WO2024081933A1 - Méthodes et compositions pour améliorer la réponse à une immunothérapie - Google Patents

Méthodes et compositions pour améliorer la réponse à une immunothérapie Download PDF

Info

Publication number
WO2024081933A1
WO2024081933A1 PCT/US2023/076913 US2023076913W WO2024081933A1 WO 2024081933 A1 WO2024081933 A1 WO 2024081933A1 US 2023076913 W US2023076913 W US 2023076913W WO 2024081933 A1 WO2024081933 A1 WO 2024081933A1
Authority
WO
WIPO (PCT)
Prior art keywords
tumor
antibody
cancer
antibodies
antigen
Prior art date
Application number
PCT/US2023/076913
Other languages
English (en)
Inventor
Tanya MAYADAS-NORTON
Huan Wang
Original Assignee
The Brigham And Women's Hospital, 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 The Brigham And Women's Hospital, Inc. filed Critical The Brigham And Women's Hospital, Inc.
Publication of WO2024081933A1 publication Critical patent/WO2024081933A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • BACKGROUND While immunotherapy using immune checkpoint inhibitors (ICIs) is a promising treatment for many cancers, its success has been limited in “cold” tumors that lack T-cell infiltration (Liu and Sun, Theranostics.2021; 11(11): 5365–5386).
  • SUMMARY The present invention is based, at least in part, on the discovery that Anti-CD16B- antigen conjugates (AACs) binding neutrophils can drive T cells into tumor tissues, turning “cold” tumors into “hot” tumors that respond to treatment with anti-PD1.
  • AACs Anti-CD16B- antigen conjugates
  • compositions comprising (i) a conjugate comprising a tumor antigen and an antibody comprising an antigen-binding domain that binds to Fc ⁇ RIII, optionally wherein the conjugate is a fusion protein or chemical conjugate, and (ii) an immune checkpoint inhibitor (ICI).
  • the tumor antigen is listed in Table A.
  • the one or more ICIs are selected from an antibody that binds to PD-1, CD40, PD-L1, Tim3, Lag3, CTLA-4, or T-cell immunoglobulin and ITIM domains (TIGIT).
  • the ICI is an antibody that binds PD-1.
  • compositions described herein for use in a method of treating a subject who has cancer.
  • the subject has a solid tumor.
  • the solid tumor does not have infiltrating leukocytes, or is immunologically cold.
  • the solid tumor is melanoma, pancreatic cancer, prostrate cancer, colon cancer, glioblastoma, or ovarian cancer.
  • methods of treating a subject who has cancer comprising administering to the subject an effective amount of a composition described herein.
  • a conjugate comprising an antigen and an antibody comprising an antigen-binding domain that binds to Fc ⁇ RIII, optionally wherein the conjugate is a fusion protein or chemical conjugate, and (ii) an immune checkpoint inhibitor (ICI).
  • the tumor antigen is shown in Table A.
  • the one or more ICIs are selected from an antibody that binds to PD-1, CD40, PD-L1, Tim3, Lag3, CTLA-4, or T-cell immunoglobulin and ITIM domains (TIGIT).
  • the ICI is an antibody that binds PD-1.
  • the subject has a solid tumor.
  • the tumor does not have infiltrating leukocytes, or is immunologically cold.
  • the tumor is melanoma, pancreatic cancer, prostrate cancer, glioblastoma, colon cancer, or ovarian cancer.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting.
  • FIGs.1A-B AAC but not anti-PD-1 increases early T cell and Natural Killer (NK) cell accumulation in an established B16F10-Ova melanoma.
  • NK Natural Killer
  • hFcJR humanized FcJR mice expressing FcJRIIIB (CD16B) and FcJRIIA (CD32A) selectively on neutrophils of mice lacking their endogenous activating FcJRs (Tsuboi et al. Immunity 2008, 28: 833).
  • B16F10-Ova murine melanoma cells expressing Ovalbumin (Ova), a model T cell-dependent antigen.
  • Ova Ovalbumin
  • OT-I na ⁇ ve Ova-specific CD8 + T cells.
  • AAC anti-FcJRIIIB conjugated to Ova.
  • IgG- Ova non-targeting isotype of anti-FcJRIIIB conjugated to Ova.
  • DPD1 anti-PD1.
  • Iso P isotype control of anti-PD-1.
  • FIGs.2A-B AAC reduces tumor growth independently and significantly enhances the efficacy of anti-PD-1.
  • a Schematic for the timeline of indicated treatments.
  • hFcJR humanized FcJR mice expressing FcJRIIIB (CD16B) and FcJRIIA (CD32A) selectively on neutrophils of mice lacking their endogenous activating FcJRs (Tsuboi et al. Immunity 2008, 28: 833).
  • B16F10-Ova murine melanoma cells expressing Ovalbumin (Ova), a model T cell-dependent antigen.
  • Ova Ovalbumin
  • OT-I na ⁇ ve Ova-specific CD8 + T cells.
  • AAC anti-FcJRIIIB conjugated to Ova.
