tumor cell in a patient, with cancer, comprising administering to said patient a combination product comprising a) a therapeutically effective amount of a TCB; and b) a therapeutically effective amount of a Treg cell depletion therapy, preferably an anti-CD25 antibody as defined herein.
  • the combination is for simultaneous or sequential administration.
  • the invention provides a combination or pharmaceutical product as described herein for use in inducing lysis of a target cell, particularly a tumor cell.
  • the invention provides a combination or pharmaceutical product for use as described herein in a method of inducing lysis of a target cell, particularly a tumor cell, in a patient with cancer, comprising administering to said patient an effective amount of the combination or pharmaceutical product to induce lysis of a target cell.
  • a further aspect of the invention is a method to delay cancer progression or development in a subject comprising administering a therapeutically effective amount of a Treg cell depletion therapy and a therapeutically effective amount of a TCB to the subject.
  • a further aspect of the invention is a method to potentiate response of a patient with cancer to a therapy comprising a TCB, by co-administering a therapeutically effective amount of a Treg cell depletion therapy to said patient.
  • the human non IL-2 blocking anti-CD25 antibody is RG6292 as disclosed herein.
  • the anti-mouse CD25 NIB is a mouse surrogate antibody of RG6292.
  • the mouse surrogate TRP1 CD3 TCB is disclosed in WO2020/127619.
  • MOXRO0916 is an exploratory antibody developed by the Applicant.
  • the human GPRC5D CD3 TCB is disclosed in WO2021/018859.
  • Ipilimumab is commercially available under the tradename Yervoy®
  • the human non IL-2 blocking anti-CD25 antibody (RG6292) was tested as monotherapy or in combination with the human CEACAM-5 CD3 TCB in a human pancreatic adenocarcinoma cancer model.
  • Ipilimumab and MOXRO0916 were tested as reference compound.
  • Ipilimumab is an immune checkpoint inhibitor, that is discussed to deplete CTLA-4 positive Treg cells and is well established in the field of cancer immunotherapy.
  • MOXRO0916 is an immunagonist targeting 0x40, that has been shown to deplete Treg cells in vitro.
  • BxPC3 cells were grafted subcutaneously in matrigel in humanized NSG mice.
  • BXPC3 cells human pancreatic adenocarcinoma cells
  • ECACC European Collection of Cell Culture
  • BXPC3 cells were cultured in RPMI containing 10% FCS (PAA Laboratories, Austria), 1 % Glutamax. The cells were cultured at 37 °C in a water-saturated atmosphere at 5 % CO2.
  • Cells were subcutaneously injected in RPMI medium (w/o) and matrigel 1 :1 (100 uL) in the flank of anaesthetized mice with a 22G to 30G needle.
  • mice were delivered by Charles River and were transplanted in house with human stem cells. Mice were maintained under specific-pathogen-free condition with daily cycles of 12 h light /12 h darkness according to committed guidelines (GV-Solas; Felasa; TierschG). Experimental study protocol was reviewed and approved by local government (ZH193-2014). After arrival animals were maintained for one week to get accustomed to new environment and for observation. Continuous health monitoring was carried out on regular basis. For humanization, mice were injected with Busulfan (20mg/kg) followed 24 hours later by injection of 100,000 human HSC (purchased from StemCell Technologies).
  • mice 14 days before cell injection mice were bled and screened for the amount of human T cells in the blood and were randomized accordingly. Mice were injected sub cutaneously on study day 0 with 1x10 6 BxPC3. Tumors were measured 2 to 3 times per week during the whole experiment by Caliper. On day14 mice were randomized for tumor size with an average tumor size of 237 mm 3 . On day 21 mice received i.p. a single injection of vehicle, RG6292 [ 4 mg/kg], MOXRO0916 [10 mg/kg] or Ipilimumab [10 mg/kg], TCB treated mice received weekly i.v. CEACAM-5 CD3 TCB [2.5 mg/kg] (day 15 and 22).
