JP7371093B2 - 腫瘍および/または転移の治療のための抗-met fab-fc - Google Patents

腫瘍および/または転移の治療のための抗-met fab-fc Download PDF

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JP7371093B2
JP7371093B2 JP2021518891A JP2021518891A JP7371093B2 JP 7371093 B2 JP7371093 B2 JP 7371093B2 JP 2021518891 A JP2021518891 A JP 2021518891A JP 2021518891 A JP2021518891 A JP 2021518891A JP 7371093 B2 JP7371093 B2 JP 7371093B2
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met
human
domain
antibody fragment
amino acid
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JPWO2020074459A5 (https=
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JP2022504392A (ja
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エリーザ ヴィニャ
クリスティーナ バジリコ
ティツィアーナ クレパルディ
パオロ マリア コモグリオ
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バーティカル バイオ アーゲー
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46Hybrid immunoglobulins
    • C07K16/461Igs containing Ig-regions, -domains or -residues form different species
    • C07K16/462Igs containing a variable region (Fv) from one specie and a constant region (Fc) from another
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/10Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14Specific host cells or culture conditions, e.g. components, pH or temperature
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35Valency
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/522CH1 domain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/524CH2 domain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/526CH3 domain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/53Hinge
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55Fab or Fab'
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732Antibody-dependent cellular cytotoxicity [ADCC]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/734Complement-dependent cytotoxicity [CDC]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94Stability, e.g. half-life, pH, temperature or enzyme-resistance

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
JP2021518891A 2018-10-09 2019-10-07 腫瘍および/または転移の治療のための抗-met fab-fc Active JP7371093B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT102018000009282A IT201800009282A1 (it) 2018-10-09 2018-10-09 Nuovo agente terapeutico per il trattamento di un tumore e/o metastasi
IT102018000009282 2018-10-09
PCT/EP2019/077116 WO2020074459A1 (en) 2018-10-09 2019-10-07 Anti-met fab-fc for the treatment of a tumor and/or metastasis

Publications (4)

Publication Number Publication Date
JP2022504392A JP2022504392A (ja) 2022-01-13
JPWO2020074459A5 JPWO2020074459A5 (https=) 2022-05-12
JP2022504392A5 JP2022504392A5 (https=) 2022-05-12
JP7371093B2 true JP7371093B2 (ja) 2023-10-30

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JP2021518891A Active JP7371093B2 (ja) 2018-10-09 2019-10-07 腫瘍および/または転移の治療のための抗-met fab-fc

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Country Link
US (2) US12209129B2 (https=)
EP (2) EP3864050B1 (https=)
JP (1) JP7371093B2 (https=)
KR (2) KR20250078600A (https=)
CN (2) CN119587692A (https=)
AU (2) AU2019358417B2 (https=)
CA (1) CA3115582A1 (https=)
CY (1) CY1125831T1 (https=)
DK (1) DK3864050T5 (https=)
ES (1) ES2938714T3 (https=)
FI (1) FI3864050T3 (https=)
HR (1) HRP20230154T1 (https=)
HU (1) HUE060843T2 (https=)
IL (1) IL282033B2 (https=)
IT (1) IT201800009282A1 (https=)
LT (1) LT3864050T (https=)
PL (1) PL3864050T3 (https=)
PT (1) PT3864050T (https=)
RS (1) RS63960B1 (https=)
SG (1) SG11202103575RA (https=)
SI (1) SI3864050T1 (https=)
SM (1) SMT202300053T1 (https=)
WO (1) WO2020074459A1 (https=)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20260019463A (ko) 2023-06-01 2026-02-10 피에르 파브르 메디카먼트 종양 및 전이의 치료를 위한 침묵화된 항체 기반의 항-met 구조물

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008504007A (ja) 2003-12-19 2008-02-14 ジェネンテック・インコーポレーテッド 治療薬として有用な一価抗体断片
JP2014533700A (ja) 2011-11-21 2014-12-15 ジェネンテック, インコーポレイテッド 抗c−MET抗体の精製
JP2016503069A (ja) 2013-01-09 2016-02-01 メセレシス・トランスレイショナル・リサーチ・ソシエタ・アノニマMetheresis Translational Research S.A. 新規な抗体フラグメント、組成物およびその使用

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2638889C (en) 2006-02-06 2015-06-02 Metheresis Translational Research S.A. Anti-met monoclonal antibody, fragments and vectors thereof, for the treatment of tumors and corresponding products
ES2547248T3 (es) * 2006-04-28 2015-10-02 Delenex Therapeutics Ag Anticuerpos que se unen al dominio extracelular del receptor Tirosina cinasa ALK
NZ591087A (en) * 2008-10-01 2012-08-31 Micromet Ag Cross-species-specific pscaxcd3, cd19xcd3, c-metxcd3, endosialinxcd3, epcamxc d3, igf-1rxcd3 or fapalpha xcd3 bispecific single chain antibody
EP2376109B1 (en) * 2008-12-19 2019-01-23 MacroGenics, Inc. Covalent diabodies and uses thereof
MX2011010265A (es) * 2009-04-01 2011-10-11 Genentech Inc Anticuerpos anti-fcrh5 e inmunoconjugados y metodos de uso.
DK2500036T3 (da) * 2011-03-18 2014-08-04 Metheresis Translational Res Sa MET-hæmmere til øgning af virkningen af radioterapi
KR20140033029A (ko) * 2011-04-01 2014-03-17 메모리얼 슬로안-케터링 캔서 센터 에이치엘에이 에이2에 의해 제공된 더블유티1 펩타이드에 특이적인 티 세포 수용체 유사 항체
EP2748197A2 (en) * 2011-08-26 2014-07-02 Merrimack Pharmaceuticals, Inc. Tandem fc bispecific antibodies
GB201403875D0 (en) * 2014-03-05 2014-04-16 Cantargia Ab Novel antibodies and uses thereof
MX2019008538A (es) * 2017-01-20 2019-11-05 Juno Therapeutics Gmbh Conjugados de superficie celular y composiciones y métodos celulares relacionados.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008504007A (ja) 2003-12-19 2008-02-14 ジェネンテック・インコーポレーテッド 治療薬として有用な一価抗体断片
JP2014533700A (ja) 2011-11-21 2014-12-15 ジェネンテック, インコーポレイテッド 抗c−MET抗体の精製
JP2016503069A (ja) 2013-01-09 2016-02-01 メセレシス・トランスレイショナル・リサーチ・ソシエタ・アノニマMetheresis Translational Research S.A. 新規な抗体フラグメント、組成物およびその使用

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Publication number Publication date
EP3864050B1 (en) 2022-11-23
SMT202300053T1 (it) 2023-03-17
ES2938714T3 (es) 2023-04-14
HUE060843T2 (hu) 2023-04-28
EP3864050A1 (en) 2021-08-18
WO2020074459A1 (en) 2020-04-16
SG11202103575RA (en) 2021-05-28
DK3864050T3 (da) 2023-02-20
IT201800009282A1 (it) 2020-04-09
EP4194469A1 (en) 2023-06-14
PL3864050T3 (pl) 2023-04-11
LT3864050T (lt) 2023-03-27
AU2019358417B2 (en) 2025-12-18
FI3864050T3 (fi) 2023-03-14
KR20250078600A (ko) 2025-06-02
AU2026201438A1 (en) 2026-03-19
KR102814490B1 (ko) 2025-06-02
KR20210075121A (ko) 2021-06-22
IL282033A (en) 2021-05-31
JP2022504392A (ja) 2022-01-13
CY1125831T1 (el) 2026-02-25
US20250101115A1 (en) 2025-03-27
US20210395372A1 (en) 2021-12-23
CA3115582A1 (en) 2020-04-16
DK3864050T5 (da) 2024-08-12
CN119587692A (zh) 2025-03-11
RS63960B1 (sr) 2023-02-28
IL282033B2 (en) 2026-02-01
IL282033B1 (en) 2025-10-01
HRP20230154T1 (hr) 2023-03-31
PT3864050T (pt) 2023-01-18
SI3864050T1 (sl) 2023-03-31
CN113330032B (zh) 2025-01-03
AU2019358417A2 (en) 2021-06-24
CN113330032A (zh) 2021-08-31
AU2019358417A1 (en) 2021-05-27
US12209129B2 (en) 2025-01-28

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