US20220378749A1 - Antibody drug conjugates comprising sting agonists - Google Patents

Antibody drug conjugates comprising sting agonists Download PDF

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Publication number
US20220378749A1
US20220378749A1 US17/221,341 US202117221341A US2022378749A1 US 20220378749 A1 US20220378749 A1 US 20220378749A1 US 202117221341 A US202117221341 A US 202117221341A US 2022378749 A1 US2022378749 A1 US 2022378749A1
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Prior art keywords
alkyl
conjugate
cancer
independently
present
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US17/221,341
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Inventor
Jeremy R. DUVALL
Keith W. Bentley
Raghida A. BUKHALID
Naniye CETINBAS
Marc I. DAMELIN
Eugene W. Kelleher
Timothy B. Lowinger
Joshua D. Thomas
Dorin Toader
Ling Xu
Liping Yang
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Mersana Therapeutics Inc
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Mersana Therapeutics Inc
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Priority to US17/221,341 priority Critical patent/US20220378749A1/en
Assigned to MERSANA THERAPEUTICS, INC. reassignment MERSANA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CETINBAS, Naniye, BUKHALID, Raghida A., YANG, LIPING, LOWINGER, TIMOTHY B., TOADER, DORIN, DAMELIN, Marc I., BENTLEY, KEITH W., DUVALL, JEREMY R., KELLEHER, EUGENE W., THOMAS, JOSHUA D., XU, LING
Publication of US20220378749A1 publication Critical patent/US20220378749A1/en
Priority to US18/068,476 priority patent/US20230321048A1/en
Priority to US18/068,936 priority patent/US20230172910A1/en
Pending legal-status Critical Current

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Definitions

  • Stimulator of interferon genes 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.
  • 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.
  • Antibody-drug conjugates 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 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 would otherwise require doses so high as to be toxic when administered systemically.
  • 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.
  • PAMPs pathogen-associated molecular patterns
  • 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
  • the present disclosure provides a conjugate of Formula (I):
  • the present disclosure provides a scaffold useful for conjugating with a PBRM, wherein the scaffold is of Formula (II):
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a conjugate described herein and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a method of activating or enhancing an activity of a stimulator of interferon genes (STING) in a subject, comprising administering to the subject a conjugate described herein or a pharmaceutically acceptable salt thereof.
  • STING stimulator of interferon genes
  • the present disclosure provides a method of preventing or treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a conjugate described herein or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a conjugate described herein, or a pharmaceutically acceptable salt thereof, for activating or enhancing an activity of STING in a subject.
  • the present disclosure provides a conjugate described herein, or a pharmaceutically acceptable salt thereof, for preventing or treating a disease or disorder in a subject.
  • the present disclosure provides a use of a conjugate described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for activating or enhancing an activity of STING in a subject.
  • the present disclosure provides a use of a conjugate described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing or treating a disease or disorder in a subject.
  • FIG. 1 A plots the red object confluency as a function of time for Conjugate 8b-1 and Conjugate 8f (each at 100, 10, and 1 nM) and Conjugate 8c-1 and Compound 1 (each at 100 and 10 nM) (conjugate concentrations were based on the payload).
  • FIG. 1 B plots the red object confluency as a function of time for Conjugate 8l and Compound 1 (each at 100, 10, and 1 nM) and Conjugate 8m (100 nM) (conjugate concentrations were based on the payload).
  • FIG. 2 shows CD14 ⁇ /CD3+ cells in PBMCs, enriched monocytes, and CD16-depleted monocyte populations.
  • FIG. 3 A and FIG. 3 B plot the red object confluency as a function of time and show the killing of STING wild type (sgNT-2) and knock out (sg #3-2) SKBR3 NucRed cells respectively by PBMCs for Conjugate 8a-3, Conjugate 8j, Conjugate 8c-2, and Compound 1 each at 100, 25, 5 and 1 nM (conjugate concentrations were based on the payload).
  • FIG. 4 A plots the red object confluency as a function of the dose response of Conjugate 8a-3, Conjugate 8-j, wild type Fc Trastuzumab and AAG Fc mutant Trastuzumab for the STING wild type SKBR3 cancer cell killing activity in SKBR3 cancer cell/PBMC co-cultures.
  • FIG. 4 B plots the red object confluency as a function of the dose response Conjugate 8a-3, Conjugate 8-j, wild type Fc Trastuzumab and AAG Fc mutant Trastuzumab for the STING knock out SKBR3 cancer cell killing activity in SKBR3 cancer cell/PBMC co-cultures.
  • FIG. 5 A plots the change of the red object confluency of OVCAR3-NucRed cancer cells as a function of time by PBMCs for Conjugate 8b-1 and Compound 1, both at 20 and 4 nM (conjugate concentration based on payload concentration).
  • FIG. 5 B plots the change of the red object confluency of OVCAR3-NucRed cancer cells as a function of time by enriched monocytes for Conjugate 8b-1 and Compound 1, both at 20 and 4 nM (conjugate concentration based on payload concentration).
  • FIG. 5 C plots the change of the red object confluency of OVCAR3-NucRed cancer cells as a function of time by CD16 depleted monocytes for Conjugate 8b-1 and Compound 1, both at 20 and 4 nM (conjugate concentration based on payload concentration).
  • FIG. 6 is a graph showing the anti-tumor efficacy of Trastuzumab (3/0 mg/kg), diABZI STING agonist (0/5 mg/kg), Conjugate 8c-1 (1/0.04 mg/kg or 3/0.12 mg/kg), Conjugate 8a-1 (1/0.03 mg/kg or 3/0.09 mg/kg) (all doses are given by antibody/payload) in a SKOV3 xenograft model in mouse.
  • FIGS. 7 A- 7 H show cytokines levels for murine CXCL-10 (IP-10; FIG. 7 A ), IL-6 ( FIG. 7 B ), TNF ⁇ ( FIG. 1 C ), IFN ⁇ ( FIG. 7 D ), CXCL1 (KC) ( FIG. 7 E ), MIG ( FIG. 7 F ), MIP-1 ⁇ ( FIG. 7 G ), and RANTES ( FIG. 7 H ) as a function of time following administration of diABZI STING agonist (0/5 mg/kg), Conjugate 8c-1 (3/0.12 mg/kg) or Conjugate 8a-1 (3/0.09 mg/kg) (all doses are written as antibody/payload) in a SKOV3 mouse model. Inserts in each plot show cytokine levels induced by Conjugate 8a-1 and Conjugate 8c-1 relative to vehicle.
  • FIGS. 8 A- 8 C show the levels of mouse CXCL10 ( FIG. 8 A ), Interferon- ⁇ ( FIG. 8 B ), and IL-6 ( FIG. 8 C ) mRNA in a SKOV3 xenograft model in mouse at 12 h and 72 h following administration of Conjugate 8c-1 (3/0.12 mg/kg), Conjugate 8a-1 (3/0.09 mg/kg), Conjugate 8c-1 (3/0.12 mg/kg) or Conjugate 8a-1 (3/0.09 mg/kg) (all doses are written as antibody/payload).
  • FIG. 9 is the CD45 immunohistochemistry (IHC) staining with rabbit anti-CD45 monoclonal antibody at 12 and 72 hours for Conjugate 8a-1 (3/0.09 mg/kg), Conjugate 8c-1 (3/0.12 mg/kg) or vehicle.
  • IHC CD45 immunohistochemistry
  • FIG. 10 is a graph showing the circulating plasma concentrations of total antibody and conjugated drug following administration of Conjugate 8a-1 (3/0.1 mg/kg) (dose is given as antibody/payload) to CB.17 SCID mice.
  • FIG. 11 shows the effect of IFN ⁇ 1 (IL29) or IFN ⁇ 2 (IL28A) neutralizing antibodies (10, 2, 0.4, 0.08 ⁇ g/mL) on the killing activity of Conjugate 8a-3 (1 nM or 0.1 nM, based on payload) in cancer cell and PBMC co-cultures.
  • FIG. 12 is a graph showing the anti-tumor efficacy of diABZI STING agonist (0/5 mg/kg), Conjugate 8c-1 (3/0.12 mg/kg), Conjugate 8b-1 (3/0.09 mg/kg) or Conjugate 8f (3/0.12 mg/kg) (all doses are given by antibody/payload) in a OVCAR3 xenograft in mouse.
  • FIG. 13 is a graph showing the anti-tumor efficacy of Conjugate 8d-2 (3/0.1 mg/kg) or Conjugate 8e (3/0.1 mg/kg) (all doses are given as antibody/payload) in a OVCAR3 xenograft in mouse.
  • FIG. 14 is a graph showing the anti-tumor efficacy of diABZI STING agonist (0/5 mg/kg), Conjugate 8c-1 (1/0.04 mg/kg) or Conjugate 8h (1/0.04 mg/kg) (all doses are given as antibody/payload) in a triple negative breast cancer xenograft in mouse.
  • FIG. 15 A is a graph showing the anti-tumor efficacy of Conjugate 8d-3 (1/0.04 mg/kg) or Conjugate 8g (0.88/0.04 mg/kg) (all doses are given as antibody/payload) in a colon cancer syngeneic mouse model.
  • FIG. 15 B shows the Kaplan Meier survival curves for Conjugate 8d-3 (1/0.04 mg/kg) or Conjugate 8g (0.88/0.04 mg/kg) (all doses are given as antibody/payload) in a colon cancer syngeneic mouse model.
  • FIG. 16 A is a graph showing anti-tumor efficacy of Conjugate 8g (0.9/0.04 mg/kg) (all doses are given as antibody/payload) for the individual mice in a colon cancer syngeneic mouse model.
  • FIG. 16 B is a graph showing the anti-tumor efficacy of Conjugate 8g (0.9/0.04 mg/kg) (all doses are given as antibody/payload) when re-challenged with syngeneic murine colon cancer cells.
  • FIG. 16 C is a graph showing the anti-tumor efficacy of Conjugate 8g (0.9/0.04 mg/kg) (all doses are given as antibody/payload) when re-challenged with syngeneic murine lung cancer cells.
  • FIG. 17 is a graph showing the anti-tumor efficacy of diABZI STING agonist (0/5 mg/kg) Conjugate 8d-3 (5.5/0.18 mg/kg) or Conjugate 8i (3.2/0.18 mg/kg) (all doses are given as antibody/payload) in a syngeneic murine embryonic cancer model.
  • FIG. 18 is a graph showing the anti-tumor efficacy of Conjugate 20a (3/0.09 mg/kg), Conjugate 34a (3/0.11 mg/kg), Conjugate 34 (3/0.11 mg/kg), or Conjugate 20-1 (3/0.10 mg/kg) (all doses are given as antibody/payload) in a SKOV3 xenograft in mouse.
  • FIG. 19 is a graph showing the anti-tumor efficacy of Conjugate 28 (0.3/0.01 mg/kg or 1/0.03 mg/kg), Conjugate 29 (0.2/0.01 mg/kg or 0.8/0.02 mg/kg), Conjugate 8-2 (0.3/0.01 mg/kg or 1/0.04 mg/kg), Conjugate 25 (0.3/0.01 mg/kg or 1/0.04 mg/kg) or Conjugate 45 (0.3/0.01 mg/kg or 1/0.04 mg/kg) (all doses are given as antibody/payload) in a SKOV3 xenograft in mouse.
  • FIG. 20 graph showing the anti-tumor efficacy of diABZI STING agonist (1.5 mg/kg q3dx3 or 0.128 mg/kg qdx1), Compound 30 (1.5 mg/kg q3dx3 or 0.128 mg/kg qdx1), Conjugate 32b-2 (3.42/0.128 mg/kg qdx1), XMT-1519 (3.00 mg/kg qdx1), Conjugate 32-5 (0.100/0.004, 0.300/0.013, 1.00/0.042 or 3.00/0.128 mg/kg qdx1), Conjugate 32e (1.00/0.039 or 3.00/0.117 mg/kg qdx1)) (all doses are given as antibody/payload) in a SKOV3 xenograft in mouse.
  • diABZI STING agonist 1.5 mg/kg q3dx3 or 0.128 mg/kg qdx1
  • Compound 30 1.5 mg/kg q3dx3 or 0.128 mg/kg
  • FIG. 21 A is a graph showing the anti-tumor efficacy in a syngeneic mouse model of Conjugate 8d-3 (1/0.04 mg/kg) or Conjugate 8k (0.9/0.04 mg/kg).
  • FIG. 21 B shows the anti-tumor efficacy in a syngeneic mouse model of the individual mice for Conjugate 8d-3 (1/0.04 mg/kg).
  • FIG. 21 C shows the anti-tumor efficacy in a syngeneic mouse model of the individual mice for Conjugate 8k (0.9/0.04 mg/kg).
  • FIG. 22 is a graph showing the anti-tumor efficacy of Conjugate 8c-2 (3.17/0.10 mg/kg), Conjugate 8a-2 (2.7/0.10 mg/kg or 0.81/0.03 mg/kg), Conjugate 8j (2.71/0.10 mg/kg or 0.81/0.03 mg/kg), or diABZI IV STING agonist (0/5 mg/kg) (all doses are given as antibody/payload) in a SKOV3 xenograft in mouse.
  • FIG. 23 is a graph showing the anti-tumor efficacy of Conjugate 32b-1 (3.39/0.10 mg/kg), Conjugate 32a (0.93/0.03 or 3.12/0.10 mg/kg), Conjugate 32c (2.12/0.10 mg/kg), Conjugate 32d (2.20/0.10 mg/kg) or diABZI IV STING agonist (0/5 mg/kg) (all doses are given as antibody/payload) in a OVCAR3 xenograft in mouse.
  • FIG. 24 is a graph showing the anti-tumor efficacy of a combination of Rituximab AF-HPA ADC (0.75/0.023 mg/kg) and Conjugate 8c-2 (4.0/0.126 mg/kg); XMT-1535 AF-HPA ADC (0.75/0.024 mg/kg); Conjugate 8b-2 (2.0/0.071 or 4.0/0.142 mg/kg); a combination of XMT-1535 AF-HPA ADC (0.75/0.024 mg/kg) and Conjugate 8c-2 (4.0/0.126 mg/kg); a combination of Rituximab AF-HPA ADC (0.75/0.023 mg/kg) and Conjugate 8b-2 (4.0/0.142 mg/kg); a combination of Rituximab AF-HPA ADC (0.75/0.023 mg/kg) and Conjugate 8b-2 (2.0/0.071 mg/kg); a combination of XMT-1535 AF-HPA ADC (0.75/0.024 mg/kg
  • FIG. 25 is a graph showing the anti-tumor efficacy of Conjugate 32b (0.85/0.03 mg/kg), Conjugate 32-2 (0.90/0.03 mg/kg), Conjugate 88 (0.87/0.03 mg/kg), Conjugate 85 (2.87/0.10 mg/kg), Conjugate 92 (2.36/0.10 mg/kg), Conjugate 100 (2.23/0.10 mg/kg), Conjugate 89 (0.99/0.030 mg/kg), Conjugate 85a (2.59/0.10 mg/kg), Conjugate 93 (2.85/0.10 mg/kg), or Conjugate 101 (2.70/0.10 mg/kg) in a SKOV3 xenograft model in mouse.
  • FIG. 26 is a graph showing the anti-tumor efficacy of with vehicle, Conjugate 28 (0.99/0.0325 mg/kg), or Conjugate 62 (0.92/0.0325 mg/kg) in a SKOV3 xenograft model in mouse.
  • FIG. 27 is a graph showing the circulating plasma concentrations for conjugated drug following administration of Conjugate 28 (3.0/0.10 mg/kg) or Conjugate 62 (2.84/0.10 mg/kg) (dose is given as antibody/payload) to CB.17 SCID mice.
  • the present disclosure provides novel antibody-drug conjugates, synthetic methods for making the conjugates or scaffolds, pharmaceutical compositions containing them, and various uses of the conjugates.
  • “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.
  • 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., el al., Sequences of Protein of immunological interest, Fifth Edition, US Department of Health and Human Services, US Government Printing Office (1991)).
  • 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, F(ab′)2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments.
  • 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.
  • class of an antibody refers to the type of constant domain or constant region possessed by its heavy chain.
  • IgA immunoglobulin
  • IgD immunoglobulin
  • IgE immunoglobulin deficiency virus
  • IgG immunoglobulin deficiency virus
  • polyclonal antibody preparations typically include different antibodies directed against different determinants (epitopes)
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
  • epitope refers to the particular site on an antigen molecule to which an antibody binds.
  • 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, —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.
  • the ligand is used for targeting and has no detectable therapeutic effect as separate from the drug which it delivers.
  • the ligand functions both as a targeting moiety and as a therapeutic or immunomodulatory agent (e.g., to enhance the activity of the active drug or prodrug).
  • PEG unit ss used herein refers to a polyethylene glycol subunit having the formula
  • the PEG unit comprises multiple PEG subunits.
  • alkyl represents a saturated, straight or branched hydrocarbon group having the specified number of carbon atoms.
  • C 1 -C 6 alkyl or “C 1-6 alkyl” refers to a methyl moiety or a straight or branched alkyl moiety comprising from 2 to 6 carbon atoms.
  • Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl and hexyl.
  • halo(alkyl) represents a saturated, straight or branched hydrocarbon group having the specified number (n) of carbon atoms and one or more (up to 2n+1) halogen atoms.
  • halo(C 1-4 alkyl) groups include, but are not limited to, —CF 3 (trifluoromethyl), —CCl 3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.
  • alkenyl refers to straight or branched hydrocarbon group having the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon double bonds. Examples include ethenyl and propenyl.
  • alkynyl refers to straight or branched hydrocarbon group having the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon triple bonds. Examples include ethynyl and propynyl.
  • alkoxy- or “(alkyl)oxy-”, as used herein, refers to an “alkyl-oxy-” group, comprising an alkyl moiety, having the specified number of carbon atoms, attached through an oxygen linking atom.
  • exemplary “C 1-4 alkoxy-” or “(C 1-4 alkyl)oxy-” groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy.
  • halo(alkoxy)- represents a saturated, straight or branched hydrocarbon group having the specified number (n) of carbon atoms and one or more (up to 2n+1) halogen atoms, attached through an oxygen linking atom.
  • exemplary “halo(C 1-4 alkoxy)-” groups include, but are not limited to, —OCHF 2 (difluoromethoxy), —OCF 3 (trifluoromethoxy), —OCH 2 CF 3 (trifluoroethoxy), and —OCH(CF 3 ) 2 (hexafluoroisopropoxy).
  • amino refers to a substituent comprising at least one nitrogen atom. Specifically, —NH 2 , —NH(C 1-4 alkyl), alkylamino, or (C 1-4 alkyl)amino- or (C 1-4 alkyl)(C 1-4 alkyl)amino- or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents are included in the term “amino”.
  • carrier refers to a cyclic group or moiety wherein the ring members are carbon atoms, which may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic).
  • cycloalkyl refers to a non-aromatic, saturated, hydrocarbon ring group comprising the specified number of carbon atoms in the ring.
  • C 3-6 cycloalkyl refers to a cyclic group having from three to six ring carbon atoms.
  • Exemplary “C 3-6 cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to a group with aromaticity, including “conjugated” or multicyclic systems with one or more aromatic rings, which does not contain any heteroatom in the ring structure.
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In some embodiments, an aryl is phenyl.
  • heterocyclic group or moiety refers to a cyclic group or moiety having, as ring members, atoms of at least two different elements, which cyclic group or moiety may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic).
  • heteroatom refers to a nitrogen, sulfur, or oxygen atom, for example a nitrogen atom or an oxygen atom.
  • heterocycloalkyl refers to a non-aromatic, monocyclic or bicyclic group comprising 3-10 ring atoms and comprising one or more (generally one or two) heteroatom ring members independently selected from oxygen, sulfur, and nitrogen.
  • the point of attachment of a heterocycloalkyl group may be by any suitable carbon or nitrogen atom.
  • heteroaryl refers to an aromatic monocyclic or bicyclic group comprising 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein at least a portion of the group is aromatic.
  • this term encompasses bicyclic heterocyclic-aryl groups comprising either a phenyl ring fused to a heterocyclic moiety or a heteroaryl ring moiety fused to a carbocyclic moiety.
  • the point of attachment of a heteroaryl group may be by any suitable carbon or nitrogen atom.
  • halogen and “halo”, as used herein, refers to a halogen radical, for example, a fluoro, chloro, bromo, or iodo substituent.
  • oxo refers to a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C ⁇ O).
  • hydroxy or “hydroxyl”, as used herein, is intended to mean the radical —OH.
  • cyano refers to a nitrile group, —C ⁇ N.
  • a group such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl group
  • ring or moiety may be unsubstituted, or the group, ring or moiety may be substituted with one or more substituent(s).
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • Suitable substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • pharmaceutically acceptable refers to those compounds, conjugates, materials, compositions, and 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.
  • treating 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 of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, 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.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • 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.
  • a therapeutically “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 effective 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 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 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.
  • 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). This includes direct phosphorylation of STING, IRF3 and/or NF-kB and could also include STAT6. In some embodiments, STING pathway activation results in increased production of type 1 interferons (mainly IFN-a and IFN-b) and/or expression of interferon-stimulated genes.
  • type 1 interferons mainly IFN-a and IFN-b
  • 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.
  • 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 are useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, fibrosarcoma, and hepatitis B.
  • 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.
  • conjugates as disclosure 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.
  • the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.
  • 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.
  • the present disclosure provides a conjugate of Formula (I):
  • the conjugate is of Formula (I-A):
  • the conjugate is of Formula (I-B):
  • the conjugate is of Formula (I-B′):
  • the present disclosure provides a scaffold useful for conjugating with a PBRM, wherein the scaffold is of Formula (II):
  • the scaffold is of Formula (II-A):
  • the scaffold is of Formula (II-B):
  • the scaffold is of Formula (II-B′):
  • variables PBRM, L C , A 1 , T 1 , M A , L D , D, and d 15 can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables PBRM, L C , A 1 , T 1 , M A , L D , D, and d 15 can be combined, where applicable, with any group described herein for one or more of the remainder of variables PBRM, L C , A 1 , T 1 , M A , L D , D, and d 15 .
  • d 15 is an integer ranging from about 2 to about 14, from about 2 to about 12, from about 2 to about 10, from about 2 to about 8, from about 2 to about 6, from about 2 to about 4, from about 4 to about 10, from about 4 to about 8, from about 4 to about 6, from about 6 to about 14, from about 6 to about 12, from about 6 to about 10, from about 6 to about 8, from about 8 to about 14, from about 8 to about 12, or from about 8 to about 10.
  • d 15 is an integer ranging from about 2 to about 8.
  • d 15 is 2, 4, 6, or 8. In some embodiments, d 15 is 6 or 8.
  • d 15 is 8. In some embodiments, d 15 is 6.
  • each A 1 independently is a divalent linker moiety connecting the PBRM to L C when L C is present, or to D when L C is absent.
  • each A 1 independently is:
  • R 7 is —O—, —NR 8 , —(C 1 -C 10 alkyl)-, —(C 1 -C 10 alkenyl)-, —(C 1 -C 10 alkynyl)-, —(C 3 -C 8 cycloalkyl)-, -aryl-, —O—(C 1 -C 8 alkyl)-, —O—(C 1 -C 10 alkenyl)-, —O—(C 1 -C 10 alkynyl)-, —(C 1 -C 10 alkyl)-(C 3 -C 8 cycloalkyl)-, —(C 1 -C 10 alkyl)-aryl-, —(C 2 -C 10 alkenyl)-(C 3 -C 8 cycloalkyl)-, —(C 2 -C 10 alkenyl)-aryl-, —(C 2 -C 10 alkenyl)-ary
  • R 7 is —O—, —NR 8 , —(C 1 -C 10 alkyl)-, —(C 3 -C 8 cycloalkyl)-, -aryl-, —O—(C 1 -C 8 alkyl)-, —(C 1 -C 10 alkyl)-aryl-, -aryl-(C 1 -C 10 alkyl)-, —(C 1 -C 10 alkyl)-(C 3 -C 8 cycloalkyl)-, —(C 3 -C 8 cycloalkyl)-(C 1 -C 10 alkyl)-, -(3- to 8-membered heterocycloalkyl)-, -(5- to 8-membered heteroaryl)-, —(C 1 -C 10 alkyl)-(3- to 8-membered heterocycloalkyl)-, —(C 1 -C 10 alkyl)-(3- to 8
  • R 7 is —(C 1 -C 10 alkyl)-, —O—(C 1 -C 8 alkyl)-, —(CH 2 CH 2 O) r —, —O—C(O)—(CH 2 CH 2 O) r —(CH 2 ) 2 — or —(CH 2 CH 2 O) r —(CH 2 ) 2 —.
  • R 7 is —O—, —NH, —N(CH 3 ), —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 5 —, —O—C(O)—(CH 2 CH 2 O) 6 —(CH 2 ) 2 —, —(CH 2 CH 2 O)—(CH 2 ) 2 —, —(CH 2 CH 2 O) 2 —(CH 2 ) 2 —, —(CH 2 CH 2 O) 4 —(CH 2 ) 2 —, or —(CH 2 CH 2 O) 6 —(CH 2 ) 2 —.
  • each A 1 independently is:
  • R 8 is H, hydroxy, or C 1-4 alkyl; r is an integer ranging from about 4 to about 6; and * denotes attachment to PBRM and ** denotes attachment to L C when L C is present, or to D when L C is absent.
  • each A 1 prior to being connected to PBRM, independently corresponds to a monovalent moiety A 1′ .
  • each A 1′ independently is:
  • R 7 , R 8 , and r are as described herein; and ** denotes attachment to L C when L C is present, or to D when L C is absent.
  • each A 1′ independently is:
  • r is an integer ranging from about 4 to about 6;
  • each L C when present, independently is:
  • M a when present, is a peptide moiety comprising at least two amino acids
  • T 1 when present, is a hydrophilic group
  • L D is a divalent linker moiety connecting D to M A when M A is present, or to A 1 when M A is absent.
  • each L D comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect.
  • each L C when present, independently is
  • each L C when present, independently is
  • each L D independently is a divalent linker moiety connecting D to M A when M A is present, or to A 1 when M A is absent.
  • each L D comprises at least one cleavable bond such that when the bond is cleaved, D is released in an active form for its intended therapeutic effect.
  • L D comprises one cleavable bond. In some embodiments, L D comprises multiple cleavage sites or bonds.
  • each L D prior to being connected to D, independently corresponds to a monovalent moiety L D′ .
  • L D′ comprises a functional group capable of forming the cleavable bond.
  • Functional groups capable of forming the cleavable bond can include, for example, sulfhydryl groups to form disulfide bonds, aldehyde, ketone, or hydrazine groups to form hydrazone bonds, hydroxylamine groups to form oxime bonds, carboxylic or amino groups to form peptide bonds, carboxylic or hydroxy groups to form ester bonds, and sugars to form glycosidic bonds.
  • each L D comprises a disulfide bond that is cleavable through disulfide exchange, an acid-labile bond that is cleavable at acidic pH, and/or bonds that are cleavable by hydrolases.
  • L D comprises a carbamate bond (i.e., —O—C(O)—NR—, wherein R is hydrogen or alkyl or the like).
  • the structure and sequence of the cleavable bond in L D can be such that the bond is cleaved by the action of enzymes present at the target site.
  • the cleavable bond can be cleavable by other mechanisms.
  • the structure and sequence of the cleavable bonds in L D can be such that the bonds are cleaved by the action of enzymes present at the target site.
  • the cleavable bonds can be cleavable by other mechanisms.
  • the cleavable bond(s) can be enzymatically cleaved by one or more enzymes, including a tumor-associated protease, to liberate the Drug unit or D, wherein the conjugate of the present disclosure, or intermediate, or scaffold thereof, is protonated in vivo upon release to provide a Drug unit or D.
  • one or more enzymes including a tumor-associated protease
  • each L D independent is N
  • L E when present, is —NH—[(CH 2 CH 2 O) p —(CH 2 ) 0-2 ] q —C(O)—, —NH—(C 1 -C 6 alkyl)-O—C(O)—, or —NH—[(CH 2 CH 2 O) P —(CH 2 ) 0-2 ] q —C(O)—NH—(C 1 -C 6 alkyl)-O—C(O)—, wherein p is an integer ranging from about 1 to about 20, and q is an integer ranging from about 1 to about 10;
  • each W independently is a natural or unnatural amino acid unit
  • w is an integer ranging from about 0 to about 12;
  • each L D independent is N
  • each L D independent is N
  • each L D independent is N
  • L E comprises at least one PEG unit.
  • the PEG unit comprises at least 1 subunit, at least 2 subunits, at least 3 subunits, at least 4 subunits, at least 5 subunits, or at least 6 subunits. In some embodiments, the PEG unit comprises at least 4 subunits, at least 3 subunits, at least 2 subunits, or at least 1 subunit. In some embodiments, the PEG unit comprises at least 1 subunit. In some embodiments, the PEG unit comprises at least 2 subunits.
  • p is an integer ranging from about 1 to about 15, from about 1 to about 10, from about 1 to about 9, from about 1 to about 8, from about 1 to about 7, from about 1 to about 6, or from about 1 to about 5.
  • p is an integer ranging from about 1 to about 6. In some embodiments, p is an integer ranging from about 1 to about 4. In some embodiments, p is an integer ranging from about 1 to about 2.
  • p is 2.
  • q is an integer ranging from about 1 to about 15, from about 1 to about 10, from about 1 to about 9, from about 1 to about 8, from about 1 to about 7, from about 1 to about 6, or from about 1 to about 5.
  • q is 1, 2, 3, 4, or 5. In some embodiments, q is 2.
  • L E when present, is —NH—(CH 2 CH 2 O) 1-4 —(CH 2 ) 2 —C(O)—. In some embodiments, L E , when present, is —NH—(CH 2 CH 2 O) 2 —(CH 2 ) 2 —C(O)—. In some embodiments, L E , when present, is —NH—(CH 2 CH 2 O) 3 —(CH 2 ) 0-2 —C(O)—. In some embodiments, L E , when present, is —NH—(CH 2 CH 2 O) 3 —(CH 2 ) l —C(O)—.
  • L E when present, is —NH—(CH 2 CH 2 O) 3 —(CH 2 ) 2 —C(O)—. In some embodiments, L E , when present, is —NH—CH 2 CH 2 O—(CH 2 ) 0-2 —C(O)—. In some embodiments, L E , when present, is —NH—CH 2 CH 2 O—C(O)—. In some embodiments, L E , when present, is —NH—(C 1 -C 6 alkyl)-O—C(O)—. In some embodiments, L E , when present, is —NH—CH 2 —CH(CH 3 )—O—C(O)—.
  • L E when present, is —NH—[(CH 2 CH 2 O) 1-4 —(CH 2 ) 2 —C(O)—NH—(C 1 -C 6 alkyl)-O—C(O)—. In some embodiments, L E , when present, is —NH—CH 2 CH 2 O—(CH 2 ) 2 —C(O)—NH—(CH 2 ) 2 —O—C(O)—.
  • w is an integer ranging from about 1 to about 12 (e.g., 1 to 6, or 1 to 4, or 1 to 3, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).
  • w is 0, 1, 2, 3, 4, or 5. In some embodiments, w is 1, 2, 3, 4, or 5.
  • w is 1. In some embodiments, w is 2. In some embodiments, w is 3.
  • each W independently is a natural or unnatural amino acid and/or a D or L isomer.
  • each W independently is an alpha, beta, or gamma amino acid that is natural or non-natural.
  • At least one W is a natural amino acid. In some embodiments, at least one W is a non-natural amino acid.
  • W w does not comprise natural amino acids. In some embodiments, W w does not comprise non-natural amino acids.
  • W w comprises a natural amino acid linked to a non-natural amino acid. In some embodiments, W w comprises a natural amino acid linked to a D-isomer of a natural amino acid.