  • Treatment groups were vehicle, RG6292, CEACAM-5 CD3 TCB, Ipilimumab and the combination of CEACAM-5 TCB + RG6292. All mice were injected i.v. with 200 pl of the appropriate solution. The mice in the vehicle group were injected with Histidine buffer. To obtain the proper amount of compound per 200 pl, the stock solutions were diluted with Histidine Buffer when necessary. No adverse events were observed and mice tolerated the treatment well. The experiment was terminated at study day 24.
  • FACS Fluorescence-activated cell sorting
  • Tumors, blood and spleen were harvested at day of termination (day 24) and were stored in PBS until preparation of single cell suspensions. Erythrolysis of whole blood samples were performed for 3 minutes at room temperature using the BD Pharm Lyse buffer (BD, Ca.No. 555899) according to manufacturers instructions. Splenocytes were isolated by homogenization of the spleen through a cell strainers (nylon filter 70um, BD Falcon) followed by erythrolysis as described above. Tumor single cell suspensions were prepared by using the gentleMACS Dissociator (Miltenyi) and digest the homogenate for 30 minutes at 37°C with DNAse I ([0.025mG/mL], RocheDiagnostics, Ca.No.
  • CD25 (clone 2A3, BD Pharmingen, Cat.-No.), CTLA-4 (clone BNI3, , Cat.-No.) and CD45 (clone, , Cat.-No.) in the presence of purified Rat anti-mouse CD16/CD32 (clone 2.4G2, BD, Ca.No. 553142) for 30 min at 4°C, dark, in FACS buffer.
  • Rat anti-mouse CD16/CD32 (clone 2.4G2, BD, Ca.No. 553142) for 30 min at 4°C, dark, in FACS buffer.
  • FoxP3 detection cells were stained using the Foxp3 Transcription Factor Staining Buffer Set (eBioscience, Cat. No.00-5523-00) and the anti-human FoxP3 (clone 150D/E, eBioscience, Cat.-No. 12-4774-42) according to manufacturers instructions.
  • mice To test the human anti CD25 antibody human immune cells and specially T cells have to be present in the mouse system. To this purpose humanized mice were used, meaning mice transferred with human stem cells. These mice develop over time a partially human immune system consisting mainly of T and B cells. BxPC-3, a CEA expressing human pancreatic adenocarcinoma cell line, was injected. CD8 T cells as well as Treg cells infiltrate with time the tumor stroma, but the CD8 T cells are not able to control tumor growth.
  • CEA is targeted by the CEACAM-5 CD3 TCB, crosslinking T cells with tumor cells and inducing T cell mediated killing of tumor cells and T cell activation.
  • CD25 is upregulated on CTLs as well.
  • the anti-mouse CD25 NIB (mouse lgG2a; mouse surrogate of RG6292) was tested as monotherapy or in combination with the mouse surrogate TRP1 CD3 TCB in the syngeneic lung metastatic melanoma B16F10 mouse cancer model.
  • B16-FAP-Fluc cells clone 106 (metastatic melanoma) were produced in Roche-Glycart by calcium transfection, expanded and deposited in Roche-Glycart internal cell bank.
  • B16-FAP-Fluc were cultured in RPMI medium containing 10% FCS (Sigma), 0.75 pg/ml Puromycin, 200 pg/ml Zeocin and 1 % of Glutamax. The cells were cultured at 37°C in a water-saturated atmosphere at 5 % CO2. Two hundred microliters (0.2x10 6 cells in RPMI medium) of cell suspension were injected into the tail vein with a 22G to 30G needle on day 0.
  • mice received i.p. a single injection of anti-mouse CD25 NIB (mouse lgG2a) [ 10 mg/kg] (CD25 monotherapy and combination treated mice).
