WO2009134870A1 - Conjugués de médicament d’agent de liaison cellulaire puissant - Google Patents

Conjugués de médicament d’agent de liaison cellulaire puissant Download PDF

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WO2009134870A1
WO2009134870A1 PCT/US2009/042091 US2009042091W WO2009134870A1 WO 2009134870 A1 WO2009134870 A1 WO 2009134870A1 US 2009042091 W US2009042091 W US 2009042091W WO 2009134870 A1 WO2009134870 A1 WO 2009134870A1
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cell
conjugate
cells
binding agent
linker
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Ravi V. J. Chari
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Immunogen Inc
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Immunogen Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6869—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
    • 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
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6859—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from liver or pancreas cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell

Definitions

  • the present invention relates to efficacious drug load in a drug cell-binding agent conjugate.
  • the present invention relates to the use of about 2 to about 8 drug molecules (drug load), for example, maytansinoid, per cell binding agent, such as an antibody, and their greater efficacy as compared to a drug load of a lesser or higher number of drugs linked to such a cell binding agent.
  • drug load for example, maytansinoid
  • cell binding agent such as an antibody
  • a major drawback with existing drug cell-binding agent conjugates is their inability to deliver a sufficient concentration of drug to the target site because of the limited number of targeted antigens and the relatively moderate cytotoxicity of cancer drugs like methotrexate, daunorubicin, maytansinoids, taxanes and vincristine.
  • cancer drugs like methotrexate, daunorubicin, maytansinoids, taxanes and vincristine.
  • linkage of a large number of drug molecules either directly to the antibody or through a polymeric carrier molecule becomes necessary.
  • heavily modified antibodies often display impaired binding to the target antigen and fast in vivo clearance from the blood stream. Therefore, there is a need to improve the ability to deliver a sufficient concentration of a drug to the target such that maximum cytotoxicity for the drug is achieved.
  • the present invention provides a drug cell-binding agent conjugate wherein the number of drug molecules per cell-binding agent molecule is about 2 to about 8.
  • This invention also encompasses the use of drug molecules (e.g., maytansinoids), as an active ingredient for the manufacture of drug cell-binding agent conjugates wherein the number of drug molecules per cell-binding agent molecule is about 2 to about 8
  • drug molecules e.g., maytansinoids
  • cell-binding agent drug conjugate is represented by formula
  • D about 2 - about 8 -L-CBA, wherein D is a drug, L is a linker, wherein the linker is selected from a cleavable linker or a linker substantially resistant to cleavage and CBA is a cell binding agent.
  • the drug cell binding agent conjugate is represented by formula (May)about 2 - about 8 -L-CBA, wherein May is a maytansinoid, L is a linker, wherein the linker is selected from a cleavable linker or a linker substantially resistant to cleavage, and CBA is a cell binding agent.
  • Figure 1 illustrates the anti-tumor effect of C242-DM1 conjugate containing variable number of DMl molecues/C242 molecule.
  • the present invention is based on the unexpected finding that when about 2 to about
  • drug load for example, maytansinoid
  • cell binding agent such as an antibody
  • Drug load refers to the number of drug molecules (e.g., a maytansinoid) that can be attached to a cell binding agent (e.g., an antibody).
  • a cell binding agent e.g., an antibody
  • the number of drug molecules that can be attached to a cell binding agent may average from about 2 to about 8 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,
  • the number of drug molecules that can be attached to a cell binding agent may average from about 2 to about 7 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1).
  • the number of drug molecules that can be attached to a cell binding agent may average from about 2 to about 6 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1).
  • the number of drug molecules that can be attached to a cell binding agent may average from about 2 to about 5 (e.g., 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1).
  • the term "average”, as used herein, is determined by spectrophotometric measurement of the absorbance of a cell binding agent (e.g., an antibody) and the drug
  • the conjugates of the present invention comprise at least about two drugs for killing selected cell populations linked to a cell-binding agent.
  • the drug cell-binding agent conjugate is represented by the formula (D) ab0Ut 2 - about s-L-CBA, wherein D is a drug (e.g., a maytansinoid, a taxane or a
  • L is a linker, wherein the linker is selected from a cleavable linker (e.g., linkers cleavable through disulfide exchange) or a linker substantially resistant to cleavage (e.g., linkers having an N-succinimidyl ester or N-sulfosuccinimidyl ester moiety for reaction with the cell-binding agent, as well as a maleimido- or haloacetyl- based moiety) and CBA is a cell binding agent (e.g., an antibody or a fragment thereof that preferentially binds to a target cell).
  • a cell binding agent e.g., an antibody or a fragment thereof that preferentially binds to a target cell.
  • the drug cell binding agent conjugate (e.g., an immunoconjugate) represented by formula (May) about 2 - about 8 -L-CBA, wherein May is a maytansinoid, L is a linker, wherein said linker is a cleavable linker or a linker substantially resistant to cleavage; and CBA is a cell binding agent, preferably an antibody or a fragment thereof that preferentially binds to a target cell.
  • an immunoconjugate represented by formula (May) about 2 - about 8 -L-CBA, wherein May is a maytansinoid, L is a linker, wherein said linker is a cleavable linker or a linker substantially resistant to cleavage; and CBA is a cell binding agent, preferably an antibody or a fragment thereof that preferentially binds to a target cell.
  • the drugs used in this invention are cytotoxic drugs capable of being linked to a cell-binding agent.
  • suitable drugs include maytansinoids, DNA-binding drugs such as CC- 1065 and its analogs, doxorubicin and its analogs, and taxoids.
  • Maytansinoids that can be used in the present invention are well known in the art and can be isolated from natural sources according to known methods or prepared synthetically according to known methods.
  • Examples of suitable maytansinoids include maytansinol and maytansinol analogues.
  • suitable maytansinol analogues include those having a modified aromatic ring and those having modifications at other positions.
  • Maytansinoids with a thiol moiety at the C-3 position, the C- 14 position, the C- 15 position or the C-20 position are all expected to be useful.
  • the C-3 position is preferred and the C-3 position of maytansinol is especially preferred.
  • an TV- methyl-alanine-containing C-3 thiol moiety maytansinoid, and an 7V-methyl-cysteine- containing C-3 thiol moiety maytansinoid, and analogues of each.
  • / is an integer of from 1 to 10; and may is a maytansinoid.
  • R 1 and R 2 are H, CH 3 or CH 2 CH 3 , and may be the same or different; m is 0, 1, 2 or 3; and may is a maytansinoid.
  • n is an integer of from 3 to 8; and may is a maytansinoid.
  • R 1 , R 2 , R 3 , R 4 are H, CH 3 or CH 2 CH 3 , and may be the same or different; m is O, 1, 2 or 3; and
  • N-methyl-cysteine-containing C-3 thiol moiety maytansinoid derivatives useful in the present invention are represented by the formulae M4 and M5.
  • M4 wherein: o is 1, 2 or 3; p is 0 or an integer of 1 to 10; and may is a maytansinoid.
  • Y 0 is Cl or H
  • X 3 is H or CH 3 .
  • Preferred maytansinoids are those described in US Patents 5,208,020; 5,416,064; 6,333.410; 6,441,163; 6,716,821; RE39,151 and 7,276,497. Of these, ⁇ ' -deacetyl-iV 2' - (3-mercapto-l-oxopropyl)-maytansine (DMl) and N 2 -deacetyl-N 2 -(4-mercapto-4- methyl-1-oxopentyl) maytansine (DM4) are preferred.
  • CC-1065 and its analogs are those described in US Patents 5,475,092; 5,595,499; 5,846,545; 6,534,660; 6,586,618; 6,756,397 and 7,049,316.
  • -Doxorubicins and its analogs are those described in US Patent 6,630,579.
  • -Taxoids Preferred taxoids are those described in US Patents 6,340,701; 6,372,738; 6.436, 931; 6,596,757; 6,706,708; 7,008,942; 7,217,819 and 7,276,499.
  • Chemotherapeutic agent is a chemical compound useful for the treatment of cancer. Chemotherapeutic agents can be used alone for conjugation with a cell binding agent or in combination with drug-cell binding agent conjugates described herein. Preferred chemotherapeutic agents are described, for example, in United States Patent 7,303,749.
  • cytotoxic drugs will readily understand that each of the drugs described herein can be modified in such a manner that the resulting compound still retains the specificity and/or activity of the starting compound. The skilled artisan will also understand that many of these compounds can be used in place of the drugs described herein.
  • the drugs of the present invention include analogues and derivatives of the compounds described herein.
  • the cell-binding agents used in this invention are proteins (e.g., immunoglobulin and non-immunoglobulin proteins) which bind specifically to target antigens on cancer cells.
  • proteins e.g., immunoglobulin and non-immunoglobulin proteins
  • -antibodies including:
  • -humanized or fully human antibodies are selected from, but not limited to, huMy9-6, huB4, huC242, huN901, DS6, CD38, IGF-IR, CNTO 95, B-B4, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab (see, e.g., U.S. Patent Nos. 5,639,641, 5,665,357; and7,342,l 10), International Patent Application WO 02/16,401, U.S. publication number 20060045877, U.S. publication number 20060127407, U.S.
  • Additional cell-binding agents include other cell binding proteins and polypeptides exemplified by, but not limited to:
  • -interferons e.g. ⁇ , ⁇ , ⁇
  • -lymphokines such as IL-2, IL-3, IL-4, IL-6;
  • -hormones such as insulin, TRH (thyrotropin releasing hormones), MSH (melanocyte-stimulating hormone), steroid hormones, such as androgens and estrogens; and
  • EGF EGF
  • TGF- ⁇ TGF- ⁇
  • IGF-I IGF-I
  • G-CSF G-CSF
  • M-CSF M-CSF
  • GM-CSF GM-CSF
  • the cell-binding agent binds to an antigen that is a polypeptide and may be a transmembrane molecule (e.g. receptor) or a ligand such as a growth factor.
  • antigens include molecules such as renin; a growth hormone, including human growth hormone and bovine growth hormone; growth hormone releasing factor; parathyroid hormone; thyroid stimulating hormone; lipoproteins; alpha- 1 -antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; clotting factors such as factor vmc, factor IX, tissue factor (TF), and von Willebrands factor; anti-clotting factors such as Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator, such as urokinase or human urine or tissue-type plasminogen activator (t-PA); bombesin;
  • erythropoietin erythropoietin
  • osteoinductive factors immunotoxins
  • a bone morphogenetic protein BMP
  • an interferon such as interferon-alpha, -beta, and -gamma
  • colony stimulating factors CSFs
  • ILs interleukins
  • superoxide dismutase T-cell receptors
  • surface membrane proteins e.g., IL-I to IL- 10
  • superoxide dismutase e.g., IL-I to IL- 10
  • superoxide dismutase T-cell receptors
  • surface membrane proteins accelerating factor
  • viral antigen such as, for example, a portion of the HIV envelope; transport proteins; homing receptors; addressins; regulatory proteins; integrins, such as CDl Ia, CDl Ib, CDl Ic, CDl 8, an ICAM, VLA-4 and VCAM; a tumor associated antigen such as HER2, HER3 or HER
  • GM-CSF which binds to myeloid cells can be used as a cell- binding agent to diseased cells from acute myelogenous leukemia.
  • IL-2 which binds to activated T-cells can be used for prevention of transplant graft rejection, for therapy and prevention of graft- versus-host disease, and for treatment of acute T-cell leukemia.
  • MSH which binds to melanocytes, can be used for the treatment of melanoma.
  • Folic acid can be used to target the folate receptor expressed on ovarian and other tumors.
  • Epidermal growth factor can be used to target squamous cancers such as lung and head and neck.
  • Somatostatin can be used to target neuroblastomas and other tumor types.
  • Cancers of the breast and testes can be successfully targeted with estrogen (or estrogen analogues) or androgen (or androgen analogues) respectively as cell-binding agents.
  • Preferred antigens for antibodies encompassed by the present invention include CD proteins such as CD2, CD3, CD4, CD5, CD6, CD8, CDl 1, CD18, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD79, CD105, CD138; members of the ErbB receptor family such as the EGF receptor, HER2, HER3 or HER4 receptor; cell adhesion molecules such as LFA-I, Macl, pi 50.95, VLA-4, ICAM-I, VCAM, EpCAM, alpha4/beta7 integrin, and alpha v/beta3 integrin including either alpha or beta subunits thereof (e.g.
  • anti-CD l la, anti-CD 18 or anti-CD l ib antibodies growth factors such as VEGF; tissue factor (TF); TGF- ⁇ .; alpha interferon (alpha-IFN); an interleukin, such as IL-8; IgE; blood group antigens Apo2, death receptor; flk2/flt3 receptor; obesity (OB) receptor; mpl receptor; CTLA-4; protein C etc.
  • growth factors such as VEGF; tissue factor (TF); TGF- ⁇ .; alpha interferon (alpha-IFN); an interleukin, such as IL-8; IgE; blood group antigens Apo2, death receptor; flk2/flt3 receptor; obesity (OB) receptor; mpl receptor; CTLA-4; protein C etc.
  • the most preferred targets herein are IGF-IR, CanAg, EGF-R, EphA2, MUCl, MUC 16, VEGF, TF, CD 19, CD20, CD22, CD33, CD37, CD38, CD40, CD44, CD56, CD138, CA6, Her2/neu, EpCAM, CRIPTO (a protein produced at elevated levels in a majority of human breast cancer cells), alpha v/beta3 integrin, alpha v/beta5 integrin, alpha v/beta6 integrin, TGF- ⁇ , CDl Ia, CD18, Apo2 and C242 or an antibody which binds to one or more tumor- associated antigens or cell-surface receptors disclosed in US Publication No. 20080171040 or US Publication No. 20080305044 and are incorporated in their entirety by reference.
  • Monoclonal antibody techniques allow for the production of specific cell-binding agents in the form of monoclonal antibodies.
  • Particularly well known in the art are techniques for creating monoclonal antibodies produced by immunizing mice, rats, hamsters or any other mammal with the antigen of interest such as the intact target cell, antigens isolated from the target cell, whole virus, attenuated whole virus, and viral proteins such as viral coat proteins.
  • Sensitized human cells can also be used.
  • Another method of creating monoclonal antibodies is the use of phage libraries of sFv (single chain variable region), specifically human sFv (see, e.g., Griffiths et al, U.S. patent no.
  • the monoclonal antibody My9 is a murine IgG 2a antibody that is specific for the CD33 antigen found on Acute Myeloid Leukemia (AML) cells (Roy et al. Blood 77:2404-2412 (1991)) and can be used to treat AML patients.
  • the monoclonal antibody anti-B4 is a murine IgG 1 , that binds to the CD 19 antigen on B cells (Nadler et al, J Immunol. 131 :244-250 (1983)) and can be used if the target cells are B cells or diseased cells that express this antigen such as in non-Hodgkin's lymphoma or chronic lymphoblastic leukemia.
  • the antibody N901 is a murine monoclonal IgGi antibody that binds to CD56 found on small cell lung carcinoma cells and on cells of other tumors of neuroendocrine origin (Roy et al. J. Nat. Cancer Inst. 88:1136-1145 (1996)), huC242 antibody that binds to the CanAg antigen, Trastuzumab that binds to HER2/neu, and anti-EGF receptor antibody that binds to EGF receptor.
  • the cell binding agent can be conjugated to the cytotoxic drugs by methods previously described (US Patent 6,013,748; 6,441,1631, 6,716,821, US Application 20050169933; WO2006/034488 A2).
  • the conjugates may be prepared by in vitro methods.
  • a linking group is used.
  • Suitable linking groups are well known in the art and include disulfide groups, acid labile groups, photolabile groups, peptidase labile groups, and esterase labile groups.
  • Preferred linking groups are disulfide groups.
  • conjugates can be constructed using a disulfide exchange reaction between the cell-binding agent and the drug.
  • the drugs also can be linked to a cell-binding agent through an intermediary carrier molecule such as serum albumin.
  • the cell-binding agent is modified by reacting a bifunctional crosslinking reagent with the cell-binding agent, thereby resulting in the covalent attachment of a linker molecule to the cell-binding agent.
  • a "bifunctional crosslinking reagent” is any chemical moiety that covalently links a cell- binding agent to a drug, such as the drugs described herein.
  • a portion of the linking moiety is provided by the drug.
  • the drug comprises a linking moiety that is part of a larger linker molecule that is used to join the cell-binding agent to the drug.
  • the side chain at the C-3 hydroxyl group of maytansine is modified to have a free sulfhydryl group (SH).
  • This thiolated form of maytansine can react with a modified cell-binding agent to form a conjugate. Therefore, the final linker is assembled from two components, one of which is provided by the crosslinking reagent, while the other is provided by the side chain from DMl .
  • any suitable bifunctional crosslinking reagent can be used in connection with the invention, so long as the linker reagent provides for retention of the therapeutic, e.g., cytotoxic, and targeting characteristics of the drug and the cell-binding agent, respectively.
  • the linker molecule joins the drug to the cell-binding agent through chemical bonds (as described above), such that the drug and the cell-binding agent are chemically coupled (e.g., covalently bonded) to each other.
  • the linking reagent is a cleavable linker. More preferably, the linker is cleaved under mild conditions, i.e., conditions within a cell under which the activity of the drug is not affected.
  • cleavable linkers examples include disulfide linkers, acid labile linkers, photolabile linkers, peptidase labile linkers, and esterase labile linkers.
  • Disulfide containing linkers are linkers cleavable through disulfide exchange, which can occur under physiological conditions.
  • Acid labile linkers are linkers cleavable at acid pH. For example, certain intracellular compartments, such as endosomes and lysosomes, have an acidic pH (pH 4-5), and provide conditions suitable to cleave acid labile linkers.
  • Photo labile linkers are useful at the body surface and in many body cavities that are accessible to light. Furthermore, infrared light can penetrate tissue.
  • Peptidase labile linkers can be used to cleave certain peptides inside or outside cells (see e.g., Trouet et al., Proc. Natl. Acad. Sci. USA, 79: 626-629 (1982), and Umemoto et al., Int. J. Cancer, 43: 677-684 (1989)).
  • the drug is linked to a cell-binding agent through a disulfide bond.
  • the linker molecule comprises a reactive chemical group that can react with the cell-binding agent.
  • Preferred reactive chemical groups for reaction with the cell-binding agent are N- succinimidyl esters and N-sulfosuccinimidyl esters.
  • the linker molecule comprises a reactive chemical group, preferably a dithiopyridyl group, that can react with the drug to form a disulfide bond.
  • linker molecules include, for example, N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) (see, e.g., Carlsson et al., Biochem. J., 173: 723-737 (1978)), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) (see, e.g., U.S.
  • SPDP N-succinimidyl 3-(2-pyridyldithio)propionate
  • SPDB N-succinimidyl 4-(2-pyridyldithio)butanoate
  • Patent 4,563,304 N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP) (see, e.g., CAS Registry number 341498-08-6), and other reactive cross-linkers, such as those described in U.S. Patent 6,913,748, which is incorporated herein in its entirety by reference.
  • SPP N-succinimidyl 4-(2-pyridyldithio)pentanoate
  • other reactive cross-linkers such as those described in U.S. Patent 6,913,748, which is incorporated herein in its entirety by reference.
  • cleavable linkers preferably are used in the inventive method
  • a non- cleavable linker also can be used to generate the above-described conjugate.
  • a non- cleavable linker is any chemical moiety that is capable of linking a drug, such as a maytansinoid, a Vinca alkaloid, a dolastatin, an auristatin, or a cryptophycin, to a cell- binding agent in a stable, covalent manner.
  • non-cleavable linkers are substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage, at conditions under which the drug or the cell-binding agent remains active.
  • non-cleavable linkers between a drug and the cell-binding agent are well known in the art.
  • non-cleavable linkers include linkers having an N-succinimidyl ester or N-sulfosuccinimidyl ester moiety for reaction with the cell-binding agent, as well as a maleimido- or haloacetyl-based moiety for reaction with the drug.
  • Crosslinking reagents comprising a maleimido-based moiety include N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), N- succinimidyl-4-(N-maleirnidomethyl)-cyclohexane- 1 -carboxy-(6-amidocaproate), which is a "long chain" analog of SMCC (LC-SMCC), ⁇ -maleimidoundecanoic acid N- succinimidyl ester (KMUA), ⁇ -maleimidobutyric acid N-succinimidyl ester (GMBS), ⁇ - maleimidocaproic acid N-hydroxysuccinimide ester (EMCS), m-maleimidobenzoyl-N- hydroxysuccinimide ester (MBS), N-( ⁇ -maleimidoacetoxy)-succinimide ester (AMAS), succinimidyl-6-( ⁇ -male
  • Cross-linking reagents comprising a haloacetyl-based moiety include N-succinimidyl-4- (iodoacetyl)-aminobenzoate (SIAB), N-succinimidyl iodoacetate (SIA), N-succinimidyl bromoacetate (SBA), and N-succinimidyl 3-(bromoacetamido)propionate (SBAP).
  • Other crosslinking reagents lacking a sulfur atom that form non-cleavable linkers can also be used in the inventive method.
  • Such linkers can be derived from dicarboxylic acid based moieties. Suitable dicarboxylic acid based moieties include, but are not limited to, ⁇ , ⁇ -dicarboxylic acids of the general formula shown below:
  • X is a linear or branched alkyl, alkenyl, or alkynyl group having 2 to 20 carbon atoms
  • Y is a cycloalkyl or cycloalkenyl group bearing 3 to 10 carbon atoms
  • Z is a substituted or unsubstituted aromatic group bearing 6 to 10 carbon atoms, or a substituted or unsubstituted heterocyclic group wherein the hetero atom is selected from N, O or S, and wherein 1, m, and n are each 0 or 1, provided that 1, m, and n are all not zero at the same time.
  • the drug can be first modified to introduce a reactive ester suitable to react with a cell-binding agent. Reaction of these maytansinoids containing an activated linker moiety with a cell-binding agent provides another method of producing a cleavable or non-cleavable cell-binding agent maytansinoid conjugate. THERAPEUTIC USE
  • the conjugates of the present invention can be administered in vitro, in vivo and/or ex vivo to treat patients and/or to modulate the growth of selected cell populations including, for example, cancer of the lung, blood, plasma, breast, colon, prostate, kidney, pancreas, brain, bones, ovary, testes, and lymphatic organs; autoimmune diseases, such as systemic lupus, rheumatoid arthritis, and multiple sclerosis; graft rejections, such as renal transplant rejection, liver transplant rejection, lung transplant rejection, cardiac transplant rejection, and bone marrow transplant rejection; graft versus host disease; viral infections, such as CMV infection, HIV infection, and AIDS; and parasite infections, such as giardiasis, amoebiasis, schistosomiasis, and the like.
  • selected cell populations including, for example, cancer of the lung, blood, plasma, breast, colon, prostate, kidney, pancreas, brain, bones, ovary, testes, and lymphatic organ
  • the conjugates and chemotherapeutic agents of the invention are administered in vitro, in vivo and/or ex vivo to treat cancer in a patient and/or to modulate the growth of cancer cells, including, for example, cancer of the blood, plasma, lung, breast, colon, prostate, kidney, pancreas, brain, bones, ovary, testes, and lymphatic organs; more preferably lung, colon prostrate, plasma, blood or colon cancer.
  • the cancer is multiple myeloma.
  • Modulating the growth of selected cell populations includes inhibiting the proliferation of selected cell populations (e.g., multiple myeloma cell populations, such as MOLP-8 cells, 0PM2 cells, H929 cells, and the like) to produce more cells; reducing the rate of increase in cell division as compared, for example, to untreated cells; killing selected cell populations; and/or preventing selected cell populations (such as cancer cells) from metastasizing.
  • the growth of selected cell populations can be modulated in vitro, in vivo or ex vivo.
  • the conjugates and chemotherapeutic agents can be administered in vitro, in vivo, or ex vivo separately or as components of the same composition.
  • the combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.
  • the conjugates and chemotherapeutic agents can be used with suitable pharmaceutically acceptable carriers, diluents, and/or excipients, which are well known, and can be determined by one of skill in the art as the clinical situation warrants.
  • Suitable carriers, diluents and/or excipients include: (1) Dulbecco's phosphate buffered saline, pH about 6.5, which would contain about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v NaCl), and (3) 5% (w/v) dextrose.
  • the compounds and compositions described herein may be administered in appropriate form, preferably parenterally, more preferably intravenously.
  • the compounds or compositions can be aqueous or nonaqueous sterile solutions, suspensions or emulsions.
  • Propylene glycol, vegetable oils and injectable organic esters, such as ethyl oleate, can be used as the solvent or vehicle.
  • the compositions can also contain adjuvants, emulsifiers or dispersants.
  • the compositions can also be in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or any other injectable sterile medium.
  • the "therapeutically effective amount" of the chemotherapeutic agents and conjugates described herein refers to the dosage regimen for modulating the growth of selected cell populations and/or treating a patient's disease, and is selected in accordance with a variety of factors, including the age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, and pharmacological considerations, such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound used.
  • the "therapeutically effective amount” can also be determined by reference to standard medical texts, such as the Physicians Desk Reference 2004.
  • the patient is preferably an animal, more preferably a mammal, most preferably a human.
  • the patient can be male or female, and can be an infant, child or adult.
  • Examples of suitable protocols of conjugate administration are as follows. Conjugates can be given daily for about 5 days either as an i.v. bolus each day for about 5 days, or as a continuous infusion for about 5 days.
  • the conjugates can be administered once a week for six weeks or longer.
  • the conjugates can be administered once every two or three weeks.
  • Bolus doses are given in about 50 to about 400 ml of normal saline to which about 5 to about 10 ml of human serum albumin can be added.
  • Continuous infusions are given in about 250 to about 500 ml of normal saline, to which about 25 to about 50 ml of human serum albumin can be added, per 24 hour period.
  • Dosages will be about 10 pg to about 1000 mg/kg per person, i.v. (average of about 100 ng to about 100 mg/kg; more preferably in the average of about 100 ng to about 10 mg/kg).
  • kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and/or compositions of the present invention, including, one or more conjugates and one or more chemotherapeutic agents.
  • kits can also include, for example, other compounds and/or compositions, a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products.
  • PDR Physician's Desk Reference
  • the PDR discloses dosages of the agents that have been used in treatment of various cancers.
  • the dosing regimen and dosages of these aforementioned chemotherapeutic agents and conjugates that are therapeutically effective will depend on the particular cancer being treated, the extent of the disease and other factors familiar to the physician of skill in the art and can be determined by the physician.
  • the 2006 edition of the Physician's Desk Reference discloses that Taxotere (see p.
  • FIG. 1 illustrates the anti-tumor effect of C242-DM1 containing 2.03, 3.67, 4.83, or 5.65 DMl molecules/C242 molecule.
  • C242-DM1 containing 2.03, 3.67, 4.83 and 5.65 DM1/C242 delayed the growth of Colo 205 tumors 5, 15, 11 and 5 days, respectively. There appeared to be a significant difference in tumor growth delay of mice treated with C242- DMl containing 3.67 DM1/C242 when compared to C242-DMI containing 2.03 and 5.65 DM1/C242, the latter two conjugates being the least efficacious.

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Abstract

La présente invention concerne l’utilisation d’environ 2 à environ 8 molécules de médicament, par exemple de maytansinoïde, par agent de liaison cellulaire, tel qu’un anticorps, avec une efficacité maximale comparée à une charge médicamenteuse d’un nombre inférieur ou supérieur de médicaments liés à un tel agent de liaison cellulaire.
PCT/US2009/042091 2008-04-30 2009-04-29 Conjugués de médicament d’agent de liaison cellulaire puissant Ceased WO2009134870A1 (fr)

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WO2014089354A1 (fr) * 2012-12-07 2014-06-12 The Regents Of The University Of California Interféron ciblant l'antigène cd138 présentant de puissantes activités apoptotiques et anti-tumorales
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US10093745B2 (en) 2013-05-29 2018-10-09 The Regents Of The University Of California Anti-CSPG4 fusions with interferon for the treatment of malignancy
US10182984B2 (en) 2007-09-21 2019-01-22 The Regents Of The University Of California Targeted interferons demonstrate potent apoptotic and anti-tumor activities
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
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US10918735B2 (en) 2012-12-04 2021-02-16 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment
US11535634B2 (en) 2019-06-05 2022-12-27 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof
US11932650B2 (en) 2017-05-11 2024-03-19 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
US12030888B2 (en) 2021-02-24 2024-07-09 Massachusetts Institute Of Technology Himastatin derivatives, and processes of preparation thereof, and uses thereof

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Publication number Priority date Publication date Assignee Title
US10182984B2 (en) 2007-09-21 2019-01-22 The Regents Of The University Of California Targeted interferons demonstrate potent apoptotic and anti-tumor activities
CN103068847A (zh) * 2010-08-24 2013-04-24 罗切格利卡特公司 可活化的双特异性抗体
US9085622B2 (en) 2010-09-03 2015-07-21 Glaxosmithkline Intellectual Property Development Limited Antigen binding proteins
US10918735B2 (en) 2012-12-04 2021-02-16 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment
US9803021B2 (en) 2012-12-07 2017-10-31 The Regents Of The University Of California CD138-targeted interferon demonstrates potent apoptotic and anti-tumor activities
WO2014089354A1 (fr) * 2012-12-07 2014-06-12 The Regents Of The University Of California Interféron ciblant l'antigène cd138 présentant de puissantes activités apoptotiques et anti-tumorales
US10975158B2 (en) 2012-12-07 2021-04-13 The Regents Of The University Of California CD138-targeted interferon demonstrates potent apoptotic and anti-tumor activities
US10093745B2 (en) 2013-05-29 2018-10-09 The Regents Of The University Of California Anti-CSPG4 fusions with interferon for the treatment of malignancy
US10822427B2 (en) 2013-05-29 2020-11-03 The Regents Of The University Of California Anti-CSPG4 fusions with interferon for the treatment of malignancy
WO2015009740A2 (fr) 2013-07-15 2015-01-22 Cell Signaling Technology, Inc. Agents de liaison anti-mucine 1 et leurs utilisations
EP3699200A1 (fr) 2013-07-15 2020-08-26 Cell Signaling Technology, Inc. Agents de liaison anti-mucin 1 et leurs utilisations
US10918627B2 (en) 2016-05-11 2021-02-16 Massachusetts Institute Of Technology Convergent and enantioselective total synthesis of Communesin analogs
WO2018112334A1 (fr) 2016-12-16 2018-06-21 Bluefin Biomedicine, Inc. Anticorps anti-protéine 1 contenant un domaine anti-cub (cdcp1), conjugués anticorps-médicament et leurs méthodes d'utilisation
US11932650B2 (en) 2017-05-11 2024-03-19 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
US11535634B2 (en) 2019-06-05 2022-12-27 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof
US12180228B2 (en) 2019-06-05 2024-12-31 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof
US12030888B2 (en) 2021-02-24 2024-07-09 Massachusetts Institute Of Technology Himastatin derivatives, and processes of preparation thereof, and uses thereof

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