  • IgG-Ova non-targeting isotype of anti- FcJRIIIB conjugated to Ova.
  • DPD1 anti-PD1.
  • Iso P isotype control of anti-PD-1.
  • FIGs.3A-C Anti-PD-1 in combination with AAC increases tumor accumulation of antigen-specific effector T cells, and T SCM and T RM memory T cells.
  • Tumors were harvested on day 19 and analyzed by flow cytometry for surface and Attorney Docket No.29618-0401WO1/BWH 2023-020 intracellular T cell markers and the number of cells per mm 3 volume of tumor is given.
  • a. Ova-specific CD8 + T cells detected with MHC-I tetramers (Tet + ).
  • B16F10 melanoma in mice has been shown to be a "cold" tumor with minimal infiltration with T cells, NK cells and other leukocytes with anti-tumor functions due to an immunosuppressive microenvironment (Urs et al., 2019, available online at biopharma.labcorp.com/industry-solutions/by-therapeutic- area/oncology/preclinical/tumor-spotlights/b16-f10-a-murine-melanoma-model.html).
  • AAC therapeutic treatment of an established B16F10-Ova melanoma reduced tumor growth and significantly increased the intratumoral infiltration of immune cells including activated CD8 + and CD4 + T cells, NK Attorney Docket No.29618-0401WO1/BWH 2023-020 cells and T SCM and T RM memory T cells, which are known to associate with anti-tumor immunity.
  • AAC administration in combination with anti-PD1 increased epitope spreading; in a mouse model of “cold” melanomas, spreading of epitope recognition toward wild-type melanocyte antigens has been shown to be associated with markedly improved anti-PD-1 efficacy (Lo et al., Sci Transl Med.2021 Feb 17;13(581):eabd8636).
  • AAC enhances the efficacy of an immune checkpoint inhibitor, anti-PD-1.
  • AAC targeting neutrophils combined with an immune checkpoint inhibitor such as anti- PD-1 represent a new immunotherapy for the treatment of solid tumors.
  • the combination should improve the efficacy of anti-PD1 and other immune checkpoint inhibitor in all tumors for which they are FDA approved (Vaddepally et al Cancers 2020, 12(3):738) as well as immunologically “cold” solid tumors resistant to immune checkpoint inhibitors.
  • pancreatic Chick et al Cancers 2023, 15(15):3967
  • prostrate Sriatura et al Cell Rep Med 2023, Sep 15:101199
  • colon Puccini et al J Immunother Cancer 2020, e000404
  • glioblastoma Dapash et al Cancers 2021, 13(18):4548
  • ovarian Le Saux et al. Semin Cancer Biol 2021, 77:127-143) cancer.
  • to “treat” cancer means to ameliorate at least one symptom of the cancer.
  • Administration of a therapeutically effective amount of a compound described herein for the treatment of a cancer can result in decreased or stabilized tumor burden, decreased or stabilized tumor size, decreased or stabilized tumor growth rate, decreased or stabilized tumor serum markers, and decreased or stabilized risk of metastasis.
  • the subjects can be, e.g., mammals, e.g., human or veterinary subjects. Although humans are used as examples herein, other mammals can also be treated using the present methods, with species-appropriate antibodies and other reagents.
  • the methods generally include identifying a subject who has a tumor, e.g., a cancer.
  • cancer refers to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth.
  • Hyperproliferative and neoplastic disease states may be categorized as pathologic, i.e., characterizing or constituting a disease state, or may be categorized as non-pathologic, i.e., a deviation from normal but not associated with a Attorney Docket No.29618-0401WO1/BWH 2023-020 disease state.
  • pathologic i.e., characterizing or constituting a disease state
  • non-pathologic i.e., a deviation from normal but not associated with a Attorney Docket No.29618-0401WO1/BWH 2023-020 disease state.
  • a cancer will be associated with the presence of one or more tumors, i.e., abnormal cell masses.
  • tumor is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. “Pathologic hyperproliferative” cells occur in disease states characterized by malignant tumor growth. In general, the methods described herein can be practiced on subjects with solid tumors or hematopoietic tumors, which are malignancies of cells of the immune system. Methods for identifying or diagnosing subjects with cancers are known in the art.
  • Tumors include malignancies of the various organ systems, such as affecting lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
  • adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
  • carcinoma is art recognized and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas.