  • mice received weekly i.v. TRP1 CD3 TCB [10 mg/kg] (TCB monotherapy and combination treated mice) or vehicle (CD25 monotherapy and vehicle control mice). All mice were injected i.v. with 200 pl of the appropriate solution. The mice in the vehicle group were injected with Histidine buffer. To obtain the proper amount of compound per 200 pl, the stock solutions were diluted with Histidine Buffer when necessary.
  • the human CD25 Mab (RG6292) was tested in combination with the human GPRC5D CD3 TCB in a human multiple myeloma cancer model.
  • NCI-H929 cells were grafted subcutaneously in matrigel in humanized NSG mice.
  • Human NCI-H929 were originally obtained from Roche Nutley and after expansion deposited in the Roche Kunststoff internal cell bank. Cells were cultured in RPMI 1640 high glucose medium containing 10% FCS, 2 mM L-Glutamine, 10 mM HEPES and 1 mM Sodiumpyruvate. Cells were cultured at 37 °C in a water-saturated atmosphere at 5 % CO2. In vitro passage 1 was used for subcutaneous injection at a viability of 95%. In order to generate tumor bearing mice, 50 microliters cell suspension (2.5 x10 6 cells) were co-injected with 50 pl Matrigel subcutaneously in the flank of anaesthetized, humanized NSG mice.
  • HSC hematopoietic stem cells
  • 33 NSG female mice were delivered by Charles River, Lyon, France. After arrival animals were maintained for one week to get accustomed to new environment and for observation.
  • the NSG mice were treated with 15 mg/kg Busulfan (i.p.) and, after 24h, 1x10 5 human hematopoietic stem cells were injected i.v.
  • Mice were maintained under specific-pathogen-free condition with daily cycles of 12 h light /12 h darkness according to committed guidelines (GV-Solas; Felasa; TierschG). Continuous health monitoring was carried out on regular basis.
  • mice Humanization status of mice was confirmed 16 weeks after HSC transfer. Experimental study protocol was reviewed and approved by local government (ROB- 55.2-2532. Vet_03-16-10). When subcutaneous tumors reached a mean volume of 230 mm 3 (98 - 441 mm 3 ), humanized mice were randomized into different treatment groups based on tumor volume and body weight. All antibodies were prepared freshly before injection and GPRC5D TCB administered intravenously (i.v.) once weekly starting at day 13. CD25 Mab (RG6292) was injected concomitant to the first TCB injection and at 2 additional times thereafter (each at 10 day intervals) intraperitoneally (i.p.) with 3 mg/kg.
  • cytokine analysis was performed in the blood plasma of treated mice. Plasma was isolated from up to 5 mice per group 48 hrs after first TCB injection and analyzed for the expression of a defined set of cytokines using the Bio-Plex Pro Human Cytokine 27-plex Assay (BioRad, #M500KCAF0Y) according to manufacturers instructions.
  • GPRC5D TCB increased the IL-10 concentration in the blood.
  • CD25 Mab (RG6292) depleted Tregs and thus prevented IL-10 secretion.
  • Tregs were not acting as IL-2 sinks anymore which in turn increased then the available IL-2 for surrounding effector T cells (Figure 3).
  • GPRC5D TCB forced 100% of established tumors into regression. However, some animals started to relapse before day 40 of the study. Treatment with CD25 Mab (RG6292) was able to delay this relapse post day 40 ( Figure 4).

Abstract

La présente invention concerne la combinaison d'un TCB, tel que défini dans la description, et d'une thérapie de déplétion de lymphocytes T régulateurs, par exemple un anticorps anti-CD25 destiné à être utilisé dans le traitement du cancer.