  • W w is a dipeptide, e.g., -Val-Cit-, -Phe-Lys-, -Val-Ala- or Glu-Ala.
  • W w is a monopeptide, a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, a decapeptide, an undecapeptide, or a dodecapeptide unit.
  • W w is a peptide (e.g., a peptide of 1 to 12 amino acids), which is conjugated directly to D.
  • the peptide is a single amino acid.
  • the peptide is a dipeptide.
  • the peptide is a tripeptide.
  • each amino acid in W w is independently selected from alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, selenocysteine, ornithine, penicillamine, aminoalkanoic acid, aminoalkynoic acid, aminoalkanedioic acid, aminobenzoic acid, amino-heterocyclo-alkanoic acid, heterocyclo-carboxylic acid, citrulline, statine, diaminoalkanoic acid, and derivatives thereof.
  • each amino acid in W w is independently selected from alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, citrulline, and derivatives thereof.
  • each amino acid in W w is independently selected from the proteinogenic and the non-proteinogenic amino acids.
  • each amino acid in W w is independently selected from L or D isomers of the following amino acids: alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, cysteine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, methionine, serine, tyrosine, threonine, tryptophan, proline, ornithine, penicillamine, aminoalkynoic acid, aminoalkanedioic acid, heterocyclo-carboxylic acid, citrulline, statine, diaminoalkanoic acid, valine, citrulline, and derivatives thereof.
  • each amino acid in W w is independently cysteine, homocysteine, penicillamine, ornithine, lysine, serine, threonine, glycine, glutamine, alanine, aspartic acid, glutamic acid, selenocysteine, proline, glycine, isoleucine, leucine, methionine, valine, citrulline, or alanine.
  • each amino acid in W w is independently selected from L-isomers of the following amino acids: alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan, citrulline, and valine.
  • each amino acid in W w is independently selected from D-isomers of the following amino acids: alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan, citrulline, and valine.
  • each amino acid in W w is alanine, ⁇ -alanine, glycine, glutamic acid, isoglutamic acid, isoaspartic acid, valine citrulline, or aspartic acid.
  • W w comprises ⁇ -alanine. In some embodiments, W comprises ( ⁇ -alanine)-(alanine). In some embodiments, W w comprises ( ⁇ -alanine) and optionally glutamic acid, isoglutamic acid, aspartic acid, isoaspartic acid, valine, (valine)-(alanine), (alanine)-(alanine), or (valine)-(citruline).
  • W w comprises (glutamic acid)-(alanine).
  • W w comprises glutamic acid and optionally alanine, glycine, isoglutamic acid, aspartic acid, isoaspartic acid, valine, (valine)-(alanine), (alanine)-(alanine), or (valine)-(citruline).
  • W w comprises 2,3-diaminopropanoic acid. In some embodiments, W w comprises (R)-2,3-diaminopropanoic acid. In some embodiments, W w comprises glutamic acid. In some embodiments, W w comprises (glutamic acid)-(alanine). In some embodiments, W w comprises (glutamic acid)-(glycine)-(alanine).
  • W w comprises L-glutamic acid, D-glutamic acid, (L-glutamic acid)-(L-alanine), (L-glutamic acid)-(D-alanine), (D-glutamic acid)-(L-alanine), (D-glutamic acid)-(D-alanine), (L-glutamic acid)-(glycine)-(L-alanine), D-glutamic acid)-(glycine)-(D-alanine), (L-glutamic acid)-(glycine)-(D-alanine), or (D-glutamic acid)-(glycine)-(L-alanine).
  • W w comprises a carbamate bond in addition to one or more amino acids.
  • L D (e.g., W w ) is selective for enzymatic cleavage (e.g., by a particular enzyme).
  • the particular enzyme is a tumor-associated protease.
  • L D (e.g., W w ) comprises a bond whose cleavage is catalyzed by cathepsin B, cathepsin C, cathepsin D, or a plasmin protease.
  • L D comprises a sugar cleavage site.
  • L D comprises a sugar moiety (Su) linked via an oxygen glycosidic bond to a self-immolative group.
  • a “self-immolative group” can be a tri-functional chemical moiety that is capable of covalently linking together three spaced chemical moieties (i.e., the sugar moiety (via a glycosidic bond), a drug unit (directly or indirectly), and M A (directly or indirectly) when M A is present or A 1 when M A is absent.
  • the glycosidic bond can be cleaved at the target site to initiate a self-immolative reaction sequence that leads to a release of the drug.
  • each L D when present, independently is:
  • each L D when present, independently is:
  • each L D when present, independently is:
  • M A comprises a peptide moiety of at least two amino acids.
  • amino acid is referred to herein as “AA” and amino acids as “AA's”.
  • M A is a moiety that is capable of forming a covalent bond with a -L D -D unit and allows for the attachment of multiple drug.
  • M A comprises a single AA unit or has two or more AA units (e.g., from 2 to 10, from 2 to 6, or 2, 3, 4, 5 or 6) wherein the AA units are each independently a natural or non-natural amino acid, an amino alcohol, an amino aldehyde, a diamine, a polyamine, or combinations thereof.
  • exemplary functionalized AA units include, for example, azido or alkyne functionalized AA units (e.g., amino acid, amino alcohol, or amino aldehyde modified to have an azide group or alkyne group).
  • M A comprises 2 to 12 AA units. In some embodiments, M A comprises 2 to 10 AA units. In some embodiments, M A comprises 2 to 6 AA units. In some embodiments, M A comprises 2, 3, 4, 5 or 6 AA units.
  • M A has 2 AA units. In some embodiments, the peptide moiety has 3 AA units. In some embodiments, the peptide moiety has 4 AA units. In some embodiments, the peptide moiety has 5 AA units. In some embodiments, the peptide moiety has 6 AA units.
  • attachment within M A or with the other components of the conjugate, intermediate thereof, or scaffold can be, for example, via amino, carboxy, or other functionalities.
  • each amino acid in M A can be independently D or L isomer of a thiol containing amino acid. In some embodiments, each amino acid in M A can be independently a D isomer of a thiol containing amino acid. In some embodiments, each amino acid in M A can be independently an L isomer of a thiol containing amino acid. In some embodiments, the thiol containing amino acid can be, for example, cysteine, homocysteine, or penicillamine.
  • each amino acid in M A can be independently the L or D isomer of the following amino acids: alanine (including ⁇ -alanine), arginine, aspartic acid, asparagine, cysteine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, methionine, serine, tyrosine, threonine, tryptophan, proline, ornithine, penicillamine, aminoalkynoic acid, aminoalkanedioic acid, heterocyclo-carboxylic acid, citrulline, statine, diaminoalkanoic acid, stereoisomers thereof, or derivatives thereof.
  • alanine including ⁇ -alanine
  • arginine aspartic acid
  • asparagine cysteine
  • histidine glycine
  • glutamic acid glutamine
  • phenylalanine lysine
  • leucine methionine
  • each amino acid in M A is independently cysteine, homocysteine, penicillamine, ornithine, lysine, serine, threonine, glycine, glutamine, alanine, aspartic acid, glutamic acid, selenocysteine, proline, glycine, isoleucine, leucine, methionine, valine, alanine, or a stereoisomers thereof.
  • M A comprises a monopeptide, a dipeptide, tripeptide, tetrapeptide, or pentapeptide. In some embodiments, M A comprises a pentapeptide.
  • M A comprises at least about five amino acids (e.g., 5, 6, 7, 8, 9, or 10 amino acids). In some embodiments, M A comprises at most about ten amino acids.
  • each amino acid in M A independently is glycine, serine, glutamic acid, lysine, aspartic acid, and cysteine.
  • M A comprises at least four glycines and at least one glutamic acid e.g., (glycine) 4 and glutamic acid, wherein the glutamic acid is at any position along the peptide chain, such as, for example, (glutamic acid)-(glycine) 4 ; (glycine)-(glutamic acid)-(glycine) 3 ; (glycine) 2 -(glutamic acid)-(glycine) 2 ; (glycine) 3 -(glutamic acid)-(glycine); or (glycine) 4 -(glutamic acid).
  • glutamic acid is at any position along the peptide chain, such as, for example, (glutamic acid)-(glycine) 4 ; (glycine)-(glutamic acid)-(glycine) 3 ; (glycine) 2 -(glutamic acid)-(glycine) 2 ; (glycine) 3 -(glutamic acid)-(g
  • M A comprises (glycine) 4 -(glutamic acid).
  • the peptide moiety comprises (glutamic acid)-(glycine) 4 .
  • M A comprises at least four glycines and at least one serine, e.g., (glycine) 4 and serine wherein the serine is at any position along the peptide chain, such as, for example, (serine)-(glycine) 4 ; (glycine)-(serine)-(glycine) 3 ; (glycine) 2 -(serine)-(glycine) 2 ; (glycine) 3 -(serine)-(glycine); or (glycine) 4 -(serine).
  • serine is at any position along the peptide chain, such as, for example, (serine)-(glycine) 4 ; (glycine)-(serine)-(glycine) 3 ; (glycine) 2 -(serine)-(glycine) 2 ; (glycine) 3 -(serine)-(glycine); or (glycine) 4 -(serine).
  • M A comprises (glycine) 4 -(serine). In some embodiments, the peptide moiety comprises (serine)-(glycine) 4 .
  • M A comprises ( ⁇ -alanine)-(glycine) 4 -(serine) wherein the serine is at any position along the peptide chain, such as, for example, ( ⁇ -alanine)-(serine)-(glycine) 4 ; ( ⁇ -alanine)-(glycine)-(serine)-(glycine) 3 ; ( ⁇ -alanine)-(glycine) 2 -(serine)-(glycine) 2 ; ( ⁇ -alanine)-(glycine) 3 -(serine)-(glycine); or ( ⁇ -alanine)-(glycine) 4 -(serine).
  • M A comprises (glycine) 4 -(serine)-(glutamic acid) wherein the serine is at any position along the peptide chain, such as, for example, (serine)-(glycine) 4 -(glutamic acid); (glycine)-(serine)-(glycine) 3 -(glutamic acid); (glycine) 2 -(serine)-(glycine) 2 -(glutamic acid); (glycine) 3 -(serine)-(glycine)-(glutamic acid); or (glycine) 4 -(serine)-(glutamic acid).
  • the peptide moiety comprises ( ⁇ -alanine)-(glycine) 4 -(serine)-(glutamic acid) wherein the serine is at any position along the peptide chain, such as, for example, ( ⁇ -alanine)-(serine)-(glycine) 4 -(glutamic acid); ( ⁇ -alanine)-(glycine)-(serine)-(glycine) 3 -(glutamic acid); ( ⁇ -alanine)-(glycine) 2 -(serine)-(glycine) 2 -(glutamic acid); ( ⁇ -alanine)-(glycine) 3 -(serine)-(glycine)-(glutamic acid); or ( ⁇ -alanine)-(glycine) 4 -(serine)-(glutamic acid).
  • M A comprises (glycine) 4 -(serine). In some embodiments, the peptide moiety comprises (serine)-(glycine) 4 .
  • M A comprises ( ⁇ -alanine)-(glycine) 4 -(serine) wherein the serine is at any position along the peptide chain.
  • M A comprises (glycine) 4 -(serine)-(glutamic acid) wherein the serine is at any position along the peptide chain.
  • M A comprises ( ⁇ -alanine)-(glycine) 4 -(serine)-(glutamic acid) wherein the serine is at any position along the peptide chain.
  • M A comprises (glutamic acid)-(glycine) 1-4 , wherein: the M A is attached to A 1 via one of the glutamic acid; M A is attached to T 1 via the glycine; and M A is attached to L D via the glutamic acid.
  • M A comprises
  • M A comprises (glutamic acid)-(glycine) 4 , wherein: the M A is attached to A 1 via the glutamic acid; M A is attached to T 1 via one of the glycine; and M A is attached to L D via the glutamic acid.
  • M comprises
  • M A comprises (glutamic acid)-(glycine), wherein: the M A is attached to A 1 via the glutamic acid; M A is attached to T 1 via the glycine; and M A is attached to L D via the glutamic acid.
  • the peptide moiety comprises
  • M A comprises (glycine) 1-4 -(glutamic acid), wherein M A is attached to A 1 via one of the glycine; M A is attached to T 1 via the glutamic acid; and M A is attached to L D via the glutamic acid.
  • M A comprises
  • M A comprises (glycine) 4 -(glutamic acid), wherein: M A is attached to A 1 via the glutamic acid; M A is attached to T 1 via the glycine; and M A is attached to L D via the glutamic acid.
  • M comprises
  • M A comprises (glycine)-(glutamic acid), wherein: M A is attached to A 1 via the glycine; M A is attached to T 1 via the glutamic acid; and the M A is attached to L D via the glutamic acid.
  • M A comprises
  • M A comprises (glycine) 1-4 -(serine), wherein: M A is attached to A 1 via one of the glycine; M A is attached to T 1 via the serine; and M A is attached to L D via the serine.
  • M comprises
  • M A comprises (glycine)-(serine), wherein: M A is attached to A 1 via the glycine; M A is attached to T 1 via the serine; and M A is attached to L D via the serine.
  • M A comprises
  • M A comprises (glycine) 4 -(serine), wherein: M A is attached to A 1 via one of the glycine; M A is attached to T 1 via the serine; and M A is attached to L D via the serine.
  • M A comprises
  • M A comprises (serine)-(glycine) 1-4 , wherein: M A is attached to A 1 via the serine; M A is attached to T 1 via one of the glycine; and M A is attached to L D via the serine.
  • M A comprises
  • M A comprises (serine)-(glycine) 4 , wherein: M A is attached to A 1 via the serine; M A is attached to T 1 via one of the glycine; and M A is attached to L u via the serine.
  • M A comprises
  • M A comprises (serine)-(glycine), wherein: M A is attached to A 1 via the serine; M A is attached to T 1 via one of the glycine; and M A is attached to L D via the serine.
  • M comprises
  • M A comprises ( ⁇ -alanine)-(glycine) 1-4 -(serine), wherein: M A is attached to A 1 via the ⁇ -alanine; M A is attached to T 1 via the serine; and M A is attached to L D via the serine.
  • M A comprises
  • M A comprises ( ⁇ -alanine)-(glycine) 4 -(serine), wherein: M A is attached to A 1 via the ⁇ -alanine; M A is attached to T 1 via the serine; and M A is attached to L D via the serine.
  • M A comprises
  • the peptide moiety comprises ( ⁇ -alanine)-(glycine)-(glutamic acid), wherein: the peptide moiety is attached to L 3 when present, or to L M when L 3 is absent, via the ⁇ -alanine; the peptide moiety is attached to T 1 when present, via the glutamic acid; and the peptide moiety is attached to L D when present, via the glutamic acid.
  • the peptide moiety comprises
  • the hydrophilic group included in the conjugates or scaffolds of the disclosure is a water-soluble and substantially non-antigenic polymer.
  • the hydrophilic group include, but are not limited to, polyalcohols, polyethers, polyanions, polycations, polyphosphoric acids, polyamines, polysaccharides, polyhydroxy compounds, polylysines, and derivatives thereof.
  • one end of the hydrophilic group can be functionalized so that it can be covalently attached to the M A linker (e.g., to an amino acid in the M A linker) by means of a non-cleavable linkage or via a cleavable linkage.
  • functionalization can be, for example, via an amine, thiol, NHS ester, maleimide, alkyne, azide, carbonyl, or other functional group.
  • the other terminus (or termini) of the hydrophilic group will be free and untethered.
  • the free and untethered end of the hydrophilic group may include a methoxy, carboxylic acid, alcohol or other suitable functional group.
  • the methoxy, carboxylic acid, alcohol, or other suitable functional group acts as a cap for the terminus or termini of the hydrophilic group.
  • a cleavable linkage refers to a linkage that is not substantially sensitive to cleavage while circulating in the plasma but is sensitive to cleavage in an intracellular or intratumoral environment.
  • a non-cleavable linkage is one that is not substantially sensitive to cleavage in any biological environment.
  • chemical hydrolysis of a hydrazone, reduction of a disulfide, and enzymatic cleavage of a peptide bond or glycosidic linkage are examples of cleavable linkages.
  • exemplary attachments of the hydrophilic group are via amide linkages, ether linkages, ester linkages, hydrazone linkages, oxime linkages, disulfide linkages, peptide linkages, or triazole linkages.
  • the attachment of the hydrophilic group to the M A linker is via an amide linkage.
  • the multiple hydrophilic groups may be the same or different chemical moieties (e.g., hydrophilic groups of different molecular weight, number of subunits, or chemical structure).
  • the multiple hydrophilic groups can be attached to the M A linker at a single attachment site or different sites.
  • the addition of the hydrophilic group may have two potential impacts upon the pharmacokinetics of the resulting conjugate.
  • the desired impact is the decrease in clearance (and consequent in increase in exposure) that arises from the reduction in non-specific interactions induced by the exposed hydrophobic elements of the drug or drug-linker.
  • the undesired impact is the decrease in volume and rate of distribution that may arise from the increase in the molecular weight of the conjugate.
  • increasing the molecular weight of the hydrophilic group increases the hydrodynamic radius of a conjugate, resulting in decreased diffusivity that may diminish the ability of the conjugate to penetrate into a tumor.
  • hydrophilic group that is sufficiently large to decrease the conjugate clearance thus increasing plasma exposure, but not so large as to greatly diminish its diffusivity, which may reduce the ability of the conjugate to reach the intended target cell population.
  • the hydrophilic group includes, but is not limited to, a sugar alcohol (also known as polyalcohol, polyhydric alcohol, alditol or glycitol, such as inositol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, galactitol, mannitol, sorbitol, and the like) or a derivative thereof (e.g., amino polyalcohol), carbohydrate (e.g., a saccharide), a polyvinyl alcohol, a carbohydrate-based polymer (e.g., dextrans), a hydroxypropylmethacrylamide (HPMA), a polyalkylene oxide, and/or a copolymer thereof.
  • a sugar alcohol also known as polyalcohol, polyhydric alcohol, alditol or glycitol, such as inositol, glyce
  • T 1 comprises a plurality of hydroxyl (“—OH”) groups, such as moieties that incorporate monosaccharides, oligosaccharides, polysaccharides, and the like.
  • —OH hydroxyl
  • T 1 comprises a plurality of —(CR 58 OH)— groups, wherein R 58 is —H or C 1-8 alkyl.
  • T 1 is —OH or
  • n 1 is an integer from 0 to about 6;
  • each R 58 is independently —H or C 1-8 alkyl
  • R 60 is a bond, a C 1-6 alkyl linker, or —CHR 59 — wherein R 59 is —H, C 1-8 alkyl, cycloalkyl, or arylalkyl;
  • R 61 is CH 2 OR 62 , COOR 62 , —(CH 2 ) n2 COOR 62 , or a heterocycloalkyl substituted with one or more hydroxyl;
  • R 62 is —H or C 1-8 alkyl
  • n 2 is an integer from 1 to about 5.
  • T 1 is —OH. In some embodiments, T 1 is
  • R 58 is —H; R 60 is a bond or a C 1-6 alkyl linker; n 1 is an integer from 1 to about 6; and R 61 is CH 2 OH or COOH.
  • R 58 is —H; R 60 is —CHR 59 —; n 1 is 0; and R 61 is a heterocycloalkyl substituted with one or more hydroxyl, e.g., a monosaccharide.
  • T 1 comprises a glucosyl-amine, a di-amine, or a tri-amine.
  • T 1 comprises one or more of the following fragments or a stereoisomer thereof:
  • R 59 is —H, C 1-8 alkyl, cycloalkyl, or arylalkyl; n 1 is an integer from 1 to about 6; n 2 is an integer from 1 to about 5; and n 3 is an integer from about 1 to about 3.
  • hydrophilic group may be derived from ribose, xylose, glucose, mannose, galactose, or other sugar and retain the stereochemical arrangements of pendant hydroxyl and alkyl groups present on those molecules.
  • n 3 is 2 or 3.
  • n 1 is 1, 2, or 3.
  • n 2 is 1.
  • R 59 is hydrogen
  • T 1 is
  • T 1 is
  • T 1 is
  • T 1 is
  • n 4 is an integer from 1 to about 25;
  • each R 63 is independently —H or C 1-8 alkyl
  • R 64 is a bond or a C 1-8 alkyl linker
  • Res is —H, C 1-8 alkyl, —(CH 2 ) n2 COOR 62 , or —(CH 2 ) n2 COR 66 ;
  • R 62 is H or C 1-8 alkyl
  • R 66 is H
  • n 2 is an integer from 1 to about 5.
  • T 1 is:
  • R 67 is: (1) —OH
  • n 4 is an integer from about 2 to about 20, from about 4 to about 16, from about 6 to about 12, from about 8 to about 12.
  • T 1 is
  • n 4 is an integer from about 2 to about 20, from about 4 to about 16, from about 6 to about 12, from about 8 to about 12.
  • n 4 is 6, 7, 8, 9, 10, 11, or 12.
  • n 4 is 8 or 12.
  • T 1 is
  • n 4 is an integer from about 2 to about 24, from about 4 to about 16, from about 6 to about 12, from about 8 to about 12.
  • n 4 is 6, 7, 8, 9, 10, 11, or 12.
  • n 4 is 8 or 12. In some embodiments, n 4 is 8.
  • T 1 is
  • n 4 is 8.
  • T 1 comprises a polyether, e.g., a polyalkylene glycol (PAO).
  • PAO includes but is not limited to, polymers of lower alkylene oxides, in particular polymers of ethylene oxide, such as, for example, propylene oxide, polypropylene glycols, polyethylene glycol (PEG), polyoxyethylenated polyols, copolymers thereof, and block copolymers thereof.
  • the polyalkylene glycol is a polyethylene glycol (PEG) including, but not limited to, polydisperse PEG, monodisperse PEG, and discrete PEG.
  • PEG polyethylene glycol
  • Polydisperse PEGs are a heterogeneous mixture of sizes and molecular weights whereas monodisperse PEGs are typically purified from heterogeneous mixtures and are therefore provide a single chain length and molecular weight.
  • the PEG units are discrete PEGs provide a single molecule with defined and specified chain length.
  • the polyethylene glycol is mPEG.
  • T 1 comprises a PEG unit which comprises one or multiple PEG chains.
  • the PEG chains can be linked together, for example, in a linear, branched or star shaped configuration.
  • the PEG unit in addition to comprising repeating PEG subunits, may also comprise non-PEG material (e.g., to facilitate coupling of multiple PEG chains to each other or to facilitate coupling to the amino acid).
  • Non-PEG material refers to the atoms in the PEG chain that are not part of the repeating —CH 2 CH 2 O— subunits.
  • the PEG chain can comprise two monomeric PEG chains linked to each other via non-PEG elements.
  • the PEG Unit can comprise two linear PEG chains attached to a central core that is attached to the amino acid (i.e., the PEG unit itself is branched).
  • the PEG unit may be covalently bound to the M A linker (e.g., to an amino acid in the M A linker) via a reactive group.
  • Reactive groups are those to which an activated PEG molecule may be bound (e.g., a free amino or carboxyl group).
  • N-terminal amino acids and lysines (K) have a free amino group; and C-terminal amino acid residues have a free carboxyl group.
  • Sulfhydryl groups e.g., as found on cysteine residues may also be used as a reactive group for attaching PEG.
  • the PEG unit may be attached to the M A linker (e.g., to an amino acid in the M A linker) by using methoxylated PEG (“mPEG”) having different reactive moieties, including, but not limited to, succinimidyl succinate (SS), succinimidyl carbonate (SC), mPEG-imidate, para-nitrophenylcarbonate (NPC), succinimidyl propionate (SPA), and cyanuric chloride.
  • mPEG methoxylated PEG having different reactive moieties, including, but not limited to, succinimidyl succinate (SS), succinimidyl carbonate (SC), mPEG-imidate, para-nitrophenylcarbonate (NPC), succinimidyl propionate (SPA), and cyanuric chloride.
  • mPEGs include, but are not limited to, mPEG-succinimidyl succinate (mPEG-SS), mPEG 2 -succinimidyl succinate (mPEG 2 -SS), mPEG-succinimidyl carbonate (mPEG-SC), mPEG 2 -succinimidyl carbonate (mPEG 2 -SC), mPEG-imidate, mPEG-para-nitrophenylcarbonate (mPEG-NPC), mPEG-imidate, mPEG 2 -para-nitrophenylcarbonate (mPEG 2 -NPC), mPEG-succinimidyl propionate (mPEG-SPA), mPEG 2 -succinimidyl propionate (mPEG 2 -SPA), mPEG-N-hydroxy-succinimide (mPEG-NHS), mPEG 2 -N-hydroxy-succinimide (
  • PEG species can be used, and substantially any suitable reactive PEG reagent can be used.
  • the reactive PEG reagent will result in formation of a carbamate or amide bond upon attachment to the Multifunctional Linker or M A linker (e.g., to an amino acid in the M A linker).
  • the reactive PEG reagents include, but are not limited to, mPEG 2 -N-hydroxy-succinimide (mPEG 2 -NHS), bifunctional PEG propionaldehyde (mPEG 2 -ALD), multi-Arm PEG, maleimide-containing PEG (mPEG(MAL) 2 , mPEG 2 (MAL)), mPEG-NH 2 , mPEG-succinimidyl propionate (mPEG-SPA), succinimide of mPEG butanoate acid (mPEG-SBA), mPEG-thioesters, mPEG-double Esters, mPEG-BTC, mPEG-ButyrALD, mPEG-acetaldehyde diethyl acetal (mPEG-ACET), heterofunctional PEGs (e.g., NH2-PEG-COOH, Boc-PEG-NHS, Fmoc-PEG-NHS, NHS-
  • the PEG unit comprises at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, at least 12 subunits, at least 13 subunits, at least 14 subunits, at least 15 subunits, at least 16 subunits, at least 17 subunits, at least 18 subunits, at least 19 subunits, at least 20 subunits, at least 21 subunits, at least 22 subunits, at least 23 subunits, or at least 24 subunits. In some such embodiments, the PEG unit comprises no more than about 72 subunits.
  • the PEG unit comprises at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, at least 12 subunits, at least 13 subunits, at least 14 subunits, at least 15 subunits, at least 16 subunits, at least 17 subunits, at least 18 subunits, at least 19 subunits, or at least 20 subunits.
  • the PEG unit comprises at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, at least 12 subunits, at least 13 subunits, at least 14 subunits, at least 15 subunits, at least 16 subunits, at least 17 subunits, or at least 18 subunits.
  • the PEG unit comprises at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, or at least 12 subunits.
  • the PEG unit comprises at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, or at least 12 subunits.
  • the PEG unit comprises at least 6 subunits, at least 7 subunits, or at least 8 subunits.
  • a linear PEG unit is:
  • M A linker indicates site of attachment to the M A linker (e.g., to an amino acid in the M A linker);
  • Y 71 is a PEG attachment unit
  • Y 72 is a PEG capping unit
  • Y 73 is an PEG coupling unit (i.e., for coupling multiple PEG subunit chains together);
  • d 9 is an integer from 2 to 72;
  • each d 10 is independently an integer from 1 to 72;
  • d 11 is an integer from 2 to 5.
  • d 9 is an integer from 2 to 24. In some embodiments, d 9 is an integer from 4 to 24. In some embodiments, d 9 is an integer from 6 to 24, from 8 to 24, from 10 to 24, or from 12 to 24.
  • d 9 is 8 or about 8, 12 or about 12, 24 or about 24.
  • each Y 72 is independently —C 1-10 alkyl, —C 2-10 alkyl-CO 2 H, —C 2-10 alkyl-OH, —C 2-10 alkyl-NH 2 , —C 2-10 alkyl-NH(C 1-3 alkyl), or C 2-10 alkyl-N(C 1-3 alkyl) 2 .
  • Y 72 is —C 1-10 alkyl, —C 2-10 alkyl-CO 2 H, —C 2-10 alkyl-OH, or —C 2-10 alkyl-NH 2 .
  • the PEG coupling unit is part of the PEG unit and is non-PEG material that acts to connect two or more chains of repeating CH 2 CH 2 O— subunits.
  • the PEG coupling unit Y 73 is —C 2-10 alkyl-C(O)—NH—, —C 2-10 alkyl-NH—C(O)—, —C 2-10 alkyl-NH—, —C 2-10 alkyl-C(O)—, —C 2-10 alkyl-O—, or —C 2-10 alkyl-S—.
  • each Y 73 is independently —C 1-10 alkyl-C(O)—NH—, —C 1-10 alkyl-NH—C(O)—, —C 2-10 alkyl-NH—, —C 2-10 alkyl-O—, —C 1-10 alkyl-S—, or —C 1-10 alkyl-NH—.
  • the PEG attachment unit is part of the PEG unit and acts to link the PEG unit to the M A linker (e.g., to an amino acid in the M A linker).
  • the amino acid has a functional group that forms a bond with the PEG Unit.
  • the functional groups for attachment of the PEG unit to the amino acid include sulfhydryl groups to form disulfide bonds or thioether bonds, aldehyde, ketone, or hydrazine groups to form hydrazone bonds, hydroxylamine to form oxime bonds, carboxylic or amino groups to form peptide bonds, carboxylic or hydroxy groups to form ester bonds, sulfonic acids to form sulfonamide bonds, alcohols to form carbamate bonds, and amines to form sulfonamide bonds or carbamate bonds or amide bonds.
  • the PEG unit can be attached to the amino acid, for example, via a disulfide, thioether, hydrazone, oxime, peptide, ester, sulfonamide, carbamate, or amide bond.
  • the reaction for attaching the PEG unit can be a cycloaddition, addition, addition/elimination or substitution reaction, or a combination thereof when applicable.
  • linear PEG units examples include:
  • each d 9 is independently an integer from 4 to 24, 6 to 24, 8 to 24, 10 to 24, 12 to 24, 14 to 24, or 16 to 24.
  • d 9 is about 8, about 12, or about 24. In some embodiments, d 9 is about 8.
  • the PEG unit is from about 300 Da to about 5 kDa; from about 300 Da to about 4 kDa; from about 300 Da to about 3 kDa; from about 300 Da to about 2 kDa; or from about 300 Da to about 1 kDa. In some embodiments, the PEG unit has at least 6 subunits or at least 8, 10 or 12 subunits. In some embodiments, the PEG unit has at least 6 subunits or at least 8, 10 or 12 subunits but no more than 24 subunits.
  • suitable polyethylene glycols may have a free hydroxy group at each end of the polymer molecule, or may have one hydroxy group etherified with a lower alkyl, e.g., a methyl group.
  • suitable polyethylene glycols are derivatives of polyethylene glycols having esterifiable carboxy groups.
  • polyethylene glycols are commercially available under the trade name PEG, usually as mixtures of polymers characterized by an average molecular weight.
  • polyethylene glycols having an average molecular weight from about 300 to about 5000.
  • polyethylene glycols having an average molecular weight from about 600 to about 1000.
  • hydrophilic groups that are suitable for the conjugates, scaffolds, and methods disclosed herein can be found in e.g., U.S. Pat. No. 8,367,065 column 13; U.S. Pat. No. 8,524,696 column 6; WO2015/057699 and WO 2014/062697, the contents of each of which are hereby incorporated by reference in their entireties.
  • the STING agonist drug moiety (D) is a compound of Formula (A):
  • Y 1 , Y 2 , Z 1 and Z 2 are each independently O, S, C or N;
  • X 1 , X 2 , W 1 and W 2 are each independently C or N;
  • X 3 and X 4 are each independently S or NR f ;
  • X 5 is N or CR A2 ;
  • X 6 is N or CR A1 ;
  • R 3 and R 5 are each independently —CON(R d )(R f ), —CH 2 N(R d )(R f ), —N(R d )(R f ), —N(R d )CO(R f ), —CH 2 N(R d )CO(R f ) or one of R 3 and R 5 is —CON(R d )(R f ), —CH 2 N(R d )(R f ), —N(R d )(R f ), —N(R d )CO(R f ) or —CH 2 N(R d )CO(R f ), and the other of R 3 and R 5 is H, —COOH, or —CO 2 (R C );
  • R c is C 1-4 alkyl
  • R A2 and R A1 are each independently H, halogen, hydroxy, amino, amino(C 1-4 alkyl)-, optionally substituted (C 1-6 alkyl), or optionally substituted (C 1-6 alkyl)oxy-, wherein C 1-6 alkyl of said optionally substituted (C 1-6 alkyl), or optionally substituted (C 1-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, C 1-4 alkoxyl, —N(R e )(R f ), —CO 2 (R f ), —CON(R e )(R f ), and —COOH;
  • each R d is independently H, hydroxy, or C 1-4 alkyl
  • R e is selected from H, (C 1-4 alkyl), —CO(C 1-4 alkyl), —OCO(C 1-4 alkyl), and —CO 2 (C 1-4 alkyl);
  • each R f is independently H, hydroxy, or (C 1-4 alkyl);
  • R 14 and R C2 are each independently absent or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted by a substituent selected from halogen, —OR c , —NR c R d , —CO 2 R c , —CONR c R d , —SO 2 NR c R d , and —OCONR c R d ;
  • R 16 and R C1 are each independently absent, H or C 1-4 alkyl
  • R 15 , R 17 , R 18 , or R 19 are each independently absent, H, or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted by a substituent selected from halogen, —OR c , —NR c R d , —CO 2 R C , —CONR c R d , —SO 2 NR c R d , and —OCONR c R d ;
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound of Formula (A-a):
  • Y 1 , Y 2 , Z 1 , Z 2 , X 1 , X 2 , W 1 , W 2 , X 3 , X 4 , R 3 , R 5 , R c , R d , R e , R f , R 14 , R C2 , R 16 , R C1 , R 15 , R 17 , R 18 , and R 19 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is halogen, hydroxyl, optionally substituted (C 1-6 alkyl), substituted (C 1-6 alkyl)oxy-, optionally substituted (C 1-6 alkyl)amino-, or optionally substituted (C 1-6 alkyl)(C 1-4 alkyl)amino-, wherein C 1-6 alkyl of said optionally substituted (C 1-6 alkyl) or substituted (C 1-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, C 1-4 alkoxyl, —N(R e )(R f ), —CO 2 (R f ), —CON(R e )(R f ), and —COOH;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-b):
  • Y 1 , Y 2 , Z 1 , Z 2 , X 1 , X 2 , W 1 , W 2 , X 4 , X 5 , X 6 , R 3 , R 5 , R c , R A2 , R A1 , R d , R e , R f , R 14 , R C2 , R 16 , R C1 , R 15 , R 17 , R 18 , and R 19 are as defined in Formula (A);
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-c):
  • Y 2 , Z 2 , X 2 , W 2 , X 3 , X 4 , X 5 , X 6 , R 3 , R 5 , R c , R A2 , R A1 , R d , R e , R f , R 14 , R C2 , R 16 , R C1 , R 15 , R 17 , R 18 , and R 19 are as defined in Formula (A);
  • W 1 , X 1 , Y 1 , and Z 1 is N and the additional W 1 , X 1 , Y 1 , and Z 1 are O, S, or C;
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-d):
  • Y 1 , Y 2 , Z 1 , Z 2 , X 1 , X 2 , W 1 , W 2 , X 3 , R 3 , R 5 , R c , R d , R e , R f , R 14 , R A2 , R C2 , R 16 , R C1 , R 15 , R 17 , R 18 , and R 19 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-e):
  • Y 1 , Y 2 , Z 1 , Z 2 , X 1 , X 2 , X 3 , W 1 , W 2 , R A1 , R 3 , R 5 , R c , R d , R e , R f , R 14 , R C2 , R 16 , R C1 , R 15 , R 17 , R 18 , and R 19 are as defined in Formula (A);
  • X 6 is CR A1 ;
  • R A1 is connected to L D via a functional group of R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-f):
  • X 2 , X 3 , X 4 , X 5 , X 6 , W 2 , Y 2 , Z 2 R 3 , R 5 , R c , R A2 , R A1 , R d , R e , R f , R 16 , R 17 , R 18 , R 19 , R C2 , and R C1 , are as defined in Formula (A), and
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-f1):
  • X 2 , X 3 , X 4 , W 2 , Y 2 , Z 2 , R 3 , R 5 , R c , R d , R e , R f , R 16 , R* 2 , R 17 , R 18 , R 19 , R C2 , and R C1 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-f2):
  • X 2 , X 4 , X 5 , X 6 , W 2 , Y 2 , Z 2 R 3 , R 5 , R c , R A2 , R A1 , R d , R e , R C1 , R C2 , R 16 , R 17 , R 18 , R 19 , and R f are as defined in Formula (A);
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-f3):
  • X 2 , X 4 , W 2 , Y 2 , Z 2 , R 3 , R 5 , R c , R d , R e , R f , R 16 , R A2 , R C2 , R 16 , R 17 , R 18 , R 19 , and R C1 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-f4):
  • X 2 , X 4 , W 2 , Y 2 , Z 2 , R 3 , R 5 , R c , R d , R e , R f , R 16 , R A2 , R C2 , R 16 , R 17 , R 18 , R 19 , and R C1 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-f5):
  • X 2 , W 2 , Y 2 , Z 2 , R 3 , R 5 , R c , R d , R e , R f , R 16 , R A2 , R C2 , R 16 , R 17 , R 18 , R 19 , and R C1 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-g):
  • X 3 , X 4 , X 5 , X 6 , R 3 , R 5 , R c , R A2 , R A1 , R C2 , R 17 , R 18 , R 19 , R d , R e , R f , R 16 , and R C1 are as defined in Formula (A);
  • Y 2 and Z 2 are each independently O, S, C or N;
  • X 2 and W 2 are each independently C or N;
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-g1):
  • X 2 , W 2 , Y 2 , Z 2 , X 3 , X 4 , X 5 , R 3 , R 5 , R c , R d , R e , R f , R* 2 , R C2 , R 17 , R 18 , R 19 , R 16 , and R C1 are as defined in Formula (A); wherein: (i) R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-g2):
  • X 2 , X 4 , X 5 , X 6 , W 2 , Y 2 , Z 2 , R 3 , R 5 , R c , R A1 , R C2 , R 17 , R 18 , R 19 , R d , R e , R f , R 16 , and R C1 are as defined in Formula (A);
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-g3):
  • X 2 , X 4 , W 2 , Y 2 , Z 2 , R 3 , R 5 , R c , R A2 , R C2 , R 17 , R 18 , R 19 , R 16 , and R C1 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 ; and
  • R A2 is connected to L D via a functional group of R A2 .
  • the STING agonist drug moiety is a compound is of Formula (A-g4):
  • X 2 , X 4 , W 2 , Y 2 , Z 2 R 3 , R 5 , R c , R d , R e , R f , R A2 , R C2 , R 17 , R 18 , R 19 , R 16 , and R C1 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-g5):
  • X 2 , W 2 , Y 2 , Z 2 , R 3 , R 5 , R c , R d , R e , R f , R A2 , R C2 , R 17 , R 18 , R 19 , R 16 , and R C1 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 is connected to L D via a functional group of R A2 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-h):
  • X 1 , W 1 , Y 1 , Z 1 , X 3 , X 4 , X 5 , X 6 , R 3 , R 5 , R c , R A2 , R A1 , R d , R e , R f , R 14 , R 15 , R 18 , R 19 , R 16 , and R C1 are as defined in Formula (A); wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-h1):
  • X 1 , X 3 , W 1 , Y 1 , Z 1 , X 5 , X 6 , R 3 , R 5 , R c , R A2 , R A1 , R d , R e , R f , R 14 , R 15 , R 18 , R 19 , R 16 , and R C1 are as defined in Formula (A);
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety is a compound is of Formula (A-h2):
  • X 1 , X 3 , W 1 , Y 1 , Z 1 , R 3 , R 5 , R c , R d , R e , R f , R A2 , R 14 , R 15 , R 18 , R 19 , R 16 , and R C1 are as defined in Formula (A);
  • X 5 is CR A2 ;
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • the STING agonist drug moiety (D) is a compound of Formula (A), wherein the compound is of Formula (A-i):
  • Y 1 , Y 2 , Z 1 , Z 2 , X 1 , X 2 , X 3 , X 6 , W 1 , W 2 , R A1 , R A2 , R c , R d , R e , R f , R 14 , R C2 , R 16 , R C1 , R 15 , R 17 , R 18 , and R 19 are as defined in Formula (A);
  • R A2 and R A1 wherein: (i) at least one of R A2 and R A1 is present, and wherein at least one of R A2 and R A1 is connected to L D via at least one functional group of the R A2 and/or R A1 ; or (ii) at least one of R C2 and R C1 is present, and wherein at least one of R C2 and R C1 is connected to L D via at least one functional group of the R C2 and/or R C1 .
  • each STING agonist drug moiety (D) independently is:
  • R 2 is absent, —O— or —NR 4 —;
  • R 4 is H or C 1-3 alkyl;
  • each STING agonist drug moiety (D) independently is:
  • R 2 is absent, —O— or —NR 4 —;
  • R 4 is H or C 1-3 alkyl;
  • each STING agonist drug moiety (D) independently is:
  • R 2 is absent, —O— or —NR 4 —;
  • R 4 is H or C 1-3 alkyl;
  • each STING agonist drug moiety (D) independently is:
  • R 2 is absent, —O— or —NR 4 —;
  • R 4 is H or C 1-3 alkyl;
  • each STING agonist drug moiety (D) independently is:
  • R 2 is absent, —O— or —NR 4 —;
  • R 4 is H or C 1-3 alkyl;
  • PBRM Protein-Based Recognition-Molecule
  • 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 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. 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.
  • 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.
  • the conjugate itself may also be an effective delivery system, without the need for specific targeting.
  • the protein-based recognition molecule can target the conjugate to a location within the cell, such as the nucleus, the cytoplasm, or the endosome, for example.
  • the protein-based recognition molecule can enhance cellular binding to receptors, or cytoplasmic transport to the nucleus and nuclear entry or release from endosomes or other intracellular vesicles.
  • the protein-based recognition molecule is an antibody, an antibody fragment, a protein, a peptide, or a peptide mimic.
  • 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.
  • 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).
  • the parent antibody or antibody fragment may be wild type or mutated.
  • 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 known in the art is engineered to form the antibody fragment (e.g., a cysteine engineered Fab antibody fragment).
  • a single site mutation of a Fab gives a single 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. 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.
  • 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, CD154, CD326, CEA, CEACAM-5, clumping factor, Clec9A, CSFR1, CTLA-4, CXCR2, DEC205,
  • 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, 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
  • 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, phosphatidyl serine, 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, flgitumumab, gemtuzumab, glembatumumab, ibritumomab, igovomab, intetumumab, inot
  • 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 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.
  • RGD peptides integrin targeting peptides
  • LHRH receptor targeting peptides LHRH receptor targeting peptides
  • ErbB2 (HER2) receptor targeting peptides ErbB2 (HER2) receptor targeting peptides
  • PSMA prostate specific membrane bound antigen
  • lipoprotein receptor LRP1 targeting
  • ApoE protein derived peptides ApoA protein peptides
  • somatostatin receptor targeting peptides chlorotoxin derived peptid
  • 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 protein-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 cell surface markers
  • 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 protein-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 protein-drug conjugates or protein conjugates used in the disclosure comprise protein-based recognition molecules are antibodies against antigens, such as, for example, Trastuzumab, Cetuximab, Rituximab, Bevacizumab, Epratuzumab, Veltuzumab, Labetuzumab, 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.
  • antigens such as, for example, Trastuzuma
  • the protein-drug conjugates or protein conjugates of the disclosure comprise protein-based recognition molecules which are CSRF1, CD11b, DEC205, clec9A, CD103, B7H4, mesothelin, PTK7, Ly6E, FAP, fibronectin-EDB, Her-2 or NaPi2b antibodies.
  • the NaPi2b antibodies suitable for conjugation bind to the extracellular region of SLC34A2.
  • the present disclosure provides NaPi2b-targeted monoclonal antibodies that specifically recognizes NaPi2b, also known as sodium-dependent phosphate transport protein 2B.
  • the NaPi2b antibodies used in the conjugates disclosed herein are capable of and useful in modulating, e.g., blocking, inhibiting, reducing, antagonizing, neutralizing or otherwise interfering with at least one biological activity of NaPi2b.
  • antibodies disclosed herein also include antibodies that bind soluble NaPi2b.
  • the NaPi2b antibodies specifically bind to an epitope on an extracellular domain (ECD) of the human NaPi2b. These antibodies are collectively referred to herein as “NaPi2b” antibodies.
  • the NaPi2b antibody-drug conjugates provided herein include antibodies that bind to a NaPi2b epitope with an equilibrium dissociation constant (K d or K D ) of ⁇ 1 ⁇ M (e.g., ⁇ 100 nM; ⁇ 10 nM; and ⁇ 1 nM).
  • K d or K D equilibrium dissociation constant
  • the NaPi2b antibodies used in the antibody-drug conjugates disclosed herein exhibit a K d in the range approximately between ⁇ 1 nM to about 1 pM.
  • the NaPi2b antibody-drug conjugates provided herein can include antibodies that serve to modulate, block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with the functional activity of NaPi2b.
  • functional activities of NaPi2b include for example, participating in the transcellular inorganic phosphate (Pi) absorption, thereby contributing to the maintenance of phosphate homeostasis in the body.
  • the NaPi2b antibodies completely or partially inhibit NaPi2b functional activity by partially or completely modulating, blocking, inhibiting, reducing antagonizing, neutralizing, or otherwise interfering with transcellular inorganic phosphate absorption.
  • the NaPi2b antibodies are considered to completely modulate, block, inhibit, reduce, antagonize, neutralize, or otherwise interfere with NaPi2b functional activity when the level of NaPi2b functional activity in the presence of the NaPi2b antibody is decreased by at least 95%, e.g., by 96%, 97%, 98%, 99%, or 100% as compared to the level of NaPi2b functional activity in the absence of binding with a NaPi2b antibody described herein.
  • the NaPi2b antibodies are considered to partially modulate, block, inhibit, reduce, antagonize, neutralize or otherwise interfere with NaPi2b functional activity when the level of NaPi2b activity in the presence of the NaPi2b 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 NaPi2b activity in the absence of binding with a NaPi2b antibody described herein.
  • exemplary antibodies disclosed herein include, the XMT-1535 antibody. These antibodies show specificity for human NaPi2b and they have been shown to inhibit NaPi2b activity.
  • NaPi2b human or humanized monoclonal antibody, XMT-1535 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.
  • the variable heavy chain region and variable light chain region for each antibody are shaded in the amino acid sequences below.
  • the complementarity determining regions (CDRs) of the heavy chain and the light chain are underlined in the amino acid sequences presented below.
  • the amino acids encompassing the complementarity determining regions (CDRs) for the XMT-1535 antibody are disclosed in U.S. Pat. No. 8,603,474.
  • XMT-1535 sequences SEQ ID NO: Sequence Description 1 XMT-1535 Heavy Chain Amino Acid Sequence 2 XMT-1535 Light Chain Amino Acid Sequence 3 XMT-1535 Heavy chain variable region 4 XMT-1535 Light chain variable region 5 XMT-1535 CDRH1 6 XMT-1535 CDRH2 7 XMT-1535 CDRH3 8 XMT-1535 CDRL1 9 XMT-1535 CDRL2 10 XMT-1535 CDRL3 11 XMT-1535 IgG1 Heavy chain constant region 12 XMT-1535 Light chain constant region 13 XMT-1535 Heavy chain variable region nucleic acid sequence 14 XMT-1535 Light chain variable region nucleic acid sequence 15 Full-length human NaPi2b sequence
  • Antibodies disclosed herein specifically bind to an epitope on an extracellular domain (ECD) of the human NaPi2b.
  • ECD extracellular domain
  • a monoclonal antibody has the same specificity as a monoclonal antibody disclosed herein (e.g., XMT-1535, 10H1.11.4B) by ascertaining whether the former prevents the latter from binding to a natural binding partner or other molecule known to be associated with NaPi2b. 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.
  • 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 NaPi2b (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 NaPi2b. 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.
  • Screening of monoclonal antibodies disclosed herein can also be carried out, e.g., by measuring NaPi2b-mediated activity, and determining whether the test monoclonal antibody is able to modulate, block, inhibit, reduce, antagonize, neutralize or otherwise interfere with NaPi2b activity.
  • the antibodies disclosed herein comprise a heavy chain variable region having an amino acid sequence at least 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: 3 and a light chain variable region having an amino acid sequence at least 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: 4.
  • the antibodies disclosed herein comprise a heavy chain amino acid sequence at least 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: 1 and a light chain amino acid sequence at least 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: 2.
  • the antibodies disclosed herein comprise the heavy chain variable region amino acid sequence of SEQ ID NO: 3 and the light chain variable region amino acid sequence of SEQ ID NO: 4.
  • the antibodies disclosed herein comprise the heavy chain amino acid sequence of SEQ ID NO: 1 and the light chain amino acid sequence of SEQ ID NO: 2.
  • 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: 8, the CDRL2 amino acid sequence of SEQ ID NO: 9, and the CDRL3 amino acid sequence of SEQ ID NO: 10.
  • the antibodies disclosed herein that comprises the amino acid sequence at least 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: 5; a CDRH2 that comprises the amino acid sequence at least 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: 6; a CDRH3 that comprises the amino acid sequence at least 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: 7; a CDRL1 that comprises the amino acid sequence at 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%
  • 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 and in some particular embodiments, up to 1, 2, 3, or 4 conservative amino acid substitutions may be present in each CDR sequence, e.g., SEQ ID NOs: 5-10.
  • a monoclonal antibody has the same specificity as a monoclonal antibody XMT-1535, by ascertaining whether the former prevents the latter from binding to a natural binding partner or other molecule known to be associated with NaPi2b. 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.
  • an alternative method for determining whether a monoclonal antibody has the specificity of a monoclonal antibody disclosed herein is to pre-incubate the monoclonal antibody disclosed herein with soluble NaPi2b (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 NaPi2b. In some embodiments, if the monoclonal antibody being tested is inhibited then it has the same, or functionally equivalent, epitopic specificity as the monoclonal antibody disclosed herein.
  • Screening of monoclonal antibodies disclosed herein can be also carried out, e.g., by measuring NaPi2b-mediated activity, and determining whether the test monoclonal antibody is able to modulate, block, inhibit, reduce, antagonize, neutralize or otherwise interfere with NaPi2b activity.
  • the NaPi2b antibodies suitable for conjugation can be generated and purified by well-known techniques e.g., WO 2009/097128, WO 2017/160754, and U.S. Ser. No. 16/136,706, each of which is incorporated herein in its entirety by reference.
  • the HER2 antibodies suitable 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, for example, the HER2 antibodies provided herein exhibit a K d 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 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 antibodies disclosed herein include, the XMT-1519 antibody. This antibody show specificity for human HER2 and they have been shown to inhibit the functional activity of HER2 in vitro.
  • HER-2 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 II below.
  • the variable heavy chain region and variable light chain region for each antibody are shaded in the amino acid sequences below.
  • the complementarity determining regions (CDRs) of the heavy chain and the light chain are underlined in the amino acid sequences presented below.
  • HER2 human or humanized monoclonal antibody XMT-1519 sequences SEQ ID NO: Sequence Description 16 Full-length human HER2 receptor 17 XMT-1519 Heavy chain variable region 18 XMT-1519 IgG1 Heavy chain constant region 19 XMT-1519 Heavy Chain Amino Acid Sequence 20 XMT-1519 CDRH1 21 XMT-1519 CDRH2 22 XMT-1519 CDRH3 23 XMT-1519 Heavy Chain variable region nucleic acid sequence 24 XMT-1519 Light chain variable region 25 XMT-1519 Light chain constant region 26 XMT-1519 Light Chain Amino Acid Sequence 27 XMT-1519 CDRL1 28 XMT-1519 CDRL2 29 XMT-1519 CDRL3 30 XMT-1519 Light Chain variable region nucleic acid sequence 31 Extracellular domain (ECD) of the human HER2 receptor
  • 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: 16.
  • 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: 31.
  • the antibodies of the present disclosure exhibit HER2 binding characteristics that differ from antibodies described in the art.
  • 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.
  • the antibodies disclosed herein can internalize efficiently into HER2-expressing cells without promoting cell proliferation.
  • 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: 16 or residues 452 to 531 of SEQ ID NO: 31.
  • 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 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: 16 or residues 529 to 627 of SEQ ID NO: 31.
  • 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: 16 or residues 452 to 500 of SEQ ID NO: 31.
  • 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: 16, and residues 521, 525, and 530 of SEQ ID NO: 31.
  • 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.
  • 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: 16 or residues 520 to 531 of SEQ ID NO: 31.
  • 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: 16 or residues 453, 456, 473, 476, 495, 496, 497 and 499 of SEQ ID NO: 31.
  • 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: 16 or residues 453, 473, 476, 495, 497 and 499 of SEQ ID NO: 31.
  • 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 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 NOs: 17 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: 24.
  • 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: 19 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: 26.
  • the antibodies disclosed herein comprise the heavy chain variable region amino acid sequence of SEQ ID NO: 17 and the light chain variable region amino acid sequence of SEQ ID NO: 24.
  • the antibodies disclosed herein comprise the heavy chain amino acid sequence of SEQ ID NO: 19 and the light chain amino acid sequence of SEQ ID NO: 26.
  • the antibodies disclosed herein comprise the CDRH1 amino acid sequence of SEQ ID NO: 20, the CDRH2 amino acid sequence of SEQ ID NO: 21, the CDRH3 amino acid sequence of SEQ ID NO: 22, the CDRL1 amino acid sequence of SEQ ID NO: 27, the CDRL2 amino acid sequence of SEQ ID NO: 28, and the CDRL3 amino acid sequence of SEQ ID NO: 29.
  • 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.
  • up to 1, 2, 3, or 4 conservative amino acid substitutions may be present in each CDR sequence, e.g., SEQ ID NOs: 20-22 and 27-29.
  • 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.
  • 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.
  • 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.
  • 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., WO 2015/195917 and PCT/US2018/019873, each of which is incorporated herein in its entirety by reference.
  • conjugates of the disclosure comprise one or more occurrences of D, wherein D is a STING agonist, wherein the one or more occurrences of D may be the same or different.
  • one or more occurrences of PBRM is attached to the Linker-Drug moiety, wherein the one or more occurrences of PBRM may be the same or different.
  • one or more Linker-Drug moieties that comprises one or more occurrences of D are connected to one PBRM (e.g., a antibody).
  • the conjugate of the disclosure comprise a PBRM that has a molecular weight of about 40 kDa or greater (e.g., about 60 kDa or greater; about 80 kDa or greater; about 100 kDa or greater; about 120 kDa or greater; about 140 kDa or greater; about 160 kDa or greater; about 180 kDa or greater; or about 200 kDa or greater, or about 40-200 kDa, about 40-180 kDa, about 40-140 kDa, about 60-200 kDa, about 60-180 kDa, about 60-140 kDa, about 80-200 kDa, about 80-180 kDa, about 80-140 kDa, about 100-200 kDa, about 100-180 kDa, or about 100-140 kDa) and has a sulfhydryl (i.e., —SH or thiol) group.
  • the total number of sulfide bonds formed between the Linker-drug moieties and the PBRM is 10 or less (e.g., 8, 6, 4, or 2).
  • the PBRM has a molecular weight of about 40 kDa or greater (e.g., about 60 kDa or greater, about 80 kDa or greater, about 100 kDa or greater, about 120 kDa or greater, about 140 kDa or greater, about 160 kDa or greater, or about 180 kDa or greater; or about 40-200 kDa, about 40-180 kDa, about 40-140 kDa, about 60-200 kDa, about 60-180 kDa, about 60-140 kDa, about 80-200 kDa, about 80-180 kDa, about 80-140 kDa, about 100-200 kDa, about 100-180 kDa, or about 100-140 kDa).
  • about 40 kDa or greater e.g., about 60 kDa or greater, about 80 kDa or greater, about 100 kDa or greater, about 120 kDa or greater, about 140
  • the PBRM for conjugation with one or more Linker-Drug moieties, has a molecular weight of about 40 kDa to about 200 kDa. In some embodiments, for conjugation with one or more Linker-Drug moieties, the PBRM has a molecular weight of about 40 kDa to about 80 kDa.
  • the PBRM for conjugation with one or more Linker-Drug moieties, has a molecular weight of 40 kDa to 200 kDa. In some embodiments, for conjugation with one or more Linker-Drug moieties, the PBRM has a molecular weight of 40 kDa to 80 kDa.
  • PBRMs in this molecular weight range include, but are not limited to, for example, antibody fragments, such as, for example, Fabs.
  • the PBRM for conjugation with one or more Linker-Drug moieties, has a molecular weight of about 60 kDa to about 120 kDa.
  • the PBRM for conjugation with one or more Linker-Drug moieties, has a molecular weight of 60 kDa to 120 kDa.
  • PBRMs in this molecular weight range include, but are not limited to, for example, camelids, Fab2, scFvFc, and the like.
  • the PBRM for conjugation with one or more Linker-Drug moieties, has a molecular weight of about 140 kDa to about 180 kDa.
  • the PBRM for conjugation with one or more Linker-Drug moieties, has a molecular weight of 140 kDa to 180 kDa.
  • PBRMs in this molecular weight range include, but are not limited to, for example, full length antibodies, such as, IgG, IgM.
  • the targeting ligands, the linkers and the drug or prodrug fragments described herein can be assembled into the conjugate or scaffold of the disclosure, for example according to the disclosed techniques and methods.
  • Therapeutic and targeting conjugates of the disclosure, and methods for producing them, are described below by way of non-limiting example.
  • the total number of sulfide bonds formed between the Linker-Drug moiety and the PBRM is 8 or less.
  • the total number of sulfide bonds formed between the Linker-Drug moiety and the PBRM is 8. In some embodiments, the total number of sulfide bonds formed between the Linker-Drug moiety and the PBRM (or total number of attachment points) is 6. In some embodiments, the total number of sulfide bonds formed between the Linker-Drug moiety and the PBRM (or total number of attachment points) is 5. In some embodiments, the total number of sulfide bonds formed between the Linker-Drug moiety and the PBRM (or total number of attachment points) is 4.
  • the total number of sulfide bonds formed between the Linker-Drug moiety and the PBRM is 3. In some embodiments, the total number of sulfide bonds formed between the Linker-Drug moiety and the PBRM (or total number of attachment points) is 2.
  • the ratio between Linker-Drug moiety and the PBRM is between about 1:1 and about 8:1. In some embodiments, the ratio between Linker-Drug moiety and the PBRM is between about 1:1 and about 6:1. In some embodiments, the ratio between Linker-Drug moiety and the PBRM is between about 1:1 and about 4:1. In some embodiments, the ratio between Linker-Drug moiety and the PBRM is between about 2:1 and about 2:1.
  • the ratio between Linker-Drug moiety and the PBRM is between about 6:1 and about 8:1.
  • the ratio between Linker-Drug moiety and the PBRM is about 8:1.
  • the ratio between Linker-Drug moiety and the PBRM is about 6:1.
  • the disclosure also relates to a Linker-Drug moiety comprising at least two moieties, wherein each moiety is capable of conjugation to a thiol group in a PBRM so as to form a protein-Linker-Drug conjugate.
  • one or more thiol groups of a PBRM are produced by reducing a protein.
  • the one or more thiol groups of the PBRM may then react with one or more Linker-Drug moieties that are capable of conjugation to a thiol group from the PBRM with the Linker-Drug moiety.
  • the at least two moieties connected to the PBRM are maleimide groups.
  • the antibodies may be activated for conjugation with Linker-Drug moiety by treatment with a reducing agent such as DTT (Cleland's reagent, dithiothreitol) or TCEP (tris(2-carboxyethyl)phosphine hydrochloride).
  • a reducing agent such as DTT (Cleland's reagent, dithiothreitol) or TCEP (tris(2-carboxyethyl)phosphine hydrochloride).
  • full length, monoclonal antibodies can be reduced with an excess of TCEP to reduce disulfide bonds (e.g., between the cysteine present in the corresponding parent antibodies) to yield a reduced form of the antibody.
  • the newly introduced and unpaired cysteine may remain available for reaction with Linker-Drug moiety to form the antibody conjugates of the present disclosure.
  • an excess of Linker-drug moiety is added to effect conjugation and form the antibody-drug conjugate, and the conjug
  • a PBRM for conjugating of the Linker-Drug moiety, has a molecular weight of 40 kDa or greater (e.g., 60 kDa or greater; 80 kDa or greater; or 100 kDa or greater; 120 kDa or greater; 140 kDa or greater; 160 kDa or greater or 180 kDa or greater).
  • the ratio of PBRM per Linker-Drug moiety is between about 1:1 and about 1:8; about 1:1 and about 1:6; between about 1:1 and about 1:5; between about 1:1 and about 1:4; between about 1:1 and about 1:3; or between about 1:1 and about 1:2.
  • PBRMs in this molecular weight range include, but are not limited to, for example, full length antibodies, such as, IgG, IgM.
  • a PBRM for conjugation with one or more Linker-Drug moieties a PBRM has a molecular weight of 60 kDa to 120 kDa. In some embodiments, the ratio of PBRM per Linker-Drug moiety is about 1:1 and about 1:8; between about 1:1 and about 1:6; between about 1:1 and about 1:5; between about 1:1 and about 1:4; between about 1:1 and about 1:3; or between about 1:1 and about 1:2.
  • PBRMs in this molecular weight range include, but are not limited to, for example, antibody fragments such as, for example Fab2, scFcFv and camelids.
  • a PBRM for conjugation with one or more Linker-Drug moieties a PBRM has a molecular weight of 40 kDa to 80 kDa. In some embodiments, the ratio of PBRM per Linker-Drug moiety is about 1:1 and about 1:8; between about 1:1 and about 1:6; between about 1:1 and about 1:5; between 1:1 and about 1:4; between about 1:1 and about 1:3, or between about 1:1 and about 1:2.
  • PBRMs in this molecular weight range include, but are not limited to, for example, antibody fragments, such as, Fabs.
  • the disclosure features a scaffold useful to conjugate with either or both of a protein-based recognition-molecule (PBRM) and a STING agonist moiety (D).
  • PBRM protein-based recognition-molecule
  • D STING agonist moiety
  • the drug-carrying scaffolds i.e., without linking to a PBRM
  • Conjugates and scaffolds disclosed herein can be purified (i.e., removal of any starting materials) by extensive diafiltration. If necessary, additional purification by size exclusion chromatography can be conducted to remove any aggregated conjugates.
  • the conjugates as purified typically contain less than 5% (e.g., ⁇ 2% w/w) aggregated conjugates as determined by SEC; less than 0.5% (e.g., ⁇ 0.1% w/w) free (unconjugated) drug as determined by RP-HPLC; less than 1% drug carrying-peptide-containing scaffolds as determined by SEC and less than 2% (e.g., ⁇ 1% w/w) unconjugated PBRM as determined by HIC-HPLC.
  • the scaffold is selected from the scaffolds described in Table A1.
  • the scaffold is selected from the scaffolds described in Table A2.
  • the conjugate is selected from the conjugates described in Table B1.
  • the conjugate is selected from the conjugates described in Table B2.
  • the conjugate is:
  • the conjugate is:
  • d 15 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R C1 , R C2 , X 3 , X 4 , X 6 , X 1 , W 1 , Y 1 , Z 1 , X 2 , W 2 , Y 2 , Z 2 , are as defined herein.
  • the conjugate is:
  • d 15 is as defined herein.
  • compositions comprising a conjugate described herein and one or more pharmaceutically acceptable carriers or excipients.
  • compositions containing conjugates of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the conjugates into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, CremophorELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the conjugates in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the conjugates into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the conjugates can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein conjugates in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the conjugates are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the conjugates are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the conjugates can be prepared with pharmaceutically acceptable carriers that will protect the conjugates against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, poly orthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of conjugates can be calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the conjugates and the particular therapeutic effect to be achieved.
  • the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease and also preferably causing complete regression of the disease.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • 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 a conjugate disclosed herein.
  • 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 a conjugate disclosed herein.
  • the present disclosure provides a method of activating or enhancing an activity of a STING in a subject, comprising administering to the subject a conjugate disclosed herein.
  • 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 conjugate disclosed herein.
  • the present disclosure provides a conjugate disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides a conjugate disclosed herein for use in treating a disease or disorder in a subject in need thereof.
  • the present disclosure provides a conjugate disclosed herein for treating a STING-mediated disease or disorder in a subject.
  • the present disclosure provides use of a conjugate disclosed herein for treating a cancer in a subject in need thereof.
  • the present disclosure provides use of a conjugate 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 conjugate 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 conjugate 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 conjugate 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 conjugate 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 conjugate disclosed herein for the treatment of a disease or disorder in a subject in need thereof.
  • the present disclosure provides use of a conjugate disclosed herein for treating a STING-mediated disease or disorder in a subject.
  • the present disclosure provides use of a conjugate disclosed herein for treatment of a cancer in a subject in need thereof.
  • the conjugate 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 efficient amount of at least one conjugate of the disclosure; wherein said conjugate releases one or more therapeutic agent 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 efficient amount of at least one conjugate of the disclosure; wherein said conjugate releases one or more therapeutic agent upon biodegradation.
  • the conjugate is an antibody-STING agonist conjugate.
  • the disease or disorder is cancer.
  • the disclosure provides methods of treatment or prevention of STING mediated diseases and disorders.
  • diseases/disorders include, but are not limited to, cancer, infectious disease (e.g., HIV, HBV, HCV, HPV, and influenza), and vaccine adjuvant.
  • the STING pathway may induce anti-tumor immunity by upregulating IFN ⁇ and interferon (IFN)-stimulated genes (ISGs) in many cell types within tumors in response to agonistic, cytosolic nucleic acids.
  • IFN interferon
  • ISGs interferon-stimulated genes
  • the present disclosure provides a conjugate disclosed herein for use as a vaccine adjuvant.
  • a conjugate disclosed herein for use as a vaccine adjuvant.
  • an immunogenic composition or vaccine adjuvant comprising a conjugate disclosed herein.
  • composition comprising a conjugate disclosed herein, and one or more immunostimulatory agents.
  • the present disclosure provides the use of a conjugate disclosed herein, in the manufacture of a vaccine. In some embodiments, the present disclosure provides use of a conjugate disclosed herein, for the manufacture of an immunogenic composition or a vaccine composition comprising an antigen or antigenic composition, for the treatment or prevention of disease.
  • the disclosure is directed to a method of treating or preventing disease comprising the administration to a human subject suffering from or susceptible to disease, an immunogenic composition or a vaccine composition comprising an antigen or antigenic composition and a conjugate disclosed herein.
  • the disease or disorder is inflammation, an autoimmune disease, an allergic disease, an infectious disease, an HIV infection, an AIDS infection, an HCV infection, influenza or a human papillomavirus (HPV) infection.
  • autoimmune disease an allergic disease
  • infectious disease an HIV infection
  • HIV infection an HIV infection
  • AIDS infection an HCV infection
  • influenza a human papillomavirus
  • cancer As used herein, the terms “cancer,” “neoplasm,” and “tumor” are used interchangeably and, in either the singular or plural form, refer to cells that have undergone a malignant transformation that makes them pathological to the host organism.
  • Primary cancer cells can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination.
  • the definition of a cancer cell includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells.
  • a “clinically detectable” tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as computed tomography (CT) scan, magnetic resonance imaging (MRI), X-ray, ultrasound or palpation on physical examination, and/or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • X-ray X-ray
  • ultrasound or palpation e.g., ultrasound or palpation on physical examination
  • Tumors may be a hematopoietic (or hematologic or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which may be referred to as “liquid tumors.”
  • liquid tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom's macroglobulinemia; lymphomas such as non-Hodgkin's lymphoma, Hodgkin's lymphoma; and the like.
  • the disease or disorder is a pre-cancerous syndrome.
  • the conjugate of the present disclosure may be used to treat inflammation of any tissue and organs of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation.
  • musculoskeletal inflammation including vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation.
  • vascular inflammation including vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation.
  • the scope of the diseases would be readily recognized by a skilled artisan in the field. In some embodiments, these diseases are as described in PCT Application No. PCT/US2020/044538, the contents of which is hereby incorporated by reference in its entirety.
  • cancer diseases and conditions wherein the conjugate of the present disclosure may have potentially beneficial antitumor effects include, but are not limited to, cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, biliary, small intestine, bowel, endocrine system, thyroid gland, parathyroid gland, adrenal gland, urethra, prostate, penis, testes, ureter or urothelial, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatoma;
  • the disease or disorder is a solid tumor.
  • the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, biliary cancer, non-small cell lung carcinoma (NSCLC), prostate cancer, colorectal cancer (CRC), colon cancer, ovarian cancer, endometrial cancer, urothelial cancer, cervical cancer, bladder cancer, papillary thyroid cancer, papillary renal cell cancer, cholangiocarcinoma, salivary duct cancer, kidney cancer, cervical cancer and pancreatic cancer.
  • the human has a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myelogenous leukemia.
  • the disease or disorder is a skin cancer (e.g., non-melanoma skin cancer, squamous cell carcinoma, basal cell carcinoma) or actinic keratosis.
  • the conjugate of the present disclosure may prevent the development of subsequent skin cancers and pre-malignant actinic keratosis in treated subjects.
  • the disease or disorder is bladder cancer, breast cancer, colorectal cancer, colon cancer, endometrial cancer, gastric cancer, esophageal cancer, biliary cancer, urothelial cancer, head and neck squamous carcinoma, melanoma, non-small cell lung cancer, ovarian cancer, or pancreatic cancer.
  • the disease or disorder is breast cancer, gastric cancer, colorectal cancer, colon cancer, esophageal cancer, biliary cancer, endometrial cancer, urothelial cancer or non-small cell lung cancer.
  • the breast cancer is HER2 amplified/overexpressed breast cancer or HER2 low breast cancer.
  • the endometrial cancer is serous endometrial cancer.
  • the conjugate of the present disclosure may also be useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the area of disorders associated with neo-vascularization and/or vascular permeability, fibrotic disorders, and metabolic disorders.
  • diseases afflicting mammals which are characterized by cellular proliferation in the area of disorders associated with neo-vascularization and/or vascular permeability, fibrotic disorders, and metabolic disorders.
  • diseases are as described in PCT Application No. PCT/US2020/044538, the contents of which is hereby incorporated by reference in its entirety.
  • the disease or disorder is a neurodegenerative diseases.
  • exemplary neurodegenerative diseases includes, but are not limited to, multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the scope of the diseases would be readily recognized by a skilled artisan in the field. In some embodiments, these diseases are as described in U.S. Provisional Application Nos. 62/882,081, 62/944,643, and 62/982,935, the contents of which are hereby incorporated by reference in their entirety.
  • the disease or disorder is an infectious disease, which is any disease instigated by or coincident with an infection from a pathogen, derived from bacteria, derived from the DNA virus families, or RNA virus families.
  • infectious disease any disease instigated by or coincident with an infection from a pathogen, derived from bacteria, derived from the DNA virus families, or RNA virus families.
  • pathogen derived from bacteria
  • DNA virus families derived from the DNA virus families
  • RNA virus families RNA virus families.
  • conjugates of the present disclosure may be employed alone or in combination with other therapeutic agents. As modulators of the immune response, the conjugates of the present disclosure may also be used in monotherapy or in combination with another therapeutic agent in the treatment of diseases and conditions wherein modulation of STING is beneficial.
  • Combination therapies according to the present disclosure thus comprise the administration of a conjugate of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent. In some embodiments, combination therapies according to the present disclosure comprise the administration of at least one conjugate of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent.
  • conjugate(s) of the present disclosure and pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) 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 conjugate(s) of the present disclosure and pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • a combination comprising a conjugate of the present disclosure or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents.
  • the conjugate of the present disclosure and pharmaceutically acceptable salts thereof may be used in combination with one or more other therapeutic agents which may be useful in the prevention or treatment of allergic disease, inflammatory disease, or autoimmune disease, for example; antigen immunotherapy, anti-histamines, steroids, NSAIDs, bronchodilators, methotrexate, leukotriene modulators, monoclonal antibody therapy, receptor therapies, or antigen non-specific immunotherapies.
  • therapeutic agents which may be useful in the prevention or treatment of allergic disease, inflammatory disease, or autoimmune disease, for example; antigen immunotherapy, anti-histamines, steroids, NSAIDs, bronchodilators, methotrexate, leukotriene modulators, monoclonal antibody therapy, receptor therapies, or antigen non-specific immunotherapies.
  • the conjugate of the present disclosure and pharmaceutically acceptable salts thereof may be used in combination with radiotherapy and/or surgery and/or at least one other therapeutic agent which may be useful in the treatment of cancer and pre-cancerous syndromes.
  • Any anti-neoplastic agent, anti-microtubule, anti-mitotic agent, hormone, hormonal analogues signal transduction pathway inhibitor, protein tyrosine kinase, or anti-angiogenic therapeutic agent may be utilized in the combination.
  • the scope of the other therapeutic agents would be readily recognized by a skilled artisan in the field.
  • the other therapeutic agent is as described in PCT Application No. PCT/US2020/044538, the contents of which is hereby incorporated by reference in its entirety.
  • Agents used in immunotherapeutic regimens, therapeutic agents used in proapoptotic regimens, or cell cycle signaling inhibitors may also be useful in combination with the conjugate of the present disclosure.
  • the combination of the present disclosure comprises a conjugate of the present disclosure or a salt, particularly a pharmaceutically acceptable salt thereof, and at least one anti-neoplastic agent, anti-microtubule, anti-mitotic agent, hormone, hormonal analogues signal transduction pathway inhibitor, protein tyrosine kinase, or anti-angiogenic therapeutic agent, or a combination thereof.
  • immuno-modulators for use in combination or co-administered with a conjugate of the present disclosure or a pharmaceutically acceptable salt thereof are immuno-modulators.
  • the combination of the present disclosure comprises a conjugate of the present disclosure or a salt, particularly a pharmaceutically acceptable salt thereof, and at least one immuno-modulator or at least one immunostimulatory agent.
  • immuno-modulators refer to any substance including monoclonal antibodies that affects the immune system. Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer.
  • immune-modulators include, but are not limited to, anti-CTLA-4 antibodies and anti-PD-1 antibodies.
  • Other immuno-modulators include, but are not limited to, ICOS antibodies, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies and GITR antibodies.
  • anti-neoplastic agent for use in combination or co-administered with a conjugate of the present disclosure are anti-PD-L1 agents (i.e. anti-PD-L1 antibodies) or PD-1 antagonists.
  • methods of treating a human in need thereof comprising administering a conjugate of the present disclosure or a salt thereof and at least one immuno-modulator.
  • the immuno-modulator is selected from an ICOS agonist antibody, an OX-40 antibody, and a PD-1 antibody.
  • the human has cancer. Also provided herein is the use of a conjugate of the present disclosure or a salt thereof in combination with at least one immuno-modulator for the treatment of a human in need thereof.
  • immunostimulatory agent refers to any agent that can stimulate the immune system.
  • immunostimulatory agents include, but are not limited to, vaccine adjuvants, such as Toll-like receptor agonists, T-cell checkpoint blockers, such as mAbs to PD-1 and CTL4 and T-cell checkpoint agonist, such as agonist mAbs to OX-40 and ICOS.
  • immunostimulatory agent refers to any agent that can stimulate the immune system.
  • immunostimulatory agents include, but are not limited to, vaccine adjuvants.
  • Toll-like receptor refers to a member of the Toll-like receptor family of proteins or a fragment thereof that senses a microbial product and/or initiates an adaptive immune response.
  • a TLR activates a dendritic cell (DC).
  • DC dendritic cell
  • Toll-like receptors are a family of pattern recognition receptors that were initially identified as sensors of the innate immune system that recognize microbial pathogens. TLRs recognize distinct structures in microbes, often referred to as “PAMPs” (pathogen associated molecular patterns). Ligand binding to TLRs invokes a cascade of intra-cellular signaling pathways that induce the production of factors involved in inflammation and immunity
  • the immunostimulatory agent for use in combination with the conjugate of the present disclosure is a TLR4 agonist.
  • methods of treating a human in need thereof comprising administering a conjugate of the present disclosure or a salt thereof and at least one immunostimulatory agent.
  • the immunostimulatory agent is a TLR4 agonist.
  • the immunostimulatory agent is an AGP.
  • the human has cancer. Also provided herein is the use a conjugate of the present disclosure or a salt thereof in combination with at least one immunostimulatory agent for the treatment of a human in need thereof.
  • compositions of the present disclosure may further comprise other therapeutic agents which, because of their adjuvant nature, can act to stimulate the immune system to respond to the cancer antigens present on the inactivated tumor cell(s).
  • adjuvants include, but are not limited to, lipids, liposomes, inactivated bacteria which induce innate immunity (e.g., inactivated or attenuated Listeriamonocytogenes), compositions which mediate innate immune activation via, (NOD)-like receptors (NLRs), Retinoic acid inducible gene-based (RIG)-I-like receptors (RLRs), and/or C-type lectin receptors (CLRs).
  • NOD non-like receptors
  • RLRs Retinoic acid inducible gene-based
  • CLRs C-type lectin receptors
  • TLR agonists may be used in combinations with other vaccines, adjuvants and/or immune modulators, and may be combined in various combinations.
  • the conjugate of the present disclosure bind to STING and induce STING-dependent TBKI activation and an inactivated tumor cell which expresses and secretes one or more cytokines which stimulate DC induction, recruitment and/or maturation, as described herein can be administered together with one or more TLR agonists for therapeutic purposes.
  • IDO inhibitors for use in combination or co-administered with the conjugate of the present disclosure are IDO inhibitors.
  • the conjugate of the disclosure may be employed in combination with at least one other therapeutic agent useful in the prevention or treatment of infectious diseases bacterial infections, viral infections, Kaposi's sarcoma-associated herpesvirus infections, TB infections, Chlamydia, Plasmodium infection, staphylococcus infections, amyotrophic lateral sclerosis (ALS), multiple sclerosis, systemic lupus erythematosus and related lupus disorders, psoriasis, or Sjogren's syndrome,
  • the conjugates of the disclosure may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic 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 typically 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 pharmaceutical compositions may be adapted for administration by intratumoral or peritumoral injection.
  • the intratumorally or peritumoral injection of a conjugate of the present disclosure directly into or adjacent to a single solid tumor is expected to elicit an immune response that can attack and destroy cancer cells throughout the body, substantially reducing and in some cases permanently eliminating the tumor from the diseased subject.
  • the activation of the immune system in this manner to kill tumors at a remote site is commonly known as the abscopal effect and has been demonstrated in animals with multiple therapeutic modalities.
  • a further advantage of local or intratumoral or peritumoral administration is the ability to achieve equivalent efficacy at much lower doses, thus minimizing or eliminating adverse events that may be observed at much higher systemic doses
  • the conjugates 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 one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a conjugate of the disclosure depend on the pharmacokinetic properties of that conjugate, 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 conjugate 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. Total daily dosages range from 1 mg to 2000 mg, preferably, total daily dosages range from 1 mg to 250 mg.
  • the conjugates of the disclosure will be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, the disclosure also is directed to pharmaceutical compositions comprising a conjugate of the disclosure and at least one pharmaceutically acceptable excipient.
  • compositions of the disclosure may be prepared and packaged in bulk form or in unit dosage form.
  • one or more tablets or capsules may be administered.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a conjugate of the present disclosure (i.e., a conjugate of the present disclosure or a salt, particularly a pharmaceutically acceptable salt, thereof).
  • the pharmaceutical compositions may contain from 1 mg to 1000 mg of a conjugate of the present disclosure.
  • unit dosage forms comprising from 1 mg to 1000 mg of a conjugate of the disclosure may be administered one, two, three, or four times per day, preferably one, two, or three times per day, and more preferably, one or two times per day, to effect treatment of a STING-mediated disease or disorder.
  • compositions of the disclosure typically contain one conjugate of the disclosure. However, in certain embodiments, the pharmaceutical compositions of the disclosure contain more than one conjugate of the disclosure. In addition, the pharmaceutical compositions of the disclosure may optionally further comprise one or more additional therapeutic agents, (e.g., pharmaceutically active conjugates).
  • additional therapeutic agents e.g., pharmaceutically active conjugates.
  • pharmaceutically acceptable excipient refers to a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the conjugate of the disclosure when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
  • the conjugates of the disclosure and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the conjugate or conjugates of the disclosure once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the disclosure.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • the disclosure is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a conjugate of the disclosure and a diluent or filler.
  • the oral solid dosage form may further comprise a disintegrant or a lubricant.
  • conjugates of the present disclosure may also be formulated with vaccines as adjuvants to modulate their activity.
  • Such compositions may contain antibody (antibodies) or antibody fragment(s) or an antigenic component, optionally together with one or more other components with adjuvant activity.
  • Certain compounds and/or conjugates of the disclosure may be potent immunomodulators and accordingly, care should be exercised in their handling.
  • the disclosure having been described, the following examples are offered by way of illustration and not limitation.
  • the conjugate is Formula BB
  • the conjugate comprises the XMT-1519 antibody comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 20); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 21); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 22); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 27); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 28); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 29), and d 15 is about 8.
  • CDRH1 comprising the amino acid
  • the conjugate is Formula CC
  • the conjugate comprises the XMT-1535 antibody comprising: a CDRH1 comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5); a CDRH2 comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6); a CDRH3 comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7); a CDRL1 comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8); a CDRL2 comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9); a CDRL3 comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10) and d 15 is about 8.
  • a conjugate of Formula BB or Formula CC is useful for treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the conjugate of Formula BB or Formula CC.
  • the disease or disorder is cancer.
  • the cancer for the conjugate of Formula BB, is breast cancer, gastric cancer, colorectal cancer, esophageal cancer, biliary cancer, endometrial cancer, urothelial cancer or non-small cell lung cancer.
  • the breast cancer is HER2 amplified/overexpressed breast cancer or HER2 low breast cancer.
  • the endometrial cancer is serous endometrial cancer.
  • the NaPi2b-expressing tumor is ovarian cancer, non-small cell lung cancer (NSCLC), papillary thyroid cancer, endometrial cancer, cholangiocarcinoma, papillary renal cell cancer, clear cell renal cancer, breast cancer, kidney cancer, cervical cancer or salivary duct cancer.
  • NSCLC non-small cell lung cancer
  • papillary thyroid cancer endometrial cancer
  • cholangiocarcinoma papillary renal cell cancer
  • clear cell renal cancer breast cancer, kidney cancer, cervical cancer or salivary duct cancer.
  • the subject has epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, platinum resistant ovarian cancer, non-squamous NSCLC cancer, progressive, radioactive iodine-refractory, loco-regional recurrent or metastatic disease papillary thyroid cancer or epithelial endometrial cancer.
  • the conjugate of Formula BB is useful for treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the conjugate of Formula BB in combination with one or more therapeutic agents.
  • the therapeutic agent is an immuno-modulator agent or an immunostimulatory agent.
  • the immune-modulator agent is an anti-CTLA-4 antibody, an anti-PD-1 antibody, an ICOS antibody, an OX-40 antibody, a PD-L1 antibody, a LAG3 antibody, a TIM-3 antibody, a 41BB antibody or a GITR antibody.
  • the conjugate of Formula BB is useful for treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the conjugate of Formula BB in combination with one or more HER2 antibodies that bind to a different epitope of HER2 than the HER2 antibody XMT-1519.
  • the HER2 antibody that binds to a different of HER2 than the HER2 antibody XMT-1519 is trastuzumab, pertuzumab, Fab37, or chA21.
  • the diABZI STING agonist was prepared as described in Ramanjulu et al (Nature, 564(7736):439-443 (2016)).
  • XMT-1535 anti-NaPi2b antibody
  • XMT-1519 anti-Her2 antibody
  • HPLC purification was performed on a Phenomenex Gemini 5 ⁇ m C18 110 ⁇ , 250 ⁇ 10 mm, semi-preparative column.
  • the drug content of the conjugates was determined spectrophotometrically, otherwise RP-HPLC or LC/MS as performed for quantitative determination of the drug content.
  • the protein content of the antibody-drug conjugates was determined spectrophotometrically or by ELISA.
  • Antibody-drug conjugates, drug carrying Scaffolds, or antibody Scaffolds were purified (i.e., removal of residual unreacted drug, unconjugated antibody, enzymes or starting materials) by extensive diafiltration, CHT chromatography or HIC, as required. If necessary, additional purification by SEC or HIC were conducted to remove aggregated antibody-drug conjugates.
  • the antibody-drug conjugates contained ⁇ 5% (w/w) (e.g., ⁇ 2% (w/w)) aggregated antibody-drug conjugates as determined by SEC; ⁇ 0.5% (w/w) (e.g., ⁇ 0.1% (w/w)) free (unconjugated) drug as determined by RP-HPLC and/or LC-MS/MS; ⁇ 1% (w/w) of free drug conjugate as determined by SEC and/or RP-HPLC; and ⁇ 10% (w/w) (e.g., ⁇ 1% (w/w)) unconjugated antibody or antibody fragments as determined by HIC-HPLC and/or RP-HPLC.
  • Reduced or partially reduced antibodies were prepared using procedures described in the literature, see, for example, Francisco et al., Blood 102 (4): 1458-1465 (2003).
  • the total drug (conjugated and unconjugated) concentration was determined by UV-Vis spectrophotometry or RP-HPLC.
  • an acidified sample was treated with acetonitrile.
  • the free drug was extracted, and the acetonitrile supernatant was analyzed.
  • the concentration of conjugated STING agonist in a non-clinical sample the sample was subjected to immunocapture using anti-human Fc antibody magnetic beads followed by exhaustive basic hydrolysis.
  • the acetonitrile supernatant containing the released drug was analyzed by LC-MS/MS.
  • the total antibody in non-clinical samples was measured using an MSD ECL immunoassay.
  • AF-HPA auristatin F hydroxypropyl amide
  • the method is quantitative for AF-HPA and AF in plasma and tissue homogenates and linear over the concentration ranges of 0.1 to 150 ng/mL.
  • the total drug released after hydrolysis with NaOH was measured under the same condition with the dynamic range from 1 ng/mL to 5000 ng/mL.
  • the total antibody standards range from 0.009 ⁇ g/mL to 20 ⁇ g/mL.
  • the drug to antibody ratio was determined by measuring the absorption of the conjugates.
  • the DAR value was calculated using the appropriate molar extinction coefficients of the antibody and the STING agonist payload.
  • a partial response (PR) is defined as a tumor volume of 50% or less for day 1 volume for three consecutive measurements and equal to or greater than 13.5 mm 3 for at least one of these three measurements.
  • a complete response (CR) is defined as a tumor volume less than 13.5 mm 3 for three consecutive measurements.
  • a tumor-free survivor (TFS) is classified as having a CR at the end of study.
  • Conjugate 8 was purified by ultrafiltration or CHT chromatography. The details of the antibody-drug conjugates 8-1 and 8-2 are given below. Conjugates 8-1 and 8-2 were prepared as described except that a higher ratio of TCEP:mAb was used in the synthesis of 8-2 compared to 8-1 (4:1 vs 3:1) as well as a higher ratio of Compound 7 to mAb (8:1 vs 6:1).
  • Conjugate 8a was prepared and characterized as described in Example 1 except that Trastuzumab was used instead of XMT-1519. The details of the antibody-drug conjugates 8a-1, 8a-2, and 8a-3 are given below.
  • Conjugate 8b was prepared and characterized as described in Example 1 except that XMT-1535 was used instead of XMT-1519.
  • the details of the antibody-drug conjugates 8b-1, 8b-2 and 8b-3 are given below.
  • Conjugates 8c was prepared and characterized as described in Example 1 except that Palivizumab was used instead of XMT-1519. The details of the antibody-drug conjugates 8c-1 and 8c-2 are given below.
  • Conjugates 8d was prepared and characterized as described in Example 1 except that Palivizumab mIgG2a was used instead of XMT-1519. The details of the antibody-drug conjugates 8d-1, 8d-2 and 8d-3 are given below.
  • Example 1e Synthesis of XMT-1535 hIgG1-mIgG2a Conjugate 8e, DAR 7.0
  • Conjugate 8e was prepared and characterized as described in Example 1 except that XMT-1535 mIgG2a was used instead of XMT-1519.
  • the purified Conjugate 8e had a STING agonist to XMT-1535 hIgG1-mIgG2a ratio of 7.0.
  • Conjugate 8f was prepared and characterized as described in Example 1 except that XMT-1535 AAG was used instead of XMT-1519.
  • the purified Conjugate 8f had a STING agonist to XMT-1535 AAG ratio of 7.4.
  • Example 1g Synthesis of Target D mIgG2a Conjugate 8g, DAR 7.4
  • Conjugate 8g was prepared and characterized as described in Example 1 except that Target D mIgG2a was used instead of XMT-1519.
  • the purified Conjugate 8g had a STING agonist to Target D_mIgG2a ratio of 7.4.
  • Conjugate 8h was prepared and characterized as described in Example 1 except that Target C hIgG1a was used instead of XMT-1519.
  • the purified Conjugate 8g had a STING agonist to Target C hIgG1a ratio of 6.9.
  • Example 1i Synthesis of Target E mIgG2a Conjugate 8i, DAR 10.0
  • Conjugate 8i was prepared and characterized as described in Example 1 except that Target E mIgG2a was used instead of XMT-1519.
  • the purified Conjugate 8g had a STING agonist to Target E mIgG2a ratio of 10.0.
  • Example 1j Synthesis of Trastuzumab AAG Conjugate 8j, DAR 7.0
  • Conjugate 8j was prepared and characterized as described in Example 1 except that Trastuzumab AAG was used instead of XMT-1519.
  • Conjugates 8j and 8j-1 are given below.
  • Example 1k Synthesis of Trastuzumab mIgG2a Conjugate 8k, DAR 8.1
  • Conjugate 8k was prepared and characterized as described in Example 1 except that Trastuzumab mIgG2a was used instead of XMT-1519.
  • the purified Conjugate 8k had a STING agonist to Trastuzumab mIgG2a ratio of 8.1.
  • Conjugate 8l was prepared and characterized as described in Example 1 except that XMT-1535 was used instead of XM/T-1519 and 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid was incorporated into the compound structure instead of (3-(2-(2-aminoethoxy)ethoxy)propanoyl)-L-alanine.
  • the purified Conjugate 8l had a STING agonist to XM4T-1535 ratio of 4.7.
  • Conjugate 8m was prepared and characterized as described in Example 1 except that Palivizumab was used instead of XMT-1519 and 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid was incorporated into the compound structure instead of (3-(2-(2-aminoethoxy)ethoxy)propanoyl)-L-alanine.
  • the purified Conjugate 8m had a STING agonist to Palivizumab ratio of 4.5.
  • a solution of XMT-1519 (10 mg, 0.069 ⁇ mol) was conjugated with Scaffold 15 ((0.823 mg, 0.347 ⁇ mol in 200 ⁇ L DMA) as described in Example 1.
  • the purified Conjugate 16 had a STING agonist to XMT-1519 ratio of 5.3.
  • Conjugate 20a was prepared and characterized as described in Example 1 except that Palivizumab was used instead of XMT-1519.
  • the purified Conjugate 20a had a STING agonist to Palivizumab ratio of 5.5.
  • XMT-1519 antibody (5 mg, 0.0347 ⁇ mol) was conjugated with Scaffold 24 (0.622 mg, 0.278 ⁇ mol) As described in Example 1.
  • the crude reaction mixture was purified by CHT column chromatography to give Conjugate 25 (3.19 mg, 64% yield).
  • Purified Conjugate 25 had a STING agonist to XMT-1519 ratio of 6.6.
  • Conjugate 28 was prepared as described in Example 1 to afford Conjugate 28.
  • the purified Conjugate 28 had a STING agonist to XMT-1519 ratio of 6.0.
  • Conjugate 28 (6.5 mg) was formulated into PBS, pH 8 with 3 cycles of concentration and dilution using a 30 kDa MWCO ultrafiltration unit. The reformulated conjugate was then incubated at 37° C. for 24 h and then reformulated to trehalose buffer pH 5.5. Ring-opening was confirmed by LCMS analysis of heavy and light chain following antibody reduction. Good resolution was observed between various light chain species: unconjugated, conjugated with intact succinimide, and conjugated with ring-opened succinimide. Ring-opening could also be observed in the corresponding heavy chain species but resolution between the various species was poor. The degree of ring-opening was therefore estimated by focusing on the light chain species. Using this approach, the percentage of ring-opened product in Conjugate 29 relative to intact succinimide was estimated as 94%. Conjugate 29 had a STING agonist to XMT-1519 ratio of 5.5.
  • Scaffold 31 was prepared as described in Example 1 except that Compound 30 (prepared as described in U.S. 62/982,935) was used instead of Compound 1. Scaffold 31 was obtained as a colorless solid (9 mg, 8% yield). ESI-MS m/z Calcd for C 101 H 151 N 23 O 42 [M+2H] 2+ : 1179.02; found 1179.21.
  • Conjugates 32-1, 32-2, 32-3, and 32-4 were prepared as described in Example 1 to afford the title conjugate.
  • the purified Conjugate 32-1, 32-2, 32-3, 32-4, and 32-5 had a STING agonist to XMT-1519 ratio as described in the table below.
  • Conjugate 32-5 had a mAb concentration of >10 mg/mL, contained ⁇ 1% of unconjugated mAb, and ⁇ 1% high molecular weight species.
  • Conjugates 32a, 32a-1, 32a-2, 32a-3, and 32a-4 were prepared and characterized as described in Example 1 except that XMT-1535 was used instead of XMT-1519.
  • the purified Conjugates 32a, 32a-1, 32a-2, 32a-3, and 32a-4 had a STING agonist to XMT-1535 ratio as described in the table below.
  • Conjugates 32b, 32b-1, and 32b-2 were prepared and characterized as described in Example 1 except that Palivizumab was used instead of XMT-1519.
  • the purified Conjugates 32b, 32b-1, and 32b-2 had a STING agonist to Palivizumab ratio as described in the table below.
  • Example 7c Synthesis of Palivizumab mIgG2a Conjugate 32c, DAR 9.1
  • Conjugate 32c was prepared and characterized as described above in Example 1 except that Palivizumab mIgG2a was used instead of XMT-1519.
  • the purified Conjugate 32c had a STING agonist to Palivizumab ratio of 9.1.
  • Conjugate 32d was prepared and characterized as described above in Example 1 except that XMT-1535 mIgG2a was used instead of XMT-1519.
  • the purified Conjugate 32d had a STING agonist to XMT-1535 mIgG2a ratio of 8.8.
  • Conjugate 32e was prepared and characterized as described in Example 1 except that XMT-1519 AAG was used instead of XMT-1519.
  • the purified Conjugate 32e had a STING agonist to XMT-1519 AAG ratio of 7.4.

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