  • the disease is renal carcinoma or melanoma.
  • exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary.
  • carcinosarcomas e.g., which include malignant tumors composed of carcinomatous and sarcomatous tissues.
  • An “adenocarcinoma” refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
  • the term “sarcoma” is art recognized and refers to malignant tumors of mesenchymal derivation.
  • cancers evaluated or treated by the methods described herein include epithelial cancers, such as a lung cancer (e.g., non-small-cell lung cancer (NSCLC)), breast cancer, colorectal cancer, kidney cancer, head and neck cancer, prostate cancer, or ovarian cancer.
  • Epithelial malignancies are cancers that affect epithelial tissues.
  • the cancers treated by the combination methods described herein are solid tumors for which immunotherapy using immune checkpoint inhibitors Attorney Docket No.29618-0401WO1/BWH 2023-020 (e.g., anti-PD1 and others) are FDA approved, as these methods can be used to improve efficacy of these modalities.
  • the combination methods described could make immunologically “cold” solid tumors responsive to the above modalities.
  • Methods for identifying cold tumors include histological analysis of patient biopsies immunostained with antibodies to examine the degree and type of immune cell infiltration (e.g., CD8+ T cells and NK cells) (Wang et al., MedComm 2020, 4(5):e343).
  • Anti-Fc ⁇ RIIIB (CD16B) antibodies conjugated to antigen Provided herein are methods in which a construct comprising an anti-Fc ⁇ RIIIB (CD16B) antibody conjugated to a tumor antigen is used, either in vitro/ex vivo to prepare cells for use in a cell therapy method, or in vivo to stimulate an immune response to the antigen.
  • the conjugate is delivered intravenously or intratumorally to a subject, in addition to treatment with anti-PD1 antibodies.
  • a construct comprising an anti-Fc ⁇ RIIIB antibody conjugated to a tumor antigen is used.
  • antigen comprises any structure that is capable of inducing an immune response in an organism either by itself or when coupled to a suitable carrier molecule or cell. Therefore, antigens according to the present invention include low molecular compounds which serve as haptens as well as whole cells such as tumor cells as well as the parts thereof such as polypeptides, oligopeptides derived therefrom, lipids such as glycolipids, polysaccharides and nucleic acids.
  • Tumor antigens can include, e.g., a Cancer Testis (CT) antigen, a protein that is normally expressed only on human germ line cells but is also present in a subset of malignant tumors, e.g., a CT antigen listed in Table A, or a neoantigen that arises from tumor- specific mutations. Neoantigens can arise from any genomic mutation altering protein sequence.
  • CT Cancer Testis
  • Tumor antigens MAGEA1 LDHC MAGEA2 50 95 MORC1 MAGEA3 DKKL1 MAGEA4 SPO11 MAGEA5 CRISP2 MAGEA6 FMR1NB MAGEA8 55 100 FTHL17 MAGEA9 NXF2 MAGEA10 TAF7L MAGEA11 TDRD1 MAGEA12 TDRD6 BAGE 60 105 TDRD4 BAGE2 TEX15 BAGE3 FATE1 BAGE4 TPTE BAGE5 CT45A1 MAGEB1 65 110 CT45A2 MAGEB2 CT45A3 MAGEB5 CT45A4 MAGEB6 CT45A5 MAGEB3 CT45A6 MAGEB4 70 115 HORMAD1 GAGE1 HORMAD2 GAGE2A CT47A1 GAGE3 CT47A2 GAGE4 CT47A3 GAGE5 75 120 CT47A4 GAGE6 CT47A5 GAGE7 CT47A6 GAGE8 CT47A7 SS
  • Anti-Fc ⁇ RIIIB antibodies are known in the art, as are methods of making them. Anti-Fc ⁇ RIIIB antibodies are commercially available, e.g., from Abbexa Ltd; Abcam; Abeomics; antibodies-online; Aviva Systems Biology; Biogems International, Inc.; BioLegend; Biorbyt; CEDARLANE; Cell Sciences; Creative Diagnostics; Elabscience Biotechnology Inc.; EXBIO Praha, a.s.; GeneTex; Invitrogen Antibodies; LifeSpan BioSciences; MBL International; Miltenyi Biotec; MyBioSource.com; NSJ Bioreagents; OriGene Technologies; Peninsula Laboratories International, Inc.; ProSci, Inc; R&D Systems; Santa Cruz Biotechnology, Inc.; Signalway Antibody LLC; Sino Biological, Inc.; SouthernBiotech; STEMCELL Technologies, Inc.; and United States Biological.
  • the antibody is 3G8 (e.g., available from biolegend, Santa Cruz Biotechnology, and others; see, e.g., Perussia and Trinchieri, J Immunol.1984 Mar;132(3):1410-5). These antibodies can be used as-is or modified, e.g., to reduce immunogenicity or alter half-life.
  • the antibody also recognizes Fc ⁇ RIIIA (CD16a: a transmembrane isoform of the GPI-linked Fc ⁇ RIIIB, CD16b) that is present on macrophages and NK cells.
  • the antibody is a Fc ⁇ RIIIB specific antibody that does not bind to Fc ⁇ RIIIA.
  • antibody refers to an immunoglobulin molecules, preferably IgG, as well as modified forms, or antigen-binding fragments, variants, or derivatives thereof.
  • the antibody can be polyclonal, monoclonal, recombinant, chimeric, de-immunized or humanized, fully human, non-human, (e.g., murine), or single chain antibody.
  • the antibody has effector function and can fix complement.
  • xenogeneic antibodies such as human-like antibodies in mice
  • xenogeneic antibodies such as human-like antibodies in mice
  • Modified forms of antibodies, or antigen-binding fragments, variants, or derivatives thereof described herein can be made from whole precursor or parent antibodies using techniques known in the art. Exemplary techniques are discussed in more detail herein.
  • Antibodies, or antigen-binding fragments, variants, or derivatives thereof described herein can be made or manufactured using techniques that are known in the art.
  • antibody molecules or fragments thereof are “recombinantly produced,” i.e., are produced using recombinant DNA technology.
  • Antibodies, or antigen-binding fragments, variants, or derivatives thereof described herein also include derivatives that are modified, e.g., by the covalent attachment of any type of molecule to the antibody such that covalent attachment does not prevent the antibody from specifically binding to its cognate epitope.
  • the antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-classical amino acids.
  • antibodies, or antigen-binding fragments, variants, or derivatives thereof described herein will not elicit a deleterious immune response in the animal to be treated, e.g., in a human.
  • binding molecules, e.g., antibodies, or antigen-binding fragments thereof described herein are derived from a patient, e.g., a human patient, and are subsequently used in the same species from which they are derived, e.g., human, alleviating or minimizing the occurrence of deleterious immune responses. De-immunization can also be used to decrease the immunogenicity of an antibody.
  • the term “de-immunization” includes alteration of an antibody to modify T cell epitopes; see, e.g., international applications WO98/52976 and WO00/34317.
  • VH and VL sequences from the starting antibody are analyzed and a human T cell epitope “map” from each V region showing the location of epitopes in relation to complementarity determining regions (CDRs) and other key residues within the sequence.
  • CDRs complementarity determining regions
  • VH and VL sequences are designed comprising combinations of amino acid substitutions and these sequences are subsequently incorporated into a range of binding polypeptides, e.g., Fc ⁇ RIII-specific antibodies or immunospecific fragments thereof for use in the diagnostic and treatment methods disclosed herein, which are then tested for function.
  • binding polypeptides e.g., Fc ⁇ RIII-specific antibodies or immunospecific fragments thereof for use in the diagnostic and treatment methods disclosed herein, which are then tested for function.
  • Complete heavy and light chain genes comprising modified V and human C regions are then cloned into expression vectors and the subsequent plasmids introduced into cell lines for the production of whole antibody.
  • Attorney Docket No.29618-0401WO1/BWH 2023-020 The antibodies are then compared in appropriate biochemical and biological assays, and the optimal variant is identified.
  • a humanized version of the 3G8 antibody is used.
  • 3G8 is a well-characterized mouse IgG k1 mAb specific for F ⁇ RIII (CD16).
  • a humanized 3G8 antibody will be as generated using standard methods. The most common method, as described for Fc ⁇ RIIA mouse antibody, IV.3 (Chen et al. Ann Rheum Dis 78, 228-237 (2019)), is the grafting of the complementary determining regions (CDR) of the heavy and light chains of the mouse 3G8 antibody on to the closest human germline variable heavy and variable kappa chain genes.
  • CDR complementary determining regions
  • an antibody polypeptide described herein may comprise, consist essentially of, or consist of a fusion protein.
  • fusion proteins are chimeric molecules which comprise, for example, an immunoglobulin Fc ⁇ RIII-binding antibody and at least one heterologous tumor antigen sequence.
  • the amino acid sequences may normally exist in separate proteins that are brought together in the fusion polypeptide or they may normally exist in the same protein but are placed in a new arrangement in the fusion polypeptide. Fusion proteins may be created, for example, by chemical synthesis, or by creating and translating a polynucleotide in which the peptide regions are encoded in the desired relationship.