PCT/EP2023/079524 2022-10-26 2023-10-24 Polythérapie pour le traitement du cancer WO2024088987A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22203714 2022-10-26
EP22203714.5 2022-10-26

Publications (1)

Publication Number Publication Date
WO2024088987A1 true WO2024088987A1 (fr) 2024-05-02

Family

ID=83996680

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/079524 WO2024088987A1 (fr) 2022-10-26 2023-10-24 Polythérapie pour le traitement du cancer

Country Status (1)

Country Link
WO (1) WO2024088987A1 (fr)

Citations (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6054297A (en) 1991-06-14 2000-04-25 Genentech, Inc. Humanized antibodies and methods for making them
WO2005040220A1 (fr) 2003-10-16 2005-05-06 Micromet Ag Element de liaison au cd3, desimmunise multispecifique
WO2005118635A2 (fr) 2004-06-03 2005-12-15 Novimmune S.A. Anticorps anti-cd3 et leurs methodes d'utilisation
WO2007042261A2 (fr) 2005-10-11 2007-04-19 Micromet Ag Compositions comportant des anticorps specifiques d'especes croisees et leurs utilisations
WO2008119567A2 (fr) 2007-04-03 2008-10-09 Micromet Ag Domaine de liaison spécifique d'espèces croisées
WO2008119565A2 (fr) 2007-04-03 2008-10-09 Micromet Ag Domaine de liaison spécifique d'espèces croisées
WO2011035884A1 (fr) 2009-09-22 2011-03-31 Volker Sandig Procédé de production de molécules contenant des structures glycanes spécialisées
WO2012162067A2 (fr) 2011-05-21 2012-11-29 Macrogenics, Inc. Molécules de liaison des cd3 capables de se lier aux cd3 humaines et non humaines
WO2013158856A2 (fr) 2012-04-20 2013-10-24 Emergent Product Development Seattle, Llc Polypeptides se liant à cd3
WO2013188693A1 (fr) 2012-06-15 2013-12-19 Imaginab, Inc. Constructions de liaison à l'antigène pour cd3
WO2013186613A1 (fr) 2012-06-14 2013-12-19 Nasvax Ltd. Anticorps humanisés pour le groupe de différentiation 3 (cd3)
WO2014047231A1 (fr) 2012-09-21 2014-03-27 Regeneron Pharmaceuticals, Inc. Anticorps anti-cd3, molécules de liaison à un antigène bispécifiques qui se lient à cd3 et cd20, et leurs utilisations
WO2014110601A1 (fr) 2013-01-14 2014-07-17 Xencor, Inc. Nouvelles protéines hétérodimères
WO2014131712A1 (fr) 2013-02-26 2014-09-04 Roche Glycart Ag Molécules de liaison à l'antigène bispécifiques activant des lymphocytes t
WO2014145806A2 (fr) 2013-03-15 2014-09-18 Xencor, Inc. Protéines hétérodimériques
WO2014191113A1 (fr) 2013-05-28 2014-12-04 Numab Ag Nouveaux anticorps
WO2015001085A1 (fr) 2013-07-05 2015-01-08 Genmab B.V. Anticorps anti-cd3 humanisés ou chimères
WO2015095392A1 (fr) 2013-12-17 2015-06-25 Genentech, Inc. Anticorps anti-cd3 et méthodes d'utilisation
WO2015172800A1 (fr) 2014-05-12 2015-11-19 Numab Ag Nouvelles molécules multispécifiques et nouvelles méthodes de traitement basées sur ces molécules multispécifiques
WO2015181098A1 (fr) 2014-05-28 2015-12-03 F. Hoffmann-La Roche Ag Anticorps se liant au cd3-epsilon humain et de singe cynomolgus
WO2016014974A2 (fr) 2014-07-25 2016-01-28 Cytomx Therapeutics, Inc. Anticorps anti-cd3, anticorps anti-cd3 activables, anticorps anti-cd3 multispécifiques, anticorps anti-cd3 activables multispécifiques et procédés d'utilisation de ces anticorps
WO2016020444A1 (fr) 2014-08-07 2016-02-11 Affimed Gmbh Domaine de liaison aux cd3
WO2016071004A1 (fr) 2013-11-04 2016-05-12 Glenmark Pharmaceuticals S.A. Immunoglobulines héréro-dimériques reciblant des lymphocytes
WO2016116626A1 (fr) 2015-01-23 2016-07-28 Sanofi Anticorps anti-cd3, anticorps anti-cd123 et anticorps bispécifiques se liant spécifiquement à cd3 et/ou cd123
WO2016166629A1 (fr) 2015-04-13 2016-10-20 Pfizer Inc. Anticorps thérapeutiques et leurs utilisations
WO2016204966A1 (fr) 2015-06-16 2016-12-22 Genentech, Inc. Anticorps anti-cd3 et leurs méthodes d'utilisation
WO2017010874A1 (fr) 2015-07-10 2017-01-19 Merus N.V. Anticorps se liant à un cd3 humain
WO2017009442A1 (fr) 2015-07-15 2017-01-19 Genmab A/S Anticorps anti-cd3 humanisés ou chimériques
WO2017053469A2 (fr) 2015-09-21 2017-03-30 Aptevo Research And Development Llc Polypeptides de liaison à cd3
WO2017053856A1 (fr) 2015-09-23 2017-03-30 Regeneron Pharmaceuticals, Inc. Anticorps bispécifiques anti-cd3 optimisés et leurs utilisations
WO2017055389A1 (fr) 2015-10-02 2017-04-06 F. Hoffmann-La Roche Ag Molécules bispécifiques de liaison à l'antigène activant les lymphocytes t anti-ceaxcd3
WO2017174331A1 (fr) 2016-04-07 2017-10-12 Cancer Research Technology Limited Anticorps bispécifiques du récepteur fc gamma anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2017201493A1 (fr) 2016-05-20 2017-11-23 Harpoon Therapeutics, Inc. Protéines se liant au fragment monocaténaire variable de cd3
WO2017223111A1 (fr) 2016-06-21 2017-12-28 Teneobio, Inc. Anticorps se liant à cd3
WO2018167104A1 (fr) 2017-03-17 2018-09-20 Tusk Therapeutics Ltd Anti-cd25 à optimisation fc pour épuisement de cellules spécifiques tumorales
WO2018219901A1 (fr) 2017-06-01 2018-12-06 F. Hoffmann-La Roche Ag Procéde de traitement
WO2019008386A1 (fr) 2017-07-06 2019-01-10 Tusk Therapeutics Ltd Composés et procédés pour la déplétion de cellules spécifiques d'une tumeur
WO2019017522A1 (fr) 2017-07-21 2019-01-24 엘지전자 주식회사 Batterie solaire en pérovskite et batterie solaire en tandem comprenant celle-ci
WO2019017524A1 (fr) 2017-07-20 2019-01-24 주식회사 파트론 Boîtier de capteur d'empreintes digitales
WO2019017526A1 (fr) 2017-07-17 2019-01-24 성균관대학교산학협력단 Système de collage à sec comportant une pluralité de structures d'imbrication inter-couches
WO2019117522A1 (fr) 2017-12-11 2019-06-20 삼성전자주식회사 Dispositif d'affichage et son procédé de commande
WO2019154890A1 (fr) 2018-02-09 2019-08-15 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d
WO2019175226A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Agents anticorps anti-cd25
WO2020127619A1 (fr) 2018-12-21 2020-06-25 F. Hoffmann-La Roche Ag Anticorps se liant à cd3
WO2021018859A2 (fr) 2019-07-31 2021-02-04 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d

Patent Citations (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6054297A (en) 1991-06-14 2000-04-25 Genentech, Inc. Humanized antibodies and methods for making them
