CN111201035A - Il-2超激动剂、激动剂及其融合体的用途和方法 - Google Patents

Il-2超激动剂、激动剂及其融合体的用途和方法 Download PDF

Info

Publication number
CN111201035A
CN111201035A CN201880053864.6A CN201880053864A CN111201035A CN 111201035 A CN111201035 A CN 111201035A CN 201880053864 A CN201880053864 A CN 201880053864A CN 111201035 A CN111201035 A CN 111201035A
Authority
CN
China
Prior art keywords
seq
mutein
cells
wild
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201880053864.6A
Other languages
English (en)
Chinese (zh)
Inventor
沙菲克·菲达
法赫尔·麦钱特
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medicenna Therapeutics Pte Ltd
Original Assignee
Medicenna Therapeutics Pte Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medicenna Therapeutics Pte Ltd filed Critical Medicenna Therapeutics Pte Ltd
Publication of CN111201035A publication Critical patent/CN111201035A/zh
Pending legal-status Critical Current

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52Cytokines; Lymphokines; Interferons
    • C07K14/54Interleukins [IL]
    • C07K14/55IL-2
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19Cytokines; Lymphokines; Interferons
    • A61K38/20Interleukins [IL]
    • A61K38/2013IL-2
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/0005Vertebrate antigens
    • A61K39/0011Cancer antigens
    • 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
    • A61K39/39541Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • 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
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76Albumins
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/283Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K19/00Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06Animal cells or tissues; Human cells or tissues
    • C12N5/0602Vertebrate cells
    • C12N5/0634Cells from the blood or the immune system
    • C12N5/0636T lymphocytes
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/51Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525Virus
    • A61K2039/5256Virus expressing foreign proteins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55522Cytokines; Lymphokines; Interferons
    • A61K2039/55527Interleukins
    • A61K2039/55533IL-2
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/76Viruses; Subviral particles; Bacteriophages
    • 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
    • C07K2319/00Fusion polypeptide
    • C07K2319/30Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/31Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011Details
    • C12N2710/10011Adenoviridae
    • C12N2710/10034Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011Details
    • C12N2710/10011Adenoviridae
    • C12N2710/10041Use of virus, viral particle or viral elements as a vector
    • C12N2710/10043Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011Details
    • C12N2710/24011Poxviridae
    • C12N2710/24111Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24134Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011Details
    • C12N2710/24011Poxviridae
    • C12N2710/24111Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24141Use of virus, viral particle or viral elements as a vector
    • C12N2710/24143Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Mycology (AREA)
  • Wood Science & Technology (AREA)
  • Toxicology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Oncology (AREA)
  • Endocrinology (AREA)
  • Virology (AREA)
  • Hematology (AREA)
  • Cell Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
CN201880053864.6A 2017-06-19 2018-06-19 Il-2超激动剂、激动剂及其融合体的用途和方法 Pending CN111201035A (zh)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201762521957P 2017-06-19 2017-06-19
US62/521,957 2017-06-19
US201862679687P 2018-06-01 2018-06-01
US62/679,687 2018-06-01
PCT/IB2018/000760 WO2018234862A1 (en) 2017-06-19 2018-06-19 Uses and methods for il-2 superagonists, agonists, and fusions thereof

Publications (1)

Publication Number Publication Date
CN111201035A true CN111201035A (zh) 2020-05-26

Family

ID=64737001

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201880053864.6A Pending CN111201035A (zh) 2017-06-19 2018-06-19 Il-2超激动剂、激动剂及其融合体的用途和方法

Country Status (7)

Country Link
US (2) US11542312B2 (enExample)
EP (1) EP3641814A4 (enExample)
JP (2) JP7433051B2 (enExample)
CN (1) CN111201035A (enExample)
AU (2) AU2018287317B2 (enExample)
CA (1) CA3067909A1 (enExample)
WO (1) WO2018234862A1 (enExample)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115768788A (zh) * 2020-07-09 2023-03-07 Eutilex股份有限公司 Il-2变体
TWI817159B (zh) * 2020-07-14 2023-10-01 美商輝瑞大藥廠 重組牛痘病毒
WO2025055790A1 (zh) * 2023-09-14 2025-03-20 重庆精准生物技术有限公司 细胞因子融合蛋白及其应用

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6576326B2 (ja) 2013-03-14 2019-09-18 ソーク インスティテュート フォー バイオロジカル スタディーズ 腫瘍溶解性アデノウイルス組成物
WO2015164815A1 (en) 2014-04-24 2015-10-29 The Board Of Trustees Of The Leland Stanford Junior University Superagonists, partial agonists and antagonists of interleukin-2
KR20220163505A (ko) 2016-02-23 2022-12-09 솔크 인스티튜트 포 바이올로지칼 스터디즈 바이러스 동역학에 미치는 영향 최소화를 위한 치료용 아데노바이러스의 외인성 유전자 발현
JP7054527B2 (ja) 2016-02-23 2022-04-14 ソーク インスティテュート フォー バイオロジカル スタディーズ アデノウイルスの複製動態を測定するための高スループットアッセイ
JP2019536468A (ja) 2016-12-12 2019-12-19 ソーク インスティテュート フォー バイオロジカル スタディーズ 腫瘍を標的にする合成アデノウイルスおよびその使用
BR112019018915A2 (pt) 2017-03-15 2020-04-14 Pandion Therapeutics Inc imunotolerância direcionada
CN111010866A (zh) 2017-05-24 2020-04-14 潘迪恩治疗公司 靶向免疫耐受性
US11542312B2 (en) 2017-06-19 2023-01-03 Medicenna Therapeutics, Inc. IL-2 superagonists in combination with anti-PD-1 antibodies
PH12020550661A1 (en) 2017-11-21 2021-04-19 Univ Leland Stanford Junior Partial agonists of interleukin-2
US10946068B2 (en) 2017-12-06 2021-03-16 Pandion Operations, Inc. IL-2 muteins and uses thereof
USRE50550E1 (en) 2017-12-06 2025-08-26 Pandion Operations, Inc. IL-2 muteins and uses thereof
US10174092B1 (en) 2017-12-06 2019-01-08 Pandion Therapeutics, Inc. IL-2 muteins
WO2020036635A2 (en) * 2018-03-19 2020-02-20 Multivir Inc. Methods and compositions comprising tumor suppressor gene therapy and cd122/cd132 agonists for the treatment of cancer
AU2019251356B2 (en) 2018-04-09 2025-06-12 Salk Institute For Biological Studies Oncolytic adenovirus compositions with enhanced replication properties
KR20210038549A (ko) * 2018-07-24 2021-04-07 비온테크 알엔에이 파마슈티컬스 게엠베하 Il2 작용제
HUE067601T2 (hu) 2018-11-14 2024-10-28 Regeneron Pharma PD-1 inhibitorok intraléziós beadása a bõrrák kezelésére
CA3125529A1 (en) * 2019-01-07 2020-07-16 Inhibrx, Inc. Polypeptides comprising modified il-2 polypeptides and uses thereof
TW202038994A (zh) * 2019-01-14 2020-11-01 美商醫格耐免疫治療公司 重組痘瘡病毒及其使用方法
EP3930848A1 (en) * 2019-02-28 2022-01-05 Regeneron Pharmaceuticals, Inc. Administration of pd-1 inhibitors for treating skin cancer
CN114126637A (zh) * 2019-03-29 2022-03-01 居里研究所 具有经修饰的生物活性的白介素-2变体
US11739146B2 (en) 2019-05-20 2023-08-29 Pandion Operations, Inc. MAdCAM targeted immunotolerance
EP3980051A4 (en) * 2019-06-05 2023-09-13 Asher Biotherapeutics, Inc. FUSIONS OF MUTANT INTERLEUKIN-2 POLYPEPTIDES WITH ANTIGEN-BINDING MOLECULES TO MODULATE THE FUNCTION OF IMMUNE CELLS
CN110256583B (zh) * 2019-07-11 2022-05-20 中国科学院生物物理研究所 一种il-2突变体与抗体的融合蛋白及其应用
CA3150978A1 (en) * 2019-08-15 2021-02-18 Cytimm Therapeutics, Inc. Modified interleukin 2 (il-2) polypeptides, conjugates and uses thereof
EP4031582A4 (en) * 2019-09-18 2023-10-04 The Regents of the University of California IMMUNOACTIVE MICROPARTICLES AND ASSOCIATED USES
US20220403026A1 (en) * 2019-09-18 2022-12-22 The Regents Of The University Of California Implantable scaffolds and uses thereof for immunotherapy and other uses
EP4031191A4 (en) * 2019-09-18 2023-10-25 The Regents of the University of California Protein producing nanoliposomes and uses thereof
