CN115087667B - Antigen binding proteins that specifically bind SARS-CoV-2 - Google Patents
Antigen binding proteins that specifically bind SARS-CoV-2 Download PDFInfo
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- CN115087667B CN115087667B CN202180013680.9A CN202180013680A CN115087667B CN 115087667 B CN115087667 B CN 115087667B CN 202180013680 A CN202180013680 A CN 202180013680A CN 115087667 B CN115087667 B CN 115087667B
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Abstract
An isolated antigen binding protein that specifically binds SARS-CoV-2 comprising at least one CDR in the light chain variable region VL, wherein said CDR comprises the amino acid sequence shown in SEQ ID NO. 95, methods of making said antigen binding protein and pharmaceutical uses thereof are provided.
Description
Technical Field
The present application relates to the field of biological medicine, and in particular to an antigen binding protein that specifically binds SARS-CoV-2.
Background
The outbreak of covd-19 caused by SARS-Cov-2 has become a global significant public health event. Preventive and therapeutic strategies for covd-19 are being developed in preclinical and clinical studies, and there are currently no very powerful drugs for treating covd-19.
Antibody-based therapy is a viable treatment option. Neutralizing antibodies are an important component of the host immune response to pathogens, and neutralizing monoclonal antibodies have been developed for the treatment of viral infections such as RSV, influenza, ebola, HIV, HCMV, and rabies. The existing monoclonal antibody preparation technology comprises hybridoma technology, EBV (electron beam Virus) transformed B lymphocyte technology, phage display technology, transgenic mouse technology, single B cell antibody preparation technology and the like.
Disclosure of Invention
The present application provides an isolated antigen binding protein that specifically binds SARS-CoV-2. The isolated antigen binding proteins described herein have at least the following beneficial effects: 1) Specifically binds SARS-CoV-2; 2) Has the activity of neutralizing SARS-CoV-2; 3) Has good preventing, treating and/or relieving effects on SARS-CoV-2 infection. The application also provides a preparation method of the isolated antigen binding protein specifically binding to SARS-CoV-2 and pharmaceutical application of the isolated antigen binding protein specifically binding to SARS-CoV-2.
In one aspect, the present application provides an isolated antigen binding protein that specifically binds SARS-CoV-2 comprising at least one CDR in the light chain variable region VL, wherein the CDR comprises the amino acid sequence of SEQ ID NO: 95.
In certain embodiments, the VL comprises an LCDR1, the LCDR1 comprising SEQ ID NO: 95.
In certain embodiments, the VL comprises an LCDR1, the LCDR1 comprising SEQ ID NO: 45. SEQ ID NO: 46. SEQ ID NO: 47. SEQ ID NO: 48. SEQ ID NO:49 and SEQ ID NO:50, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the VL comprises an LCDR2, the LCDR2 comprising SEQ ID NO: 51. SEQ ID NO: 52. SEQ ID NO:53 and SEQ ID NO:54, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the VL comprises an LCDR3, the LCDR3 comprising SEQ ID NO: 55. SEQ ID NO: 56. SEQ ID NO: 57. SEQ ID NO: 58. SEQ ID NO: 59. SEQ ID NO:60 and SEQ ID NO:61, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the VL comprises LCDR1 and LCDR2, the LCDR1 comprising the amino acid sequence of SEQ ID NO:95, and the LCDR2 comprises the amino acid sequence of SEQ ID NO: 51. SEQ ID NO: 52. SEQ ID NO:53 and SEQ ID NO:54, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the VL comprises LCDR1 and LCDR3, the LCDR1 comprising the amino acid sequence of SEQ ID NO:95, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 55. SEQ ID NO: 56. SEQ ID NO: 57. SEQ ID NO: 58. SEQ ID NO: 59. SEQ ID NO:60 and SEQ ID NO:61, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the VL comprises LCDR1, LCDR2, and LCDR3, the LCDR1 comprising SEQ ID NO:95, and the LCDR2 comprises the amino acid sequence of SEQ ID NO: 51. SEQ ID NO: 52. SEQ ID NO:53 and SEQ ID NO:54, or a sequence of any one of the amino acids set forth in seq id no; the LCDR3 comprises SEQ ID NO: 55. SEQ ID NO: 56. SEQ ID NO: 57. SEQ ID NO: 58. SEQ ID NO: 59. SEQ ID NO:60 and SEQ ID NO:61, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the VL comprises framework regions L-FR1, L-FR2, L-FR3 and L-FR4, wherein the C-terminus of said L-FR1 is directly or indirectly linked to the N-terminus of said LCDR1 and said L-FR1 comprises the amino acid sequence of SEQ ID NO: 62. SEQ ID NO:63 and SEQ ID NO:64, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the L-FR2 is located between the LCDR1 and the LCDR2, and the L-FR2 comprises the amino acid sequence of SEQ ID NO: 65. SEQ ID NO: 66. SEQ ID NO: 67. SEQ ID NO: 68. SEQ ID NO: 69. SEQ ID NO:70 and SEQ ID NO:71, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the L-FR3 is located between the LCDR2 and the LCDR3, and the L-FR3 comprises the amino acid sequence of SEQ ID NO: 72. SEQ ID NO: 73. SEQ ID NO: 74. SEQ ID NO: 75. SEQ ID NO: 76. SEQ ID NO:77 and SEQ ID NO:78, and a polypeptide comprising the amino acid sequence as set forth in any one of claims.
In certain embodiments, the N-terminus of the L-FR4 is directly or indirectly linked to the C-terminus of the LCDR3, and the L-FR4 comprises the amino acid sequence of SEQ ID NO:79 and SEQ ID NO:80, and an amino acid sequence set forth in any one of seq id nos.
In certain embodiments, the VL comprises SEQ ID NO: 88. SEQ ID NO: 89. SEQ ID NO: 90. SEQ ID NO: 91. SEQ ID NO: 92. SEQ ID NO:93 and SEQ ID NO:94, and a polypeptide comprising the amino acid sequence of any one of seq id no.
In certain embodiments, the isolated antigen binding protein comprises an antibody light chain constant region.
In certain embodiments, the isolated antigen binding protein comprises a heavy chain variable region VH comprising HCDR1, the HCDR1 comprising the amino acid sequence of SEQ ID NO: 1. SEQ ID NO: 2. SEQ ID NO: 3. SEQ ID NO: 4. SEQ ID NO: 5. SEQ ID NO:6 and SEQ ID NO: 7.
In certain embodiments, the VH comprises HCDR2, the HCDR2 comprising SEQ ID NO: 8. SEQ ID NO: 9. SEQ ID NO: 10. SEQ ID NO: 10. SEQ ID NO: 11. SEQ ID NO: 12. SEQ ID NO:13 and SEQ ID NO:14, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the VH comprises HCDR3, the HCDR3 comprising SEQ ID NO: 15. SEQ ID NO: 16. SEQ ID NO: 17. SEQ ID NO: 18. SEQ ID NO: 19. SEQ ID NO:20 and SEQ ID NO: 21.
In certain embodiments, the isolated antigen binding protein comprises a heavy chain variable region VH comprising HCDR1, HCDR2 and HCDR3, the HCDR1 comprising the amino acid sequence of SEQ ID NO: 1. SEQ ID NO: 2. SEQ ID NO: 3. SEQ ID NO: 4. SEQ ID NO: 5. SEQ ID NO:6 and SEQ ID NO: 7; the HCDR2 comprises SEQ ID NO: 8. SEQ ID NO: 9. SEQ ID NO: 10. SEQ ID NO: 10. SEQ ID NO: 11. SEQ ID NO: 12. SEQ ID NO:13 and SEQ ID NO:14, or a sequence of any one of the amino acids set forth in seq id no; the HCDR3 comprises SEQ ID NO: 15. SEQ ID NO: 16. SEQ ID NO: 17. SEQ ID NO: 18. SEQ ID NO: 19. SEQ ID NO:20 and SEQ ID NO: 21.
In certain embodiments, the VH comprises framework regions H-FR1, H-FR2, H-FR3, and H-FR4, wherein the C-terminus of the H-FR1 is directly or indirectly linked to the N-terminus of the HCDR1, and the H-FR1 comprises SEQ ID NO: 22. SEQ ID NO: 23. SEQ ID NO: 24. SEQ ID NO: 25. SEQ ID NO: 26. SEQ ID NO:27 and SEQ ID NO: 28.
In certain embodiments, the H-FR2 is located between the HCDR1 and the HCDR2, and the H-FR2 comprises the amino acid sequence of SEQ ID NO: 29. SEQ ID NO: 30. SEQ ID NO: 31. SEQ ID NO: 32. SEQ ID NO:33 and SEQ ID NO:34, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the H-FR3 is located between the HCDR2 and the HCDR3, and the H-FR3 comprises the amino acid sequence of SEQ ID NO: 35. SEQ ID NO: 36. SEQ ID NO: 37. SEQ ID NO: 38. SEQ ID NO: 39. SEQ ID NO:40 and SEQ ID NO:41, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the N-terminus of the H-FR4 is directly or indirectly linked to the C-terminus of the HCDR3, and the H-FR4 comprises the amino acid sequence of SEQ ID NO: 42. SEQ ID NO:43 and SEQ ID NO:44, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In certain embodiments, the VH comprises SEQ ID NO: 81. SEQ ID NO: 82. SEQ ID NO: 83. SEQ ID NO: 84. SEQ ID NO: 85. SEQ ID NO:86 and SEQ ID NO: 87.
In certain embodiments, the isolated antigen binding protein comprises an antibody heavy chain constant region.
In certain embodiments, the isolated antigen binding protein has activity in neutralizing SARS-CoV-2.
In certain embodiments, the isolated antigen binding protein comprises an antibody or antigen binding fragment thereof.
