Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
  • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
  • C07K9/003—Peptides being substituted by heterocyclic radicals, e.g. bleomycin, phleomycin

Definitions

• the invention provides antibody conjugates, also known as immunconjugates, comprising agonists of STING (stimulator of interferon genes) receptor, and the use of such conjugates for the treatment of cancer.
• Innate immunity is a rapid nonspecific immune response that fights against
• environmental insults including, but not limited to, pathogens such as bacteria or viruses.
• Adaptive immunity is a slower but more specific immune response, which confers long-lasting or protective immunity to the host and involves differentiation and activation of naive T lymphocytes into CD4+ T helper cells and/or CD8+ cytotoxic T cells, to promote cellular and humoral immunity.
• Antigen presentation cells of the innate immune system such as dendritic cells or macrophages, serve as a critical link between the innate and adaptive immune systems by phagocytosing and processing the foreign antigens and presenting them on the cell surface to the T cells, thereby activating T cell response.
• STING (stimulator of interferon genes) is an endoplasmic reticulum adaptor that facilitates innate immune signaling (Ishikawa and Barber, Nature 2008, 455(7213) :674-678). It was reported that STING comprises four putative transmembrane regions (Ouyang et al., Immunity (2012) 36, 1073), predominantly resides in the endoplasmic reticulum and is able to activate NF-kB, STAT6, and IRF3 transcription pathways to induce expression of type I interferon (e.g., IFN-a and IFN- ⁇ ) and exert a potent anti-viral state following expression
• type I interferon e.g., IFN-a and IFN- ⁇
• the invention provides immunoconjugates comprising antibodies conjugated with STING agonists, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, which are useful for the treatment of diseases, in particular, cancer.
• the invention further provides methods of treating, preventing, or ameliorating cancer comprising administering to a subject in need thereof an effective amount of an immunoconjugate of the invention.
• immunoconjugate and “antibody conjugate” are used interchangeably herein.
• the invention also provides compounds comprising STING agonists and a linker which are useful to conjugate to an antibody and thereby make the immunostimmulatory conjugates (or Immune Stimulator Antibody Conjugates (ISACs)) of the invention.
• Various embodiments of the invention are described herein.
• this application discloses an immunoconjugate comprising an antibody (Ab), or a functional fragment thereof, coupled to an agonist of Stimulator of Interferon Genes (STING) receptor (D) via a linker (L), wherein the linker optionally comprises one or more cleavage elements.
• Ab antibody
• STING Stimulator of Interferon Genes
• the immunoconjugate comprises Formula (I):
• Ab is an antibody or a functional fragment thereof
• L is a linker comprising one or more cleavage elements
• D is a drug moiety that has agonist activity against STING receptor
• n is an integer from 1 to 8.
• n is an integer from 1 to 20.
• the immunoconjugate comprises Formula (I):
• Ab is an antibody or a functional fragment thereof
• L is a linker
• D is a drug moiety that binds to STING receptor
• n is an integer from 1 to 8.
• n is an integer from 1 to 20;
• the immunconjugate comprises Formula (I): Ab-(L-(D)m)n (Formula (I))
• Ab is an antibody or a functional fragment thereof
• L is a linker
• D is a drug moiety that binds to STING receptor
• n is an integer from 1 to 8.
• n is an integer from 1 to 20; wherein the immunoconjugate delivers D, or a cleavage product thereof, to a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity.
• the immunoconjugate comprises Formula (I):
• Ab is an antibody or a functional fragment thereof
• L is a linker comprising one or more cleavage elements
• D is a drug moiety that binds to STING receptor
• n is an integer from 1 to 8.
• n is an integer from 1 to 20;
• the immunoconjugate releases D, or a cleavage product thereof, in a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity.
• the immunoconjugate comprises Formula (I):
• Ab is an antibody or a functional fragment thereof
• L is a linker comprising one or more cleavage elements
• D is a drug moiety that has agonist activity against STING receptor
• n is an integer from 1 to 8.
• n is an integer from 1 to 20;
• the immunoconjugate releases D, or a cleavage product thereof, in a cell targeted by the Ab, and wherein D, or the cleavage product thereof, has STING agonist activity in the cell.
• the present application discloses an immunoconjugate for delivery of a STING receptor agonist to a cell, the immunoconjugate comprising Formula (I) :
• Ab is an antibody or a functional fragment thereof
• L is a linker comprising one or more cleavage elements
• D is a drug moiety that binds to STING receptor
• n is an integer from 1 to 8.
• n is an integer from 1 to 20;
• the immunoconjugate specifically binds to an antigen expressed on the cell surface and is internalized into the cell, and wherein D, or a cleavage product thereof, is cleaved from L and has STING agonist activity as determined by one or more STING agonist assays selected from: an interferon stimulation assay, a hSTING wt assay, a THP1-Dual assay, a TANK binding kinase 1 (TBK1) assay, or an interferon-y-inducible protein 10 (IP-10) secretion assay.
• STING agonist assays selected from: an interferon stimulation assay, a hSTING wt assay, a THP1-Dual assay, a TANK binding kinase 1 (TBK1) assay, or an interferon-y-inducible protein 10 (IP-10) secretion assay.
• D or the cleavage product thereof, has STING agonist activity if it binds to STING and is able to stimulate production of one or more STING-dependent cytokines in a STING-expressing cell at least 1.1-fold, 1 .2-fold, 1 .3-fold, 1 .4-fold, 1 .5-fold, 1.6- fold, 1 .7-fold, 1 .8-fold, 1.9-fold, 2-fold or greater than an untreated STING-expressing cell.
• the STING-dependent cytokine is selected from interferon, type 1 interferon, IFN-a, IFN- ⁇ , type 3 interferon, IFN , IP10, TNF, IL-6, CXCL9, CCL4, CXCL1 1 , CCL5, CCL3, or CCL8.
• D, or the cleavage product thereof has STING agonist activity if it binds to STING and is able to stimulate phosphorylation of TBK1 in a STING- expressing cell at least 1.1 -fold, 1.2-fold, 1.3-fold, 1 .4-fold, 1.5-fold, 1 .6-fold, 1.7-fold, 1 .8-fold, 1.9-fold, 2-fold or greater than an untreated STING-expressing cell.
• D, or the cleavage product thereof has STING agonist activity if it binds to STING and is able to stimulate expression of a STING-dependent transcript selected from any one of the transcripts listed in Fig. 1A - Fig. 10 and Fig. 2A - Fig. 2L in a STING-expressing cell at least 5-fold or greater than the expression level in an untreated STING-expressing cell.
• expression of the STING-dependent transcript is increased 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 1 1-fold, 12-fold, 13-fold, 14-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 700-fold or greater.
• D or the cleavage product thereof, has STING agonist activity if it binds to STING and is able to stimulate expression of a luciferase reporter gene controlled by interferon (IFN)-stimulated response elements in a STING-expressing cell at an EC50 of 20 micromolar ⁇ M), 15 ⁇ , 10 ⁇ , 9 ⁇ , 8 ⁇ , 7 ⁇ , 6 ⁇ , 5 ⁇ , 4 ⁇ , 3 ⁇ , 2 ⁇ , 1 ⁇ , or less.
• IFN interferon
• D or the cleavage product thereof, has STING agonist activity if it binds to STING and is able to stimulate expression of a luciferase reporter gene controlled by interferon (IFN)-stimulated response elements in a STING-expressing cell to a level equal to or greater than the level of stimulation of 50 ⁇ of 2'3'-cGAMP.
• IFN interferon
• the STING-expressing cell is THP1 -Dual cell
• the luciferase reporter gene is the IRF-Lucia reporter gene in THP1 -Dual cell
• the STING agonist activity is determined by the THP1 -Dual assay described for Table 7.
• the luciferase reporter gene is the 5xlSRE-mlFNb-GL4 reporter gene and the STING-expressing cell is a cell expressing wild-type human STING protein, and optionally the STING agonist activity is determined by the hSTING wt assay described in Table 7.
• the immunoconjugate stimulates IP-10 secretion from a STING-expressing cell targeted by the Ab at an EC50 of 5 nanomolar (nM) or less in an IP-10 secretion assay.
• the immunoconjugate is parenterally administered. In other embodiments, the immunoconjugate comprises an Ab that specifically binds a target antigen. In some embodiments, the target antigen is a tumor antigen. In some embodiments, the Ab is human or humanized. In other embodiments, the Ab is a monoclonal antibody.
• the Ab comprises a modified Fc region.
• the Ab comprises cysteine at one or more of the following positions, which are numbered according to EU numbering:
• L is attached to the Ab via conjugation to one or more modified cysteine residues in the Ab.
• L is conjugated to the Ab via modified cysteine residues at positions 152 and 375 of the heavy chain of the Ab, wherein the positions are determined according to EU numbering.
• L is conjugated via a maleimide linkage to the cysteine.
• D is a dinudeotide.
• D is a cyclic dinudeotide (CDN).
• CDN cyclic dinudeotide
• D is a compound selected from any one of the compounds of Table 1 , Table 2, Table 3, or Table 4.
• D is a compound selected from
• the present application discloses immunconjugates wherein L is a cleavable linker comprising one or more cleavage elements.
• L comprises two or more cleavage elements, and each cleavage element is independently selected from a self-immolative spacer and a group that is susceptible to cleavage.
• the cleavage is selected from acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase- induced cleavage, phosphatase-induced cleavage, protease- induced cleavage, lipase-induced cleavage, or disulfide bond cleavage.
• L has a structure selected from:
• Lc is a linker component and each Lc is independently selected from a linker component as disclosed herein;
• D is the compound selected from any one of embodiments 55 to 69;
• each cleavage element (C E ) is independently selected from a self-immolative spacer and a group that is susceptible to cleavage selected from acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage.
• L has a structure selected from the following, or L comprises a structural
• the immunoconjugate is selected from the
• each Gi is independently
• XD is C, and each Z 4 is N;
• Y 3 is OH, 0-, OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se , BH 3 , SH or S
• Y 4 is OH, 0 " , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se " , BH 3 , SH or S
• Ys is -CHr, -NH-, -0- or -S;
• Y 6 is -CHr, -NH-, -0- or -S;
• Y 8 is 0 or S
• Y 9 is -CHr, -NH-, -0- or -S;
• Yio is -CHr, -NH-, -0- or -S;
• q is 1 , 2 or 3;
• R 1 is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from 0, N or S, or a tautomer thereof, wherein R 1 is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from -NHL ⁇ R 115 , F, CI, Br, OH, SH, NH 2 , D, CD 3 , d-C e alkyl, Ci-Cealkoxyalkyl, d- C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -0(C r C 6 alkyl), -0(C 3 -C 8 cycloalkyl), -S(C r C 6 alkyl), - S(C r C 6
• R 1a is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from 0, N or S, or a tautomer thereof, wherein R 1a is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from -NHUR 115 , F, CI, Br, OH, SH, NH 2 , D, CD 3 , C r C 6 alkyl, C r C 6 alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -0(C r C 6 alkyl), -0(C 3 -C 8 cycloalkyl), -S(C r C 6 alkyl), - S(C r C 6
• R 1 is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from 0, N or S, or a tautomer thereof, wherein R 1b is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from -NHUR 115 , F, CI, Br, OH, SH, NH 2 , D, CD 3 , d-C 6 alkyl, C r C 6 alkoxyalkyl, d- C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -0(C r C 6 alkyl), -0(C 3 -C 8 cycloalkyl), -S(C r C 6 alkyl), - S(C r C 6 amino
• OC(0)C 2 -C 6 alkynyl of R 5 are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• each R 11 is independently selected from H and CrCsalkyl
• each R 12 is independently selected from H and CrCealkyl
• R 3 and R 6 are connected to form CrCsalkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - 0-CrC 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 3 and R 6 are connected, the 0 is bound at the R 3 position
• R 3a and R 6a are connected to form CrCsalkylene, C 2 -C 5 alkenylene, C 2 -C 6 alkynylene, -O-CrCsalkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 3a and R 6a are connected, the 0 is bound at the R 3a position;
• R 2 and R 3 are connected to form CrCgalkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - O-CrCsalkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 2 and R 3 are connected, the 0 is bound at the R 3 position;
• R 2a and R 3a are connected to form C r C 3 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 2a and R 3a are connected, the 0 is bound at the R 3a position;
• R 4 and R 3 are connected to form CrCsalkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - O-CrCsalkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 4 and R 3 are connected, the 0 is bound at the R 3 position;
• R and R are connected to form C ⁇ Csalkylene, C 2 -C 3 alkenylene, C 2 -C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 4a and R 3a are connected, the 0 is bound at the R 3a position;
• R 5 and R 6 are connected to form CrCealkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - ⁇ -C ! -Cealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5 and R 6 are connected, the 0 is bound at the R 5 position;
• R 5a and R 6a are connected to form CrCgalkylene, C 2 -C 8 alkenylene, C 2 -C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5a and R 6a are connected, the 0 is bound at the R 5a position;
• R 5 and R 7 are connected to form CrCealkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - ⁇ -C ! -Cealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5 and R 7 are connected, the 0 is bound at the R 5 position;
• R 5a and R 7a are connected to form C ⁇ Csalkylene, C 2 -C 3 alkenylene, C 2 -C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5a and R 7a are connected, the 0 is bound at the R 5a position;
• R 8 and R 9 are connected to form a CrCealkylene, C 2 -C 6 alkenylene, C 2 -C 3 alkynylene, and
• R 8a and R 9a are connected to form a Ci-C 6 alkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene,
• L- ! is a linker
• R 1J is H or methyl
• R 14 is H, -CH 3 or phenyl
• each R 110 is independently selected from H, d-Cealkyl, F, CI, and -OH;
• each R 111 is independently selected from H, C r C 6 alkyl, F, CI, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -
• Ab is an antibody or a functional fragment thereof
• y is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10.
• the immunoconjugate has in vivo anti-tumor activity.
• the present application also discloses a pharmaceutical composition
• a pharmaceutical composition comprising an immunconjugate as disclosed herein and a pharmaceutically acceptable excipient.
• the present application also discloses an immunoconjugate as disclosed herein for use in combination with one or more additional therapeutic agents.
• the additional therapeutic agent is selected from the group consisting of an inhibitor of a co- inhibitory molecule, an activator of a co-stimulatory molecule, a cytokine, an agent that reduces cytokine release syndrome (CRS), a chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a vaccine, or a cell therapy.
• the additional therapeutic agent is an inhibitor of a co-inhibitory molecule, an activator of a co-stimulatory molecule, or a cytokine, wherein:
• the co-inhibitory molecule is selected from Programmed death-1 (PD-1), Programmed death- ligand 1 (PD-L1), Lymphocyte activation gene-3 (LAG-3), or T-cell immunoglobulin domain and mucin domain 3 (TIM-3),
• PD-1 Programmed death-1
• PD-L1 Programmed death- ligand 1
• LAG-3 Lymphocyte activation gene-3
• TIM-3 T-cell immunoglobulin domain and mucin domain 3
• the co-stimulatory molecule is Glucocorticoid-induced TNFR-related protein (GITR), and
• the cytokine is IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra).
• immunconjugate a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein.
• the present application also discloses use of an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein for treatment of a cancer in a subject in need thereof.
• this application discloses an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein for use in the treatment of cancer.
• an immunconjugate in yet another embodiment, disclosed herein is the use an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein in the manufacture of a medicament for use in the treatment of cancer.
• the cancer is selected from sarcomas, adenocarcinomas, blastomas, carcinomas, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, breast cancer, lymphoid cancer, colon cancer, renal cancer, urothelial cancer, prostate cancer, cancer of the pharynx, rectal cancer, renal cell carcinoma, cancer of the small intestine, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, colorectal cancer, cancer of the anal region, cancer of the peritoneum, stomach or gastric cancer, esophageal cancer, salivary gland carcinoma, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, penile carcinoma, glioblastoma,
• neuroblastoma cervical cancer , Hodgkin lymphoma, non-Hodgkin lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, neuroendocrine tumors (including carcinoid tumor
• myelogenous leukemia A L
• acute lymphoid leukemia ALL
• chronic myelogenous leukemia CML
• chronic lymphoid leukemia CLL
• myelodysplastic syndromes B-cell acute lymphoid leukemia ("BALL”)
• T-cell acute lymphoid leukemia B cell prolymphocytic leukemia
• blastic plasmacytoid dendritic cell neoplasm Burkitt's lymphoma
• diffuse large B cell lymphoma Follicular lymphoma
• Hairy cell leukemia small cell- or a large cell-follicular lymphoma
• malignant lymphoproliferative conditions MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia, myelodysplastic syndrome, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom
• the immunoconjugate is administered to the subject.
• the present application also discloses an immunconjugate, a pharmaceutical composition thereof, or a composition comprising an immunoconjugate in combination with one or more additional therapeutic agents, as disclosed herein for use as a medicament.
• This application also discloses a method of manufacturing any of the immunoconjugates as disclosed herein comprising the steps of:
• this application discloses a compound having a structure selected from Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (F)
• each Gi is independently selected from * indicates the point of attachment to -CR 1
• X B is Z 2 is N; * indicates the point of attachment to -
• X D is C, and each Z 4 is N;
• Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se , BH 3 , SH or S
• Y4 is OH, 0-, OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se , BH 3 , SH or S
• Y 5 is -CH 2 -, -NH-, -0- or -S;
• Ye is -CH ri -NH-, -0- or -S;
• Ys is 0 or S
• Y 9 is -CHr, -NH-, -0- or -S;
• Y 10 is -CH 2 -, -NH-, -0- or -S;
• q is 1 , 2 or 3;
• R 1 is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from 0, N or S, or a tautomer thereof, wherein R 1 is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from -NHUR 15 , F, CI, Br, OH, SH, NH 2 , D, CD 3 , Ci-C e alkyl, C r C 6 alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -0(C r C 6 alkyl), -0(C 3 -C 8 cycloalkyl), -S(C r C 6 alkyl), - S(C r C 6 aminoalky
• R 1a is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from 0, N or S, or a tautomer thereof, wherein R 1a is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from -NHL ⁇ R 15 , F, CI, Br, OH, SH, NH 2 , D, CD 3 , CrCealkyl, C r C 6 alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2
• R 1 is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from 0, N or S, or a tautomer thereof, wherein R 1b is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from -NHUR 15 , F, CI, Br, OH, SH, NH 2 , D, CD 3 , d-Cealkyl, C r C 6 alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -0(C r C 6 alkyl), -0(C 3 -C 8 cycloalkyl), -S(C r C 6 alkyl), - S(C r C 6 aminoal
• each R 11 is independently selected from H and CrCsalkyl
• each R 12 is independently selected from H and CrCsalkyl
• R 3 and R 6 are connected to form CrC 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - 0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 3 and R 6 are connected, the 0 is bound at the R 3 position
• R 3a and R 6a are connected to form Ci-C 3 alkylene, C 2 -C 3 alkenylene, C 2 -C 6 alkynylene, -0-CrC 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 3a and R 6a are connected, the 0 is bound at the R 3a position;
• R 2 and R 3 are connected to form CrC 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - 0-CrC 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 2 and R 3 are connected, the 0 is bound at the R 3 position;
• R and R are connected to form C ⁇ Csalkylene, C 2 -C 3 alkenylene, C 2 -C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 2a and R 3a are connected, the 0 is bound at the R 3a position;
• R 4 and R 3 are connected to form CrCealkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - ⁇ -C ! -Cealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 4 and R 3 are connected, the 0 is bound at the R 3 position;
• R a and R 3a are connected to form CrCgalkylene, C 2 -C 8 alkenylene, C 2 -C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 4a and R 3a are connected, the 0 is bound at the R 3a position;
• R 5 and R 6 are connected to form CrCealkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - ⁇ -C ! -Cealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5 and R 6 are connected, the 0 is bound at the R 5 position;
• R 5a and R 6a are connected to form C ⁇ Csalkylene, C 2 -C 3 alkenylene, C 2 -C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5a and R 6a are connected, the 0 is bound at the R 5a position;
• R 5 and R 7 are connected to form CrCealkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - 0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5 and R 7 are connected, the 0 is bound at the R 5 position;
• R 5a and R 7a are connected to form C ⁇ Csalkylene, C 2 -C 3 alkenylene, C 2 -C 6 alkynylene, -0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5a and R 7a are connected, the 0 is bound at the R 5a position;
• R 8 and R s are connected to form a CrCealkylene, C 2 -C 6 alkenylene, C 2 -C 3 alkynylene, and
• R 8a and R 9a are connected to form a C Cealkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene,
• Xi is chment to X 2 ; X 2 is
• X 4 is -0(CH 2 ) n SSC(R 12 ) 2 (CH 2 ) n - or -(CH 2 ) n C(R 12 ) 2 SS(CH 2 ) n O-;
• X 5 is where the ** indicates orientation toward the Drug moiety;
• X 6 is or, where the ** indicates orientation toward the Drug moiety
• R 17 is 2-pyridyl or 4-pyridyl
• each R 11 is independently selected from H and CrCealkyl
• each R 12 is independently selected from H and d-Cealkyl
• each m is independently selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17 and 18.
• each R 110 is independently selected from H, CrCealkyl, F, CI, and -OH;
• each R 111 is independently selected from H, C r C 6 alkyl, F, CI, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -
• R 1 , R 1a or R 1b is substituted with -NHL1R 15 , or at least one of R 3 , R 4 ,
• R 5 , R 7 , R 3a , R a , R 5a or R 7a is -OLiR 15 .
• FIG. 1A-10 are a series of a tables listing various transcripts in HCC1954 cells whose expression increased by at least 5-fold upon exposure to either cGAMP or compound T1 -1.
• FIG. 2A-2L are a series of tables listing various transcripts in THP1 dual cells whose expression increased by at least 5-fold upon exposure to compound T1 -2.
• FIG. 3 is a line graph showing STING agonist payload retention as determined by IPMS (intact protein mass spectrometry).
• FIG. 4 is a line graph showing the anti-HER2-STING agonist conjugates induce IP-10 secretion from HER2+ HCC1954 breast cancer cells.
• FIG. 5 is a line graph showing the anti-HER2 mAb1 -C1 conjugate inhibits N87 gastric tumor growth in mice.
• FIG. 6 is a line graph showing the anti-HER2 mAb1 -C1 conjugate is well tolerated in the N87 gastric tumor xenograft mice.
• FIG. 7 is a line graph showing the anti-HER2 mAb1 -C1 conjugate inhibits HCC1954 breast tumor growth in mice.
• FIG. 8 is a line graph showing the anti-HER2 mAb1 -C1 conjugate is well tolerated in the HCC1954 breast tumor xenograft mice.
• FIG. 9A is a line graph showing the anti-HER2 mAb1-C1 conjugate inhibits SKOV3 ovarian carcinoma growth in mice.
• FIG. 9B is a line graph showing the anti-HER2 mAb1-C1 conjugate is well tolerated in the SKOV3 ovarian carcinoma xenograft mice.
• FIG. 10 illustrates certain compounds which can be used as a Drug moiety.
• FIG. 1 1 illustrates certain compounds which can be used as a Drug moiety.
• FIG. 12 illustrates certain compounds which can be used as a Drug moiety.
• FIG. 13A is a graph depicting efficacy of P-Cad mAb1 -C1 conjugate in an C38 murine colon adenocarcinoma model in mice.
• FIG. 13B is a graph showing that P-Cad mAb1 -C1 conjugate is well tolerated in the MC38 murine colon adenocarcinoma model in mice.
• FIG. 14 is a graph depicting efficacy of Target B mAb1 -C1 in a breast cancer xenograft model in mice.
• FIG. 15 is a graph depicting efficacy of Target C mAb1-C1 conjugate in a lung cancer xenograft model in mice.
• C r C 6 alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
• Non-limiting examples of “CrCealkyl” groups include methyl, ethyl, 1 -methylethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and hexyl.
• C 2 -C 6 alkenyr refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond.
• Non-limiting examples of "C 2 -C 6 alkenyl” groups include ethenyl, prop-1 -enyl, but-1 -enyl, pent-1 -enyl, pent-4-enyl and penta-1 ,4-dienyl.
• C 2 -C 6 alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
• Non-limiting examples of "C 2 -C 6 alkynyl” groups include ethynyl, prop-1-ynyl, but-1 -ynyl, pent-1 -ynyl, pent-4-ynyl and penta-1 , 4-diynyl.
• CrCealkylene refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms.
• C 2 -C 6 alkenyl refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to six carbon atoms.
• C 2 -C 6 alkynyl refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms.
• C ⁇ alkoxyalkyl refers to a radical of the formula -Ra-O-Ra, where each Ra is independently a Ci -6 alkyl radical as defined above.
• the oxygen atom may be bonded to any carbon atom in either alkyl radical. Examples of include, but are not limited to, methoxy-methyl, methoxy-ethyl, ethoxy-ethyl, 1 -ethoxy-propyl and 2-methoxy-butyl.
• C r C 6 hydroxyalkyl refers to a C 1-6 alkyl radical as defined above, wherein one of the hydrogen atoms of the C 1-6 alkyl radical is replaced by OH.
• hydroxyC ⁇ alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy- propyl, 3-hydroxy-propyl and 5-hydroxy-pentyl
• C 3 -C 8 cycloalkyl refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system.
• Non-limiting examples of fused bicyclic or bridged polycyclic ring systems include bicyclo[1 .1 .1 ]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1 ]octane, bicyclo[2.2.2]octane and adamantanyl.
• Non-limiting examples monocyclic C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
• C r C 6 haloalkyl refer to the respective "CrC 6 alkyl", as defined herein, wherein at least one of the hydrogen atoms of the "CrC 6 alkyl” is replaced by a halo atom.
• the CrC 6 haloalkyl groups can be monoCrC 6 haloalkyl, wherein such C r C s haloalkyl groups have one iodo, one bromo, one chloro or one fluoro.
• the C r C 6 haloalkyl groups can be diCrC 6 haloalkyl wherein such CrCehaloalkyl groups can have two halo atoms independently selected from iodo, bromo, chloro or fluoro.
• the CrCshaloalkyl groups can be polyC r C 6 haloalkyl wherein such C r C 6 haloalkyl groups can have two or more of the same halo atoms or a combination of two or more different halo atoms.
• Such polyCr C 6 haloalkyl can be perhaloCrC 6 haloalkyl where all the hydrogen atoms of the respective d- C 6 alkyl have been replaced with halo atoms and the halo atoms can be the same or a combination of different halo atoms.
• Non-limiting examples of CrC 6 haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
• C 2 -C 6 haloalkenyl refer to the respective "C r C 6 alkenyl", as defined herein, wherein at least one of the hydrogen atoms of the "C r C 6 alkenyl” is replaced by a halo atom.
• the C 2 -C 6 haloalkenyl groups can be monoC r C 6 haloalkenyl, wherein such C r C 6 haloalkenyl groups have one iodo, one bromo, one chloro or one fluoro.
• the C 2 - C 6 haloalkenyl groups can be diC 2 -C 6 haloalkenyl wherein such C 2 -C 6 haloalkenyl groups can have two halo atoms independently selected from iodo, bromo, chloro or fluoro.
• the C 2 -C 6 haloalkenyl groups can be polyC 2 -C 6 haloalkenyl wherein such C 2 -C 6 haloalkenyl groups can have two or more of the same halo atoms or a combination of two or more different halo atoms.
• C 2 -C 6 haloalkynyl refer to the respective “CrC 6 alkynyl", as defined herein, wherein at least one of the hydrogen atoms of the "C r C 6 alkynyl” is replaced by a halo atom.
• the C 2 -C 6 haloalkynyl groups can be monoC r C 6 haloalkynyl, wherein such C r C 6 haloalkynyl groups have one iodo, one bromo, one chloro or one fluoro.
• the C 2 - C 6 haloalkynyl groups can be diC 2 -C 6 haloalkynyl wherein such C 2 -C 6 haloalkynyl groups can have two halo atoms independently selected from iodo, bromo, chloro or fluoro.
• the C 2 -C 6 haloalkynyl groups can be polyC 2 -C 6 haloalkynyl wherein such C 2 -C 6 haloalkenyl groups can have two or more of the same halo atoms or a combination of two or more different halo atoms.
• heteroalkyl refers to an "alkyl” moiety wherein at least one of the carbon atoms has been replaced with a heteroatom such as 0 S, or N.
• 3 to 6 membered heterocycloalkyl refers to a monocyclic ring structure having 3 to 6 ring members, wherein one to two of the ring members are
• Non-limiting examples of 3-6 membered heterocycloalkyl groups include aziridin-1 -yl, aziridin-2-yl, aziridin-3-yl, azetadinyl, azetadin-1 -yl, azetadin-2-yl, azetadin-3-yl, oxetanyl, oxetan-2-yl, oxetan-3-yl, oxetan-4-yl, thietanyl, thietan-2-yl, thietan-3-yl, thietan-4-yl, pyrrolidinyl, pyrrolidin-1 -yl, pyrrol id in-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidinyl, pyrrolidin-1 -yl, pyrrol id in-2-yl, pyrrolidin-3-y
• heterocyclyl includes partially saturated or aromatic monocyclic or fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S. In a preferred embodiment, the heteroatoms are nitrogen.
• substituents include oxo, halo, C 1-6 alkyl, C ⁇ alkoxy, amino, C ⁇ alkylamino, di-C ⁇ alkylamino.
• the heterocyclic group can be attached at a heteroatom or a carbon atom.
• the system can be fully aromatic (i.e. both rings are aromatic).
• the heterocyclyl can be referred to as heteroaryl.
• aromatic bicyclic heteroaryl include 9-10 membered fused bicyclic heteroaryl having 2-5 heteroatoms, preferably nitrogen atoms.
• Non-limiting examples are: pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4- c]pyridinyl, pyrazolo[3,4-d]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1 ,2-a]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, pyrrolo[1 ,2-b]pyridazinyl, imidazo[1 ,2-c]pyrimidinyl, pyri
• bicyclic heterocyclyl ring systems include heterocyclyl ring systems wherein one of the fused rings is aromatic but the other is non-aromatic.
• the heterocyclyl is said to be partially saturated.
• partially saturated bicyclic system are for example dihydropurinones such as 2-amino-1 ,9-dihydro-6H-purin-9-yl-6-one and 1 ,9- dihydro-6H-purin-9-yl-6-one.
• Other examples of partially saturated bicyclic system are examples of partially saturated bicyclic system.
• Heterocyclyl also includes a 5- or 6- membered ring aromatic heterocyclyl having 2 to 3 heteroatom (preferably nitrogen) (also referred to as 5- to 6-membered heteroaryl).
• monocyclic heteroaryl are: imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, 1 , 2, 3-oxadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5- thiadiazolyl, 1 ,3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol- 4-yl, oxazol-5-yl, isoxazol-3-yl
• Heterocyclyl also includes 6-membered monocyclic partially saturated ring having 1-3 heteroatoms (preferably nitrogen).
• Examples of partially saturated monocyclic heterocyclyl are pyrimidine-one and pyrimidine-dione, specifically pyrimidin-2(1 H)-one and pyrimidin-1 -yl-2,4(1 H, 3H)-dione.
• Heterocyclyl can exist in various tautomeric forms.
• a heterocyclyl moiety when substituted with an oxo group next to a nitrogen atom, the invention also pertains to its hydroxy tautomeric form.
• 2-amino-1 ,9-dihydro-6H-purin-6-one can tautomerize into 2-amino-9H-purin-6-ol.
• the tautomerization is represented as follow:
• tautomer is used to designate 2 molecules with the same molecular formula but different connectivity, which can interconvert in a rapid equilibrium.
• tautomers are phosporothioic acid which can exist in an equilibrium as shown below.
• phosphoric acid exists as 2 tautomeric forms which interconvert in an equilibrium.
• tautomers are phosporothioic acid which can exist in an equilibrium as shown below.
• phosphoric acid exists as 2 tautomeric forms which interconvert in an equilibrium.
• phosporothioic acid and phosphoric acid moieties can exist in the respective equilibrium as shown below.
• Drug moiety refers to a compound which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more functional groups each of which is capable of forming a covalent bond with a linker.
• functional groups include, but are not limited to, primary amines, secondary amines, hydroxyls, thiols, alkenes, alkynes and azides.
• such functional groups include reactive groups of Table 5 provided herein.
• Tvw wavy line
• HER2 refers to a transmembrane tyrosine kinase receptor of the epidermal growth factor (EGF) receptor family.
• EGF epidermal growth factor
• HER2 comprises an extracellular binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain.
• HER2 does not have a ligand binding domain of its own and therefore cannot bind growth factors.
• HER2 binds tightly to other ligand-bound EGF receptor family members such as HER1 or HER3, to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways.
• the human HER2/NEU gene is mapped to chromosomal location 17q12, and the genomic sequence of HER2/NEU gene can be found in GenBank at NG_007503.1.
• GenBank GenBank at NG_007503.1.
• a human HER2 protein also encompasses proteins that have over its full length at least about 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with HER2 isoforms: A, B, C, D, and E, wherein such proteins still have at least one of the functions of HER2.
• HER2 isoform A The mRNA and protein sequences for human HER2 isoform A, the longest isoform, are: Homo sapiens erb-b2 receptor tyrosine kinase 2 (ERBB2), transcript variant 1 , mRNA [NM_004448.3]
• Receptor tyrosine-protein kinase erbB-2 isoform a precursor [Homo sapiens] [NP_004439.2]
• HER2 isoform B NM_001005862.2 (mRNA) ⁇ NP_001005862.1 (protein);
• HER2 isoform C NM_001289936.1 (mRNA) ⁇ NP_001276865.1 (protein);
• HER2 isoform D NM_001289937.1 (mRNA) ⁇ NP_001276866.1 (protein);
• HER2 isoform E NM_001289938.1 (mRNA) ⁇ NP_001276867.1 (protein).
• antibody refers to a protein, or polypeptide sequence derived from an immunoglobulin molecule that specifically binds to an antigen.
• Antibodies can be polyclonal or monoclonal, multiple or single chain, or intact immunoglobulins, and may be derived from natural sources or from recombinant sources.
• a naturally occurring "antibody” is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region
• VH a heavy chain constant region
• the heavy chain constant region is comprised of three domains, CH1 , CH2 and CH3.
• Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
• the light chain constant region is comprised of one domain, CL.
• the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
• CDR complementarity determining regions
• Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxyl- terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
• the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
• the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1 q) of the classical complement system.
• An antibody can be a monoclonal antibody, human antibody, humanized antibody, camelised antibody, or chimeric antibody.
• the antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG 1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass.
• antibody fragment or "antigen-binding fragment” or “functional fragment” refers to at least one portion of an antibody, that retains the ability to specifically interact with (e.g., by binding, steric hinderance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen.
• antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), a Fd fragment consisting of the VH and CH 1 domains, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, multi-specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody.
• An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1 126-1 136, 2005).
• Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3) (see U.S. Patent No.: 6,703, 199, which describes fibronectin polypeptide minibodies).
• Fn3 fibronectin type III
• scFv refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked, e.g., via a synthetic linker, e.g., a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived.
• a synthetic linker e.g., a short flexible polypeptide linker
• an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL.
• CDR complementarity determining region
• HCDR1 , HCDR2, and HCDR3 three CDRs in each heavy chain variable region
• LCDR1 , LCDR2, and LCDR3 three CDRs in each light chain variable region
• the precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest,” 5th Ed.
• the CDRs correspond to the amino acid residues that are defined as part of the Kabat CDR, together with the amino acid residues that are defined as part of the Chothia CDR.
• the CDRs defined according to the "Chothia" number scheme are also sometimes referred to as "hypervariable loops.”
• VH heavy chain variable domain
• HCDR1 e.g., insertion(s) after position 35
• HCDR2 HCDR2
• HCDR3 CDR amino acid residues in the light chain variable domain
• VL CDR amino acid residues in the light chain variable domain
• LCDR1 e.g., insertion(s) after position 27
• 50-56 LCDR2
• LCDR3 CDR amino acid residues in the light chain variable domain
• the CDR amino acids in the VH are numbered 26-32 (HCDR1) (e.g., insertion(s) after position 31), 52-56 (HCDR2), and 95-102 (HCDR3)
• the amino acid residues in VL are numbered 26-32 (LCDR1) (e.g., insertion(s) after position 30), 50-52 (LCDR2), and 91 -96 (LCDR3).
• the CDRs comprise or consist of, e.g., amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL.
• the CDR amino acid residues in the VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2) and 93-102 (CDR3), and the CDR amino acid residues in the VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3) (numbering according to "Kabat").
• the CDR regions of an antibody can be determined using the program IMGT/DomainGap Align.
• epitope includes any protein determinant capable of specific binding to an immunoglobulin or otherwise interacting with a molecule.
• Epitopic determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics.
• An epitope may be "linear" or
• Conformational and linear epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
• the phrases "monoclonal antibody” or “monoclonal antibody composition” as used herein refers to polypeptides, including antibodies, bispecific antibodies, etc., that have substantially identical amino acid sequence or are derived from the same genetic source. This term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
• human antibody includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region is also derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik, et al. (2000. J Mol Biol 296, 57-86).
• immunoglobulin variable domains e.g., CDRs
• CDRs immunoglobulin variable domains
• the structures and locations of immunoglobulin variable domains may be defined using well known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia, and
• ImMunoGenTics (IMGT) numbering (see, e.g., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services (1991), eds. Kabat et al.; Al Lazikani et al., (1997) J. Mol. Bio. 273:927 948); Kabat et al., (1991) Sequences of Proteins of
• the human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote stability or
• human antibody as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
• recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of all or a portion of a human immunoglobulin gene, sequences to other DNA sequences.
• Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences.
• such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
• Fc region refers to a polypeptide comprising the CH3, CH2 and at least a portion of the hinge region of a constant domain of an antibody.
• an Fc region may include a CH4 domain, present in some antibody classes.
• An Fc region may comprise the entire hinge region of a constant domain of an antibody.
• the invention comprises an Fc region and a CH1 region of an antibody.
• the invention comprises an Fc region CH3 region of an antibody.
• the invention comprises an Fc region, a CH1 region and a Ckappa/lambda region from the constant domain of an antibody.
• a binding molecule of the invention comprises a constant region, e.g., a heavy chain constant region.
• a constant region is modified compared to a wild-type constant region.
• the polypeptides of the invention disclosed herein may comprise alterations or modifications to one or more of the three heavy chain constant domains (CH1 , CH2 or CH3) and/or to the light chain constant region domain (CL).
• Example modifications include additions, deletions or substitutions of one or more amino acids in one or more domains. Such changes may be included to optimize effector function, half-life, etc.
• binding specificity refers to the ability of an individual antibody combining site to react with one antigenic determinant and not with a different antigenic determinant.
• the combining site of the antibody is located in the Fab portion of the molecule and is constructed from the hypervariable regions of the heavy and light chains. Binding affinity of an antibody is the strength of the reaction between a single antigenic determinant and a single combining site on the antibody. It is the sum of the attractive and repulsive forces operating between the antigenic determinant and the combining site of the antibody.
• affinity refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable region of the antibody “arm” interacts through weak non-covalent forces with antigen at numerous sites; the more interactions, the stronger the affinity.
• conservative sequence modifications refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody or antibody fragment of the invention by standard techniques known in the art, such as site- directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art.
• amino acids with basic side chains e.g., lysine, arginine, histidine
• acidic side chains e.g., aspartic acid, glutamic acid
• uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan
• nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
• beta- branched side chains e.g., threonine, valine, isoleucine
• aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine
• one or more amino acid residues within an antibody can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested using the functional assays described herein.
• homologous refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules.
• two nucleic acid molecules such as, two DNA molecules or two RNA molecules
• polypeptide molecules between two polypeptide molecules.
• a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are homologous or identical at that position.
• the homology between two sequences is a direct function of the number of matching or homologous positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 of 10), are matched or homologous, the two sequences are 90% homologous.
• Percentage of "sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the amino acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences.
• the percentage can be calculated by determining the number of positions at which the identical amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity.
• the output is the percent identity of the subject sequence with respect to the query sequence.
• the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
• the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
• the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1 , 2, 3, 4, 5, or 6.
• the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1 , 2, 3, 4, 5, or 6.
• a particularly preferred set of parameters are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
• the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4: 1 1 -17) which has been incorporated into the ALIGN program (version 2.0), using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
• nucleic acid and protein sequences described herein can be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences.
• Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10.
• Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402.
• the default parameters of the respective programs e.g., XBLAST and NBLAST
• XBLAST and NBLAST can be used. See www.ncbi.nlm.nih.gov.
• cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
• cancer include, but are not limited to, solid tumors and hematological cancers, including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies.
• solid tumors and hematological cancers including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma),
• cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, neuroblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary tract cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, tumors of the biliary tract, as well as head and neck cancer. Additional cancer indications are disclosed herein.
• lung cancer including small-cell lung cancer, non-small cell lung cancer, aden
• tumor antigen or “cancer associated antigen” interchangeably refer to a molecule (typically a protein, carbohydrate or lipid) that is expressed on the surface of a cancer cell, either entirely or as a fragment (e.g., MHC/peptide), and which is useful for the preferential targeting of a pharmacological agent to the cancer cell.
• a tumor antigen is a marker expressed by both normal cells and cancer cells, e.g., a lineage marker, e.g., CD19 on B cells.
• a tumor antigen is a cell surface molecule that is
• a tumor antigen is a cell surface molecule that is inappropriately synthesized in the cancer cell, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell.
• a tumor antigen will be expressed exclusively on the cell surface of a cancer cell, entirely or as a fragment (e.g., MHC/peptide), and not synthesized or expressed on the surface of a normal cell.
• MHC Major histocompatibility complex
• TCRs T cell receptors
• the MHC class I complexes are constitutively expressed by all nucleated cells.
• virus-specific and/or tumor-specific peptide/MHC complexes represent a unique class of cell surface targets for immunotherapy.
• tumor-supporting antigen or “cancer-supporting antigen” interchangeably refer to a molecule (typically a protein, carbohydrate or lipid) that is expressed on the surface of a cell that is, itself, not cancerous, but supports the cancer cells, e.g., by promoting their growth or survival e.g., resistance to immune cells.
• the tumor-supporting antigen itself need not play a role in supporting the tumor cells so long as the antigen is present on a cell that supports cancer cells.
• a "HER2-positive cancer” or "HER2-expressing cancer” is a cancer comprising cells that have HER2 protein present at their cell surface. Many methods are known in the art for detecting or determining the presence of HER2 on a cancer cell. For example, in some embodiments, the presence of HER2 on the cell surface may be determined by
• IHC immunohistochemistry
• flow cytometry Western blotting
• immunofluorescent assay immunofluorescent assay
• radioimmunoassay RIA
• enzyme-linked immunosorbent assay ELISA
• homogeneous time resolved fluorescence HTRF
• PET positron emission tomography
• ком ⁇ онент or “pharmaceutical combination,” as used herein mean a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
• fixed combination means that the active ingredients, by way of example, a compound of the invention and one or more additional therapeutic agent, are administered to a subject simultaneously in the form of a single entity or dosage.
• non-fixed combination means that the active ingredients, by way of example, a compound of of the invention and one or more additional therapeutic agent, are administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the subject.
• cocktail therapy e.g. the administration of 3 or more active ingredients.
• composition refers to a mixture of a compound of the invention with at least one and optionally more than one other pharmaceutically acceptable chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• pharmaceutically acceptable chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• an optical isomer or "a stereoisomer”, as used herein, refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
• the term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
• a 1 :1 mixture of a pair of enantiomers is a "racemic" mixture.
• the term is used to designate a racemic mixture where appropriate.
• "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-lngold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
• Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
• Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
• P-cadherin (also known as P-Cadherin, P-cad, P-Cad, Pcad, PCad, Cadherin 3, Cadherin-3, Cad3, Cad-3, CAD3, CAD-3, CDH3 or CDH-3) refers to the nucleic acid and amino acid sequences of P-cadherin, which have been published in GenBank Accession Nos. NP_ 001784, NP_001784.2 (amino acid sequence), and N _001793.4, GenBank Accession Nos. AA14462, NG_009096, and NG_009096.1 (nucleotide sequences). Sequence information for human P-cadherin domains 1 -5 are extracellular and are published in GenBank Acession Nos. NM_001793.4 and NP_001784.
• P-cadherin also refers to proteins and amino acid sequences that over their full length have at least about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of the above GenBank accession Nos.
• a P-cadherin nucleic acid sequence has over its extracellular domain at least about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the nucleic acid sequence of GenBank accession numbers NM_001793.4, GenBank Accession Nos. AA14462, NG_009096, and NG_009096.1 .
• pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
• pharmaceutically acceptable salt refers to a salt which does not abrogate the biological activity and properties of the compounds of the invention, and does not cause significant irritation to a subject to which it is administered.
• subject encompasses mammals and non-mammals.
• mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like.
• non-mammals include, but are not limited to, birds, fish and the like. Frequently the subject is a human.
• a subject in need of such treatment refers to a subject which would benefit biologically, medically or in quality of life from such treatment.
• STING refers to STtimulator of INterferon Genes receptor, also known as
• STING and “STING receptor” are used interchangeably, and include different isoforms and variants of STING.
• the mRNA and protein sequences for human STING isoform 1 are:
• TME 173 Homo sapiens transmembrane protein 173 (TME 173), transcript variant 1 , mRNA
• gagccccagc agaagaatgg agaggaggag gaggctgagt ttggggtatt gaatcccccg
• the mRNA and protein sequences for human STING isoform 2, a shorter isoform, are:
• TAE 173 Homo sapiens transmembrane protein 173 (TME 173), transcript variant 2, mRNA
• Homo sapiens stimulator of interferon genes protein isoform 2 [NP_001288667.1 ]
• polymorphisms include the following and those described in Yi, PLoS One. 2013 Oct 21 ;
• hSTING wt wild type: Reference SNP (refSNP) Cluster Report: rs1 131769
• STING agonist refers to a compound or antibody conjugate capable of binding to STING and activating STING.
• Activation of STING activity may include, for example, stimulation of inflammatory cytokines, including interferons, such as type 1 interferons, including IFN-a, IFN- ⁇ , type 3 interferons, e.g., IFN , IP10, TNF, IL-6, CXCL9, CCL4, CXCL11 , CCL5, CCL3, or CCL8.
• interferons such as type 1 interferons, including IFN-a, IFN- ⁇ , type 3 interferons, e.g., IFN , IP10, TNF, IL-6, CXCL9, CCL4, CXCL11 , CCL5, CCL3, or CCL8.
• STING agonist activity may also include stimulation of TANK binding kinase (TBK) 1 phosphorylation, interferon regulatory factor (IRF) activation (e.g., IRF3 activation), secretion of interferon-Y-inducible protein (IP-10), or other inflammatory proteins and cytokines.
• TK TANK binding kinase
• IRF interferon regulatory factor
• IP-10 interferon-Y-inducible protein
• STING Agonist activity may be determined, for example, by the ability of a compound to stimulate activation of the STING pathway as detected using an interferon stimulation assay, a reporter gene assay (e.g., a hSTING wt assay, or a THP-1 Dual assay), a TBK1 activation assay, IP-10 assay, a STING Biochemical [3H]cGAMP Competition Assay, or other assays known to persons skilled in the art.
• STING Agonist activity may also be determined by the ability of a compound to increase the level of transcription of genes that encode proteins activated by STING or the STING pathway. Such activity may be detected, for example, using an RNAseq assay.
• an assay to test for activity of a compound in a STING knock-out cell line may be used to determine if the compound is specific for STING, wherein a compound that is specific for STING would not be expected to have activity in a cell line wherein the STING pathway is partially or wholly deleted.
• the terms “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
• “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
• “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
• the term “prevent”, “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder
• terapéuticaally effective amount or “therapeutically effective dose” interchangeably refers to an amount sufficient to effect the desired result (i.e., reduction or inhibition of an enzyme or a protein activity, amelioration of symptoms, alleviation of symptoms or conditions, delay of disease progression, a reduction in tumor size, inhibition of tumor growth, prevention of metastasis, inhibition or prevention of viral, bacterial, fungal or parasitic infection).
• a therapeutically effective amount does not induce or cause undesirable side effects.
• a therapeutically effective amount induces or causes side effects but only those that are acceptable by the healthcare providers in view of a patient's condition.
• a therapeutically effective amount can be determined by first administering a low dose, and then incrementally increasing that dose until the desired effect is achieved.
• a “prophylactically effective dose” or a “prophylactically effect amount”, of the molecules of the invention can prevent the onset of disease symptoms, including symptoms associated with cancer.
• a “therapeutically effective dose” or a “therapeutically effective amount” of the molecules of the invention can result in a decrease in severity of disease symptoms, including symptoms associated with cancer.
• the compound names provided herein were obtained using ChemDraw Ultra version 14.0 (CambridgeSoft®).
• the Drug moiety (D) of the immunoconjugates of the invention is a compound which binds to Stimulator of Interferon Genes (STING) receptor and which comprises one or more reactive moieties each of which is capable of forming a covalent bond with a linker (L).
• Drug moiety (D) of the immunoconjugates of the invention is a dinucleotide which binds to Stimulator of Interferon Genes (STING) which comprises one or more reactive moieties capable of forming a covalent bond with a linker (L).
• Drug moiety (D) of the immunoconjugates of the invention is a cyclic dinucleotide which binds to Stimulator of Interferon Genes (STING) which comprises one or more reactive moieties capable of forming a covalent bond with a linker (L).
• STING Stimulator of Interferon Genes
• the Drug moiety (D) of the immunoconjugates of the invention is a compound having the structure of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (
• X B is C, and each Z 2 is N;
• G 2 is * indicates the point of attachment to -CR 8a R 9a -;
• X D is C, and each Z 4 is N;
• Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se " , BH 3 , SH or S " ;
• Y 4 is OH, 0 " , OR 10 , N(R 10 ) 2 , SR 10 , SeH, Se " , BH 3 , SH or S " ;
• Y 5 is -CH 2 -, -NH-, -0- or -S;
• Y 6 is -CH 2 -, -NH-, -0- or -S;
• Y 7 is 0 or S
• Y 8 is 0 or S
• Yg is -CHr, -NH-, -O- or -S;
• Y 10 is -CH 2 -, -NH-, -0- or -S;
• q is 1 , 2 or 3;
• R 1 is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1 is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from F, CI, Br, OH, SH, NH 2 , D, CD 3 , Ci-C 6 alkyl, C r C s alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, - ⁇ (C Cealkyl), -
• R 1a is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1a is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from F, CI, Br, OH, SH, NH 2 , D, CD 3 , d-Csalkyl,
• C r C s alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -Oid-Cealkyl), - 0(C 3 -C 8 cycloalkyl), -S(C r Csalkyl), -StCrCsaminoalkyl), -S(C r C 6 hydroxyalkyl), -S(C 3 - Cgcycloalkyl), -NH(C r C 6 alkyl), -NH(C 3 -C 8 cycloalkyl), -N(C r C 6 alkyl) 2 , -NCd-Cealkyl) (C 3 - C 8 cycloalkyl), -CN, -P( 0)(OH) 2 , -O(CH 2 ) 1 . 10 C(
• R 1b is a partially saturated or aromatic monocyclic heterocyclyl or partially saturated or aromatic fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, or a tautomer thereof, wherein R 1b is substituted with 0, 1 , 2, 3 or 4 substituents independently selected from F, CI, Br, OH, SH, NH 2 , D, CD 3 , CrC s alkyl,
• C r C s alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -0(CrC 6 alkyl), - 0(C 3 -C 8 cycloalkyl), -S(C r C s alkyl), -S(C r C 6 aminoalkyl), -S(C r C 6 hydroxyalkyl), -S(C 3 - C 8 cycloalkyl), -NH(C r C 6 alkyl), -NH(C 3 -C 8 cycloalkyl), -N(CrC 6 alkyl) 2 , -N(CrC 6 alkyl) (C 3 - Cscycloalkyl), -CN, -P( 0)(OH) 2 , -O(CH 2 ) 1 . 10 C(
• -OC(0)OCrC 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, - OC(0)C r C 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 2 are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• each R 3 is independently selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , CrCsalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrC 6 haloalkyl, C 2 -C 3 haloalkenyl, C 2 -
• CrCshaloalkyl C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r C 6 alkyl), -0(C 2 -C 3 alkenyl), - 0(C 2 -C 6 alkynyl), -OC(0)OCrC 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, - OC(0)C r C 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3 are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• -OC(0)OCrC 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, - OC(0)C r C 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 4 are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• each R 5 is independently selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , CrCsalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrC 6 haloalkyl, C 2 -C 3 haloalkenyl, C 2 -
• CrCshaloalkyl C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r C 6 alkyl), -0(C 2 -C 3 alkenyl), - 0(C 2 -C 6 alkynyl), -OC(0)OCrC 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, - OC(0)CrC 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 5 are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• C r C s alkyl, C 2 -C 3 alkenyl and C 2 -C 6 alkynyl of the C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrCshaloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(CrC 6 alkyl), -0(C 2 -C 3 alkenyl), - 0(C 2 -C 6 alkynyl), -OC(0)OCi-C 6 alkyl, -0C(0)0C 2 -C 6 alkenyl, -0C(0)0C 2 -C 6 alkynyl, - OC(0)C r C 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R s are substituted by 0,1 , 2 or
• OC(0)C 2 -C 6 alkynyl wherein the -OC(0)Ophenyl of R 3a and the C r C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl of the CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrCghaloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r C 6 alkyl), -0(C 2 -C 6 alkenyl), -0(C 2 -C 6 alkynyl), - OC(0)OC r C 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, -OC(0)C r C 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC
• OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 4a are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• OC(0)OC r C 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, -OC(0)C r C 6 alkyl, - OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 5a are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• R 6a is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , CrCealkyl, C 2 -C 3 alkenyl, C 2 -C 6 alkynyl, C r C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r
• OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 6a are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• OC(0)OC r C 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, -OC(0)C r C 6 alkyl, - OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 7a are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• R 8a is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , CrCealkyl, C 2 -C 3 alkenyl, C 2 -C 6 alkynyl, C r C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r
• C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r C 6 alkyl), -0(C 2 -C 6 alkenyl), -0(C 2 -C 6 alkynyl), - OC(0)OC r C 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, -OC(0)C r C 6 alkyl, - OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 8 are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• each R 10 is independently selected from the group consisting of H, d-C ⁇ alkyl, C r
• each R 11 is independently selected from H and Chalky!
• each R 12 is independently selected from H and CrCsalkyl
• R 3 and R 6 are connected to form d-Calkylene, C 2 -C 6 alkenylene, C 2 -
• R 3a and R 6a are connected to form Crdalkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, -0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 3a and R 6a are connected, the O is bound at the R 3a position;
• R 2 and R 3 are connected to form d-Calkylene, C 2 -C 6 alkenylene, C 2 -
• R 2a and R 3a are connected to form Crdalkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 2a and R 3a are connected, the O is bound at the R 3a position;
• R 4 and R 3 are connected to form Crdalkylene, C 2 -C 6 alkenylene, C 2 -
• R 5 and R 6 are connected to form C ⁇ Cealkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, -0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5 and R 6 are connected, the 0 is bound at the R 5 position;
• R 5a and R 6a are connected to form CrQjalkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, -0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5a and R 6a are connected, the O is bound at the R 5a position;
• R 5 and R 7 are connected to form C ⁇ Cealkylene, C 2 -C 6 alkenylene, C 2 -
• R 5a and R 7a are connected to form CrCsalkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, -0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5a and R 7a are connected, the O is bound at the R 5a position;
• R 8 and R 9 are connected to form a d-Calkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, and
• R 8a and R 9a are connected to form a CrC 6 alkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene.
• Embodiment 1 A compound of Formula (A-1), Formula (B-1), Formula (C-1), Formula (D- 1), Formula (E-1) or Formula (F-1), or stereoisomers or pharmaceutically acceptable salts thereof
• Formula (E-1) Formula (F-1) wherein R 1 , R 1a , R 1 b , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , Y t l Y 2 , Y 3 , Y 4 , Y5, ⁇ , Y7, Ye, Y9, Y10 and Yn are as defined above for compounds of Formula (A) , Formula (B), Formula (C), Formula (D), Formula (E) and Formula (F).
• Embodiment 2 A compound of Formula( A), Formula (B), Formula (C), Formula (D), Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1), or Formula (F- 1), wherein R 1 is pyrimidine or purine nucleic acid base or analogue thereof, R 1a is pyrimidine or purine nucleic acid base or analogue thereof, and R 1 is a pyrimidine or purine nucleic acid base or analogue thereof, each of which is substituted as described in R 1 , R 1a or R 1 for Formula (A), Formula (BB, Formula (C), Formula (D), Formula (A-1), Formula (B-1), Formula (C-1), Formula (D-1), Formula (E-1), or Formula (F-1).
• Embodiment 3 A compound of Formula (A-2), Formula (B-2), Formula (C-2), Formula (D- 2), Formula (E-2) or Formula (F-2):
• Formula (E-2) Formula (F-2) wherein R 1 , R 1a , R 1 , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , Y, , Y 2 , Y 3 , Y 4 , Y5, Ye, Y7, Ys, Y9, Y1 0 and Y are as defined above for compounds of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E) and Formula (F).
• Embodiment 4 A compound of Formula (A), Formula (A-1) or Formula (A-2) of
• Embodiment 1 , 2 or 3 wherein:
• C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3 or R 4 are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• R 7 and R 7a are H
• R 6 and R 6a are H
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
• C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3a or R 4a are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 .
• Embodiment 5 A compound of Formula (A), Formula (A-1) or Formula (A-2) of
• Embodiment 1 2, 3 or 4 wherein:
• Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 4 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 5 and Y 6 are 0 or S;
• Y 7 and Y 8 are 0 or S;
• Y 9 and Y 10 are 0 or S;
• R 2 , R 2a , R 6 , R 6a , R 7 and R 7a are H;
• R 3a and R a is H and the other is H, OH or F
• one of R 3 and R 4 is H and the other is H, OH or F
• R 8a , R 9a , R 8 and R 9 are independently selected from H or CrCealk l.
• Embodiment 6 A compound of Formula (B), Formula (B-1) or Formula (B-2) of
• Embodiment 1 , 2 or 3 wherein:
• R 2 and R 2a are H
• C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3a or R a are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• R 7a and R 6a are H
• R s and R 4 are H
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
• C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 5 or R 7 are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 .
• Embodiment 7 A compound of Formula (B), Formula (B-1) or Formula (B-2) of
• Embodiment 1 2, 3 or 6 wherein:
• ⁇ ⁇ and Y 2 are O, CH 2 or S;
• Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 4 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ; Y 5 and Y 6 are 0 or S;
• Y 7 and Y 8 are 0 or S;
• Y g and Y 10 are 0 or S;
• R 2 , R 2a , R 7a , R Sa , R 6 and R 4 are H;
• R 3a and R 4a are H and the other is H, OH or F;
• R 5 and R 7 are H and the other is H, OH or F, and
• R 8a , R 9a , R 8 and R 9 are independently selected from H or C 1 -C 3 alkyl.
• Embodiment 8 A compound of Formula (C), Formula (C-1) or Formula (C-2) of
• Embodiment 1 , 2 or 3 wherein:
• R 2 and R 2a are H
• R 4a and R 6a are H;
• R 6 and R 7 are H
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
• Embodiment 1 , 2, 3 or 8 wherein:
• Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 4 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 5 and Y 6 are 0 or S;
• Y 7 and Y 8 are 0 or S;
• Y 9 and Yio are 0 or S;
• R 2 , R 2a , R 4a , R 8a , R 6 and R 7 are H;
• R 3 and R 4 is H and the other is H, OH or F;
• R 5a and R 7a are H and the other is H, OH or F, and
• Embodiment 10 A compound of Formula (D), Formula (D-1) or Formula (D-2) of
• Embodiment 1 , 2 or 3 wherein:
• R 2 and R 2a are H
• C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 5a or R 7a are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• R a and R 6a are H
• R 6 and R 4 are H
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
• Embodiment 11 A compound of Formula (D), Formula (D-1) or Formula (D-2) of
• Embodiment 1 1, 2, 3 or 10 wherein:
• Y 1 and Y 2 are 0, CH 2 or S;
• Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 4 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 5 and Y 6 are 0 or S;
• Y 7 and Y 8 are 0 or S;
• Y 9 and Y 10 are 0 or S;
• R 2 , R 2a , R 4a , R Sa , R 6 and R 4 are H;
• R 5a , R 7a is H and the other is H, OH or F;
• R 5 and R 7 are H and the other is H, OH or F, and
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl.
• Embodiment 12 A compound of Formula (E), Formula (E-1) or Formula (E-2) of
• Embodiment 1 , 2 or 3 wherein:
• R 2 and R 2a are H
• R 6 and R 6a are H
• R 7a is H
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
• R 3a and R 4a is H and the other is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrCehaloalkyl, C 2 -
• C 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, -OC ⁇ CrCealkyl, -OC(0)C 2 - C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3 or R 4 are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 , and one of R 5 and R 7 is H and the other is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r Csal
• C 6 alkenyl and -0C(0)C 2 -C 6 alkynyl of R 5 or R 7 are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 .
• Embodiment 13 A compound of Formula (E), Formula (E-1) or Formula (E-2) of
• Embodiment 1 1, 2, 3 or 12 wherein:
• Y 1 and Y 2 are O, CH 2 or S;
• Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 5 is O or S
• Y 7 is O or S
• Y 9 is O or S
• R 2 , R 2a , R 5a , R 8a , R 6 and R 7a are H;
• R 3a , R a is H and the other is H, OH, OCH 3 or F;
• R 3 , R 4 is H and the other is H, OH, OCH 3 or F;
• R 5 and R 7 are H and the other is H, OH, OCH 3 or F, and
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl.
• Embodiment 14 A compound of Formula (F), Formula (F-1) or Formula (F-2) of
• Embodiment 1 , 2 or 3 wherein:
• R 2 and R 2a are H; each R e and R ea are H;
• each R 7a and R 7 are H;
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
• R 3a and R a is H and the other is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r C 6 haloalkyl, C 2 -
• C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3 or R 4 are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 , and
• R 5 is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r
• Embodiment 15 A compound of Formula (F), Formula (F-1) or Formula (F-2) of
• Embodiment 1 1, 2, 3 or 12 wherein:
• Y 1 and Y 2 are 0, CH 2 or S;
• each Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• each Y 5 is O or S
• each Y 7 is independently 0 or S;
• each Y g is independently 0 or S;
• Y 11 is O, CH 2 or S
• R 2 , R 2a , R 6 , R 6a , R 6 , R 7 and R 7a are H;
• R 3a , R 4a is H and the other is H, OH, OCH 3 or F;
• R 3 , R 4 is H and the other is H, OH, OCH 3 or F;
• R 5 is H, OH, OCH 3 or F
• R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl.
• Embodiment 16 A compound of any one of Embodiments 1 to 15 wherein:
• R is substituted with 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, OH, SH, NH 2 , D, CD 3 , C r C s alkyl, C r
• C 6 alkoxyalkyl, Ci-C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -CHCrCealkyl), - 0(C 3 -C 8 cycloalkyl), -S(C r C s alkyl), -S(C r C 6 aminoalkyl), -S(C r C 6 hydroxyalkyl), -S(C 3 - Cgcycloalkyl), -NH(C r C 6 alkyl), -NH(C 3 -C 8 cycloalkyl), -N(C r C 6 alkyl)2, -NCd-Csalkyl) (C 3 - Cgcycloalkyl), -CN, -P( 0)(OH) 2 , -O(CH 2 ) 1 .
• R is substituted with 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, OH, SH, NH 2 , D, CD 3 , C r C 6 alkyl, C r
• R is substituted with 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, OH, SH, NH 2 , D, CD 3 , C r C s alkyl, C r
• C 6 alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -C CrCealkyl), - 0(C 3 -C 8 cycloalkyl), -S(C r C 3 alkyl), -S(C r C 6 aminoalkyl), -S(C r C 6 hydroxyalkyl), -S(C 3 - Cgcycloalkyl), -NH(C r C 6 alkyl), -NH(C 3 -C 8 cycloalkyl), -N(C r C 6 alkyl) 2 , -N d-Cealkyl) (C 3 - Cgcycloalkyl), -CN, -P( 0)(OH) 2 , -O(CH 2 ) 1 .
• Embodiment 17 A compound of Formula (A-3), Formula (B-3), Formula (C-3) , Formula -3), Formula (E-3) or Formula (F-3):
• Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 4 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
• Y 7 is 0 or S
• R is substituted with 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, OH, SH, NH 2 , D, CD 3 , C r C 6 alkyl, C r C s alkoxyalkyl, C r C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a 3 to 6 membered heterocyclyl having 1 to 2 heteroatoms independently selected from 0, N and S, -C ⁇ CrCsalkyl), - 0(C 3 -C 8 cycloalkyl), -S(C r C 3 alkyl), -S(C r C 6 aminoalkyl), -S(C r C 6 hydroxyalkyl), -S(C 3 - Cgcycloalkyl), -NH(C r C 6 alkyl), -NH(C 3 -C 8 cycloalkyl), -N(C r C 6 alkyl) 2 , -
• -OC(0)OCrC 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, - OC(0)C r C 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 5 are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
• each R 6 is independently selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrCehaloalkyl, C 2 -C 3 haloalkenyl, C 2 -
• CrCshaloalkyl C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r C 6 alkyl), -0(C 2 -C 3 alkenyl), - 0(C 2 -C 6 alkynyl), -OC(0)OCrC 6 alkyl, -0C(0)0C 2 -C 6 alkenyl, -0C(0)0C 2 -C 6 alkynyl, - OC(0)C r C 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R s are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;

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