WO2005040220A1 (fr) 2003-10-16 2005-05-06 Micromet Ag Element de liaison au cd3, desimmunise multispecifique
WO2005118635A2 (fr) 2004-06-03 2005-12-15 Novimmune S.A. Anticorps anti-cd3 et leurs methodes d'utilisation
WO2007042261A2 (fr) 2005-10-11 2007-04-19 Micromet Ag Compositions comportant des anticorps specifiques d'especes croisees et leurs utilisations
WO2008119567A2 (fr) 2007-04-03 2008-10-09 Micromet Ag Domaine de liaison spécifique d'espèces croisées
WO2008119565A2 (fr) 2007-04-03 2008-10-09 Micromet Ag Domaine de liaison spécifique d'espèces croisées
WO2011035884A1 (fr) 2009-09-22 2011-03-31 Volker Sandig Procédé de production de molécules contenant des structures glycanes spécialisées
WO2012162067A2 (fr) 2011-05-21 2012-11-29 Macrogenics, Inc. Molécules de liaison des cd3 capables de se lier aux cd3 humaines et non humaines
WO2013158856A2 (fr) 2012-04-20 2013-10-24 Emergent Product Development Seattle, Llc Polypeptides se liant à cd3
WO2013186613A1 (fr) 2012-06-14 2013-12-19 Nasvax Ltd. Anticorps humanisés pour le groupe de différentiation 3 (cd3)
WO2013188693A1 (fr) 2012-06-15 2013-12-19 Imaginab, Inc. Constructions de liaison à l'antigène pour cd3
WO2014047231A1 (fr) 2012-09-21 2014-03-27 Regeneron Pharmaceuticals, Inc. Anticorps anti-cd3, molécules de liaison à un antigène bispécifiques qui se lient à cd3 et cd20, et leurs utilisations
WO2014110601A1 (fr) 2013-01-14 2014-07-17 Xencor, Inc. Nouvelles protéines hétérodimères
WO2014131712A1 (fr) 2013-02-26 2014-09-04 Roche Glycart Ag Molécules de liaison à l'antigène bispécifiques activant des lymphocytes t
WO2014145806A2 (fr) 2013-03-15 2014-09-18 Xencor, Inc. Protéines hétérodimériques
WO2014191113A1 (fr) 2013-05-28 2014-12-04 Numab Ag Nouveaux anticorps
WO2015001085A1 (fr) 2013-07-05 2015-01-08 Genmab B.V. Anticorps anti-cd3 humanisés ou chimères
WO2016071004A1 (fr) 2013-11-04 2016-05-12 Glenmark Pharmaceuticals S.A. Immunoglobulines héréro-dimériques reciblant des lymphocytes
WO2015095392A1 (fr) 2013-12-17 2015-06-25 Genentech, Inc. Anticorps anti-cd3 et méthodes d'utilisation
WO2015104346A1 (fr) 2014-01-09 2015-07-16 Genmab B.V. Anticorps anti-cd3 humanisés ou chimériques
WO2015172800A1 (fr) 2014-05-12 2015-11-19 Numab Ag Nouvelles molécules multispécifiques et nouvelles méthodes de traitement basées sur ces molécules multispécifiques
WO2015181098A1 (fr) 2014-05-28 2015-12-03 F. Hoffmann-La Roche Ag Anticorps se liant au cd3-epsilon humain et de singe cynomolgus
WO2016014974A2 (fr) 2014-07-25 2016-01-28 Cytomx Therapeutics, Inc. Anticorps anti-cd3, anticorps anti-cd3 activables, anticorps anti-cd3 multispécifiques, anticorps anti-cd3 activables multispécifiques et procédés d'utilisation de ces anticorps
WO2016020444A1 (fr) 2014-08-07 2016-02-11 Affimed Gmbh Domaine de liaison aux cd3
WO2016116626A1 (fr) 2015-01-23 2016-07-28 Sanofi Anticorps anti-cd3, anticorps anti-cd123 et anticorps bispécifiques se liant spécifiquement à cd3 et/ou cd123
WO2016166629A1 (fr) 2015-04-13 2016-10-20 Pfizer Inc. Anticorps thérapeutiques et leurs utilisations
WO2016204966A1 (fr) 2015-06-16 2016-12-22 Genentech, Inc. Anticorps anti-cd3 et leurs méthodes d'utilisation
WO2017010874A1 (fr) 2015-07-10 2017-01-19 Merus N.V. Anticorps se liant à un cd3 humain
WO2017009442A1 (fr) 2015-07-15 2017-01-19 Genmab A/S Anticorps anti-cd3 humanisés ou chimériques
WO2017053469A2 (fr) 2015-09-21 2017-03-30 Aptevo Research And Development Llc Polypeptides de liaison à cd3
WO2017053856A1 (fr) 2015-09-23 2017-03-30 Regeneron Pharmaceuticals, Inc. Anticorps bispécifiques anti-cd3 optimisés et leurs utilisations
WO2017055389A1 (fr) 2015-10-02 2017-04-06 F. Hoffmann-La Roche Ag Molécules bispécifiques de liaison à l'antigène activant les lymphocytes t anti-ceaxcd3
WO2017174331A1 (fr) 2016-04-07 2017-10-12 Cancer Research Technology Limited Anticorps bispécifiques du récepteur fc gamma anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2017201493A1 (fr) 2016-05-20 2017-11-23 Harpoon Therapeutics, Inc. Protéines se liant au fragment monocaténaire variable de cd3
WO2017223111A1 (fr) 2016-06-21 2017-12-28 Teneobio, Inc. Anticorps se liant à cd3
WO2018167104A1 (fr) 2017-03-17 2018-09-20 Tusk Therapeutics Ltd Anti-cd25 à optimisation fc pour épuisement de cellules spécifiques tumorales
WO2018219901A1 (fr) 2017-06-01 2018-12-06 F. Hoffmann-La Roche Ag Procéde de traitement
WO2019008386A1 (fr) 2017-07-06 2019-01-10 Tusk Therapeutics Ltd Composés et procédés pour la déplétion de cellules spécifiques d'une tumeur
WO2019017526A1 (fr) 2017-07-17 2019-01-24 성균관대학교산학협력단 Système de collage à sec comportant une pluralité de structures d'imbrication inter-couches
WO2019017524A1 (fr) 2017-07-20 2019-01-24 주식회사 파트론 Boîtier de capteur d'empreintes digitales
WO2019017522A1 (fr) 2017-07-21 2019-01-24 엘지전자 주식회사 Batterie solaire en pérovskite et batterie solaire en tandem comprenant celle-ci
WO2019117522A1 (fr) 2017-12-11 2019-06-20 삼성전자주식회사 Dispositif d'affichage et son procédé de commande
WO2019154890A1 (fr) 2018-02-09 2019-08-15 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d
WO2019175220A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2019175217A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2019175223A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2019175226A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Agents anticorps anti-cd25
WO2019175224A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2019175215A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2019175216A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2019175222A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2020127619A1 (fr) 2018-12-21 2020-06-25 F. Hoffmann-La Roche Ag Anticorps se liant à cd3
WO2021018859A2 (fr) 2019-07-31 2021-02-04 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
"GenBank", Database accession no. AXQ57813
"Leukocyte Typing II.", 1986, SPRINGER VERLAG
"Molecular Biology", vol. 66, 1996, article "Epitope Mapping Protocols in Methods"
"NCBI", Database accession no. NP_000724.1