In certain embodiments, the antigen binding fragment comprises a Fab, fab ', F (ab) 2, fv fragment, F (ab') 2, scFv, di-scFv, and/or dAb.
In certain embodiments, the antibody is a fully human antibody.
In another aspect, the present application provides an isolated nucleic acid molecule or molecules encoding the VL in an isolated antigen binding protein described herein.
In another aspect, the present application provides an isolated nucleic acid molecule or molecules encoding said VH in an isolated antigen binding protein described herein.
In another aspect, the present application provides an isolated nucleic acid molecule or molecules encoding an isolated antigen binding protein described herein.
In another aspect, the present application provides a vector comprising a nucleic acid molecule as described herein.
In another aspect, the present application provides a cell comprising a nucleic acid molecule described herein or a vector described herein.
In certain embodiments, the cell expresses an isolated antigen binding protein described herein.
In another aspect, the present application provides a method of making an isolated antigen binding protein described herein, the method comprising culturing a cell according to the present application under conditions such that the isolated antigen binding protein described herein is expressed.
In another aspect, the present application provides a pharmaceutical composition comprising an isolated antigen binding protein described herein, a nucleic acid molecule described herein, a vector described herein and/or a cell described herein, and optionally a pharmaceutically acceptable adjuvant.
In another aspect, the present application provides the use of an isolated antigen binding protein described herein, a nucleic acid molecule described herein, a vector described herein, a cell described herein, and/or a pharmaceutical composition described herein in the manufacture of a medicament for preventing, alleviating and/or treating an infection by a coronavirus.
In certain embodiments, the infection with a coronavirus comprises a covd-19.
In another aspect, the present application provides a method of preventing, alleviating and/or treating an infection by a coronavirus comprising administering an isolated antigen binding protein described herein, a nucleic acid molecule described herein, a vector described herein, a cell described herein and/or a pharmaceutical composition described herein.
In another aspect, the present application provides an isolated antigen binding protein described herein, a nucleic acid molecule described herein, a vector described herein, a cell described herein, and/or a pharmaceutical composition described herein for use in preventing, alleviating and/or treating an infection by a coronavirus.
In another aspect, the present application provides a method of detecting SARS-CoV-2 comprising the step of administering an isolated antigen binding protein described herein, a nucleic acid molecule described herein, a vector described herein, a cell described herein, and/or a pharmaceutical composition described herein.
Other aspects and advantages of the present application will become readily apparent to those skilled in the art from the following detailed description. Only exemplary embodiments of the present application are shown and described in the following detailed description. As those skilled in the art will recognize, the present disclosure enables one skilled in the art to make modifications to the disclosed embodiments without departing from the spirit and scope of the invention as described herein. Accordingly, the drawings and descriptions herein are to be regarded as illustrative in nature and not as restrictive.
Drawings
The specific features of the invention related to this application are set forth in the appended claims. The features and advantages of the invention that are related to the present application will be better understood by reference to the exemplary embodiments and the drawings that are described in detail below. The brief description of the drawings is as follows:
FIG. 1 shows the results of specific binding of isolated antigen binding proteins described herein to the SARS-CoV-2S protein trimer.
FIG. 2 shows the neutralizing activity of the isolated antigen binding proteins described herein against SARS-CoV-2 pseudovirus.
FIG. 3 shows the neutralizing activity of the isolated antigen binding proteins described herein against SARS-CoV-2 pseudovirus.
FIG. 4 shows the construction method of a mouse infection model.
FIG. 5 shows the effect of the isolated antigen binding proteins described herein on body weight of a mouse infection model.
FIG. 6 shows the results of clinical scoring of a mouse infection model by an isolated antigen binding protein described herein.
FIG. 7 shows the effect of isolated antigen binding proteins described herein on survival curves of mice infection models.
FIG. 8 shows the construction of rhesus infection model.
FIG. 9 shows the effect of the isolated antigen binding proteins described herein on viral RNA content in rhesus infection models (pharyngeal swab detection).
FIG. 10 shows the effect of the isolated antigen binding proteins described herein on viral RNA content in rhesus infection models (anal swab detection)
FIG. 11 shows the effect of the isolated antigen binding proteins described herein on viral RNA content in various tissues and organs of rhesus infection models.
FIGS. 12a-12g show the results of a cryoelectron microscopy analysis of the isolated antigen binding protein and S protein complexes described herein.
FIGS. 13a-13b show a flow of a cryoelectron microscopy process for the isolated antigen binding protein and S protein complexes described herein.
FIG. 14 shows data collection, 3D model reconstruction and model statistics for the isolated antigen binding protein and S protein complexes described herein.
FIGS. 15a-15e show the structure of a cryoelectron microscope of the isolated antigen binding protein and S protein complexes described herein.
FIGS. 16a-16c show binding pattern analysis of isolated antigen binding proteins and S protein complexes described herein.
Detailed Description
Further advantages and effects of the invention of the present application will become apparent to those skilled in the art from the disclosure of the present application, from the following description of specific embodiments.
Definition of terms
In this application, the term "SARS-CoV-2" refers generally to severe acute respiratory syndrome coronavirus type 2, designated by the full English name Severe Acute Respiratory Syndrome Coronavirus 2.SARS-CoV-2 belongs to the Coronaviridae (Coronaviridae) genus B coronavirus (Betacorovirus) Sha Bei subgenera (Sarbecovirus). SARS-CoV-2 is a enveloped, non-segmented, positive-stranded single-stranded RNA virus. SARS-CoV-2 can cause a new form of coronavirus pneumonia (COVID-19). In the present application, the SARS-CoV-2 can comprise an S protein (spike protein).
In this application, the term "covd-19" generally refers to a novel coronavirus pneumonia (Corona Virus Disease 2019), or 2019 coronavirus disease, which is a respiratory disease caused by the SARS-CoV-2 virus. Common symptoms of covd-19 may include fever, cough, fatigue, shortness of breath, and loss of flavor and taste, some of which may develop into viral pneumonia, multiple organ failure or cytokine storm. The disease is transmitted primarily upon intimate contact from person to person, for example, by small droplets produced by coughing, sneezing and speaking. The world health organization announced that the outbreak of COVID-19 was pandemic (pandemic) on day 3 and 11 of 2020. There is currently no vaccine or specific treatment available against covd-19.
In the present application, the term "S protein of coronavirus" generally refers to spike protein (spike protein) of coronaprotein. The S proteins can be combined into trimers (i.e., S protein trimers), which contain about 1300 amino acids. The S protein may belong to a first class of membrane fusion proteins (Class I viral fusion protein). The S protein may typically contain two subunits (subt), S1 and S2. S1 mainly comprises a receptor binding region (receptor binding domain RBD), which may be responsible for recognizing the receptor of the cell. S2 contains the essential elements required for the membrane fusion process, including an intrinsic membrane fusion peptide (HR), two 7 peptide repeats (heptde repeat), an aromatic amino acid-rich membrane proximal region (membrane proximal external region, MPER), and a transmembrane region (TM). The S1 protein can be further divided into two regions (domains), namely an N-terminal domain (NTD) and a C-terminal domain (CTD). The S protein can determine the host range and specificity of the virus (e.g., coronavirus SARS-CoV-2), can also be an important site of action for neutralizing antibodies in the host, and/or can be a critical target for vaccine design. The S protein may be the S protein of SARS-CoV-2, for example, the structure of which can be found in Daniel Wrapp et al, cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, science.
In the present application, the term "ACE2" generally refers to Angiotensin converting enzyme II (Angiotenin-converting enzyme 2) or a functional fragment thereof. The angiotensin converting enzyme II may catalyze the conversion of angiotensin I to angiotensin- (1-9) or angiotensin II to angiotensin- (1-7) exopeptidase. The ACE2 may include an N-terminal PD region (peptidase domain) and a C-terminal CLD region (collector-like domain). The angiotensin converting enzyme II may be a receptor for SARS-CoV-2, e.g., the extracellular domain of ACE2 (e.g., the PD region of ACE 2) may bind RBD of the S protein of SARS-CoV-2. Human angiotensin converting enzyme II has accession number Q9BYF1 in the UniProt database. The human ACE2 gene may comprise 18 exons, see Tipnis, s.r., hooper, n.m., hyde, r., karman, e., christie, g., turner, a.j.a. human homolog of angiotensin-converting enzyme: cloning and functional expression as a captopril-intrinsic carboxypepidiase.j.biol. Chem.275: table 1 of 33238-33243, 2000. In the present application, the ACE2 may comprise a truncate or variant of the complete ACE2 protein, provided that the functional fragment still functions as a coronavirus (e.g. SARS-CoV and/or SARS-CoV-2) receptor.
In the present application, the term "infection with coronavirus" generally refers to a disease and/or symptom caused by coronavirus infection. The Coronavirus belongs to the genus Coronavirusof the family Coronaviridae (Coronaviridae) of the order Coronavirales (Nidovirales). The coronavirus may be a single stranded RNA virus. The infection with coronavirus may include an infection of the respiratory tract, such as an upper respiratory tract infection. The coronavirus infection may include fever, runny nose, chills, vomiting, and/or fatigue.
In the present application, the term "neutralization" generally refers to the neutralizing activity of an antigen binding protein, i.e. an antigen binding protein may prevent and/or neutralize the biochemical activity of its corresponding antigen. In some cases, the antigen binding protein having such neutralizing activity may be resistant to and inactive against an antigen that attacks the immune system (e.g., a retrovirus, e.g., the antigen may be SARS-CoV-2). In some cases, the antigen binding proteins having such neutralizing activity do not require leukocyte involvement in neutralizing the biochemical activity of their corresponding antigens.
In the present application, the term "antigen binding protein" generally refers to a protein comprising an antigen binding moiety, and optionally a scaffold or backbone moiety that allows the antigen binding moiety to adopt a conformation that facilitates binding of the antigen binding protein to an antigen. Examples of antigen binding proteins include, but are not limited to, antibodies, antigen binding fragments (Fab, fab ', F (ab) 2, fv fragments, F (ab') 2, scFv, di-scFv, and/or dAb), immunoconjugates, multispecific antibodies (e.g., bispecific antibodies), antibody fragments, antibody derivatives, antibody analogs, or fusion proteins, and the like, so long as they exhibit the desired antigen binding activity.
In the present application, the term "Fab" generally refers to a fragment containing a heavy chain variable domain and a light chain variable domain, and also contains the constant domain of the light chain and the first constant domain of the heavy chain (CH 1); the term "Fab'" generally refers to a fragment that differs from Fab by the addition of a small number of residues (including one or more cysteines from the antibody hinge region) at the carboxy terminus of the heavy chain CH1 domain; the term "F (ab ') 2" generally refers to a dimer of Fab' and an antibody fragment that contains two Fab fragments linked by a disulfide bridge in the hinge region. The term "Fv" generally refers to the smallest antibody fragment that contains the complete antigen recognition and binding site. In some cases, the fragment may consist of a dimer of one heavy chain variable region and one light chain variable region in tight non-covalent association; the term "dsFv" generally refers to disulfide stabilized Fv fragments in which the linkage between a single light chain variable region and a single heavy chain variable region is disulfide. The term "dAb fragment" generally refers to an antibody fragment consisting of a VH domain. In the present application, the term "scFv" generally refers to a monovalent molecule formed by the covalent linkage of one heavy chain variable domain and one light chain variable domain of an antibody to each other via a flexible peptide linker; such scFv molecules may have the general structure: NH (NH) 2 -VL-linker-VH-COOH or NH 2 -VH-linker-VL-COOH.
In the present application, the term "antibody" generally refers to an immunoglobulin that can undergo a specific binding reaction with a corresponding antigen. The antibodies may be secreted by immune cells (e.g., effector B cells). The antibody may be a monoclonal antibody (including full length monoclonal antibodies comprising two light chains and two heavy chains), a polyclonal antibody, a multispecific antibody (e.g., bispecific antibody), a humanized antibody, a fully human antibody, a chimeric antibody and/or a camelized single domain antibody. An "antibody" may generally comprise a protein of at least two Heavy Chains (HC) and two Light Chains (LC), or antigen-binding fragments thereof, interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (VH) and a heavy chain constant region. In certain naturally occurring IgG, igD, and IgA antibodies, the heavy chain constant region comprises three domains, CH1, CH2, and CH3. In certain naturally occurring antibodies, each light chain comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region comprises one domain, CL. VH and VL regions can be further subdivided into regions of hypervariability, termed Complementarity Determining Regions (CDRs), alternating with regions of greater conservation termed Framework Regions (FR). Each VH and VL comprises three CDRs and four Framework Regions (FR), arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The variable domains of the natural heavy and light chains each comprise four FR regions (H-FR 1, H-FR2, H-FR3, H-FR4, L-FR1, L-FR2, L-FR3, L-FR 4), mostly in the β -sheet configuration, connected by three CDRs, forming a loop connection, and in some cases forming part of a β -sheet structure. The CDRs in each chain are in close proximity by the FR region and form together with the CDRs from the other chain an antigen binding site of the antibody. The constant region of an antibody may mediate the binding of an immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (Clq).
In the present application, the term "variable" generally refers to the fact that certain parts of the sequence of the variable domain of an antibody vary strongly, which results in the binding and specificity of various specific antibodies for their specific antigens. However, variability is not evenly distributed throughout the variable regions of antibodies. It focuses on three segments in the light and heavy chain variable regions, known as Complementarity Determining Regions (CDRs) or hypervariable regions (HVRs). The more highly conserved parts in the variable domain are called Frameworks (FR). In the art, CDRs of antibodies can be defined by a variety of methods, such as Kabat definition rules based on sequence variability (see, kabat et al, immunological protein sequences, fifth edition, national institutes of health, besseda, maryland (1991)), chothia definition rules based on structural loop region position (see, A1-Lazikani et al, jmol Biol 273:927-48, 1997), and KABAT definition rules based on the concept of the IMGT ONTOLOGY (IMGT-ONTOLOGY) and the rule of the IMGT Scientific chart. IMGT refers to the International ImMunogenetics information System, a global reference database of ImMunoGeneTics and immunoinformatics (http:// www.imgt.org). IMGT specifically studies Immunoglobulins (IG) or antibodies, T cell receptors (TR), major Histocompatibility (MH) from humans and other vertebrates, as well as immunoglobulin superfamily (IgSF), MH superfamily (MhSF) and immune system Related Proteins (RPI) from vertebrates and non-vertebrates.
In the present application, the term "isolated" antigen binding protein generally refers to an antigen binding protein that has been recognized, isolated and/or recovered from components of its production environment (e.g., natural or recombinant). The environmental pollution components that they produce are typically substances that interfere with their research, diagnostic or therapeutic uses and may include enzymes, hormones and other proteinaceous or non-proteinaceous solutes. An isolated antigen binding protein or antibody will typically be prepared by at least one purification step.
In the present application, the term "monoclonal antibody" generally refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies in the population are identical except for the small number of natural mutations that may be present. Monoclonal antibodies are generally highly specific for a single antigenic site. Moreover, unlike conventional polyclonal antibody preparations (which typically have different antibodies directed against different determinants), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies have the advantage that they can be synthesized by hybridoma culture without contamination by other immunoglobulins. The modifier "monoclonal" refers to the characteristics of the antibody as obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies as used herein may be prepared in hybridoma cells or may be prepared by recombinant DNA methods.
In the present application, the term "fully human antibody" generally refers to an antibody expressed by an animal by transferring a gene encoding a human antibody into a genetically engineered antibody gene-deleted animal. All parts of an antibody (including the variable and constant regions of an antibody) are encoded by genes of human origin. The fully human antibody can greatly reduce the immune side reaction of the heterologous antibody to human body. Methods for obtaining fully human antibodies in the art can include phage display technology, transgenic mouse technology, ribosome display technology, RNA-polypeptide technology, and the like.
In this application, the terms "bind," "specific binding," or "pair..specific" generally refer to a measurable and reproducible interaction, such as binding between an antigen and an antibody, which can determine the presence of a target in the presence of a heterogeneous population of molecules (including biological molecules). For example, an antibody binds to an epitope through its antigen binding domain, and this binding requires some complementarity between the antigen binding domain and the epitope. For example, an antibody that specifically binds to a target (which may be an epitope) is one that binds to that target with greater affinity, avidity, more readily, and/or for a greater duration than it binds to other targets. An antibody is said to "specifically bind" to an epitope when it will bind to the epitope more readily through its antigen binding domain than it will bind to a random, unrelated epitope. An "epitope" refers to a single click or click of a particular atom on an antigen that binds to an antigen binding protein (e.g., an antibody) where text is entered. Clicking or clicking here enters text. Clicking or clicking here enters text. A group (e.g., sugar side chain, phosphoryl, sulfonyl) or amino acid.
In the present application, the term "reference antibody" generally refers to an antibody with which the antigen binding proteins described herein compete for binding to an antigen (e.g., RBD of S protein of SARS-CoV-2).
In this application, the term "between" generally means that the C-terminus of a certain amino acid fragment is directly or indirectly linked to the N-terminus of a first amino acid fragment, and that the N-terminus thereof is directly or indirectly linked to the C-terminus of a second amino acid fragment. In the light chain, for example, the N-terminus of the L-FR2 is directly or indirectly linked to the C-terminus of the LCDR1, and the C-terminus of the L-FR2 is directly or indirectly linked to the N-terminus of the LCDR 2. For another example, the N-terminus of the L-FR3 is directly or indirectly linked to the C-terminus of the LCDR2, and the C-terminus of the L-FR3 is directly or indirectly linked to the N-terminus of the LCDR 3. In the heavy chain, for example, the N-terminus of the H-FR2 is directly or indirectly linked to the C-terminus of the HCDR1, and the C-terminus of the H-FR2 is directly or indirectly linked to the N-terminus of the HCDR 2. For another example, the N-terminus of the H-FR3 is directly or indirectly linked to the C-terminus of the HCDR2, and the C-terminus of the H-FR3 is directly or indirectly linked to the N-terminus of the HCDR 3. In the present application, the "first amino acid fragment" and the "second amino acid fragment" may be any one of the same or different amino acid fragments.
In the present application, the term "isolated nucleic acid molecule" or "isolated polynucleotide" refers generally to DNA or RNA of genomic, mRNA, cDNA or synthetic origin or a certain combination thereof. The isolated nucleic acid molecule may not associate with all or a portion of a polynucleotide found in nature, or be linked to a polynucleotide to which it is not linked in nature.
In the present application, the term "vector" generally refers to a nucleic acid molecule capable of self-replication in a suitable host, which transfers the inserted nucleic acid molecule into and/or between host cells. The vector may include a vector mainly used for inserting DNA or RNA into a cell, a vector mainly used for replicating DNA or RNA, and a vector mainly used for expression of transcription and/or translation of DNA or RNA. The carrier also includes a carrier having a plurality of functions as described above. The vector may be a polynucleotide capable of transcription and translation into a polypeptide when introduced into a suitable host cell. Typically, the vector will produce the desired expression product by culturing a suitable host cell comprising the vector.
In the present application, the term "cell" generally refers to an individual cell, cell line or cell culture that may or has contained a plasmid or vector comprising a nucleic acid molecule as described herein, or that is capable of expressing an antibody or antigen binding fragment thereof as described herein. The cell may comprise progeny of a single host cell. The daughter cells may not necessarily be identical in morphology or in genome to the original parent cells due to natural, unexpected or deliberate mutation, but are capable of expressing the antibodies or antigen-binding fragments thereof described herein. The cells may be obtained by transfecting the cells in vitro using the vectors described herein. The cells may be prokaryotic cells (e.g., E.coli) or eukaryotic cells (e.g., yeast cells, e.g., COS cells, chinese Hamster Ovary (CHO) cells, heLa cells, HEK293 cells, COS-1 cells, NS0 cells, or myeloma cells). In the present application, the cells may include cells into which the vector is introduced. The cells include not only a particular cell but also the progeny of such a cell.
In this application, the term "pharmaceutically acceptable adjuvant" generally includes pharmaceutically acceptable carriers, excipients or stabilizers which are non-toxic to the cells or mammals to which they are exposed at the dosages and concentrations employed. Typically, the physiologically acceptable carrier is an aqueous pH buffered solution.
As used herein, the term "administering" generally refers to the application of an exogenous pharmaceutical, therapeutic, diagnostic, or composition to an animal, human, subject, cell, tissue, organ, or biological fluid. "administration" may refer to therapeutic, pharmacokinetic, diagnostic, research and experimental methods. The treatment of the cell may include contacting the cell with an agent (e.g., an agent comprising the isolated antigen binding protein), contacting the cell with a fluid, and contacting the cell with a reagent. "administration" also means in vitro and ex vivo treatment by an agent, diagnosis, binding composition, or by another cell. "treatment" when applied to a human, animal or study subject refers to therapeutic treatment, prophylactic or preventative measures, study and diagnosis; for example, contact of the isolated antigen binding protein with a human or animal, subject, cell, tissue, physiological compartment or physiological fluid may be included.
As used herein, the term "treatment" refers to administration of an internal or external therapeutic agent, e.g., a pharmaceutical composition comprising any of the isolated antigen binding proteins of the present application, and/or comprising the isolated antigen binding proteins, to a patient having one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the patient is administered an amount of the therapeutic agent (therapeutically effective amount) effective to alleviate one or more symptoms of the disease. Desirable effects of treatment include reducing the rate of disease progression, improving or alleviating the disease state, and regression or improved prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are reduced or eliminated, including, but not limited to, reducing (or destroying) cancer cell proliferation, reducing symptoms derived from the disease, improving the quality of life of those individuals suffering from the disease, reducing the dosage of other drugs required to treat the disease, delaying the progression of the disease, and/or prolonging survival of the individual.
In this application, the terms "comprises," "comprising," and "includes" are used in their plain, inclusive, and open-ended meaning. In some cases, the meaning of "as", "consisting of.
In this application, the term "about" generally means ranging from 0.5% to 10% above or below the specified value, e.g., ranging from 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the specified value.
Detailed Description
Antigen binding proteins
In one aspect, the present application provides an isolated antigen binding protein that specifically binds SARS-CoV-2 comprising at least one CDR in the light chain variable region VL, wherein the CDR comprises the amino acid sequence of SEQ ID NO: 95. For example, the CDR may comprise SEQ ID NO: 96. SEQ ID NO: 97. SEQ ID NO:98 or SEQ ID NO: 99.
In the present application, the VL may comprise LCDR1, and the LCDR1 may comprise SEQ ID NO:95, amino acid sequence shown in seq id no: TG X 3 SS X 6 X 7 G X 9 X 10 X 11 X 12 V X 14 Wherein X is 3 Is Ser or Thr; x is X 6 Is Asp or Asn, X 7 Is Ile or Val, X 9 Is Ala, gly or Ser; x is X 10 Gly, ser or Tyr; x is X 11 Asp, phe, asn or Tyr; x is X 12 Asp, leu or Tyr; x is X 14 His or Ser. For example, the sequence may be a sequence determined according to KABAT definition rules.
In the present application, the VL may comprise LCDR1, and the LCDR1 may comprise SEQ ID NO:96, amino acid sequence shown in seq id no: TG X 3 SSDVGX 9 X 10 X 11 X 12 VS, where X 3 Is Ser or Thr; x is X 9 Gly or Ser; x is X 10 Is Ser or Tyr; x is X 11 Asp or Asn; x is X 12 Leu or Tyr. For example, the sequence may be a sequence determined according to KABAT definition rules.
In the present application, the VL may comprise LCDR1, and the LCDR1 may comprise SEQ ID NO:97, and an amino acid sequence shown in seq id no: TGTSSDVGX 9 X 10 NX 12 VS, where X 9 Gly or Ser; x is X 10 Is Ser or Tyr; x is X 12 Leu or Tyr. For example, the sequence may be a sequence determined according to KABAT definition rules.
In the present application, the VL may comprise LCDR1, and the LCDR1 may comprise SEQ ID NO:98, an amino acid sequence shown in seq id no: TGTSSDVGGX 10 NYVS, where X 10 Is Ser or Tyr. For example, the sequence may be a sequence determined according to KABAT definition rules.
In the present application, the VL may comprise LCDR1, and the LCDR1 may comprise SEQ ID NO:99, amino acid sequence shown in seq id no: TGSSSNIGAG X 11 DVH, wherein X 11 Phe or Tyr. For example, the sequence may be a sequence determined according to KABAT definition rules.
For example, the VL may comprise LCDR1, and the LCDR1 may comprise SEQ ID NO: 45. SEQ ID NO: 46. SEQ ID NO: 47. SEQ ID NO: 48. SEQ ID NO:49 and SEQ ID NO:50, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In the present application, the VL may comprise LCDR2, and the LCDR2 may comprise SEQ ID NO: 51. SEQ ID NO: 52. SEQ ID NO:53 and SEQ ID NO:54, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
In the present application, the VL may comprise LCDR3, and the LCDR3 may comprise SEQ ID NO: 55. SEQ ID NO: 56. SEQ ID NO: 57. SEQ ID NO: 58. SEQ ID NO: 59. SEQ ID NO:60 and SEQ ID NO:61, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the VL may comprise LCDR1 and LCDR2, and the LCDR1 may comprise SEQ ID NO:95, said LCDR2 may comprise the amino acid sequence of SEQ ID NO: 51. SEQ ID NO: 52. SEQ ID NO:53 and SEQ ID NO:54, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the VL may comprise LCDR1 and LCDR3, and the LCDR1 may comprise SEQ ID NO:95, and said LCDR3 may comprise the amino acid sequence of SEQ ID NO: 55. SEQ ID NO: 56. SEQ ID NO: 57. SEQ ID NO: 58. SEQ ID NO: 59. SEQ ID NO:60 and SEQ ID NO:61, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the VL may comprise LCDR1, LCDR2, and LCDR3, and the LCDR1 may comprise SEQ ID NO:95, said LCDR2 may comprise the amino acid sequence of SEQ ID NO: 51. SEQ ID NO: 52. SEQ ID NO:53 and SEQ ID NO:54, or a sequence of any one of the amino acids set forth in seq id no; the LCDR3 can comprise SEQ ID NO: 55. SEQ ID NO: 56. SEQ ID NO: 57. SEQ ID NO: 58. SEQ ID NO: 59. SEQ ID NO:60 and SEQ ID NO:61, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the VL may comprise SEQ ID NO: 88. SEQ ID NO: 89. SEQ ID NO: 90. SEQ ID NO: 91. SEQ ID NO: 92. SEQ ID NO:93 and SEQ ID NO:94, and a polypeptide comprising the amino acid sequence of any one of seq id no.
For example, the isolated antigen binding protein may comprise a heavy chain variable region VH, which VH may comprise HCDR1, which HCDR1 may comprise the amino acid sequence of SEQ ID NO: 1. SEQ ID NO: 2. SEQ ID NO: 3. SEQ ID NO: 4. SEQ ID NO: 5. SEQ ID NO:6 and SEQ ID NO: 7.
For example, the VH may comprise HCDR2, and the HCDR2 may comprise SEQ ID NO: 8. SEQ ID NO: 9. SEQ ID NO: 10. SEQ ID NO: 10. SEQ ID NO: 11. SEQ ID NO: 12. SEQ ID NO:13 and SEQ ID NO:14, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the VH may comprise HCDR3, and the HCDR3 may comprise SEQ ID NO: 15. SEQ ID NO: 16. SEQ ID NO: 17. SEQ ID NO: 18. SEQ ID NO: 19. SEQ ID NO:20 and SEQ ID NO: 21.
For example, the isolated antigen binding protein may comprise a heavy chain variable region VH, which VH may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise SEQ ID NO: 1. SEQ ID NO: 2. SEQ ID NO: 3. SEQ ID NO: 4. SEQ ID NO: 5. SEQ ID NO:6 and SEQ ID NO: 7; the HCDR2 may comprise SEQ ID NO: 8. SEQ ID NO: 9. SEQ ID NO: 10. SEQ ID NO: 10. SEQ ID NO: 11. SEQ ID NO: 12. SEQ ID NO:13 and SEQ ID NO:14, or a sequence of any one of the amino acids set forth in seq id no; the HCDR3 may comprise SEQ ID NO: 15. SEQ ID NO: 16. SEQ ID NO: 17. SEQ ID NO: 18. SEQ ID NO: 19. SEQ ID NO:20 and SEQ ID NO: 21.
For example, the VH may comprise SEQ ID NO: 81. SEQ ID NO: 82. SEQ ID NO: 83. SEQ ID NO: 84. SEQ ID NO: 85. SEQ ID NO:86 and SEQ ID NO: 87.
An isolated antigen binding protein as described herein is capable of competing with a reference antibody for RBD binding to the S protein of SARS-CoV-2, wherein the reference antibody may comprise a heavy chain variable region and a light chain variable region, the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise SEQ ID NO:2, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:8, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:15, and the LCDR1 may comprise the amino acid sequence of SEQ ID NO:45, and said LCDR2 may comprise the amino acid sequence of SEQ ID NO:51, and the LCDR3 may comprise the amino acid sequence of SEQ ID NO:55, and a nucleotide sequence shown in seq id no.
An isolated antigen binding protein as described herein is capable of competing with a reference antibody for RBD binding to the S protein of SARS-CoV-2, wherein the reference antibody may comprise a heavy chain variable region and a light chain variable region, the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise SEQ ID NO:1, and the HCDR2 may comprise the amino acid sequence of SEQ ID NO:9, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:16, the LCDR1 may comprise the amino acid sequence of SEQ ID NO:46, and the LCDR2 may comprise the amino acid sequence of SEQ ID NO:51, and the LCDR3 may comprise the amino acid sequence of SEQ ID NO:56, and a sequence of amino acids shown in seq id no.
An isolated antigen binding protein as described herein is capable of competing with a reference antibody for RBD binding to the S protein of SARS-CoV-2, wherein the reference antibody may comprise a heavy chain variable region and a light chain variable region, the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise SEQ ID NO:3, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:10, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:17, said LCDR1 may comprise the amino acid sequence of SEQ ID NO:47, said LCDR2 may comprise the amino acid sequence of SEQ ID NO:52, and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 57.
An isolated antigen binding protein as described herein is capable of competing with a reference antibody for RBD binding to the S protein of SARS-CoV-2, wherein the reference antibody may comprise a heavy chain variable region and a light chain variable region, the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise SEQ ID NO:4, and the HCDR2 may comprise the amino acid sequence of SEQ ID NO:11, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:18, and the LCDR1 may comprise the amino acid sequence of SEQ ID NO:48, said LCDR2 may comprise the amino acid sequence of SEQ ID NO:53, and the LCDR3 may comprise the amino acid sequence of SEQ ID NO:58, and a sequence of amino acids shown in seq id no.
An isolated antigen binding protein as described herein is capable of competing with a reference antibody for RBD binding to the S protein of SARS-CoV-2, wherein the reference antibody may comprise a heavy chain variable region and a light chain variable region, the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise SEQ ID NO:5, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:12, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:19, said LCDR1 may comprise the amino acid sequence shown in SEQ ID NO:64, said LCDR2 may comprise the amino acid sequence of SEQ ID NO:53, and the LCDR3 may comprise the amino acid sequence of SEQ ID NO: 59.
An isolated antigen binding protein as described herein is capable of competing with a reference antibody for RBD binding to the S protein of SARS-CoV-2, wherein the reference antibody may comprise a heavy chain variable region and a light chain variable region, the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise SEQ ID NO:7, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:14, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:21, said LCDR1 may comprise the amino acid sequence of SEQ ID NO:49, and said LCDR2 may comprise the amino acid sequence of SEQ ID NO:54, and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 60.
An isolated antigen binding protein as described herein is capable of competing with a reference antibody for RBD binding to the S protein of SARS-CoV-2, wherein the reference antibody may comprise a heavy chain variable region and a light chain variable region, the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise SEQ ID NO:6, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:13, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:20, and the LCDR1 may comprise the amino acid sequence of SEQ ID NO:50, and the LCDR2 may comprise the amino acid sequence of SEQ ID NO:51, and the LCDR3 may comprise the amino acid sequence of SEQ ID NO:61, and a sequence of amino acids shown in seq id no.
In the present application, the isolated antigen binding protein may comprise antibody light chain variable region cdrs—lcdr1, LCDR2 and LCDR3, the LCDR1 may comprise SEQ ID NO:45, and said LCDR2 may comprise the amino acid sequence of SEQ ID NO:51, and the LCDR3 can comprise the amino acid sequence of SEQ ID NO:55, and a nucleotide sequence shown in seq id no.
In the present application, the isolated antigen binding protein may comprise antibody light chain variable region cdrs—lcdr1, LCDR2 and LCDR3, the LCDR1 may comprise SEQ ID NO:46, and said LCDR2 may comprise the amino acid sequence of SEQ ID NO:51, and the LCDR3 can comprise the amino acid sequence of SEQ ID NO:56, and a sequence of amino acids shown in seq id no.
In the present application, the isolated antigen binding protein may comprise antibody light chain variable region cdrs—lcdr1, LCDR2 and LCDR3, the LCDR1 may comprise SEQ ID NO:47, said LCDR2 may comprise the amino acid sequence of SEQ ID NO:52, and the LCDR3 can comprise the amino acid sequence shown in SEQ ID NO: 57.
In the present application, the isolated antigen binding protein may comprise antibody light chain variable region cdrs—lcdr1, LCDR2 and LCDR3, the LCDR1 may comprise SEQ ID NO:48, and said LCDR2 may comprise the amino acid sequence of SEQ ID NO:53, and the LCDR3 can comprise the amino acid sequence of SEQ ID NO:58, and a sequence of amino acids shown in seq id no.
In the present application, the isolated antigen binding protein may comprise antibody light chain variable region cdrs—lcdr1, LCDR2 and LCDR3, the LCDR1 may comprise SEQ ID NO:64, and the LCDR2 may comprise the amino acid sequence of SEQ ID NO:53, and the LCDR3 can comprise the amino acid sequence of SEQ ID NO: 59.
In the present application, the isolated antigen binding protein may comprise antibody light chain variable region cdrs—lcdr1, LCDR2 and LCDR3, the LCDR1 may comprise SEQ ID NO:49, and said LCDR2 may comprise the amino acid sequence of SEQ ID NO:54, and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 60.
In the present application, the isolated antigen binding protein may comprise antibody light chain variable region cdrs—lcdr1, LCDR2 and LCDR3, the LCDR1 may comprise SEQ ID NO:50, and the LCDR2 may comprise the amino acid sequence of SEQ ID NO:51, and the LCDR3 can comprise the amino acid sequence of SEQ ID NO:61, and a sequence of amino acids shown in seq id no.
In this application, the isolated antigen binding protein may comprise antibody heavy chain variable region CDRs-HCDR 1, HCDR2 and HCDR3, the HCDR1 may comprise SEQ ID NO:2, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:8, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:15, and a polypeptide having the amino acid sequence shown in seq id no.
In this application, the isolated antigen binding protein may comprise antibody heavy chain variable region CDRs-HCDR 1, HCDR2 and HCDR3, the HCDR1 may comprise SEQ ID NO:1, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:9, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:16, and a polypeptide having the amino acid sequence shown in seq id no.
In this application, the isolated antigen binding protein may comprise antibody heavy chain variable region CDRs-HCDR 1, HCDR2 and HCDR3, the HCDR1 may comprise SEQ ID NO:3, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:10, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:17, and a sequence of amino acids shown in seq id no.
In this application, the isolated antigen binding protein may comprise antibody heavy chain variable region CDRs-HCDR 1, HCDR2 and HCDR3, the HCDR1 may comprise SEQ ID NO:4, and the HCDR2 may comprise the amino acid sequence of SEQ ID NO:11, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:18, and a polypeptide having the amino acid sequence shown in seq id no.
In this application, the isolated antigen binding protein may comprise antibody heavy chain variable region CDRs-HCDR 1, HCDR2 and HCDR3, the HCDR1 may comprise SEQ ID NO:5, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:12, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:19, and a polypeptide comprising the amino acid sequence shown in seq id no.
In this application, the isolated antigen binding protein may comprise antibody heavy chain variable region CDRs-HCDR 1, HCDR2 and HCDR3, the HCDR1 may comprise SEQ ID NO:7, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:14, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:21, and a polypeptide comprising the amino acid sequence shown in seq id no.
In this application, the isolated antigen binding protein may comprise antibody heavy chain variable region CDRs-HCDR 1, HCDR2 and HCDR3, the HCDR1 may comprise SEQ ID NO:6, said HCDR2 may comprise the amino acid sequence of SEQ ID NO:13, and the HCDR3 may comprise the amino acid sequence of SEQ ID NO:20, and a polypeptide having the amino acid sequence shown in seq id no.
In the present application, the isolated antigen binding protein may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, the HCDR1 may comprise the indicated amino acid sequence, the HCDR2 may comprise the indicated amino acid sequence, and the HCDR3 may comprise the indicated amino acid sequence, the LCDR1 may comprise the indicated amino acid sequence, the LCDR2 may comprise the indicated amino acid sequence, and the LCDR3 may comprise the indicated amino acid sequence.
In the present application, the isolated antigen binding protein may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, the HCDR1 may comprise the indicated amino acid sequence, the HCDR2 may comprise the indicated amino acid sequence, and the HCDR3 may comprise the indicated amino acid sequence, the LCDR1 may comprise the indicated amino acid sequence, the LCDR2 may comprise the indicated amino acid sequence, and the LCDR3 may comprise the indicated amino acid sequence.
In the present application, the isolated antigen binding protein may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, the HCDR1 may comprise the indicated amino acid sequence, the HCDR2 may comprise the indicated amino acid sequence, and the HCDR3 may comprise the indicated amino acid sequence, the LCDR1 may comprise the indicated amino acid sequence, the LCDR2 may comprise the indicated amino acid sequence, and the LCDR3 may comprise the indicated amino acid sequence.
In the present application, the isolated antigen binding protein may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, the HCDR1 may comprise the indicated amino acid sequence, the HCDR2 may comprise the indicated amino acid sequence, and the HCDR3 may comprise the indicated amino acid sequence, the LCDR1 may comprise the indicated amino acid sequence, the LCDR2 may comprise the indicated amino acid sequence, and the LCDR3 may comprise the indicated amino acid sequence.
In the present application, the isolated antigen binding protein may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, the HCDR1 may comprise the indicated amino acid sequence, the HCDR2 may comprise the indicated amino acid sequence, and the HCDR3 may comprise the indicated amino acid sequence, the LCDR1 may comprise the indicated amino acid sequence, the LCDR2 may comprise the indicated amino acid sequence, and the LCDR3 may comprise the indicated amino acid sequence.
In the present application, the isolated antigen binding protein may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, the HCDR1 may comprise the indicated amino acid sequence, the HCDR2 may comprise the indicated amino acid sequence, and the HCDR3 may comprise the indicated amino acid sequence, the LCDR1 may comprise the indicated amino acid sequence, the LCDR2 may comprise the indicated amino acid sequence, and the LCDR3 may comprise the indicated amino acid sequence.
In the present application, the isolated antigen binding protein may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, the HCDR1 may comprise the indicated amino acid sequence, the HCDR2 may comprise the indicated amino acid sequence, and the HCDR3 may comprise the indicated amino acid sequence, the LCDR1 may comprise the indicated amino acid sequence, the LCDR2 may comprise the indicated amino acid sequence, and the LCDR3 may comprise the indicated amino acid sequence.
In the present application, the isolated antigen binding protein may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, the HCDR1 may comprise the indicated amino acid sequence, the HCDR2 may comprise the indicated amino acid sequence, and the HCDR3 may comprise the indicated amino acid sequence, the LCDR1 may comprise the indicated amino acid sequence, the LCDR2 may comprise the indicated amino acid sequence, and the LCDR3 may comprise the indicated amino acid sequence.
For example, the VL may comprise framework regions L-FR1, L-FR2, L-FR3, and L-FR4.
For example, the C-terminus of the L-FR1 can be directly or indirectly linked to the N-terminus of the LCDR1, and the L-FR1 can comprise the amino acid sequence of SEQ ID NO: 62. SEQ ID NO:63 and SEQ ID NO:64, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the L-FR2 may be located between the LCDR1 and the LCDR2, and the L-FR2 may comprise the amino acid sequence of SEQ ID NO: 65. SEQ ID NO: 66. SEQ ID NO: 67. SEQ ID NO: 68. SEQ ID NO: 69. SEQ ID NO:70 and SEQ ID NO:71, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the L-FR3 may be located between the LCDR2 and the LCDR3, and the L-FR3 may comprise the amino acid sequence of SEQ ID NO: 72. SEQ ID NO: 73. SEQ ID NO: 74. SEQ ID NO: 75. SEQ ID NO: 76. SEQ ID NO:77 and SEQ ID NO:78, and a polypeptide comprising the amino acid sequence as set forth in any one of claims.
For example, the N-terminus of the L-FR4 can be directly or indirectly linked to the C-terminus of the LCDR3, and the L-FR4 can comprise the amino acid sequence of SEQ ID NO:79 and SEQ ID NO:80, and an amino acid sequence set forth in any one of seq id nos.
In this application, the VL may comprise SEQ ID NO: 88. SEQ ID NO: 89. SEQ ID NO: 90. SEQ ID NO: 91. SEQ ID NO: 92. SEQ ID NO:93 and SEQ ID NO:94, and a nucleotide sequence shown in seq id no.
For example, the isolated antigen binding protein may comprise an antibody light chain constant region, and the antibody light chain constant region comprises a human igκ constant region or a human igλ constant region.
In this application, the gene encoding the human igκ constant region may be as shown in GenBank accession number 50802 of NCBI database; the gene encoding the human Ig lambda constant region may be as shown in GenBank accession No. 3535 of NCBI database.
For example, the VH can include framework regions H-FR1, H-FR2, H-FR3, and H-FR4.
For example, the C-terminus of the H-FR1 can be directly or indirectly linked to the N-terminus of the HCDR1, and the H-FR1 can comprise the amino acid sequence of SEQ ID NO: 22. SEQ ID NO: 23. SEQ ID NO: 24. SEQ ID NO: 25. SEQ ID NO: 26. SEQ ID NO:27 and SEQ ID NO: 28.
For example, the H-FR2 may be located between the HCDR1 and the HCDR2, and the H-FR2 may comprise the amino acid sequence of SEQ ID NO: 29. SEQ ID NO: 30. SEQ ID NO: 31. SEQ ID NO: 32. SEQ ID NO:33 and SEQ ID NO:34, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the H-FR3 may be located between the HCDR2 and the HCDR3, and the H-FR3 may comprise the amino acid sequence of SEQ ID NO: 35. SEQ ID NO: 36. SEQ ID NO: 37. SEQ ID NO: 38. SEQ ID NO: 39. SEQ ID NO:40 and SEQ ID NO:41, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the N-terminus of the H-FR4 can be directly or indirectly linked to the C-terminus of the HCDR3, and the H-FR4 can comprise the amino acid sequence of SEQ ID NO: 42. SEQ ID NO:43 and SEQ ID NO:44, and a polypeptide comprising the amino acid sequence of any one of the above-mentioned amino acid sequences.
For example, the VH may comprise SEQ ID NO: 81. SEQ ID NO: 82. SEQ ID NO: 83. SEQ ID NO: 84. SEQ ID NO: 85. SEQ ID NO:86 and SEQ ID NO: 87.
In the present application, the isolated antigen binding protein may comprise a light chain variable region VL and a heavy chain variable region VH, which VL may comprise the amino acid sequence of SEQ ID NO:88, said VH may comprise the amino acid sequence set forth in SEQ ID NO:81, and an amino acid sequence shown in seq id no.
In the present application, the isolated antigen binding protein may comprise a light chain variable region VL and a heavy chain variable region VH, which VL may comprise the amino acid sequence of SEQ ID NO:89, said VH may comprise the amino acid sequence set forth in SEQ ID NO: 82.
In the present application, the isolated antigen binding protein may comprise a light chain variable region VL and a heavy chain variable region VH, which VL may comprise the amino acid sequence of SEQ ID NO:90, said VH may comprise the amino acid sequence set forth in SEQ ID NO:83, and a sequence of amino acids shown in seq id no.
In the present application, the isolated antigen binding protein may comprise a light chain variable region VL and a heavy chain variable region VH, which VL may comprise the amino acid sequence of SEQ ID NO:91, said VH may comprise the amino acid sequence set forth in SEQ ID NO: 84.
In the present application, the isolated antigen binding protein may comprise a light chain variable region VL and a heavy chain variable region VH, which VL may comprise the amino acid sequence of SEQ ID NO:92, said VH may comprise the amino acid sequence set forth in SEQ ID NO: 85.
In the present application, the isolated antigen binding protein may comprise a light chain variable region VL and a heavy chain variable region VH, which VL may comprise the amino acid sequence of SEQ ID NO:93, said VH may comprise the amino acid sequence set forth in SEQ ID NO: 87.
In the present application, the isolated antigen binding protein may comprise a light chain variable region VL and a heavy chain variable region VH, which VL may comprise the amino acid sequence of SEQ ID NO:94, said VH may comprise the amino acid sequence set forth in SEQ ID NO:86, and a polypeptide having the amino acid sequence shown in seq id no.
The protein, polypeptide and/or amino acid sequences referred to in this application are also understood to comprise at least the following ranges: variants or homologues having the same or similar function as the protein or polypeptide.
In the present application, the variant may be a protein or polypeptide in which one or more amino acids have been substituted, deleted or added in the amino acid sequence of the protein and/or the polypeptide (e.g., antigen binding protein described herein). For example, the functional variant may comprise a protein or polypeptide that has been altered in amino acids by at least 1, such as 1-30, 1-20, or 1-10, and yet another such as 1, 2, 3, 4, or 5 amino acid substitutions, deletions, and/or insertions. The functional variant may substantially retain the biological properties of the protein or the polypeptide prior to alteration (e.g., substitution, deletion, or addition). For example, the functional variant may retain at least 60%,70%,80%,90%, or 100% of the biological activity (e.g., antigen binding capacity) of the protein or the polypeptide prior to alteration. For example, the substitution may be a conservative substitution.
In the present application, a part of the amino acid sequence of the antigen binding protein may be homologous to a corresponding amino acid sequence in an antibody from a specific species, or belong to a specific class. For example, the variable and constant portions of the antigen binding protein may be derived from the variable and constant regions of antibodies of one animal species (e.g., human). In the present application, the homolog may be a protein or polypeptide having at least about 85% (e.g., having at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence of the protein and/or the polypeptide (e.g., the antigen binding protein described herein).
In this application, homology generally refers to similarity, similarity or association between two or more sequences. "percent sequence homology" can be calculated by: the two sequences to be aligned are compared in a comparison window, the number of positions in the two sequences where the same nucleobase (e.g., A, T, C, G) or the same amino acid residue (e.g., ala, pro, ser, thr, gly, val, leu, ile, phe, tyr, trp, lys, arg, his, asp, glu, asn, gln, cys and Met) is present is determined to give the number of matched positions, the number of matched positions is divided by the total number of positions in the comparison window (i.e., window size), and the result is multiplied by 100 to produce the percent sequence homology. Alignment to determine percent sequence homology can be accomplished in a variety of ways known in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One skilled in the art can determine suitable parameters for aligning sequences, including any algorithms needed to achieve maximum alignment over the full length sequence being compared or over the region of the target sequence. The homology can also be determined by the following method: FASTA and BLAST. For a description of FASTA algorithm, see w.r.pearson and d.j.lipman, "improved tools for biological sequence comparison", proc.Natl. Acad.Sci., U.S. Proc., 85:2444-2448, 1988; "quick sensitive protein similarity search" by d.j.lipman and w.r.pearson, science,227:1435-1441, 1989. For a description of the BLAST algorithm, see "a basic local contrast (alignment) search tool", journal of molecular biology, 215:403-410, 1990.
For example, the isolated antigen binding protein may comprise an antibody heavy chain constant region, and the antibody heavy chain constant region comprises a human IgG constant region.
For example, the isolated antigen binding protein may comprise an antibody heavy chain constant region, and the antibody heavy chain constant region comprises a human IgG1 constant region.
In this application, the gene encoding the human IgG1 constant region may be as shown in GenBank accession number 3500 of NCBI database.
In the present application, the isolated antigen binding protein may comprise an antibody or antigen binding fragment thereof. For example, isolated antigen binding proteins described herein may include, but are not limited to, recombinant antibodies, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, bispecific antibodies, single chain antibodies, diabodies, triabodies, tetrabodies, fv fragments, scFv fragments, fab 'fragments, F (ab') 2 fragments, and camelized single domain antibodies.
The humanized antibody may be selected from any class of immunoglobulins, including IgM, igD, igG, igA and IgE. In this application, the antibody is an IgG antibody, and an IgG1 subtype is used. Also, any type of light chain may be used in the compounds and methods herein. For example, kappa, lambda chains or variants thereof are suitable for use in the present application.
In the present application, the antigen binding fragment may comprise a Fab, fab ', F (ab) 2, fv fragment, F (ab') 2, scFv, di-scFv and/or dAb.
The antigen binding proteins described herein (e.g., SARS-CoV-2 antibodies) are capable of specifically binding the RBD of the S protein of SARS-CoV-2. An antigen binding protein (e.g., an antibody) that "specifically binds" to a SARS-CoV-2 antigen (e.g., the RBD of the S protein of SARS-CoV-2) can generally bind with about an EC50 value or higher (e.g., about) to the RBD of the S protein of SARS-CoV-2, but not to other proteins lacking the sequence of SARS-CoV-2. Whether an antigen binding protein (e.g., an antibody) binds to a SARS-CoV-2 antigen (e.g., the RBD of the S protein of SARS-CoV-2) can be determined using any assay known in the art. For example, by flow assay techniques and enzyme-linked immunosorbent assay.
Antigen binding proteins described herein (e.g., SARS-CoV-2 antibody; e.g., monoclonal antibody 2G 1) are capable of specifically binding to the S protein trimers of WA1/2020, alpha, beta, gamma, kappa, and Delta. The antigen binding proteins described herein (e.g., SARS-CoV-2 antibody; e.g., monoclonal antibody 2G 1) are capable of neutralizing WA1/2020, alpha, beta, gamma, kappa, and Delta pseudoviruses. The antigen binding proteins described herein (e.g., SARS-CoV-2 antibody; e.g., monoclonal antibody 2G 1) are capable of neutralizing the ARS-CoV-2WA1/2020 (US_WA-1/2020 isolate), alpha (B.1.1.7/UK, strain: SARS-CoV-2/huma/CA_CDC_5574/2020), beta (B.1.351/SA, stress: hCoV-19/USA/MD-HP 01542/2021), gamma (P.1/Brazil, stress: SARS-CoV-2/huma/USA/MD-MDH-0841/2021), and Delta variants (B.1.617.2/Indian, strain: GNL-751) mutant viruses.
The antigen binding proteins described herein (e.g., SARS-CoV-2 antibody; e.g., monoclonal antibody 2G 1) are capable of treating an animal model (e.g., a mouse animal model; and/or a rhesus model) infected with SARS-CoV-2 (US_WA-1/2020 isolate), beta- (B.1.351/SA, strain: hCoV-19/USA/MD-HP 01542/2021) or a Delta variant.
The antigen binding proteins described herein (e.g., SARS-CoV-2 antibodies) are capable of blocking the binding of RBD of the S protein of SARS-CoV-2 or a functional fragment thereof to human ACE 2. Blocking assays can be performed using competition methods, e.g., mixing the antigen binding protein (e.g., SARS-CoV-2 antibody) with an antigen (or cells that express an antigen) and a ligand of the antigen (or cells that express a ligand), and reacting the ability of the antigen binding protein to competitively bind to the ligand of the antigen based on the intensity (e.g., fluorescence intensity or concentration) of the detectable label.
The protein and/or amino acid sequences referred to in this application are also understood to comprise at least the following ranges: variants or homologues having the same or similar function as the protein.
In the present application, the variant may be a protein or polypeptide having one or more amino acids substituted, deleted or added in the amino acid sequence of the protein (e.g., antigen binding protein described herein). For example, the functional variant may comprise a protein or polypeptide that has been altered in amino acids by at least 1, such as 1-30, 1-20, or 1-10, and yet another such as 1, 2, 3, 4, or 5 amino acid substitutions, deletions, and/or insertions. The functional variant may substantially retain the biological properties of the protein or the polypeptide prior to alteration (e.g., substitution, deletion, or addition). For example, the functional variant may retain at least 60%,70%,80%,90%, or 100% of the biological activity (e.g., antigen binding capacity) of the protein or the polypeptide prior to alteration. For example, the substitution may be a conservative substitution.
In the present application, a part of the amino acid sequence of the antigen binding protein may be homologous to a corresponding amino acid sequence in an antibody from a specific species, or belong to a specific class. For example, the variable and constant regions of an antibody may be derived from the variable and constant regions of an antibody of an animal species (e.g., human). In the present application, the homolog may be a protein or polypeptide having at least about 85% (e.g., having at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology to the amino acid sequence of the protein and/or the polypeptide (e.g., the antigen binding protein described herein).
In this application, homology generally refers to similarity, similarity or association between two or more sequences. "percent sequence homology" can be calculated by: the two sequences to be aligned are compared in a comparison window, the number of positions in the two sequences where the same nucleobase (e.g., A, T, C, G) or the same amino acid residue (e.g., ala, pro, ser, thr, gly, val, leu, ile, phe, tyr, trp, lys, arg, his, asp, glu, asn, gln, cys and Met) is present is determined to give the number of matched positions, the number of matched positions is divided by the total number of positions in the comparison window (i.e., window size), and the result is multiplied by 100 to produce the percent sequence homology. Alignment to determine percent sequence homology can be accomplished in a variety of ways known in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One skilled in the art can determine suitable parameters for aligning sequences, including any algorithms needed to achieve maximum alignment over the full length sequence being compared or over the region of the target sequence. The homology can also be determined by the following method: FASTA and BLAST. For a description of FASTA algorithm, see w.r.pearson and d.j.lipman, "improved tools for biological sequence comparison", proc.Natl. Acad.Sci., U.S. Proc., 85:2444-2448, 1988; "quick sensitive protein similarity search" by d.j.lipman and w.r.pearson, science,227:1435-1441, 1989. For a description of the BLAST algorithm, see "a basic local contrast (alignment) search tool", journal of molecular biology, 215:403-410, 1990.
Pharmaceutical composition
In another aspect, the present application provides a pharmaceutical composition that may comprise an isolated antigen binding protein described herein, a nucleic acid molecule described herein, a vector described herein, and/or a cell described herein, and optionally a pharmaceutically acceptable adjuvant.
The pharmaceutical compositions described herein can be used directly to bind the S protein of SARS-CoV-2 and thus can be used to prevent and treat diseases associated with coronavirus infection (e.g., COVID-19). In addition, other therapeutic agents may also be used simultaneously.
The pharmaceutical compositions of the present application may contain a safe and effective amount (e.g., 0.001-99 wt%) of the antigen binding proteins described herein, and a pharmaceutically acceptable adjuvant (which may include a carrier or excipient). The pharmaceutical formulation should be compatible with the mode of administration. The pharmaceutical compositions described herein may be formulated for injection, for example, by conventional methods using physiological saline or aqueous solutions containing glucose and other adjuvants. The pharmaceutical compositions, such as injections, solutions are preferably manufactured under sterile conditions. The amount of active ingredient administered is a therapeutically effective amount. In addition, the antigen binding proteins described herein may also be used with other therapeutic agents.
The antigen binding proteins or pharmaceutical compositions described herein may be formulated, administered, and administered in a manner consistent with good medical practice. Considerations in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the etiology of the disorder, the site of agent delivery, the method of administration, and other factors known to medical practitioners. The therapeutic agent (e.g., the antigen binding proteins and/or the pharmaceutical compositions described herein) need not be, but is optionally formulated and/or administered simultaneously with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of therapeutic agent (e.g., antigen binding protein described herein and/or pharmaceutical composition described) present in the formulation, the type of disorder or treatment, and other factors discussed above. These agents can generally be used in any dosage that is empirically/clinically determined to be appropriate and by any route that is empirically/clinically determined to be appropriate. The dosage of antibody administered in combination therapy may be reduced compared to single therapy. The progress of this therapy is readily monitored by conventional techniques.
Use of the same
In another aspect, the present application provides the use of an isolated antigen binding protein described herein, a nucleic acid molecule described herein, a vector described herein, a cell described herein and/or a pharmaceutical composition described herein in the manufacture of a medicament for preventing, alleviating and/or treating an infection by a coronavirus.
The present application provides a method of preventing, alleviating and/or treating an infection by a coronavirus comprising administering to a subject in need thereof an isolated antigen binding protein as described herein, a nucleic acid molecule as described herein, a vector as described herein, a cell as described herein and/or a pharmaceutical composition as described herein.
The present application provides isolated antigen binding proteins, nucleic acid molecules described herein, vectors described herein, cells described herein, and/or pharmaceutical compositions described herein, which can prevent, ameliorate and/or treat coronavirus infections.
In this application, the infection with coronavirus may include covd-19.
In this application, administration of the isolated antigen binding proteins described herein, the nucleic acid molecules described herein, the vectors described herein, the cells described herein, and/or the pharmaceutical compositions described herein may have potent neutralizing capacity against pseudoviruses of covd-19 (e.g., pseudoviruses prepared against WA1/2020, alpha, beta, gamma, kappa, and Delta S protein trimers (Spike trimers).
In this application, administration of the isolated antigen binding protein described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein and/or the pharmaceutical composition described herein may have potent neutralizing capacity against different strains of COVID-19 (e.g., SARS-CoV-2WA1/2020 (US_WA-1/2020 isolate), alpha (B.1.1.7/UK, strain: SARS-CoV-2/human/USA/CA_CDC_5574/2020), beta (B.1.351/SA, strain: hCoV-19/USA/MD-HP 01542/2021), gamma (P.1/Brazil, strain: SARS-CoV-2/human/USA/MD-MDH-0841/2021) and Delta variants (B.1.617.2/Ind, strain: GNL-751).
In this application, administration of the isolated antigen binding protein described herein, the nucleic acid molecule described herein, the vector described herein, the cell described herein and/or the pharmaceutical composition described herein may have good therapeutic effects on animal models (e.g., mouse models) of different strains (e.g., SARS-CoV-2WA1/2020 (US_WA-1/2020 isolate), alpha (B.1.1.7/UK, strain: SARS-CoV-2/human/USA/CA_CDC_5574/2020), beta (B.1.351/SA, strain: hCoV-19/USA/MD-HP 01542/2021), gamma (P.1/Brazil, strain: SARS-CoV-2/human/USA/MD-MDH-0841/2021) and Delta variants (B.1.617.2/Ind, strain: GNL-751)) that have been infected with COVID-19.
In another aspect, the present application provides a method of detecting SARS-CoV-2 comprising the step of administering an isolated antigen binding protein described herein, a nucleic acid molecule described herein, a vector described herein, a cell described herein, and/or a pharmaceutical composition described herein. In the present application, the isolated antigen binding protein, the nucleic acid molecule described herein, the vector described herein, the cell described herein and/or the pharmaceutical composition described herein are capable of specifically and/or with high affinity binding to SARS-CoV-2, e.g., to S protein trimers (Spike trimers) of strains WA1/2020, alpha, beta, gamma, kappa, and Delta.
The antigen binding proteins of the present application can be used in detection applications, for example for detecting samples, thereby providing diagnostic information. For example, the antibodies and/or methods described herein can be used to detect a specimen (e.g., a pharyngeal swab test sample, such as serum, whole blood, sputum, oral/nasopharyngeal secretions or washes, urine, feces, pleuroperitoneal fluid, cerebrospinal fluid, and tissue specimens) of a subject (e.g., a patient suspected of being infected with SARS-CoV-2, or having been infected with SARS-CoV-2) as an indicator of efficacy observations and whether there is infectivity and isolation is desired. For example, the antibodies and/or methods described herein can provide a monitoring regimen for therapeutic intervention.
In the present application, a sample (specimen) is taken to include a cell, a tissue sample, and a biopsy specimen. The term "biopsy" as used herein shall include all kinds of biopsies known to a person skilled in the art. A biopsy as used in this application may thus include tissue samples prepared, for example, by endoscopic methods or by puncture or needle biopsy of an organ. For example, the sample may comprise a fixed or preserved cell or tissue sample.
The present application also provides a kit comprising the antigen binding proteins of the present application. In some cases, the kit may further comprise a container, instructions for use, buffers, and the like. For example, the pro-binding proteins of the present application may be immobilized to a detection plate.
Without intending to be limited by any theory, the following examples are presented merely to illustrate the isolated antigen binding proteins, methods of preparation, uses, and the like of the present application and are not intended to limit the scope of the invention of the present application.
Examples
Example 1 preparation of candidate antibodies
Flow cytometry was performed to isolate memory B cells from peripheral blood of a patient recovering from COVID-19, which recognize SARS-CoV-2 RBD, and to sort individual B cells from these isolated memory B cells. Cloning to obtain antibody V region gene and reconstructing IgG antibody by single cell PCR method.
The resulting candidate antibodies comprise the amino acid sequences as shown in table 1:
TABLE 1
Example 2 affinity assay of candidate antibodies binding to SARS-CoV-2S trimeric protein
The day before the experiment, the antigen SARS-CoV-2 Spike primer protein (i.e.S protein trimer) was added to the coating buffer (pH 9.6,0.05M carbonate buffer) to a final concentration of 2. Mu.g/mL. 100 μl of liquid was added to each well and gently shaken until the liquid was spread evenly over the bottom of each well. Placing the ELISA plate containing the antigen into a sealing bag, and sealing and placing the sealing bag into a refrigerator at 4 ℃ for antigen adsorption overnight;
the next day, the supernatant was discarded, and the mixture was dried on clean absorbent paper, 250. Mu.L/well of wash solution (pH 7.4 PBST) was added, and the mixture was kept for 5 minutes each time, and the supernatant was discarded, and the drying was repeated 3 times on clean absorbent paper. 250. Mu.L/well of blocking solution (PBST+3% skimmed milk powder) was added, and the mixture was placed in a new envelope pocket and blocked at 37℃for 1h. The supernatant was discarded, and the residue was dried on a clean absorbent paper, washed with 250. Mu.L/well of wash solution, kept for 5min each time, and repeated 3 times.
The candidate antibody prepared in example 1 was subjected to gradient dilution using an antibody diluent (PBS at pH 7.4).
The diluted candidate antibody sample is sucked by 100 mu L/hole and added into the enzyme label plate after treatment, and the enzyme label plate is placed into a new sealing bag for incubation at 37 ℃ for 1h. Removing supernatant, drying on clean absorbent paper, washing with 250 μl/hole of washing solution, holding for 5min each time, The supernatant was discarded and the residue was dried on clean absorbent paper and repeated 3 times. Anti-human IgG HRP secondary antibody was added at a 1:5000 dilution per 100. Mu.L/well, placed in a new envelope and incubated for 1h at 37 ℃. The supernatant was discarded, and the residue was dried on a clean absorbent paper, washed with 250. Mu.L/well of wash solution, kept for 5min each time, and repeated 3 times. Adding TMB color development solution at 100 μl/well, coating with tin foil, developing at room temperature under dark condition for 15min, observing blue reaction, adding stop solution at 50 μl/well (2M H) 2 SO 4 ) Immediately after mixing, the microplate reader reads at 450 nm. Wherein the control is a human ACE2-Fc fusion protein (which comprises the amino acid sequence as shown in SEQ ID NO: 100).
The results are shown in fig. 1 and table 2. As a result, the candidate antibodies were found to have higher affinity for S-trimer protein.
TABLE 2
Sequence number | Clone number | EC50(μg/ml) | Sequence number | Clone number | EC50(μg/ml) |
1 | 13H8 | 0.013 | 5 | 8G4 | 0.014 |
2 | 2G1 | 0.135 | 6 | 8G9 | 0.088 |
3 | 5H10 | 0.020 | 7 | 6F12 | 0.012 |
4 | 7G10 | 0.011 | 8 | Control | 1.065 |
EXAMPLE 3 determination of neutralizing Activity of candidate antibody against pseudo SARS-CoV-2 Virus
The day before the experiment, HEK293T-ACE2 cells to be infected were inoculated into 96-well cell culture plates at an inoculum size of about 1X 10 4 Individual cells/well, 5% co 2 The incubator was incubated overnight at 37 ℃. The next day, when the cell density is about 30%, virus infection is carried out, frozen pseudoviruses are taken out and placed on ice to be melted or the pseudoviruses are placed at 4 ℃ to be melted completely, the virus usage amount is 0.25 mu L/hole, the candidate antibodies prepared in the example 1 with different dilution concentrations are respectively mixed at 37 ℃ for 30min, and the mixture is added into a cell culture system to infect target cells. 6h after virus infection, the supernatant was aspirated and 100. Mu.L of complete medium was added for further 48 hours. And (4) 48 hours after the replacement of the pseudovirus infected cells, observing the green fluorescent protein expression and detecting the luciferase activity through a fluorescence microscope to judge the infection efficiency. To the direction of 100 mu L of One-Glo luciferase is added into each hole, the mixture is mixed by shaking, and the mixture is read by an enzyme label instrument after 3 min.
The results are shown in FIG. 2 and Table 3. As a result, it was found that the candidate antibodies each had a good neutralizing activity against the pseudo SARS-CoV-2 virus, and could effectively inhibit the continued amplification of the SARS-CoV-2 virus. Wherein the control is a human ACE2-Fc fusion protein (which comprises the amino acid sequence as shown in SEQ ID NO: 100).
TABLE 3 Table 3
Sequence number | Clone number | EC50(μg/ml) | Sequence number | Clone number | IC50(μg/ml) |
1 | 13H8 | 0.013 | 5 | 8G4 | 0.061 |
2 | 2G1 | 0.011 | 6 | 8G9 | 0.042 |
3 | 5H10 | 0.058 | 7 | 6F12 | 0.100 |
4 | 7G10 | 0.322 | 8 | Control | 0.404 |
EXAMPLE 4 determination of neutralizing Activity of candidate antibody against real SARS-CoV-2 Virus
The day before the experiment, vero-E6 cells to be infected were inoculated into cell culture plates and cultured overnight. And on the next day, carrying out virus infection, taking out frozen virus, melting, respectively mixing and incubating candidate antibodies with different dilution concentrations, and adding the mixture into a cell culture system to infect target cells. After virus infection, the supernatant was aspirated and the culture was continued with the addition of complete medium. Cytopathy is observed for 3 to 5 days, and the neutralization activity is judged.
The following experimental procedures were completed in the BSL-3 laboratory as follows:
(1) Samples were prepared in MEM medium (containing 1% diabodies) as 200. Mu.g/ml solution, then 10-fold serial dilutions were made, 200. Mu.g/ml, 20. Mu.g/ml, 2. Mu.g/ml, 0.2. Mu.g/ml, 0.02. Mu.g/ml, 0.002. Mu.g/ml for a total of 6 dilutions, 2 multiplex wells per concentration, 50. