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WO2025140478A1 - Utilisation d'un anticorps bispécifique anti-pd-l1/cd47 en polythérapie - Google Patents

Utilisation d'un anticorps bispécifique anti-pd-l1/cd47 en polythérapie Download PDF

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Publication number
WO2025140478A1
WO2025140478A1 PCT/CN2024/142981 CN2024142981W WO2025140478A1 WO 2025140478 A1 WO2025140478 A1 WO 2025140478A1 CN 2024142981 W CN2024142981 W CN 2024142981W WO 2025140478 A1 WO2025140478 A1 WO 2025140478A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
acid sequence
seq
antibody
antigen
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Pending
Application number
PCT/CN2024/142981
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English (en)
Chinese (zh)
Inventor
张鑫朗
符子艺
巢传琦
陈奕藩
苏紫琪
秦超
宋述强
俞金泉
李胜峰
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Bio Thera Solutions Ltd
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Bio Thera Solutions Ltd
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Publication of WO2025140478A1 publication Critical patent/WO2025140478A1/fr
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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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to the application of anti-PD-L1/CD47 bispecific antibodies in combined medication.
  • Bispecific antibodies can simultaneously bind to two antigens or two different epitopes of an antigen, block or activate different signaling pathways, and more effectively mediate the killing of tumor cells by immune cells, so it may achieve better therapeutic effects.
  • variable region a comprises VHa and VLa; the variable region b comprises VHb and VLb; the VHa comprises the amino acid sequence shown in SEQ ID NO:10, the VHb comprises the amino acid sequence shown in SEQ ID NO:11, and the VLa and VLb both comprise the amino acid sequence shown in SEQ ID NO:12.
  • the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment further comprises a heavy chain constant region a (CHa), a light chain constant region a (CLa), a heavy chain constant region b (CHb) and a light chain constant region b (CLb).
  • CHa heavy chain constant region a
  • CLa light chain constant region a
  • CHb heavy chain constant region b
  • CLb light chain constant region b
  • the CHa is of IgG1 subtype. In some embodiments, the CHb is of IgG1 subtype.
  • the CHa and/or CHb comprises one or more of the following amino acid mutations: Y349C, S354C, T366W, T366S, L368A, and Y407V, wherein the amino acid positions are numbered according to Eu.
  • the CHa and/or CHb comprises the following amino acid mutation: N297A, wherein the amino acid positions are numbered according to Eu.
  • one of the heavy chain constant regions of CHa and CHb comprises one or more of the following amino acid mutations: N297A, Y349C, T366S, L368A and Y407V, wherein the amino acid positions are numbered in Eu.
  • the other of the heavy chain constant regions of CHa and CHb comprises one or more of the following amino acid mutations: N297A, S354C and T366W, wherein the amino acid positions are numbered in Eu.
  • the CHa comprises the amino acid sequence shown in SEQ ID NO:13 or 15, or an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO:13 or 15, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:13 or 15;
  • the CHb comprises the amino acid sequence shown in SEQ ID NO:13 or 15, or an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO:13 or 15, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:13 or 15.
  • the CHa comprises the amino acid sequence shown in SEQ ID NO: 13
  • the CHb comprises the amino acid sequence shown in SEQ ID NO: 15.
  • the CHa comprises the amino acid sequence shown in SEQ ID NO: 15
  • the CHb comprises the amino acid sequence shown in SEQ ID NO: 13.
  • the CLa or CLb comprises the amino acid sequence shown in SEQ ID NO:14, or an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO:14, or an amino acid sequence having one or more conservative amino acid substitutions with the amino acid sequence shown in SEQ ID NO:14.
  • both CLa and CLb contain the amino acid sequence shown in SEQ ID NO:14.
  • the anti-PD-L1/CD47 bispecific antibody comprises heavy chain a, heavy chain b, light chain a, and light chain b.
  • the heavy chain a comprises the amino acid sequence shown in SEQ ID NO:16, or an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO:16, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:16;
  • the heavy chain b comprises the amino acid sequence shown in SEQ ID NO:17, or an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO:17, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:17.
  • the light chain a and light chain b comprise the same amino acid sequence.
  • the light chain a or light chain b comprises the amino acid sequence shown in SEQ ID NO: 18, or an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 18, or an amino acid sequence having one or more conservative amino acid substitutions with the amino acid sequence shown in SEQ ID NO: 18.
  • the anti-PD-L1/CD47 bispecific antibody comprises the heavy chain a shown in SEQ ID NO:16, the heavy chain b shown in SEQ ID NO:17, and the light chain a and light chain b shown in SEQ ID NO:18.
  • the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention to PD-L1 is ⁇ 10nM. In some embodiments, the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention to PD-L1 is ⁇ 1nM. In some embodiments, the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention to PD-L1 is ⁇ 0.5nM. In some embodiments, the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention to PD-L1 is ⁇ 0.2nM.
  • the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention to CD47 is ⁇ 100nM. In some embodiments, the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention to CD47 is ⁇ 30nM. In some embodiments, the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention has an affinity index KD ⁇ 10nM for CD47. In some embodiments, the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention has an affinity index KD ⁇ 5nM for CD47.
  • the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention has an affinity index KD ⁇ 4nM for CD47. In some embodiments, the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment provided by the present invention has an affinity for PD-L1 greater than the affinity for CD47.
  • the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment to PD-L1 is ⁇ 1 nM
  • the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment to CD47 is ⁇ 30 nM.
  • the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment to PD-L1 is ⁇ 1 nM
  • the affinity index KD of the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment to CD47 is ⁇ 10 nM.
  • the anti-PD-L1/CD47 bispecific antibody is antibody BsAb-71-N297A, comprising heavy chain a shown in SEQ ID NO:16, heavy chain b shown in SEQ ID NO:17, and light chain a and light chain b shown in SEQ ID NO:18.
  • the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment is expressed by CHO cells.
  • the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment can also be expressed by other cells (e.g., HEK cells (such as HEK293F cells), BHK cells, Cos1 cells, Cos7 cells, CV1 cells, or mouse L cells).
  • the anti-PD-L1/CD47 bispecific antibody or antigen-binding fragment is selected from the bispecific antibodies or antigen-binding fragments disclosed in patent WO2022095970A.
  • the anti-CTLA-4 antibody is selected from tremelimumab ( or its biosimilars), ipilimumab ( or their biosimilars), antibodies huC1D1-V1 to huC1D1-V12, huD1D5-V1 to huD1D5-V12 in patent CN115443291A, antibody 1, antibody 1-1, antibody 1-2, antibody 2, antibody 2-1 to 2-6 in patent CN113490687A, antibodies BA-087-05-19, BA-087-08-32 in patent CN112996813A, antibodies AH01672, AH01674, AH01679, AH01686, AH01695, AH01696, AH01704 in patent CN115850475A.
  • the anti-CTLA-4 antibody or antigen-binding fragment comprises one or more amino acid sequences of (1)-(6):
  • VH CDR1 comprising the amino acid sequence shown in SEQ ID NO: 19, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO: 19;
  • VH CDR2 which comprises the amino acid sequence shown in SEQ ID NO: 20, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO: 20;
  • VH CDR3 comprising the amino acid sequence shown in SEQ ID NO:21, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:21;
  • VL CDR2 which comprises the amino acid sequence shown in SEQ ID NO: 23, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO: 23;
  • VL CDR3 which comprises the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having one or more conservative amino acid substitutions compared to the amino acid sequence shown in SEQ ID NO:24.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne l'utilisation d'un anticorps bispécifique anti-PD-L1/CD47 en polythérapie, comprenant l'administration d'une quantité efficace de l'anticorps bispécifique anti-PD-L1/CD47 et d'un anticorps anti-CTLA-4 à un patient en ayant besoin.
PCT/CN2024/142981 2023-12-29 2024-12-27 Utilisation d'un anticorps bispécifique anti-pd-l1/cd47 en polythérapie Pending WO2025140478A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202311861904 2023-12-29
CN202311861904.9 2023-12-29

Publications (1)

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WO2025140478A1 true WO2025140478A1 (fr) 2025-07-03

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PCT/CN2024/142981 Pending WO2025140478A1 (fr) 2023-12-29 2024-12-27 Utilisation d'un anticorps bispécifique anti-pd-l1/cd47 en polythérapie

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473578A (zh) * 2015-12-22 2018-08-31 瑞泽恩制药公司 治疗癌症的抗pd-1抗体和双特异性抗cd20/抗cd3抗体组合
CN111133004A (zh) * 2017-07-27 2020-05-08 瑞泽恩制药公司 抗ctla-4抗体和其用途
CN111801352A (zh) * 2017-10-03 2020-10-20 拜奥卡德联合股份公司 对cd47和pd-l1特异性的抗体
CN113372449A (zh) * 2020-03-10 2021-09-10 中国科学院微生物研究所 一种非红细胞凝集的抗pd-l1/cd47双特异抗体及其在抗肿瘤治疗中的应用
CN114437227A (zh) * 2020-11-06 2022-05-06 百奥泰生物制药股份有限公司 双特异抗体及其应用
CN114793422A (zh) * 2019-12-25 2022-07-26 百奥泰生物制药股份有限公司 抗ctla-4单克隆抗体及其制备方法与应用
CN115397853A (zh) * 2019-12-17 2022-11-25 辉瑞大药厂 对cd47、pd-l1具特异性的抗体及其用途
CN115702931A (zh) * 2021-08-06 2023-02-17 百奥泰生物制药股份有限公司 抗pd-l1/cd47双特异抗体在治疗疾病中的应用
CN116917322A (zh) * 2021-02-19 2023-10-20 沙裴隆有限公司 针对pd-l1及cd47的双特异性单域抗体及其用途
WO2023224412A1 (fr) * 2022-05-19 2023-11-23 (주)샤페론 Anticorps bispécifique à domaine unique humanisé dirigé contre pd-l1 et cd47 et son utilisation
CN117279948A (zh) * 2021-05-07 2023-12-22 益免安协公司 与cd47和pd-l1特异性结合的双特异性抗体

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473578A (zh) * 2015-12-22 2018-08-31 瑞泽恩制药公司 治疗癌症的抗pd-1抗体和双特异性抗cd20/抗cd3抗体组合
CN111133004A (zh) * 2017-07-27 2020-05-08 瑞泽恩制药公司 抗ctla-4抗体和其用途
CN111801352A (zh) * 2017-10-03 2020-10-20 拜奥卡德联合股份公司 对cd47和pd-l1特异性的抗体
CN115397853A (zh) * 2019-12-17 2022-11-25 辉瑞大药厂 对cd47、pd-l1具特异性的抗体及其用途
CN114793422A (zh) * 2019-12-25 2022-07-26 百奥泰生物制药股份有限公司 抗ctla-4单克隆抗体及其制备方法与应用
CN113372449A (zh) * 2020-03-10 2021-09-10 中国科学院微生物研究所 一种非红细胞凝集的抗pd-l1/cd47双特异抗体及其在抗肿瘤治疗中的应用
CN114437227A (zh) * 2020-11-06 2022-05-06 百奥泰生物制药股份有限公司 双特异抗体及其应用
CN116917322A (zh) * 2021-02-19 2023-10-20 沙裴隆有限公司 针对pd-l1及cd47的双特异性单域抗体及其用途
CN117279948A (zh) * 2021-05-07 2023-12-22 益免安协公司 与cd47和pd-l1特异性结合的双特异性抗体
CN115702931A (zh) * 2021-08-06 2023-02-17 百奥泰生物制药股份有限公司 抗pd-l1/cd47双特异抗体在治疗疾病中的应用
WO2023224412A1 (fr) * 2022-05-19 2023-11-23 (주)샤페론 Anticorps bispécifique à domaine unique humanisé dirigé contre pd-l1 et cd47 et son utilisation

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