  • heterologous as applied to a polynucleotide or a polypeptide, means that the polynucleotide or polypeptide is derived from a distinct entity from that of the rest of the entity to which it is being compared.
  • a “heterologous polypeptide” to be fused to an antibody, or an antigen-binding fragment, variant, or analog thereof is derived from a non-immunoglobulin polypeptide of the same species, or an immunoglobulin or non-immunoglobulin polypeptide of a different species.
  • antibodies, or antigen-binding fragments, variants, or derivatives thereof described herein may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalent and non-covalent conjugations) to polypeptides or other compositions.
  • a given antibody may contain many types of modifications.
  • Antibodies may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic antibodies may result from posttranslation natural processes or may be made by synthetic methods.
  • Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphatidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer- RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination; see, e.g
  • the antibody-antigen conjugates can be fusion proteins, or can be chemical conjugates assembled using a variety of techniques.
  • cross-linking reagents include glutaraldehyde (links molecules to N-terminus of peptides), carbodiimide (EDC) (attaches to C-terminus of peptide); succinimide esters (e.g., MBS, SMCC) (binds free amino group and Cysteine residues); benzidine (BDB) (links to Tyrosine residues), periodate (attaches to carbohydrate groups); isothiocyanate; carbodiimide/activated ester (EDC/NHS) coupling;
  • a reactive azide group can be site specifically introduced to the protein surface using enzymatic ligation as a posttranslational modification, which can in turn be conjugated to an alkyne- containing polymer using highly efficient click chemistry.
  • conjugates with biotin can be prepared, e.g., by reacting an FC ⁇ RIII- antibody polypeptide with an activated ester of biotin such as the biotin N- hydroxysuccinimide ester.
  • the antibody-antigen conjugates described herein can also be fused to other heterologous polypeptides, e.g., to increase the in vivo half-life of the polypeptides.
  • PEG can be conjugated to the antibodies described herein to increase their half-life in vivo; see, e.g., Leong et al., Cytokine 16 (2001), 106- 119; Adv. In Drug Deliv. Rev.54 (2002), 531; or Weir et al., Biochem. Soc. Transactions 30 (2002), 512.
  • the AACs described herein can synergize with other immunomodulatory pharmaceutical agents.
  • the present methods include administering one or more immunotherapy agents, e.g., immune checkpoint inhibitors, e.g., an inhibitor of PD-1 signaling, e.g., an antibody that binds to PD-1, CD40, or PD-L1, or an inhibitor of Tim3 Attorney Docket No.29618-0401WO1/BWH 2023-020 or Lag3, e.g., an antibody that binds to Tim3 or Lag3, or an antibody that binds to CTLA- 4, or an antibody that binds to T-cell immunoglobulin and ITIM domains (TIGIT).
  • an anti-PD-1 antibody is used.
  • Exemplary anti-PD-1 antibodies that can be used in the methods described herein include those that bind to human PD-1; an exemplary PD-l protein sequence is provided at NCBI Accession No. NP_005009.2. Exemplary antibodies are described in US8008449; US9073994; and US20110271358, including PF-06801591, AMP-224, BGB-A317, BI 754091, JS001, MEDI0680, PDR001, REGN2810, SHR-1210, TSR-042, pembrolizumab, nivolumab, avelumab, pidilizumab, and atezolizumab.
  • Exemplary anti-CD40 antibodies that can be used in the methods described herein include those that bind to human CD40; exemplary CD40 protein precursor sequences are provided at NCBI Accession No. NP_001241.1, NP_690593.1, NP_001309351.1, NP_001309350.1 and NP_001289682.1.
  • Exemplary antibodies include those described in WO2002/088186; WO2007/124299; WO2011/123489; WO2012/149356; WO2012/111762; WO2014/070934; US20130011405; US20070148163; US20040120948; US20030165499; and US8591900, including dacetuzumab, lucatumumab, bleselumab, teneliximab, ADC-1013, CP-870,893, Chi Lob 7/4, HCD122, SGN-4, SEA-CD40, BMS-986004, and APX005M.
  • the anti-CD40 antibody is a CD40 agonist, and not a CD40 antagonist.
  • Exemplary CTLA-4 antibodies that can be used in the methods described herein include those that bind to human CTLA-4; exemplary CTLA-4 protein sequences are provided at NCBI Acc No. NP_005205.2. Exemplary antibodies include those described in Tarhini and Iqbal, Onco Targets Ther.3:15-25 (2010); Storz, Mabs.2016 Jan; 8(1):10– 26; US2009025274; US7605238; US6984720; EP1212422; US5811097; US5855887; US6051227; US6682736; EP1141028; and US7741345; and include ipilimumab, Tremelimumab, and EPR1476.
  • Exemplary anti-PD-L1 antibodies that can be used in the methods described herein include those that bind to human PD-L1; exemplary PD-L1 protein sequences are provided at NCBI Accession No. NP_001254635.1, NP_001300958.1, and NP_054862.1.
  • Exemplary antibodies are described in US20170058033; WO2016/061142A1; WO2016/007235A1; WO2014/195852A1; and Attorney Docket No.29618-0401WO1/BWH 2023-020 WO2013/079174A1, including BMS-936559 (MDX-1105), FAZ053, KN035, Atezolizumab (Tecentriq, MPDL3280A), Avelumab (Bavencio), and Durvalumab (Imfinzi, MEDI-4736).
  • Exemplary anti-Tim3 also known as hepatitis A virus cellular receptor 2 or HAVCR2 antibodies that can be used in the methods described herein include those that bind to human Tim3; exemplary Tim3 sequences are provided at NCBI Accession No. NP_116171.3. Exemplary antibodies are described in WO2016071448; US8552156; and US PGPub. Nos.20180298097; 20180251549; 20180230431; 20180072804; 20180016336; 20170313783; 20170114135; 20160257758; 20160257749; 20150086574; and 20130022623, and include LY3321367, DCB-8, MBG453 and TSR-022.
  • Exemplary anti-Lag3 antibodies that can be used in the methods described herein include those that bind to human Lag3; exemplary Lag3 sequences are provided at NCBI Accession No. NP_002277.4. Exemplary antibodies are described in Andrews et al., Immunol Rev.2017 Mar;276(1):80-96; Antoni et al., Am Soc Clin Oncol Educ Book. 2016;35:e450-8; US PGPub. Nos.20180326054; 20180251767; 20180230431; 20170334995; 20170290914; 20170101472; 20170022273; 20160303124, and include BMS-986016.
  • Exemplary anti-TIGIT antibodies that can be used in the methods described herein include those that bind to human TIGIT; an exemplary human TIGIT sequence is provided at NCBI Accession No. NP_776160.2.
  • Exemplary antibodies include AB154; MK ⁇ 7684; BMS ⁇ 986207; ASP8374; Tiragolumab (MTIG7192A; RG6058); (Etigilimab (OMP ⁇ 313M32)); 313R12. See, e.g., Harjun university and Guillerey, Clin Exp Immunol 2019 Dec 11[Online ahead of print], DOI: 10.1111/cei.13407; 20200062859; and 20200040082.
  • compositions and Methods of Administration can include the use of pharmaceutical compositions comprising an anti-Fc ⁇ RIII antibody-antigen complex (AAC) as an active ingredient, and compositions comprising anti-PD1 antibodies as an active ingredient.
  • AAC anti-Fc ⁇ RIII antibody-antigen complex
  • anti-PD1 antibodies as an active ingredient.
  • the AAC and anti-PD1 antibodies are combined in a single composition for co-administration, or are administered in separate compositions (e.g., the AAC is Attorney Docket No.29618-0401WO1/BWH 2023-020 given first and then anti-PD1 at different intervals followed by a repetition of this regimen).
  • Pharmaceutical compositions typically include a pharmaceutically acceptable carrier.
  • compositions can also include an adjuvant to increase T cell response.
  • nanoparticles that enhance T cell response can be included, e.g., as described in Stano et al., Vaccine (2012) 30:7541–6 and Swaminathan et al., Vaccine (2016) 34:110–9.
  • an adjuvant comprising poly-ICLC (carboxymethylcellulose, polyinosinic- polycytidylic acid, and poly-L-lysine double-stranded RNA), Imiquimods, CpG oligodeoxynuceotides and formulations (IC31, QB10), AS04 (aluminium salt formulated with 3-O-desacyl-4′-monophosphoryl lipid A (MPL)), AS01 (MPL and the saponin QS- 21), and/or MPLA can also be used.
  • ICLC carboxymethylcellulose, polyinosinic- polycytidylic acid, and poly-L-lysine double-stranded RNA
  • Imiquimods CpG oligodeoxynuceotides and formulations
  • AS04 aluminium salt formulated with 3-O-desacyl-4′-monophosphoryl lipid A (MPL)
  • AS01 MPL and the saponin QS- 21
  • MPLA
  • compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous administration.
  • solutions or suspensions used for parenteral, application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as Attorney Docket No.29618-0401WO1/BWH 2023-020 ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisul
  • compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No.4,522,811. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • mice All mice are on a C57Bl/6 background.
  • Neutrophil humanized Fc ⁇ R mice (Tsuboi et al, Immunity 2008) are ⁇ ⁇ / ⁇ mice lacking all endogenous mouse activating Fc ⁇ Rs that express human Fc ⁇ Rs, Fc ⁇ RIIIB (CD16B) and Fc ⁇ RIIA (CD32A) selectively on neutrophils (CD16B-CD32A/ ⁇ ⁇ / ⁇ ).
  • OT-I mice express a transgenic T cell receptor (TCR) recognizing Ovalbumin (Ova) residues 257–264 (SIINFEKL) in the context of H2K b on CD8 T cells (The Jackson Laboratory #003831).
  • TCR transgenic T cell receptor
  • Ova Ovalbumin residues 257–264
  • OT-I/ ⁇ actin-GFP were obtained by crossing OT-I mice with ⁇ actin-GFP mice. Animals were maintained in a specific pathogen-free facility. All in vivo experiments were conducted with age and sex matched Attorney Docket No.29618-0401WO1/BWH 2023-020 animals. The Brigham and Women’s Hospital Animal Care and Use Committee approved all procedures in this study.
  • Reagents Anti-CD16B (3G8) or mouse IgG ⁇ (non-targeting isotype control for the CD16B antibody) (Biolegend) were biochemically conjugated to FITC-Ova (#O23020, Thermofisher) as a custom order (Biolegend) to generate AAC and IgG-Ova, respectively.
  • H-2 K b Ova Tetramer (Ova 257–264 ) was from the NIH Tetramer Core Facility, and anti-PD-1 (clone RMP1-14) and Isotype control were from BioXcell.
  • B16F10-Ova tumor challenge and treatment B16F10 cells expressing soluble Ova were cultured in vitro in DMEM/high glucose supplemented with 10% fetal calf serum and maintained at sub-confluent density. Mice were anesthetized, shaved and injected in the flank subcutaneously with 1 ⁇ 10 5 tumor cells in 100 ⁇ l HBSS. Tumors were measured with a caliper every 2 days once palpable in any one group (long diameter and short diameter) and tumor volume was calculated using an ellipsoid formula (1/2XDxd 2 ) where “D” and “d” are the longer and shorter diameter respectively.
  • mice were injected with 1x10 6 na ⁇ ve CD8 + T-cells isolated from the spleen and lymph nodes of OT-I mice using a negative selection kit (Miltenyi Biotec).
  • AAC (10ug) or IgG-Ova (10ug) were injected i.v. via the retro-orbital plexus, and anti-PD-1 (250ug) was given intraperitoneally at the times indicated in the schematic. Tumor harvest and flow cytometric analysis Tumors were surgically removed and processed.
  • the tumors were gently dissociated in FACS buffer (PBS supplemented with 2% FCS and 2 mM EDTA) by shearing the tissue on a 70 ⁇ m nylon cell strainer (FisherBrand) using a 3 ml syringe plunger. Tumors were minced/digested in Collagenase type I and dissociated using gentle MACS Dissociator 1X and resuspended in FACS buffer. Cells were subjected to red blood cell lysis using ACK lysis buffer solution (Lonza Cat 10-548E) for 2 min at room temperature, washed once with PBS and resuspended in FACS buffer.
  • FACS buffer PBS supplemented with 2% FCS and 2 mM EDTA
  • Fig 1b The observed AAC induced early increase in T cell and NK cells in an established B16F10-Ova melanoma (Fig 1b) predicts that AAC would reduce tumor growth and improve the efficacy of immune checkpoint inhibitors such as anti-PD-1, which rely on pre-existing intratumoral T cells.
  • CD16B-CD32A/ ⁇ - /- mice were injected with na ⁇ ve Ova-specific CD8 + T cells, followed at day 6 by AAC or IgG-Ova and anti-PD-1 or isotype antibody at day 9, 12 and 15.
  • Melanoma was measured in individual mice with calipers over time and harvested at day 19 after euthanizing animals (Fig 2a).
  • AAC therapeutically reduces B16F10-Ova tumor growth independently and significantly enhances the efficacy of anti- PD-1.
  • Example 3 AAC in combination with anti-PD-1 increases tumor accumulation of antigen-specific effector CD8 + T cells, and T SCM and T RM memory T cells. Tumors harvested at day 19 (Fig 2a) were analyzed for tumor-infiltrating immune cell populations by flow cytometry.
  • FIG. 3a A larger number of Ova-specific CD8 + T cells (Fig 3a) and those expressing markers of effector functions (granzyme B, perforin, IFN ⁇ and TNF ⁇ ) (Fig 3b) were observed in mice treated with a combination of AAC plus anti-PD- 1 compared to those given IgG-Ova control, AAC or anti-PD-1. The same was observed for Stem Cell Memory T cells (T SCM , PD-1 + TCF1 hi ) and Tissue-Resident memory T cells (T RM , CD103 + CD69 + ) (Fig 2b), which are known to associate with anti-tumor immunity.
  • T SCM Stem Cell Memory T cells
  • PD-1 + TCF1 hi Tissue-Resident memory T cells
  • T RM Tissue-Resident memory T cells

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des méthodes et des compositions destinées à être utilisées dans la génération ou la promotion d'une réponse immunitaire au cancer, comprenant l'administration d'une combinaison d'une immunothérapie à l'aide d'un inhibiteur de point de contrôle immunitaire, par exemple, des anticorps anti-PD-1, et un conjugué comprenant un antigène et un anticorps anti-FcγRIIIB.
PCT/US2023/076913 2022-10-13 2023-10-13 Méthodes et compositions pour améliorer la réponse à une immunothérapie WO2024081933A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263415926P 2022-10-13 2022-10-13
US63/415,926 2022-10-13

Publications (1)

Publication Number Publication Date
WO2024081933A1 true WO2024081933A1 (fr) 2024-04-18

Family

ID=90670216

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/076913 WO2024081933A1 (fr) 2022-10-13 2023-10-13 Méthodes et compositions pour améliorer la réponse à une immunothérapie

Country Status (1)

Country Link
WO (1) WO2024081933A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120039916A1 (en) * 2010-08-13 2012-02-16 Baylor Research Institute Novel vaccine adjuvants based on targeting adjuvants to antibodies directly to antigen-presenting cells
US20190336615A1 (en) * 2017-01-27 2019-11-07 Silverback Therapeutics, Inc. Tumor targeting conjugates and methods of use thereof
US20220106566A1 (en) * 2019-01-22 2022-04-07 The Brigham And Women`S Hospital, Inc. Antigen-Presenting Neutrophil-Derived Dendritic Cells and Methods of Use Thereof
US20220143009A1 (en) * 2016-12-12 2022-05-12 Daiichi Sankyo Company, Limited Combination of antibody-drug conjugate and immune checkpoint inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120039916A1 (en) * 2010-08-13 2012-02-16 Baylor Research Institute Novel vaccine adjuvants based on targeting adjuvants to antibodies directly to antigen-presenting cells
US20220143009A1 (en) * 2016-12-12 2022-05-12 Daiichi Sankyo Company, Limited Combination of antibody-drug conjugate and immune checkpoint inhibitor
US20190336615A1 (en) * 2017-01-27 2019-11-07 Silverback Therapeutics, Inc. Tumor targeting conjugates and methods of use thereof
US20220106566A1 (en) * 2019-01-22 2022-04-07 The Brigham And Women`S Hospital, Inc. Antigen-Presenting Neutrophil-Derived Dendritic Cells and Methods of Use Thereof

Similar Documents

Publication Publication Date Title
US20210179735A1 (en) Trispecific binding proteins and methods of use
Gall et al. Trastuzumab increases HER2 uptake and cross-presentation by dendritic cells
US10633450B2 (en) Methods for enhancing anti-tumor antibody therapy
He et al. A novel human cancer vaccine elicits cellular responses to the tumor-associated antigen, human chorionic gonadotropin β
JP7325959B2 (ja) 腫瘍特異的細胞の枯渇のための抗ＣＤ２５ ＦＣγ受容体二重特異性抗体
US20190225702A1 (en) Innate immune cell trispecific binding proteins and methods of use
ES2782834T3 (es) Uso de moléculas inhibidoras de semaforina-4D en combinación con una terapia inmunomoduladora para inhibir el crecimiento tumoral y la metástasis
US20210024649A1 (en) Methods and Compositions for Antibody and Antibody-loaded Dendritic Cell Mediated Therapy
US8440188B2 (en) Therapeutic and diagnostic anti-HSP70 antibodies
JP2020200346A (ja) 腫瘍療法のためのｉｌ−１２とｔ細胞阻害分子遮断薬とを含む医薬組成物
US20180147257A1 (en) Btn3a ectodomain proteins and methods of use
CN105579058A (zh) Cd38激动剂的医学用途
US20160000914A1 (en) Combination of tumor-associated surface protein antigens and tumor-associated sugars in the treatment and diagnosis of cancer
CN109734777A (zh) 用于各种癌症免疫治疗的新型肽、肽组合物和支架
JP2022511337A (ja) 免疫チェックポイント治療に抵抗性のある癌の治療のための方法および医薬組成物
US11851497B2 (en) CD137 antibodies and tumor antigen-targeting antibodies and uses thereof
US20220106566A1 (en) Antigen-Presenting Neutrophil-Derived Dendritic Cells and Methods of Use Thereof
JP2009536217A (ja) Ｂ細胞障害の治療における免疫グロブリン結合細胞表面決定基
WO2024081933A1 (fr) Méthodes et compositions pour améliorer la réponse à une immunothérapie
US20230181753A1 (en) New method to treat cutaneous t-cell lymphomas and tfh derived lymphomas
JP2019531703A (ja) 腫瘍関連マクロファージを標的化する抗体及びその使用
US20230040928A1 (en) Antibodies having specificity to her4 and uses thereof
US20220378876A1 (en) Treatment Involving Therapeutic Antibody and Interleukin-2 (IL2)
Semwal et al. Natural antibodies: Protecting role of IgM in glioblastoma and brain tumours
EP4319809A1 (fr) Polythérapie avec dexaméthasone et lymphocytes t spécifiques d'une tumeur mettant en contact des anticorps multispécifiques pour le traitement du cancer

Legal Events

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

Ref document number: 23878324

Country of ref document: EP

Kind code of ref document: A1