"Uniprot", Database accession no. P01589
"UniProt", Database accession no. P07766
ATSCHUL ET AL., J. MOLEC. BIOL., vol. 215, 1990, pages 403
BURNS ET AL., J IMMUNOL, vol. 129, 1982, pages 1451 - 1457
COULIE ET AL., EUR J IMMUNOL, vol. 21, 1991, pages 1703 - 1709
DEVEREUX ET AL., NUCLEIC ACIDS RESEARCH, vol. 12, 1984, pages 387
HODI ET AL., PROC. NATL. ACAD. SCI. USA, vol. 105, 2008, pages 3005 - 3010
INN LIST 84; WHO DRUG INFORMATION, vol. 34, no. 3, 2020, pages 701 - 703
JP GREGORY ET AL., J. PERS. MED., vol. 11, no. 5, 2021, pages 355
KABAT ET AL., J BIOL CHEM, vol. 252, 1977, pages 6609 - 6616
KEARNS JD ET AL., MOL CANCER THER., vol. 14, 2015, pages 1625 - 36
KORISTKA ET AL., BLOOD CANCER JOURNAL, vol. 4, 2014, pages 199
KUNG ET AL., SCIENCE, vol. 206, 1979, pages 347 - 349
M. YASANUGA ET AL., PHARMACEUTICALS, vol. 14, no. 11, 2021, pages 1172
NOOIJ ET AL., EUR J IMMUNOL, vol. 19, 1986, pages 981 - 984
PESSANO ET AL., EMBO J, vol. 4, 1985, pages 337 - 340
QUEZADA ET AL., J CLIN INVEST., vol. 116, no. 7, 2006, pages 1935 - 45
RODRIGUES ET AL., INT J CANCER SUPPL, vol. 7, 1992, pages 45 - 50
SHANG ET AL., SCI REP., vol. 5, 2015, pages 15179
SIMPSON ET AL., J EXP MED, vol. 210, 2013, pages 1695 - 710
SKERRA, FEBS J, vol. 275, 2008, pages 2677 - 83
SOLOMON I ET AL., NATURE CANCER, vol. 1, 2020, pages 1153 - 1166
SPITS ET AL., J IMMUNOL, vol. 135, 1985, pages 1922
VERKLEIJ CP ET AL., BLOOD ADVANCES, vol. 5, no. 8, 2021, pages 2196 - 2215
WEBER, J NUCL MED, vol. 50, 2009, pages 1S - 10S

Similar Documents

Publication Publication Date Title
US20230265200A1 (en) Anti cd25 fc gamma receptor bispecific antibodies for tumor specific cell depletion
EP3596123B1 (fr) Anticoprs anti cd25 optimisés dans leur partie fc impliquant la déplétion de cellules spécifiques aux tumeurs
JP7225135B2 (ja) 腫瘍特異的細胞枯渇のための化合物及び方法
AU2014351308B2 (en) Compositions comprising anti-CEACAM1 and anti-PD antibodies for cancer therapy
US11167029B2 (en) Combination of a CD30XCD16 antibody with a PD-1 antagonist for therapy
US20170015758A1 (en) Compositions And Methods For Modulating And Redirecting Immune Responses
US11168137B2 (en) Method for reducing side effects of immune checkpoint control agent
US20230348619A1 (en) Combination Of T-Cell Redirecting Multifunctional Antibodies With Immune Checkpoint Modulators And Uses Thereof
WO2022003156A1 (fr) Liants non bloquants ccr8
EP4055055B1 (fr) Anticorps bispécifiques contre ceacam5 et cd47
EP4267618A1 (fr) Liants ccr8 humains non bloquants
WO2024088987A1 (fr) Polythérapie pour le traitement du cancer
JP2024518200A (ja) Ｔ細胞リダイレクト治療薬及び抗ｃｄ４４治療薬を含む組成物
WO2023208990A1 (fr) Polythérapie pour le traitement du cancer comprenant un antagoniste de l'axe fas et un antagoniste d'agent de déplétion des lymphocytes t-reg,
TW202207977A (zh) 包含ｔ細胞重導向治療劑及ｖｌａ－４黏附路徑抑制劑之組成物
NZ786026A (en) Anti CD25 Fc gamma receptor bispecific antibodies for tumor specific cell depletion
WO2023242351A1 (fr) Polythérapie d'anticorps bispécifiques dirigés contre ceacam5 et cd47 et anticorps bispécifiques dirigés contre ceacam5 et cd3