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WO2019035649A1 - Conjugués anticorps-médicament comprenant un anticorps contre egfrviii - Google Patents

Conjugués anticorps-médicament comprenant un anticorps contre egfrviii Download PDF

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Publication number
WO2019035649A1
WO2019035649A1 PCT/KR2018/009362 KR2018009362W WO2019035649A1 WO 2019035649 A1 WO2019035649 A1 WO 2019035649A1 KR 2018009362 W KR2018009362 W KR 2018009362W WO 2019035649 A1 WO2019035649 A1 WO 2019035649A1
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Prior art keywords
antibody
solvate
pharmaceutically acceptable
acceptable salt
alkyl
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PCT/KR2018/009362
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English (en)
Korean (ko)
Inventor
정철웅
박윤희
최효정
송호영
박경은
김성민
김형래
김용주
오영수
채제욱
남도현
박현규
박창식
최민지
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Samsung Life Public Welfare Foundation
Ligachem Biosciences Inc
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Samsung Life Public Welfare Foundation
Legochem Biosciences Inc
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Priority claimed from KR1020180095186A external-priority patent/KR20190018400A/ko
Publication of WO2019035649A1 publication Critical patent/WO2019035649A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present invention relates to novel antibody-drug conjugates (ADCs) targeting EGFRvIII, active metabolites of these ADCs, methods for making these ADCs, use of these ADCs for the treatment and /
  • the invention also relates to the use of these ADCs for the production of medicaments for the treatment and / or prophylaxis of diseases, more particularly hyperproliferative and / or angiogenic diseases, such as cancer, and more particularly to the use of these EGFRvIII (Epidermal Growth Factor Receptor Variant III) or an antigen-binding fragment thereof, and a pharmaceutical composition comprising the antibody-drug conjugate.
  • ADCs antibody-drug conjugates
  • Cancer is a disease caused by abnormally grown lumps due to autonomous overgrowth of body tissues and is the result of uncontrolled cell growth in various tissues. Early stage tumors can be removed by surgical and radiotherapy, and metastasized tumors usually undergo palliative treatment by chemotherapeutic agents.
  • chemotherapeutic agents can induce serious effects of unwanted side effects and even toxicity as a result of systemic administration, and thus, through improved application of these chemotherapeutic agents in tumor cells or adjacent tissues, Has focused on the development of novel chemotherapeutic agents to simultaneously increase drug efficacy and minimize toxicity / side effects.
  • ADCs Antibody-drug conjugates
  • ADCs are target-directed new technologies that bind toxins or drugs to an antibody that binds to an antigen and then release toxic substances inside the cells, leading to the death of cancer cells. It is a technology that can exert more efficacy than antibody therapy itself and greatly reduce the risk of side effects compared to existing anticancer drugs because it allows drugs to be delivered precisely to target cancer cells while minimally affecting healthy cells and released only under specific conditions.
  • the basic structure of this antibody-drug conjugate is composed of " antibody-linker-low molecular drug (toxin) ".
  • the linker not only has a functional role of linking the antibody and the drug, but also stably reaches the target cell in the body, and after the antibody-drug conjugate enters the cell, the antibody-drug dissociation phenomenon (for example, The result is that the drug is well-cleaved by the drug, and the drug is effective against the target cancer cells.
  • Linkers play an important role in the safety of antibody-drug conjugates and systemic toxicity, depending on the stability of the linker (Discovery Medicine 2010, 10 (53): 329-39).
  • the inventors of the present invention have developed a linker that contains an effective self-immolative group that is more stable in plasma and stable even in the circulation in the body and can easily release drugs in cancer cells to exhibit drug efficacy. (Korean Registered Patent No. 1,628,872, etc.).
  • Monoclonal antibodies are suitable for target-directed addressing of tumor tissues and tumor cells.
  • Antibody drug conjugates have become powerful and novel therapeutic options for the treatment of lymphoma and solid cancer, and immunosuppressive antibodies have recently achieved considerable clinical success.
  • the development of therapeutic antibodies is based on cancer serology, protein engineering techniques and their function, mechanisms of resistance, and a deep understanding of the interaction between the immune system and cancer cells.
  • an antigen expressed on the cell surface of human cancer refers to a wide range of targets that are overexpressed or mutated and selectively expressed compared to normal tissues.
  • the key problem is to identify the appropriate antigen for antibody-based therapies. These agents mediate changes in antigen or receptor function (ie, function as antagonists, as stimulants), regulate the immune system through Fc and T cell activation, and mediate the delivery of specific drugs that bind to antibodies targeted to specific antigens Effective. Molecular techniques that can alter antibody pharmacokinetics, function, size, and immunostimulation have emerged as key elements in the development of new antibody-based therapies.
  • Evidence from clinical trials of therapeutic antibodies directed against cancer patients suggests that optimized antibodies, including affinity and binding of the target antigen and antibodies, antibody structure selection, therapeutic approaches (signaling blocking or immune function) It emphasizes the importance of approaches for selection.
  • EGFR epithelial growth factor receptor
  • EGFR epithelial growth factor receptor
  • the sequence of the EGFR gene is known.
  • the EGFR gene was originally a cellular homolog of the erbB oncogene identified in avian erythroblastosis virus. Activation of the oncogene by gene amplification was observed in a variety of human tumors.
  • EGFR is overexpressed for various types of human solid tumors. EGFR overexpression was observed in some lungs, breast, colon, stomach, brain, bladder, head and neck, ovary, kidney and prostate carcinoma. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) have been shown to bind to EGFR and to induce cell proliferation and tumor growth. Size mutant EGFR genes and amplification have also been reported in some human cancers.
  • EGF epidermal growth factor
  • TGF-alpha transforming growth factor-alpha
  • EGFR mutants are caused by gene rearrangement accompanied by EGFR gene amplification.
  • (Iv) EGFRvIV comprises deletion in the cytoplasmic domain of EGFR
  • (Vi) EGFR.TDM / 2-7 comprises the replication of exons 2-7 in the extracellular domain of EGFR
  • (vii) EGFR.TDM / 18-25 contains deletion in the cytoplasmic domain of EGFR
  • (Viii) EGFR.TDM / 18-26 includes a copy of exons 18-26 in the tyrosine kinase of EGFR.
  • EGFRvIII is a variant of epithelial growth factor (EGF), which is the most commonly occurring in human cancers, and is expressed in about 30% of patients with glioblastoma (GBM) and is not expressed in normal tissues.
  • EGF epithelial growth factor
  • GBM glioblastoma
  • Such variants of the EGFR receptor contribute to tumor progression through structural signaling in a ligand independent manner.
  • Mutations or rearrangements of genes that potentially induce tumorigenesis can be identified in many cancers. It has been reported that cancer-causing proteins can contribute to the pathways associated with cancer stem cells. The products of these altered genes suggest evidence that they can be used to identify and potentially target cancer stem cells. In fact, this approach is not an easy method because these major mutations exist throughout cancer cells and do not exist only in specific cancer cell subtypes. Therefore, mutant proteins generally do not play a direct role in cancer stem cells, but they generally promote tumor growth. In addition, most modified proteins are internal to the cell.
  • EGFRvIII Adiabatic tumors are known to frequently express EGFRvIII, an EGFR variant expressed through gene rearrangement and amplification. Since the tyrosine phosphorylation site is always present in an activated form, it exhibits strong tumorigenicity. However, despite this modification, the expression of EGFRvIII is limited. Cancer stem cells are defined as EGFRvIII is highly expressed with CD133 and EGFRvIII + / CD133 + cells have high regeneration and tumor initiation capability. EGFRvIII + cells were associated with stem / precursor markers whereas differentiation markers were found in EGFRvIII- cells. EGFRvIII expression was lost in normal cell culture but maintained in tumor protoplast culture and cell cultured cells simultaneously express and regenerate EGFRvIII + / CD133 + and have tumor-initiating ability.
  • an anti-EGFRvIII antibody capable of binding with high affinity to EGFRvIII and inhibiting the growth of cancer cells is required.
  • Antibody therapeutic agents such as Cetuximab, which specifically binds specifically to EGFR, have been developed. However, these antibody therapeutic agents have a problem that antigen specificity against EGFRvIII mutant cancer cells is very low, and inhibition of cancer cell growth is not shown.
  • the inventors of the present invention have made efforts to develop an antibody for chemotherapy which specifically binds to EGFRvIII.
  • the present inventors have developed an anti-EGFRvIII antibody that binds to EGFRvIII with high affinity using phage display technology, and confirmed that such anti-EGFRvIII antibody can significantly inhibit the growth of cancer cells.
  • the present invention includes an effective self-immolative group that is more stable in plasma and stable even in the circulation in order to further enhance the effect of the antibody and can easily release the drug in cancer cells (ADC) that targets EGFRvIII effective for the treatment and / or prevention of hyperproliferative and / or metastatic cancer diseases can be provided by applying a linker that specifically binds to EGFRvIII, And the present invention has been completed.
  • ADC cancer cells
  • the present invention is intended to provide novel antibody-linker drug conjugates or salts, solvates thereof, targeting EGFRvIII.
  • the present invention provides an antibody-drug conjugate comprising an antibody that specifically binds to EGFRvIII and a drug that binds to the antibody, and a pharmaceutical composition comprising the same.
  • the present invention also relates to a linker technique which is more stable in plasma and stable even in the body and which includes a self-sacrifice which can be easily released in cancer cells to maximize the drug efficacy, so that the drug and / Ligand-linker-drug (toxin) system which can stably reach the cell, effectively exhibiting the drug efficacy, while greatly reducing the toxicity.
  • Ab is an antibody that binds to EGFRvIII (Epidermal Growth Factor Receptor Variant III) or an antigen-binding fragment thereof,
  • Linker is a linker
  • D is a drug or toxin
  • n is an integer of 1 to 20;
  • the antibody or antigen-binding fragment thereof that binds to EGFRvIII is an antibody or an antigen-binding fragment thereof which is characterized in that it binds to an epitope of EGFRvIII having the sequence of SEQ ID NO:
  • the antibody or antigen-binding fragment thereof that binds to EGFRvIII comprises a CDR (complementarity determining region) having a sequence selected from the group consisting of SEQ ID NOS: 2, 3, 17, 18, CDRH2 having a sequence selected from the group consisting of H1, SEQ ID NOs: 4, 5, 19, 20 and 33, and SEQ ID NOs: 6, 7, 21, 22 and 34
  • a heavy chain variable region comprising CDRH3 having a sequence;
  • a light chain variable region comprising CDRL3 having the sequence represented by SEQ ID NO: 12, 27,
  • the antibody or antigen-binding fragment thereof that binds to EGFRvIII comprises a heavy chain variable region having the sequence of SEQ ID NO: 13, 28 or 38.
  • the antibody or antigen-binding fragment thereof that binds to EGFRvIII comprises a light chain variable region having the sequence of SEQ ID NO: 14, 29 or 39.
  • sequence information is as follows:
  • G is sugar, sugar acid, or sugar derivatives
  • W is -C (O) -, -C ( O) NR'-, -C (O) O-, -S (O) 2 NR'-, -P (O) R''NR'-, -S (O) and NR'-, or -PO 2 NR'-,
  • Each Z are each independently hydrogen, (C 1 -C 8) alkyl, halogen, cyano or nitro,
  • n is an integer of 1 to 3
  • n 0 or 1
  • At least one branching unit (BR) and at least one connection unit are At least one branching unit (BR) and at least one connection unit,
  • R 1 and R 2 are each independently hydrogen, (C 1 -C 8 ) alkyl or (C 3 -C 8 ) cycloalkyl, or
  • R 1 and R 2 together with the carbon atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring,
  • the * indicates the site to which the drug or toxin is linked.
  • the sugar or the saccharic acid is a monosaccharide.
  • G is a compound of the formula (IIIa) structure:
  • R < 3 > is hydrogen or a carboxyl protecting group
  • Each R < 4 > is independently hydrogen or a hydroxyl protecting group.
  • R < 3 > is hydrogen and each R < 4 > is hydrogen.
  • W is -C (O) NR'-, wherein C (O) is connected to a phenyl ring and NR 'is connected to a linker.
  • Z is hydrogen and n is 3.
  • R 1 and R 2 are each hydrogen.
  • G is a compound having the structure of the formula (IIIa)
  • R < 3 > is hydrogen or a carboxyl protecting group
  • Each R < 4 > is independently hydrogen or a hydroxyl protecting group
  • W is -C (O) NR'-, where is C (O) phenyl ring is connected to NR 'is connected with the Linker, each Z is hydrogen, n is 3, m is 1, R 1, and R < 2 > are each hydrogen.
  • the at least one branching unit is alkylene having from 1 to 100 carbon atoms, wherein the carbon atom of the alkylene is optionally substituted with one or more heteroatoms selected from the group consisting of N, O and S And the alkylene may be further substituted with one or more alkyl having 1 to 20 carbon atoms.
  • the at least one branching unit is a hydrophilic amino acid.
  • the hydrophilic amino acid may be arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine, or threonine.
  • the hydrophilic amino acid may be an amino acid comprising a side chain having a moiety having charge at neutral pH in an aqueous solution.
  • the hydrophilic amino acid is aspartate or glutamate.
  • the hydrophilic amino acid is ornithine or lysine.
  • the hydrophilic amino acid is arginine.
  • At least one branching unit is -C (O) -, -C ( O) NR'-, -C (O) O-, -S (O) 2 NR'-, -P ( O) R''NR'-, -S (O) NR'-, or -PO 2 NR'-, and, R 'and R''are each independently hydrogen, (C 1 -C 8) alkyl, (C 3 -C 8) cycloalkyl, (C 1 -C 8) alkoxy, (C 1 -C 8) alkylthio, mono- or di - (C 1 -C 8) alkylamino, (C 3 -C 20) heteroaryl aryl, or (C 6 -C 20) aryl.
  • At least one of the branching units is -C (O) NR'- and R 'is hydrogen.
  • connection unit is - (CH 2 ) r (V (CH 2 ) p ) q -, where r is an integer from 0 to 10, p is an integer from 0 to 12 , q is an integer of 1 to 20, and V is a single bond, -O- or -S-.
  • r is 2.
  • p is 2.
  • q is an integer from 6 to 20.
  • r is 2
  • p is 2
  • q is 2, 5 or 11
  • V is -O-.
  • the at least one connection unit is at least one polyethylene glycol unit, or .
  • the at least one connection unit is 1 to 12-OCH 2 CH 2 - units, or 5 to 12 -OCH 2 CH 2 - units, or 6 to 12 -OCH 2 CH 2 - units.
  • the at least one connection unit is - (CH 2 CH 2 X) w-,
  • X is a single bond, -O-, (C 1 -C 8 ) alkylene, or -NR 21 -;
  • R 21 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl (C 6 -C 20 ) aryl or (C 1 -C 6 ) alkyl (C 3 -C 20 ) heteroaryl ,
  • w is an integer of 1 to 20, specifically 1, 3, 6, or 12;
  • X is -O- and w is an integer of 6 to 20.
  • the linker can be a 1,3-dipolar cycloaddition reaction, a hetero-Diels-Alder reaction, a nucleophilic substitution reaction, a non-aldol carbonyl reaction, carbon-carbon multiple bond, oxidation, or a click reaction.
  • the binding unit is formed by a reaction between acetylene and an azide, or a reaction between an aldehyde or ketone group and a hydrazine or alkoxyamine.
  • L 1 is a single bond or alkylene having 1 to 30 carbon atoms
  • R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, specifically methyl,
  • L 2 is alkylene having 1 to 30 carbon atoms.
  • the branching unit or to be.
  • the at least one isoprenyl unit is a substrate of an isoprenoid transferase or a product of an isoprenoid transferase.
  • the isoprenyl unit of the Linker is covalently bonded to the antibody by a thioether linkage, and the thioether linkage includes the cysteine sulfur of the antibody.
  • the antibody comprises an amino acid motif recognized by an isoprenoid transferase, and the thioether bond comprises a cysteine sulfur atom of an amino acid motif.
  • the antibody or antigen-binding fragment thereof that binds to EGFRvIII comprises an amino acid motif recognized by an isoprenoid transferase, wherein the thioether bond comprises a cysteine sulfur atom of an amino acid motif.
  • the amino acid motif is a sequence selected from the group consisting of CXX, CXC, XCXC, XXCC, and CYYX, wherein C represents cysteine; Y represents in each case independently an aliphatic amino acid; X independently in each occurrence represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; The thioether bond includes the cysteine sulfur atom of the amino acid motif.
  • the amino acid motif is the CYYX sequence and Y is independently in each case alanine, isoleucine, leucine, methionine or valine.
  • the amino acid motif is a CVIM or CVLL sequence.
  • At least one of the seven amino acids preceding the amino acid motif is glycine.
  • three or more of the seven amino acids preceding the amino acid motif may be independently selected from glycine, arginine, aspartic acid, and serine.
  • one to ten amino acids preceding the amino acid motif are glycine, in particular at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids Is glycine.
  • the antibody may comprise the amino acid sequence of GGGGGGGCVIM.
  • connection unit connects the trigger unit and the binding unit, the trigger unit and the branching unit or the branching unit and the binding unit,
  • the one or more trigger units are capable of releasing one or more drugs or toxins
  • the branching unit connects the connection unit and the trigger unit, or the connection unit to another connection unit.
  • the trigger unit has the structure of the following formula (IIb):
  • G is sugar, sugar acid, or sugar derivatives
  • W is -C (O) -, -C ( O) NR'-, -C (O) O-, -S (O) 2 NR'-, -P (O) R''NR'-, -S (O) and NR'-, or -PO 2 NR'-,
  • Each Z are each independently hydrogen, (C 1 -C 8) alkyl, halogen, cyano or nitro,
  • n is an integer of 1 to 3
  • n 0 or 1
  • R 1 and R 2 are each independently hydrogen, (C 1 -C 8 ) alkyl or (C 3 -C 8 ) cycloalkyl, or
  • R 1 and R 2 together with the carbon atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring.
  • the sugar or the saccharic acid is a monosaccharide.
  • G is a compound of the formula (IIIa) structure:
  • R < 3 > is hydrogen or a carboxyl protecting group
  • Each R < 4 > is independently hydrogen or a hydroxyl protecting group.
  • R < 3 > is hydrogen and each R < 4 > is hydrogen.
  • W is -C (O) NR'-, wherein C (O) is connected to the phenyl ring and NR 'is connected to the connection unit.
  • Z is hydrogen
  • R 1 and R 2 are each hydrogen.
  • connection unit is - (CH 2) r (V (CH 2) p) q -, - ((CH 2) p V) q -, - (CH 2) r (V (CH 2 ) p) q Y-, - ( (CH 2) p V) q (CH 2) r -, -Y ((CH 2) p V) q - or - (CH 2) r (V (CH 2) p ) q YCH 2 - it becomes expressed as,
  • r is an integer from 0 to 10;
  • p is an integer from 1 to 10;
  • q is an integer of 1 to 20
  • V and Y are each independently a single bond, -O-, -S-, -NR 21 -, -C (O) NR 22 -, -NR 23 C (O) -, -NR 24 SO 2 - SO 2 NR < 25 > -,
  • R 21 to R 25 are each independently hydrogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkyl (C 6 -C 20) aryl or (C 1 -C 6) alkyl (C 3 -C 20 ) heteroaryl.
  • r is 2.
  • p is 2.
  • q is an integer from 6 to 20.
  • q is 2, 5, or 11.
  • V and Y are each independently -O-.
  • the branching unit comprises:
  • L 1 , L 2 , and L 3 are each independently a direct bond or -C n H 2n -
  • n is an integer from 1 to 30,
  • G 1 , G 2 and G 3 are each independently a direct bond, ego,
  • R 3 is hydrogen or C 1 -C 30 alkyl
  • R 4 is hydrogen or -L 4 -COOR 5 , wherein L 4 is a direct bond or -C n H 2n - wherein n is an integer from 1 to 10 and R 5 is hydrogen or C 1 -C Lt; / RTI >
  • the branching unit ego
  • L & lt ; 1 &gt is a direct bond or alkylene having from 1 to 30 carbon atoms
  • R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, specifically methyl,
  • L 2 is alkylene having 1 to 30 carbon atoms
  • the branching unit connects the connection unit and the antibody.
  • L < 1 > is alkylene having 12 carbon atoms.
  • R < 11 > is methyl.
  • L < 2 > is alkylene having 11 carbon atoms.
  • the branching unit or to be.
  • the binding unit is covalently bonded to the antibody by a thioether bond, and the thioether bond comprises a cysteine sulfur atom of the antibody.
  • the antibody comprises an amino acid motif recognized by an isoprenoid transferase, and the thioether bond comprises a cysteine sulfur atom of an amino acid motif.
  • the amino acid motif is a sequence selected from the group consisting of CXX, CXC, XCXC, XXCC, and CYYX, wherein C represents cysteine; Y represents in each case independently an aliphatic amino acid; X independently in each occurrence represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; The thioether bond includes the cysteine sulfur atom of the amino acid motif.
  • the amino acid motif is the CYYX sequence and Y is independently in each case alanine, isoleucine, leucine, methionine or valine.
  • the amino acid motif is a CVIM or CVLL sequence.
  • At least one of the seven amino acids preceding the amino acid motif is glycine.
  • three or more of the seven amino acids preceding the amino acid motif may be independently selected from glycine, arginine, aspartic acid, and serine.
  • one to ten amino acids preceding the amino acid motif are glycine, in particular at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids Is glycine.
  • the antibody may comprise the amino acid sequence of GGGGGGGCVIM.
  • an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein said D is a prophylactic or therapeutic agent for hyperproliferative, cancerous or angiogenic diseases.
  • D may be selected from the following list, but is not limited to:
  • Aclacinomysins actinomycin, antrmycin, azaserine, bleomycins, cactinomycin, carabicin, carnino Carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-5-oxo-L 6-diazo-5-oxo-L-norleucine, doxorubicin, But are not limited to, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin, deoxydoxirubicin, (eg, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, the compounds of the present invention may be used in combination with other drugs such as olivomycins,
  • affinity ligand selected from the group consisting of a substrate, an inhibitor, an activator, a neurotransmitter, a radioisotope, or a combination thereof;
  • radioactive label 32P, 35S, fluorescent dye, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, An immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination thereof;
  • an immunomodulatory compound an anti-cancer agent, an anti-viral agent, an anti-bacterial agent, an anti-fungal agent, agents, and anti-parasitic agents, or combinations thereof;
  • a pharmaceutical composition for preventing or treating hyperproliferative, cancer, or angiogenic diseases which comprises an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • composition further comprising an inert, non-toxic, or pharmaceutically acceptable excipient.
  • composition further comprising at least one anti-hyperplasia, cytostatic or cytotoxic agent.
  • an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the prophylaxis or treatment of hyperproliferative, cancerous or angiogenic diseases.
  • a pharmaceutical composition for preventing or treating hyperproliferative, cancer, or angiogenic diseases which comprises an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as an active ingredient,
  • a method of preventing or treating hyperproliferative, cancer, or angiogenic diseases is provided, wherein a method of administering one or more anti-hypertrophy, cytostatic or cytotoxic agents in combination is also provided.
  • the antibody-drug conjugate according to the present invention includes an anti-EGFRvIII antibody that specifically binds to EGFRvIII expressing cells and is internalized into cells, thereby effectively and specifically and selectively delivering the drug, and the drug is stably bound to the antibody Saccharide, which is capable of exhibiting the desired cytotoxicity while maintaining in vivo stability, is more stable in plasma, stable even in the circulation in the body, and capable of easily releasing the drug in cancer cells to maximize the drug efficacy
  • Linker-ligand system capable of stably reaching the target cells, effectively exhibiting the drug effect, and greatly reducing the toxicity, by introducing the linker technology to the target cell.
  • Conjugates refers to cell binding agents that are covalently linked to one or more molecules of a cytotoxic compound.
  • cell binding agent is a molecule having affinity for a biological target, for example, a ligand, a protein, an antibody, specifically a monoclonal antibody, a protein or antibody fragment, a peptide, an oligonucleotide or an oligosaccharide , The binding agent serves to direct the biologically active compound to the biological target.
  • the conjugate can be designed to target tumor cells through cell surface antigens.
  • the antigen may be a cell surface antigen that is overexpressed or expressed in an abnormal cell type.
  • the target antigen may be expressed only on proliferative cells (e.g., tumor cells).
  • Target antigens may be selected based on different expression, usually between proliferative and normal tissues.
  • a ligand is bonded to a linker.
  • &quot refers to a compound that covalently attaches a cytotoxic compound to a binding agent.
  • the linker disclosed in Korean Patent Laid-Open Nos. 2015-0137015, PCT / US2016 / 063564, and PCT / US2016 / 063595 may be used.
  • EGFRvIII refers to a mutant form of epidermal growth factor receptor that is recognized by MR1 scFv and is characterized by an 801 basepair infrequent deletion of 2-7 exons near the amino terminus. Is highly expressed in about 50-60% of glioblastoma and appears to be present in about 70-80% of breast and ovarian carcinomas and about 16% of non-small cell lung carcinomas. Mutant receptors are expressed on the cell surface and produce new tumor-specific cell surface epitopes at the deletion junctions.
  • antibody means an anti-EGFRvIII antibody that specifically binds to EGFRvIII.
  • the scope of the present invention encompasses not only the complete antibody form specifically binding to EGFRvIII but also antigen binding fragments of the antibody molecule.
  • a complete antibody is a structure having two full-length light chains and two full-length heavy chains, each light chain linked by a disulfide bond with a heavy chain.
  • the heavy chain constant region has gamma (gamma), mu (mu), alpha (alpha), delta (delta) and epsilon (epsilon) types and subclasses gamma 1 (gamma 1), gamma 2 ), Gamma 4 (gamma 4), alpha 1 (alpha 1) and alpha 2 (alpha 2).
  • the constant region of the light chain has kappa (kappa) and lambda (lambda) types.
  • An antigen binding fragment or an antibody fragment of an antibody refers to a fragment having an antigen binding function and includes Fab, F (ab ') 2, F (ab') 2 and Fv.
  • Fabs in the antibody fragment have one antigen-binding site in a structure having a variable region of a light chain and a heavy chain, a constant region of a light chain, and a first constant region (CH1) of a heavy chain.
  • the F (ab ') 2 antibody is produced when the cysteine residue of the hinge region of the Fab' forms a disulfide bond.
  • Such an antibody fragment can be obtained using a protein hydrolyzing enzyme (for example, when the whole antibody is cleaved with papain, a Fab can be obtained, and when cut with pepsin, an F (ab ') 2 fragment can be obtained) It can also be produced through recombinant technology.
  • a protein hydrolyzing enzyme for example, when the whole antibody is cleaved with papain, a Fab can be obtained, and when cut with pepsin, an F (ab ') 2 fragment can be obtained
  • It can also be produced through recombinant technology.
  • Heavy chain means both the variable length domain VH comprising the amino acid sequence with sufficient variable region sequence to confer specificity to the antigen and the full length heavy chain comprising the three constant region domains CHl, CH2 and CH3, and fragments thereof .
  • Light chain refers to both full length light chains and fragments thereof, including variable region domains VL and constant region domains CL comprising amino acid sequences with sufficient variable region sequences to confer specificity to the antigen.
  • Antibody variable domain refers to the light and heavy chain portions of an antibody molecule comprising the amino acid sequences of the complementarity determining regions (CDRs; i.e., CDR1, CDR2, and CDR3), and the framework region (FR).
  • CDRs complementarity determining regions
  • FR framework region
  • VH refers to the variable domain of the heavy chain.
  • VL refers to the variable domain of the light chain.
  • CDRs i.e., CDR1, CDR2, and CDR3
  • CDR1, CDR2, and CDR3 refer to the amino acid residues of an antibody variable domain that are necessary for antigen binding.
  • Each variable domain typically has three CDR regions identified as CDR1, CDR2 and CDR3.
  • the CDR region can be determined using Kabat, IMGT method, Chothia method, AbM method, and the present invention uses the Kabat, IMGT method to determine the CDR region.
  • a "framework region” is a variable domain residue other than a CDR residue.
  • Each variable domain typically has four FRs identified as FR1, FR2, FR3, and FR4.
  • Fv fragment is an antibody fragment that contains complete antibody recognition and binding sites. This region consists of one heavy chain variable domain and one light chain variable domain, for example dimers substantially tightly covalently associated with scFv.
  • a “Fab” fragment contains the variable and constant domains of the light chain and the variable and first constant domain (CH1) of the heavy chain.
  • F (ab ') 2 antibody fragments generally comprise a pair of Fab fragments covalently linked by their hinge cysteine near their carboxy ends.
  • a " single chain Fv " or " scFv " antibody fragment comprises the VH and VL domains of an antibody, which domains are within a single polypeptide chain.
  • the Fv polypeptide may further comprise a polypeptide linker between the VH domain and the VL domain such that the scFv can form the desired structure for antigen binding.
  • therapeutic agent is an agent that exerts cytotoxicity, cell proliferation inhibition and / or immunomodulatory effects on cancer cells or activated immune cells.
  • therapeutic agents include cytotoxic agents, chemotherapeutic agents, cell proliferation inhibitors, and immunomodulators.
  • drug or toxin is a chemical compound useful in the treatment of cancer.
  • unsubstituted or substituted refers to a parent group that may be unsubstituted or substituted
  • substituted refers to a parent group having one or more substituents
  • substitutetuent refers to a mosquito refers to a chemical moiety covalently bonded to a parent group or fused to a parent group.
  • halo or halogen refers to fluorine, chlorine, bromine, iodine, and the like.
  • alkyl is a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or alicyclic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound.
  • saturated alkyls include methyl, ethyl, Butyl, n-pentyl (amyl), n-hexyl, n-heptyl and the like, saturated cyclic alkyl groups such as methyl, ethyl, Isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl and the like.
  • alkoxy means -OR where R is an alkyl group, and examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.
  • aryl means a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having a ring atom.
  • alkenyl is at least one carbon - an alkyl having a carbon double bond
  • alkylene refers to a divalent atomic group except two hydrogen atoms bonded to two other carbon atoms of an aliphatic saturated hydrocarbon, represented by the general formula C n H 2n -, and includes ethylene, propylene, butyl Naphthalene, naphthalene, and the like.
  • heteroaryl refers to aryl containing one or more heteroatoms, such as pyridine, pyrimidine, benzothiophene, furyl, dioxolanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, More specifically benzofuran, isobenzofuran, indole, isoindole, indolizine, indolin, isoindoline, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, benzodioxole, benzofuran, benzotriazole, benzo thio furan, benzothiazole, benzo thiadiazole a 20,000 C 9, chromene, iso-chromene, chroman, iso croissant having two fused rings, derived from benzo Two fused rings derived from dioxane, quino
  • an acid addition salt modified by a pharmaceutically acceptable free acid can be used, and as the free acid, an organic acid or an inorganic acid can be used.
  • the organic acids include, but are not limited to, citric, acetic, lactic, tartaric, maleic, fumaric, formic, propionic, oxalic, trifluoroacetic, benzoic, gluconic, methosulfonic, glycolic, succinic, Glutamic acid and aspartic acid.
  • the inorganic acid also includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth metal cations such as Ca 2+ and Mg 2+ and other cations such as Al 3+ .
  • suitable organic cations include an ammonium ion (i.e., NH 4 +) and substituted ammonium ions (e.g. NH 3 R +, NH 2 R 2 +, NHR 3 +, NR 4 +) , but is not limited to this.
  • substituted ammonium ions examples include those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine , Phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine.
  • An example of a typical quaternary ammonium ion is N (CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfuric acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid.
  • Suitable organic anions include, but are not limited to, those derived from organic acids such as: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, But are not limited to, disulfonic acid, ethanesulfonic acid, fumaric acid, glutaronic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, But are not limited to, malic acid, methanesulfonic acid, mucilous acid, oleic acid, oxalic acid, palmitic acid, pamic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tarta
  • solvate refers to a molecular complex between a compound according to the present invention and solvent molecules, examples of which include water, isopropanol, ethanol, methanol, dimethylsulfoxide but are not limited to, compounds according to the invention in combination with dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixed solvent thereof.
  • solvate is used herein in its conventional sense to refer to solutes (such as active compounds, salts of active compounds) and complexes of solvents.
  • solutes such as active compounds, salts of active compounds
  • complexes of solvents such as water
  • the solvate may conveniently be referred to as a hydrate, such as monohydrate, dihydrate, trihydrate, and the like.
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include macromolecules that are typically metabolized slowly, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, lipid aggregates, and the like, Acceptable carriers may be appropriately selected and used by those skilled in the art.
  • composition comprising a pharmaceutically acceptable carrier can be of various oral or parenteral formulations.
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, .
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, .
  • lubricants such as magnesium stearate, talc, and the like may also be used.
  • the protein or peptide is extinguished. Therefore, when formulating the composition in the form of an oral composition, it is necessary to protect the active ingredient from being coated or decomposed at the top.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like.
  • excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
  • the pharmaceutical composition may be selected from the group consisting of injections, tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze- Or < / RTI >
  • the active ingredient may be in the form of an acceptable aqueous solution for parenteral administration, which is pyrogen-free and has suitable pH, isotonicity and stability.
  • suitable solutions using isotonic vehicles such as, for example, aqueous sodium chloride solution, Ringer's solution, lactate Ringer's solution and the like, and may be included as needed with preservatives, stabilizers, buffers, antioxidants or other additives.
  • Solid forms suitable for injection may also be prepared as emulsions or in the form of polypeptides encapsulated in liposomes.
  • the conjugate according to the present invention may be administered by any device capable of moving the active substance to the target cell.
  • the phrase " effective amount " or " therapeutically effective amount” refers to the amount required to achieve the desired therapeutic result (for dose and duration and means of administration).
  • An effective amount is at least the minimum amount of active agent required to confer a therapeutic benefit to a subject, and is less than the toxic amount.
  • the dosage can be administered in the range of about 100 ng to about 100 mg / kg per patient, more typically in the range of about 1 ⁇ g / kg to about 10 mg / kg.
  • the active compound is a salt, an ester, an amide, a prodrug, etc.
  • the dosage is calculated on the basis of the parent compound, so that the actual weight used is proportionally increased.
  • the drug or toxin may be formulated to include, but is not limited to, 0.01 mg to 3000 mg, 0.1 mg to 2000 mg, and 1 mg to 1000 mg of the active ingredient per unit dosage form.
  • the active ingredient may be administered to obtain a peak plasma concentration of the active compound of from about 0.05 [mu] M to 100 [mu] M, 1 [mu] M to 50 [mu] M, 5 [mu] M to 30 [mu] M.
  • a peak plasma concentration of the active compound of from about 0.05 [mu] M to 100 [mu] M, 1 [mu] M to 50 [mu] M, 5 [mu] M to 30 [mu] M.
  • a peak plasma concentration of the active compound of from about 0.05 [mu] M to 100 [mu] M, 1 [mu] M to 50 [mu] M, 5 [mu] M to 30 [mu] M.
  • a 0.1 w / v% to 5 w / v% solution of the active
  • the concentration of the active compound in the pharmaceutical composition may be determined by absorption, inactivation and release rates of the drug and other factors known to those skilled in the art.
  • the dosage may vary depending on the severity of the condition / disorder.
  • the dose and the dosage regimen for a specific patient can be adjusted according to the occupational judgment of the administration supervisor taking into consideration the degree of the patient's symptom / disorder, necessity, age, response to the drug, etc., The scope is merely exemplary and is not intended to limit the embodiments of the claimed composition to these.
  • the active ingredient may be administered once, or a smaller dose may be administered several times.
  • Antibody-linker-drug (toxin) conjugate compounds according to the present invention may be used to treat a proliferative disease, particularly cancer.
  • proliferative disease refers to undesirable or uncontrolled cell proliferation of undesirable excessive or abnormal cells, such as neoplastic or hyperplastic growth, in vitro or in vivo.
  • Proliferative disorders include, but are not limited to, neoplasms, tumors, cancers, leukemias, psoriasis, bone diseases, fibrosing disorders, atherosclerosis, and the like, including benign, total malignant or malignant cell proliferation .
  • the cancer is selected from the group consisting of lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, breast cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, But is not limited thereto.
  • Cancer that overexpresses EGFRvIII refers to a cancer that has EGFRvIII on the cancer cell surface at a significantly higher level compared to non-cancerous cells of the same tissue type.
  • Cancer the disease to which the conjugate according to the present invention is applied, may be an overexpressing cancer of EGFRvIII, and may be, for example, glioblastoma, astrocytoma, glioma, neuroblastoma, testicular cancer, colon cancer, melanoma, pancreatic cancer, lung cancer, breast cancer, , Lung cancer, ovarian cancer, prostate cancer, and squamous cell cancer.
  • the compound of Formula 1 was prepared according to the method described in Korean Patent No. 1,628,872 (Example 8).
  • the compounds 2, 3, 4, 5, 6, 7, 8 and 9 were prepared by the method described in WO2017-189895.
  • Antibody-drug conjugates were prepared using the compounds 1, 2, 3, 4, 5, 6, 7, 8 and 9 as described in WO2017-189895.
  • the ADC was named as follows according to the combination of each antibody and compound.
  • DKMG glioblastoma cell line
  • PDC brain cancer patient derived cell line
  • Each cancer cell line was seeded on a 96-well plate at 5,000 cells per well and cultured for 4 hours (PDC) or 24 hours (CDC), and treated with the drug. After 72 hours or 168 hours the living cells were measured by the CellTiter-Glo ® Luminescent Cell Viability Assay (Promega, G7570). Evaluation of efficacy at 72 hours was shown in Table 4, and evaluation of efficacy at 168 hours was shown in Table 5 and Table 6, respectively.
  • EGFRvIII is expressed in the patient-derived cells and cancer cells in the unit nM showed excellent efficacy below.
  • the normal cell NT352T1 not expressing EGFRvIII no toxicity was observed up to 100 nM, and it was confirmed that the selectivity was excellent. Therefore, it can be seen that the antibody-drug conjugate according to the present invention has a sufficient safety.

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Abstract

La présente invention concerne : de nouveaux conjugués anticorps-médicament (ADC) ciblant EGFRvIII ; un métabolite pour activer les ADC ; un procédé de production des ADC ; des utilisations des ADC dans le traitement prophylactique et/ou thérapeutique de maladies ; et des utilisations des ADC dans la production de médicaments destinés au traitement prophylactique et/ou thérapeutique de maladies, plus spécifiquement, de l'hyperplasie et/ou de l'angiogenèse par exemple, et de maladies cancéreuses. Plus spécifiquement, la présente invention concerne : un conjugué anticorps-médicament qui comprend un anticorps se liant à la variante III du récepteur du facteur de croissance épidermique (EGFRvIII), ou comprend un fragment de liaison à l'antigène de l'anticorps ; et une composition pharmaceutique le comprenant.
PCT/KR2018/009362 2017-08-14 2018-08-14 Conjugués anticorps-médicament comprenant un anticorps contre egfrviii Ceased WO2019035649A1 (fr)

Applications Claiming Priority (4)

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KR10-2017-0103096 2017-08-14
KR20170103096 2017-08-14
KR1020180095186A KR20190018400A (ko) 2017-08-14 2018-08-14 EGFRvIII에 대한 항체를 포함하는 항체 약물 접합체
KR10-2018-0095186 2018-08-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12247071B2 (en) 2016-12-21 2025-03-11 Amgen Inc. Anti-TNF alpha antibody formulations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050222059A1 (en) * 2002-02-25 2005-10-06 Tang Careen K Egfrviii specific monoclonal antibody and egfrviii ribozymes and use to detect, treat or prevent egfrviii associated cancer
KR20140035393A (ko) * 2011-05-08 2014-03-21 주식회사 레고켐 바이오사이언스 단백질-활성제 접합체 및 이의 제조 방법
KR101531400B1 (ko) * 2003-06-27 2015-06-26 암젠 프레몬트 인코포레이티드 상피 성장 인자 수용체의 결실 돌연변이체 지향 항체 및 그용도
KR20150137015A (ko) * 2014-05-28 2015-12-08 주식회사 레고켐 바이오사이언스 자가-희생 기를 포함하는 화합물
WO2017089895A1 (fr) * 2015-11-25 2017-06-01 Legochem Biosciences, Inc. Conjugués anticorps-médicament comprenant des lieurs ramifiés et procédés connexes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050222059A1 (en) * 2002-02-25 2005-10-06 Tang Careen K Egfrviii specific monoclonal antibody and egfrviii ribozymes and use to detect, treat or prevent egfrviii associated cancer
KR101531400B1 (ko) * 2003-06-27 2015-06-26 암젠 프레몬트 인코포레이티드 상피 성장 인자 수용체의 결실 돌연변이체 지향 항체 및 그용도
KR20140035393A (ko) * 2011-05-08 2014-03-21 주식회사 레고켐 바이오사이언스 단백질-활성제 접합체 및 이의 제조 방법
KR20150137015A (ko) * 2014-05-28 2015-12-08 주식회사 레고켐 바이오사이언스 자가-희생 기를 포함하는 화합물
WO2017089895A1 (fr) * 2015-11-25 2017-06-01 Legochem Biosciences, Inc. Conjugués anticorps-médicament comprenant des lieurs ramifiés et procédés connexes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12247071B2 (en) 2016-12-21 2025-03-11 Amgen Inc. Anti-TNF alpha antibody formulations

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