WO2024061272A1 - Anticorps anti-pd-l1 et son utilisation - Google Patents

Anticorps anti-pd-l1 et son utilisation Download PDF

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WO2024061272A1
WO2024061272A1 PCT/CN2023/120060 CN2023120060W WO2024061272A1 WO 2024061272 A1 WO2024061272 A1 WO 2024061272A1 CN 2023120060 W CN2023120060 W CN 2023120060W WO 2024061272 A1 WO2024061272 A1 WO 2024061272A1
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antibody
cancer
antigen
binding fragment
cells
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PCT/CN2023/120060
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English (en)
Chinese (zh)
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闫鑫甜
郎国竣
李双琦
方小鹏
孔超
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三优生物医药(上海)有限公司
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Publication of WO2024061272A1 publication Critical patent/WO2024061272A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione

Definitions

  • the invention belongs to the field of biomedicine.
  • the present invention relates to anti-PD-L1 antibodies and uses thereof.
  • Antigen presenting cells recognize the antigen peptide MHC I/II complex through the T cell receptor (TCR) and initiate T cell-mediated immunity.
  • TCR T cell receptor
  • a variety of costimulatory and inhibitory signals mediated by the interaction between APC and different T cell surface molecules trigger T cell activation and proliferation and ultimately trigger their inhibition.
  • Programmed death-1 (PD-1) is an inhibitory member of the extended CD28/CTLA-4 family of T cell regulators, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA.
  • the original members of this family, CD28 and ICOS were discovered by adding monoclonal antibodies to enhance T cell proliferation.
  • Two cell surface glycoprotein ligands of PD-1 have been identified, PD-L1 and PD-L2.
  • PD-L1 and PD-L2 are both B7 homologues that bind PD-1 but not other CD28 family members.
  • PD-L1 (also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)) is a 40 kDa type I transmembrane protein. PD-L1 binds to the receptor PD-1 present on activated T cells, B cells, and myeloid cells to regulate activation or inhibition. PD-L1 is expressed in the placenta, spleen, lymph nodes, thymus, heart, fetal liver, and is also found in many tumors or cancer cells. Binding of PD-L1 and its receptor induces signaling to inhibit TCR-mediated activation of cytokine production and T cell proliferation. Thus, PD-L1 plays a major role in suppressing the immune system during certain events (e.g., pregnancy, autoimmune diseases, tissue allografts) and is thought to allow tumors or cancer cells to bypass immune checkpoints and evade immune responses.
  • CD274 cluster of differentiation 274
  • B7-H1 B7 homolog 1
  • One aspect of the present invention provides an antibody against PD-L1 (PD-L1 antibody) or an antigen-binding fragment thereof, which specifically recognizes and binds to PD-L1, wherein the antibody or antigen thereof
  • the binding fragment comprises a single variable domain of an immunoglobulin, wherein the single variable domain comprises:
  • CDR3 which comprises the amino acid sequence shown in SEQ ID NO:3.
  • the single variable domain comprises the amino acid sequence set forth in SEQ ID NO:4 or is identical to SEQ ID NO:4 ID NO:4 has an amino acid sequence that has at least 85%, at least 90%, at least 95% or greater sequence identity.
  • the antibody or antigen-binding fragment thereof is a single domain antibody, a heavy chain antibody, a humanized antibody, or a chimeric antibody.
  • the antibody or antigen-binding fragment thereof further comprises an Fc fragment of human IgG1.
  • the antibody or antigen-binding fragment thereof comprises the amino acid sequence shown in SEQ ID NO:5 or has at least 85%, at least 90%, at least 95% or higher sequence identity with SEQ ID NO:5 sexual amino acid sequence.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody of the present invention or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides use of the antibody or antigen-binding fragment thereof of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer.
  • the invention provides a method of treating cancer, comprising administering an antibody of the invention or an antigen-binding fragment thereof or a pharmaceutical composition of the invention to a subject in need thereof.
  • the invention relates to the antibody of the invention or the antigen-binding fragment thereof or the pharmaceutical composition of the invention for use in the treatment of cancer.
  • the invention also provides an isolated nucleic acid molecule encoding an anti-PD-L1 antibody of the invention or an antigen-binding fragment thereof.
  • the invention also relates to expression vectors comprising the nucleic acid molecules of the invention.
  • the invention also relates to host cells comprising the nucleic acid molecules or expression vectors of the invention.
  • the invention also relates to a method of producing an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • Figures 1A and 1B show the results of FACS detection of the binding activity of anti-PD-L1 antibody m18 to human PD-L1-CHO cells overexpressing cell lines and PD-L1-positive cells HCC827 cells.
  • Figure 1A shows the results of binding activity to human PD-L1-CHO cells.
  • Figure 1B shows the results of binding activity to HCC827 cells.
  • Figures 2A and 2B show the results of using FACS to detect the binding activity of anti-PD-L1 antibody m18 to overexpression cell lines of different species.
  • Figure 2A shows the results of binding activity to mouse PD-L1-CHO cells.
  • Figure 2B shows the results of binding activity to cynomolgus monkey PD-L1-CHO cells.
  • Figure 3 shows the results of using ELISA to detect the specific binding activity of anti-PD-L1 antibody m18 to B7-H1 and cognate proteins.
  • Figure 4 shows the anti-tumor effect of anti-PD-L1 antibody m18 in the MC38 mouse tumor model.
  • Figure 5 shows the body weight changes of the MC38 mouse tumor model during the experiment.
  • At least one or “one or more” may mean 1, 2, 3, 4, 5, 6, 7, 8 or more ( kind).
  • the expressions “comprises,” “comprises,” “contains,” and “having” are open-ended and mean the inclusion of recited elements, steps or components but not the exclusion of other unrecited elements, steps or components.
  • the expression “consisting of” does not include any element, step or component not specified.
  • the expression “consisting essentially of” means that the scope is limited to the specified elements, steps or components plus the optional presence of elements, steps or components that do not materially affect the basic and novel properties of the claimed subject matter. It will be understood that the expressions “consisting essentially of” and “consisting of” are encompassed within the meaning of the expression “including”.
  • the conjunctive term "and/or” between multiple recited elements is to be understood to include both individual and combined options.
  • “and/or” includes “and” and “or.”
  • a and/or B includes A, B, and A+B.
  • A, B and/or C include A, B, C and any combination thereof, such as A+B, A+C, B+C and A+B+C.
  • Further elements qualified by “and/or” are to be understood in a similar manner and include any one and any combination thereof.
  • any numerical value or range of values such as a concentration or range of concentrations, is to be understood in all cases as modified by the term "about.” Therefore, numerical values generally include ⁇ 10% of the stated value. For example, a concentration of 1 mg/mL includes 0.9 mg/mL to 1.1 mg/mL. Likewise, the concentration range of 1% to 10% (w/v) includes 0.9% (w/v) to 11% (w/v). As used herein, the use of a numerical range expressly includes all possible subranges and all individual values within the range, including integers and fractions within the range, unless the context clearly indicates otherwise.
  • immunoglobulin single variable domain or “single variable domain” refers to a single variable region (variable domain) having antigen-binding activity. Different from the functional antigen-binding unit composed of a pair of VH and VL in conventional antibodies, a single variable domain can form a functional antigen-binding unit alone. Single variable domains can be derived from naturally occurring light chain-less antibodies, such as the variable domain of heavy chain of heavy-chain antibodies (VHH) of camelids (such as camels and alpacas).
  • VHH variable domain of heavy chain of heavy-chain antibodies
  • the single variable domain (IgNAR variable single-domain, VNAR) of shark neoantigen receptors can also be screened from full-length antibodies, such as the light chain variable domain and heavy chain variable domain with antigen-binding activity in human antibodies.
  • VHH usually contains three highly variable "Complementarity Determining Regions (CDR)” and four relatively conserved “Framework Regions (FR)", and is organized from N-terminus to C-terminus in the order of FR1-CDR1-FR2-CDR2-FR3-CDR3 -FR4 sequential connection.
  • CDR Complementarity Determining Regions
  • FR Framework Regions
  • single domain antibody refers to an antibody that contains a single immunoglobulin variable domain (single variable domain) as a functional antigen-binding fragment. Similar to the variable regions of full-length antibodies, single variable domains typically contain CDR1, CDR2, and CDR3 that form the antigen-binding site and a supporting framework. district. Unlike full-length antibodies, which typically contain two heavy chains and two light chains, single-domain antibodies typically contain a single peptide chain consisting of a single variable domain with a molecular weight of only about 15 kDa.
  • the single variable domain may be, for example, the variable domain of heavy-chain antibody (VHH) of alpaca, the IgNAR variable domain of shark, or the variable domain of human light chain antibody.
  • heavy-chain-only antibody and “heavy-chain antibody” are used interchangeably and in their broadest sense, referring to the absence of A conventional antibody light chain antibody that contains only a VHH and a heavy chain constant region (e.g., Fc fragment) that does not contain CH1.
  • Fc fragment generally refers to a crystallizable fragment of a conventional antibody or heavy chain antibody digested with papain.
  • the Fc fragment of IgG and heavy chain antibodies may contain part of the hinge region, CH2, and CH3.
  • the Fc fragment may comprise at least part of the hinge region (eg all or part of the hinge region), CH2 and CH3.
  • variable region i.e., "binding domain” allows the binding molecule to selectively recognize an epitope on an antigen and specifically bind to the epitope. That is, the VL domain and the VH domain of the binding molecule of an antibody, or these complementary determining regions (CDR) subgroups combine to form a variable region that determines a three-dimensional antigen binding site. More specifically, the antigen binding site is determined by three CDRs on each VH and VL chain.
  • CDR complementary determining regions
  • the remaining amino acids in the binding domain are called "framework (FR)" regions, which show smaller intermolecular differences.
  • the binding domain formed by the positioned CDRs determines a surface that is complementary to an epitope on an immunoreactive antigen. This complementary surface promotes the non-covalent binding of an antibody to its complementary epitope.
  • the amino acids that make up the CDRs and framework regions, respectively, in any given heavy or light chain variable region can be identified by conventional methods (see, "Sequences of Proteins of Immunological Interest", Kabat, E. et al., U.S. Department of Health and Human Services, (1983); and Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987), which are incorporated herein by reference in their entireties).
  • the CDRs of a single variable domain of an immunoglobulin may be referred to as CDR1, CDR2, and CDR3.
  • the amino acid sequences of CDRs are all shown in accordance with the AbM definition rules (the claims of the present invention are also sequences shown in accordance with the AbM definition rules).
  • the CDRs of an antibody can be defined by a variety of methods in the art, such as Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loops (see, e.g., Chothia, C. et al., Nature, 342,877 -883 (1989); and Al-Lazikani, B. et al., J. Mol.
  • the scope of said antibody also encompasses antibodies whose variable region sequences comprise said specific CDR sequence but which differ due to the application of different protocols (e.g. Different assignment system rules or combinations) cause the claimed CDR boundaries to be different from the specific CDR boundaries defined in the present invention.
  • framework region and “framework region” may be used interchangeably.
  • framework region refers to those amino acid residues in an antibody variable region other than the CDR sequences as defined above.
  • hinge region includes the portion of the heavy chain molecule connecting the CH1 domain and the CH2 domain.
  • the hinge region contains approximately 25 amino acids and is flexible, thus allowing the two N-terminal antigen-binding regions to move independently.
  • disulfide bond includes a covalent bond formed between two sulfur atoms.
  • the amino acid cysteine contains a thiol group that can form a disulfide bond or bridge a second thiol group.
  • chimeric antibody refers to an antibody in which the immunoreactive region or site is obtained or derived from a first species and the constant region (which may be intact, partial or modified) is obtained from a second species .
  • the target binding region or site will be from a non-human source (eg, mouse or primate) and the constant region is human.
  • humanized antibody refers to an antibody in which a non-human antibody has been modified to increase sequence homology with a human antibody.
  • Humanized antibodies generally retain the antigen-binding capabilities of the non-human antibodies from which they are derived and are less immunogenic in humans.
  • Humanized antibodies can be obtained by antibody engineering of any non-human species antibody or an antibody containing sequences derived from a non-human species (eg, a chimeric antibody).
  • Non-human species may include, for example, mice, rats, rabbits, alpacas, sharks, or non-human primates. Techniques for obtaining humanized antibodies from non-human antibodies are well known to those skilled in the art.
  • the CDR sequences of a non-human antibody are grafted into the human antibody framework region.
  • the key amino acid residues of the framework sequence of the non-human antibody can be retained in the human antibody framework region, that is, " "Reverse mutation” (see, e.g., Morrison et al. (1984) Proc. Natl. Acad. Sci. 81 (21): 6851-6855; Neuberger et al. (1984) Nature 312: 604-608).
  • human antibody refers to an antibody produced by a human or prepared using any technique known in the art An antibody having an amino acid sequence corresponding to an antibody produced by a human.
  • the definition of human antibodies encompasses intact or full-length antibodies, fragments thereof and/or antibodies comprising at least one human heavy chain and/or light chain polypeptide.
  • an "affinity matured" antibody contains one or more modifications (e.g., substitutions of amino acid residues) in one or more CDRs such that the affinity matured antibody is less effective than a parent antibody that does not contain such modifications.
  • the affinity of the antigen is improved.
  • Methods for affinity maturation of antibodies are known in the art, see, e.g., Marks et al., Bio/Technology 10:779-783 (1992); Barbas et al., Proc. Nat. Acad. Sci. USA 91:3809 -3813 (1994); Scier et al., Gene 169:147-155 (1995); and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).
  • percent (%) sequence identity or “sequence identity” of an amino acid sequence has art-accepted definitions and refers to two amino acid sequences determined by sequence alignment (eg, by manual inspection or a publicly known algorithm). The percentage of identity between peptide sequences. This can be determined using methods known to those skilled in the art, for example using publicly available computer software such as BLAST, BLAST-2, Clustal Omega and FASTA software.
  • an amino acid sequence "derived from” or “derived from” a reference amino acid sequence is identical or homologous to part or all of the reference amino acid sequence.
  • the amino acid sequence derived from a heavy chain constant region of a human immunoglobulin may be at least 80%, at least 85%, at least 90%, at least 91% identical to the wild-type sequence of the human immunoglobulin heavy chain constant region from which it is derived. , at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity.
  • Avidity or “binding affinity” is a measure of how strongly an antibody and antigen bind to each other through non-covalent interactions. Affinity can be measured using conventional techniques known in the art, such as biofilm interference techniques (for example, the Octet Fortebio detection system can be used), radioimmunoassay, surface plasmon resonance, enzyme-linked immunoassay (ELISA) or flow cytometry (FACS). )wait.
  • biofilm interference techniques for example, the Octet Fortebio detection system can be used
  • radioimmunoassay for example, the Octet Fortebio detection system can be used
  • ELISA enzyme-linked immunoassay
  • FACS flow cytometry
  • binds generally means that a binding molecule, such as an antibody or fragment, variant or derivative thereof, binds an epitope through its antigen-binding domain and that binding requires some complementarity between the antigen-binding domain and the epitope.
  • a binding molecule is said to "specifically bind” an epitope when it binds to an epitope through its antigen-binding domain more readily than it binds to a random, unrelated epitope.
  • the term “specificity” is used herein to qualitatively analyze the relative affinity of an antibody for binding to a certain epitope.
  • binding molecule "A” can be said to have higher specificity for a given epitope than binding molecule "B”, or it can be said that binding molecule "A” has higher specificity for a related epitope “D” Specific binding epitope "C”.
  • a binding molecule such as an antibody or a fragment, variant or derivative thereof, is said to preferentially bind to an epitope if it preferentially binds to that epitope to an extent that blocks the binding of the reference antibody or antigen-binding fragment to that epitope.
  • an antibody or fragment, variant or derivative thereof competitively inhibits the binding of a reference antibody or antigen-binding fragment to a given epitope.
  • Competitive inhibition can be determined by any method known in the art, for example, a competition ELISA assay. It can be said that the binding molecule competitively inhibits at least 90%, at least 80%, at least 70%, at least 60%, or at least 50% of the binding of the reference antibody or antigen-binding fragment to a given epitope.
  • PD-L1 refers to programmed cell death ligand 1 (PD-L1, see e.g. Freeman et al. al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000 Oct 2; 192(7)).
  • PD-L1 belongs to the B7 family.
  • Alternative names or synonyms for PD-L1 include PDCD1L1, PDL1, B7 homolog 1 (B7-H1), surface antigen cluster of differentiation 274 (CD274) or B7-H, etc.
  • PD-L1 The representative amino acid sequence of human PD-L1 is disclosed under NCBI accession number NP_054862.1, and the representative nucleic acid sequence encoding human PD-L1 is shown under NCBI accession number: NM_014143.4.
  • PD-L1 is expressed in the placenta, spleen, lymph nodes, thymus, heart, fetal liver, and is also found in many tumors or cancer cells.
  • PD-L1 binds to its receptor PD-1 or B7-1, which is expressed on activated T cells, B cells and myeloid cells. Binding of PD-L1 and its receptor induces signaling to inhibit TCR-mediated activation of cytokine production and T cell proliferation.
  • PD-L1 plays a major role in suppressing the immune system during certain events (e.g., pregnancy, autoimmune diseases, tissue allografts) and is thought to allow tumors or cancer cells to bypass immune checkpoints and evade immune responses.
  • B7 family refers to a class of structurally similar costimulatory factors in the body's immune process. It belongs to the immunoglobulin class and is related to the activation of T and B cells and the body's immunity.
  • polynucleotide and “nucleic acid” are used interchangeably to refer to a polymer of deoxyribonucleotides (DNA) or a polymer of ribonucleotides (ribonucleic acid, RNA ).
  • Polynucleotide sequence “nucleic acid sequence,” and “nucleotide sequence” are used interchangeably to refer to the ordering of nucleotides in a polynucleotide.
  • DNA coding strand (sense strand) and the RNA it codes for can be regarded as having the same nucleotide sequence, and the deoxythymidylate in the DNA coding strand sequence corresponds to the uridylic acid in the RNA sequence it codes for. .
  • an isolated nucleic acid molecule is a nucleic acid molecule separated from other nucleic acid molecules present in the natural source of the nucleic acid molecule.
  • An "isolated" nucleic acid molecule such as a cDNA molecule, may be substantially free of other cellular material or culture medium when prepared by recombinant techniques, or substantially free of chemical precursors or other chemical components when chemically synthesized.
  • Exemplary isolated nucleic acid molecules provided herein include isolated nucleic acid molecules encoding the provided antibodies or antigen-binding fragments.
  • expression includes the transcription and/or translation of a nucleotide sequence. Thus, expression may involve the production of transcripts and/or polypeptides.
  • a "vector” is a vehicle used to introduce an exogenous polynucleotide into a host cell so that when the vector is transformed into an appropriate host cell, the exogenous polynucleotide is amplified or expressed.
  • the vector usually remains episomal, but can be designed to integrate the gene or part thereof into the chromosome of the genome.
  • the definition of vector encompasses plasmids, linearized plasmids, viral vectors, cosmids, phage vectors, phagemids, artificial chromosomes (eg, yeast artificial chromosomes and mammalian artificial chromosomes), and the like.
  • Viral vectors include, but are not limited to, retroviral vectors (including lentiviral vectors), adenoviral vectors, adeno-associated virus vectors, herpes virus vectors, poxvirus vectors, and baculovirus vectors.
  • host cell is a cell that is used to receive, maintain, replicate and amplify a vector. Host cells can also be used to express polypeptides encoded by the vector. When the host cell divides, the nucleic acid contained in the vector replicates, thereby amplifying the nucleic acid.
  • the host cell can be a eukaryotic cell or a prokaryotic cell. Suitable host cells include, but are not limited to, CHO cells, various COS cells, HeLa cells, HEK cells such as HEK 293 cells.
  • a "subject in need” may include a subject already suffering from a disease; a subject susceptible to suffering from a disease; and a subject in need of prevention of a disease.
  • therapeutic effect means an effect resulting from treatment of an individual that alters, generally ameliorates, or ameliorates the symptoms of a disease or disease condition, or cures a disease or disease condition.
  • a therapeutically effective amount refers to an amount of an antibody, polypeptide, polynucleotide, small organic molecule or other drug that is effective to "treat” a disease or condition in a subject or mammal.
  • a therapeutically effective amount of a drug reduces the number of cancer cells; blocks or stops cancer cell division, reduces or blocks the increase in tumor size; inhibits, e.g., suppresses, blocks, prevents, stops, delays, or reverses Invasion of cancer cells into surrounding organs, including, for example, spread of cancer into soft tissue and bone; inhibition, for example, to suppress, block, prevent, shrink, stop, delay or reverse tumor metastasis; inhibition, for example, to suppress, block, prevent, Stop, delay, or reverse tumor growth; alleviate one or more symptoms associated with cancer to some extent and reduce morbidity and mortality; improve quality of life; or a combination of these effects.
  • a drug prevents growth and/or kills existing cancer cells, it may be referred to as
  • the term "subject" refers to a mammal, such as a human.
  • the antibody numbers used herein are only used to distinguish or identify the antibodies or products, and are not intended to indicate that such identification is a characteristic of the antibodies or products of the invention.
  • Those skilled in the art will understand that, for example, for the purpose of differentiation or identification, other antibodies or products may also use such identification, but this does not mean that they are the same or equivalent antibodies or products.
  • similar numbers or labels used in the examples are only for convenience of illustration, and the antibodies or products of the invention are defined by the features described in the appended claims.
  • the present invention provides an antibody against PD-L1 (PD-L1 antibody) or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof specifically recognizes and binds to PD-L1.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof of the invention is a single domain antibody, a heavy chain antibody, a humanized antibody, or a chimeric antibody.
  • the antibody or antigen-binding fragment thereof is a human antibody.
  • the antibody or antigen-binding fragment thereof has at least one of the following characteristics:
  • tumors targeted include, but are not limited to, those described below with respect to neoplastic diseases.
  • the antibodies or antigen-binding fragments thereof of the invention are capable of inhibiting tumor growth by at least about 10%, preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50% %, more preferably at least about 60%, more preferably at least about 70%, more preferably at least about 80%.
  • the anti-PD-L1 antibody comprises PD-L1 antibody m18-VHH or m18.
  • the invention provides an antibody m18-VHH or an antigen-binding fragment thereof directed against PD-L1,
  • said antibody or antigen-binding fragment thereof comprises a single variable domain of an immunoglobulin, wherein
  • the single variable domain contains:
  • CDR3 which comprises the amino acid sequence shown in SEQ ID NO:3.
  • the PD-L1 antibody m18-VHH or an antigen-binding fragment thereof comprises a single variable domain of an immunoglobulin
  • the single variable domain comprises the amino acid sequence shown in SEQ ID NO:4 or an amino acid sequence having at least 85%, at least 90%, at least 95% or higher sequence identity with SEQ ID NO:4.
  • the present invention also provides an antibody m18 or an antigen-binding fragment thereof against PD-L1,
  • the antibody or antigen-binding fragment thereof comprises a single variable domain of an immunoglobulin, wherein
  • the single variable domain contains:
  • CDR2 which comprises the amino acid sequence shown in SEQ ID NO:2,
  • CDR3 which contains the amino acid sequence shown in SEQ ID NO:3.
  • the PD-L1 antibody m18 or an antigen-binding fragment thereof comprises a single variable domain of an immunoglobulin
  • the single variable domain comprises the amino acid sequence shown in SEQ ID NO:4 or an amino acid sequence having at least 85%, at least 90%, at least 95% or higher sequence identity with SEQ ID NO:4.
  • the PD-L1 antibody m18 or its antigen-binding fragment further comprises an Fc fragment of human IgG1.
  • the Fc fragment of human IgG1 comprises the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody m18 or an antigen-binding fragment thereof comprises the amino acid sequence shown in SEQ ID NO:5 or has at least 85%, at least 90%, at least 95% or higher sequence identity with SEQ ID NO:5 amino acid sequence.
  • the invention provides a nucleic acid molecule comprising a polynucleotide sequence encoding an anti-PD-L1 antibody of the invention or an antigen-binding fragment thereof.
  • a nucleic acid molecule of the invention encodes an anti-PD-L1 antibody of the invention or an antigen-binding fragment thereof.
  • nucleic acid molecules of the invention can be obtained using methods known in the art.
  • nucleic acid molecules of the invention can be isolated from phage display libraries, yeast display libraries, immunized animals, immortalized cells (eg, mouse B cell hybridoma cells, EBV-mediated immortalized B cells), or chemically synthesized.
  • Nucleic acid molecules of the invention can be codon-optimized for the host cell used for expression.
  • the invention also provides expression vectors comprising the nucleic acid molecules of the invention.
  • the expression vector may further contain additional polynucleotide sequences, such as regulatory sequences and antibiotic resistance genes.
  • Nucleic acid molecules of the invention may be present in one or more expression vectors.
  • the nucleic acid molecules of the invention are prepared as recombinant nucleic acids. Recombinant nucleic acids can be prepared using techniques well known in the art, such as chemical synthesis, DNA recombinant technology (such as polymerase chain reaction (PCR) technology), and the like.
  • the invention also provides a host cell comprising the nucleic acid molecule or expression vector of the invention.
  • a host cell comprising the nucleic acid molecule or expression vector of the invention.
  • Various methods known in the art can be used to introduce the nucleic acid molecules or expression vectors of the invention into suitable host cells. Such methods include, but are not limited to, lipofection, electroporation, viral transduction, calcium phosphate transfection, etc.
  • host cells are used to express the anti-PD-L1 antibodies of the invention or antigen-binding fragments thereof.
  • host cells include, but are not limited to, prokaryotic cells (eg bacteria, eg E. coli) and eukaryotic cells (eg yeast, insect cells, mammalian cells).
  • Mammalian host cells suitable for antibody expression include, but are not limited to, human cervical cancer cells (HeLa cells), human embryonic kidney cells (HEK cells, such as HEK 293 cells), Chinese hamster ovary (CHO) cells, and others suitable for antibody expression. mammalian cells.
  • the invention also provides a method for producing the anti-PD-L1 antibody or antigen-binding fragment thereof of the invention, which includes the following steps:
  • the present invention also provides a pharmaceutical composition, which contains the anti-PD-L1 antibody or antigen fragment thereof of the present invention and a pharmaceutically acceptable carrier.
  • the above-mentioned antibody includes anti-PD-L1 antibody m18 or m18-VHH.
  • compositions provided herein may be in a variety of dosage forms, including, but not limited to, solid, semi-solid, liquid, powder, or lyophilized forms.
  • preferred dosage forms may generally be, for example, injection solutions and lyophilized powders.
  • compositions provided herein may be administered to a subject by any method known in the art, such as by systemic or local administration.
  • Routes of administration include, but are not limited to, parenteral (e.g., intravenous, intraperitoneal, intradermal, intramuscular) intranasal, subcutaneous, or intracavity), local (e.g., intratumoral), epidural, or mucosal (e.g., intranasal, oral, vaginal, rectal, sublingual, or local).
  • parenteral e.g., intravenous, intraperitoneal, intradermal, intramuscular intranasal, subcutaneous, or intracavity
  • local e.g., intratumoral
  • epidural e.g., intranasal, oral, vaginal, rectal, sublingual, or local
  • mucosal e.g., intranasal, oral, vaginal, rectal, sublingual, or local.
  • the exact dosage administered will depend on various factors such as the metabolic kinetic properties of the pharmaceutical composition, the duration of treatment, the excretion rate of the particular compound, the purpose of treatment, the route of administration and the subject conditions, such as the patient's age, health, weight, gender, diet, medical history, and other factors known in the medical field.
  • the anti-PD-L1 antibodies or antigen-binding fragments thereof of the present invention are administered at a dosage range of about 0.0001-100 mg/kg, more typically 0.01-20 mg/kg of subject body weight.
  • the dosage may be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight, 10 mg/kg body weight, 11 mg/kg body weight or 20 mg/kg body weight, or in the range of 1-20 mg/kg .
  • Exemplary treatment regimens call for weekly dosing, twice weekly dosing, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months, once every 3-6 months , or the initial dosing interval is slightly shorter and the later dosing interval is longer.
  • a "therapeutically effective dose” refers to a dose that results in a reduction in the severity of symptoms of a disease, an increase in the frequency and duration of symptom-free periods of the disease, or the prevention of impairment or disability due to distress from the disease. For example, for antiproliferative effects, preventing further tumor development, reducing tumor size, reducing tumor blood vessels, reducing the number of cancer cells, inhibiting, delaying or reducing tumor and/or malignant cell growth and/or metastasis in cancer patients, and/or reducing A therapeutically effective dose at which one or more symptoms associated with the disease may be observed.
  • the therapeutically effective dose can vary depending on many different factors, including the mode of administration, the target site, the patient's physiological state, whether the patient is human or other animals, what other drugs are administered, and whether the treatment is prophylactic. Still therapeutic.
  • the patient is a human, but non-human mammals, including transgenic animals, may also be treated.
  • Therapeutic doses can be titrated to optimize safety and efficacy using conventional methods known to those skilled in the art.
  • a "therapeutically effective dose" of an antibody or antigen-binding fragment thereof of the present invention preferably inhibits cell growth or tumor growth by at least about 10%, preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50%, more preferably at least about 60%, more preferably at least about 70%, more preferably at least about 80%.
  • the ability to inhibit tumor growth can be evaluated in an animal model system that predicts the efficacy of human tumors. Alternatively, it can also be evaluated by examining the ability to inhibit cell growth, which inhibition can be determined in vitro by experiments known to those skilled in the art.
  • An effective amount of an antibody or antigen-binding fragment thereof of the present invention can reduce tumor size, or otherwise alleviate symptoms of a subject such as preventing and/or treating metastasis or recurrence. Those skilled in the art can determine this amount based on factors such as the size of the subject, the severity of the subject's symptoms, and the specific composition or route of administration selected.
  • the invention relates to the use of the anti-PD-L1 antibody or antigen-binding fragment thereof or pharmaceutical composition of the invention for the preparation of a medicament for treating a disease in a subject.
  • the present invention also relates to the anti-PD-L1 antibody or antigen-binding fragment thereof or pharmaceutical composition of the present invention, which is used to treat Treat diseases.
  • the present invention also provides a method of treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody of the present invention or an antigen-binding fragment thereof or a pharmaceutical composition.
  • the disease is cancer.
  • cancer includes, but is not limited to, hematological tumors and solid tumors.
  • solid tumors include, for example, squamous cell carcinoma, adenocarcinoma, basal cell carcinoma, renal cell carcinoma, breast ductal carcinoma, soft tissue sarcoma, osteosarcoma, melanoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma , peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, pancreatic cancer, neuroendocrine cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, brain cancer, hepatoma, breast cancer, colon cancer , colorectal cancer, endometrial or uterine cancer, esophageal cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, etc.
  • Hematomas include, for example, leukemia, lymphoma, myeloma, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple Myeloma, etc. or any combination thereof.
  • the cancer can also be metastatic. "Metastasis" is when cancer cells spread from their original site to other parts of the body.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof or pharmaceutical composition of the present invention can be used in combination with other treatment methods, including but not limited to: surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, hormones Treatment, angiogenesis inhibition, and palliative care.
  • the anti-PD-L1 antibodies or antigen-binding fragments thereof or pharmaceutical compositions of the invention may also be administered in combination with at least one or more therapeutic agents described herein.
  • therapeutic agents described herein There are no restrictions on the mode of combined administration.
  • the therapeutic agents described below can be administered all at once or separately. When administered separately (in the case of mutually different administration regimens), they may be administered continuously without interruption or at predetermined intervals.
  • the anti-PD-L1 antibodies or antigen-binding fragments or pharmaceutical compositions thereof of the invention are further used in combination with one or more therapeutic agents selected from the group consisting of: chemotherapeutic agents, radioactive isotopes, and tumor antigen targeting drug.
  • chemotherapeutic agents may include, for example: antimetabolites, alkylating agents, cytotoxic agents, topoisomerase inhibitors, microtubule inhibitors.
  • Tumor antigen-targeting drugs include, but are not limited to, drugs targeting tumor-associated antigens and tumor-specific antigens.
  • therapeutic agents may include, for example: angiogenesis inhibitors, deacetylase (HDAC) inhibitors, Hedgehog signaling pathway blockers, mTOR inhibitors, p53/mdm2 inhibitors, PARP inhibitors, proteasome Inhibitors (eg bortezomib, carfilzomib, ixazomib, marizomib, Oprozomib) and tyrosine kinase inhibitors (eg BTK inhibitors).
  • HDAC deacetylase
  • Hedgehog signaling pathway blockers e.g., mTOR inhibitors, p53/mdm2 inhibitors, PARP inhibitors, proteasome Inhibitors (eg bortezomib, carfilzomib, ixazomib, marizomib, Oprozomib) and tyrosine kinase inhibitors (eg BTK inhibitors).
  • BTK inhibitors tyrosine kinas
  • the anti-PD-L1 antibodies or antigen-binding fragments thereof or pharmaceutical compositions of the invention are used in combination with chemotherapeutic agents. In yet other embodiments, the anti-PD-L1 antibodies or antigen-binding fragments thereof or pharmaceutical compositions of the invention are used in combination with radioactive isotopes. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof or pharmaceutical composition of the present invention is used in combination with a tumor antigen-targeting drug.
  • kits which contains the anti-PD-L1 antibody of the present invention or its antigen-binding fragment or pharmaceutical composition, and instructions for use.
  • the kit may also contain suitable containers.
  • the kit further includes a device for administering the drug.
  • Kits generally include labels indicating the intended use and/or method of use of the contents of the kit.
  • label includes any written or recorded material on or provided with the kit or otherwise provided with the kit.
  • the above-mentioned antibody includes anti-PD-L1 antibody m18 or m18-VHH.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof of the present invention has at least one of the following beneficial effects: 1) having affinity activity for PD-L1 positive cells; 2) being able to specifically bind to PD-L1 protein; 3) inhibiting tumors growth; 4) has excellent mouse cross-activity.
  • the antibody NB22D-21-huVH2 (see, for example, CN112745391A) is subjected to affinity maturation transformation to improve antibody affinity and other biological activities.
  • Affinity maturation transformation is based on M13 phage display technology, using codon-based primers (during the primer synthesis process, a single codon consists of NNK) to introduce mutations in the CDR region to construct four phage display libraries:
  • Library 1 is a single Point combination mutations
  • library 1 is a CDR1+CDR2+CDR3 combination mutation
  • library 2 library 3 and library 4 are double point combination mutations
  • library 2 is a double point combination mutation of CDR1+CDR3
  • library 3 is a double point combination of CDR2+CDR3 Combination mutation
  • library 4 is a double-point combination mutation of CDR1+CDR2.
  • the specific library construction method first synthesize primers containing point mutations (Jinweizhi Biotechnology Co., Ltd.); secondly, use the coding sequence of the antibody to be modified (hereinafter referred to as the parent antibody) NB22D-21-huVH2 as a PCR amplification template. Amplify the sequence containing mutations in the CDR region, combine the fragments containing different CDR mutations by bridging PCR, and then connect the point mutation antibody to the phage display vector through double enzyme digestion (HindIII and NotI) and double sticky end ligation. Finally, the antibody sequence with the mutation site was transferred into E. coli SS320 by electroporation.
  • the obtained antibody was named m18-VHH.
  • the amino acid sequence of the variable region of the obtained antibody is shown in Table 1.
  • the CDR sequence was determined using AbM to define CDR.
  • a fusion expression vector is constructed by connecting the C-terminus of the VHH gene sequence to the N-terminus of the human IgG1 Fc segment gene sequence to fuse the m18-VHH antibody obtained through affinity maturation and the human IgG1 Fc segment (SEQ ID NO: 6), and express the fusion
  • the vector plasmid is transformed into ExpiCHO cells and induced to express to obtain the VHH-Fc chimeric antibody protein (SEQ ID NO: 5) fused with the Fc fragment.
  • the VHH-Fc antibody is named m18 antibody below.
  • the antibody was expressed using the ExpiCHO transient expression system, using ExpiCHO TM expression medium (Gibco, A29100-01) and Gibco TM ExpiFectamine TM CHO transfection kit (Gibco, A29129).
  • the specific method is as follows: Passage ExpiCHO cells one day before transfection. In a 25 mL system, mix 25 ⁇ g of the constructed plasmid with the transfection reagent, add dropwise to 25 ml of ExpiCHO cell culture, and mix thoroughly. After expression at 37°C for 18-22 hours, add feed medium according to the instructions in the kit. After feeding, the cells were cultured at 32°C.
  • the second feed was added and the cells were cultured at 32°C. After 10-12 days, the expressed cell suspension was centrifuged at high speed to obtain the supernatant. The supernatant was filtered with 0.22 ⁇ m and purified using the Protein A/G affinity purification method, and washed with 100mM glycinate (pH3.0). The target protein was removed, then neutralized with 1M Tris-HCl, and finally the resulting antibody protein was exchanged into PBS buffer through an ultrafiltration concentration tube (Millipore, UFC901096).
  • the affinity matured modified VHH-Fc antibody and PD-L1 overexpressing cells human PD-L1-CHO cells, human non-small cell lung cancer cell line HCC827 cells, and mouse PD-L1- For the binding ability of CHO cells and cynomolgus PD-L1-CHO cells, please refer to the patent application CN112745391A for the source or preparation method of the above cell lines.
  • human PD-L1-CHO cells were used to evaluate the binding activity of antibodies to human PD-L1 overexpressing cells.
  • the specific method is as follows: collect the cultured human PD-L1-CHO cells (for the preparation process of PD-L1-CHO cells, please refer to Example 1 in CN112745391A), centrifuge at 300g to remove the supernatant, and resuspend the cells in the prepared FACS buffer. Count and adjust the density of the cell suspension to 2 ⁇ 10 6 cells/mL; add 100 ⁇ L of human PD-L1-CHO cells to each well of a 96-well plate, and centrifuge at 300g to remove the supernatant; add gradient dilutions of m18 antibody to the corresponding wells.
  • Diluent, parent antibody diluent and positive control antibody Avelumab (preparation method is described in patent WO2013079174) diluent, use a volley gun to blow the cells evenly and place them at 4°C for 30 minutes to incubate; centrifuge the incubated cell mixture at 300g Remove the supernatant, add 200 ⁇ L to the corresponding well and use a volley gun to resuspend the cells; repeat the centrifugation, resuspension and washing step of cells twice, 300g Centrifuge to remove the supernatant; add PE-labeled anti-human IgG Fc flow cytometry antibody (Abcam, ab98596), blow the cells evenly with a volley gun and incubate at 4°C for 30 minutes; centrifuge at 300g to remove the supernatant, add FACS buffer and resuspend Cells; repeat the cell centrifugation resuspension and washing steps twice, add FACS buffer to the wells
  • the human non-small cell lung cancer cell line HCC827 cells were used to evaluate the binding activity of the antibody to the PD-L1 protein on human tumor cells.
  • the specific method is as follows: digest HCC827 cells (ATCC: CRL-2868) with Trypsin containing 0.25% EDTA, collect the cells and centrifuge at 300g to remove the supernatant, resuspend the cells in the prepared FACS buffer, count and adjust the density of the cell suspension.
  • the concentration is 2 ⁇ 10 6 cells/mL; add 100 ⁇ L of HCC827 cells per well to a 96-well plate, and centrifuge at 300 g to remove the supernatant; add gradient dilutions of m18 antibody dilution, parent antibody dilution, and positive control antibody dilution to the corresponding wells.
  • Centrifuge twice at 300g to remove the supernatant add 100 ⁇ L of m18 antibody, parent antibody dilution and positive control antibody dilution (1 ⁇ g/mL) to the corresponding wells, resuspend the cells and incubate them at 4°C for 30 minutes; After incubation, centrifuge the cell mixture at 300g to remove the supernatant, add 200 ⁇ L to the corresponding well and use a volute gun to resuspend the cells; repeat the steps of centrifugation and resuspension to clean the cells twice, and centrifuge at 300g to remove the supernatant; add PE-labeled anti-biotin Flow cytometry antibody (Abcam), use a volley gun to blow the cells evenly and place them at 4°C for 30 minutes; centrifuge at 300g to remove the supernatant, add FACS buffer and resuspend the cells; repeat the centrifugation, resuspension and washing step of cells twice, and add to the
  • mouse PD-L1-CHO cells and cynomolgus monkey PD-L1-CHO cells were used to evaluate the cross-binding activity with monkey and mouse PD-L1.
  • the specific method is as follows: collect cultured mouse PD-L1-CHO cells and cynomolgus monkey PD-L1-CHO cells (for the preparation process of mouse PD-L1-CHO cells and cynomolgus monkey PD-L1-CHO cells, please refer to Example 1 of CN112745391A ), centrifuge at 300g to remove the culture medium, resuspend the cells in prepared FACS buffer, count and adjust the cell suspension density to 2 ⁇ 10 6 /mL; separate mouse PD-L1-CHO cells and cynomolgus monkey PD -L1-CHO cells were added to a 96-well plate at 100 ⁇ L per well, and centrifuged at 300g to remove the supernatant; add gradient dilutions of m18 antibody diluent, parent antibody diluent, and positive control antibody diluent to the corresponding wells, and blow the cells with a volley gun.
  • ELISA is used to detect the binding activity of the VHH-Fc antibody to other proteins of the B7 family after affinity maturation to evaluate the specificity of the m18 antibody for the PD-L1 protein.
  • the specific method is as follows:
  • B7-H1 i.e., PD-L1
  • B7-H2, B7-H3, B7-H4, B7-DC the above proteins were purchased from Sino Biological, with catalog numbers 10084-HNAH, 11559-H08H, 11188-H08H, 10738-H08H, 10292-H08H-B
  • other protein diluents with a final concentration of 2 ⁇ g/mL
  • the m18 antibody has no binding activity to B7 family molecules other than B7-H1 (i.e., PD-L1), but only has binding activity to B7-H1. This binding is specific. The nature is consistent with the maternal antibody.
  • mouse colorectal cancer cell MC38 purchased from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
  • MC38 mouse tumor model was used to verify the anti-tumor effect of the m18 antibody in animals.
  • the specific method is as follows:
  • Each C57BL/6 mouse was injected subcutaneously with 2 ⁇ 10 6 MC38 cells.
  • the tumor-bearing volume reached about 100 mm 3 (on the 6th day after tumor-bearing)
  • the cells were grouped into cages and administered.
  • the mice were divided into 2 groups, the negative control group and the m18 single-dose group, with 6 tumor-bearing C57BL/6 mice in each group.
  • the method of administration was intraperitoneal injection, and 11 mpk of m18 antibody and an equal volume of PBS were administered to the m18 single-dose group and the negative control group respectively.
  • the drug was administered every 3-4 days, twice a week and the tumor volume was measured twice, for a total of 4 times/2 weeks.
  • V tumor volume
  • the tumor volume detection results are shown in Figure 4.
  • the mice in the PBS negative control group had the fastest tumor growth. Compared with the PBS group, the growth rate of tumor volume in the mice in the m18 single-dose group was significantly slower. This shows that the m18 antibody has a significant inhibitory effect on tumors. tumor effect.
  • the results of mouse weight detection are shown in Figure 5. After administration, the weight of mice in the m18 single-dose group and the control group increased, and there was no significant difference in mouse weight. This shows that the m18 antibody has no obvious toxic side effects on mice and is safe.

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Abstract

L'invention concerne un anticorps anti-PD-L1, une composition pharmaceutique comprenant l'anticorps et une utilisation associée. L'invention concerne en outre un polynucléotide codant pour l'anticorps, un vecteur d'expression et un procédé de production de l'anticorps.
PCT/CN2023/120060 2022-09-21 2023-09-20 Anticorps anti-pd-l1 et son utilisation WO2024061272A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017020801A1 (fr) * 2015-07-31 2017-02-09 苏州康宁杰瑞生物科技有限公司 Anticorps à domaine unique pour le ligand du récepteur de mort cellulaire programmée (pd-l1) et protéine dérivée de celui-ci
CN111328286A (zh) * 2017-08-09 2020-06-23 奥里尼斯生物科学有限公司 Pd-1和pd-l1结合剂
CN111848800A (zh) * 2020-07-31 2020-10-30 三优生物医药(上海)有限公司 Pd-l1单结构域抗体及其用途
CN112745391A (zh) * 2019-10-30 2021-05-04 三优生物医药(上海)有限公司 Pd-l1结合分子
CN113825774A (zh) * 2019-05-17 2021-12-21 南京金斯瑞生物科技有限公司 抗cd47/抗pd-l1多抗原结合蛋白及其使用方法
WO2022042715A1 (fr) * 2020-08-31 2022-03-03 杭州九源基因工程有限公司 PROTÉINE DE FUSION BIFONCTIONNELLE CIBLANT PD-L1 ET TGFβ, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
CN114430746A (zh) * 2019-09-25 2022-05-03 上海药明生物技术有限公司 新型抗pd-l1抗体
WO2022105832A1 (fr) * 2019-12-05 2022-05-27 启愈生物技术(上海)有限公司 Nanocorps anti-pd-l1 et protéine de fusion trifonctionnelle

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017020801A1 (fr) * 2015-07-31 2017-02-09 苏州康宁杰瑞生物科技有限公司 Anticorps à domaine unique pour le ligand du récepteur de mort cellulaire programmée (pd-l1) et protéine dérivée de celui-ci
CN111328286A (zh) * 2017-08-09 2020-06-23 奥里尼斯生物科学有限公司 Pd-1和pd-l1结合剂
CN113825774A (zh) * 2019-05-17 2021-12-21 南京金斯瑞生物科技有限公司 抗cd47/抗pd-l1多抗原结合蛋白及其使用方法
CN114430746A (zh) * 2019-09-25 2022-05-03 上海药明生物技术有限公司 新型抗pd-l1抗体
CN112745391A (zh) * 2019-10-30 2021-05-04 三优生物医药(上海)有限公司 Pd-l1结合分子
WO2022105832A1 (fr) * 2019-12-05 2022-05-27 启愈生物技术(上海)有限公司 Nanocorps anti-pd-l1 et protéine de fusion trifonctionnelle
CN111848800A (zh) * 2020-07-31 2020-10-30 三优生物医药(上海)有限公司 Pd-l1单结构域抗体及其用途
WO2022042715A1 (fr) * 2020-08-31 2022-03-03 杭州九源基因工程有限公司 PROTÉINE DE FUSION BIFONCTIONNELLE CIBLANT PD-L1 ET TGFβ, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI YUMEI, WU LINGJUN, LIU YUEYING, MA SIWEN, HUANG BIYI, FENG XIANJING, WANG HUI: "A novel multifunctional anti-PD-L1-CD16a-IL15 induces potent cancer cell killing in PD-L1-positive tumour cells", TRANSLATIONAL ONCOLOGY, NEOPLASIA PRESS, UNITED STATES, vol. 21, 26 April 2022 (2022-04-26), United States , pages 101424, XP093148738, ISSN: 1936-5233, DOI: 10.1016/j.tranon.2022.101424 *
LIU JINLONG; HONG HAOFEI; SHI JIE; XIE YUNTIAN; LU ZHONGKAI; LIU ZHICHENG; ZHOU ZHIFANG; BIAN ZEHUA; HUANG ZHAOHUI; WU ZHIMENG: "Dinitrophenol-mediated modulation of an anti-PD-L1 VHH for Fc-dependent effector functions and prolonged serum half-life", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER AMSTERDAM, NL, vol. 165, 10 July 2021 (2021-07-10), NL , XP086725186, ISSN: 0928-0987, DOI: 10.1016/j.ejps.2021.105941 *

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