WO2022225182A1 - 안지오포이에틴-2에 특이적으로 결합하는 항체, 또는 이의 단편 - Google Patents
안지오포이에틴-2에 특이적으로 결합하는 항체, 또는 이의 단편 Download PDFInfo
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/32—Immunoglobulins specific features characterized by aspects of specificity or valency specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/75—Agonist effect on antigen
Definitions
- the present invention provides an antibody or antigen-binding fragment thereof that specifically binds to angiopoietin 2 (Ang2) and induces Tie2 activation,
- the antibody or antigen-binding fragment thereof in one embodiment, the antibody or antigen-binding fragment thereof
- CDR heavy chain complementarity determining region
- the antibody or antigen-binding fragment thereof is a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 16, SEQ ID NO: 24 and SEQ ID NO: 32, and SEQ ID NO: 9 , preferably including a light chain variable region selected from the group consisting of SEQ ID NO: 17, SEQ ID NO: 25 and SEQ ID NO: 33, but is not limited thereto.
- humanized antibody includes an antibody in which CDR sequences derived from the germline of another mammalian species, such as mouse, are grafted onto human framework regions. Additional framework region modifications may be made in human framework sequences as well as in CDR sequences derived from the germline of another mammalian species.
- the present invention also provides an isolated nucleic acid encoding the anti-Ang2 antibody or antigen-binding fragment thereof of the present invention.
- the antigen-binding fragment is preferably selected from the group consisting of scFv, (scFv) 2 , scFv-Fc, Fab, Fab' and F(ab') 2 , but is not limited thereto.
- the present invention includes the anti-Ang2 antibody or antigen-binding fragment thereof of the present invention as an active ingredient, Alzheimer's disease; inflammatory autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or psoriasis; ophthalmic diseases such as age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy (DR), or glaucoma; Or it provides a pharmaceutical composition for the prevention or treatment of a coronavirus infectious disease, such as coronavirus 19.
- inflammatory autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or psoriasis
- ophthalmic diseases such as age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy (DR), or glaucoma
- AMD age-related macular degeneration
- DME diabetic macular edema
- DR diabetic retinopathy
- peptide + antibody refers to a fusion protein in which all or part of a constant region such as an Fc region of an antibody is fused with a peptide, wherein the peptide is an antigen-binding region (heavy chain and/or light chain CDRs or variable regions). By acting, it refers to a protein having a framework and function similar to that of an antibody.
- bispecific antibody or “multispecific antibody” refers to recognizing and/or binding two (bispecific antibodies) or more (multispecific antibodies) different antigens, or recognizing and/or binding different sites of the same antigen. It refers to an antibody that binds, and one antigen-binding site of the bispecific antibody or the multispecific antibody may include the polypeptide.
- the polypeptide molecule comprises a polypeptide comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 10, SEQ ID NO: 18 or 26, or the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 19 or SEQ ID NO: 27 at least one selected from the group consisting of a polypeptide comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 12, SEQ ID NO: 20 or SEQ ID NO: 28;
- the bispecific antibody or multispecific antibody is an antibody that simultaneously recognizes and/or binds two or more antigens, including respective antigen binding sites for two or more different antigens.
- one of the antigen-binding sites may include the polypeptide molecule described above.
- the polypeptide molecule serving as the Ang2 antigen binding site may form a dimer or multimer with an antigen binding site for another antigen to constitute a bispecific antibody or a multispecific antibody.
- a bispecific antibody or multispecific antibody is provided comprising said polypeptide molecule as an Ang2 antigen binding site.
- antibodies include animal-derived antibodies, chimeric antibodies, humanized antibodies, and human antibodies.
- An animal-derived antibody produced by immunizing an animal to be immunized with a desired antigen may cause an immune rejection reaction when administered to a human for therapeutic purposes.
- a chimeric antibody is one in which the constant region of an animal-derived antibody causing an anti-isotype reaction is substituted with that of a human antibody using a genetic engineering method. Chimeric antibodies have significantly improved anti-isotype response compared to animal-derived antibodies, but still have animal-derived amino acids in the variable region, potentially causing side effects on anti-idiotypic responses. are doing A humanized antibody was developed to improve these side effects. This is produced by grafting complementarity determining regions (CDRs), which play an important role in antigen binding, into a human antibody framework among variable regions of a chimeric antibody.
- CDRs complementarity determining regions
- the antibody may be a mouse-derived antibody, a mouse-human chimeric antibody, a humanized antibody, or a human antibody.
- CDR complementarity determining region
- antigen-binding fragment refers to a fragment of the entire immunoglobulin structure, and refers to a portion of a polypeptide including an antigen-binding portion. For example, it may be scFv, (scFv)2, scFv-Fc, Fab, Fab' or F(ab') 2 , but is not limited thereto.
- the antigen-binding fragment can be obtained using a proteolytic enzyme (for example, by restriction digestion of the whole antibody with papain, Fab can be obtained, and when digested with pepsin, F(ab') 2 fragment can be obtained), It can be produced through genetic recombination technology.
- a proteolytic enzyme for example, by restriction digestion of the whole antibody with papain, Fab can be obtained, and when digested with pepsin, F(ab') 2 fragment can be obtained
- It can be produced through genetic recombination technology.
- hinge region refers to a region included in the heavy chain of an antibody, which exists between the CH1 and CH2 regions, and functions to provide flexibility of an antigen-binding site in the antibody.
- the hinge may be derived from a human antibody, and specifically, may be derived from IgA, IgE, or IgG, such as IgG1, IgG2, IgG3, or IgG4.
- Another example provides a pharmaceutical composition for reducing vascular permeability comprising the anti-Ang2 antibody or antigen-binding fragment thereof as an active ingredient.
- Another example provides a method for reducing vascular permeability, comprising administering to a patient in need thereof a pharmaceutically effective amount of the anti-Ang2 antibody or antigen-binding fragment thereof.
- the method for reducing vascular permeability may further include identifying a patient in need of reduced vascular permeability prior to the administering.
- Another example provides a pharmaceutical composition for preventing and/or treating diseases associated with Ang2 overexpression, angiogenesis, and/or increased vascular permeability, comprising the anti-Ang2 antibody or antigen-binding fragment thereof as an active ingredient.
- Another example comprises administering a pharmaceutically effective amount of the anti-Ang2 antibody or antigen-binding fragment thereof to a patient in need of prevention and/or treatment of a disease associated with Ang2 overexpression, angiogenesis and/or increased vascular permeability.
- the method for preventing and/or treating may further comprise identifying a patient in need of prevention and/or treatment of a disease associated with Ang2 overexpression, angiogenesis and/or increased vascular permeability prior to the administering. have.
- the antibody-producing hybridoma cells obtained above were cultured in DMEM (Dulbeco's Modified Eagle's Mediaum) containing 10% (v/v) FBS at 37 °C, 5% CO 2 conditions, and then centrifuged to produce antibody cells. was removed and the antibody secreted culture was separated, and the antibody was purified using an affinity column (Protein A/G agarose column, Protein A/G (GenDEPOT)).
- Table 5 shows the CDR sequences of mouse anti-Ang2 antibody 1D3.
- the anti-Ang2 antibody and biotin-labeled Ang2 complex were prepared by adding anti-Ang2 antibody to a concentration of 1.2 ⁇ M in 1% BSA and serially diluting 5 times with 1% BSA to prepare 10 concentrations, and then adding biotin-labeled human Ang2 to 1 It was prepared by mixing 1:1 with a sample diluted to 1 ⁇ g/mL in % BSA, and a mixture of biotin-labeled human Ang2 and unlabeled human Ang2 was prepared by adding Ang2 to 1% BSA at a concentration of 1.2 ⁇ M in 1% BSA.
- LLC lung cancer model In order to confirm the effect of co-administration of anti-Ang2 antibody with other anticancer drugs, a test of co-administration of Ang2 antibody 2C8 and cisplatin was performed in LLC lung cancer model.
- the LLC cell line was cultured in DMEM (Welgene) supplemented with 10% FBS (Gibco). After subcutaneous inoculation of LLC cells (1 ⁇ 10 6 in 100 ⁇ L of PBS) into C57BL/6 mice (orient) of the same genotype, when the tumor volume reached 50-100 mm 3 3 times a week for 2 weeks
- the Ang2 antibody was administered intraperitoneally at a dose of 5 mg/kg.
- Cisplatin (Sigma) was administered once at a dose of 5 mg/kg. Experiments were performed in Ig (control group), 2C8 group, cisplatin group, and 2C8+cisplatin group.
- the MC38 cell line was cultured in DMEM (Welgene) supplemented with 10% FBS (Welgene).
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Abstract
Description
Domain | CDR | CDR sequence | 서열번호 |
Heavy chain | CDRH1-Kabat | DYWIG | 서열번호 2 |
CDRH2-Kabat | DIYPGGGYTNCNEKFKG | 서열번호 3 | |
CDRH3-Kabat | SDYRNDEGFAD | 서열번호 4 | |
Light chain | CDRL1-Kabat | SASSSVSSSYLH | 서열번호 5 |
CDRL2-Kabat | RTSNLAS | 서열번호 6 | |
CDRL3-Kabat | QQWSGYPYT | 서열번호 7 |
Domain | Variable region sequence | 서열번호 |
Heavy chain | QVQLQQSGAELVRPGTSVKMSCKAAGYTFTDYWIGWVKQRPGHGLEWIGDIYPGGGYTNCNEKFKGKATLTADTSSSTAYMQLSSLTSEDSAIYYCSRSDYRNDEGFADWGQGTLVTVSAAK | 서열번호 8 |
Light chain | ENVLTQSPAIMTASLGQKVTMTCSASSSVSSSYLHWYQQKSGASPKPLIHRTSNLASGVPARFSGSGSGTSYSLTISSVEAEDDATYYCQQWSGYPYTFGGGTKLEIKRADAAPTVS | 서열번호 9 |
Domain | CDR | CDR sequence | 서열번호 |
Heavy chain | CDRH1-Kabat | NYWIG | 서열번호 10 |
CDRH2-Kabat | DIYPGGGYTNYNEKFKG | 서열번호 11 | |
CDRH3-Kabat | SDYRDDEGFAY | 서열번호 12 | |
Light chain | CDRL1-Kabat | SASSSVSSSYLH | 서열번호 13 |
CDRL2-Kabat | RTSNLAS | 서열번호 14 | |
CDRL3-Kabat | QQWSGYPYT | 서열번호 15 |
Domain | Variable region sequence | 서열번호 |
Heavy chain | QVHLQQSGAELVRPGTSVKMSCKAAGYTFTNYWIGWVKQRPGHGLEWIGDIYPGGGYTNYNEKFKGKATLTADTSSSTAYMQLSSLTSEDSAIYYCSRSDYRDDEGFAYWGQGTLVTVSAAKTTPPKLYPLA | 서열번호 16 |
Light chain | ENVLTQSPAIMAASLGQKVTMTCSASSSVSSSYLHWYQQKSGASPKPLIHRTSNLASGVPARFSGSGSGTSYSLTISTVEAEDAATYYCQQWSGYPYTFGGGTKLEIKRADAAPTVSAAASLS | 서열번호 17 |
Domain | CDR | CDR sequence | 서열번호 |
Heavy chain | CDRH1-Kabat | SDYGWN | 서열번호 18 |
CDRH2-Kabat | YISYSGTTSYNPSLKS | 서열번호 19 | |
CDRH3-Kabat | SEGTGFYAMDY | 서열번호 20 | |
Light chain | CDRL1-Kabat | KASQSVSNDVA | 서열번호 21 |
CDRL2-Kabat | YASNRYT | 서열번호 22 | |
CDRL3-Kabat | QQDYSSPT | 서열번호 23 |
Domain | Variable region sequence | 서열번호 |
Heavy chain | DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYGWNWIRQFPGNKLEWMGYISYSGTTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCARSEGTGFYAMDYWGQGTSVTVSSAKTTPPKLY | 서열번호 24 |
Light chain | SIVMTQTPKFLLVSAGDRVTIICKASQSVSNDVAWYQQKPGQSPKLLIYYASNRYTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYSSPTFGGGTKLEIKRA | 서열번호 25 |
Domain | CDR | CDR sequence | 서열번호 |
Heavy chain | CDRH1-Kabat | NYWIG | 서열번호 26 |
CDRH2-Kabat | IYPGGGYTNYNEKFK | 서열번호 27 | |
CDRH3-Kabat | SDYRFDEGFAY | 서열번호 28 | |
Light chain | CDRL1-Kabat | SASSSVSSSYLH | 서열번호 29 |
CDRL2-Kabat | RTSNLAS | 서열번호 30 | |
CDRL3-Kabat | QQWSGYPYT | 서열번호 31 |
Domain | Variable region sequence | 서열번호 |
Heavy chain | QVQLQQSGAELVRPGTSVKMSCKATGYTFTNYWIGWVKQRPGHGLEWIGDIYPGGGYTNYNEKFKGKATLTADTSSSTACMQLSSLTSEDSAIYYCARSDYRFDEGFAYWGQGTLVTIS | 서열번호 32 |
Light chain | ENVLTQSPAIMAASLGQKVTMTCSASSSVSSSYLHWYQQKSGASPKPLIHRTSNLASGVPARFSGSGSGTSYSLTISSVEAEDDATYYCQQWSGYPYTFGGGTKLEIKRA | 서열번호 33 |
Claims (16)
- 안지오포이에틴2 (Ang2)에 특이적으로 결합하고, Tie2 활성화를 유도하는 항체 또는 이의 항원 결합 단편으로,(a)서열번호 2, 서열번호 10, 서열번호 18, 또는 서열번호 26의 아미노산 서열의 CDRH1,서열번호 3, 서열번호 11, 서열번호 19, 또는 서열번호 27의 아미노산 서열의 CDRH2, 및서열번호 4, 서열번호 12, 서열번호 20, 또는 서열번호 28의 아미노산 서열의 CDRH3를 포함하는 중쇄 상보성 결정 영역 (CDR); 및(b)서열번호 5, 서열번호 13, 서열번호 21, 또는 서열번호 29의 아미노산 서열의 CDRL1,서열번호 6, 서열번호 14, 서열번호 22, 또는 서열번호 30의 아미노산 서열의 CDRL2, 및서열번호 7, 서열번호 15, 서열번호 23, 또는 서열번호 31의 아미노산 서열의 CDRL3를 포함하는 경쇄 CDR;을 포함하는 것을 특징으로 하는 항 Ang2 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서, 상기 항체 또는 이의 항원 결합 단편은(a)서열번호 2의 아미노산 서열의 CDRH1, 서열번호 3의 아미노산 서열의 CDRH2, 및 서열번호4의 CDRH3를 포함하는 중쇄 상보성 결정 영역 (CDR); 및(b)서열번호 5의 아미노산 서열의 CDRL1, 서열번호6의 아미노산 서열의 CDRL2, 및 서열번호7의 아미노산 서열의 CDRL3를 포함하는 경쇄 CDR;을 포함하는 것을 특징으로 하는 항 Ang2 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서, 상기 항체 또는 이의 항원 결합 단편은(a)서열번호 10의 아미노산 서열의 CDRH1, 서열번호 11의 아미노산 서열의 CDRH2, 및 서열번호12의 CDRH3를 포함하는 중쇄 상보성 결정 영역 (CDR); 및(b)서열번호 13의 아미노산 서열의 CDRL1, 서열번호14의 아미노산 서열의 CDRL2, 및 서열번호15의 아미노산 서열의 CDRL3를 포함하는 경쇄 CDR;을 포함하는 것을 특징으로 하는 항 Ang2 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서, 상기 항체 또는 이의 항원 결합 단편은(a)서열번호 18의 아미노산 서열의 CDRH1, 서열번호 19의 아미노산 서열의 CDRH2, 및 서열번호20의 CDRH3를 포함하는 중쇄 상보성 결정 영역 (CDR); 및(b)서열번호 21의 아미노산 서열의 CDRL1, 서열번호 22의 아미노산 서열의 CDRL2, 및 서열번호23의 아미노산 서열의 CDRL3를 포함하는 경쇄 CDR;을 포함하는것을 특징으로 하는 항 Ang2 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서, 상기 항체 또는 이의 항원 결합 단편은(a)서열번호 26의 아미노산 서열의 CDRH1, 서열번호 27의 아미노산 서열의 CDRH2, 및 서열번호 28의 CDRH3를 포함하는 중쇄 상보성 결정 영역 (CDR); 및(b)서열번호 29의 아미노산 서열의 CDRL1, 서열번호 30의 아미노산 서열의 CDRL2, 및 서열번호 31의 아미노산 서열의 CDRL3를 포함하는 경쇄 CDR;을 포함하는것을 특징으로 하는 항 Ang2 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서, 상기 항체 또는 이의 항원 결합 단편은 서열번호 8, 서열번호 16, 서열번호 24 및 서열번호 32로 이루어진 군에서 선택된 아미노산 서열을 포함하는 중쇄 가변부위, 및 서열번호 9, 서열번호17, 서열번호 25 및 서열번호 33으로 이루어진 군에서 선택된 경쇄 가변 부위를 포함하는, 항 Ang2 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서, 상기 항체 또는 이의 단편은 안지오포이에틴-2에 특이적으로 결합하고, Ang2와 함께 Tie2 수용체에 결합하는 항 Ang2 항체 또는 이의 단편.
- 제1항 내지 제7항 중 어느 한 항의 항 Ang2 항체 또는 이의 항원 결합 단편을 코딩하는 분리된 핵산.
- 제1항 내지 제7항 중 어느 한 항에 있어서, 상기 항원 결합 단편은 scFv, (scFv)2, scFv-Fc, Fab, Fab' 및 F(ab')2로 이루어진 군에서 선택되는 것인, 항 Ang2 항체 또는 이의 항원 결합 단편.
- 제 1항 내지 제7항 중 어느 한 항에 있어서, 상기 항체 또는 이의 항원 결합 단편은 쥐(murine) 항체, 키메라(chimeric) 항체 또는 인간화(humanized) 항체인 항 Ang2 항체 또는 이의 항원 결합 단편.
- 제1항 내지 제7항 중 어느 한 항의 항 Ang2 항체 또는 이의 항원 결합 단편을 유효성분으로 포함하는, Ang2 과발현, 신생혈관 형성, 또는 혈관 투과성 증가와 관련된 질병의 예방 또는 치료를 위한 약학 조성물.
- 제11항에 있어서,상기 Ang2 과발현, 신생혈관 형성, 또는 혈관 투과성 증가와 관련된 질병은 암, 암전이, 염증 질환, 감염, 심혈관질환, 신장 질환, 유전성 출혈성 모세혈관 확장증, 천식, 또는 부종인 약학 조성물.
- 제1항 내지 제7항 중 어느 한 항의 항 Ang2 항체 또는 이의 항원 결합 단편을 유효성분으로 포함하는, 정상 혈관 생성 감소와 관련된 질병의 예방 또는 치료를 위한 약학 조성물.
- 제13항에 있어서, 상기 정상 혈관 생성 감소와 관련된 질병은 심근경색, 협심증, 뇌경색, 뇌졸중, 버거씨병, 무혈관 괴사, 족부궤양, 또는 발기부전인, 약학 조성물.
- 제1항 내지 제7항 중 어느 한 항의 항 Ang2 항체 또는 이의 항원 결합 단편을 유효성분으로 포함하는,알츠하이머 질환;류마티스 관절염, 다발성 경화증, 또는 건선과 같은 염증성 자가면역 질환;노화관련 황반 변성(AMD), 당뇨황반부종(DME), 당뇨성 망막증(DR), 또는 녹내장과 같은 안과 질환; 또는코로나바이러스 19와 같은 코로나바이러스 감염 질환의 예방 또는 치료를 위한 약학 조성물.
- 제1항 내지 제7항 중 어느 한 항의 항 Ang2 항체 또는 이의 항원 결합 단편을 방사선 조사, 화학요법제, 세포독성제 및/또는 면역독성제와 동시적으로, 개별적으로, 또는 순차적으로 투여하는 것을 포함하는 암 치료에 사용하기 위한 병용 치료용 조성물.
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- 2022-03-10 WO PCT/KR2022/003351 patent/WO2022225182A1/ko active Application Filing
- 2022-03-10 EP EP22791882.8A patent/EP4328242A1/en active Pending
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