WO2021069806A1 (en) 2019-10-11 2021-04-15 Tilt Biotherapeutics Oy An oncolytic virus vector coding for variant interleukin-2 (vil-2) polypeptide
KR102400884B1 (ko) * 2019-11-15 2022-05-23 주식회사 제넥신 변형된 인터루킨-7 및 인터루킨-2를 포함하는 융합단백질 및 이의 용도
US20210188934A1 (en) 2019-12-20 2021-06-24 Regeneron Pharmaceuticals, Inc. Novel il2 agonists and methods of use thereof
MX2022008547A (es) * 2020-01-09 2022-08-10 Pfizer Virus de vacuna recombinante.
AU2021206449A1 (en) 2020-01-10 2022-07-21 Bright Peak Therapeutics Ag Modified IL-2 polypeptides and uses thereof
JP7303391B2 (ja) 2020-01-14 2023-07-04 シンセカイン インコーポレイテッド バイアス型il2ムテイン、方法、および組成物
US11981715B2 (en) 2020-02-21 2024-05-14 Pandion Operations, Inc. Tissue targeted immunotolerance with a CD39 effector
KR102545250B1 (ko) 2020-03-31 2023-06-21 한미약품 주식회사 신규한 면역 활성 인터루킨 2 아날로그
EP4149554A4 (en) 2020-05-13 2024-05-29 Bonum Therapeutics, Inc. Compositions of protein complexes and methods of use thereof
WO2021253360A1 (en) * 2020-06-18 2021-12-23 Proviva Therapeutics (Hong Kong) Limited Activatable procytokines
US20230365642A1 (en) * 2020-06-24 2023-11-16 Medicenna Therapeutics, Inc. Bifunctional superkines and uses thereof
US20230340054A1 (en) * 2020-09-01 2023-10-26 Takeda Pharmaceutical Company Limited Interleukin-2 muteins and uses thereof
TWI815194B (zh) 2020-10-22 2023-09-11 美商基利科學股份有限公司 介白素2-Fc融合蛋白及使用方法
CN116761883A (zh) * 2021-01-19 2023-09-15 塞内卡治疗公司 武装的塞尼卡谷病毒溶瘤性治疗组合物及其方法
TW202245843A (zh) * 2021-02-12 2022-12-01 美商欣爍克斯公司 Il-2接合物及西米普利單抗(cemiplimab)之皮膚癌組合療法
AU2022275666A1 (en) 2021-05-19 2023-12-07 Asher Biotherapeutics, Inc. Il-21 polypeptides and targeted constructs
EP4352091A1 (en) * 2021-05-27 2024-04-17 Innovative Cellular Therapeutics Holdings, Ltd. Modified chimeric antigen receptor and use thereof
JP2023024168A (ja) * 2021-08-06 2023-02-16 国立大学法人 長崎大学 がんの治療剤
EP4384204A1 (en) 2021-08-13 2024-06-19 Cytune Pharma Il-2/il-15rbetagamma agonist combination with antibody-drug conjugates for treating cancer
CN115838424A (zh) * 2021-09-22 2023-03-24 上海康岱生物医药技术股份有限公司 靶向tigit的单克隆抗体
WO2023092006A1 (en) * 2021-11-17 2023-05-25 Good Therapeutics, Inc. Compositions of protein complexes and methods of use thereof
JP2025508823A (ja) 2022-02-23 2025-04-10 ブライト ピーク セラピューティクス エージー 免疫抗原特異的il-18免疫サイトカイン及びその使用
JP2025532554A (ja) * 2022-09-14 2025-10-01 メディシナ セラピューティクス インコーポレイテッド Il-2スーパーアンタゴニストコンストラクト、方法、及びそれらの使用
EP4638497A1 (en) * 2022-12-22 2025-10-29 Anaveon AG Il-2 fusion protein
EP4431525A1 (en) * 2023-03-16 2024-09-18 Anaveon AG Il-2 fusion protein
WO2024216089A1 (en) * 2023-04-13 2024-10-17 Bolt Biotherapeutics, Inc. Anti-dectin-2 antibody combination therapy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014500868A (ja) * 2010-11-12 2014-01-16 セントロ ド インムノロジア モレキュラー 癌及び慢性感染の治療のための作動薬活性を有するil−2由来のポリペプチド
US9428567B2 (en) * 2010-12-22 2016-08-30 The Board Of Trustees Of The Leland Stanford Junior University Antagonists of interleukin-2 receptor
CN106659757A (zh) * 2014-04-24 2017-05-10 利兰斯坦福初级大学董事会 白介素2的超级激动剂、部分激动剂和拮抗剂

Family Cites Families (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816249A (en) 1981-11-17 1989-03-28 The Board Of Trustees Of The Leland Stanford Junior University Monoclonal anti-idiotype antibodies
EP0091539B2 (en) 1982-03-31 1996-11-27 Ajinomoto Co., Inc. Gene coding for interleukin-2 polypeptide, recombinant DNA carrying said gene, cell lines possessing the recombinant DNA,and method for producing interleukin-2 using said cells
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5068177A (en) 1983-12-28 1991-11-26 Scripps Clinic And Research Foundation Anti-idiotype antibodies induced by synthetic polypeptides
US4604377A (en) 1984-03-28 1986-08-05 Cetus Corporation Pharmaceutical compositions of microbially produced interleukin-2
US4656132A (en) 1984-03-28 1987-04-07 Cetus Corporation Method of improving the yield of heterologous protein produced by cultivating recombinant bacteria
US4530787A (en) 1984-03-28 1985-07-23 Cetus Corporation Controlled oxidation of microbially produced cysteine-containing proteins
US4569790A (en) 1984-03-28 1986-02-11 Cetus Corporation Process for recovering microbially produced interleukin-2 and purified recombinant interleukin-2 compositions
US4572798A (en) 1984-12-06 1986-02-25 Cetus Corporation Method for promoting disulfide bond formation in recombinant proteins
US4748234A (en) 1985-06-26 1988-05-31 Cetus Corporation Process for recovering refractile bodies containing heterologous proteins from microbial hosts
GB8601597D0 (en) 1986-01-23 1986-02-26 Wilson R H Nucleotide sequences
US4931543A (en) 1987-05-11 1990-06-05 Cetus Corporation Process for recovering microbially produced interleukin-2
GB8809129D0 (en) 1988-04-18 1988-05-18 Celltech Ltd Recombinant dna methods vectors and host cells
US5227159A (en) 1989-01-31 1993-07-13 Miller Richard A Anti-idiotype antibodies reactive with shared idiotopes expressed by B cell lymphomas and autoantibodies
NZ234674A (en) 1989-08-02 1992-02-25 Seragen Inc Mutant interleukin-2,dna encoding it, host cells, cytotoxic and toxin-mutant il-2 conjugates
US5858784A (en) 1991-12-17 1999-01-12 The Regents Of The University Of California Expression of cloned genes in the lung by aerosol- and liposome-based delivery
IL104570A0 (en) 1992-03-18 1993-05-13 Yeda Res & Dev Chimeric genes and cells transformed therewith
DK0668777T3 (da) 1992-11-05 2007-02-19 Sloan Kettering Inst Cancer Prostataspecifikt membran-antigen
US5635599A (en) 1994-04-08 1997-06-03 The United States Of America As Represented By The Department Of Health And Human Services Fusion proteins comprising circularly permuted ligands
US6451308B1 (en) 1996-04-26 2002-09-17 Beth Israel Deaconess Medical Center Antagonists of interleukin-15
US5856445A (en) 1996-10-18 1999-01-05 Washington University Serine substituted mutants of BCL-XL /BCL-2 associated cell death regulator
US6645490B2 (en) 1998-03-02 2003-11-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Chimeric proteins with cell-targeting specificity and apoptosis-inducing activities
DZ2788A1 (fr) 1998-05-15 2003-12-01 Bayer Ag Agonistes et antagonistes selectifs à IL-2.
EE05627B1 (et) 1998-12-23 2013-02-15 Pfizer Inc. CTLA-4 vastased inimese monoklonaalsed antikehad
ATE316982T1 (de) 1999-08-09 2006-02-15 Lexigen Pharm Corp Mehrere zytokin-antikörper komplexen
US7605238B2 (en) 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
CN1371416B (zh) 1999-08-24 2012-10-10 梅达里克斯公司 人ctla-4抗体及其应用
US6399857B1 (en) * 1999-09-22 2002-06-04 Paradigm Genetics, Inc. Modified nucleotide sequence encoding a LexA DNA binding domain optimized for arabidopsis species
WO2001027156A1 (en) 1999-10-08 2001-04-19 Curagen Corporation Interleukin-2 like protein and nucleic acids encoding same
DK1230378T3 (da) 1999-11-15 2007-10-08 Onyx Pharma Inc Et onkolytisk adenovirus
AU2001233027A1 (en) 2000-01-27 2001-08-07 Genetics Institute, Llc Antibodies against ctla4 (cd152), conjugates comprising same, and uses thereof
US20030138405A1 (en) 2001-04-17 2003-07-24 Juan Fueyo Conditionally replicative adenovirus to target the Rb and Rb-related pathways
DK1454138T3 (da) 2001-12-04 2012-02-13 Merck Patent Gmbh Immunocytokiner med moduleret selektivitet
US6894527B1 (en) 2003-05-12 2005-05-17 Xilinx, Inc. Evolved circuits for bitstream protection
US7569215B2 (en) 2003-07-18 2009-08-04 Massachusetts Institute Of Technology Mutant interleukin-2 (IL-2) polypeptides
US7288638B2 (en) 2003-10-10 2007-10-30 Bristol-Myers Squibb Company Fully human antibodies against human 4-1BB
KR20070003934A (ko) 2004-03-05 2007-01-05 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 치료제의 환자 내약성을 예측하기 위한 시험관 내 테스트시스템
WO2005086922A2 (en) 2004-03-10 2005-09-22 Board Of Regents, University Of Texas System Oncolytic adenovirus armed with therapeutic genes
CN100361710C (zh) * 2004-06-07 2008-01-16 成都康弘生物科技有限公司 肿瘤细胞专一表达免疫调节因子gm-csf的溶瘤性腺病毒重组体的构建及其应用
TWI309240B (en) 2004-09-17 2009-05-01 Hoffmann La Roche Anti-ox40l antibodies
CA2595959A1 (en) 2005-01-27 2006-08-03 Novartis Vaccines And Diagnostics, Inc. Methods for treating renal cell carcinoma
EP1866339B8 (en) 2005-03-25 2021-12-01 GITR, Inc. Gitr binding molecules and uses therefor
EP2418278A3 (en) 2005-05-09 2012-07-04 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
KR101607288B1 (ko) 2005-07-01 2016-04-05 이. 알. 스퀴부 앤드 선즈, 엘.엘.씨. 예정 사멸 리간드 1 (피디-엘1)에 대한 인간 모노클로날 항체
JP5114418B2 (ja) 2005-09-09 2013-01-09 ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ・アズ リプレゼンテッド バイ ザ セクレタリー・デパートメント オブ ヘルス アンド ヒューマン サービシーズ 細胞死を抑制する又は細胞増殖を高めるための方法及び組成物
WO2009046104A1 (en) * 2007-10-01 2009-04-09 University Of Miami Aptamer-targeted sirna to prevent attenuation or suppression of t cell function
EP2057972A1 (en) 2007-11-07 2009-05-13 N.V. Organon Intrauterine deposit
AR072999A1 (es) 2008-08-11 2010-10-06 Medarex Inc Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos
US20110171219A1 (en) 2008-09-19 2011-07-14 Fahar Merchant Treating cancer stem cells using targeted cargo proteins
US20100183545A1 (en) 2008-10-14 2010-07-22 The United States Of America, As Represented By The Secretary, Targeted cargo protein combination therapy
TWI729512B (zh) 2008-12-09 2021-06-01 美商建南德克公司 抗pd-l1抗體及其於增進t細胞功能之用途
CA2749539C (en) 2009-01-21 2022-07-19 Amgen Inc. Compositions and methods comprising interleukin-2 mutants for treating inflammatory and autoimmune diseases
BRPI1008692B8 (pt) 2009-02-17 2021-05-25 Ucb Biopharma Sprl anticorpo antagonista tendo especificidade para ox40 humano, sequência de dna isolado, vetor de clonagem ou de expressão, célula hospedeira, processo para a produção do referido anticorpo, composição farmacêutica, uso do 5 referido anticorpo e proteína de fusão
CU23734A1 (es) 2009-11-27 2011-11-15 Centro Inmunologia Molecular Polipéptidos inmunomoduladores derivados de la il-2 con actividad antagonista de esta citocina útiles en la terapia del cáncer y enfermedades infecciosas crónicas
NZ705128A (en) 2010-03-04 2015-04-24 Macrogenics Inc Antibodies reactive with b7-h3, immunologically active fragments thereof and uses thereof
US20120213771A1 (en) 2010-04-13 2012-08-23 Celldex Therapeutics Inc. Antibodies that bind human cd27 and uses thereof
BR112012026227A2 (pt) 2010-04-13 2020-08-04 Celldex Therapeutics, Inc. anticorpo monoclonal humano ou humanizado, molécula biespecífica, vetor de expressão, célula transformada, composição, e, usos de um anticorpo
SG10201912092VA (en) 2010-09-09 2020-02-27 Pfizer 4-1bb binding molecules
US8962804B2 (en) 2010-10-08 2015-02-24 City Of Hope Meditopes and meditope-binding antibodies and uses thereof
WO2012054929A2 (en) 2010-10-22 2012-04-26 Protox Therapeutics Corp. Use of human serum albumin to decrease antigenicity of therapeutic proteins
WO2012119093A1 (en) 2011-03-03 2012-09-07 Board Of Trustees Of The Leland Stanford Junior University Superagonists and antagonists of interleukin-2
GB201103955D0 (en) 2011-03-09 2011-04-20 Antitope Ltd Antibodies
WO2013006490A2 (en) 2011-07-01 2013-01-10 Cellerant Therapeutics, Inc. Antibodies that specifically bind to tim3
FI20115914L (fi) 2011-09-16 2013-03-17 Oncos Therapeutics Ltd Muunnettu onkolyyttinen virus
KR101981873B1 (ko) 2011-11-28 2019-05-23 메르크 파텐트 게엠베하 항-pd-l1 항체 및 그의 용도
US20150250837A1 (en) * 2012-09-20 2015-09-10 Morningside Technology Ventures Ltd. Oncolytic virus encoding pd-1 binding agents and uses of the same
US9810692B2 (en) * 2012-10-26 2017-11-07 Institut Gustave Roussy Methods for predicting the sensitivity of a subject to immunotherapy
DK2956175T3 (da) 2013-02-15 2017-11-27 Univ California Kimærisk antigenreceptor og fremgangsmåder til anvendelse deraf
RU2702108C2 (ru) 2013-07-16 2019-10-04 Дженентек, Инк. Способы лечения рака с использованием антагонистов, связывающих с осью pd-1, и ингибиторов tigit
CA2925421C (en) * 2013-09-24 2023-08-29 Medicenna Therapeutics, Inc. Interleukin-2 fusion proteins and uses thereof
US10711272B2 (en) * 2014-01-21 2020-07-14 City Of Hope CTLA-4 aptamer siRNA species
MX379210B (es) 2014-02-07 2025-03-10 Univ Mcmaster Acoplador trifuncional de antígeno de células t y métodos y usos del mismo.
HRP20210377T1 (hr) * 2014-02-21 2021-04-16 Nektar Therapeutics Il-2rbeta-selektivni agonisti u kombinaciji s anti-ctla-4 protutijelom ili anti-pd-1 protutijelom
DK3186283T3 (da) * 2014-08-29 2020-03-02 Hoffmann La Roche Kombinationsbehandling med tumormålrettede IL-2- immuncytokinervarianter og antistoffer mod humant PD-L1
ES2966099T3 (es) * 2014-12-05 2024-04-18 Memorial Sloan Kettering Cancer Center Receptores de antígeno quiméricos dirigidos al antígeno de maduración de células B y usos de los mismos
JP2018510151A (ja) 2015-03-06 2018-04-12 ソレント・セラピューティクス・インコーポレイテッド Tim3に結合する抗体医薬
US20180044429A1 (en) 2015-03-09 2018-02-15 Celldex Therapeutics, Inc. Cd27 agonists
CN107406859A (zh) * 2015-03-17 2017-11-28 倾斜生物医疗公司 编码双特异性抗体的溶瘤腺病毒及与其相关的方法和用途
EP3288568A4 (en) * 2015-04-30 2019-01-02 University of Southern California Secretory tnt car cell immunotherapy
CN107949573B (zh) 2015-09-01 2022-05-03 艾吉纳斯公司 抗-pd-1抗体及其使用方法
EP3387155A4 (en) 2015-12-10 2019-06-12 Definiens AG METHOD FOR THE TREATMENT AND SELECTION OF PATIENTS THAT APPLY TO IMMUNE-ACTED CANCER THERAPY
IL261188B (en) 2016-03-04 2022-08-01 Jn Biosciences Llc An anti-tigit antibody that binds to the tigit polypeptide on one or more amino acid residues
US11542312B2 (en) 2017-06-19 2023-01-03 Medicenna Therapeutics, Inc. IL-2 superagonists in combination with anti-PD-1 antibodies
US10849960B2 (en) 2017-09-08 2020-12-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Synergistic combination of IL-4, interferon gamma, and interferon alpha in treating ovarian cancer
WO2019239213A2 (en) 2018-06-01 2019-12-19 Medicenna Therapeutics Inc. Uses and methods for oncolytic virus targeting of il-4/il-13 and fusions thereof
CA3102097A1 (en) 2018-06-01 2019-12-05 The Board Of Trustees Of The Leland Stanford Junior Unversity Il-13/il-4 superkines: immune cell targeting constructs and methods of use thereof
AU2019343251B2 (en) 2018-09-21 2022-06-09 Innovent Biologics (Suzhou) Co., Ltd. Novel interleukin 2 and use thereof
CN113728232A (zh) 2019-02-07 2021-11-30 梅迪塞纳医疗股份有限公司 作为癌症中的生物标志物的il-4r
EP4225377A4 (en) 2020-10-12 2024-11-27 Medicenna Therapeutics, Inc. COMBINATION THERAPY WITH MDNS55 AND A VASCULAR ENDOTHELIAL GROWTH FACTOR A (VEGF-A)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014500868A (ja) * 2010-11-12 2014-01-16 セントロ ド インムノロジア モレキュラー 癌及び慢性感染の治療のための作動薬活性を有するil−2由来のポリペプチド
US9428567B2 (en) * 2010-12-22 2016-08-30 The Board Of Trustees Of The Leland Stanford Junior University Antagonists of interleukin-2 receptor
US20170015722A1 (en) * 2010-12-22 2017-01-19 The Board of Trustees of the Leland Stanford Junior University, Office of the General Counsel Superagonists and antagonists of interleukin-2
CN106659757A (zh) * 2014-04-24 2017-05-10 利兰斯坦福初级大学董事会 白介素2的超级激动剂、部分激动剂和拮抗剂

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ARON M. LEVIN ET AL.: ""Exploiting a natural conformational switch to engineer an Interleukin-2 superkine"" *
S-M. HUANG ET AL.: ""IL-2 synergizes with PD-1/PD-L1 blockade via CD28/CHK1 pathway to enhance CD81 T cell responses in lung squamous cell carcinoma"" *
TANIA CARMENATE ET AL.: ""Human IL-2 Mutein with Higher Antitumor Efficacy Than Wild Type IL-2"" *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115768788A (zh) * 2020-07-09 2023-03-07 Eutilex股份有限公司 Il-2变体
TWI817159B (zh) * 2020-07-14 2023-10-01 美商輝瑞大藥廠 重組牛痘病毒
WO2025055790A1 (zh) * 2023-09-14 2025-03-20 重庆精准生物技术有限公司 细胞因子融合蛋白及其应用

Also Published As

Publication number Publication date
JP7747716B2 (ja) 2025-10-01
US20190062395A1 (en) 2019-02-28
WO2018234862A1 (en) 2018-12-27
AU2018287317B2 (en) 2024-06-20
JP2020524174A (ja) 2020-08-13
US20230080403A1 (en) 2023-03-16
EP3641814A1 (en) 2020-04-29
US12338269B2 (en) 2025-06-24
JP2024028986A (ja) 2024-03-05
US11542312B2 (en) 2023-01-03
AU2018287317A1 (en) 2020-02-06
JP7433051B2 (ja) 2024-02-19
AU2024219911A1 (en) 2024-10-10
EP3641814A4 (en) 2021-06-23
CA3067909A1 (en) 2018-12-27

Similar Documents

Publication Publication Date Title
US12338269B2 (en) IL-2 superagonists in combination with anti-PD-1 antibodies
US20230365642A1 (en) Bifunctional superkines and uses thereof
WO2010030002A1 (ja) 外来性gitrリガンド発現細胞
US12331079B2 (en) Oncolytic virus platform to treat cancers with myxoma virus
KR102056066B1 (ko) 세포외 기질 분해 인자를 발현하는 재조합 아데노바이러스를 포함하는 항암용 조성물
US20240092852A1 (en) Multi-armed myxoma virus
CN114657150A (zh) 用于改善免疫疗法的重组溶瘤腺病毒及其应用
US20250387474A1 (en) Uses and methods for il-2, il-13, and il-4 cytokine bifunctional molecules
CN116254230A (zh) 用于制备和扩增通用型人源化抗cd19 car-nk细胞的方法及其用途
CN119156405A (zh) Il-2、il-13和il-4细胞因子双功能性分子的用途和方法
CN114716564B (zh) 基于sectm1构建的嵌合抗原受体免疫细胞制备及其应用
CN119923267A (zh) 表达白介素-12的重组病毒与pd-1/pd-l1抑制剂的组合
CN115477705A (zh) 一种基于颗粒酶b构建的嵌合抗原受体免疫细胞制备及其应用
HK1230236A1 (en) Adenovirus expressing immune cell stimulatory receptor agonist(s)

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination