WO2018183494A1 - Conjugués anticorps-médicament ciblant cd19 - Google Patents

Conjugués anticorps-médicament ciblant cd19 Download PDF

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WO2018183494A1
WO2018183494A1 PCT/US2018/024840 US2018024840W WO2018183494A1 WO 2018183494 A1 WO2018183494 A1 WO 2018183494A1 US 2018024840 W US2018024840 W US 2018024840W WO 2018183494 A1 WO2018183494 A1 WO 2018183494A1
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cell
seq
lymphoma
antibody
hub4
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PCT/US2018/024840
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WO2018183494A8 (fr
Inventor
Stuart William HICKS
Jutta Deckert
Kathleen R. Whiteman
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Immunogen, Inc.
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Publication of WO2018183494A8 publication Critical patent/WO2018183494A8/fr

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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
    • A61K47/6867—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 a blood cancer
    • 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
    • A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine

Definitions

  • the present invention is directed to anti-CD 19 antibody-drug conjugates and their for the treatment of B-cell malignancies.
  • CD 19 is a cell surface membrane protein expressed in most mature and immature B-cell neoplasms, making it a promising target for antibody drug conjugate (ADC) therapy for B-cell malignancies.
  • ADC antibody drug conjugate
  • the present invention is based on the preclinical activity of a CD19-targeting ADC, huB4-DGN462 and huB4-DGN549.
  • HuB4-DGN462 is an antibody-drug conjugate composed of a humanized IgGl monoclonal antibody, huB4, which specifically targets the CD 19 antigen, conjugated through a disulfide linker, sulfo-SPDB, to the cytotoxic benzodiazepine dimer compound DGN462, a DNA alkylating agent.
  • huB4-DGN549 is an antibody-drug conjugate composed huB4 conjugated to the cytotoxic benzodiazepine dimer compound DGN549, a DNA alkylating agent
  • the present invention provides an anti-CD 19 antibody-drug conjugate represented by the following formula:
  • a light chain CDR1 comprising SASSGVNYMH (SEQ ID NO: 1); a light chain CDR2 comprising DTSKLAS (SEQ ID NO: 2); and a light chain CDR3 comprising HQRGSYT (SEQ ID NO: 3); and
  • a heavy chain CDR1 comprising SNWMH (SEQ ID NO: 4); a heavy chain CDR2 comprising EIDPSDSYTN (SEQ ID NO: 5); and a heavy chain CDR3 comprising
  • the present invention provides an anti-CD 19 antibody-drug conjugate represented by the following formula:
  • r is an integer from 1 to 10
  • Y is - S0 3 H
  • the antibody is an anti-CD 19 antibody that specifically binds to a CD 19 antigen and comprises:
  • the present invention provides an anti-CD 19 antibody- drug conjugate represented by the following formula:
  • the antibody is an anti-CD 19 antibody that specifically binds to a CD 19 antigen and comprises:
  • composition comprising the conjugate of the present invention described herein and a pharmaceutically acceptable carrier.
  • FIG. 1 shows the anti-proliferative activity of huB4-DGN462 and its unconjugated toxin, DGN462SMe, in non-Hodgkin lymphoma cell lines. Cells were treated for 72h with a large range of concentration of a single agent.
  • FIG. 2 shows in vivo efficacy of huB4-DGN462 in mice bearing DoHH2 tumor cells.
  • FIG. 3 shows in vivo efficacy of huB4-DGN462 in mice bearing Farage tumor cells.
  • FIG. 4 shows in vitro cytotoxicity of huB4-DGN462 as compared to huB4-SPDB- DM4 in B-NHL and B-ALL cell lines.
  • FIG. 6 shows in vivo efficacy of huB4-s-SPDB-DGN462 and huB4-DGN549 in mice bearing OCI-Lyl8 tumor cells as compared huB4-SPDB-DM4.
  • cytotoxic compound or "cytotoxic compound,” “cytotoxic dimer” and “cytotoxic dimer compound” are used interchangeably. They are intended to include compounds for which a structure or formula or any derivative thereof has been disclosed in the present invention or a structure or formula or any derivative thereof that has been incorporated by reference.
  • the term also includes, stereoisomers, geometric isomers, tautomers, solvates, metabolites, and salts (e.g., pharmaceutically acceptable salts) of a compound of all the formulae disclosed in the present invention.
  • salts e.g., pharmaceutically acceptable salts
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomer refers to compounds which have identical chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as crystallization, electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • optically active compounds i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and I or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include
  • conjugate refers to a compound described herein or a derivative thereof that is linked to an anti-CD 19 antibody described herein.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate,” ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure.
  • a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells, and/or benign or pre-cancerous cells. Examples of cancers include, but are not limited to, B-cell malignancies or T-cell malignancies. In certain embodiments, the cancer is a leukemia or lymphoma.
  • B-cell lymphomas including non-Hodgkin' s lymphoma (NHL), precursor B-cell lymphoblastic leukemia/lymphoma and mature B-cell neoplasms, such as B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), including low-grade, intermediate-grade and high-grade FL, cutaneous follicle center lymphoma, marginal zone B-cell lymphoma (MALT type, nodal type, and splenic marginal zone lymphoma (SMZL), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), activated B cell like diffuse large B-cell lymphoma (ABC-DLBCL), germinal center B cell like diffuse
  • NHL non-Hodgkin' s
  • the cancer is B-ALL.
  • the cancer is NHL, DLBCL, FL or MCL.
  • the cancer is ABC-DLBCL or GCB- DLBCL.
  • the antibody-drug conjugates (ADCs) of the present invention comprises an anti-
  • CD 19 antibody linked to one or more cytotoxic compounds of the present invention via a disulfide linker specifically the N-succinimidyl-4-(2-pyridyldithio)2-sulfobutanoate (sulfo- SPDB) linker:
  • cytotoxic compound of the present invention is represented by the following formu
  • Y is -SO 3 H.
  • the pharmaceutically acceptable salt is a sodium salt or a potassium salt.
  • Y is -S0 3 Na or -S0 3 K.
  • Y is -S0 3 Na.
  • the antibody-drug conjugate of the present invention is:
  • the antibody is an anti-CD 19 antibody
  • r is an integer from 1 to 10
  • Y is -S0 3 H.
  • the pharmaceutically acceptable salt is a sodium salt or a potassium salt.
  • Y is -S0 3 Na or -S0 3 K.
  • Y is -S0 3 Na.
  • DGN462 is the compound of formula (sDl). In certain embodiments, DGN462 is the compound of formula (Dl). In certain embodiments, DGN462 is a mixture of compound Dl and compound sDl .
  • the antibody-drug conjugates (ADCs) of the present invention comprises an anti-CD 19 antibody linked directly to one or more cytotoxic compounds of the present invention.
  • the cytotoxic compound of the present invention is represented by the follo ing formula:
  • Y is -SO 3 H.
  • the pharmaceutically acceptable salt is a sodium salt or a potassium salt.
  • Y is -S0 3 Na or -S0 3 K.
  • Y is -S0 3 Na.
  • DGN549 is compound of formula sD2.
  • DGN549 is the compound of formula (D2). In certain embodiments, DGN549 is a mixture of compound D2 and compound sD2.
  • the antibody-drug conjugate of the present invention is:
  • the antibody is an anti-CD 19 antibody
  • r is an integer from 1 to 10
  • Y is -SO 3 H.
  • the pharmaceutically acceptable salt is a sodium salt or a potassium salt.
  • Y is -S0 3 Na or -S0 3 K.
  • Y is -S0 3 Na.
  • the conjugates described herein may comprise 1-10 cytotoxic compounds, 2-9 cytotoxic compounds, 3-8 cytotoxic compounds, 4-7 cytotoxic compounds, 5-6 cytotoxic compounds, or 2-5 cytotoxic compounds and each cytotoxic compound on the conjugate is the same.
  • a composition of the ADC of the present invention has an average drug to antibody ratio (DAR) of 1.0 to 5.0, 1.5 to 4.0, 2.0 to 3.5, 2.5 to 3.1, or 2.7 to 2.9. In one embodiment, the DAR is 2.8.
  • DAR drug to antibody ratio
  • the cytotoxic compound of the present invention is represented by the follo ing formula:
  • Y is -SO 3 H.
  • the pharmaceutically acceptable salt is a sodium salt or a potassium salt.
  • Y is -S0 3 Na or -S0 3 K.
  • Y is -S0 3 Na.
  • the antibody-drug conjugate of the present invention is:
  • the antibody is an anti-CD 19 antibody, r c is 1 or 2, and Y is -S0 3 H.
  • the pharmaceutically acceptable salt is a sodium salt or a potassium salt.
  • Y is -S0 3 Na or -S0 3 K.
  • Y is -S0 3 Na.
  • the anti-CD19 antibody binds specifically to CD 19 and comprises six complementary determining regions (CDRs) including: i) a light chain CDRl comprising SASSGVNYMH (SEQ ID NO: 1); a light chain CDR2 comprising DTSKLAS (SEQ ID NO: 2); and a light chain CDR3 comprising
  • HQRGSYT (SEQ ID NO: 3); and ii) a heavy chain CDRl comprising SNWMH (SEQ ID NO:4); a heavy chain CDR2 comprising EIDPSDSYTN (SEQ ID NO:5); and a heavy chain CDR3 comprising GSNPYYYAMDY (SEQ ID NO:6).
  • the anti-CD19 antibody in the conjugates of the present invention comprises a light chain, wherein the sequence of the light chain has at least 60%, at least 75%, at least 85%, at least 95% or at least 99% identity with the sequence displayed in SEQ ID NO: 7.
  • the anti-CD19 antibody in the conjugates of the present invention comprises a heavy chain, wherein the sequence of the heavy chain has at least 60%, at least 75%, at least 85%, at least 95% or at least 99% identity with the sequence displayed in SEQ ID NO: 8.
  • compositions comprise a therapeutically effective amount of the conjugates of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete), excipient, or vehicle with which the therapeutic is administered.
  • adjuvant e.g., Freund's adjuvant (complete and incomplete)
  • excipient or vehicle with which the therapeutic is administered.
  • the ingredients of compositions of the invention are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with a conjugate of the present invention, alone or with such
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • kits that can be used in the above methods.
  • a kit can comprise any of the conjugates of the present invention.
  • compositions of the present invention may be provided for the treatment, prophylaxis, and amelioration of one or more symptoms associated with a disease, disorder by administering to a subject a therapeutically effective amount a conjugate of the invention.
  • such compositions are substantially purified (i.e. , substantially free from substances that limit its effect or produce undesired side effects).
  • the subject is an animal, preferably a mammal such as non-primate (e.g. , bovine, equine, feline, canine, rodent, etc.) or a primate (e.g. , monkey such as, a cynomolgus monkey, human, etc.)
  • the subject is a human.
  • the conjugates may be administered to a subject, in a pharmaceutically acceptable dosage form.
  • Methods of administering a conjugate of the invention include, but are not limited to, parenteral administration (e.g. , intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural, and mucosal (e.g. , intranasal and oral routes).
  • parenteral administration e.g. , intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous
  • epidural e.g. , intranasal and oral routes
  • mucosal e.g. , intranasal and oral routes.
  • the conjugates of the present invention are administered intramuscularly, intravenously, or subcutaneously.
  • the compositions may be administered by any convenient route, for example, by infusion or bolus injection, and may be administered together with other biologically active agents. Administration can be systemic or local.
  • an "therapeutically effective amount" of a pharmaceutical composition is an amount sufficient to effect beneficial or desired results including, without limitation, clinical results such as decreasing symptoms of cancer (e.g., the proliferation, of cancer cells, tumor presence, tumor metastases, etc.), thereby increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication such as via targeting and/or internalization, delaying the progression of the disease, and/ or prolonging survival of individuals.
  • clinical results such as decreasing symptoms of cancer (e.g., the proliferation, of cancer cells, tumor presence, tumor metastases, etc.), thereby increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication such as via targeting and/or internalization, delaying the progression of the disease, and/ or prolonging survival of individuals.
  • the present invention provides a method of treating a cancer in a mammal (e.g. a human) comprising administering to the mammal a therapeutically effective amount of any one or more conjugates described herein.
  • a mammal e.g. a human
  • the cancer is a B-cell malignancy.
  • the cancer is a leukemia or lymphoma.
  • the cancer is selected from the group consisting of B-cell lymphomas including non-Hodgkin's lymphoma (NHL), precursor B-cell lymphoblastic leukemia/lymphoma and mature B-cell neoplasms, such as B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), including low-grade, intermediate-grade and high-grade FL, cutaneous follicle center lymphoma, marginal zone B- cell lymphoma (MALT type, nodal type, and splenic marginal zone lymphoma (SMZL), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), activated B cell like diffuse large B-cell lymphoma (ABC-DLBCL), germinal center B cell like diffuse
  • the cancer is B-ALL.
  • the cancer is a T-cell malignancy.
  • the humanized anti-CD 19 antibody, huB4 was conjugated to DGN462 via a cleavable disulfide linker, sulfo-SPDB.
  • a cleavable disulfide linker sulfo-SPDB.
  • In vitro activity of the huB4-DGN462 ADC or the unconjugated DGN462SMe toxin was evaluated in 54 lymphoma cell lines (27 diffuse large B cell lymphomas (DLBCL); 10 mantle cell lymphomas; 6 marginal zone lymphomas; 5 anaplastic large T-cell lymphomas; 6 others). Cell proliferation/viability after 72h of exposure was measured using a MTT assay.
  • mice were weighed twice a week and were monitored for clinical signs throughout the duration of the study. The measured end-point was survival. Animals were euthanized when hind leg paralysis was present, body weight decreased by >20% of pre- treatment weight, a visible tumor appeared, or any signs of distress were visible.
  • Tumor Growth Delay is calculated as T-C, where T is the median survival time (in days) of a treated group and C is the median survival time (in days) of the vehicle control group.
  • Anti-tumor activity was evaluated as per NCI standards for disseminated models: ILS > 25% is minimum active, ILS > 40% is active, and ILS > 50% is highly active.
  • mice were weighed twice a week and were monitored for clinical signs throughout the duration of the study. Animals were euthanized when hind leg paralysis was present, body weight decreased by >20% of pre-treatment weight, tumor ulceration occurred, or when any signs of distress were visible.
  • Tumor volumes were measured one to two times weekly in three dimensions using a caliper.
  • Activity was assessed as described in Bissery et al., Cancer Res. 51: 4845-52 (1991).
  • Increased Life Span (% ILS) (T-C)/C X100%.
  • huB4-DGN462 conjugate demonstrated a greater than 2-log superior in vitro cytotoxicity activity in all B-ALL cell lines tested as compared to the huB4-SPDB-DM4 conjugate.
  • huB4-s-SPDB-DGN462 and huB4-DGN549 were used as described in the protocol below.
  • mice Female CB.17 SCID mice were each inoculated with 10x106 DoHH2 cells, a human DLBCL cell line, in 100 ⁇ ⁇ serum free medium, subcutaneously in the right flank. On day 10 post-DoHH2 inoculation, mice were randomized into the study groups.
  • mice received a single intravenous injection, in the lateral tail vein, of vehicle, 5.8 ⁇ g/kg (by DGN462; 0.3 mg/kg by huB4) huB4-s-SPDB-DGN462, 11.7 ⁇ g/kg (by DGN462; 0.6 mg/kg by huB4) huB4-s-SPDB-DGN462, 23.4 ⁇ g/kg (by DGN462; 1.2 mg/kg by huB4) huB4-s-SPDB-DGN462, 9.5 ⁇ g/kg (by DGN462; 0.6 mg/kg by chKTI) chKTI-s-SPDB-DGN462 control conjugate, 19 ⁇ g/kg (by DGN462; 1.2 mg/kg by chKTI) chKTI-s-SPDB-DGN462 control conjugate, 1.3 ⁇ g/kg (by DGN549; 0.0
  • the 0.3 and 0.6 mg/kg (by huB4) doses of huB4-s-SPBD-DGN462 were active, generating a 32 %T/C and a 24 %T/C, respectively, and 0/6 CRs each.
  • the 1.2 mg/kg (by huB4) dose of huB4-s-SPDB-DGN462 was highly active, generating a 4 %T/C and 2/6 CRs.
  • the 0.075 mg/kg (by huB4) dose of huB4-DGN549 was active, generating a 36 %T/C and 0/6 CRs, while the 0.15 and 0.3 mg/kg (by huB4) doses of huB4-DGN549 were both highly active, generating an 8 %T/C and a 0 %T/C, respectively, and 0/6 CRs and 5/6 CRs, respectively.
  • the 0.15 mg/kg (by huB4) dose of chKTI-DGN549 control conjugate was inactive, generating a 74 %T/C and 0/6 CRs.
  • huB4-s-SPDB-DGN462 and huB4-DGN549 were used as described in the protocol below.
  • mice Female CB.17 SCID mice were each inoculated with 10x106 OCI-Lyl8 cells, a human DLBCL cell line, in 100 ⁇ ⁇ Matrigel/ serum free medium, subcutaneously in the right flank. On day 12 post-OCI-Lyl8 inoculation, mice were randomized into the study groups.
  • mice received a single intravenous injection, in the lateral tail vein, of vehicle, 5.8 ⁇ g/kg (by DGN462; 0.3 mg/kg by huB4) huB4-s-SPDB- DGN462, 11.7 ⁇ g/kg (by DGN462; 0.6 mg/kg by huB4) huB4-s-SPDB-DGN462, 23.4 ⁇ g/kg (by DGN462; 1.2 mg/kg by huB4) huB4-s-SPDB-DGN462, 9.5 ⁇ g/kg (by DGN462; 0.6 mg/kg by chKTI) chKTI-s-SPDB-DGN462 control conjugate, 19 ⁇ g/kg (by DGN462; 1.2 mg/kg by chKTI) chKTI-s-SPDB-DGN462 control conjugate, 1.3 ⁇ g/kg (by DGN5
  • the 0.3 mg/kg (by huB4) dose of huB4-s-SPDB-DGN462 was inactive, generating a 53 %T/C and 0/6 CRs.
  • the 0.6 and 1.2 mg/kg (by huB4) doses of huB4-s-SPBD-DGN462 were active, generating a 21 %T/C and a 19 %T/C, respectively, and 0/6 CRs and 1/6 CRs, respectively.
  • the 0.075 mg/kg (by huB4) dose of huB4-DGN549 was inactive, generating a 46 %T/C and 1/6 CRs, while the 0.15 and 0.3 mg/kg (by huB4) doses of huB4- DGN549 were both active, generating a 14 %T/C and an 18 %T/C, respectively, and 0/6 CRs and 2/6 CRs, respectively.
  • the 0.15 and 0.3 mg/kg (by huB4) doses of chKTI- DGN549 control conjugate were inactive, generating a 68 %T/C and a 44% T/C,
  • huB4-s-SPDB-DM4 Colduximab ravtansine
  • huB4-s-SPDB-DGN462 1.2 23.4 19 1/6 1/6 Active chKTI-s-SPDB-DGN462 0.6 9.5 69 0/6 0/6 Inactive chKTI-s-SPDB-DGN462 1.2 19 81 0/6 0/6 Inactive huB4-DGN549 0.075 1.3 46 1/6 1/6 Inactive huB4-DGN549 0.15 2.7 14 0/6 0/6 Active huB4-DGN549 0.3 5.3 18 3/6 2/6 Active chKTI-DGN549 0.15 2.4 68 0/6 0/6 Inactive chKTI-DGN549 0.3 4.7 44 0/6 0/6 Inactive huB4-s-SPDB-DM4, 5 106.3 5 4/6 1/6 Highly Active (Coltuximab ravtansine)

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Cell Biology (AREA)
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Abstract

La présente invention concerne des conjugués anticorps-médicament anti-CD19 et leur utilisation pour le traitement de malignités de lymphocytes B.
PCT/US2018/024840 2017-03-31 2018-03-28 Conjugués anticorps-médicament ciblant cd19 WO2018183494A1 (fr)

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