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WO2024192017A1 - Antibody drug conjugates comprising sting agonists, combinations and methods of use - Google Patents

Antibody drug conjugates comprising sting agonists, combinations and methods of use Download PDF

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Publication number
WO2024192017A1
WO2024192017A1 PCT/US2024/019560 US2024019560W WO2024192017A1 WO 2024192017 A1 WO2024192017 A1 WO 2024192017A1 US 2024019560 W US2024019560 W US 2024019560W WO 2024192017 A1 WO2024192017 A1 WO 2024192017A1
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antibody
cancer
combination
her2
conjugate
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French (fr)
Inventor
Naniye CETINBAS
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Mersana Therapeutics Inc
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Mersana Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • 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
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • STING is a 378 amino acid protein, which mainly contains three structural domains: (i) N-terminal transmembrane domain (aa 1–154); (ii) central globular domain (aa 155–341); and (iii) C-terminal tail (aa 342– 379).
  • STING may form symmetrical dimers combined with its ligands in V-shaped conformation, while not completely covering the bound ligands.
  • a STING agonist can bind into the pocket region of STING. However, the STING activation process is easily inhibited in some severe disease conditions, resulting in the inactivation of the STING pathway.
  • ADCs Antibody-drug conjugates
  • ADCs are comprised of a drug like small molecule, covalently linked to an antibody.
  • the antibody represents a targeting mechanism tuned to a specific site of action.
  • the ADC is designed to release a small molecule, the drug, allowing it to perform its designed function in a targeted manner, as opposed to diffusing systemically through the entire body of the subject. This targeted approach allows for treatment with drugs that ⁇ Attorney Docket No.
  • MRSN-043/001WO 322140-2698 would otherwise require doses so high as to be toxic when administered systemically and minimizes potential for on-target, off-tumor toxicity.
  • a key feature of the innate immune system is the recognition and elimination of foreign substances. Identification of these pathogenic invaders occurs through host recognition of evolutionarily conserved microbial structures known as pathogen- associated molecular patterns (PAMPs). Host recognition may occur by multiple pathways, such as activation of pattern recognition receptors (PRRs), which ultimately lead to downstream signaling events and culminate in the mounting of an immune response.
  • PRRs pattern recognition receptors
  • the antibody-drug conjugates of this disclosure modulate the activity of STING, and accordingly, may provide a beneficial therapeutic impact in treatment of diseases, disorders and/or conditions wherein modulation of STING (Stimulator of Interferon Genes) is beneficial, including, but not limited to, inflammation, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes, and as vaccine adjuvants.
  • STING Stimulator of Interferon Genes
  • combination therapy in which two or more drugs are used in certain dosing regimen or administration form can enhance potency by exploiting additive or synergistic effects in the biological activity of the two or more drugs.
  • the present disclosure provides, inter alia, a combination therapy comprising at least one protein-based recognition molecule (PBRM)-STING agonist conjugate and at least one natural killer (NK) cell therapy, wherein the conjugate comprises an antibody or antigen binding fragment thereof that specifically binds to a target.
  • PBRM protein-based recognition molecule
  • NK natural killer
  • the present disclosure provides, a combination therapy comprising at least one PBRM-STING agonist conjugate and at least one antibody that exhibits therapy ADCC function, wherein the conjugate comprises an antibody or antigen binding fragment thereof that specifically binds to a target.
  • the PBRM-STING agonist conjugate is a conjugate of Formula (A-1): ⁇ Attorney Docket No.
  • compositions comprising the combination therapy comprising at least one PBRM-STING agonist conjugate and at least one NK cell therapy.
  • the PBRM-STING agonist conjugate enhances the efficacy of the NK cell therapy.
  • the PBRM-STING agonist conjugate enhances the efficacy of the one or more antibody that has ADCC function.
  • the present disclosure provides compositions comprising the combination therapy comprising at least one PBRM-STING agonist conjugate and at least one antibody that exhibits ADCC function.
  • the PBRM-STING agonist conjugate and at least one antibody that exhibits ADCC function synergize with the STING pathway and enhance the cancer cell-killing activity of FcgRIII-expressing cells.
  • the present disclosure provides, a combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one natural killer (NK) cell therapy, wherein the conjugate comprises an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor.
  • the present disclosure provides, a combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that exhibits ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 therapy ADCC function, wherein the conjugate comprises an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor.
  • the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (A): or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises a HER2 antibody comprising a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity
  • CDRH1 compris
  • the HER2 antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1 or residues 452 to 531 of SEQ ID NO: 16. ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 [0018]
  • the present disclosure provides compositions comprising the combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy.
  • the HER2-targeted STING agonist antibody-drug conjugate enhances the efficacy of the NK cell therapy.
  • the HER2-targeted STING agonist antibody-drug conjugate enhances the efficacy of one or more antibody that has ADCC function.
  • at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy.
  • the present disclosure provides compositions comprising the combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that exhibits ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that exhibits ADCC function synergize with the STING pathway and enhance the cancer cell-killing activity of FcgRIII-expressing cells.
  • the combination comprising a HER2-targeted STING agonist antibody- drug conjugate of the disclosure is administered in combination with at least one NK cell therapy.
  • the combination of the disclosure is administered in combination with at least one antibody that has ADCC function.
  • PBRM-STING agonist conjugates or HER2-targeted STING agonist antibody-drug conjugates and NK cell therapy or antibody that has ADCC function are useful in treating pathologies such as, for example, a cancer in a subject.
  • the combinations comprising PBRM-STING agonist conjugates and at least one NK cell therapy or at least one antibody that has ADCC function disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of a cancer (e.g., a HER2-positive cancer) in a subject.
  • the combinations comprising the PBRM-STING agonist conjugates or the HER2-targeted STING agonist antibody-drug conjugates and at least one NK cell therapy or at least one antibody that has ADCC function disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of a cancer (e.g., a HER2- positive cancer) in a subject.
  • a cancer e.g., a HER2- positive cancer
  • the cancer is, for example, selected from the group consisting of anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer and gastric esophagogastric junction cancer.
  • anal cancer astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer
  • the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, a symptom of gastric cancer, a symptom of gastric esophagogastric junction cancer, a symptom of non-small cell lung cancer (NSCLC) or a symptom of colorectal cancer in a subject.
  • the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer in a subject.
  • the cancer is a HER2-positive cancer.
  • the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, in a subject. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of HER2+ breast cancer, in a subject. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of HER2- breast cancer, in a subject.
  • the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of metastatic HER2+ breast cancer, in a subject. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of metastatic HER2+ breast cancer, in a subject who has received at least one, at least two, at least three, or at least four prior lines of breast cancer therapy. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of metastatic HER2+ breast cancer, in a subject who has received three or more prior lines of breast cancer therapy. ⁇ Attorney Docket No.
  • the combination comprising a PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function used in any of the aspect of the methods and uses provided herein can be administered at any stage of the disease.
  • a combination therapy can be administered to a patient suffering cancer of any stage, from early to metastatic.
  • the combination comprising a HER2-targeted STING agonist antibody- drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function used in any of the aspect of the methods and uses provided herein can be administered at any stage of the disease.
  • such a combination therapy can be administered to a patient suffering cancer of any stage, from early to metastatic.
  • a combination therapy comprising a PBRM- STING agonist conjugate or a HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function used in any of the aspect of these methods and uses can be administered either without another therapeutic agent, or in combination with one or more chemotherapeutic agents or other agents.
  • the additional agent is any of the toxins described herein.
  • the additional agent is (1) an EGFR inhibitor (e.g., tyrosine kinase inhibitors or targeted anti-EGFR antibodies), (2) a BRAF inhibitor, (3) an ALK inhibitor, (4) a hormone receptor inhibitor, (5) a mTOR inhibitor, (6) a VEGF inhibitor, or (7) a cancer vaccine.
  • an EGFR inhibitor e.g., tyrosine kinase inhibitors or targeted anti-EGFR antibodies
  • the additional agent is a standard, first line chemotherapeutic agent, such as, for example, ado-trastuzumab emtansine (Kadcyla), lapatinib, anastrozole, letrozole, exemestane, everolimus, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxymesterone, ethinyl estradiol, paclitaxel, capecitabine, gemcitabine, eribulin, vinorelbine, cyclophosphamide, carboplatin, docetaxel, albumin-bound paclitaxel, cisplatin, epirubicin, ixabepilone, doxorubicin, fluorouracil, oxaliplatin, fluoropyrimidine, irinotecan, ramucirumab, mitomycin, leucovorin, cetuximab, be
  • the additional agent is Kadcyla (ado-trastuzumab emtansine).
  • the combination comprising the PBRM-STING agonist conjugate or the HER2-targeted STING agonist antibody-drug conjugate and NK cell therapy or antibody that has ADCC function and additional agent(s) is formulated into a single therapeutic composition, and the components are administered simultaneously.
  • the PBRM-STING agonist 7 Attorney Docket No.
  • MRSN-043/001WO 322140-2698 conjugate or the HER2-targeted STING agonist antibody-drug conjugate, NK cell therapy or antibody that has ADCC function and additional agent, if any, are separate from each other, e.g., each is formulated into a separate therapeutic composition, and can be administered simultaneously, or at different times during a treatment regimen.
  • the PBRM-STING agonist conjugate is administered prior to the administration of the NK cell therapy or antibody that has ADCC function combination; the PBRM-STING agonist conjugate is administered after the administration of the NK cell therapy or antibody that has ADCC function combination.
  • the PBRM-STING agonist conjugate and the NK cell therapy or antibody that has ADCC function combination is administered in single doses or in multiple doses.
  • the HER2-STING agonist conjugate is administered prior to the administration of the NK cell therapy or antibody that has ADCC function combination; the HER2-STING agonist conjugate is administered after the administration of the NK cell therapy or antibody that has ADCC function combination.
  • the HER2-STING agonist conjugate and the NK cell therapy or antibody that has ADCC function combination is administered in single doses or in multiple doses.
  • Pharmaceutical compositions according to the disclosure can include a suitable carrier. These pharmaceutical compositions can be included in kits, such as, for example, diagnostic kits.
  • FIG. 1 is a series of graphs depicting percent viable SKBR3-NR and immune cell co- cultures in the presence of indicated treatments.
  • SKBR3-NR cells co-cultured with (A) PBMC (B) PBMCs depleted of Fc ⁇ -RI expressing cells (CD14 + monocytes) and (C) PBMCs co-depleted of Fc ⁇ -RI + and Fc ⁇ -RIII + immune cells and treated with (i) XMT-2056, (ii) Fc mutant-XMT-1519 ADC and (iii) non-binding control ADC.
  • FIG. 2 is a series of graphs depicting the cancer cell-killing ability of (i) XMT-2056 (ii) XMT-1519 (iii) STING agonist payload (iv) combination of XMT-1519 and STING agonist payload and (v) combination of Fc mutant XMT-1519 and STING agonist payload in SKBR3- NR cell co-cultured with (A) PBMCs (B) PBMCs depleted of Fc ⁇ -RI expressing cells (CD14 + monocytes) and (C) PBMCs co-depletion of Fc ⁇ -RI + and Fc ⁇ -RIII + immune cells using an IncuCyte killing assay.
  • FIG. 4 is a series of graphs depicting the synergy between XMT-2056-mediated STING pathway activation and the ADCC function of trastuzumab in SKBR3-NR cell and (A) myeloid cell or (B) NK cell co-cultures vitro for (i) XMT-2056 (ii) combination of XMT-2056 and trastuzumab (iii) combination of XMT-2056 and Fc mutant trastuzumab (iv) non-binding control ADC or (v) combination of non-binding control ADC and trastuzumab.
  • FIG. 5 is a graph showing the anti-tumor efficacy of XMT-2056 (0.30/0.013 mg/kg), trastuzumab (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and trastuzumab (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and Fc-mutant trastuzumab, or a ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 combination of XMT-1519 (0.30 mg/kg) and trastuzumab (3 mg/kg) at varying dose levels and dosing regimens.
  • FIG. 6 is a graph showing the anti-tumor efficacy of XMT-2056 (0.30/0.013 mg/kg), XMT-1519 (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and XMT-1519 (3 mg/kg), or a combination of XMT-2056 (0.30/0.013 mg/kg) and Fc-mutant XMT-1519 at varying dose levels and dosing regimens DETAILED DESCRIPTION [0047]
  • the present disclosure provides targeted STING agonist antibody-drug conjugates, pharmaceutical compositions containing them, and various uses of the conjugates.
  • the targeted STING agonist antibody-drug conjugates described herein have been shown to exhibit ADCC (antibody-dependent cell-mediated cytotoxicity) function, which synergizes with STING pathway activation and induces potent cancer cell-killing activity in co-cultures of tumor associated antigen expressing cancer cells and Fc ⁇ -RIII+ (CD16+) immune cells.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CD16+ Fc ⁇ -RIII+
  • the targeted STING agonist ADC was capable of engaging both Fc ⁇ -RI+ myeloid cells and Fc ⁇ -RIII+ NK cells, activating both STING-mediated innate immune responses and ADCC function in triple cultures with tumor associated antigen expressing cancer cells.
  • the chemical names provided for the intermediate compounds and/or the compounds of this disclosure described herein may refer to any one of the tautomeric representations of such ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 compounds (in some instances, such alternate names are provided with the experimental).
  • any reference to a named compound (an intermediate compound or a compound of the disclosure) or a structurally depicted compound (an intermediate compound or a compound of the disclosure) is intended to encompass all tautomeric forms including zwitterionic forms of such compounds and any mixture thereof.
  • the terms “In some aspect”, “In some aspect of the present disclosure”, and “In some aspect of a compound of the present disclosure” may be used interchangeably where appropriate.
  • the term “about”, “approximately”, or “approximate”, when used in connection with a numerical value, means that a collection or range of values is included.
  • “about X” includes a range of values that are ⁇ 25%, ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 5%, ⁇ 2%, ⁇ 1%, ⁇ 0.5%, ⁇ 0.2%, or ⁇ 0.1% of X, where X is a numerical value.
  • the term “about” refers to a range of values which are 5% more or less than the specified value.
  • the term “about” refers to a range of values which are 2% more or less than the specified value.
  • the term “about” refers to a range of values which are 1% more or less than the specified value.
  • ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.
  • the expressions “x being an integer between 1 and 6” and “x being an integer of 1 to 6” both mean “x being 1, 2, 3, 4, 5, or 6”, i.e., the terms “between X and Y” and “range from X to Y, are inclusive of X and Y and the integers there between.
  • PBRM Protein-based recognition-molecule
  • a cell surface marker or receptor such as, a transmembrane protein, surface immobilized protein, or proteoglycan.
  • the PBRM comprises an engineered cysteine.
  • PBRMs include but are not limited to, antibodies, peptides, lipocalins, proteins, peptides or peptide mimics, and the like.
  • the protein-based recognition molecule in addition to targeting the conjugate to a specific cell, tissue or location, may also have certain therapeutic effect such as antiproliferative (cytostatic and/or cytotoxic) activity against a target cell or pathway.
  • the protein-based recognition molecule comprises or may be engineered to comprise at least one chemically reactive group such as, -COOH, primary amine, secondary amine –NHR, ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 -SH, or a chemically reactive amino acid moiety or side chains such as, for example, tyrosine, histidine, cysteine, or lysine.
  • a PBRM may be a ligand (LG) or targeting moiety which specifically binds or complexes with a cell surface molecule, such as a cell surface receptor or antigen, for a given target cell population.
  • LG ligand
  • a ligand that “specifically binds or complexes with” or “targets” a cell surface molecule preferentially associates with a cell surface molecule via intermolecular forces.
  • the ligand can preferentially associate with the cell surface molecule with a Kd of less than about 50 nM, less than about 5 nM, or less than 500 pM.
  • HER2 also known as ErbB-2, NEU, HER-2, and CD340
  • HER2 human epidermal growth factor receptor 2
  • WissProt P04626 human epidermal growth factor receptor 2
  • HER2 antibody or “anti-HER2 antibody” is an antibody which binds specifically to the antigen HER2.
  • antibody is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.
  • antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and that binds the antigen to which the intact antibody binds.
  • antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g.
  • antibody that binds to a target refers to any antibody that is optimized to preferentially bind to a specific antigen or a combination of antigens.
  • antibody that binds to the same epitope refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more.
  • An exemplary competition assay is provided herein.
  • the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to HER2, An antibody “blocks” or “cross-blocks” one or more other antibodies from binding to HER2 if the antibody competes with the one or more other antibodies 25% or more, with 25%-74% representing “partial block” and 75%-400% representing “full block”. Unless otherwise defined or negated by context, the terms “competes with”, “cross-competes with”, “blocks” or “cross- blocks” when used herein is also intended to cover such pairs of antibodies. [0062] The term “epitope” refers to the particular site on an antigen molecule to which an antibody binds.
  • composition refers to a mixture, formulation, or solution comprising at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order or treat a particular disease or condition affecting the subject.
  • a subject e.g., a mammal or human
  • the present pharmaceutical combinations can be formulated in suitable pharmaceutical compositions for enteral or parenteral administration, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example ⁇ Attorney Docket No.
  • MRSN-043/001WO 322140-2698 by means of various conventional mixing, comminution, direct compression, granulating, sugar- coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units.
  • One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden.
  • the amount of each carrier used may vary within ranges conventional in the art.
  • compositions provided herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as a solution in l,3-butane-diol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • the term “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound or combination of the present disclosure, or a pharmaceutically acceptable salt, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs.
  • the subject is a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the subject is a human.
  • the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease.
  • a subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein.
  • a subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein.
  • a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
  • a subject in need thereof can have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment).
  • the subject may be resistant at the start of treatment or may become resistant during treatment.
  • the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein.
  • the subject in need thereof received at least one prior therapy.
  • terapéuticaally effective amount refers to an amount of an active compound or pharmaceutical agent, including a conjugate of the disclosure, which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated.
  • An "effective amount” is intended to mean that amount of a conjugate that, when administered to a patient in need of such treatment, is sufficient to effectively treat or prevent, as defined herein.
  • the amount of a given conjugate that will correspond to such an amount will vary depending upon factors such as the particular conjugate (e.g., the potency (pICso), efficacy (EC 50 ), and the biological half-life of the particular conjugate), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the particular conjugate e.g., the potency (pICso), efficacy (EC 50 ), and the biological half-life of the particular conjugate
  • disease condition and its severity e.g., the identity of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • composition refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • STING agonist refers to a compound or moiety which is capable of interacting with STING, e.g., by binding to STING and/or inducing downstream signal transduction (e.g., characterized by activation of the molecules associated with STING function).
  • STING pathway activation results in increased production of type 1 interferons (mainly IFN-a and IFN-b) and/or expression of interferon-stimulated genes.
  • STING agonist drug moiety refers to a moiety derived from a STING agonist and capable of interacting with STING.
  • the STING agonist drug moiety is a moiety derived from a STING agonist to allow the moiety being linked to the rest of a conjugate of the present disclosure.
  • NK cell therapy refers to a type of cellular immunotherapy.
  • the NK cell therapy comprises an NK cell engager.
  • the NK cell therapy comprises a population of NK cells.
  • the NK cell therapy comprises autologous NK cells (e.g., derived from the subject to which they are administered.)
  • the NK cell therapy comprises allogeneic NK cells (e.g., derived from a subject that is different from the subject to which they are administered).
  • the NK cell therapy comprises genetically engineered NK cells, such as, for example, a CAR NK.
  • NK cells refers to cells of the immune system that kill target cells in the absence of a specific antigenic stimulus, and without restriction according to major histocompatibility complex (MHC) class.
  • Target cells may be tumor cells or cells harboring a ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 pathogen, such as, for example, a virus.
  • NK cells are characterized by the presence of CD56 and the absence of CD3 surface markers.
  • NK cell engager refers to an NK cell that mediates binding to and activation of an NK cell, or an NK cell that mediates binding to but not activation of an NK cell.
  • CAR NK refers to genetically modified NK cells and derivatives thereof that express a chimeric antigen receptor (CAR) on the cell surface.
  • CAR chimeric antigen receptor
  • CAR refers to an extracellular antigen-binding domain that is fused to an intracellular signaling domain. CARs can be expressed in T cells or NK cells to increase cytotoxicity. In general, the extracellular antigen-binding domain is a scFv that is specific for an antigen found on a cell of interest.
  • “Combination Therapy” as used herein refers to a treatment in which a subject is given two or more therapeutic agents, such as at least two or at least three therapeutic agents, for treating a disease or disorder.
  • a combination therapy includes therapy with a HER2- targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function.
  • co-administration refers to the administration of at least two different therapeutic agents sufficiently close in time. Such administration may be done in any order, including simultaneous administration, as well as temporally spaced order from a few seconds up to several days apart. Such administration may also include more than a single administration of one agent and/or independently the other agent. The administration of the agents may be by the same or different routes.
  • spontaneous administration refers to the administration of medicaments such that the individual medicaments are present within a subject at the same time.
  • simultaneous administration may include the administration of the medicaments (via the same or an alternative route) at different times.
  • at least one item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.
  • kits refers to a combination of components, such as a combination of the compositions herein and another item for a purpose including, but not limited to, ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 reconstitution, activation and instruments/devices for delivery, administration, diagnosis and assessment of a biological activity or property. Kits optionally include instructions of use.
  • immuno response relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression.
  • the conjugates of the disclosure are useful in methods for treating or ameliorating a viral infection, disease, a syndrome, a condition or a disorder that is affected by the agonism of STING.
  • Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and/or prevention, a therapeutically effective amount of a conjugate of the disclosure, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
  • conjugates of the disclosure or “conjugate(s) of the present disclosure”, as used herein, mean a conjugate as defined herein, in any form, i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non- solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • any form i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g
  • the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers.
  • a mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • a bond denoted by a “ ” indicates the presence of a mixture of stereoisomers that feature different stereochemistry at the position to which is connected but are otherwise identical.
  • ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 [0091] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C-13 and C-14.
  • conjugates as disclosed herein, in any salt or non-salt form and any physical form thereof, and mixtures of various forms While such are included within the present disclosure, it will be understood that the conjugates of the present disclosure, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes.
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
  • the protein-based recognition molecule directs the conjugates to specific tissues, cells, or locations in a cell.
  • the protein-based recognition molecule can direct the conjugate in culture or in a whole organism, or both.
  • the protein-based recognition molecule may have a ligand that is present on the cell surface of the targeted cell(s) to which it binds with an effective specificity, affinity, and avidity.
  • the protein-based recognition molecule targets the conjugate to tissues other than ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 the liver.
  • the protein-based recognition molecule targets the conjugate to a specific tissue such as the liver, kidney, lung, or pancreas.
  • the protein-based recognition molecule can target the conjugate to a target cell such as a cancer cell, such as a receptor expressed on a cell such as a cancer cell, a matrix tissue, or a protein associated with cancer such as tumor antigen.
  • a target cell such as a cancer cell, such as a receptor expressed on a cell such as a cancer cell, a matrix tissue, or a protein associated with cancer such as tumor antigen.
  • cells comprising the tumor vasculature may be targeted.
  • the protein-based recognition molecules can direct the conjugate to specific types of cells such as specific targeting to hepatocytes in the liver as opposed to Kupffer cells.
  • protein-based recognition molecules can direct the conjugate to cells of the reticular endothelial or lymphatic system, or to professional phagocytic cells such as macrophages or eosinophils. In some embodiments, the conjugate itself may also be an effective delivery system, without the need for specific targeting. [0096] In some embodiments, the protein-based recognition molecule can target the conjugate to a tumor antigen or a tumor associated antigen. [0097] In some embodiments, the protein-based recognition molecule is an antibody, an antibody fragment, a protein, a peptide, or a peptide mimic. [0098] In some embodiments, the protein-based recognition molecule is an antibody.
  • the protein-based recognition molecule is an antibody fragment. In some embodiments, the protein-based recognition molecule is a protein. In some embodiments, the protein-based recognition molecule is a peptide. In some embodiments, the protein-based recognition molecule is a peptide mimic. [0099] In some embodiments, the antibody or antibody fragment is an antibody or antibody fragment wherein one or more amino acids of the corresponding parent antibody or antibody fragment (e.g., the corresponding wild type antibody or antibody fragment) are substituted with cysteines (e.g., engineered cysteine). In some embodiments, the parent antibody or antibody fragment may be wild type or mutated. [00100] In some embodiments, the antibody or antibody fragment may be a mutated antibody or antibody fragment.
  • a monoclonal antibody known in the art is engineered to form the antibody.
  • an antibody fragment e.g., a Fab antibody fragment
  • an antibody fragment e.g., a cysteine engineered Fab antibody fragment
  • a single site mutation of a Fab gives a single ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 residue in a Fab whereas a single site mutation in an antibody yields two amino acids in the resulting antibody due to the dimeric nature of the IgG antibody.
  • the antibody or antibody fragment retains the antigen binding capability of its corresponding wild type antibody or antibody fragment.
  • the antibody or antibody fragment is capable of binding to the one or more antigens for its corresponding wild type antibody or antibody fragment.
  • exemplary antibodies or antibodies derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments specific to the cell surface markers include, but are not limited to, 5T4, AOC3, ALK, AXL, B7-H4, C242, C4.4a, CA-125, CCL11, CCR 5, CD2, CD3, CD4, CD5, CD15, CA15-3, CD18, CD19, CA19-9, CDH6, CD20, CD22, CD23, CD25, CD28, CD30, CD31, CD33, CD37, CD38, CD40, CD41, CD44, CD44 v6, CD51, CD52, CD54, CD56, CD62E, CD62P, CD62L, CD70, CD74, CD79-B, CD80, CD125, CD103, CD138, CD141, CD147, CD152, CD 154, CD32
  • the antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments specific to the cell surface markers include CA-125, C242, CD3, CD11b, CD19, CD22, CD25, CD30, CD31, CD33, CD37, CD40, CD44, CD51, CD54, CD56, CD62E, CD62P, CD62L, CD70, CD103, CD138, CD141, CD326, CEA, Clec9A, CSFR1, ⁇ Attorney Docket No.
  • the antibodies are directed to cell surface markers for 5T4, CA-125, CEA, CDH6, CD3, CD11b, CD19, CD20, CD22, CD30, CD33, CD40, CD44, CD51, CD-103, CTLA-4, CEACAM5, Clec9A, CSFR1, DEC205, EpCAM, HER2, EGFR (HER1), FAP, fibronectin-EDB, folate receptor, GCC (GUCY2C), HGF, integrin ⁇ v ⁇ 3, integrin ⁇ 5 ⁇ 1, IGF-1 receptor, GD3, GPNMB, mucin, LIV1, LY6E, mesothelin, MUC1, MUC13, NaPi2b, PTK7, phosphatidylserine, prostatic carcinoma cells, PDGFR ⁇ , TAG-72, tenascin C, TRAIL-R2, VEGF- A and VEGFR2.
  • the antibodies include but are not limited to, abagovomab, adecatumumab, alacizumab, altumomab, anatumomab, arcitumomab, bavituximab, bevacizumab (AVASTIN®), bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, capromab, cetuximab, citatuzumab, clivatuzumab, conatumumab, dacetuzumab, edrecolomab, epratuzumab, ertumaxomab, etaracizumab, farletuzumab, figitumumab, gemtuzumab, glembatumumab, ibritumomab, igovomab, intetumumab, inotuzum
  • the antibodies directed to cell surface markers for HER2 are pertuzumab or trastuzumab and for EGFR (HER1) the antibody is cetuximab or panitumumab; and for CD20 the antibody is rituximab and for VEGF-A is bevacizumab and for CD-22 the antibody is epratuzumab or veltuzumab and for CEA the antibody is labetuzumab.
  • Exemplary peptides or peptide mimics include integrin targeting peptides (RGD peptides), LHRH receptor targeting peptides, ErbB2 (HER2) receptor targeting peptides, prostate ⁇ Attorney Docket No.
  • PSMA specific membrane bound antigen
  • the peptides or peptide mimics are LHRH receptor targeting peptides and ErbB2 (HER2) receptor targeting peptides.
  • Exemplary proteins comprise insulin, transferrin, fibrinogen-gamma fragment, thrombospondin, claudin, apolipoprotein E, Affibody molecules such as, for example, ABY-025, Ankyrin repeat proteins, ankyrin-like repeats proteins and synthetic peptides.
  • the PBRM-drug conjugates comprise broad spectrum cytotoxins in combination with cell surface markers for HER2, such as, for example, pertuzumab or trastuzumab; for EGFR such as cetuximab and panitumumab; for CEA such as labetuzumab; for CD20 such as rituximab; for VEGF-A such as bevacizumab; or for CD-22 such as epratuzumab or veltuzumab.
  • HER2 such as, for example, pertuzumab or trastuzumab
  • EGFR such as cetuximab and panitumumab
  • CEA such as labetuzumab
  • CD20 such as rituximab
  • VEGF-A such as bevacizumab
  • CD-22 such as epratuzumab or veltuzumab.
  • the PBRM-drug conjugates or protein conjugates used in the disclosure comprise combinations of two or more protein-based recognition molecules, such as, for example, combination of bispecific antibodies directed to the EGF receptor (EGFR) on tumor cells and to CD3 and CD28 on T cells; combination of antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments and peptides or peptide mimetics; combination of antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy- chain fragments and proteins; combination of two bispecific antibodies such as CD3-CD19 plus CD28-CD22 bispecific antibodies.
  • EGFR EGF receptor
  • the PBRM-drug conjugates or protein conjugates used in the disclosure comprise protein-based recognition molecules that are antibodies against antigens, such as, for example, Trastuzumab, Cetuximab, Rituximab, Bevacizumab, Epratuzumab, Veltuzumab, Labetuzumab, or antibodies binding to a target antigen such as, for example, B7-H4, B7-H3, CD11b, CD103, CA125, CDH6, CD33, CXCR2, CEACAM5, Clec9A, CSFR1, DEC205, EGFR, FAP, fibronectin-EDB, FGFR1, FGFR2, FGFR3, FGFR4, GCC (GUCY2C), HER2, LIV1, LY6E, NaPi2b, c-Met, mesothelin, NOTCH1, NOTCH2, NOTCH3, NOTCH4, PD-L1, PTK7, c- Kit, MUC1,
  • antigens such as,
  • the PBRM-STING agonist conjugates or protein conjugates of the disclosure comprise protein-based recognition molecules which are CSRF1, CD11b, ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 DEC205, clec9A, CD103, B7H4, mesothelin, PTK7, Ly6E, FAP, fibronectin-EDB, HER-2 or NaPi2b antibodies.
  • the PBRM-STING agonist conjugates or protein conjugates of the disclosure comprise a PBRM which binds HER2, such as, for example, a HER2 antibody (e.g., as described herein).
  • the HER2 antibodies suitable for conjugation bind the human HER2 in soluble form, or membrane bound (i.e., when expressed on a cell surface).
  • the present disclosure provides monoclonal antibodies that bind HER2 and are humanized or fully human.
  • the present disclosure provides monoclonal antibodies that bind HER2 specifically. These antibodies are collectively referred to herein as “HER2” antibodies.
  • the HER2 antibodies suitable for conjugation bind to a HER2 epitope with an equilibrium dissociation constant (K d or K D ) of ⁇ 1 ⁇ M (e.g., ⁇ 100 nM; ⁇ 10 nM; ⁇ 1 nM).
  • K d or K D equilibrium dissociation constant
  • the present disclosure provides monoclonal antibodies that bind HER2 and are humanized or fully human.
  • the HER2 antibodies provided herein exhibit a Kd in the range approximately between ⁇ 1 nM to about 1 pM.
  • the HER2 antibodies disclosed herein serve to modulate, block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with the functional activity of HER2.
  • functional activities of HER2 include for example, modulation of PI3K-Akt pathway activity.
  • the HER2 antibodies completely or partially inhibit HER2 functional activity by partially or completely modulating, blocking, inhibiting, reducing antagonizing, neutralizing, or otherwise interfering with PI3K-Akt pathway activity.
  • PI3K-Akt pathway activity is assessed using any art-recognized method for detecting PI3K-Akt pathway activity, including, but not limited to detecting levels of phosphorylated Akt in the presence and absence of an antibody or antigen binding fragment disclosed herein.
  • the HER2 antibodies are considered to completely modulate, block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with HER2 functional activity when the level of HER2 functional activity in the presence of the HER2 antibody is decreased by at least 80%, e.g., by 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% as compared to the level of HER2 functional activity ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 in the absence of binding with a HER2 antibody described herein.
  • the HER2 antibodies are considered to partially modulate, block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with HER2 functional activity when the level of HER2 activity in the presence of the HER2 antibody is decreased by less than 95%, e.g., 10%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 85%, or 90% as compared to the level of HER2 activity in the absence of binding with a HER2 antibody described herein.
  • exemplary HER2 antibodies disclosed herein include, the XMT- 1519 antibody. This antibody shows specificity for human HER2 and has been shown to inhibit the functional activity of HER2 in vitro.
  • the antibodies or antigen-binding fragments thereof disclosed herein comprising the HER2 monoclonal antibody XMT-1519 includes a heavy chain (HC), heavy chain variable region (VH), light chain (LC), and a light chain variable region (VL), as shown in the amino acid and corresponding nucleic acid sequences presented in Table I below.
  • Table I HER2 human or humanized monoclonal antibody XMT-1519 sequences [ ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 [00121]
  • Antibodies and antigen binding fragments thereof disclosed herein specifically bind to an epitope on the full-length human HER2 receptor comprising the amino acid sequence of SEQ ID NO: 1.
  • the antibodies disclosed herein are fully human monoclonal antibodies that bind to novel epitopes and/or have other favorable properties for therapeutic use.
  • exemplary properties include, but are not limited to, favorable binding characteristics to cancer cells expressing human HER2 at high or low levels, specific binding to recombinant human and cynomolgus monkey HER2, efficient internalization upon binding to HER2, high capacity for killing cancer cells expressing high or low levels of HER2 when administered as an antibody drug conjugate (ADC), no substantial agonistic effect on the proliferation of HER2-expressing cancer cells, and/or provide for effective antibody-dependent cellular cytotoxicity (ADCC)-mediated killing of HER2-expressing cells, as well as any combination of the foregoing properties.
  • ADC antibody drug conjugate
  • ADCC antibody-dependent cellular cytotoxicity
  • the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1 or residues 452 to 531 of SEQ ID NO: 16.
  • the antibodies disclosed herein include an antibody or an antigen binding fragment thereof that binds at least a portion of the N-terminus of domain IV of human HER2 receptor but does not cross-compete with an antibody that binds to epitope 4D5 of the human HER2 receptor.
  • the antibodies or antigen binding fragments thereof described herein do not cross-compete with trastuzumab for binding to the human HER2 ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 receptor, as trastuzumab is known to bind epitope 4D5 of the human HER2 receptor.
  • epitope 4D5 of the human HER2 receptor refers to amino acid residues 529 to 627 of the extracellular domain of the human HER2 receptor, residues 551 to 649 of SEQ ID NO: 1 or residues 529 to 627 of SEQ ID NO: 16.
  • the antibody or antigen binding fragment thereof also binds at least one epitope on cynomolgus monkey HER2 receptor.
  • the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 500 of the extracellular domain of the human HER2 receptor, residues 474 to 522 of SEQ ID NO: 1 or residues 452 to 500 of SEQ ID NO: 16.
  • the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes at least one of amino acid residue selected from amino acid residues E521, L525 and R530 of the extracellular domain of the human HER2 receptor, e.g., residues 543, 547, and 552 of SEQ ID NO: 1, and residues 521, 525, and 530 of SEQ ID NO: 16.
  • the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least two amino acid residues selected from amino acid residues E521, L525 and R530 of the extracellular domain of the human HER2 receptor. In some embodiments, the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes at least amino acid residues E521, L525 and R530 of the extracellular domain of the human HER2 receptor. In some embodiments, any or all of these antibodies or antigen binding fragments thereof also bind at least one epitope on cynomolgus monkey HER2 receptor.
  • antibodies disclosed herein also include an antibody or an antigen binding fragment thereof that binds to at least a portion of domain III and at least a portion of the N-terminus of domain IV of human HER2 receptor but does not cross-compete with Fab37 monoclonal antibody or an antibody that binds to epitope 4D5 of the human HER2 receptor.
  • the antibodies or antigen binding fragments thereof described herein do not cross-compete with the Fab37 monoclonal antibody and/or trastuzumab for binding to the human HER2 receptor.
  • the antibody or antigen binding fragment thereof also binds at least one epitope on cynomolgus monkey HER2 receptor. ⁇ Attorney Docket No.
  • the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes residues 520 to 531 of the extracellular domain of the human HER2 receptor, residues 542 to 553 of SEQ ID NO: 1 or residues 520 to 531 of SEQ ID NO: 16.
  • the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes at least one amino acid residue selected from residues C453, H456, H473, N476, R495, G496, H497, and W499 of the extracellular domain of the human HER2 receptor, e.g., residues 475, 478, 495, 498, 517, 518, 519, and 521 of SEQ ID NO: 1 or residues 453, 456, 473, 476, 495, 496, 497 and 499 of SEQ ID NO: 16.
  • the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least two amino acid residues, at least three amino acid residues, at least four amino acid residues, at least five amino acid residues, or at least six amino acid residues selected from amino acid residues C453, H456, H473, N476, R495, G496, H497, and W499 of the extracellular domain of the human HER2 receptor.
  • the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least amino acid residues C453, H456, H473, N476, R495, G496, H497, and W499 of the extracellular domain of the human HER2 receptor. In some embodiments, any or all of these antibodies or antigen binding fragments thereof also bind at least one epitope on cynomolgus monkey HER2 receptor.
  • the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes at least one amino acid residue selected from residues C453, H473, N476, R495, H497, and W499 of the extracellular domain of the human HER2 receptor, e.g., residues 475, 495, 498, 517, 519, and 521 of SEQ ID NO: 1 or residues 453, 473, 476, 495, 497 and 499 of SEQ ID NO: 16.
  • the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least two amino acid residues, at least three amino acid residues, at least four amino acid residues, at least five amino acid residues, or at least six amino acid residues selected from amino acid residues C453, H473, N476, R495, H497, and W499 of the ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 extracellular domain of the human HER2 receptor.
  • the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least amino acid residues C453, H473, N476, R495, H497, and W499 of the extracellular domain of the human HER2 receptor. In some embodiments, any or all of these antibodies or antigen binding fragments thereof also bind at least one epitope on cynomolgus monkey HER2 receptor.
  • these antibodies show specificity for human HER2, and they have been shown to modulate, e.g., block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with the PI3K-Akt pathway which promotes cell survival by reducing levels of phosphorylated AKT.
  • these antibodies internalize from the cell surface of HER2-expressing cells at a rate that is the same or substantially similar to the rate at which trastuzumab or a biosimilar thereof internalizes.
  • these antibodies and antigen binding fragments have a rate of internalization that is about 50% of the total surface bound at time 0 being internalized by 4 hours.
  • the antibodies disclosed herein comprise a heavy chain variable region having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence selected from SEQ ID NO: 2 and a light chain variable region having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence selected from SEQ ID NOs: 9.
  • the antibodies disclosed herein comprise a heavy chain amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 4 and a light chain amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 11.
  • the antibodies disclosed herein comprise the heavy chain variable region amino acid sequence of SEQ ID NO: 2 and the light chain variable region amino acid sequence of SEQ ID NO: 9. [00137] In some embodiments, the antibodies disclosed herein comprise the heavy chain amino acid sequence of SEQ ID NO: 4 and the light chain amino acid sequence of SEQ ID NO: 11. ⁇ Attorney Docket No.
  • the antibodies disclosed herein comprise the CDRH1 amino acid sequence of SEQ ID NO: 5, the CDRH2 amino acid sequence of SEQ ID NO: 6, the CDRH3 amino acid sequence of SEQ ID NO: 7, the CDRL1 amino acid sequence of SEQ ID NO: 12, the CDRL2 amino acid sequence of SEQ ID NO: 13, and the CDRL3 amino acid sequence of SEQ ID NO: 14.
  • the antibodies disclosed herein include one or more conservative amino acid substitutions in a variable domain sequence such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more conservative substitutions in a variable domain sequence.
  • these conservative amino acid substitutions are in a CDR region, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more conservative substitutions are made cumulatively across all CDRs. In some embodiments, up to 1, 2, 3, or 4 conservative amino acid substitutions may be present in each CDR sequence, e.g., SEQ ID NOs: 5-7 and 12-14. [00140] Those skilled in the art will recognize that it is possible to determine, without undue experimentation, if a monoclonal antibody has the same specificity as a monoclonal antibody XMT-1519, by ascertaining whether the former prevents the latter from binding to a natural binding partner or other molecule known to be associated with HER2.
  • an alternative method for determining whether a monoclonal antibody has the specificity of monoclonal antibody disclosed herein is to pre-incubate the monoclonal antibody disclosed herein with soluble HER2 (with which it is normally reactive), and then add the monoclonal antibody being tested to determine if the monoclonal antibody being tested is inhibited in its ability to bind HER2.
  • screening of monoclonal antibodies disclosed herein can be also carried out, e.g., by measuring HER2-mediated PI3K-Akt pathway activity, and determining whether the test monoclonal antibody is able to modulate, block, inhibit, reduce, antagonize, neutralize or otherwise interfere with PI3K-Akt pathway activity.
  • the HER2 antibodies suitable for conjugation can be generated and purified by well-known techniques e.g., ⁇ Attorney Docket No.
  • the PBRM-STING agonist conjugate is a conjugate of Formula (A-1): (A-1) or a pharmaceutically acceptable salt thereof.
  • the PBRM-STING agonist conjugate is a conjugate of Formula (B-1): ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 (B-1) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the PBRM-STING agonist conjugate is a conjugate of Formula (C-1): (C-1) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the PBRM-STING agonist conjugate is a conjugate of Formula (D-1): ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 (D-1) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the PBRM-STING agonist conjugate is a conjugate of Formula (E-1): (E-1) or a pharmaceutically acceptable salt or stereoisomer thereof. ⁇ Attorney Docket No.
  • the PBRM-STING agonist conjugate is a conjugate of Formula (F-1): (F-1) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the PBRM-STING agonist conjugate comprises a mixture of an antibody-drug conjugate having Formula (E-1) and an antibody drug conjugate having Formula (F-1).
  • the PBRM-STING agonist conjugate comprises a stereoisomer of any compound described herein (e.g., a stereoisomer of a compound of Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1), or Formula (F-1)).
  • the PBRM is a HER2-targeted antibody, for example as described herein.
  • HER2-Targeted STING Agonist Antibody Conjugates [00152] The invention pertains to combination therapies involving immunoconjugates comprising an HER2-targeted antibody conjugated to a STING agonist.
  • the present disclosure provides, inter alia, combination therapies comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein the conjugate ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 comprises an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor.
  • the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (A): or a pharmaceutically acceptable salt thereof.
  • the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (B): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (C): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (D): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (E): or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the HER2-targeted STING agonist antibody-drug conjugate or a pharmaceutically acceptable salt or stereoisomer thereof ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698
  • the HER2-targeted STING agonist antibody-drug conjugate comprises a mixture of an antibody-drug conjugate having Formula (E) and an antibody drug conjugate having Formula (F).
  • the HER2-targeted STING agonist antibody-drug conjugate comprises a stereoisomer of any compound described herein (e.g., a stereoisomer of a compound of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (F)).
  • the HER2-targeted STING agonist antibody-drug conjugates of any of Formula (A) to Formula (F) comprises a HER2 antibody comprising a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino amino acid sequence
  • the HER2 antibody comprises a light chain variable region sequence comprising SEQ ID NO: 9 and a heavy chain variable region sequence comprising SEQ ID NO: 2.
  • the HER2-antibody comprises a light chain sequence comprising SEQ ID NO: 11 and a heavy chain sequence comprising SEQ ID NO: 4.
  • the HER2-targeted STING agonist antibody-drug conjugate of the methods described herein is XMT-2056 (see, e.g., NCT05514717).
  • the PBRM e.g., HER2-targeted antibody
  • STING agonist conjugate is calotatug ginistinag which is also referred to herein as XMT-2056.
  • d 15 is 2, 4, 6, or 8.
  • d 15 is 6 or 8.
  • d15 is 8.
  • d15 is 6.
  • NK cell therapies [00169] NK cells are innate immune effectors and are found mainly in the bone marrow, peripheral blood, spleen and liver. NK cells possess cytotoxic features similar to those of CD8+ T cells and play important roles in tumor immunology. CD8+ T-cell-mediated cytotoxicity relies on the combination of the T-cell receptor (TCR) and an antigen presented by major histocompatibility complex-I (MHC-I). NK cells can recognize MHC-I expressed on healthy cells and avoid attacking them.
  • TCR T-cell receptor
  • MHC-I major histocompatibility complex-I
  • NK cells can down-modulate MHC-I to escape CD8+ T-cell- mediated cytotoxicity, while NK cells can be activated through the loss of MHC-I and control the proliferation and metastasis of tumors. Thus, NK cells have more specific anti-tumor effects and are associated with fewer off-target complications.
  • Any suitable NK cell therapy has been contemplated herein for use in the combinations and methods of the disclosure.
  • the NK cell therapy is a NK cell engager or a CAR NK cell therapy.
  • the NK cell engager is chosen from an antibody molecule that binds to the NK cell and the tumor antigen e.g., an antigen binding domain, or ligand that binds to (e.g., activates): NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16 (e.g., CD16a, CD16b, or both), CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, or CD160.
  • the tumor antigen e.g., an antigen binding domain, or ligand that binds to (e.g., activates): NKp30, NKp40,
  • the NK cell engager is an antibody molecule that binds to the NK cell and the tumor antigen, e.g., an antigen binding domain.
  • the NK cell engager is an antibody molecule, e.g., an antigen binding domain, that binds to NKp30 or NKp46.
  • the NK cell engager is a ligand, optionally, the ligand further comprises an immunoglobulin constant region, e.g., an Fc region.
  • the NK cell engager is a ligand of NKp44 or NKp46, e.g., a viral HA.
  • the NK cell engager is a ligand of DAP10, e.g., a coreceptor for NKG2D.
  • the NK cell engager is a ligand of CD16, e.g., a CD16a/b ligand, e.g., a CD16a/b ligand further comprising an antibody Fc region.
  • Examples of NK cell engagers include ABBV-303 (cMET-targeted ⁇ Attorney Docket No.
  • MRSN-043/001WO 322140-2698 trispecific NK cell engager therapy ; Dragonfly Therapeutics and Abbvie), BMS986315 (anti- NKG2A antibody; e.g., NCT06094296), DF-1001 (Dragonfly Therapeutics), DF-9001 (Dragonfly Therapeutics), HY0102 (Shanghai HyaMab Biotech), IMT-009 (Immunitas Therapeutics), SAR443579 (Sanofi and Innate Pharma), SAR445514 (Sanofi and Innate Pharma), monalizumab (Innate Pharma), nadunolimab (Cantargia), and S095029 (Servier).
  • the NK cell therapy comprises a population of NK cells.
  • the population on NK cells comprises CAR NK cells.
  • Functional CAR molecules [00174]
  • the NK cell therapy is a CAR NK cell therapy.
  • Examples of NK cell therapies include AB-101 (an allogeneic NK cell therapy; Artiva Biotherapeutics), ACE-1702 (anti-HER2-conjugated allogeneic NK cell therapy; Acepodia).
  • Anti-BCMA CAR-NK cell therapies being developed by Sichuan Kelun Pharma (e.g., NCT050008536) and Shenzhen Pregene Biopharma (e.g., NCT05652530), AP-44 (autologous NK cell therapy; Alphageneron Phamra), BCM6100 (allogeneic CD-19 CAR NK cell therapy; Immunecyte), CNTY-101 (Century Therapeutics), CTX-131 (CRISPR Therapeutics and Nkarta), CYNK-101 (Cularity), CYTO NK-102 (CytoImmune), DVX-201 (Deverra Therapeutics, e.g., NCT04900454), E-10H (Guangzhou Double Bioproducts), evencaleucel (XNK Therapeutics), FT-522 (Fate Therapeutics), FT-576 (Fate Therapeutics), GAIA-102 (GAIA BioMedicine), GDA-201 (Gamida Cell), HR-012 (
  • Antibody-dependent cellular cytotoxicity also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection. ADCC is independent of the immune complement system that also lyses targets but does not require any other cell.
  • ADCC requires an effector cell which classically are known to be natural killer (NK) cells that typically interact with immunoglobulin G (IgG) antibodies.
  • NK natural killer
  • IgG immunoglobulin G
  • macrophages, neutrophils and eosinophils can also mediate ADCC.
  • Any suitable antibody directed to a tumor antigen that exhibits therapy ADCC function has been contemplated herein for use in the combinations and methods of the disclosure.
  • antibodies with ADCC function are afucosylated or have other Fc modifications to enhance the binding of the antibody to Fc-gamma receptor III or enhance the ADCC of the antibody.
  • the antibody with ADCC function binds to the same biological target as the PBRM or HER-2 ANTIBODY of the antibody-drug conjugate, optionally wherein the antibody with ADCC function binds to a different epitope of the biological target than the PBRM or HER-2 ANTIBODY of the antibody-drug conjugate.
  • the antibody with ADCC function does not cross-compete for binding to the biological target with the PBRM or HER-2 ANTIBODY of the antibody-drug conjugate, optionally as measured by a Biacore assay.
  • the antibody with ADCC function binds to a different biological target than the PBRM or HER-2 ANTIBODY of the antibody-drug conjugate.
  • the ADCC function of the antibody synergizes with the STING pathway activation and induces potent cancer cell-killing activity of cancer cells and Fc ⁇ RIII + (CD16 + ) immune cells.
  • the ADCC function of the antibody synergizes with the STING pathway activation and induces potent cancer cell-killing activity of HER2-expressing cancer cells and Fc ⁇ RIII + (CD16 + ) immune cells.
  • the ADCC function of an antibody can be evaluated using co-cultures of cancer cells expressing the target antigen and NK cells as Fc ⁇ -RIII-expressing effector cells.
  • Target + cancer cells can be co-cultured with NK cells at different target : effector cell ratios in the presence of increasing concentrations of the cancer cell-targeted antibody, Fc- mutant targeted antibody, and non-binding control antibody followed by incubation in a 37 °C, %5 CO 2 incubator for 3-4 days.
  • Cancer cell viability can be measured using a cell-titer Glo (CTG) assay normalized to the untreated control co-cultures.
  • CCG cell-titer Glo
  • IncuCyte cancer cell-killing assay can also be performed to measure cancer cell viability using the target+ cancer cells expressing a nuclear- restricted fluorescent protein, which allows for tracing the fluorescence intensity (cancer cells) over time in an IncuCyte instrument.
  • HER2 + cancer cells are co-cultured with NK effector cells at a ratio that leads to incomplete killing of cancer cells following treatment with single agents (antibody that has ADCC function alone or the HER2-targeted STING agonist antibody-drug conjugate alone), which would allow for the measurement of the enhanced killing of cancer cells with combination treatment.
  • HER2 + cancer cells can be co-cultured with the target+ cancer cells expressing the fluorescent protein (traced cells) in the presence of NK cells and the cancer cell-killing activity of the HER2-targeted STING agonist antibody-drug conjugate and the antibody of interest as single agents or in combination can be measured using the IncuCyte killing assay as described above.
  • the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one PBRM-STING agonist conjugate and at least one NK cell therapy and/or at least one antibody that has an ADCC function.
  • the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one HER2-targeted STING agonist antibody- ⁇ Attorney Docket No.
  • the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function.
  • the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject at least one NK cell therapy or at least one antibody that has ADCC function.
  • the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject at least one NK cell therapy or at least one antibody that has ADCC function.
  • the present disclosure provides a method of activating or enhancing an activity of STING in a subject, comprising administering to the subject a combination therapy disclosed herein i.e. at least one antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function.
  • the present disclosure provides a method of activating or enhancing an activity of STING in a subject, comprising administering to the subject a combination therapy disclosed herein i.e.
  • the present disclosure provides a method of activating or enhancing an activity of STING in a subject, comprising administering to the subject a combination therapy disclosed herein i.e. at least one NK cell therapy or at least one antibody that has ADCC function.
  • the present disclosure relates to a method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a combination therapy disclosed herein.
  • the present disclosure relates to a method of treating a cancer in a subject in need thereof, comprising administering to the subject a combination therapy disclosed herein.
  • a combination therapy disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides a combination therapy disclosed herein for use in treating a disease or disorder in a subject in need thereof.
  • the present disclosure provides a combination therapy disclosed herein for treating a STING-mediated disease or disorder in a subject.
  • the present disclosure provides use of a combination therapy disclosed herein for treating or preventing a disease or disorder in a subject in need thereof. [00198] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treating a disease or disorder in a subject in need thereof. [00199] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treating a cancer in a subject in need thereof. [00200] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treating a STING-mediated disease or disorder in a subject in need thereof.
  • the present disclosure provides use of a combination therapy disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.
  • the present disclosure provides use of a combination therapy disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides use of a combination therapy disclosed herein in the manufacture of a medicament for treating a STING-mediated disease or disorder in a subject.
  • the present disclosure provides use of a combination therapy disclosed herein in the manufacture of a medicament for treating a cancer in a subject in need thereof.
  • the present disclosure provides use of a combination therapy disclosed herein for the treatment or prevention of a disease or disorder in a subject in need thereof.
  • the present disclosure provides use of a combination therapy disclosed herein for the treatment of a disease or disorder in a subject in need thereof. ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 [00207]
  • the present disclosure provides use of a combination therapy disclosed herein for treating a STING-mediated disease or disorder in a subject.
  • the present disclosure provides use of a combination therapy disclosed herein for treatment of a cancer in a subject in need thereof.
  • the combination comprises at least one PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. In some embodiments, the combination therapy disclosed herein is administered to the subject. [00210] In some embodiments, the combination comprises at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. In some embodiments, the combination therapy disclosed herein is administered to the subject.
  • the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of at least one PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein said PBRM-STING agonist conjugate releases one or more therapeutic agent(s).
  • the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein said HER2-targeted STING agonist antibody-drug conjugate releases one or more therapeutic agent(s) upon biodegradation.
  • the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of at least one conjugate of the disclosure; wherein said conjugate releases one or more therapeutic agents.
  • the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of at least one HER2-targeted STING agonist antibody-drug conjugate of the disclosure; wherein said HER2-targeted STING agonist antibody-drug conjugate releases one or more therapeutic agents upon biodegradation.
  • a HER2-targeted STING agonist antibody-drug conjugate induces immune-mediated concomitant killing of HER2-negative cancer cells.
  • the disease or disorder is a cancer.
  • the cancer is selected from the group consisting of anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer (CRC), throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer and gastric esophagogastric junction cancer.
  • anal cancer astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer,
  • the cancer is selected from the group consisting of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer.
  • the breast cancer is metastatic breast cancer.
  • the breast cancer is HER2 positive (HER2+) breast cancer. In some embodiments, the breast cancer is HER2 negative (HER2-) breast cancer. In some embodiments, the HER2+ breast cancer is metastatic HER2+ breast cancer. In some embodiments, the HER2- breast cancer is metastatic HER2- breast cancer. [00221] In some embodiments, a subject having breast cancer has received at least one, at least two, at least three, or at least four prior lines of breast cancer therapy. In some aspects, a subject has received three or more prior lines of breast cancer therapy. In some aspects, a subject having HER2+ metastatic breast cancer has received three or more lines of breast cancer therapy.
  • the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of gastric cancer. ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 [00223] In some embodiments, the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of gastric esophagogastric junction cancer. [00224] In some embodiments, the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of colorectal cancer.
  • the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of non- small cell lung cancer (NSCLC).
  • NSCLC non- small cell lung cancer
  • the subject has recurrent or metastatic solid tumors with HER 2+ expression.
  • the disease or disorder is a pre-cancerous syndrome.
  • the combination therapies comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function.
  • the combination therapies comprising at least one PBRM- STING agonist conjugate and at least one NK cell therapy are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • the combination therapies comprising at least one PBRM- STING agonist conjugate and at least one NK cell therapy are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • the combination therapies comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one NK cell therapy are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • the combination therapies comprising at least one PBRM- STING agonist conjugate and at least one antibody that has ADCC function.
  • the combination therapies comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function. are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • the combination therapy comprising at least one PBRM- STING agonist conjugate is administered in combination with at least one NK cell therapy or at least one antibody that has ADCC function for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • NSCLC non-small cell lung cancer
  • the combination therapy comprising at least one HER2- targeted STING agonist antibody-drug conjugate is administered in combination with at least one NK cell therapy or at least one antibody that has ADCC function for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • NSCLC non-small cell lung cancer
  • the combination therapy comprising at least one HER2- targeted STING agonist antibody-drug conjugate of the disclosure is administered in combination with, at least one NK cell therapy for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • NSCLC non-small cell lung cancer
  • the combination therapy comprises at least one HER2- targeted STING agonist antibody-drug conjugate of the disclosure in combination with at least one antibody that has ADCC function are useful for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer.
  • NSCLC non-small cell lung cancer
  • the methods include identifying or otherwise refining, e.g., stratifying, a patient population suitable for therapeutic administration of the combination therapies thereof disclosed herein by identifying the HER2 score of a subject by IHC test or FISH (fluorescence in situ hybridization negative) measurements prior to treatment with the combination therapies disclosed herein.
  • the IHC test measures the amount of HER2 receptor protein on the surface of cells in a cancer tissue sample, e.g., a breast cancer tissue sample or a gastric cancer ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 sample and assigns the detected level of cell surface HER2 receptor a HER2 score of 0, 1+, 2+ or 3+.
  • the subject is identified as having a scoring of 2+ or 3+ for HER2 expression as detected by immunohistochemistry (IHC) analysis performed on a test cell population, and the subject is also ER positive.
  • the subject is identified as having a scoring of 2+ or 3+ for HER2 expression as detected by immunohistochemistry (IHC) analysis performed on a test cell population, and the subject also is ER negative.
  • the subject is identified as having a scoring of 3+ for HER2 expression or evidence of gene amplification by FISH. In some embodiments, the subject is identified as having a scoring of 2+ for HER2 expression or evidence of gene amplification by FISH. In some embodiments, the subject is identified as having a scoring of 1+ for HER2 expression or evidence of gene amplification by FISH. In some embodiments, the subject is identified as having a high HER2 expression. In some embodiments, the subject is identified as having a low HER2 expression. In some embodiments, the test cell population is derived from fresh, unfrozen tissue from a biopsy sample. In some embodiments, the test cell population is derived from a frozen tissue from a biopsy sample.
  • the combination therapy comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function.
  • disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer or non-small cell lung cancer (NSCLC) in patients who have HER2 IHC 2+ or HER2 IHC 3+.
  • the breast cancer patient is also ER positive.
  • the breast cancer patient is also ER negative.
  • the combination therapy comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function.
  • disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer or non-small cell lung cancer (NSCLC) in patients who have HER2 IHC 1+ or HER2 IHC 2+.
  • NSCLC non-small cell lung cancer
  • the combination comprising a HER2-targeted STING agonist antibody-drug conjugate and at least NK cell therapy or at least one antibody that has ADCC function. disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer or non-small cell lung cancer (NSCLC) in patients who have HER2 IHC 1+ or HER2 IHC 2+.
  • NSCLC non-small cell lung cancer
  • the combination comprising a PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function.
  • the combination therapy can be administered at any stage of the disease.
  • the combination therapy can be administered to a patient suffering cancer of any stage, from early to metastatic.
  • the combination comprising a HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function.
  • used in any of the embodiments of the methods and uses provided herein can be administered at any stage of the disease.
  • the combination therapy can be administered to a patient suffering cancer of any stage, from early to metastatic.
  • a combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least NK cell therapy or at least one antibody that has ADCC function.
  • the additional agent is any of the toxins described herein.
  • the additional agent is (1) EGFR inhibitors (e.g., tyrosine kinase inhibitors or targeted anti-EGFR antibodies), (2) BRAF inhibitors, (3) ALK inhibitors, (4) hormone receptor inhibitors, (5) mTOR inhibitors, (6) VEGF inhibitors, or (7) cancer vaccines.
  • the additional agent is a standard, first line chemotherapeutic agent, such as, for example, ado-trastuzumab emtansine (Kadcyla), lapatinib, anastrozole, letrozole, exemestane, everolimus, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxymesterone, ethinyl estradiol, paclitaxel, capecitabine, gemcitabine, eribulin, vinorelbine, cyclophosphamide, carboplatin, docetaxel, albumin-bound paclitaxel, cisplatin, epirubicin, ixabepilone, doxorubicin, fluorouracil, oxaliplatin, fluoropyrimidine, irinotecan, ramucirumab, mitomycin, leucovorin, cetuximab,
  • the additional agent is Kadcyla (ado-trastuzumab emtansine)
  • the combination therapies of the present disclosure may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the components of the combination of the present disclosure and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • compositions of the disclosure may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered daily, weekly, biweekly, monthly, bimonthly, every 6 months or annually. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for the compositions of the disclosure depend on the pharmacokinetic properties of that composition, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a composition of the disclosure depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • the combination therapy can include one or more conjugates disclosed herein co-formulated with, and/or co-administered with, one or more NK cell therapies or one or more antibody that has ADCC function disclosed herein.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a conjugate disclosed herein) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • the dosage will also depend on the route of administration.
  • the pharmaceutical compositions are formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a conjugate disclosed herein) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • the combination therapy can include one or more conjugates disclosed herein co-formulated with, and/or co-administered with, one or more NK cell therapies or one or more antibody that has ADCC function disclosed herein.
  • the combinations comprising PBRM-STING agonist conjugates and NK cell therapies or antibodies that have ADCC function and additional agent(s) are formulated into a single therapeutic composition, and the components are administered simultaneously.
  • the PBRM-STING agonist conjugate, NK cell therapy, antibody that has ADCC function and additional agent, if any, are separate from each other, e.g., each is formulated into a separate therapeutic composition, and can be administered simultaneously, or at different times during a treatment regimen.
  • the PBRM-STING agonist is ⁇ Attorney Docket No.
  • the PBRM-STING agonist is administered after the administration of the NK cell therapy or the antibody that has ADCC function.
  • the PBRM-STING agonist and the NK cell therapy or the antibody that has ADCC function combination are administered in single doses or in multiple doses.
  • the combinations comprising HER2-targeted STING agonist antibody-drug conjugates and NK cell therapies or antibodies that have ADCC function and additional agent(s) are formulated into a single therapeutic composition, and the components are administered simultaneously.
  • the HER2-targeted STING agonist antibody-drug conjugate, NK cell therapy, antibody that has ADCC function and additional agent, if any, are separate from each other, e.g., each is formulated into a separate therapeutic composition, and can be administered simultaneously, or at different times during a treatment regimen.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered prior to the administration of the NK cell therapy or the antibody that has ADCC function; the HER2-targeted STING agonist antibody-drug conjugate is administered after the administration of the NK cell therapy or the antibody that has ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function combination are administered in single doses or in multiple doses.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof.
  • ratios of the antibody-drug conjugate of Formula (E- 1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F- 1) or a pharmaceutically acceptable salt thereof; and ratios of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof are molar ratios (e.g., as determined by chiral column chromatography, e.g., as described herein).
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and ⁇ Attorney Docket No.
  • the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between 20:80 and 80:20, between about 25:75 and 75:25, between about 30:70 and 70:30, between about 35:65 and 65:35, between about 40:60 and 60:40, between about 45:55 and 55:45, or about 50:50.
  • the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between 30:70 and 70:30. In some embodiments, the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between 40:60 and 60:40. In some embodiments, the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between about 40:60 and 60:40, between about 41:59 and 59:41, between about 42:58 and 58:42, between about 43:57 and 57:43, between about 44:56 and 56:44, between about 45:55 and 55:44, between about 46:54 and 54:46, between about 47:53 and 53:47, between about 48:52 and 52:48, between about 49:51 and 51:49, or 50:50.
  • the ratio e.g., molar ratio
  • the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between 45:55 and 55:45.
  • the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is about 50:50. In some embodiments, the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof.
  • the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 20:80 and 80:20, between about 25:75 and 75:25, between about 30:70 and 70:30, between about 35:65 and 65:35, between about 40:60 and 60:40, between about 45:55 and 55:45, or about 50:50.
  • the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 30:70 and 70:30. In some embodiments, the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 40:60 and 60:40. In some embodiments, the ratio is a molar ratio. ⁇ Attorney Docket No.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between about 40:60 and 60:40, between about 41:59 and 59:41, between about 42:58 and 58:42, between about 43:57 and 57:43, between about 44:56 and 56:44, between about 45:55 and 55:44, between about 46:54 and 54:46, between about 47:53 and 53:47, between about 48:52 and 52:48, between about 49:51 and 51:49, or 50:50.
  • the ratio e.g., molar ratio
  • the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 45:55 and 55:45.
  • the ratio is a molar ratio.
  • the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is about 50:50. In some embodiments, the ratio is a molar ratio.
  • the ratio (e.g., molar ratio) of one or more stereoisomers in a mixture is determined by chiral column chromatography.
  • the chiral chromatography is performed on a precursor to the final antibody-drug conjugate (e.g., on the drug-linker scaffold, or an intermediate thereof, prior to conjugation to the antibody), wherein the additional chemical and/or biological manipulation of the precursor to generate the antibody-drug conjugate will not alter the stereochemistry (or ratio of stereochemistries in the mixture) at the stereocenter(s) of interest.
  • the combination therapy provided herein, comprising a PBRM-STING agonist conjugate and a NK cell therapy or an antibody that has ADCC function combination is administered in single doses or in multiple doses is administered in an amount sufficient to exert a therapeutically useful effect.
  • the active agents are administered in an amount that does not result in undesirable side effects of the patient being treated, or that minimizes or reduces the observed side effects as compared to dosages and amounts required for single treatment with one of the above agents.
  • the combination therapy comprising a PBRM-STING agonist conjugate and a NK cell therapy or an antibody that has ADCC function combination are administered in single doses or in multiple doses.
  • the amount of a NK cell therapy or an antibody that has ADCC function that can be administered in the combination therapy provided herein, compared to the amount of the NK cell therapy or the antibody that has ADCC function administered alone or using a known method is reduced, while achieving substantially the same or improved therapeutic efficacy.
  • side effects associated with the NK cell therapy or the antibody that has ADCC function administration such as immune-related adverse events, described elsewhere or herein, are reduced, minimized or avoided.
  • the combination therapy provided herein comprising a HER2-targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function combination is administered in single doses or in multiple doses is administered in an amount sufficient to exert a therapeutically useful effect.
  • the active agents are administered in an amount that does not result in undesirable side effects of the patient being treated, or that minimizes or reduces the observed side effects as compared to dosages and amounts required for single treatment with one of the above agents.
  • the combination therapy comprising a HER2-targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function combination are administered in single doses or in multiple doses.
  • the amount of a NK cell therapy or an antibody that has ADCC function that can be administered in the combination therapy provided herein, compared to the amount of the NK cell therapy or the antibody that has ADCC function administered alone or using a known method is reduced, while achieving substantially the same or improved therapeutic efficacy.
  • side effects associated with ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 the NK cell therapy or the antibody that has ADCC function administration, such as immune- related adverse events, described elsewhere or herein, are reduced, minimized or avoided.
  • dosage and duration of treatment is a function of the tissue or tumor being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data and/or can be determined from known dosing regimens of the particular agent. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated, the weight of the individual, the route of administration and/or the extent or severity of the disease and other factors that are within the level of a skilled medical practitioner to consider. Generally, dosage regimens are chosen to limit toxicity. It should be noted that the treating physician would know how to and when to terminate, interrupt or adjust therapy to lower dosage due to toxicity, or bone marrow, liver or kidney or other tissue dysfunctions.
  • the treating physician would also know how to and when to adjust treatment to higher levels if the clinical response is not adequate (precluding toxic side effects). It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope thereof.
  • the PBRM-STING agonist conjugate combination is administered in a therapeutically effective amount to decrease the tumor volume.
  • the HER2-targeted STING agonist antibody-drug conjugate combination is administered in a therapeutically effective amount to decrease the tumor volume.
  • the amount of a PBRM-STING agonist conjugate administered for the treatment of a disease or condition, for example a cancer or solid tumor can be determined by standard clinical techniques. In addition, in vitro assays and animal models can be employed to help identify optimal dosage ranges. The precise dosage, which can be determined empirically, can depend on the route of administration, the type of disease to be treated and the seriousness of the disease. [00276] The amount of a HER2-targeted STING agonist antibody-drug conjugate administered for the treatment of a disease or condition, for example a cancer or solid tumor can be determined by standard clinical techniques.
  • in vitro assays and animal models can be employed to help identify optimal dosage ranges.
  • the precise dosage which can be determined empirically, can depend on the route of administration, the type of disease to be treated and the seriousness of the disease.
  • the NK cell therapy or the antibody that has ADCC function can be provided in a therapeutically effective amount for the particular dosage regimen.
  • Therapeutically effective concentrations can be determined empirically by testing the compounds in known in vitro and in vivo systems, such as the assays provided herein.
  • the concentration of a selected NK cell therapy or antibody that has ADCC function in the composition depends on absorption, inactivation and excretion rates of the complex, the physicochemical characteristics of the complex, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • the amount of a selected NK cell therapy or antibody that has ADCC function to be administered for the treatment of cancers can be determined by standard clinical techniques or other methods as described herein.
  • in vitro assays and animal models can be employed to help identify optimal dosage ranges.
  • the precise dosage which can be determined empirically, can depend on route of administration, the type of cancer to be treated and the progression of the disease.
  • a particular dosage and duration and treatment protocol can be empirically determined or extrapolated. Dosage levels can be determined based on a variety of factors, such as body weight of the individual, general health, age, the activity of the specific compound employed, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, and the patient's disposition to the disease and the judgment of the treating physician. [00279]
  • the combinations of the disclosure may also be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is, for example, by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • the PBRM-STING agonist conjugates and NK cell therapy or antibody that has ADCC function are administered as an infusion every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks.
  • the HER2-targeted STING agonist antibody-drug conjugates and NK cell therapy or antibody that has ADCC function are administered as an infusion every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks.
  • the PBRM-STING agonist conjugates and NK cell therapy or antibody that has ADCC function is administered as an infusion every three weeks or every four weeks.
  • the HER2-targeted STING agonist antibody-drug conjugates and NK cell therapy or antibody that has ADCC function is administered as an infusion every three weeks or every four weeks.
  • the PBRM-STING agonist conjugate and the NK cell therapy or antibody that has ADCC function are administered by infusion simultaneously. In some embodiments, the PBRM-STING agonist conjugate is administered by infusion prior to the administration of the NK cell therapy or antibody that has ADCC function. In some embodiments, the PBRM-STING agonist conjugate is administered by infusion after the administration of the NK cell therapy or antibody that has ADCC function. As described herein, the PBRM-STING agonist conjugate and the NK cell therapy or antibody that has ADCC function combination can be administered in single doses or in multiple doses.
  • the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or antibody that has ADCC function are administered by infusion ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 simultaneously.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered by infusion prior to the administration of the NK cell therapy or antibody that has ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered by infusion after the administration of the NK cell therapy or antibody that has ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or antibody that has ADCC function combination can be administered in single doses or in multiple doses.
  • the frequency and timing of administration, and the dosage amounts, can be administered periodically over a cycle of administration to maintain a continuous and/or long-term effect of the active agents for a desired length of time.
  • the provided combination can be administered hourly, daily, weekly, monthly, yearly or once.
  • the length of time of the cycle of administration can be empirically determined, and is dependent on the disease to be treated, the severity of the disease, the particular patient, and other considerations within the level of skill of the treating physician.
  • the length of time of treatment with a combination therapy provided herein can be one week, two weeks, one month, several months, one year, several years or more.
  • exemplary doses of intravenously administered antibodies that have ADCC function can be used as a starting point to determine appropriate dosages. Dosage levels can be determined based on a variety of factors, such as body weight of the individual, general health, age, the activity of the specific compound employed, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, and the patient's disposition resulting from the disease and the judgment of the treating physician.
  • the amount to administer will be a function of the type of cancer being treated, the route of administration, and the tolerability of possible side effects. If necessary, dosage can be empirically determined.
  • one or more, or all, of the agents used in the combination therapy can be administered by push or bolus, by infusion, or via a combination thereof.
  • the infusion time can be about 1 minute to three hours, such as about 1 minute to about two hours, about 1 minute to about 60 minutes, about 1 minute to about 90 minutes, or about 1 minute to about 120 minutes.
  • the agents can be administered by concurrent infusion or by subsequent infusion. For example, the administered agents are administered separately and are provided in separate bags for separate infusions.
  • the PBRM-STING ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 conjugate composition and the NK cell therapy or the antibody that has ADCC function composition are formulated and administered separately.
  • the PBRM-STING agonist conjugate composition and the NK cell therapy or the antibody that has ADCC function composition are formulated and administered separately.
  • the HER2-targeted antibody-drug conjugate composition and the NK cell therapy or the antibody that has ADCC function composition are formulated and administered separately.
  • the PBRM-STING agonist antibody-drug conjugate can be administered prior to, simultaneously with or near simultaneously with, sequentially with or intermittently with the NK cell therapy or the antibody that has ADCC function.
  • the PBRM-STING agonist conjugate and the NK cell therapy or the antibody that has ADCC function e.g., an anti-immune checkpoint protein antibody (e.g., an anti-CTLA4 or anti-PD-1 antibody) can be co-administered or separately.
  • an anti-immune checkpoint protein antibody e.g., an anti-CTLA4 or anti-PD-1 antibody
  • the HER2-targeted STING agonist antibody-drug conjugate can be administered prior to, simultaneously with or near simultaneously with, sequentially with or intermittently with the NK cell therapy or the antibody that has ADCC function.
  • the HER2-targeted antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function can be co- administered or separately.
  • an anti-immune checkpoint protein antibody e.g., an anti-CTLA4 or anti-PD-1 antibody
  • the PBRM-STING agonist conjugate is administered prior to the NK cell therapy or the antibody that has ADCC function.
  • the PBRM-STING agonist conjugate is administered up to about 48 hours prior to administering the NK cell therapy or the antibody that has ADCC function.
  • the PBRM-STING agonist conjugate is administered about 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 40 hours, or up to about 48 hours prior to administration of the NK cell therapy or the antibody that has ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered prior to the NK cell therapy or the antibody that has ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered up to about 48 hours ⁇ Attorney Docket No.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered about 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 40 hours, or up to about 48 hours prior to administration of the NK cell therapy or the antibody that has ADCC function.
  • the PBRM-STING agonist conjugate is administered after the NK cell therapy or the antibody that has ADCC function.
  • the PBRM-STING agonist conjugate is administered up to about 48 hours after administering the NK cell therapy or the antibody that has ADCC function.
  • the PBRM-STING agonist conjugate is administered about 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 40 hours, or up to about 48 hours after administration of the NK cell therapy or the antibody that has ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered after the NK cell therapy or the antibody that has ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered up to about 48 hours after administering the NK cell therapy or the antibody that has ADCC function.
  • the HER2-targeted STING agonist antibody-drug conjugate is administered about 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 40 hours, or up to about 48 hours after administration of the NK cell therapy or the antibody that has ADCC function.
  • the frequency and timing of administration, and the dosage amounts can be administered periodically over a cycle of administration to maintain a continuous and/or long-term effect of the active agents for a desired length of time and need not be the same for the PBRM- STING agonist conjugate and the NK cell therapy or the antibody that has ADCC function.
  • the frequency and timing of administration, and the dosage amounts can be administered periodically over a cycle of administration to maintain a continuous and/or long-term effect of the active agents for a desired length of time and need not be the same for the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function.
  • compositions of each active agent or combinations thereof can be administered hourly, daily, weekly, monthly, yearly or once.
  • the length of time of the cycle of administration can be ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 empirically determined, and is dependent on the disease to be treated, the severity of the disease, the disposition of the patient, and other considerations within the level of skill of the treating physician.
  • the length of time of treatment with a combination therapy provided herein can be one week, two weeks, one month, several months, one year, several years or more.
  • the frequency of administration of the PBRM-STING agonist conjugate is once a day, every other day, twice weekly, once weekly, once every 2 weeks, once every 3 weeks or once every 4 weeks.
  • the dosages can be divided into a plurality of cycles of administration during the course of treatment.
  • the PBRM-STING agonist conjugate can be administered at the frequency over a period of about a month, 2 months, 3 months, 4 months, 5 months, 6 months, a year or more.
  • the frequency of administration can be the same throughout the period of the cycle or can differ.
  • an exemplary dosage frequency is two times a week at least for the first week of a cycle of administration. After the first week, the frequency can continue at twice a week, can increase to more than twice a week, or can be reduced to no more than once a week.
  • the frequency of administration of the HER2-targeted STING agonist antibody-drug conjugate is once a day, every other day, twice weekly, once weekly, once every 2 weeks, once every 3 weeks or once every 4 weeks.
  • the dosages can be divided into a plurality of cycles of administration during the course of treatment.
  • the HER2-targeted STING agonist antibody-drug conjugate can be administered at the frequency over a period of about a month, 2 months, 3 months, 4 months, 5 months, 6 months, a year or more.
  • the frequency of administration can be the same throughout the period of the cycle or can differ.
  • an exemplary dosage frequency is two times a week at least for the first week of a cycle of administration. After the first week, the frequency can continue at twice a week, can increase to more than twice a week, or can be reduced to no more than once a week. It is within the level of a skilled person to determine the particular dosage frequency and cycle of administration based on the particular dosage being administered, the disease or condition being treated, the severity of the disease or condition, the age of the subject and other similar factors. ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 [00301]
  • the NK cell therapy or the antibody that has ADCC function can be administered at the same frequency or at a different frequency.
  • each administration of the NK cell therapy or the antibody that has ADCC function is preceded by an administration of the PBRM- STING agonist conjugate by not more than 48 hours.
  • each dose of the PBRM-STING agonist conjugate is followed 24 to 48 hr later by a dose of the NK cell therapy or the antibody that has ADCC function.
  • the NK cell therapy or the antibody that has ADCC function is administered less frequently than the PBRM-STING agonist conjugate, but each dose of the NK cell therapy or the antibody that has ADCC function is preceded by a dose of the PBRM-targeted antibody-drug conjugate.
  • the NK cell therapy or the antibody that has ADCC function is administered twice weekly, once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, and in a manner that is preceded by administration of a PBRM-STING agonist conjugate.
  • each dose of the PBRM-STING agonist conjugate is preceded by a dose of the NK cell therapy or the antibody that has ADCC function.
  • the NK cell therapy or the antibody that has ADCC function is administered more frequently than the PBRM-STING agonist conjugate.
  • the NK cell therapy or the antibody that has ADCC function is administered twice weekly, once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, and in a manner that some but not all NK cell therapy dosages or antibodies that have ADCC function dosages are followed by administration of a PBRM-STING agonist conjugate.
  • the NK cell therapy or the antibody that has ADCC function can be administered at the same frequency or at a different frequency.
  • each administration of the NK cell therapy or the antibody that has ADCC function is preceded by an administration of the HER2- targeted STING agonist antibody-drug conjugate by not more than 48 hours.
  • each dose of the HER2-targeted STING agonist antibody-drug conjugate is followed 24 to 48 hr later by a dose of the NK cell therapy or the antibody that has ADCC function.
  • the NK cell therapy or the antibody that has ADCC function is administered less frequently than the HER2-targeted STING agonist antibody-drug conjugate, but each dose of the NK cell therapy or the antibody that has ADCC function is preceded by a dose of the HER2-targeted antibody-drug ⁇ Attorney Docket No.
  • the NK cell therapy or the antibody that has ADCC function is administered twice weekly, once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, and in a manner that is preceded by administration of a HER2-targeted STING agonist antibody-drug conjugate.
  • each dose of the HER2-targeted STING agonist antibody-drug conjugate is preceded by a dose of the NK cell therapy or the antibody that has ADCC function.
  • the NK cell therapy or the antibody that has ADCC function is administered more frequently than the HER2-targeted STING agonist antibody-drug conjugate.
  • the NK cell therapy or the antibody that has ADCC function is administered twice weekly, once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, and in a manner that some but not all NK cell therapy dosages or antibodies that have ADCC function dosages are followed by administration of a HER2-targeted STING agonist antibody-drug conjugate.
  • the cycle of administration of the PBRM-STING agonist conjugate and/or NK cell therapy and/or antibody that has ADCC function can be tailored to add periods of discontinued treatment in order to provide a rest period from exposure to the agents.
  • the length of time for the discontinuation of treatment can be for a predetermined time or can be empirically determined depending on how the patient is responding or depending on observed side effects.
  • the treatment can be discontinued for one week, two weeks, one month or several months.
  • the period of discontinued treatment is built into a cycle of dosing regimen for a patient.
  • the cycle of administration of the HER2-targeted STING agonist antibody-drug conjugate and/or NK cell therapy and/or antibody that has ADCC function can be tailored to add periods of discontinued treatment in order to provide a rest period from exposure to the agents.
  • the length of time for the discontinuation of treatment can be for a predetermined time or can be empirically determined depending on how the patient is responding or depending on observed side effects.
  • the treatment can be discontinued for one week, two weeks, one month or ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 several months.
  • the period of discontinued treatment is built into a cycle of dosing regimen for a patient.
  • An exemplary dosing regimen is a treatment cycle or cycle of administration of 21 or 28 days.
  • the agent such as the PBRM-STING agonist conjugate disclosed herein, can be administered on day 1, followed by administration of a NK cell therapy or an antibody that has ADCC function of the disclosure, such as a NK cell therapy or an antibody that has ADCC function on day 2, followed by 19 or 26 days without dosing. It is understood that the above description is for exemplification purposes only and that variations of the above can be employed. Further, similar cycles of administration can be applied to all administered agents, or each administered agent can be employed in its own dosing regimen in the combination therapy provided herein.
  • An exemplary dosing regimen is a treatment cycle or cycle of administration of 21 or 28 days.
  • the agent such as the HER2-targeted STING agonist antibody-drug conjugate disclosed herein, can be administered on day 1, followed by administration of a NK cell therapy or an antibody that has ADCC function of the disclosure, such as a NK cell therapy or an antibody that has ADCC function on day 2, followed by 19 or 26 days without dosing.
  • a NK cell therapy or an antibody that has ADCC function of the disclosure such as a NK cell therapy or an antibody that has ADCC function on day 2
  • 19 or 26 days without dosing can be administered.
  • similar cycles of administration can be applied to all administered agents, or each administered agent can be employed in its own dosing regimen in the combination therapy provided herein.
  • the cycle of administration can be for any desired length of time.
  • the 21-day or 28-day cycle of administration can be repeated for any length of time. It is within the level of skill of the treating physician to adopt a cycle of administration and dosing regimen that meets the needs of the patient depending on personal considerations specific to the patient and disease to be treated. Diagnostic and Prophylactic Formulations [00309]
  • the conjugates and NK cell therapy or antibody that has ADCC function disclosed herein are used in diagnostic and prophylactic formulations.
  • a PBRM-STING agonist conjugate and a NK cell therapy or an antibody that has ADCC function disclosed herein are administered to patients that are at risk of developing one or more of the aforementioned ⁇ Attorney Docket No.
  • MRSN-043/001WO 322140-2698 diseases such as for example, without limitation, cancer.
  • a HER2-targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function disclosed herein are administered to patients that are at risk of developing one or more of the aforementioned diseases, such as for example, without limitation, cancer.
  • a patient’s or organ’s predisposition to one or more of the aforementioned indications can be determined using genotypic, serological or biochemical markers.
  • a PBRM-STING agonist conjugate and an antibody that has ADCC function disclosed herein are administered to human individuals diagnosed with a clinical indication associated with one or more of the aforementioned diseases, such as for example, without limitation, cancer.
  • a PBRM-STING agonist conjugate and a NK cell therapy or an antibody that has ADCC function disclosed herein are administered to mitigate or reverse the effects of the clinical indication associated with one or more of the aforementioned diseases.
  • a HER2-targeted STING agonist antibody-drug conjugate and an antibody that has ADCC function disclosed herein are administered to human individuals diagnosed with a clinical indication associated with one or more of the aforementioned diseases, such as for example, without limitation, cancer.
  • a HER2-targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function disclosed herein are administered to mitigate or reverse the effects of the clinical indication associated with one or more of the aforementioned diseases.
  • a method for identifying a breast cancer patient amenable to treatment with the combinations of conjugates and NK cell therapy or antibody that has ADCC function disclosed herein comprise measuring the status of certain characteristics in a tumor sample obtained from the patient, and identifying the patient for treatment based on the status of certain characteristics in the tumor sample.
  • Antibodies disclosed herein are also useful in the detection of HER2 in patient samples and accordingly are useful as diagnostics.
  • HER2 antibodies disclosed herein are used in in vitro assays, e.g., ELISA, to detect HER2 levels in a patient sample.
  • a HER2 antibody disclosed herein is immobilized on a solid support (e.g., the well(s) of a microtiter plate).
  • the immobilized antibody serves as a capture antibody for any HER2 that may be present in a test sample.
  • the solid support Prior to contacting the immobilized ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 antibody with a patient sample, the solid support is rinsed and treated with a blocking agent such as milk protein or albumin to prevent nonspecific adsorption of the analyte.
  • a blocking agent such as milk protein or albumin
  • Such a sample is, e.g., a serum sample from a subject suspected of having levels of circulating antigen considered to be diagnostic of a pathology.
  • the solid support is treated with a second antibody that is detectably labeled.
  • the labeled second antibody serves as a detecting antibody.
  • the level of detectable label is measured, and the concentration of HER2 antigen in the test sample is determined by comparison with a standard curve developed from the standard samples.
  • samples of blood are taken from subjects diagnosed as being at various stages in the progression of the disease, and/or at various points in the therapeutic treatment of the disease.
  • a range of concentrations of the antigen that may be considered characteristic of each stage is designated.
  • MRSN-043/001WO 322140-2698 (A-1) or a pharmaceutically acceptable salt thereof, wherein: d 15 is about 8.
  • Enumerated Embodiment No. 2. The combination of Enumerated Embodiment No.1, comprising at least one PBRM-STING agonist conjugate and at least one NK cell therapy.
  • Enumerated Embodiment No. 3. The combination of Enumerated Embodiment No. 1, comprising at least one PBRM-STING agonist conjugate and at least one antibody that has ADCC function.
  • Enumerated Embodiment No.4 The combination therapy of any one of Enumerated Embodiment Nos.
  • PBRM-STING agonist conjugate is a HER2-targeted STING agonist antibody-drug conjugate of Formula (A): ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 or a pharmaceutically acceptable salt thereof, wherein the HER-2 ANTIBODY comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence RAS
  • Enumerated Embodiment No.5. The conjugate of Enumerated Embodiment No. 4, wherein the HER-2 ANTIBODY specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1, or residues 452 to 531 of SEQ ID NO: 16.
  • Enumerated Embodiment No. 6 The combination of Enumerated Embodiment No. 4, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy. ⁇ Attorney Docket No.
  • Enumerated Embodiment No. 7 The combination of Enumerated Embodiment No. 4, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function. [00325] Enumerated Embodiment No.8.
  • any one of Enumerated Embodiment Nos.1, 3, 4, and 7, wherein at least one antibody that has ADCC function comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 5
  • Enumerated Embodiment No.9 The combination of any one of Enumerated Embodiment Nos. 1-8, wherein at least one antibody-drug conjugate enhances the efficacy of the one or more NK cell therapy or the one or more antibody that has ADCC function.
  • Enumerated Embodiment No.10 The combination of any one of Enumerated Embodiment Nos. 1-2, 4-6, and 8-9, wherein at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy.
  • Enumerated Embodiment No.11 The combination of any one of Enumerated Embodiment Nos. 1-2, 4-6, and 8-9, wherein at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy.
  • a method for treating, preventing, delaying the progression of, or otherwise ameliorating a symptom of a cancer comprising administering the combination of any one of Enumerated Embodiment Nos.1-10.
  • a cancer e.g., a HER2-positive cancer
  • Enumerated Embodiment No.12 The method of Enumerated Embodiment No.
  • the cancer is anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine ⁇ Attorney Docket No.
  • MRSN-043/001WO 322140-2698 cancer ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer, or gastric esophagogastric junction cancer.
  • NSCLC non-small cell lung cancer
  • pancreatic cancer pancreatic cancer
  • renal cancer gastric cancer
  • gastric esophagogastric junction cancer pancreatic cancer
  • gastric cancer gastric cancer
  • gastric esophagogastric junction cancer pancreatic cancer
  • gastric cancer gastric esophagogastric junction cancer
  • colorectal cancer colorectal cancer
  • non-small cell lung cancer or non-small cell lung cancer.
  • Enumerated Embodiment Nos.11-13 wherein the one or more NK cell therapy and one or more HER2-targeted STING agonist antibody-drug conjugate are administered simultaneously.
  • Enumerated Embodiment No. 15 The method of any one of Enumerated Embodiment Nos. 11-14, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more antibody that has ADCC function are administered simultaneously.
  • Enumerated Embodiment No. 16 The method of any one of Enumerated Embodiment Nos.
  • MRSN-043/001WO 322140-2698 (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 45:55 and 55:45.
  • Enumerated Embodiment No. 31 The combination, method, or kit of Enumerated Embodiment No.27, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is about 50:50.
  • a PBRM-targeted STING agonist antibody-drug conjugate of Formula (A-1) for use in combination with a PBRM-targeted STING agonist antibody-drug conjugate of Formula (A-1).
  • a method of treating, preventing, delaying the progression of, or otherwise ameliorating a symptom of a disease or disorder in a subject in need thereof comprising administering at least one PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein the one or more PBRM-STING agonist conjugate is each independently a conjugate of Formula (A-1): (A-1) or a pharmaceutically acceptable salt thereof, wherein: d 15 is about 8.
  • Enumerated Embodiment No.41 The method of Enumerated Embodiment No. 40, comprising administering at least one PBRM-STING agonist conjugate and at least one NK cell therapy.
  • Enumerated Embodiment No.42 The method of Enumerated Embodiment No. 40, comprising administering at least one PBRM-STING agonist conjugate and at least one antibody that has ADCC function.
  • Enumerated Embodiment No. 43 The method of any one of Enumerated Embodiment Nos.
  • HER-2 ANTIBODY comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light
  • Enumerated Embodiment No.44 The method of Enumerated Embodiment No. 43, wherein the HER-2 ANTIBODY specifically binds to an epitope of the human HER2 receptor ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1, or residues 452 to 531 of SEQ ID NO: 16.
  • Enumerated Embodiment No.45 The method of Enumerated Embodiment No.
  • Enumerated Embodiment No. 43 comprising administering at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy.
  • Enumerated Embodiment No.46 The method of Enumerated Embodiment No. 43, comprising administering at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function.
  • Enumerated Embodiment No. 47 The method of any one of Enumerated Embodiment Nos.
  • variable heavy chain complementarity determining region 1 comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14).
  • CDRH1 comprising the amino acid sequence FTFSSYSMN
  • CDRH2 comprising the amino acid sequence YISSSSSTIYY
  • Enumerated Embodiment No. 48 The method of any one of Enumerated Embodiment Nos. 40-47, wherein at least one antibody-drug conjugate enhances the efficacy of the one or more NK cell therapy or the one or more antibody that has ADCC function.
  • Enumerated Embodiment No. 49 The method of any one of Enumerated Embodiment Nos. 40-41, 43-45, and 47-48, wherein at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy.
  • Enumerated Embodiment No. 50 The method of any one of Enumerated Embodiment Nos. 40-41, 43-45, and 47-48, wherein at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy.
  • Enumerated Embodiment No.51 The method of Enumerated Embodiment No. 50, wherein the cancer is anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye ⁇ Attorney Docket No.
  • MRSN-043/001WO 322140-2698 cancer laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer, or gastric esophagogastric junction cancer.
  • NSCLC non-small cell lung cancer
  • Enumerated Embodiment No. 53 The method of any one of Enumerated Embodiment Nos.40-52, wherein the one or more NK cell therapy and one or more HER2-targeted STING agonist antibody-drug conjugate are administered simultaneously.
  • Enumerated Embodiment No. 54 The method of any one of Enumerated Embodiment Nos. 40-52, wherein one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more antibody that has ADCC function are administered simultaneously.
  • Enumerated Embodiment No. 55 The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are administered sequentially in either order or in alternation.
  • Enumerated Embodiment No. 56 The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate is administered prior to the one or more NK cell therapy or the one or more antibody that has ADCC function.
  • Enumerated Embodiment No. 57 The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate is administered after the one or more NK cell therapy or the one or more antibody that has ADCC function.
  • Enumerated Embodiment No. 58 The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are formulated in the same formulation.
  • Enumerated Embodiment No. 59 The method of any one of Enumerated Embodiment Nos.
  • a combination therapy comprising at least one PBRM-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein the PBRM-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (B): or a pharmaceutically acceptable salt or stereoisomer thereof wherein: PBRM denotes a protein- based recognition-molecule; and d15 is about 8.
  • PBRM denotes a protein- based recognition-molecule
  • d15 is about 8.
  • Enumerated Embodiment No.61 The combination of Enumerated Embodiment No.60, comprising at least one PBRM-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy.
  • Enumerated Embodiment No.62 The combination of Enumerated Embodiment No.60, comprising at least one PBRM-targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function.
  • Enumerated Embodiment No.63 The combination therapy of claim 1, wherein the least one PBRM-targeted STING agonist antibody-drug conjugate is a HER2-targeted STING agonist antibody-drug conjugate of Formula (A): ⁇ Attorney Docket No.
  • the conjugate comprises a HER2 antibody comprising a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14), and
  • Enumerated Embodiment No.64 The conjugate of Enumerated Embodiment No. 63, wherein the HER-2 antibody specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1 or residues 452 to 531 of SEQ ID NO: 16.
  • Enumerated Embodiment No. 65 The combination of Enumerated Embodiment No.63, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy.
  • the cancer is anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer or gastric esophagogastric junction cancer.
  • NSCLC non-small cell lung cancer
  • Enumerated Embodiment No.72 The method of Enumerated Embodiment No. 70, wherein the cancer is breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer or non-small cell lung cancer. ⁇ Attorney Docket No. MRSN-043/001WO 322140-2698 [00388] Enumerated Embodiment No.73 The method of Enumerated Embodiment No. 70, wherein the NK cell therapy and the conjugate are administered simultaneously. [00389] Enumerated Embodiment No.74 The method of Enumerated Embodiment No.
  • Enumerated Embodiment No.75 The method of Enumerated Embodiment No. 70, wherein the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function are administered sequentially in either order or in alternation.
  • Enumerated Embodiment No.76 The method of Enumerated Embodiment No.
  • Enumerated Embodiment No.77 The method of Enumerated Embodiment No. 70, wherein the HER2-targeted STING agonist antibody-drug conjugate is administered after the NK cell therapy or the antibody that has ADCC function.
  • Enumerated Embodiment No. 78 The combination of Enumerated Embodiment No.60, wherein the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function are formulated in the same formulation.
  • Enumerated Embodiment No. 79 The combination of Enumerated Embodiment No.60, wherein the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function are formulated in separate formulations.
  • Enumerated Embodiment No.80 A kit comprising the combination of Enumerated Embodiment No.60 and an instruction for administration.
  • EXAMPLES [00396] The following examples illustrate the disclosure. These examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to the skilled artisan to prepare and use the Compounds, compositions, and methods of the present disclosure.
  • XMT-2056 a HER2-targeted antibody-drug conjugate comprising a HER2 antibody (XMT-1519) is disclosed in US 17/221,341 filed April 2, 2021, the entire contents of which are incorporated herein by reference. XMT-2056 is also referred to herein as calotatug ginistinag.
  • Fc mutant XMT-1519 is a HER-2 Fc mutant antibody, XMT-1519 AAG antibody.
  • Fc mutant XMT-1519 antibody-drug conjugate (ADC) is identical to XMT-2056 except it comprises Fc mutant XMT-1519 instead of XMT-1519 (wt). ⁇ Attorney Docket No.
  • Body weight change (%) ((weight study day X – weight study day 1 ) / weight study day 1 ) *100.
  • Tumor volumes are reported as mean ⁇ standard error of the mean (SEM).
  • Tumor growth inhibition (%TGI) was defined as the percent difference in mean tumor volumes (MTVs) between treated and control groups. Tumor size was measured throughout each efficacy study to determine tumor growth inhibition (TGI).
  • Example 1 Immune-mediated concomitant killing of HER2 negative/ultra-low cancer cells by HER2 STING Agonist Antibody-Drug Conjugates in co-cultures with HER2-expressing cancer cells and PBMCs in vitro
  • Immune-mediated concomitant killing of HER2-negative cancer cells by HER2 STING agonist antibody-drug conjugate (XMT-2056) was evaluated by an IncuCyte cancer cell- killing assay.
  • MDA-MB-231 cells stably expressing nuclear restricted mKate fluorescent ⁇ red protein ⁇ were generated by transduction with ⁇ IncuCyte ⁇ NucLight ⁇ Red Lentivirus reagent (Sartorius, Cat# 4476).
  • Stably transduced cells (designated as MDA-MB-231-NR) were selected in puromycin-containing media (2 ⁇ g/mL) for 2-3 days and expanded in culture medium.
  • HER2- negative / ultra-low MDA-MB-231-NR cells (traced) were seeded together with unlabeled HER2- expressing SKBR3 cells (targeted) at 0:1 (MDA-MB-231-NR cells only), 1:1, or 1:4 ratio for a total of 12,000 cancer cells per well and allowed to attach overnight in an incubator (37 °C, 5% CO2).
  • culture medium was replaced with fresh assay medium (100 ⁇ L/well, RPMI-1640, 10% FBS, 1% penicillin/streptomycin) and XMT-2056, or free STING agonist payload were added with a range of dilutions (0.01 nM to 200 nM based on payload; 4-fold serial dilutions in growth medium) at 4x concentration in 50 ⁇ L/well assay medium.
  • fresh assay medium 100 ⁇ L/well, RPMI-1640, 10% FBS, 1% penicillin/streptomycin
  • XMT-2056 free STING agonist payload
  • MRSN-043/001WO 322140-2698 peripheral blood mononuclear cells were thawed according to the supplier’s instructions (StemCell Technologies) and were added to each well (40,000 PBMCs/well in 50 ⁇ L media) and the plate was placed in an IncuCyte ⁇ live cell imaging instrument in an incubator (37 oC, 5% O2), scanned every 4 hours over 4 days. Red object area (MDA-MB-231-NR cancer cells) over time was quantified using IncuCyte Zoom software. Percent viable cells were calculated relative to the average of the red object area of control (untreated) wells. Dose response curves were generated using GraphPad Prism software.
  • IC 50 values were determined from a four-parameter curve fitting by the Prism.
  • Table 1 provides the IC 50 values of the indicated treatments for percent viable MDA-MB-231-NR cells in co-cultures with SKBR3 cells at 0:1, 1:1, and 1:4 ratio in the presence of PBMCs.
  • XMT-2056 induced killing of MDA-MB-231-NR cells at low levels in the absence of SKBR3 cells with an IC50 of 1.94 nM, which was increased by > 200-fold with addition of SKBR3 cells at a 1:1 or 1:4 ratio.
  • the free agonist payload (JM) induced similar levels of killing in MDA-MB-231-NR cells regardless of the ratio of SKBR3 cells.
  • Control-ADC did not induce significant killing activity.
  • XMT-2056 does not induce any killing in cancer cells in the absence of PBMCs.
  • the experiment was repeated with a different range of doses (0.005 nM to 6.25 nM) of XMT-2056, non-binding control ADC and free payload.
  • XMT-2056 induced killing of the MDA-MB-231-NR cells with an IC50 of >6.25 nM, 0.34nM and 0.25nM in the 0:1, 1:4, and 1:1 (SKBR3 : MDA-MB-231-NR) cocultures, respectively.
  • SKBR3 MDA-MB-231-NR
  • XMT-1519 unconjugated parental antibody
  • MDA- MB-231-NR cells Binding of XMT-1519 (unconjugated parental antibody) to SKBR3 and MDA- MB-231-NR cells was determined by flow cytometry analysis and used as a proxy for HER2 expression levels in these cell lines.
  • Cells were plated in 96 well U-bottom plates, at a density of 50,000 cells/well in DMEM with 6% normal goat serum and incubated on ice for 2-3 hours with increasing concentrations of XMT-1519 (0.024 nM to 400 nM with 4-fold serial dilutions) in DMEM with 6% normal goat serum.
  • the cells were washed with ice cold PBS, pelleted at 1,000 ⁇ RPM, resuspended in DMEM with 2% goat serum, and incubated with a secondary fluorescently labeled antibody, Alexa Fluor® 647-labelled goat anti-human IgG (6 ⁇ g/mL) for 1 hour on ice.
  • the cells were washed once with ice cold PBS, resuspended in ice cold PBS with 1% paraformaldehyde (150 ⁇ L) and run on a MACSQuant Flow Cytometer. Data analysis was performed using FlowJo software using the fcs data files. Geometric mean values for each treatment were plotted, and EC 50 values were calculated with GraphPad Prism software by four- parameter curve fitting.
  • Table 2 provides the EC 50 (cell binding) and Bmax (maximum fluorescence / geometric mean) values for XMT-1519 binding to SKBR3 and MDA-MB-231-NR cells.
  • XMT- 1519 bound to SKBR3 cells strongly with an EC50 value of 4.2 nM, whereas no significant binding to MDA-MB-231-NR cells was observed demonstrating the ultra-low expression of HER2 on these cells compared to the expression on SKBR3 cells.
  • Table 2 Example 2: XMT-2056 elicits significant cancer cell-killing activity in HER2 + cancer cell and Fc ⁇ -RI-depleted PBMC co-cultures ⁇ Attorney Docket No.
  • XMT-2056 exhibited significant cancer cell- killing activity in HER2 + cancer cells co-cultured with PBMCs, which was partially retained when PBMCs were depleted of Fc ⁇ -RI expressing cells in an Fc-effector function dependent manner. This cancer cell-killing activity is completely abrogated by co-depletion of Fc ⁇ -RI + and Fc ⁇ -RIII + immune cells thereby suggesting an ADCC function.
  • Flow cytometry assay confirmed the efficient removal of Fc ⁇ -RI + or Fc ⁇ -RIII + cells from human PBMCs using positive selection magnetic beads.
  • SKBR3-NR cells were generated as described in Example 1.
  • FIG.1 A, B, and C plots the percent viable cancer cells as a function of the payload concentration and shows that XMT-2056 exhibits significant cancer cell-killing activity in HER2 + cancer cells co-cultured with PBMCs, which was partially retained when PBMCs were depleted of Fc ⁇ -RI expressing cells in an Fc-effector function dependent manner.
  • Example 3 XMT-2056 ADCC function synergizes with STING pathway activation [00413] The cancer cell-killing ability of (i) XMT-2056 (ii) XMT-1519, (iii) STING agonist payload, (iv) combination of XMT-1519 and STING agonist payload, and (v) combination of Fc- mutant XMT-1519 and STING agonist payload in SKBR3-NR cancer cells co-cultured with (A) PBMCs, (B) PBMCs depleted of Fc ⁇ -RI expressing cells (CD14 + monocytes), and (C) PBMCs co- depleted of Fc ⁇ -RI + and Fc ⁇ -RIII + immune cells was evaluated using an IncuCyte killing assay as described in Example 1.
  • FIG.2 A, B, and C plots the percent viable cancer cells as a function of the payload concentration and shows that the ADCC function of XMT-2056 synergizes with the STING pathway activation.
  • Example 4 XMT-2056-mediated STING pathway activation in myeloid cells and cancer cells synergizes with trastuzumab-mediated ADCC function in NK cell co-cultures
  • CM conditioned media
  • SKBR3-NR cells (15 K) were co-cultured with NK cells (15 K) in the presence of (A) 20 nM CM or (B) 2 nM CM and treated with (i) trastuzumab without CM (serves as no CM control), (ii) non-binding control mAb with CM, and (iii) trastuzumab with CM.
  • FIG. 3 A and B plots the percent viable cancer cells as a function of the antibody concentration and shows that XMT-2056-mediated STING pathway activation in myeloid cell and cancer cell co-cultures synergizes with trastuzumab-mediated ADCC activity in NK cell co- cultures.
  • Example 5 XMT-2056-mediated STING activation synergizes with ADCC function of trastuzumab and confers combination benefit in cancer cell and NK cell co-cultures in vitro [00417] The synergy between XMT-2056-mediated STING pathway activation and the ADCC function of trastuzumab as a combination treatment was investigated in co-cultures of cancer cells and myeloid cells vs NK cells using the IncuCyte killing assay as described in Example 1.
  • FIG. 4 A, B, and C plots the percent viable cancer cells as a function of the antibody concentration.
  • the data demonstrate that the mechanism of XMT-2056 and trastuzumab combination benefit is dependent on the Fc-effector function of trastuzumab.
  • FIG. 5 provides the results for the tumor volumes of SKOV3 tumor-bearing mice treated with vehicle, XMT-2056, trastuzumab, a combination of XMT-2056and trastuzumab, or a combination of XMT-2056 and Fc-mutant trastuzumab.
  • MRSN-043/001WO 322140-2698 XMT-1519 (0.3 mg/kg) (matched to XMT-2056 mAb dose) and trastuzumab (3 mg/kg) did not result in any significant anti-tumor activity.
  • Example 7 Tumor Growth Response to Administration of HER2 STING Agonist Antibody-Drug Conjugates in Combination with XMT-1519 in SKOV3 Ovarian Cancer [00421]
  • Female CB.17 SCID mice were inoculated subcutaneously with SKOV3 human ovarian cancer cells (10 x 10 6 cells/mouse). SKOV3 cells are an ovarian cancer cell line having high HER2 expression.
  • XMT-2056 (0.30/0.013 mg/kg), XMT-1519 (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and XMT-1519 (3 mg/kg), or a combination of XMT-2056 (0.30/0.013 mg/kg) and Fc-mutant XMT-1519 (3 mg/kg) were dosed qwkx3 on days 1, 8 and 15.
  • IV intravenously
  • IP intraperitoneally
  • the data demonstrate that combination of XMT-2056 with the XMT-1519 is not beneficial in this model, indicating the requirement of the mAb-binding to a non-competing epitope on HER2 for synergy between XMT-2056 and the ADCC effector function of the mAb.

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Abstract

The present disclosure provides combinations comprising PBRM-STING agonist antibody-drug conjugates and NK cell therapies or antibodies that have ADCC function. The present disclosure also provides uses of the combinations in treatment, e.g., treatment of cancer.

Description

Attorney Docket No. MRSN-043/001WO 322140-2698 ANTIBODY DRUG CONJUGATES COMPRISING STING AGONISTS, COMBINATIONS AND METHODS OF USE RELATED APPLICATIONS [0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/489,975 filed March 13, 2023. The contents of this application is hereby incorporated by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (MRSN_043_001WO_SeqList_ST26.xml; Size: 18,756 bytes; and Date of Creation: March 12, 2024) are herein incorporated by reference in its entirety. BACKGROUND [0003] Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen derived- and self-DNA. STING is a 378 amino acid protein, which mainly contains three structural domains: (i) N-terminal transmembrane domain (aa 1–154); (ii) central globular domain (aa 155–341); and (iii) C-terminal tail (aa 342– 379). STING may form symmetrical dimers combined with its ligands in V-shaped conformation, while not completely covering the bound ligands. A STING agonist can bind into the pocket region of STING. However, the STING activation process is easily inhibited in some severe disease conditions, resulting in the inactivation of the STING pathway. Therefore, screening and designing potent STING agonists is of great importance for cancer immune therapy and other infectious diseases treatments, including, but not limited to, obesity, liver injury, sugar-lipid metabolism, and virus infection. Specific targeting of immune pathways presents opportunities for cancer therapy, potentially offering greater specificity than cell population-based therapeutic approaches. [0004] Antibody-drug conjugates (ADCs) are comprised of a drug like small molecule, covalently linked to an antibody. The antibody represents a targeting mechanism tuned to a specific site of action. Upon reaching the site, the ADC is designed to release a small molecule, the drug, allowing it to perform its designed function in a targeted manner, as opposed to diffusing systemically through the entire body of the subject. This targeted approach allows for treatment with drugs that ^ Attorney Docket No. MRSN-043/001WO 322140-2698 would otherwise require doses so high as to be toxic when administered systemically and minimizes potential for on-target, off-tumor toxicity. [0005] A key feature of the innate immune system is the recognition and elimination of foreign substances. Identification of these pathogenic invaders occurs through host recognition of evolutionarily conserved microbial structures known as pathogen- associated molecular patterns (PAMPs). Host recognition may occur by multiple pathways, such as activation of pattern recognition receptors (PRRs), which ultimately lead to downstream signaling events and culminate in the mounting of an immune response. [0006] The antibody-drug conjugates of this disclosure modulate the activity of STING, and accordingly, may provide a beneficial therapeutic impact in treatment of diseases, disorders and/or conditions wherein modulation of STING (Stimulator of Interferon Genes) is beneficial, including, but not limited to, inflammation, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes, and as vaccine adjuvants. In addition, combination therapy in which two or more drugs are used in certain dosing regimen or administration form, can enhance potency by exploiting additive or synergistic effects in the biological activity of the two or more drugs. There remains a need for new immunotherapies for the treatment of diseases, in particular cancer. SUMMARY [0007] In some aspects, the present disclosure provides, inter alia, a combination therapy comprising at least one protein-based recognition molecule (PBRM)-STING agonist conjugate and at least one natural killer (NK) cell therapy, wherein the conjugate comprises an antibody or antigen binding fragment thereof that specifically binds to a target. [0008] In some aspects, the present disclosure provides, a combination therapy comprising at least one PBRM-STING agonist conjugate and at least one antibody that exhibits therapy ADCC function, wherein the conjugate comprises an antibody or antigen binding fragment thereof that specifically binds to a target. [0009] In some aspects, the PBRM-STING agonist conjugate is a conjugate of Formula (A-1): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000004_0001
(A-1) or a pharmaceutically acceptable salt thereof, wherein: d15 is about 8. [0010] In some aspects, the present disclosure provides compositions comprising the combination therapy comprising at least one PBRM-STING agonist conjugate and at least one NK cell therapy. [0011] In some aspects, the PBRM-STING agonist conjugate enhances the efficacy of the NK cell therapy. In some aspects, the PBRM-STING agonist conjugate enhances the efficacy of the one or more antibody that has ADCC function. [0012] In some aspects, the present disclosure provides compositions comprising the combination therapy comprising at least one PBRM-STING agonist conjugate and at least one antibody that exhibits ADCC function. [0013] In some aspects, the PBRM-STING agonist conjugate and at least one antibody that exhibits ADCC function synergize with the STING pathway and enhance the cancer cell-killing activity of FcgRIII-expressing cells. [0014] In some aspects, the present disclosure provides, a combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one natural killer (NK) cell therapy, wherein the conjugate comprises an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor. [0015] In some aspects, the present disclosure provides, a combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that exhibits ^ Attorney Docket No. MRSN-043/001WO 322140-2698 therapy ADCC function, wherein the conjugate comprises an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor. [0016] In some aspects, the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (A):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises a HER2 antibody comprising a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14), and d15 is about 8. [0017] In some aspects, the HER2 antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1 or residues 452 to 531 of SEQ ID NO: 16. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [0018] In some aspects, the present disclosure provides compositions comprising the combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy. [0019] In some aspects, the HER2-targeted STING agonist antibody-drug conjugate enhances the efficacy of the NK cell therapy. [0020] In some aspects, the HER2-targeted STING agonist antibody-drug conjugate enhances the efficacy of one or more antibody that has ADCC function. [0021] In some aspects, at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy. [0022] In some aspects, the present disclosure provides compositions comprising the combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that exhibits ADCC function. [0023] In some aspects, the HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that exhibits ADCC function synergize with the STING pathway and enhance the cancer cell-killing activity of FcgRIII-expressing cells. [0024] In some aspects, the combination comprising a HER2-targeted STING agonist antibody- drug conjugate of the disclosure is administered in combination with at least one NK cell therapy. [0025] In some aspects, the combination of the disclosure is administered in combination with at least one antibody that has ADCC function. The combination of PBRM-STING agonist conjugates or HER2-targeted STING agonist antibody-drug conjugates and NK cell therapy or antibody that has ADCC function are useful in treating pathologies such as, for example, a cancer in a subject. For example, the combinations comprising PBRM-STING agonist conjugates and at least one NK cell therapy or at least one antibody that has ADCC function disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of a cancer (e.g., a HER2-positive cancer) in a subject. [0026] For example, the combinations comprising the PBRM-STING agonist conjugates or the HER2-targeted STING agonist antibody-drug conjugates and at least one NK cell therapy or at least one antibody that has ADCC function disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of a cancer (e.g., a HER2- positive cancer) in a subject. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [0027] In some embodiments, the cancer is, for example, selected from the group consisting of anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer and gastric esophagogastric junction cancer. [0028] In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, a symptom of gastric cancer, a symptom of gastric esophagogastric junction cancer, a symptom of non-small cell lung cancer (NSCLC) or a symptom of colorectal cancer in a subject. [0029] In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer in a subject. [0030] In some aspects, the cancer is a HER2-positive cancer. [0031] In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, in a subject. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of HER2+ breast cancer, in a subject. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of HER2- breast cancer, in a subject. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of metastatic HER2+ breast cancer, in a subject. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of metastatic HER2+ breast cancer, in a subject who has received at least one, at least two, at least three, or at least four prior lines of breast cancer therapy. In some aspects, the combination therapy disclosed herein is useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of metastatic HER2+ breast cancer, in a subject who has received three or more prior lines of breast cancer therapy. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [0032] In some aspects, the combination comprising a PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function used in any of the aspect of the methods and uses provided herein can be administered at any stage of the disease. For example, such a combination therapy can be administered to a patient suffering cancer of any stage, from early to metastatic. [0033] In some aspects, the combination comprising a HER2-targeted STING agonist antibody- drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function used in any of the aspect of the methods and uses provided herein can be administered at any stage of the disease. For example, such a combination therapy can be administered to a patient suffering cancer of any stage, from early to metastatic. [0034] A combination therapy comprising a PBRM- STING agonist conjugate or a HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function used in any of the aspect of these methods and uses can be administered either without another therapeutic agent, or in combination with one or more chemotherapeutic agents or other agents. In some aspects, the additional agent is any of the toxins described herein. In some aspects, the additional agent is (1) an EGFR inhibitor (e.g., tyrosine kinase inhibitors or targeted anti-EGFR antibodies), (2) a BRAF inhibitor, (3) an ALK inhibitor, (4) a hormone receptor inhibitor, (5) a mTOR inhibitor, (6) a VEGF inhibitor, or (7) a cancer vaccine. In some aspects, the additional agent is a standard, first line chemotherapeutic agent, such as, for example, ado-trastuzumab emtansine (Kadcyla), lapatinib, anastrozole, letrozole, exemestane, everolimus, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxymesterone, ethinyl estradiol, paclitaxel, capecitabine, gemcitabine, eribulin, vinorelbine, cyclophosphamide, carboplatin, docetaxel, albumin-bound paclitaxel, cisplatin, epirubicin, ixabepilone, doxorubicin, fluorouracil, oxaliplatin, fluoropyrimidine, irinotecan, ramucirumab, mitomycin, leucovorin, cetuximab, bevacizumab, erlotinib, afatinib, crizotinib, permetrexed, ceritinib, etoposide, vinblastine, vincristine, ifosfamid, liposomal doxorubicin, topotecan, altretamine, melphalan or leuprolide acetate. In some aspects, the additional agent is Kadcyla (ado-trastuzumab emtansine). [0035] In some aspects, the combination comprising the PBRM-STING agonist conjugate or the HER2-targeted STING agonist antibody-drug conjugate and NK cell therapy or antibody that has ADCC function and additional agent(s) is formulated into a single therapeutic composition, and the components are administered simultaneously. Alternatively, the PBRM-STING agonist 7 ^ Attorney Docket No. MRSN-043/001WO 322140-2698 conjugate or the HER2-targeted STING agonist antibody-drug conjugate, NK cell therapy or antibody that has ADCC function and additional agent, if any, are separate from each other, e.g., each is formulated into a separate therapeutic composition, and can be administered simultaneously, or at different times during a treatment regimen. [0036] For example, the PBRM-STING agonist conjugate is administered prior to the administration of the NK cell therapy or antibody that has ADCC function combination; the PBRM-STING agonist conjugate is administered after the administration of the NK cell therapy or antibody that has ADCC function combination. As described herein, the PBRM-STING agonist conjugate and the NK cell therapy or antibody that has ADCC function combination is administered in single doses or in multiple doses. [0037] For example, the HER2-STING agonist conjugate is administered prior to the administration of the NK cell therapy or antibody that has ADCC function combination; the HER2-STING agonist conjugate is administered after the administration of the NK cell therapy or antibody that has ADCC function combination. As described herein, the HER2-STING agonist conjugate and the NK cell therapy or antibody that has ADCC function combination is administered in single doses or in multiple doses. [0038] Pharmaceutical compositions according to the disclosure can include a suitable carrier. These pharmaceutical compositions can be included in kits, such as, for example, diagnostic kits. [0039] Unless otherwise defined, 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 disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. [0040] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 BRIEF DESCRIPTION OF THE FIGURES [0041] FIG. 1 is a series of graphs depicting percent viable SKBR3-NR and immune cell co- cultures in the presence of indicated treatments. SKBR3-NR cells co-cultured with (A) PBMC (B) PBMCs depleted of FcȖ-RI expressing cells (CD14+ monocytes) and (C) PBMCs co-depleted of FcȖ-RI+ and FcȖ-RIII+ immune cells and treated with (i) XMT-2056, (ii) Fc mutant-XMT-1519 ADC and (iii) non-binding control ADC. The plots show the percent viable cancer cells as a function of the payload concentration (T=84 hours). [0042] FIG. 2 is a series of graphs depicting the cancer cell-killing ability of (i) XMT-2056 (ii) XMT-1519 (iii) STING agonist payload (iv) combination of XMT-1519 and STING agonist payload and (v) combination of Fc mutant XMT-1519 and STING agonist payload in SKBR3- NR cell co-cultured with (A) PBMCs (B) PBMCs depleted of FcȖ-RI expressing cells (CD14+ monocytes) and (C) PBMCs co-depletion of FcȖ-RI+ and FcȖ-RIII+ immune cells using an IncuCyte killing assay. The plots show the percent viable cancer cells as a function of the payload concentration (T=84 hours). [0043] FIG.3 is a series of graphs depicting the cancer cell-killing ability of NK cells treated with (i) XMT-1519 without conditioned media (ii) non-binding control antibody and conditioned media and (iii) XMT-1519 and conditioned media in the presence of (A) 20 mM conditioned media or (B) 2 mM conditioned media The plots show the percent viable cancer cells as a function of the antibody concentration (T=84 hours). [0044] FIG. 4 is a series of graphs depicting the synergy between XMT-2056-mediated STING pathway activation and the ADCC function of trastuzumab in SKBR3-NR cell and (A) myeloid cell or (B) NK cell co-cultures
Figure imgf000010_0001
vitro for (i) XMT-2056 (ii) combination of XMT-2056 and trastuzumab (iii) combination of XMT-2056 and Fc mutant trastuzumab (iv) non-binding control ADC or (v) combination of non-binding control ADC and trastuzumab. (C) SKBR3-NR cell and NK cell co-cultures in vitro for (i) XMT-2056 (ii) combination of XMT-2056 and XMT-1519 (iii) combination of XMT-2056 and Fc mutant XMT-1519. The plots show the percent viable cancer cells as a function of the ADC antibody concentration (T=84 hours). [0045] FIG. 5 is a graph showing the anti-tumor efficacy of XMT-2056 (0.30/0.013 mg/kg), trastuzumab (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and trastuzumab (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and Fc-mutant trastuzumab, or a ^ Attorney Docket No. MRSN-043/001WO 322140-2698 combination of XMT-1519 (0.30 mg/kg) and trastuzumab (3 mg/kg) at varying dose levels and dosing regimens. [0046] FIG. 6 is a graph showing the anti-tumor efficacy of XMT-2056 (0.30/0.013 mg/kg), XMT-1519 (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and XMT-1519 (3 mg/kg), or a combination of XMT-2056 (0.30/0.013 mg/kg) and Fc-mutant XMT-1519 at varying dose levels and dosing regimens DETAILED DESCRIPTION [0047] The present disclosure provides targeted STING agonist antibody-drug conjugates, pharmaceutical compositions containing them, and various uses of the conjugates. The targeted STING agonist antibody-drug conjugates described herein have been shown to exhibit ADCC (antibody-dependent cell-mediated cytotoxicity) function, which synergizes with STING pathway activation and induces potent cancer cell-killing activity in co-cultures of tumor associated antigen expressing cancer cells and FcȖ-RIII+ (CD16+) immune cells. [0048] Surprisingly, it was discovered that both the targeted STING agonist ADC as well as the unconjugated parental antibody retain significant cancer cell-killing activity in an Fc-effector function dependent manner in peripheral blood mononuclear cell (PBMC) co-cultures depleted of FcȖ-RI-expressing myeloid cells. This activity is abrogated by co-depletion of FcȖ-RIII+ immune cells, illustrating the ADCC function of the HER2-targeted STING agonist ADC. In this setting, targeted STING agonist ADC cancer cell-killing activity was significantly increased compared to the parental antibody suggesting that the STING payload contributes to the differential activity observed with ADC treatment alone . Indeed, co-treatment of cancer cell and immune cell co- cultures with free parental antibody and free STING agonist payload enhanced the anti-tumor responses, although to a lesser extent than the ADC, suggesting a synergy between the ADCC function and STING pathway activation. [0049] Notably, the targeted STING agonist ADC was capable of engaging both FcȖ-RI+ myeloid cells and FcȖ-RIII+ NK cells, activating both STING-mediated innate immune responses and ADCC function in triple cultures with tumor associated antigen expressing cancer cells. Definitions [0050] The chemical names provided for the intermediate compounds and/or the compounds of this disclosure described herein may refer to any one of the tautomeric representations of such ^ Attorney Docket No. MRSN-043/001WO 322140-2698 compounds (in some instances, such alternate names are provided with the experimental). It is to be understood that any reference to a named compound (an intermediate compound or a compound of the disclosure) or a structurally depicted compound (an intermediate compound or a compound of the disclosure) is intended to encompass all tautomeric forms including zwitterionic forms of such compounds and any mixture thereof. [0051] It is to be understood that the terms “In some aspect”, “In some aspect of the present disclosure”, and “In some aspect of a compound of the present disclosure” may be used interchangeably where appropriate. [0052] The term “about”, “approximately”, or “approximate”, when used in connection with a numerical value, means that a collection or range of values is included. In some aspects, “about X” includes a range of values that are ±25%, ±20%, ±15%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of X, where X is a numerical value. In some aspects, the term “about” refers to a range of values which are 5% more or less than the specified value. In some aspects, the term “about” refers to a range of values which are 2% more or less than the specified value. In some aspects, the term “about” refers to a range of values which are 1% more or less than the specified value. [0053] Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. A range used herein, unless otherwise specified, includes the two limits of the range. In some aspects, the expressions “x being an integer between 1 and 6” and “x being an integer of 1 to 6” both mean “x being 1, 2, 3, 4, 5, or 6”, i.e., the terms “between X and Y” and “range from X to Y, are inclusive of X and Y and the integers there between. [0054] The term “Protein-based recognition-molecule” or “PBRM” refers to a molecule that recognizes and binds to a cell surface marker or receptor such as, a transmembrane protein, surface immobilized protein, or proteoglycan. In some embodiments, the PBRM comprises an engineered cysteine. Examples of PBRMs include but are not limited to, antibodies, peptides, lipocalins, proteins, peptides or peptide mimics, and the like. The protein-based recognition molecule, in addition to targeting the conjugate to a specific cell, tissue or location, may also have certain therapeutic effect such as antiproliferative (cytostatic and/or cytotoxic) activity against a target cell or pathway. The protein-based recognition molecule comprises or may be engineered to comprise at least one chemically reactive group such as, -COOH, primary amine, secondary amine –NHR, ^ Attorney Docket No. MRSN-043/001WO 322140-2698 -SH, or a chemically reactive amino acid moiety or side chains such as, for example, tyrosine, histidine, cysteine, or lysine. In some embodiments, a PBRM may be a ligand (LG) or targeting moiety which specifically binds or complexes with a cell surface molecule, such as a cell surface receptor or antigen, for a given target cell population. Following specific binding or complexing of the ligand with its receptor, the cell is permissive for uptake of the ligand or ligand-drug- conjugate, which is then internalized into the cell. As used herein, a ligand that “specifically binds or complexes with” or “targets” a cell surface molecule preferentially associates with a cell surface molecule via intermolecular forces. In some embodiments, the ligand can preferentially associate with the cell surface molecule with a Kd of less than about 50 nM, less than about 5 nM, or less than 500 pM. Techniques for measuring binding affinity of a ligand to a cell surface molecule are well-known; for example, one suitable technique, is termed surface plasmon resonance (SPR). In some embodiments, the ligand is used for targeting and has no detectable therapeutic effect as separate from the drug which it delivers. [0055] As used herein, the terms “HER2” (also known as ErbB-2, NEU, HER-2, and CD340), when used herein, refers to human epidermal growth factor receptor 2 (SwissProt P04626) and includes any variants, isoforms and species homologs of HER2 which are naturally expressed by cells, including tumor cells, or are expressed on cells transfected with the HER2 gene. Species homologs include rhesus monkey HER2 (macaca mulatta; Genbank accession No. GI:109114897). These terms are synonymous and may be used interchangeably. [0056] As used herein, the term “HER2 antibody” or “anti-HER2 antibody” is an antibody which binds specifically to the antigen HER2. [0057] The term "antibody" as used herein, is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity. The numbering of the antibody amino acids is according to Kabat EU Index (See Kabat, E.A., et al., Sequences of Protein of immunological interest, Fifth Edition, US Department of Health and Human Services, US Government Printing Office (1991)). [0058] The term "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, ^ Attorney Docket No. MRSN-043/001WO 322140-2698 F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments. [0059] The term "antibody that binds to a target" as used herein, refers to any antibody that is optimized to preferentially bind to a specific antigen or a combination of antigens. [0060] The term "antibody that binds to the same epitope" as a reference antibody as used herein, refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more. An exemplary competition assay is provided herein. [0061] When used herein in the context of two or more antibodies, the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to HER2, An antibody “blocks” or “cross-blocks” one or more other antibodies from binding to HER2 if the antibody competes with the one or more other antibodies 25% or more, with 25%-74% representing “partial block” and 75%-400% representing “full block”. Unless otherwise defined or negated by context, the terms “competes with”, “cross-competes with”, “blocks” or “cross- blocks” when used herein is also intended to cover such pairs of antibodies. [0062] The term "epitope" refers to the particular site on an antigen molecule to which an antibody binds. [0063] The term "independently", as used herein, means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. [0064] The term "pharmaceutically acceptable", as used herein, refers to those compounds, conjugates, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0065] The term “pharmaceutical composition” as used herein, refers to a mixture, formulation, or solution comprising at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order or treat a particular disease or condition affecting the subject. The present pharmaceutical combinations can be formulated in suitable pharmaceutical compositions for enteral or parenteral administration, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example ^ Attorney Docket No. MRSN-043/001WO 322140-2698 by means of various conventional mixing, comminution, direct compression, granulating, sugar- coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units. One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden. The amount of each carrier used may vary within ranges conventional in the art. The pharmaceutical compositions provided herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as a solution in l,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. [0066] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound or combination of the present disclosure, or a pharmaceutically acceptable salt, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. [0067] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. [0068] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, ^ Attorney Docket No. MRSN-043/001WO 322140-2698 dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human. [0069] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy. [0070] The term “therapeutically effective amount” refers to an amount of an active compound or pharmaceutical agent, including a conjugate of the disclosure, which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated. [0071] An "effective amount" is intended to mean that amount of a conjugate that, when administered to a patient in need of such treatment, is sufficient to effectively treat or prevent, as defined herein. The amount of a given conjugate that will correspond to such an amount will vary depending upon factors such as the particular conjugate (e.g., the potency (pICso), efficacy (EC50), and the biological half-life of the particular conjugate), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the conjugate will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular conjugate and its properties (e.g., pharmacokinetic ^ Attorney Docket No. MRSN-043/001WO 322140-2698 properties), disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art. [0072] The term “composition” refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts. [0073] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. [0074] The term “STING agonist”, as used herein, refers to a compound or moiety which is capable of interacting with STING, e.g., by binding to STING and/or inducing downstream signal transduction (e.g., characterized by activation of the molecules associated with STING function). This includes direct phosphorylation of STING, IRF3 and/or NF-kB and could also include STAT6. In some aspects, STING pathway activation results in increased production of type 1 interferons (mainly IFN-a and IFN-b) and/or expression of interferon-stimulated genes. [0075] The term “STING agonist drug moiety”, as used herein, refers to a moiety derived from a STING agonist and capable of interacting with STING. In some aspects, the STING agonist drug moiety is a moiety derived from a STING agonist to allow the moiety being linked to the rest of a conjugate of the present disclosure. [0076] The term “NK cell therapy” or “natural killer cell therapy” refers to a type of cellular immunotherapy. In exemplary embodiments, the NK cell therapy comprises an NK cell engager. In exemplary embodiments, the NK cell therapy comprises a population of NK cells. In exemplary embodiments, the NK cell therapy comprises autologous NK cells (e.g., derived from the subject to which they are administered.) In other embodiments, the NK cell therapy comprises allogeneic NK cells (e.g., derived from a subject that is different from the subject to which they are administered). In exemplary embodiments, the NK cell therapy comprises genetically engineered NK cells, such as, for example, a CAR NK. [0077] The term “natural killer (NK) cells” refers to cells of the immune system that kill target cells in the absence of a specific antigenic stimulus, and without restriction according to major histocompatibility complex (MHC) class. Target cells may be tumor cells or cells harboring a ^ Attorney Docket No. MRSN-043/001WO 322140-2698 pathogen, such as, for example, a virus. NK cells are characterized by the presence of CD56 and the absence of CD3 surface markers. [0078] The term “NK cell engager” refers to an NK cell that mediates binding to and activation of an NK cell, or an NK cell that mediates binding to but not activation of an NK cell. [0079] The term “CAR NK” refers to genetically modified NK cells and derivatives thereof that express a chimeric antigen receptor (CAR) on the cell surface. [0080] The term “chimeric antigen receptor” (CAR), refers to an extracellular antigen-binding domain that is fused to an intracellular signaling domain. CARs can be expressed in T cells or NK cells to increase cytotoxicity. In general, the extracellular antigen-binding domain is a scFv that is specific for an antigen found on a cell of interest. [0081] "Combination Therapy" as used herein refers to a treatment in which a subject is given two or more therapeutic agents, such as at least two or at least three therapeutic agents, for treating a disease or disorder. For purposes herein, a combination therapy includes therapy with a HER2- targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function. [0082] As used herein “co-administration”, “co-administering” or “co-administered” refers to the administration of at least two different therapeutic agents sufficiently close in time. Such administration may be done in any order, including simultaneous administration, as well as temporally spaced order from a few seconds up to several days apart. Such administration may also include more than a single administration of one agent and/or independently the other agent. The administration of the agents may be by the same or different routes. [0083] The term “simultaneous administration” as used herein in relation to the administration of medicaments refers to the administration of medicaments such that the individual medicaments are present within a subject at the same time. In addition to the concomitant administration of medicaments (via the same or alternative routes), simultaneous administration may include the administration of the medicaments (via the same or an alternative route) at different times. [0084] As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list. [0085] As used herein a “kit” refers to a combination of components, such as a combination of the compositions herein and another item for a purpose including, but not limited to, ^ Attorney Docket No. MRSN-043/001WO 322140-2698 reconstitution, activation and instruments/devices for delivery, administration, diagnosis and assessment of a biological activity or property. Kits optionally include instructions of use. [0086] As used herein, the term “immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression. [0087] The conjugates of the disclosure are useful in methods for treating or ameliorating a viral infection, disease, a syndrome, a condition or a disorder that is affected by the agonism of STING. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and/or prevention, a therapeutically effective amount of a conjugate of the disclosure, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof. [0088] The terms "conjugate(s) of the disclosure" or "conjugate(s) of the present disclosure", as used herein, mean a conjugate as defined herein, in any form, i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non- solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms. [0089] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” [0090] When present in a structure or Formula, a bond denoted by a “ ” indicates the presence of a mixture of stereoisomers that feature different stereochemistry at the position to which is connected but are otherwise identical. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [0091] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. [0092] Accordingly, included within the present disclosure are the conjugates as disclosed herein, in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present disclosure, it will be understood that the conjugates of the present disclosure, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes. [0093] It is understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [0094] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. Protein-Based Recognition Molecule (PBRM) [0095] In some embodiments, the protein-based recognition molecule directs the conjugates to specific tissues, cells, or locations in a cell. In some embodiments, the protein-based recognition molecule can direct the conjugate in culture or in a whole organism, or both. In each case, the protein-based recognition molecule may have a ligand that is present on the cell surface of the targeted cell(s) to which it binds with an effective specificity, affinity, and avidity. In some embodiments, the protein-based recognition molecule targets the conjugate to tissues other than ^ Attorney Docket No. MRSN-043/001WO 322140-2698 the liver. In some embodiments the protein-based recognition molecule targets the conjugate to a specific tissue such as the liver, kidney, lung, or pancreas. The protein-based recognition molecule can target the conjugate to a target cell such as a cancer cell, such as a receptor expressed on a cell such as a cancer cell, a matrix tissue, or a protein associated with cancer such as tumor antigen. Alternatively, cells comprising the tumor vasculature may be targeted. The protein-based recognition molecules can direct the conjugate to specific types of cells such as specific targeting to hepatocytes in the liver as opposed to Kupffer cells. In some embodiments, protein-based recognition molecules can direct the conjugate to cells of the reticular endothelial or lymphatic system, or to professional phagocytic cells such as macrophages or eosinophils. In some embodiments, the conjugate itself may also be an effective delivery system, without the need for specific targeting. [0096] In some embodiments, the protein-based recognition molecule can target the conjugate to a tumor antigen or a tumor associated antigen. [0097] In some embodiments, the protein-based recognition molecule is an antibody, an antibody fragment, a protein, a peptide, or a peptide mimic. [0098] In some embodiments, the protein-based recognition molecule is an antibody. In some embodiments, the protein-based recognition molecule is an antibody fragment. In some embodiments, the protein-based recognition molecule is a protein. In some embodiments, the protein-based recognition molecule is a peptide. In some embodiments, the protein-based recognition molecule is a peptide mimic. [0099] In some embodiments, the antibody or antibody fragment is an antibody or antibody fragment wherein one or more amino acids of the corresponding parent antibody or antibody fragment (e.g., the corresponding wild type antibody or antibody fragment) are substituted with cysteines (e.g., engineered cysteine). In some embodiments, the parent antibody or antibody fragment may be wild type or mutated. [00100] In some embodiments, the antibody or antibody fragment may be a mutated antibody or antibody fragment. In some embodiments, a monoclonal antibody known in the art is engineered to form the antibody. In some embodiments, an antibody fragment (e.g., a Fab antibody fragment) known in the art is engineered to form the antibody fragment (e.g., a cysteine engineered Fab antibody fragment). In some embodiments, a single site mutation of a Fab gives a single ^ Attorney Docket No. MRSN-043/001WO 322140-2698 residue in a Fab whereas a single site mutation in an antibody yields two amino acids in the resulting antibody due to the dimeric nature of the IgG antibody. [00101] In some embodiments, the antibody or antibody fragment retains the antigen binding capability of its corresponding wild type antibody or antibody fragment. In some embodiments, the antibody or antibody fragment is capable of binding to the one or more antigens for its corresponding wild type antibody or antibody fragment. [00102] In some embodiments, exemplary antibodies or antibodies derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments specific to the cell surface markers, include, but are not limited to, 5T4, AOC3, ALK, AXL, B7-H4, C242, C4.4a, CA-125, CCL11, CCR 5, CD2, CD3, CD4, CD5, CD15, CA15-3, CD18, CD19, CA19-9, CDH6, CD20, CD22, CD23, CD25, CD28, CD30, CD31, CD33, CD37, CD38, CD40, CD41, CD44, CD44 v6, CD51, CD52, CD54, CD56, CD62E, CD62P, CD62L, CD70, CD74, CD79-B, CD80, CD125, CD103, CD138, CD141, CD147, CD152, CD 154, CD326, CEA, CEACAM-5, clumping factor, Clec9A, CSFR1, CTLA- 4, CXCR2, DEC205, EGFR (HER1), ErbB1, ErbB2, ErbB3, EpCAM, EPHA2, EPHB2, EPHB4, FAP, FGFR (i.e. FGFR1, FGFR2, FGFR3, FGFR4), FLT3, fibronectin-EDB, folate receptor, GD2, GD3, GPNMB, GCC (GUCY2C), HGF, HER2, HER3, HMI.24, ICAM, ICOS-L, IGF-1 receptor, VEGFR1, EphA2, TRPV1, CFTR, gpNMB, CA9, Cripto, c-KIT, c-MET, ACE, APP, adrenergic receptor-beta2, Claudine 3, LIV1, LY6E, Mesothelin, MUC1, MUC13, NaPi2b, NOTCH1, NOTCH2, NOTCH3, NOTCH4, RON, ROR1, PD-L1, PD-L2, PTK7, B7-H3, B7-B4, IL-2 receptor, IL-4 receptor, IL-13 receptor, TROP-2, frizzled-7, integrins (including Į4, Įvȕ3, Į vȕ5, Įvȕ6, Į1ȕ4, Į4ȕ1, Į4ȕ7, Į5ȕ1, Į6ȕ4, ĮIIbȕ3 integrins), IFN-Į, IFN-Ȗ, IgE, IgE, IGF-1 receptor, IL-1, IL-12, IL-23, IL-13, IL-22, IL-4, IL-5, IL-6, interferon receptor, ITGB2 (CD18), LFA-1 (CD11a), CD11b, L-selectin (CD62L), mucin, myostatin, NCA-90, NGF, PDGFRĮ, phosphatidylserine, prostatic carcinoma cell, Pseudomonas aeruginosa, rabies, RANKL, respiratory syncytial virus, Rhesus factor, SLAMF7, sphingosine-1-phosphate, TAG-72, T-cell receptor, tenascin C, TGF-1, TGF- ȕ 2, TGF-ȕ, TNF-Į, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGFR2, vimentin, and the like. [00103] In some embodiments the antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments specific to the cell surface markers include CA-125, C242, CD3, CD11b, CD19, CD22, CD25, CD30, CD31, CD33, CD37, CD40, CD44, CD51, CD54, CD56, CD62E, CD62P, CD62L, CD70, CD103, CD138, CD141, CD326, CEA, Clec9A, CSFR1, ^ Attorney Docket No. MRSN-043/001WO 322140-2698 CTLA-4, DEC205, EGFR (HER1), ErbB2, ErbB3, FAP, fibronectin-EDB, folate receptor, IGF-1 receptor, GD3, GPNMB, HGF, HER2, VEGF-A, VEGFR2, VEGFR1, EphA2, EpCAM, 5T4, PTK7, TAG-72, tenascin C, TRPV1, CFTR, gpNMB, CA9, Cripto, ACE, APP, PDGFR Į, phosphatidylserine, prostatic carcinoma cells, adrenergic receptor-beta2, Claudine 3, mucin, MUC1, NaPi2b, B7H3, B7H4, C4.4a, CEACAM-5, MUC13, TROP-2, frizzled-7, Mesothelin, IL- 2 receptor, IL-4 receptor, IL-13 receptor and integrins (including Į v ȕ 3, Į v ȕ 5, Į v ȕ 6, Į 1 ȕ 4, Į 4 ȕ 1, Į 5 ȕ 1, Į 6 ȕ 4 intergins), tenascin C, TRAIL-R2, and vimentin. [00104] In some embodiments, the antibodies are directed to cell surface markers for 5T4, CA-125, CEA, CDH6, CD3, CD11b, CD19, CD20, CD22, CD30, CD33, CD40, CD44, CD51, CD-103, CTLA-4, CEACAM5, Clec9A, CSFR1, DEC205, EpCAM, HER2, EGFR (HER1), FAP, fibronectin-EDB, folate receptor, GCC (GUCY2C), HGF, integrin Įvȕ3, integrin Į5ȕ1, IGF-1 receptor, GD3, GPNMB, mucin, LIV1, LY6E, mesothelin, MUC1, MUC13, NaPi2b, PTK7, phosphatidylserine, prostatic carcinoma cells, PDGFR Į, TAG-72, tenascin C, TRAIL-R2, VEGF- A and VEGFR2. In this embodiment the antibodies, include but are not limited to, abagovomab, adecatumumab, alacizumab, altumomab, anatumomab, arcitumomab, bavituximab, bevacizumab (AVASTIN®), bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, capromab, cetuximab, citatuzumab, clivatuzumab, conatumumab, dacetuzumab, edrecolomab, epratuzumab, ertumaxomab, etaracizumab, farletuzumab, figitumumab, gemtuzumab, glembatumumab, ibritumomab, igovomab, intetumumab, inotuzumab, labetuzumab, lexatumumab, lintuzumab, lucatumumab, matuzumab, mitumomab, naptumomab estafenatox, necitumumab, oportuzumab, oregovomab, panitumumab, pemtumomab, pertuzumab, pritumumab, rituximab (RITUXAN®), rilotumumab, robatumumab, satumomab, sibrotuzumab, taplitumomab, tenatumomab, tenatumomab, ticilimumab (tremelimumab), tigatuzumab, trastuzumab (HERCEPTIN®), tositumomab, tremelimumab, tucotuzumab celmoleukin, volociximab, and zalutumumab. [00105] In some embodiments the antibodies directed to cell surface markers for HER2 are pertuzumab or trastuzumab and for EGFR (HER1) the antibody is cetuximab or panitumumab; and for CD20 the antibody is rituximab and for VEGF-A is bevacizumab and for CD-22 the antibody is epratuzumab or veltuzumab and for CEA the antibody is labetuzumab. [00106] Exemplary peptides or peptide mimics include integrin targeting peptides (RGD peptides), LHRH receptor targeting peptides, ErbB2 (HER2) receptor targeting peptides, prostate ^ Attorney Docket No. MRSN-043/001WO 322140-2698 specific membrane bound antigen (PSMA) targeting peptides, lipoprotein receptor LRP1 targeting, ApoE protein derived peptides, ApoA protein peptides, somatostatin receptor targeting peptides, chlorotoxin derived peptides, and bombesin. [00107] In some embodiments, the peptides or peptide mimics are LHRH receptor targeting peptides and ErbB2 (HER2) receptor targeting peptides. [00108] Exemplary proteins comprise insulin, transferrin, fibrinogen-gamma fragment, thrombospondin, claudin, apolipoprotein E, Affibody molecules such as, for example, ABY-025, Ankyrin repeat proteins, ankyrin-like repeats proteins and synthetic peptides. [00109] In some embodiments, the PBRM-drug conjugates comprise broad spectrum cytotoxins in combination with cell surface markers for HER2, such as, for example, pertuzumab or trastuzumab; for EGFR such as cetuximab and panitumumab; for CEA such as labetuzumab; for CD20 such as rituximab; for VEGF-A such as bevacizumab; or for CD-22 such as epratuzumab or veltuzumab. [00110] In some embodiments, the PBRM-drug conjugates or protein conjugates used in the disclosure comprise combinations of two or more protein-based recognition molecules, such as, for example, combination of bispecific antibodies directed to the EGF receptor (EGFR) on tumor cells and to CD3 and CD28 on T cells; combination of antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments and peptides or peptide mimetics; combination of antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy- chain fragments and proteins; combination of two bispecific antibodies such as CD3-CD19 plus CD28-CD22 bispecific antibodies. [00111] In some embodiments, the PBRM-drug conjugates or protein conjugates used in the disclosure comprise protein-based recognition molecules that are antibodies against antigens, such as, for example, Trastuzumab, Cetuximab, Rituximab, Bevacizumab, Epratuzumab, Veltuzumab, Labetuzumab, or antibodies binding to a target antigen such as, for example, B7-H4, B7-H3, CD11b, CD103, CA125, CDH6, CD33, CXCR2, CEACAM5, Clec9A, CSFR1, DEC205, EGFR, FAP, fibronectin-EDB, FGFR1, FGFR2, FGFR3, FGFR4, GCC (GUCY2C), HER2, LIV1, LY6E, NaPi2b, c-Met, mesothelin, NOTCH1, NOTCH2, NOTCH3, NOTCH4, PD-L1, PTK7, c- Kit, MUC1, MUC13. and 5T4. [00112] In some embodiments, the PBRM-STING agonist conjugates or protein conjugates of the disclosure comprise protein-based recognition molecules which are CSRF1, CD11b, ^ Attorney Docket No. MRSN-043/001WO 322140-2698 DEC205, clec9A, CD103, B7H4, mesothelin, PTK7, Ly6E, FAP, fibronectin-EDB, HER-2 or NaPi2b antibodies. [00113] In some embodiments the PBRM-STING agonist conjugates or protein conjugates of the disclosure comprise a PBRM which binds HER2, such as, for example, a HER2 antibody (e.g., as described herein). HER2 Antibodies [00114] In some aspects, the HER2 antibodies suitable for conjugation bind the human HER2 in soluble form, or membrane bound (i.e., when expressed on a cell surface). In some aspects, the present disclosure provides monoclonal antibodies that bind HER2 and are humanized or fully human. In some aspects, the present disclosure provides monoclonal antibodies that bind HER2 specifically. These antibodies are collectively referred to herein as “HER2” antibodies. [00115] In some aspects, the HER2 antibodies suitable for conjugation bind to a HER2 epitope with an equilibrium dissociation constant (Kd or KD) of ^1 μM (e.g., ^ 100 nM; ^ 10 nM; ^ 1 nM). In some aspects, the present disclosure provides monoclonal antibodies that bind HER2 and are humanized or fully human. for example, the HER2 antibodies provided herein exhibit a Kd in the range approximately between ^ 1 nM to about 1 pM. [00116] In some aspects, the HER2 antibodies disclosed herein serve to modulate, block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with the functional activity of HER2. In some aspects, functional activities of HER2 include for example, modulation of PI3K-Akt pathway activity. In some aspects, the HER2 antibodies completely or partially inhibit HER2 functional activity by partially or completely modulating, blocking, inhibiting, reducing antagonizing, neutralizing, or otherwise interfering with PI3K-Akt pathway activity. PI3K-Akt pathway activity is assessed using any art-recognized method for detecting PI3K-Akt pathway activity, including, but not limited to detecting levels of phosphorylated Akt in the presence and absence of an antibody or antigen binding fragment disclosed herein. [00117] In some aspects, the HER2 antibodies are considered to completely modulate, block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with HER2 functional activity when the level of HER2 functional activity in the presence of the HER2 antibody is decreased by at least 80%, e.g., by 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% as compared to the level of HER2 functional activity ^ Attorney Docket No. MRSN-043/001WO 322140-2698 in the absence of binding with a HER2 antibody described herein. In some aspects, the HER2 antibodies are considered to partially modulate, block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with HER2 functional activity when the level of HER2 activity in the presence of the HER2 antibody is decreased by less than 95%, e.g., 10%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 85%, or 90% as compared to the level of HER2 activity in the absence of binding with a HER2 antibody described herein. [00118] In some aspects, exemplary HER2 antibodies disclosed herein include, the XMT- 1519 antibody. This antibody shows specificity for human HER2 and has been shown to inhibit the functional activity of HER2 in vitro. [00119] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprising the HER2 monoclonal antibody XMT-1519 includes a heavy chain (HC), heavy chain variable region (VH), light chain (LC), and a light chain variable region (VL), as shown in the amino acid and corresponding nucleic acid sequences presented in Table I below. Table I: HER2 human or humanized monoclonal antibody XMT-1519 sequences [
Figure imgf000026_0001
Figure imgf000026_0002
^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00121] Antibodies and antigen binding fragments thereof disclosed herein specifically bind to an epitope on the full-length human HER2 receptor comprising the amino acid sequence of SEQ ID NO: 1. [00122] Antibodies and antigen binding fragments thereof disclosed herein specifically bind to an epitope on the extracellular domain (ECD) of the human HER2 receptor comprising the amino acid sequence of SEQ ID NO: 16. [00123] In some embodiments, the antibodies of the present disclosure exhibit HER2 binding characteristics that differ from antibodies described in the art. In some embodiments, the antibodies disclosed herein bind to a different epitope of HER2, in that they cross-block each other but not trastuzumab, pertuzumab, Fab37, or chA21 from binding to HER2. Further, as opposed to the known antibodies, the antibodies disclosed herein can internalize efficiently into HER2- expressing cells without promoting cell proliferation. [00124] In some embodiments, the antibodies disclosed herein are fully human monoclonal antibodies that bind to novel epitopes and/or have other favorable properties for therapeutic use. In some embodiments, exemplary properties include, but are not limited to, favorable binding characteristics to cancer cells expressing human HER2 at high or low levels, specific binding to recombinant human and cynomolgus monkey HER2, efficient internalization upon binding to HER2, high capacity for killing cancer cells expressing high or low levels of HER2 when administered as an antibody drug conjugate (ADC), no substantial agonistic effect on the proliferation of HER2-expressing cancer cells, and/or provide for effective antibody-dependent cellular cytotoxicity (ADCC)-mediated killing of HER2-expressing cells, as well as any combination of the foregoing properties. [00125] In some embodiments, the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1 or residues 452 to 531 of SEQ ID NO: 16. [00126] In some embodiments, the antibodies disclosed herein include an antibody or an antigen binding fragment thereof that binds at least a portion of the N-terminus of domain IV of human HER2 receptor but does not cross-compete with an antibody that binds to epitope 4D5 of the human HER2 receptor. In some embodiments, the antibodies or antigen binding fragments thereof described herein do not cross-compete with trastuzumab for binding to the human HER2 ^ Attorney Docket No. MRSN-043/001WO 322140-2698 receptor, as trastuzumab is known to bind epitope 4D5 of the human HER2 receptor. As used herein, the term epitope 4D5 of the human HER2 receptor refers to amino acid residues 529 to 627 of the extracellular domain of the human HER2 receptor, residues 551 to 649 of SEQ ID NO: 1 or residues 529 to 627 of SEQ ID NO: 16. In some embodiments, the antibody or antigen binding fragment thereof also binds at least one epitope on cynomolgus monkey HER2 receptor. [00127] In some embodiments, the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 500 of the extracellular domain of the human HER2 receptor, residues 474 to 522 of SEQ ID NO: 1 or residues 452 to 500 of SEQ ID NO: 16. [00128] In some embodiments, the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes at least one of amino acid residue selected from amino acid residues E521, L525 and R530 of the extracellular domain of the human HER2 receptor, e.g., residues 543, 547, and 552 of SEQ ID NO: 1, and residues 521, 525, and 530 of SEQ ID NO: 16. In some embodiments, the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least two amino acid residues selected from amino acid residues E521, L525 and R530 of the extracellular domain of the human HER2 receptor. In some embodiments, the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes at least amino acid residues E521, L525 and R530 of the extracellular domain of the human HER2 receptor. In some embodiments, any or all of these antibodies or antigen binding fragments thereof also bind at least one epitope on cynomolgus monkey HER2 receptor. [00129] In some embodiments, antibodies disclosed herein also include an antibody or an antigen binding fragment thereof that binds to at least a portion of domain III and at least a portion of the N-terminus of domain IV of human HER2 receptor but does not cross-compete with Fab37 monoclonal antibody or an antibody that binds to epitope 4D5 of the human HER2 receptor. In some embodiments, the antibodies or antigen binding fragments thereof described herein do not cross-compete with the Fab37 monoclonal antibody and/or trastuzumab for binding to the human HER2 receptor. In some embodiments, the antibody or antigen binding fragment thereof also binds at least one epitope on cynomolgus monkey HER2 receptor. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00130] In some embodiments, the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes residues 520 to 531 of the extracellular domain of the human HER2 receptor, residues 542 to 553 of SEQ ID NO: 1 or residues 520 to 531 of SEQ ID NO: 16. [00131] In some embodiments, the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes at least one amino acid residue selected from residues C453, H456, H473, N476, R495, G496, H497, and W499 of the extracellular domain of the human HER2 receptor, e.g., residues 475, 478, 495, 498, 517, 518, 519, and 521 of SEQ ID NO: 1 or residues 453, 456, 473, 476, 495, 496, 497 and 499 of SEQ ID NO: 16. In some embodiments, the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least two amino acid residues, at least three amino acid residues, at least four amino acid residues, at least five amino acid residues, or at least six amino acid residues selected from amino acid residues C453, H456, H473, N476, R495, G496, H497, and W499 of the extracellular domain of the human HER2 receptor. In some embodiments, the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least amino acid residues C453, H456, H473, N476, R495, G496, H497, and W499 of the extracellular domain of the human HER2 receptor. In some embodiments, any or all of these antibodies or antigen binding fragments thereof also bind at least one epitope on cynomolgus monkey HER2 receptor. [00132] In some embodiments, the antibodies disclosed herein also include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes at least one amino acid residue selected from residues C453, H473, N476, R495, H497, and W499 of the extracellular domain of the human HER2 receptor, e.g., residues 475, 495, 498, 517, 519, and 521 of SEQ ID NO: 1 or residues 453, 473, 476, 495, 497 and 499 of SEQ ID NO: 16. In some embodiments, the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least two amino acid residues, at least three amino acid residues, at least four amino acid residues, at least five amino acid residues, or at least six amino acid residues selected from amino acid residues C453, H473, N476, R495, H497, and W499 of the ^ Attorney Docket No. MRSN-043/001WO 322140-2698 extracellular domain of the human HER2 receptor. In some embodiments, the antibodies disclosed herein include an antibody or antigen binding fragment thereof that specifically binds to an epitope of the extracellular domain of the human HER2 receptor that includes at least amino acid residues C453, H473, N476, R495, H497, and W499 of the extracellular domain of the human HER2 receptor. In some embodiments, any or all of these antibodies or antigen binding fragments thereof also bind at least one epitope on cynomolgus monkey HER2 receptor. [00133] In some embodiments, these antibodies show specificity for human HER2, and they have been shown to modulate, e.g., block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with the PI3K-Akt pathway which promotes cell survival by reducing levels of phosphorylated AKT. In some embodiments, these antibodies internalize from the cell surface of HER2-expressing cells at a rate that is the same or substantially similar to the rate at which trastuzumab or a biosimilar thereof internalizes. In some embodiments, these antibodies and antigen binding fragments have a rate of internalization that is about 50% of the total surface bound at time 0 being internalized by 4 hours. [00134] In some embodiments the antibodies disclosed herein comprise a heavy chain variable region having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence selected from SEQ ID NO: 2 and a light chain variable region having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence selected from SEQ ID NOs: 9. [00135] In some embodiments, the antibodies disclosed herein comprise a heavy chain amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 4 and a light chain amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 11. [00136] In some embodiments, the antibodies disclosed herein comprise the heavy chain variable region amino acid sequence of SEQ ID NO: 2 and the light chain variable region amino acid sequence of SEQ ID NO: 9. [00137] In some embodiments, the antibodies disclosed herein comprise the heavy chain amino acid sequence of SEQ ID NO: 4 and the light chain amino acid sequence of SEQ ID NO: 11. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00138] In some embodiments, the antibodies disclosed herein comprise the CDRH1 amino acid sequence of SEQ ID NO: 5, the CDRH2 amino acid sequence of SEQ ID NO: 6, the CDRH3 amino acid sequence of SEQ ID NO: 7, the CDRL1 amino acid sequence of SEQ ID NO: 12, the CDRL2 amino acid sequence of SEQ ID NO: 13, and the CDRL3 amino acid sequence of SEQ ID NO: 14. [00139] In some embodiments, the antibodies disclosed herein include one or more conservative amino acid substitutions in a variable domain sequence such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more conservative substitutions in a variable domain sequence. In some embodiments, these conservative amino acid substitutions are in a CDR region, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more conservative substitutions are made cumulatively across all CDRs. In some embodiments, up to 1, 2, 3, or 4 conservative amino acid substitutions may be present in each CDR sequence, e.g., SEQ ID NOs: 5-7 and 12-14. [00140] Those skilled in the art will recognize that it is possible to determine, without undue experimentation, if a monoclonal antibody has the same specificity as a monoclonal antibody XMT-1519, by ascertaining whether the former prevents the latter from binding to a natural binding partner or other molecule known to be associated with HER2. In some embodiments, if the monoclonal antibody being tested competes with the monoclonal antibody disclosed herein, as shown by a decrease in binding by the monoclonal antibody disclosed herein, then the two monoclonal antibodies bind to the same, or a closely related, epitope. [00141] In some embodiments, an alternative method for determining whether a monoclonal antibody has the specificity of monoclonal antibody disclosed herein is to pre-incubate the monoclonal antibody disclosed herein with soluble HER2 (with which it is normally reactive), and then add the monoclonal antibody being tested to determine if the monoclonal antibody being tested is inhibited in its ability to bind HER2. If the monoclonal antibody being tested is inhibited then, in all likelihood, it has the same, or functionally equivalent, epitopic specificity as the monoclonal antibody disclosed herein. [00142] In some embodiments, screening of monoclonal antibodies disclosed herein, can be also carried out, e.g., by measuring HER2-mediated PI3K-Akt pathway activity, and determining whether the test monoclonal antibody is able to modulate, block, inhibit, reduce, antagonize, neutralize or otherwise interfere with PI3K-Akt pathway activity. In some embodiments, the HER2 antibodies suitable for conjugation can be generated and purified by well-known techniques e.g., ^ Attorney Docket No. MRSN-043/001WO 322140-2698 WO 2015/195917 and PCT/US2018/019873, each of which is incorporated herein in its entirety by reference. PBRM-STING Agonist Conjugates [00143] In some embodiments, the PBRM-STING agonist conjugate is a conjugate of Formula (A-1):
Figure imgf000032_0001
(A-1) or a pharmaceutically acceptable salt thereof. [00144] In some embodiments, the PBRM-STING agonist conjugate is a conjugate of Formula (B-1): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000033_0001
(B-1) or a pharmaceutically acceptable salt or stereoisomer thereof. [00145] In some embodiments, the PBRM-STING agonist conjugate is a conjugate of Formula (C-1):
Figure imgf000033_0002
(C-1) or a pharmaceutically acceptable salt or stereoisomer thereof. [00146] In some embodiments, the PBRM-STING agonist conjugate is a conjugate of Formula (D-1): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000034_0001
(D-1) or a pharmaceutically acceptable salt or stereoisomer thereof. [00147] In some embodiments, the PBRM-STING agonist conjugate is a conjugate of Formula (E-1):
Figure imgf000034_0002
(E-1) or a pharmaceutically acceptable salt or stereoisomer thereof. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00148] In some embodiments, the PBRM-STING agonist conjugate is a conjugate of Formula (F-1):
Figure imgf000035_0001
(F-1) or a pharmaceutically acceptable salt or stereoisomer thereof. [00149] In some embodiments, the PBRM-STING agonist conjugate comprises a mixture of an antibody-drug conjugate having Formula (E-1) and an antibody drug conjugate having Formula (F-1). [00150] In embodiments, the PBRM-STING agonist conjugate comprises a stereoisomer of any compound described herein (e.g., a stereoisomer of a compound of Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1), or Formula (F-1)). [00151] In some embodiments the PBRM is a HER2-targeted antibody, for example as described herein. HER2-Targeted STING Agonist Antibody Conjugates [00152] The invention pertains to combination therapies involving immunoconjugates comprising an HER2-targeted antibody conjugated to a STING agonist. [00153] In some embodiments, the present disclosure provides, inter alia, combination therapies comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein the conjugate ^ Attorney Docket No. MRSN-043/001WO 322140-2698 comprises an antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor. [00154] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (A):
Figure imgf000036_0001
or a pharmaceutically acceptable salt thereof. [00155] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (B):
Figure imgf000036_0002
or a pharmaceutically acceptable salt or stereoisomer thereof. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00156] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (C):
Figure imgf000037_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. [00157] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (D):
Figure imgf000037_0002
or a pharmaceutically acceptable salt or stereoisomer thereof. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00158] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (E):
Figure imgf000038_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. [00159] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate
Figure imgf000038_0002
or a pharmaceutically acceptable salt or stereoisomer thereof. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00160] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate comprises a mixture of an antibody-drug conjugate having Formula (E) and an antibody drug conjugate having Formula (F). [00161] In embodiments, the HER2-targeted STING agonist antibody-drug conjugate comprises a stereoisomer of any compound described herein (e.g., a stereoisomer of a compound of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (F)). [00162] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugates of any of Formula (A) to Formula (F) comprises a HER2 antibody comprising a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14), and d15 is about 8. [00163] In some embodiments, the HER2 antibody comprises a light chain variable region sequence comprising SEQ ID NO: 9 and a heavy chain variable region sequence comprising SEQ ID NO: 2. [00164] In some embodiments, the HER2-antibody comprises a light chain sequence comprising SEQ ID NO: 11 and a heavy chain sequence comprising SEQ ID NO: 4. [00165] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate of the methods described herein is XMT-2056 (see, e.g., NCT05514717). In embodiments, the PBRM (e.g., HER2-targeted antibody) STING agonist conjugate is calotatug ginistinag which is also referred to herein as XMT-2056. [00166] In some embodiments, the HER2 antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1 or residues 452 to 531 of SEQ ID NO: 16. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00167] In some embodiments, d15 is 2, 4, 6, or 8. In some embodiments, d15 is 6 or 8. [00168] In some embodiments, d15 is 8. In some embodiments, d15 is 6. NK cell therapies [00169] NK cells are innate immune effectors and are found mainly in the bone marrow, peripheral blood, spleen and liver. NK cells possess cytotoxic features similar to those of CD8+ T cells and play important roles in tumor immunology. CD8+ T-cell-mediated cytotoxicity relies on the combination of the T-cell receptor (TCR) and an antigen presented by major histocompatibility complex-I (MHC-I). NK cells can recognize MHC-I expressed on healthy cells and avoid attacking them. Tumor cells can down-modulate MHC-I to escape CD8+ T-cell- mediated cytotoxicity, while NK cells can be activated through the loss of MHC-I and control the proliferation and metastasis of tumors. Thus, NK cells have more specific anti-tumor effects and are associated with fewer off-target complications. [00170] Any suitable NK cell therapy has been contemplated herein for use in the combinations and methods of the disclosure. In some embodiments, the NK cell therapy is a NK cell engager or a CAR NK cell therapy. [00171] In some embodiments, the NK cell engager is chosen from an antibody molecule that binds to the NK cell and the tumor antigen e.g., an antigen binding domain, or ligand that binds to (e.g., activates): NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16 (e.g., CD16a, CD16b, or both), CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, or CD160. [00172] In some embodiments, the NK cell engager is an antibody molecule that binds to the NK cell and the tumor antigen, e.g., an antigen binding domain. In some embodiments, the NK cell engager is an antibody molecule, e.g., an antigen binding domain, that binds to NKp30 or NKp46. In some embodiments, the NK cell engager is a ligand, optionally, the ligand further comprises an immunoglobulin constant region, e.g., an Fc region. In some embodiments, the NK cell engager is a ligand of NKp44 or NKp46, e.g., a viral HA. In some embodiments, the NK cell engager is a ligand of DAP10, e.g., a coreceptor for NKG2D. In some embodiments, the NK cell engager is a ligand of CD16, e.g., a CD16a/b ligand, e.g., a CD16a/b ligand further comprising an antibody Fc region. Examples of NK cell engagers include ABBV-303 (cMET-targeted ^ Attorney Docket No. MRSN-043/001WO 322140-2698 trispecific NK cell engager therapy; Dragonfly Therapeutics and Abbvie), BMS986315 (anti- NKG2A antibody; e.g., NCT06094296), DF-1001 (Dragonfly Therapeutics), DF-9001 (Dragonfly Therapeutics), HY0102 (Shanghai HyaMab Biotech), IMT-009 (Immunitas Therapeutics), SAR443579 (Sanofi and Innate Pharma), SAR445514 (Sanofi and Innate Pharma), monalizumab (Innate Pharma), nadunolimab (Cantargia), and S095029 (Servier). [00173] In some embodiments, the NK cell therapy comprises a population of NK cells. In embodiments, the population on NK cells comprises CAR NK cells. Functional CAR molecules
Figure imgf000041_0001
[00174] In some embodiments, the NK cell therapy is a CAR NK cell therapy. Examples of NK cell therapies (including CAR NK cell therapies) include AB-101 (an allogeneic NK cell therapy; Artiva Biotherapeutics), ACE-1702 (anti-HER2-conjugated allogeneic NK cell therapy; Acepodia). Anti-BCMA CAR-NK cell therapies being developed by Sichuan Kelun Pharma (e.g., NCT050008536) and Shenzhen Pregene Biopharma (e.g., NCT05652530), AP-44 (autologous NK cell therapy; Alphageneron Phamra), BCM6100 (allogeneic CD-19 CAR NK cell therapy; Immunecyte), CNTY-101 (Century Therapeutics), CTX-131 (CRISPR Therapeutics and Nkarta), CYNK-101 (Celularity), CYTO NK-102 (CytoImmune), DVX-201 (Deverra Therapeutics, e.g., NCT04900454), E-10H (Guangzhou Double Bioproducts), evencaleucel (XNK Therapeutics), FT-522 (Fate Therapeutics), FT-576 (Fate Therapeutics), GAIA-102 (GAIA BioMedicine), GDA-201 (Gamida Cell), HR-012 (Hrain Biotechnology), IDP-023 (Indapta Therapeutics, e.g., NCT06119685), Inaleucel (Glycostem Therapeutics), JD123 (Beijing JD Biotech), KD-496 (Nanjing KAEDI Biotech), Magicell-NK (Medigen Biotechnology), MYJ- 1633-SCS (Immunisbio), MYJ-1633-SCSa (Immunisbio), NK-510 (Base Therapeutics), PB-101 (Precision Biotech Taiwan Corp), PB-103 (Precision Biotech Taiwan Corp), QN-019a (Hangzhou Qihan Biotechnology), and SAR445419 (Sanofi), TAK-007 (Takeda), Taniraleucel (Celularity). ^ Attorney Docket No. MRSN-043/001WO 322140-2698 Antibodies that exhibit Antibody-dependent cellular cytotoxicity (ADCC) function [00175] Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody- dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection. ADCC is independent of the immune complement system that also lyses targets but does not require any other cell. ADCC requires an effector cell which classically are known to be natural killer (NK) cells that typically interact with immunoglobulin G (IgG) antibodies. However, macrophages, neutrophils and eosinophils can also mediate ADCC. [00176] Any suitable antibody directed to a tumor antigen that exhibits therapy ADCC function has been contemplated herein for use in the combinations and methods of the disclosure. In embodiments, antibodies with ADCC function are afucosylated or have other Fc modifications to enhance the binding of the antibody to Fc-gamma receptor III or enhance the ADCC of the antibody. [00177] In some embodiments, the antibody with ADCC function binds to the same biological target as the PBRM or HER-2 ANTIBODY of the antibody-drug conjugate, optionally wherein the antibody with ADCC function binds to a different epitope of the biological target than the PBRM or HER-2 ANTIBODY of the antibody-drug conjugate. [00178] In some embodiments, the antibody with ADCC function does not cross-compete for binding to the biological target with the PBRM or HER-2 ANTIBODY of the antibody-drug conjugate, optionally as measured by a Biacore assay. [00179] In some embodiments, the antibody with ADCC function binds to a different biological target than the PBRM or HER-2 ANTIBODY of the antibody-drug conjugate. [00180] In some embodiments, in the combinations the ADCC function of the antibody (that is directed to a target) synergizes with the STING pathway activation and induces potent cancer cell-killing activity of cancer cells and FcȖRIII+ (CD16+) immune cells. [00181] In some embodiments, in the combinations the ADCC function of the antibody synergizes with the STING pathway activation and induces potent cancer cell-killing activity of HER2-expressing cancer cells and FcȖRIII+ (CD16+) immune cells. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00182] In some embodiments, the ADCC function of an antibody can be evaluated using co-cultures of cancer cells expressing the target antigen and NK cells as FcȖ-RIII-expressing effector cells. Target+ cancer cells can be co-cultured with NK cells at different target : effector cell ratios in the presence of increasing concentrations of the cancer cell-targeted antibody, Fc- mutant targeted antibody, and non-binding control antibody followed by incubation in a 37 °C, %5 CO2 incubator for 3-4 days. Cancer cell viability can be measured using a cell-titer Glo (CTG) assay normalized to the untreated control co-cultures. IncuCyte cancer cell-killing assay can also be performed to measure cancer cell viability using the target+ cancer cells expressing a nuclear- restricted fluorescent protein, which allows for tracing the fluorescence intensity (cancer cells) over time in an IncuCyte instrument. [00183] In some embodiments, to measure the synergy between the ADCC function of the antibody of interest and the HER2-targeted STING agonist antibody-drug conjugate, HER2+ cancer cells are co-cultured with NK effector cells at a ratio that leads to incomplete killing of cancer cells following treatment with single agents (antibody that has ADCC function alone or the HER2-targeted STING agonist antibody-drug conjugate alone), which would allow for the measurement of the enhanced killing of cancer cells with combination treatment. Due to the immune-mediated concomitant cancer cell-killing activity of HER2-targeted STING agonist antibody-drug conjugate downstream of STING pathway activation, the target of antibody with ADCC function does not have to be expressed on the HER2+ cancer cells. In this case, HER2+ cancer cells can be co-cultured with the target+ cancer cells expressing the fluorescent protein (traced cells) in the presence of NK cells and the cancer cell-killing activity of the HER2-targeted STING agonist antibody-drug conjugate and the antibody of interest as single agents or in combination can be measured using the IncuCyte killing assay as described above. Methods of Use [00184] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one PBRM-STING agonist conjugate and at least one NK cell therapy and/or at least one antibody that has an ADCC function. [00185] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one HER2-targeted STING agonist antibody- ^ Attorney Docket No. MRSN-043/001WO 322140-2698 drug conjugate and at least one NK cell therapy and/or at least one antibody that has an ADCC function. [00186] In some embodiments, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. [00187] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject at least one NK cell therapy or at least one antibody that has ADCC function. [00188] In some embodiments, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject at least one NK cell therapy or at least one antibody that has ADCC function. [00189] In some embodiments, the present disclosure provides a method of activating or enhancing an activity of STING in a subject, comprising administering to the subject a combination therapy disclosed herein i.e. at least one antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. [00190] In some embodiments, the present disclosure provides a method of activating or enhancing an activity of STING in a subject, comprising administering to the subject a combination therapy disclosed herein i.e. at least one HER-2targeted STING agonist antibody- drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. [00191] In some embodiments, the present disclosure provides a method of activating or enhancing an activity of STING in a subject, comprising administering to the subject a combination therapy disclosed herein i.e. at least one NK cell therapy or at least one antibody that has ADCC function. [00192] In some embodiments, the present disclosure relates to a method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a combination therapy disclosed herein. [00193] In some embodiments, the present disclosure relates to a method of treating a cancer in a subject in need thereof, comprising administering to the subject a combination therapy disclosed herein. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00194] In some embodiments, the present disclosure provides a combination therapy disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. [00195] In some embodiments, the present disclosure provides a combination therapy disclosed herein for use in treating a disease or disorder in a subject in need thereof. [00196] In some embodiments, the present disclosure provides a combination therapy disclosed herein for treating a STING-mediated disease or disorder in a subject. [00197] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treating or preventing a disease or disorder in a subject in need thereof. [00198] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treating a disease or disorder in a subject in need thereof. [00199] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treating a cancer in a subject in need thereof. [00200] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treating a STING-mediated disease or disorder in a subject in need thereof. [00201] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof. [00202] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [00203] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein in the manufacture of a medicament for treating a STING-mediated disease or disorder in a subject. [00204] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein in the manufacture of a medicament for treating a cancer in a subject in need thereof. [00205] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for the treatment or prevention of a disease or disorder in a subject in need thereof. [00206] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for the treatment of a disease or disorder in a subject in need thereof. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00207] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treating a STING-mediated disease or disorder in a subject. [00208] In some embodiments, the present disclosure provides use of a combination therapy disclosed herein for treatment of a cancer in a subject in need thereof. [00209] In some embodiments, the combination comprises at least one PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. In some embodiments, the combination therapy disclosed herein is administered to the subject. [00210] In some embodiments, the combination comprises at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. In some embodiments, the combination therapy disclosed herein is administered to the subject. [00211] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of at least one PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein said PBRM-STING agonist conjugate releases one or more therapeutic agent(s). [00212] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein said HER2-targeted STING agonist antibody-drug conjugate releases one or more therapeutic agent(s) upon biodegradation. [00213] In some embodiments, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of at least one conjugate of the disclosure; wherein said conjugate releases one or more therapeutic agents. [00214] In some embodiments, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of at least one HER2-targeted STING agonist antibody-drug conjugate of the disclosure; wherein said HER2-targeted STING agonist antibody-drug conjugate releases one or more therapeutic agents upon biodegradation. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00215] In some embodiments, a HER2-targeted STING agonist antibody-drug conjugate induces immune-mediated concomitant killing of HER2-negative cancer cells. [00216] In some embodiments, the disease or disorder is a cancer. [00217] In some embodiments, the cancer is selected from the group consisting of anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer (CRC), throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer and gastric esophagogastric junction cancer. [00218] In some embodiments, the cancer is selected from the group consisting of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00219] In some embodiments, the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00220] In some embodiments, the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is HER2 positive (HER2+) breast cancer. In some embodiments, the breast cancer is HER2 negative (HER2-) breast cancer. In some embodiments, the HER2+ breast cancer is metastatic HER2+ breast cancer. In some embodiments, the HER2- breast cancer is metastatic HER2- breast cancer. [00221] In some embodiments, a subject having breast cancer has received at least one, at least two, at least three, or at least four prior lines of breast cancer therapy. In some aspects, a subject has received three or more prior lines of breast cancer therapy. In some aspects, a subject having HER2+ metastatic breast cancer has received three or more lines of breast cancer therapy. [00222] In some embodiments, the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of gastric cancer. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00223] In some embodiments, the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of gastric esophagogastric junction cancer. [00224] In some embodiments, the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of colorectal cancer. [00225] In some embodiments, the combination therapies disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of non- small cell lung cancer (NSCLC). [00226] In some embodiments, the subject has recurrent or metastatic solid tumors with HER 2+ expression. [00227] In some embodiments, the disease or disorder is a pre-cancerous syndrome. [00228] In some embodiments, the combination therapies comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00229] In some embodiments, the combination therapies comprising at least one PBRM- STING agonist conjugate and at least one NK cell therapy are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00230] In some embodiments, the combination therapies comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one NK cell therapy are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00231] In some embodiments, the combination therapies comprising at least one PBRM- STING agonist conjugate and at least one antibody that has ADCC function. are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00232] In some embodiments, the combination therapies comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function. are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00233] In some embodiments, the combination therapy comprising at least one PBRM- STING agonist conjugate is administered in combination with at least one NK cell therapy or at least one antibody that has ADCC function for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00234] In some embodiments, the combination therapy comprising at least one HER2- targeted STING agonist antibody-drug conjugate is administered in combination with at least one NK cell therapy or at least one antibody that has ADCC function for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00235] In some embodiments, the combination therapy comprising at least one HER2- targeted STING agonist antibody-drug conjugate of the disclosure is administered in combination with, at least one NK cell therapy for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00236] In some embodiments, the combination therapy comprises at least one HER2- targeted STING agonist antibody-drug conjugate of the disclosure in combination with at least one antibody that has ADCC function are useful for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, non-small cell lung cancer (NSCLC) or colorectal cancer. [00237] In some embodiments, the methods include identifying or otherwise refining, e.g., stratifying, a patient population suitable for therapeutic administration of the combination therapies thereof disclosed herein by identifying the HER2 score of a subject by IHC test or FISH (fluorescence in situ hybridization negative) measurements prior to treatment with the combination therapies disclosed herein. The IHC test measures the amount of HER2 receptor protein on the surface of cells in a cancer tissue sample, e.g., a breast cancer tissue sample or a gastric cancer ^ Attorney Docket No. MRSN-043/001WO 322140-2698 sample and assigns the detected level of cell surface HER2 receptor a HER2 score of 0, 1+, 2+ or 3+. If the subject’s HER2 score is in the range of 0 to 1+, the cancer is deemed to be “HER2 negative.” If the score is 2+, the cancer is referred to as “borderline,” and a score of 3+ signifies that the cancer is “HER2 positive.” [00238] In some embodiments, the subject is identified as having a scoring of 2+ or 3+ for HER2 expression as detected by immunohistochemistry (IHC) analysis performed on a test cell population, and the subject is also ER positive. In some embodiments, the subject is identified as having a scoring of 2+ or 3+ for HER2 expression as detected by immunohistochemistry (IHC) analysis performed on a test cell population, and the subject also is ER negative. In some embodiments, the subject is identified as having a scoring of 3+ for HER2 expression or evidence of gene amplification by FISH. In some embodiments, the subject is identified as having a scoring of 2+ for HER2 expression or evidence of gene amplification by FISH. In some embodiments, the subject is identified as having a scoring of 1+ for HER2 expression or evidence of gene amplification by FISH. In some embodiments, the subject is identified as having a high HER2 expression. In some embodiments, the subject is identified as having a low HER2 expression. In some embodiments, the test cell population is derived from fresh, unfrozen tissue from a biopsy sample. In some embodiments, the test cell population is derived from a frozen tissue from a biopsy sample. [00239] In some embodiments, the combination therapy comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer or non-small cell lung cancer (NSCLC) in patients who have HER2 IHC 2+ or HER2 IHC 3+. In some embodiments, the breast cancer patient is also ER positive. In some embodiments, the breast cancer patient is also ER negative. [00240] In some embodiments, the combination therapy comprising at least one HER2- targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer or non-small cell lung cancer (NSCLC) in patients who have HER2 IHC 1+ or HER2 IHC 2+. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00241] In some embodiments, the combination comprising a HER2-targeted STING agonist antibody-drug conjugate and at least NK cell therapy or at least one antibody that has ADCC function. disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer or non-small cell lung cancer (NSCLC) in patients who have HER2 IHC 1+ or HER2 IHC 2+. [00242] In some embodiments, the combination comprising a PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. used in any of the embodiments of the methods and uses provided herein can be administered at any stage of the disease. For example, the combination therapy can be administered to a patient suffering cancer of any stage, from early to metastatic. [00243] In some embodiments, the combination comprising a HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function. used in any of the embodiments of the methods and uses provided herein can be administered at any stage of the disease. For example, the combination therapy can be administered to a patient suffering cancer of any stage, from early to metastatic. A combination therapy comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least NK cell therapy or at least one antibody that has ADCC function. can be used in any of the embodiments of these methods and uses can be administered either without another therapeutic agent, or in further combination with one or more chemotherapeutic agents or other agents. In some embodiments, the additional agent is any of the toxins described herein. In some embodiments, the additional agent is (1) EGFR inhibitors (e.g., tyrosine kinase inhibitors or targeted anti-EGFR antibodies), (2) BRAF inhibitors, (3) ALK inhibitors, (4) hormone receptor inhibitors, (5) mTOR inhibitors, (6) VEGF inhibitors, or (7) cancer vaccines. In some embodiments, the additional agent is a standard, first line chemotherapeutic agent, such as, for example, ado-trastuzumab emtansine (Kadcyla), lapatinib, anastrozole, letrozole, exemestane, everolimus, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxymesterone, ethinyl estradiol, paclitaxel, capecitabine, gemcitabine, eribulin, vinorelbine, cyclophosphamide, carboplatin, docetaxel, albumin-bound paclitaxel, cisplatin, epirubicin, ixabepilone, doxorubicin, fluorouracil, oxaliplatin, fluoropyrimidine, irinotecan, ramucirumab, mitomycin, leucovorin, cetuximab, bevacizumab, erlotinib, afatinib, crizotinib, permetrexed, ceritinib, etoposide, ^ Attorney Docket No. MRSN-043/001WO 322140-2698 vinblastine, vincristine, ifosfamid, liposomal doxorubicin, topotecan, altretamine, melphalan or leuprolide acetate. In some embodiments, the additional agent is Kadcyla (ado-trastuzumab emtansine) Combination Therapies and Formulations [00244] The combination therapies of the present disclosure may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the components of the combination of the present disclosure and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. [00245] The compositions of the disclosure may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered daily, weekly, biweekly, monthly, bimonthly, every 6 months or annually. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for the compositions of the disclosure depend on the pharmacokinetic properties of that composition, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a composition of the disclosure depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. [00246] It will be appreciated that administration of the conjugates of the disclosure and an NK cell therapy or antibody that has ADCC function in the combinations of the disclosure will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington’s Pharmaceutical Sciences (15th ed., Mack Publishing Company, Easton, PA (1975)), particularly Chapter 87 by Blaug, Seymour, therein. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00247] For example, the combination therapy can include one or more conjugates disclosed herein co-formulated with, and/or co-administered with, one or more NK cell therapies or one or more antibody that has ADCC function disclosed herein. [00248] In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a conjugate disclosed herein) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. [00249] The pharmaceutical compositions are formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. [00250] In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a conjugate disclosed herein) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. [00251] For example, the combination therapy can include one or more conjugates disclosed herein co-formulated with, and/or co-administered with, one or more NK cell therapies or one or more antibody that has ADCC function disclosed herein. [00252] In some embodiments, the combinations comprising PBRM-STING agonist conjugates and NK cell therapies or antibodies that have ADCC function and additional agent(s) are formulated into a single therapeutic composition, and the components are administered simultaneously. Alternatively, the PBRM-STING agonist conjugate, NK cell therapy, antibody that has ADCC function and additional agent, if any, are separate from each other, e.g., each is formulated into a separate therapeutic composition, and can be administered simultaneously, or at different times during a treatment regimen. For example, the PBRM-STING agonist is ^ Attorney Docket No. MRSN-043/001WO 322140-2698 administered prior to the administration of the NK cell therapy or the antibody that has ADCC function; the PBRM-STING agonist is administered after the administration of the NK cell therapy or the antibody that has ADCC function. As described herein, the PBRM-STING agonist and the NK cell therapy or the antibody that has ADCC function combination are administered in single doses or in multiple doses. [00253] In some embodiments, the combinations comprising HER2-targeted STING agonist antibody-drug conjugates and NK cell therapies or antibodies that have ADCC function and additional agent(s) are formulated into a single therapeutic composition, and the components are administered simultaneously. Alternatively, the HER2-targeted STING agonist antibody-drug conjugate, NK cell therapy, antibody that has ADCC function and additional agent, if any, are separate from each other, e.g., each is formulated into a separate therapeutic composition, and can be administered simultaneously, or at different times during a treatment regimen. For example, the HER2-targeted STING agonist antibody-drug conjugate is administered prior to the administration of the NK cell therapy or the antibody that has ADCC function; the HER2-targeted STING agonist antibody-drug conjugate is administered after the administration of the NK cell therapy or the antibody that has ADCC function. As described herein, the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function combination are administered in single doses or in multiple doses. [00254] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof. Throughout this disclosure, unless expressly noted otherwise, ratios of the antibody-drug conjugate of Formula (E- 1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F- 1) or a pharmaceutically acceptable salt thereof; and ratios of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof are molar ratios (e.g., as determined by chiral column chromatography, e.g., as described herein). [00255] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and ^ Attorney Docket No. MRSN-043/001WO 322140-2698 the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between 20:80 and 80:20, between about 25:75 and 75:25, between about 30:70 and 70:30, between about 35:65 and 65:35, between about 40:60 and 60:40, between about 45:55 and 55:45, or about 50:50. In some embodiments, the ratio is a molar ratio. [00256] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between 30:70 and 70:30. In some embodiments, the ratio is a molar ratio. [00257] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between 40:60 and 60:40. In some embodiments, the ratio is a molar ratio. [00258] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between about 40:60 and 60:40, between about 41:59 and 59:41, between about 42:58 and 58:42, between about 43:57 and 57:43, between about 44:56 and 56:44, between about 45:55 and 55:44, between about 46:54 and 54:46, between about 47:53 and 53:47, between about 48:52 and 52:48, between about 49:51 and 51:49, or 50:50. In some embodiments, the ratio is a molar ratio.In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is between 45:55 and 55:45. In some embodiments, the ratio is a molar ratio. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00259] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E-1) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F-1) or a pharmaceutically acceptable salt thereof is about 50:50. In some embodiments, the ratio is a molar ratio. [00260] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof. In some embodiments, the ratio is a molar ratio. [00261] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 20:80 and 80:20, between about 25:75 and 75:25, between about 30:70 and 70:30, between about 35:65 and 65:35, between about 40:60 and 60:40, between about 45:55 and 55:45, or about 50:50. In some embodiments, the ratio is a molar ratio. [00262] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 30:70 and 70:30. In some embodiments, the ratio is a molar ratio. [00263] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 40:60 and 60:40. In some embodiments, the ratio is a molar ratio. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00264] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between about 40:60 and 60:40, between about 41:59 and 59:41, between about 42:58 and 58:42, between about 43:57 and 57:43, between about 44:56 and 56:44, between about 45:55 and 55:44, between about 46:54 and 54:46, between about 47:53 and 53:47, between about 48:52 and 52:48, between about 49:51 and 51:49, or 50:50. In some embodiments, the ratio is a molar ratio. [00265] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 45:55 and 55:45. In some embodiments, the ratio is a molar ratio. [00266] In some embodiments, the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is about 50:50. In some embodiments, the ratio is a molar ratio. [00267] In embodiments, the ratio (e.g., molar ratio) of one or more stereoisomers in a mixture (e.g., the mixtures disclosed herein, e.g., the mixtures comprising the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof) is determined by chiral column chromatography. In embodiments, the chiral chromatography is performed on a precursor to the final antibody-drug conjugate (e.g., on the drug-linker scaffold, or an intermediate thereof, prior to conjugation to the antibody), wherein the additional chemical and/or biological manipulation of the precursor to generate the antibody-drug conjugate will not alter the stereochemistry (or ratio of stereochemistries in the mixture) at the stereocenter(s) of interest. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 Dosage and Administration [00268] The combination therapy provided herein, comprising a PBRM-STING agonist conjugate and a NK cell therapy or an antibody that has ADCC function combination is administered in single doses or in multiple doses is administered in an amount sufficient to exert a therapeutically useful effect. In some embodiments, the active agents are administered in an amount that does not result in undesirable side effects of the patient being treated, or that minimizes or reduces the observed side effects as compared to dosages and amounts required for single treatment with one of the above agents. For example, the combination therapy comprising a PBRM-STING agonist conjugate and a NK cell therapy or an antibody that has ADCC function combination are administered in single doses or in multiple doses. Thus, it is possible that the amount of a NK cell therapy or an antibody that has ADCC function that can be administered in the combination therapy provided herein, compared to the amount of the NK cell therapy or the antibody that has ADCC function administered alone or using a known method is reduced, while achieving substantially the same or improved therapeutic efficacy. By virtue of the decreased dosage that can be administered, side effects associated with the NK cell therapy or the antibody that has ADCC function administration, such as immune-related adverse events, described elsewhere or herein, are reduced, minimized or avoided. [00269] The combination therapy provided herein, comprising a HER2-targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function combination is administered in single doses or in multiple doses is administered in an amount sufficient to exert a therapeutically useful effect. In some embodiments, the active agents are administered in an amount that does not result in undesirable side effects of the patient being treated, or that minimizes or reduces the observed side effects as compared to dosages and amounts required for single treatment with one of the above agents. For example, the combination therapy comprising a HER2-targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function combination are administered in single doses or in multiple doses. Thus, it is possible that the amount of a NK cell therapy or an antibody that has ADCC function that can be administered in the combination therapy provided herein, compared to the amount of the NK cell therapy or the antibody that has ADCC function administered alone or using a known method is reduced, while achieving substantially the same or improved therapeutic efficacy. By virtue of the decreased dosage that can be administered, side effects associated with ^ Attorney Docket No. MRSN-043/001WO 322140-2698 the NK cell therapy or the antibody that has ADCC function administration, such as immune- related adverse events, described elsewhere or herein, are reduced, minimized or avoided. [00270] It is within the level of one of skill in the art to determine the precise amounts of active agents, including PBRM-STING agonist conjugates and NK cell therapy or antibody that has ADCC function to be administered to a subject. The dosages of such agents in a combination therapy can be chosen based on standard dosing regimens for that agent under a given route of administration. [00271] It is within the level of one of skill in the art to determine the precise amounts of active agents, including HER2-targeted STING agonist antibody-drug conjugates and NK cell therapy or antibody that has ADCC function to be administered to a subject. The dosages of such agents in a combination therapy can be chosen based on standard dosing regimens for that agent under a given route of administration. [00272] It is understood that the precise dosage and duration of treatment is a function of the tissue or tumor being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data and/or can be determined from known dosing regimens of the particular agent. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated, the weight of the individual, the route of administration and/or the extent or severity of the disease and other factors that are within the level of a skilled medical practitioner to consider. Generally, dosage regimens are chosen to limit toxicity. It should be noted that the treating physician would know how to and when to terminate, interrupt or adjust therapy to lower dosage due to toxicity, or bone marrow, liver or kidney or other tissue dysfunctions. Conversely, the treating physician would also know how to and when to adjust treatment to higher levels if the clinical response is not adequate (precluding toxic side effects). It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope thereof. [00273] In some embodiments, the PBRM-STING agonist conjugate combination is administered in a therapeutically effective amount to decrease the tumor volume. [00274] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate combination is administered in a therapeutically effective amount to decrease the tumor volume. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00275] The amount of a PBRM-STING agonist conjugate administered for the treatment of a disease or condition, for example a cancer or solid tumor can be determined by standard clinical techniques. In addition, in vitro assays and animal models can be employed to help identify optimal dosage ranges. The precise dosage, which can be determined empirically, can depend on the route of administration, the type of disease to be treated and the seriousness of the disease. [00276] The amount of a HER2-targeted STING agonist antibody-drug conjugate administered for the treatment of a disease or condition, for example a cancer or solid tumor can be determined by standard clinical techniques. In addition, in vitro assays and animal models can be employed to help identify optimal dosage ranges. The precise dosage, which can be determined empirically, can depend on the route of administration, the type of disease to be treated and the seriousness of the disease. [00277] The NK cell therapy or the antibody that has ADCC function can be provided in a therapeutically effective amount for the particular dosage regimen. Therapeutically effective concentrations can be determined empirically by testing the compounds in known in vitro and in vivo systems, such as the assays provided herein. The concentration of a selected NK cell therapy or antibody that has ADCC function in the composition depends on absorption, inactivation and excretion rates of the complex, the physicochemical characteristics of the complex, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. [00278] The amount of a selected NK cell therapy or antibody that has ADCC function to be administered for the treatment of cancers can be determined by standard clinical techniques or other methods as described herein. In addition, in vitro assays and animal models can be employed to help identify optimal dosage ranges. Hence, the precise dosage, which can be determined empirically, can depend on route of administration, the type of cancer to be treated and the progression of the disease. If necessary, a particular dosage and duration and treatment protocol can be empirically determined or extrapolated. Dosage levels can be determined based on a variety of factors, such as body weight of the individual, general health, age, the activity of the specific compound employed, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, and the patient's disposition to the disease and the judgment of the treating physician. [00279] The combinations of the disclosure may also be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic ^ Attorney Docket No. MRSN-043/001WO 322140-2698 administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is, for example, by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin. [00280] In some embodiments, the PBRM-STING agonist conjugates and NK cell therapy or antibody that has ADCC function are administered as an infusion every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks. [00281] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugates and NK cell therapy or antibody that has ADCC function are administered as an infusion every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks. [00282] In some embodiments, the PBRM-STING agonist conjugates and NK cell therapy or antibody that has ADCC function is administered as an infusion every three weeks or every four weeks. [00283] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugates and NK cell therapy or antibody that has ADCC function is administered as an infusion every three weeks or every four weeks. [00284] In some embodiments, the PBRM-STING agonist conjugate and the NK cell therapy or antibody that has ADCC function are administered by infusion simultaneously. In some embodiments, the PBRM-STING agonist conjugate is administered by infusion prior to the administration of the NK cell therapy or antibody that has ADCC function. In some embodiments, the PBRM-STING agonist conjugate is administered by infusion after the administration of the NK cell therapy or antibody that has ADCC function. As described herein, the PBRM-STING agonist conjugate and the NK cell therapy or antibody that has ADCC function combination can be administered in single doses or in multiple doses. [00285] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or antibody that has ADCC function are administered by infusion ^ Attorney Docket No. MRSN-043/001WO 322140-2698 simultaneously. In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is administered by infusion prior to the administration of the NK cell therapy or antibody that has ADCC function. In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is administered by infusion after the administration of the NK cell therapy or antibody that has ADCC function. As described herein, the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or antibody that has ADCC function combination can be administered in single doses or in multiple doses. [00286] The frequency and timing of administration, and the dosage amounts, can be administered periodically over a cycle of administration to maintain a continuous and/or long-term effect of the active agents for a desired length of time. The provided combination can be administered hourly, daily, weekly, monthly, yearly or once. The length of time of the cycle of administration can be empirically determined, and is dependent on the disease to be treated, the severity of the disease, the particular patient, and other considerations within the level of skill of the treating physician. The length of time of treatment with a combination therapy provided herein can be one week, two weeks, one month, several months, one year, several years or more. [00287] In some embodiments, exemplary doses of intravenously administered antibodies that have ADCC function, can be used as a starting point to determine appropriate dosages. Dosage levels can be determined based on a variety of factors, such as body weight of the individual, general health, age, the activity of the specific compound employed, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, and the patient's disposition resulting from the disease and the judgment of the treating physician. [00288] It is understood that the amount to administer will be a function of the type of cancer being treated, the route of administration, and the tolerability of possible side effects. If necessary, dosage can be empirically determined. [00289] For intravenous administration, one or more, or all, of the agents used in the combination therapy can be administered by push or bolus, by infusion, or via a combination thereof. The infusion time can be about 1 minute to three hours, such as about 1 minute to about two hours, about 1 minute to about 60 minutes, about 1 minute to about 90 minutes, or about 1 minute to about 120 minutes. The agents can be administered by concurrent infusion or by subsequent infusion. For example, the administered agents are administered separately and are provided in separate bags for separate infusions. In some embodiments, the PBRM-STING ^ Attorney Docket No. MRSN-043/001WO 322140-2698 conjugate composition and the NK cell therapy or the antibody that has ADCC function composition are formulated and administered separately. [00290] In some embodiments, the PBRM-STING agonist conjugate composition and the NK cell therapy or the antibody that has ADCC function composition are formulated and administered separately. [00291] In some embodiments, the HER2-targeted antibody-drug conjugate composition and the NK cell therapy or the antibody that has ADCC function composition are formulated and administered separately. [00292] The PBRM-STING agonist antibody-drug conjugate can be administered prior to, simultaneously with or near simultaneously with, sequentially with or intermittently with the NK cell therapy or the antibody that has ADCC function. For example, the PBRM-STING agonist conjugate and the NK cell therapy or the antibody that has ADCC function, e.g., an anti-immune checkpoint protein antibody (e.g., an anti-CTLA4 or anti-PD-1 antibody) can be co-administered or separately. [00293] The HER2-targeted STING agonist antibody-drug conjugate can be administered prior to, simultaneously with or near simultaneously with, sequentially with or intermittently with the NK cell therapy or the antibody that has ADCC function. For example, the HER2-targeted antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function, e.g., an anti-immune checkpoint protein antibody (e.g., an anti-CTLA4 or anti-PD-1 antibody) can be co- administered or separately. [00294] In some embodiments, the PBRM-STING agonist conjugate is administered prior to the NK cell therapy or the antibody that has ADCC function. For example, the PBRM-STING agonist conjugate is administered up to about 48 hours prior to administering the NK cell therapy or the antibody that has ADCC function. For example, the PBRM-STING agonist conjugate is administered about 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 40 hours, or up to about 48 hours prior to administration of the NK cell therapy or the antibody that has ADCC function. [00295] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is administered prior to the NK cell therapy or the antibody that has ADCC function. For example, the HER2-targeted STING agonist antibody-drug conjugate is administered up to about 48 hours ^ Attorney Docket No. MRSN-043/001WO 322140-2698 prior to administering the NK cell therapy or the antibody that has ADCC function. For example, the HER2-targeted STING agonist antibody-drug conjugate is administered about 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 40 hours, or up to about 48 hours prior to administration of the NK cell therapy or the antibody that has ADCC function. [00296] In some embodiments, the PBRM-STING agonist conjugate is administered after the NK cell therapy or the antibody that has ADCC function. For example, the PBRM-STING agonist conjugate is administered up to about 48 hours after administering the NK cell therapy or the antibody that has ADCC function. For example, the PBRM-STING agonist conjugate is administered about 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 40 hours, or up to about 48 hours after administration of the NK cell therapy or the antibody that has ADCC function. [00297] In some embodiments, the HER2-targeted STING agonist antibody-drug conjugate is administered after the NK cell therapy or the antibody that has ADCC function. For example, the HER2-targeted STING agonist antibody-drug conjugate is administered up to about 48 hours after administering the NK cell therapy or the antibody that has ADCC function. For example, the HER2-targeted STING agonist antibody-drug conjugate is administered about 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 40 hours, or up to about 48 hours after administration of the NK cell therapy or the antibody that has ADCC function. [00298] The frequency and timing of administration, and the dosage amounts, can be administered periodically over a cycle of administration to maintain a continuous and/or long-term effect of the active agents for a desired length of time and need not be the same for the PBRM- STING agonist conjugate and the NK cell therapy or the antibody that has ADCC function. The frequency and timing of administration, and the dosage amounts, can be administered periodically over a cycle of administration to maintain a continuous and/or long-term effect of the active agents for a desired length of time and need not be the same for the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function. The provided compositions of each active agent or combinations thereof can be administered hourly, daily, weekly, monthly, yearly or once. The length of time of the cycle of administration can be ^ Attorney Docket No. MRSN-043/001WO 322140-2698 empirically determined, and is dependent on the disease to be treated, the severity of the disease, the disposition of the patient, and other considerations within the level of skill of the treating physician. The length of time of treatment with a combination therapy provided herein can be one week, two weeks, one month, several months, one year, several years or more. [00299] For example, the frequency of administration of the PBRM-STING agonist conjugate is once a day, every other day, twice weekly, once weekly, once every 2 weeks, once every 3 weeks or once every 4 weeks. The dosages can be divided into a plurality of cycles of administration during the course of treatment. For example, the PBRM-STING agonist conjugate can be administered at the frequency over a period of about a month, 2 months, 3 months, 4 months, 5 months, 6 months, a year or more. The frequency of administration can be the same throughout the period of the cycle or can differ. For example, an exemplary dosage frequency is two times a week at least for the first week of a cycle of administration. After the first week, the frequency can continue at twice a week, can increase to more than twice a week, or can be reduced to no more than once a week. It is within the level of a skilled person to determine the particular dosage frequency and cycle of administration based on the particular dosage being administered, the disease or condition being treated, the severity of the disease or condition, the age of the subject and other similar factors. [00300] For example, the frequency of administration of the HER2-targeted STING agonist antibody-drug conjugate is once a day, every other day, twice weekly, once weekly, once every 2 weeks, once every 3 weeks or once every 4 weeks. The dosages can be divided into a plurality of cycles of administration during the course of treatment. For example, the HER2-targeted STING agonist antibody-drug conjugate can be administered at the frequency over a period of about a month, 2 months, 3 months, 4 months, 5 months, 6 months, a year or more. The frequency of administration can be the same throughout the period of the cycle or can differ. For example, an exemplary dosage frequency is two times a week at least for the first week of a cycle of administration. After the first week, the frequency can continue at twice a week, can increase to more than twice a week, or can be reduced to no more than once a week. It is within the level of a skilled person to determine the particular dosage frequency and cycle of administration based on the particular dosage being administered, the disease or condition being treated, the severity of the disease or condition, the age of the subject and other similar factors. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00301] The NK cell therapy or the antibody that has ADCC function can be administered at the same frequency or at a different frequency. For example, each administration of the NK cell therapy or the antibody that has ADCC function is preceded by an administration of the PBRM- STING agonist conjugate by not more than 48 hours. For example, each dose of the PBRM-STING agonist conjugate is followed 24 to 48 hr later by a dose of the NK cell therapy or the antibody that has ADCC function. In certain embodiments, the NK cell therapy or the antibody that has ADCC function is administered less frequently than the PBRM-STING agonist conjugate, but each dose of the NK cell therapy or the antibody that has ADCC function is preceded by a dose of the PBRM-targeted antibody-drug conjugate. For example, the NK cell therapy or the antibody that has ADCC function is administered twice weekly, once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, and in a manner that is preceded by administration of a PBRM-STING agonist conjugate. In another example, each dose of the PBRM-STING agonist conjugate is preceded by a dose of the NK cell therapy or the antibody that has ADCC function. In certain embodiments, the NK cell therapy or the antibody that has ADCC function is administered more frequently than the PBRM-STING agonist conjugate. For example, the NK cell therapy or the antibody that has ADCC function is administered twice weekly, once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, and in a manner that some but not all NK cell therapy dosages or antibodies that have ADCC function dosages are followed by administration of a PBRM-STING agonist conjugate. [00302] The NK cell therapy or the antibody that has ADCC function can be administered at the same frequency or at a different frequency. For example, each administration of the NK cell therapy or the antibody that has ADCC function is preceded by an administration of the HER2- targeted STING agonist antibody-drug conjugate by not more than 48 hours. For example, each dose of the HER2-targeted STING agonist antibody-drug conjugate is followed 24 to 48 hr later by a dose of the NK cell therapy or the antibody that has ADCC function. In certain embodiments, the NK cell therapy or the antibody that has ADCC function is administered less frequently than the HER2-targeted STING agonist antibody-drug conjugate, but each dose of the NK cell therapy or the antibody that has ADCC function is preceded by a dose of the HER2-targeted antibody-drug ^ Attorney Docket No. MRSN-043/001WO 322140-2698 conjugate. For example, the NK cell therapy or the antibody that has ADCC function is administered twice weekly, once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, and in a manner that is preceded by administration of a HER2-targeted STING agonist antibody-drug conjugate. In another example, each dose of the HER2-targeted STING agonist antibody-drug conjugate is preceded by a dose of the NK cell therapy or the antibody that has ADCC function. In certain embodiments, the NK cell therapy or the antibody that has ADCC function is administered more frequently than the HER2-targeted STING agonist antibody-drug conjugate. For example, the NK cell therapy or the antibody that has ADCC function is administered twice weekly, once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, and in a manner that some but not all NK cell therapy dosages or antibodies that have ADCC function dosages are followed by administration of a HER2-targeted STING agonist antibody-drug conjugate. [00303] If disease symptoms persist in the absence of discontinued treatment, treatment can be continued for an additional length of time. Over the course of treatment, evidence of disease and/or treatment-related toxicity or side effects can be monitored. [00304] The cycle of administration of the PBRM-STING agonist conjugate and/or NK cell therapy and/or antibody that has ADCC function can be tailored to add periods of discontinued treatment in order to provide a rest period from exposure to the agents. The length of time for the discontinuation of treatment can be for a predetermined time or can be empirically determined depending on how the patient is responding or depending on observed side effects. For example, the treatment can be discontinued for one week, two weeks, one month or several months. Generally, the period of discontinued treatment is built into a cycle of dosing regimen for a patient. [00305] The cycle of administration of the HER2-targeted STING agonist antibody-drug conjugate and/or NK cell therapy and/or antibody that has ADCC function can be tailored to add periods of discontinued treatment in order to provide a rest period from exposure to the agents. The length of time for the discontinuation of treatment can be for a predetermined time or can be empirically determined depending on how the patient is responding or depending on observed side effects. For example, the treatment can be discontinued for one week, two weeks, one month or ^ Attorney Docket No. MRSN-043/001WO 322140-2698 several months. Generally, the period of discontinued treatment is built into a cycle of dosing regimen for a patient. [00306] An exemplary dosing regimen is a treatment cycle or cycle of administration of 21 or 28 days. The agent, such as the PBRM-STING agonist conjugate disclosed herein, can be administered on day 1, followed by administration of a NK cell therapy or an antibody that has ADCC function of the disclosure, such as a NK cell therapy or an antibody that has ADCC function on day 2, followed by 19 or 26 days without dosing. It is understood that the above description is for exemplification purposes only and that variations of the above can be employed. Further, similar cycles of administration can be applied to all administered agents, or each administered agent can be employed in its own dosing regimen in the combination therapy provided herein. [00307] An exemplary dosing regimen is a treatment cycle or cycle of administration of 21 or 28 days. The agent, such as the HER2-targeted STING agonist antibody-drug conjugate disclosed herein, can be administered on day 1, followed by administration of a NK cell therapy or an antibody that has ADCC function of the disclosure, such as a NK cell therapy or an antibody that has ADCC function on day 2, followed by 19 or 26 days without dosing. It is understood that the above description is for exemplification purposes only and that variations of the above can be employed. Further, similar cycles of administration can be applied to all administered agents, or each administered agent can be employed in its own dosing regimen in the combination therapy provided herein. [00308] It is within the level of one of skill in the art to determine the precise cycle of administration and dosing schedule. As noted above, the cycle of administration can be for any desired length of time. Hence, the 21-day or 28-day cycle of administration can be repeated for any length of time. It is within the level of skill of the treating physician to adopt a cycle of administration and dosing regimen that meets the needs of the patient depending on personal considerations specific to the patient and disease to be treated. Diagnostic and Prophylactic Formulations [00309] The conjugates and NK cell therapy or antibody that has ADCC function disclosed herein are used in diagnostic and prophylactic formulations. In one embodiment, a PBRM-STING agonist conjugate and a NK cell therapy or an antibody that has ADCC function disclosed herein are administered to patients that are at risk of developing one or more of the aforementioned ^ Attorney Docket No. MRSN-043/001WO 322140-2698 diseases, such as for example, without limitation, cancer. In one embodiment, a HER2-targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function disclosed herein are administered to patients that are at risk of developing one or more of the aforementioned diseases, such as for example, without limitation, cancer. A patient’s or organ’s predisposition to one or more of the aforementioned indications can be determined using genotypic, serological or biochemical markers. [00310] In some embodiments, a PBRM-STING agonist conjugate and an antibody that has ADCC function disclosed herein are administered to human individuals diagnosed with a clinical indication associated with one or more of the aforementioned diseases, such as for example, without limitation, cancer. Upon diagnosis, a PBRM-STING agonist conjugate and a NK cell therapy or an antibody that has ADCC function disclosed herein are administered to mitigate or reverse the effects of the clinical indication associated with one or more of the aforementioned diseases. [00311] In some embodiments, a HER2-targeted STING agonist antibody-drug conjugate and an antibody that has ADCC function disclosed herein are administered to human individuals diagnosed with a clinical indication associated with one or more of the aforementioned diseases, such as for example, without limitation, cancer. Upon diagnosis, a HER2-targeted STING agonist antibody-drug conjugate and a NK cell therapy or an antibody that has ADCC function disclosed herein are administered to mitigate or reverse the effects of the clinical indication associated with one or more of the aforementioned diseases. [00312] In some embodiments, a method for identifying a breast cancer patient amenable to treatment with the combinations of conjugates and NK cell therapy or antibody that has ADCC function disclosed herein, comprise measuring the status of certain characteristics in a tumor sample obtained from the patient, and identifying the patient for treatment based on the status of certain characteristics in the tumor sample. [00313] Antibodies disclosed herein are also useful in the detection of HER2 in patient samples and accordingly are useful as diagnostics. For example, HER2 antibodies disclosed herein are used in in vitro assays, e.g., ELISA, to detect HER2 levels in a patient sample. [00314] In some embodiments, a HER2 antibody disclosed herein is immobilized on a solid support (e.g., the well(s) of a microtiter plate). The immobilized antibody serves as a capture antibody for any HER2 that may be present in a test sample. Prior to contacting the immobilized ^ Attorney Docket No. MRSN-043/001WO 322140-2698 antibody with a patient sample, the solid support is rinsed and treated with a blocking agent such as milk protein or albumin to prevent nonspecific adsorption of the analyte. [00315] Subsequently the wells are treated with a test sample suspected of containing the antigen, or with a solution containing a standard amount of the antigen. Such a sample is, e.g., a serum sample from a subject suspected of having levels of circulating antigen considered to be diagnostic of a pathology. After rinsing away the test sample or standard, the solid support is treated with a second antibody that is detectably labeled. The labeled second antibody serves as a detecting antibody. The level of detectable label is measured, and the concentration of HER2 antigen in the test sample is determined by comparison with a standard curve developed from the standard samples. [00316] It will be appreciated that based on the results obtained using the HER2 antibody disclosed herein in an in vitro diagnostic assay, it is possible to stage a disease in a subject based on expression levels of the HER2 antigen. For a given disease, samples of blood are taken from subjects diagnosed as being at various stages in the progression of the disease, and/or at various points in the therapeutic treatment of the disease. Using a population of samples that provides statistically significant results for each stage of progression or therapy, a range of concentrations of the antigen that may be considered characteristic of each stage is designated. [00317] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. ^ Enumerated Embodiments [00318] Enumerated Embodiment No.1. A combination therapy comprising at least one PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein the one or more PBRM-STING agonist antibody-drug conjugate is each independently a conjugate of Formula (A-1): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000071_0001
(A-1) or a pharmaceutically acceptable salt thereof, wherein: d15 is about 8. [00319] Enumerated Embodiment No. 2. The combination of Enumerated Embodiment No.1, comprising at least one PBRM-STING agonist conjugate and at least one NK cell therapy. [00320] Enumerated Embodiment No. 3. The combination of Enumerated Embodiment No. 1, comprising at least one PBRM-STING agonist conjugate and at least one antibody that has ADCC function. [00321] Enumerated Embodiment No.4. The combination therapy of any one of Enumerated Embodiment Nos. 1-3, wherein at least one PBRM-STING agonist conjugate is a HER2-targeted STING agonist antibody-drug conjugate of Formula (A): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000072_0001
or a pharmaceutically acceptable salt thereof, wherein the HER-2 ANTIBODY comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14), and d15 is about 8. [00322] Enumerated Embodiment No.5. The conjugate of Enumerated Embodiment No. 4, wherein the HER-2 ANTIBODY specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1, or residues 452 to 531 of SEQ ID NO: 16. [00323] Enumerated Embodiment No. 6. The combination of Enumerated Embodiment No. 4, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00324] Enumerated Embodiment No. 7. The combination of Enumerated Embodiment No. 4, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function. [00325] Enumerated Embodiment No.8. The combination of any one of Enumerated Embodiment Nos.1, 3, 4, and 7, wherein at least one antibody that has ADCC function comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14). [00326] Enumerated Embodiment No.9. The combination of any one of Enumerated Embodiment Nos. 1-8, wherein at least one antibody-drug conjugate enhances the efficacy of the one or more NK cell therapy or the one or more antibody that has ADCC function. [00327] Enumerated Embodiment No.10. The combination of any one of Enumerated Embodiment Nos. 1-2, 4-6, and 8-9, wherein at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy. [00328] Enumerated Embodiment No.11. A method for treating, preventing, delaying the progression of, or otherwise ameliorating a symptom of a cancer (e.g., a HER2-positive cancer) in a subject comprising administering the combination of any one of Enumerated Embodiment Nos.1-10. [00329] Enumerated Embodiment No.12. The method of Enumerated Embodiment No. 11, wherein the cancer is anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine ^ Attorney Docket No. MRSN-043/001WO 322140-2698 cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer, or gastric esophagogastric junction cancer. [00330] Enumerated Embodiment No.13. The method of Enumerated Embodiment No. 12, wherein the cancer is breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer, or non-small cell lung cancer. [00331] Enumerated Embodiment No. 14. The method of any one of Enumerated Embodiment Nos.11-13, wherein the one or more NK cell therapy and one or more HER2-targeted STING agonist antibody-drug conjugate are administered simultaneously. [00332] Enumerated Embodiment No. 15. The method of any one of Enumerated Embodiment Nos. 11-14, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more antibody that has ADCC function are administered simultaneously. [00333] Enumerated Embodiment No. 16. The method of any one of Enumerated Embodiment Nos. 11-14, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are administered sequentially in either order or in alternation. [00334] Enumerated Embodiment No. 17. The method of any one of Enumerated Embodiment Nos.11-14 and 16, wherein the one or more HER2-targeted STING agonist antibody- drug conjugate is administered prior to the one or more NK cell therapy or the one or more antibody that has ADCC function. [00335] Enumerated Embodiment No. 18. The method of any one of Enumerated Embodiment Nos.11-14 and 16, wherein the one or more HER2-targeted STING agonist antibody- drug conjugate is administered after the one or more NK cell therapy or the one or more antibody that has ADCC function. [00336] Enumerated Embodiment No.19. The combination of any one of Enumerated Embodiment Nos. 1-10, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are formulated in the same formulation. [00337] Enumerated Embodiment No.20. The combination of any one of Enumerated Embodiment Nos. 1-10, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are formulated in separate formulations. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00338] Enumerated Embodiment No.21. A kit comprising the combination of any one of Enumerated Embodiment Nos.1-10 and an instruction for administration. [00339] Enumerated Embodiment No.22. The combination, method, or kit of any one of Enumerated Embodiment Nos.1-21, wherein at least one antibody-drug conjugate is a conjugate
Figure imgf000075_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. [00340] Enumerated Embodiment No.23. The combination, method, or kit of any one of Enumerated Embodiment Nos.1-21, wherein at least one antibody-drug conjugate is a conjugate of Formula (C):
Figure imgf000075_0002
^ Attorney Docket No. MRSN-043/001WO 322140-2698 or a pharmaceutically acceptable salt or stereoisomer thereof. [00341] Enumerated Embodiment No.24. The combination, method, or kit of any one of Enumerated Embodiment Nos.1-21, wherein at least one antibody-drug conjugate is a conjugate of Formula (D):
Figure imgf000076_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. [00342] Enumerated Embodiment No.25. The combination, method, or kit of any one of Enumerated Embodiment Nos.1-21, wherein at least one antibody-drug conjugate is a conjugate of Formula (E):
Figure imgf000076_0002
^ Attorney Docket No. MRSN-043/001WO 322140-2698 or a pharmaceutically acceptable salt or stereoisomer thereof. [00343] Enumerated Embodiment No.26. The combination, method, or kit of any one of Enumerated Embodiment Nos.1-21, wherein at least one antibody-drug conjugate is a conjugate of Formula (F):
Figure imgf000077_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. [00344] Enumerated Embodiment No.27. The combination, method, or kit of any one of Enumerated Embodiment Nos. 1-26, wherein the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof. [00345] Enumerated Embodiment No. 28. The combination, method, or kit of Enumerated Embodiment No.27, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 30:70 and 70:30. [00346] Enumerated Embodiment No. 29. The combination, method, or kit of Enumerated Embodiment No.27, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 40:60 and 60:40. [00347] Enumerated Embodiment No. 30. The combination, method, or kit of Enumerated Embodiment No.27, wherein the ratio (e.g., molar ratio) of the conjugate of Formula ^ Attorney Docket No. MRSN-043/001WO 322140-2698 (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 45:55 and 55:45. [00348] Enumerated Embodiment No. 31. The combination, method, or kit of Enumerated Embodiment No.27, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is about 50:50. [00349] Enumerated Embodiment No.32. The combination, method, or kit of any one of the preceding Enumerated Embodiment Nos., wherein the PBRM or the HER-2 ANTIBODY comprises a light chain variable region sequence comprising SEQ ID NO: 9 and a heavy chain variable region sequence comprising SEQ ID NO: 2. [00350] Enumerated Embodiment No.33. The combination, method, or kit of any one of the preceding Enumerated Embodiment Nos., wherein the PBRM or the HER-2 ANTIBODY comprises a light chain sequence comprising SEQ ID NO: 11 and a heavy chain sequence comprising SEQ ID NO: 4. [00351] Enumerated Embodiment No.34. The combination, method, or kit of any one of Enumerated Embodiment Nos. 1, 3-5, and 7-33, wherein the antibody with ADCC function is not trastuzumab. [00352] Enumerated Embodiment No.35. The combination, method, or kit of any one of Enumerated Embodiment Nos. 1, 3-5, and 7-33, wherein the antibody with ADCC function binds to the same biological target as the PBRM or HER-2 ANTIBODY, optionally wherein the antibody with ADCC binds to a different epitope of the biological target than the PBRM or HER- 2 ANTIBODY. [00353] Enumerated Embodiment No. 36. The combination, method, or kit of Enumerated Embodiment No. 35, wherein the antibody with ADCC function does not cross- compete for binding to the biological target with the PBRM or HER-2 ANTIBODY, optionally as measured by a Biacore assay. [00354] Enumerated Embodiment No.37. The combination, method, or kit of any one of Enumerated Embodiment Nos. 1-34 and 36, wherein the antibody with ADCC function binds to a different biological target than the PBRM or HER-2 ANTIBODY. 77 ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00355] Enumerated Embodiment No. 38. A PBRM-targeted STING agonist antibody- drug conjugate of Formula (A-1), for use in combination with an NK cell therapy or an antibody that has ADCC function. [00356] Enumerated Embodiment No. 39. A NK cell therapy or antibody with ADCC function, for use in combination with a PBRM-targeted STING agonist antibody-drug conjugate of Formula (A-1). [00357] Enumerated Embodiment No.40. A method of treating, preventing, delaying the progression of, or otherwise ameliorating a symptom of a disease or disorder in a subject in need thereof comprising administering at least one PBRM-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein the one or more PBRM-STING agonist conjugate is each independently a conjugate of Formula (A-1):
Figure imgf000079_0001
(A-1) or a pharmaceutically acceptable salt thereof, wherein: d15 is about 8. [00358] Enumerated Embodiment No.41. The method of Enumerated Embodiment No. 40, comprising administering at least one PBRM-STING agonist conjugate and at least one NK cell therapy. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00359] Enumerated Embodiment No.42. The method of Enumerated Embodiment No. 40, comprising administering at least one PBRM-STING agonist conjugate and at least one antibody that has ADCC function. [00360] Enumerated Embodiment No. 43. The method of any one of Enumerated Embodiment Nos. 40-42, wherein at least one PBRM-STING agonist conjugate is a HER2- targeted STING agonist antibody-drug conjugate of Formula (A):
Figure imgf000080_0001
or a pharmaceutically acceptable salt thereof, wherein the HER-2 ANTIBODY comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14), and d15 is about 8. [00361] Enumerated Embodiment No.44. The method of Enumerated Embodiment No. 43, wherein the HER-2 ANTIBODY specifically binds to an epitope of the human HER2 receptor ^ Attorney Docket No. MRSN-043/001WO 322140-2698 that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1, or residues 452 to 531 of SEQ ID NO: 16. [00362] Enumerated Embodiment No.45. The method of Enumerated Embodiment No. 43, comprising administering at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy. [00363] Enumerated Embodiment No.46. The method of Enumerated Embodiment No. 43, comprising administering at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function. [00364] Enumerated Embodiment No. 47. The method of any one of Enumerated Embodiment Nos. 40, 42, 43, and 46, wherein at least one antibody that has ADCC function comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14). [00365] Enumerated Embodiment No. 48. The method of any one of Enumerated Embodiment Nos. 40-47, wherein at least one antibody-drug conjugate enhances the efficacy of the one or more NK cell therapy or the one or more antibody that has ADCC function. [00366] Enumerated Embodiment No. 49. The method of any one of Enumerated Embodiment Nos. 40-41, 43-45, and 47-48, wherein at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy. [00367] Enumerated Embodiment No. 50. The method of any one of Enumerated Embodiment Nos.40-49, wherein the disease or disorder is cancer (e.g., a HER2-positive cancer). [00368] Enumerated Embodiment No.51. The method of Enumerated Embodiment No. 50, wherein the cancer is anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye ^ Attorney Docket No. MRSN-043/001WO 322140-2698 cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer, or gastric esophagogastric junction cancer. [00369] Enumerated Embodiment No.52. The method of Enumerated Embodiment No. 51, wherein the cancer is breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer, or non-small cell lung cancer. [00370] Enumerated Embodiment No. 53. The method of any one of Enumerated Embodiment Nos.40-52, wherein the one or more NK cell therapy and one or more HER2-targeted STING agonist antibody-drug conjugate are administered simultaneously. [00371] Enumerated Embodiment No. 54. The method of any one of Enumerated Embodiment Nos. 40-52, wherein one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more antibody that has ADCC function are administered simultaneously. [00372] Enumerated Embodiment No. 55. The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are administered sequentially in either order or in alternation. [00373] Enumerated Embodiment No. 56. The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate is administered prior to the one or more NK cell therapy or the one or more antibody that has ADCC function. [00374] Enumerated Embodiment No. 57. The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate is administered after the one or more NK cell therapy or the one or more antibody that has ADCC function. [00375] Enumerated Embodiment No. 58. The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are formulated in the same formulation. [00376] Enumerated Embodiment No. 59. The method of any one of Enumerated Embodiment Nos. 40-52, wherein the one or more HER2-targeted STING agonist antibody-drug ^ Attorney Docket No. MRSN-043/001WO 322140-2698 conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are formulated in separate formulations. [00377] Enumerated Embodiment No. 60. A combination therapy comprising at least one PBRM-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein the PBRM-targeted STING agonist antibody-drug conjugate is a conjugate of Formula (B):
Figure imgf000083_0001
or a pharmaceutically acceptable salt or stereoisomer thereof wherein: PBRM denotes a protein- based recognition-molecule; and d15 is about 8. Enumerated Embodiment No.61 The combination of Enumerated Embodiment No.60, comprising at least one PBRM-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy. Enumerated Embodiment No.62 The combination of Enumerated Embodiment No.60, comprising at least one PBRM-targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function. [00378] Enumerated Embodiment No.63 The combination therapy of claim 1, wherein the least one PBRM-targeted STING agonist antibody-drug conjugate is a HER2-targeted STING agonist antibody-drug conjugate of Formula (A): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000084_0001
(A)wherein the conjugate comprises a HER2 antibody comprising a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14), and d15 is about 8. [00379] Enumerated Embodiment No.64 The conjugate of Enumerated Embodiment No. 63, wherein the HER-2 antibody specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1 or residues 452 to 531 of SEQ ID NO: 16. [00380] Enumerated Embodiment No. 65 The combination of Enumerated Embodiment No.63, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy. [00381] Enumerated Embodiment No. 66 The combination of Enumerated Embodiment No.63, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00382] Enumerated Embodiment No. 67 The combination of Enumerated Embodiment No.63, where the at least one antibody that has ADCC function comprising a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14), [00383] Enumerated Embodiment No. 68 The combination of Enumerated Embodiment No.60, wherein the PBRM-targeted STING agonist antibody-drug conjugate enhances the efficacy of the NK cell therapy or the antibody that has ADCC function. [00384] Enumerated Embodiment No. 69 The combination of Enumerated Embodiment No.60, wherein the NK cell therapy is a NK cell engager or a CAR NK cell therapy. [00385] Enumerated Embodiment No. 70 A method for treating, preventing, delaying the progression of or otherwise ameliorating a symptom of a cancer (e.g., a HER2-positive cancer) in a subject comprising administering the combination of Enumerated Embodiment No.60. [00386] Enumerated Embodiment No.71 The method of Enumerated Embodiment No. 70, wherein the cancer is anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer or gastric esophagogastric junction cancer. [00387] Enumerated Embodiment No.72 The method of Enumerated Embodiment No. 70, wherein the cancer is breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer or non-small cell lung cancer. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00388] Enumerated Embodiment No.73 The method of Enumerated Embodiment No. 70, wherein the NK cell therapy and the conjugate are administered simultaneously. [00389] Enumerated Embodiment No.74 The method of Enumerated Embodiment No. 70, wherein the HER2-targeted STING agonist antibody-drug conjugate and the antibody that has ADCC function are administered simultaneously. [00390] Enumerated Embodiment No.75 The method of Enumerated Embodiment No. 70, wherein the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function are administered sequentially in either order or in alternation. [00391] Enumerated Embodiment No.76 The method of Enumerated Embodiment No. 70, wherein the HER2-targeted STING agonist antibody-drug conjugate is administered prior to the NK cell therapy or the antibody that has ADCC function [00392] Enumerated Embodiment No.77 The method of Enumerated Embodiment No. 70, wherein the HER2-targeted STING agonist antibody-drug conjugate is administered after the NK cell therapy or the antibody that has ADCC function. [00393] Enumerated Embodiment No. 78 The combination of Enumerated Embodiment No.60, wherein the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function are formulated in the same formulation. [00394] Enumerated Embodiment No. 79 The combination of Enumerated Embodiment No.60, wherein the HER2-targeted STING agonist antibody-drug conjugate and the NK cell therapy or the antibody that has ADCC function are formulated in separate formulations. [00395] Enumerated Embodiment No.80 A kit comprising the combination of Enumerated Embodiment No.60 and an instruction for administration. EXAMPLES [00396] The following examples illustrate the disclosure. These examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to the skilled artisan to prepare and use the Compounds, compositions, and methods of the present disclosure. While particular embodiments of the present disclosure are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the disclosure. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00397] It will be understood that certain Compounds of the disclosure may be potent immunomodulators and accordingly, care should be exercised in their handling. [00398] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Abbreviations [00399] The following abbreviations are used in the reaction schemes and synthetic examples, which follow. This list is not meant to be an all-inclusive list of abbreviations used in the application as additional standard abbreviations, which are readily understood by those skilled in the art of organic synthesis, can also be used in the synthetic schemes and examples. MTV Mean tumor volume PR Partial response SEM Standard error of the mean TGD Tumor growth delay TGI Tumor growth inhibition TFS Tumor-free survivor General Information [00400] All ADCs were prepared as described in US 17/221,341 (US Publication US20220378749A1), filed April 2, 2021. [00401] XMT-1519 (anti-Her2 antibody) is disclosed in US 9,555,112, issued January 31, 2017, and US 9,738,720, issued August 22, 2017, the entire contents of which are incorporated herein by reference. [00402] XMT-2056, a HER2-targeted antibody-drug conjugate comprising a HER2 antibody (XMT-1519) is disclosed in US 17/221,341 filed April 2, 2021, the entire contents of which are incorporated herein by reference. XMT-2056 is also referred to herein as calotatug ginistinag. [00403] Fc mutant XMT-1519 is a HER-2 Fc mutant antibody, XMT-1519 AAG antibody. [00404] Fc mutant XMT-1519 antibody-drug conjugate (ADC) is identical to XMT-2056 except it comprises Fc mutant XMT-1519 instead of XMT-1519 (wt). ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00405] The STING agonist payload, the payload in XMT-2056, is disclosed in US 11,155,567 issued October 26, 2021, the entire contents of which are incorporated herein by reference. [00406] Tumors were measured twice weekly using digital calipers and tumor volumes were calculated using the formula: tumor volume (mm3) = (width2 x length)/2. Body weights were recorded daily for the first week and twice weekly thereafter. Animals remained on study until individual tumor volume reached ^ 1000mm3 , ^ 1500mm3 or as indicated. Percent change in body weight was calculated using the formula: body weight change (%) = ((weight study day X – weight study day 1) / weight study day 1) *100. Tumor volumes are reported as mean ± standard error of the mean (SEM). Tumor growth inhibition (%TGI) was defined as the percent difference in mean tumor volumes (MTVs) between treated and control groups. Tumor size was measured throughout each efficacy study to determine tumor growth inhibition (TGI). Percent tumor regression was calculated using the formula: % regression = (1-(mean tumor volume final)/ (mean tumor volume day 1)) *100. Example 1: Immune-mediated concomitant killing of HER2 negative/ultra-low cancer cells by HER2 STING Agonist Antibody-Drug Conjugates in co-cultures with HER2-expressing cancer cells and PBMCs in vitro [00407] Immune-mediated concomitant killing of HER2-negative cancer cells by HER2 STING agonist antibody-drug conjugate (XMT-2056) was evaluated by an IncuCyte cancer cell- killing assay. MDA-MB-231 cells stably expressing nuclear restricted mKate fluorescentௗred proteinௗwere generated by transduction withௗIncuCyte©ௗNucLightௗRed Lentivirus reagent (Sartorius, Cat# 4476). Stably transduced cells (designated as MDA-MB-231-NR) were selected in puromycin-containing media (2 μg/mL) for 2-3 days and expanded in culture medium. HER2- negative / ultra-low MDA-MB-231-NR cells (traced) were seeded together with unlabeled HER2- expressing SKBR3 cells (targeted) at 0:1 (MDA-MB-231-NR cells only), 1:1, or 1:4 ratio for a total of 12,000 cancer cells per well and allowed to attach overnight in an incubator (37 °C, 5% CO2). The following day culture medium was replaced with fresh assay medium (100 ^L/well, RPMI-1640, 10% FBS, 1% penicillin/streptomycin) and XMT-2056, or free STING agonist payload were added with a range of dilutions (0.01 nM to 200 nM based on payload; 4-fold serial dilutions in growth medium) at 4x concentration in 50 ^L/well assay medium. Frozen human ^ Attorney Docket No. MRSN-043/001WO 322140-2698 peripheral blood mononuclear cells (PBMCs) were thawed according to the supplier’s instructions (StemCell Technologies) and were added to each well (40,000 PBMCs/well in 50 μL media) and the plate was placed in an IncuCyte© live cell imaging instrument in an incubator (37 ºC, 5% O2), scanned every 4 hours over 4 days. Red object area (MDA-MB-231-NR cancer cells) over time was quantified using IncuCyte Zoom software. Percent viable cells were calculated relative to the average of the red object area of control (untreated) wells. Dose response curves were generated using GraphPad Prism software. IC50 values were determined from a four-parameter curve fitting by the Prism. [00408] Table 1 provides the IC50 values of the indicated treatments for percent viable MDA-MB-231-NR cells in co-cultures with SKBR3 cells at 0:1, 1:1, and 1:4 ratio in the presence of PBMCs. XMT-2056 induced killing of MDA-MB-231-NR cells at low levels in the absence of SKBR3 cells with an IC50 of 1.94 nM, which was increased by > 200-fold with addition of SKBR3 cells at a 1:1 or 1:4 ratio. On the other hand, the free agonist payload (JM) induced similar levels of killing in MDA-MB-231-NR cells regardless of the ratio of SKBR3 cells. Control-ADC did not induce significant killing activity. XMT-2056 does not induce any killing in cancer cells in the absence of PBMCs. The experiment was repeated with a different range of doses (0.005 nM to 6.25 nM) of XMT-2056, non-binding control ADC and free payload. XMT-2056 induced killing of the MDA-MB-231-NR cells with an IC50 of >6.25 nM, 0.34nM and 0.25nM in the 0:1, 1:4, and 1:1 (SKBR3 : MDA-MB-231-NR) cocultures, respectively. Neither treatment with free STING agonist payload nor with non-binding control ADC resulted in any cancer cell killing activity at any concentration tested. Taken together, these results demonstrate the ability of XMT-2056 to induce immune-mediated killing of HER2 negative/low expressing tumor cells, an effect which is greatly increased (e.g., up to 200-fold) when strongly HER2-expressing cells are also present, even when the highly expressing cells represent only 20% of the tumor cell population. These data demonstrate the immune-mediated concomitant killing of HER2-negative / ultra-low cancer cells by XMT-2056 in the presence of HER2-expressing cancer cells in a target-dependent manner. Table 1
Figure imgf000089_0001
^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000090_0001
[00409] Binding of XMT-1519 (unconjugated parental antibody) to SKBR3 and MDA- MB-231-NR cells was determined by flow cytometry analysis and used as a proxy for HER2 expression levels in these cell lines. Cells were plated in 96 well U-bottom plates, at a density of 50,000 cells/well in DMEM with 6% normal goat serum and incubated on ice for 2-3 hours with increasing concentrations of XMT-1519 (0.024 nM to 400 nM with 4-fold serial dilutions) in DMEM with 6% normal goat serum. The cells were washed with ice cold PBS, pelleted at 1,000 × RPM, resuspended in DMEM with 2% goat serum, and incubated with a secondary fluorescently labeled antibody, Alexa Fluor® 647-labelled goat anti-human IgG (6 ^g/mL) for 1 hour on ice. The cells were washed once with ice cold PBS, resuspended in ice cold PBS with 1% paraformaldehyde (150^L) and run on a MACSQuant Flow Cytometer. Data analysis was performed using FlowJo software using the fcs data files. Geometric mean values for each treatment were plotted, and EC50 values were calculated with GraphPad Prism software by four- parameter curve fitting. [00410] Table 2 provides the EC50 (cell binding) and Bmax (maximum fluorescence / geometric mean) values for XMT-1519 binding to SKBR3 and MDA-MB-231-NR cells. XMT- 1519 bound to SKBR3 cells strongly with an EC50 value of 4.2 nM, whereas no significant binding to MDA-MB-231-NR cells was observed demonstrating the ultra-low expression of HER2 on these cells compared to the expression on SKBR3 cells. Table 2
Figure imgf000090_0002
Example 2: XMT-2056 elicits significant cancer cell-killing activity in HER2+ cancer cell and FcȖ-RI-depleted PBMC co-cultures ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00411] The cancer cell-killing ability of (i) XMT-2056, (ii) Fc-mutant XMT-1519 ADC and (iii) non-binding control ADC in HER2+ SKBR3-NR cells co-cultured with (A) PBMCs, (B) PBMCs depleted of FcȖ-RI expressing cells (CD14+ monocytes), and (C) PBMCs co-depleted of FcȖ-RI+ and FcȖ-RIII+ immune cells was evaluated using the IncuCyte killing assay (T=84 hours) as described in Example 1. The results showed that XMT-2056 exhibited significant cancer cell- killing activity in HER2+ cancer cells co-cultured with PBMCs, which was partially retained when PBMCs were depleted of FcȖ-RI expressing cells in an Fc-effector function dependent manner. This cancer cell-killing activity is completely abrogated by co-depletion of FcȖ-RI+ and FcȖ-RIII+ immune cells thereby suggesting an ADCC function. Flow cytometry assay confirmed the efficient removal of FcȖ-RI+ or FcȖ-RIII+ cells from human PBMCs using positive selection magnetic beads. SKBR3-NR cells were generated as described in Example 1. [00412] FIG.1 A, B, and C plots the percent viable cancer cells as a function of the payload concentration and shows that XMT-2056 exhibits significant cancer cell-killing activity in HER2+ cancer cells co-cultured with PBMCs, which was partially retained when PBMCs were depleted of FcȖ-RI expressing cells in an Fc-effector function dependent manner. Example 3: XMT-2056 ADCC function synergizes with STING pathway activation [00413] The cancer cell-killing ability of (i) XMT-2056 (ii) XMT-1519, (iii) STING agonist payload, (iv) combination of XMT-1519 and STING agonist payload, and (v) combination of Fc- mutant XMT-1519 and STING agonist payload in SKBR3-NR cancer cells co-cultured with (A) PBMCs, (B) PBMCs depleted of FcȖ-RI expressing cells (CD14+ monocytes), and (C) PBMCs co- depleted of FcȖ-RI+ and FcȖ-RIII+ immune cells was evaluated using an IncuCyte killing assay as described in Example 1. The results show that the XMT-2056 activity was greater than that of XMT-1519 thereby suggesting an additional contribution of the STING pathway activation mediated by the STING agonist payload. A combination of XMT-1519 and STING agonist payload enhanced the cancer cell-killing activity, demonstrating a synergy between the ADCC function of the XMT-1519 (antibody in XMT-2056) and the STING pathway activation. The XMT-2056 response remained more potent highlighting the contribution of the ADC to more effectively delivering the STING agonist payload. XMT-2056 and XMT-1519 (wt) activity was abrogated with co-depletion of FcȖ-RI+ & FcȖ-RIII+ cells. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 [00414] FIG.2 A, B, and C plots the percent viable cancer cells as a function of the payload concentration and shows that the ADCC function of XMT-2056 synergizes with the STING pathway activation. Example 4: XMT-2056-mediated STING pathway activation in myeloid cells and cancer cells synergizes with trastuzumab-mediated ADCC function in NK cell co-cultures [00415] Cancer cell-killing ability of the trastuzumab alone or in the presence of conditioned media (CM) harvested from HER2+ cancer cell and myeloid cell co-cultures treated (24 hours) with 20 nM or 2 nM Fc-mutant XMT-1519 ADC was evaluated using an IncuCyte killing assay as described in Example 1. SKBR3-NR cells (15 K) were co-cultured with NK cells (15 K) in the presence of (A) 20 nM CM or (B) 2 nM CM and treated with (i) trastuzumab without CM (serves as no CM control), (ii) non-binding control mAb with CM, and (iii) trastuzumab with CM. The ADCC-mediated cancer cell-killing activity induced by trastuzumab in cancer cell and NK cell co-cultures was significantly enhanced in the presence of CM (20 nM), demonstrating that the soluble factors released from the cancer cell and myeloid cell co-cultures downstream of STING pathway activation (Fc-mutant XMT-1519 ADC treatment) potentiates the ADCC activity of NK cells. [00416] FIG. 3 A and B plots the percent viable cancer cells as a function of the antibody concentration and shows that XMT-2056-mediated STING pathway activation in myeloid cell and cancer cell co-cultures synergizes with trastuzumab-mediated ADCC activity in NK cell co- cultures. Example 5: XMT-2056-mediated STING activation synergizes with ADCC function of trastuzumab and confers combination benefit in cancer cell and NK cell co-cultures in vitro [00417] The synergy between XMT-2056-mediated STING pathway activation and the ADCC function of trastuzumab as a combination treatment was investigated in co-cultures of cancer cells and myeloid cells vs NK cells using the IncuCyte killing assay as described in Example 1. SKBR3-NR cells were co-cultured with (A) myeloid cells (monocytes isolated from PBMCs) or (B) NK cells in the presence of (i) XMT-2056, (ii) combination of XMT-2056 and trastuzumab, (iii) combination of XMT-2056 and Fc mutant trastuzumab (iv) non-binding control ADC or (v) combination of non-binding control ADC and trastuzumab and the cancer cells were traced in an ^ Attorney Docket No. MRSN-043/001WO 322140-2698 IncuCyte instrument. The results indicate that the combination of XMT-2056 and trastuzumab shows benefit specifically in the NK cell but not in myeloid cell co-cultures, and this benefit is dependent on the trastuzumab Fc-effector function as well as binding to a non-competing epitope of HER2 (the combination of XMT-2056 and the XMT-1519 antibody, which binds to the same epitope as XMT-2056, does not exhibit the same synergistic effect in NK cell co-cultures as seen with the combination of XMT-2056 and trastuzumab (FIG.4 C)). [00418] FIG. 4 A, B, and C plots the percent viable cancer cells as a function of the antibody concentration. Example 6: Tumor Growth Response to Administration of HER2 STING Agonist Antibody-Drug Conjugates in Combination with Trastuzumab in SKOV3 Ovarian Cancer [00419] Female CB.17 SCID mice were inoculated subcutaneously with SKOV3 human ovarian cancer cells (10 x 106 cells/mouse). SKOV3 cells are an ovarian cancer cell line having high HER2 expression. Animals were randomized into treatment groups when tumor volumes were between 63 - 113 mm3 (mean = 82.8 - 84 mm3/group). The vehicle, XMT-2056 (0.30/0.013 mg/kg), trastuzumab (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and trastuzumab (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and Fc-mutant trastuzumab (3 mg/kg) or a combination of XMT-1519 (0.3 mg/kg) and trastuzumab (3 mg/kg) were dosed qwkx3 on days 1, 8 and 15. XMT-2056 was dosed intravenously (IV); XMT-1519, trastuzumab and Fc- mutant trastuzumab were dosed intraperitoneally (IP); XMT-2056 doses are given as antibody/payload; n=10 for each group. The data demonstrate that the mechanism of XMT-2056 and trastuzumab combination benefit is dependent on the Fc-effector function of trastuzumab. [00420] FIG. 5 provides the results for the tumor volumes of SKOV3 tumor-bearing mice treated with vehicle, XMT-2056, trastuzumab, a combination of XMT-2056and trastuzumab, or a combination of XMT-2056 and Fc-mutant trastuzumab. Treatment with XMT-2056 (0.30/ 0.013 mg/kg, qwkx3) resulted in 1 PR, 2 CR and no TFS. Treatment with XMT-2056 (0.30/0.013 mg/kg, qwkx3) and trastuzumab (3 mg/kg, qwkx3) resulted in 9 CR, all of which were TFS. Treatment with XMT-2056 (0.30/0.013 mg/kg, qwkx3) and Fc-mutant trastuzumab (3 mg/kg, qwkx3) resulted in 3 CR and no TFS. Treatment with trastuzumab (3 mg/kg, qwkx3) or combination of ^ Attorney Docket No. MRSN-043/001WO 322140-2698 XMT-1519 (0.3 mg/kg) (matched to XMT-2056 mAb dose) and trastuzumab (3 mg/kg)did not result in any significant anti-tumor activity. Example 7: Tumor Growth Response to Administration of HER2 STING Agonist Antibody-Drug Conjugates in Combination with XMT-1519 in SKOV3 Ovarian Cancer [00421] Female CB.17 SCID mice were inoculated subcutaneously with SKOV3 human ovarian cancer cells (10 x 106 cells/mouse). SKOV3 cells are an ovarian cancer cell line having high HER2 expression. Animals were randomized into treatment groups when tumor volumes were between 63 - 113 mm3 (mean = 82.8 - 84 mm3/group). The vehicle, XMT-2056 (0.30/0.013 mg/kg), XMT-1519 (3 mg/kg), a combination of XMT-2056 (0.30/0.013 mg/kg) and XMT-1519 (3 mg/kg), or a combination of XMT-2056 (0.30/0.013 mg/kg) and Fc-mutant XMT-1519 (3 mg/kg) were dosed qwkx3 on days 1, 8 and 15. XMT-2056 was dosed intravenously (IV); XMT- 1519 and Fc-mutant XMT-1519 were dosed intraperitoneally (IP); XMT-2056 doses are given as antibody / payload; n=10 for each group. The data demonstrate that combination of XMT-2056 with the XMT-1519 is not beneficial in this model, indicating the requirement of the mAb-binding to a non-competing epitope on HER2 for synergy between XMT-2056 and the ADCC effector function of the mAb. [00422] FIG. 6 provides the results for the tumor volumes of SKOV3 tumor-bearing mice treated with vehicle, XMT-2056, XMT-1519, a combination of XMT-2056 and XMT-1519, or a combination of XMT-2056 and Fc-mutant XMT-1519. EQUIVALENTS [00423] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as ^ Attorney Docket No. MRSN-043/001WO 322140-2698 commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. [00424] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto. ^ ^

Claims

Attorney Docket No. MRSN-043/001WO 322140-2698 What is claimed is: 1. A combination therapy comprising at least one protein based recognition molecule (PBRM)-STING agonist conjugate and at least one NK cell therapy or at least one antibody that has ADCC function, wherein the one or more PBRM-STING agonist conjugate is each independently a conjugate of Formula (A-1):
Figure imgf000096_0001
(A-1) or a pharmaceutically acceptable salt thereof, wherein: d15 is about 8. 2. The combination of claim 1, comprising at least one PBRM-STING agonist conjugate and at least one NK cell therapy. 3. The combination of claim 1, comprising at least one PBRM-STING agonist conjugate and at least one antibody that has ADCC function. 4. The combination therapy of any one of claims 1-3, wherein at least one PBRM-STING agonist conjugate is a HER2-targeted STING agonist antibody-drug conjugate of Formula (A): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000097_0001
or a pharmaceutically acceptable salt thereof, wherein the HER-2 ANTIBODY comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14), and d15 is about 8. 5. The combination of claim 4, wherein the HER-2 ANTIBODY of the conjugate specifically binds to an epitope of the human HER2 receptor that includes residues 452 to 531 of the extracellular domain of the human HER2 receptor, residues 474 to 553 of SEQ ID NO: 1, or residues 452 to 531 of SEQ ID NO: 16. 6. The combination of claim 4, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one NK cell therapy. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 7. The combination of claim 4, comprising at least one HER2-targeted STING agonist antibody-drug conjugate and at least one antibody that has ADCC function. 8. The combination of any one of claims 1, 3, 4, and 7, wherein at least one antibody that has ADCC function comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 5); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 6); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 7); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 12); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 13); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 14). 9. The combination of any one of claims 1-8, wherein at least one antibody-drug conjugate enhances the efficacy of the one or more NK cell therapy or the one or more antibody that has ADCC function. 10. The combination of any one of claims 1-2, 4-6, and 8-9, wherein at least one NK cell therapy is a NK cell engager or a CAR NK cell therapy. 11. A method for treating, preventing, delaying the progression of, or otherwise ameliorating a symptom of a cancer in a subject comprising administering the combination of any one of claims 1-10. 12. The method of claim 11, wherein the cancer is anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, colorectal cancer, throat cancer, bladder cancer, breast cancer, urothelial cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, non- ^ Attorney Docket No. MRSN-043/001WO 322140-2698 small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, gastric cancer, or gastric esophagogastric junction cancer. 13. The method of claim 12, wherein the cancer is breast cancer, gastric cancer, gastric esophagogastric junction cancer, colorectal cancer, or non-small cell lung cancer. 14. The method of any one of claims 11-13, wherein the one or more NK cell therapy and one or more HER2-targeted STING agonist antibody-drug conjugate are administered simultaneously. 15. The method of any one of claims 11-13, wherein one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more antibody that has ADCC function are administered simultaneously. 16. The method of any one of claims 11-13, wherein one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are administered sequentially in either order or in alternation. 17. The method of any one of claims 11-14 and 16, wherein one or more HER2-targeted STING agonist antibody-drug conjugate is administered prior to the one or more NK cell therapy or the one or more antibody that has ADCC function. 18. The method of any one of claims 11-14 and 16, wherein one or more HER2-targeted STING agonist antibody-drug conjugate is administered after the one or more NK cell therapy or the one or more antibody that has ADCC function. 19. The method of any one of claims 11-18, wherein the cancer is a HER2-positive cancer. 20. The combination of any one of claims 1-10, wherein one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are formulated in the same formulation. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 21. The combination of any one of claims 1-10, wherein one or more HER2-targeted STING agonist antibody-drug conjugate and the one or more NK cell therapy or the one or more antibody that has ADCC function are formulated in separate formulations. 22. A kit comprising the combination of any one of claims 1-10 and 20-21 and an instruction for administration. 23. The combination, method, or kit of any one of claims 1-22, wherein at least one antibody- drug conjugate is a conjugate of Formula (B):
Figure imgf000100_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. 24. The combination, method, or kit of any one of claims 1-22, wherein at least one antibody- drug conjugate is a conjugate of Formula (C): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000101_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. 25. The combination, method, or kit of any one of claims 1-22, wherein at least one antibody- drug conjugate is a conjugate of Formula (D):
Figure imgf000101_0002
or a pharmaceutically acceptable salt or stereoisomer thereof. 26. The combination, method, or kit of any one of claims 1-22, wherein at least one antibody- drug conjugate is a conjugate of Formula (E): ^ Attorney Docket No. MRSN-043/001WO 322140-2698
Figure imgf000102_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. 27. The combination, method, or kit of any one of claims 1-22, wherein at least one antibody- drug conjugate is a conjugate of Formula (F):
Figure imgf000102_0002
or a pharmaceutically acceptable salt or stereoisomer thereof. 28. The combination, method, or kit of any one of claims 1-27, wherein the combination comprises a mixture of the antibody-drug conjugate of Formula (E) or a pharmaceutically ^ Attorney Docket No. MRSN-043/001WO 322140-2698 acceptable salt thereof, and the antibody drug conjugate of Formula (F) or a pharmaceutically acceptable salt thereof. 29. The combination, method, or kit of claim 28, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 30:70 and 70:30. 30. The combination, method, or kit of claim 28, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 40:60 and 60:40. 31. The combination, method, or kit of claim 28, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is between 45:55 and 55:45. 32. The combination, method, or kit of claim 28, wherein the ratio (e.g., molar ratio) of the conjugate of Formula (E) or a pharmaceutically acceptable salt thereof, and the conjugate of Formula (F) or a pharmaceutically acceptable salt thereof is about 50:50. 33. The combination, method, or kit of any one of the preceding claims, wherein the PBRM or the HER-2 ANTIBODY comprises a light chain variable region sequence comprising SEQ ID NO: 9 and a heavy chain variable region sequence comprising SEQ ID NO: 2. 34. The combination, method, or kit of any one of the preceding claims, wherein the PBRM or the HER-2 ANTIBODY comprises a light chain sequence comprising SEQ ID NO: 11 and a heavy chain sequence comprising SEQ ID NO: 4. 35. The combination, method, or kit of any one of claims 1, 3-5, and 7-34, wherein the antibody with ADCC function is not trastuzumab. ^ Attorney Docket No. MRSN-043/001WO 322140-2698 36. The combination, method, or kit of any one of claims 1, 3-5, and 7-34, wherein the antibody with ADCC function binds to the same biological target as the PBRM or HER-2 ANTIBODY, optionally wherein the antibody with ADCC binds to a different epitope of the biological target than the PBRM or HER-2 ANTIBODY. 37. The combination, method, or kit of claim 36, wherein the antibody with ADCC function does not cross-compete for binding to the biological target with the PBRM or HER-2 ANTIBODY, optionally as measured by a Biacore assay. 38. The combination, method, or kit of any one of claims 1-35 and 37, wherein the antibody with ADCC function binds to a different biological target than the PBRM or HER-2 ANTIBODY. ^
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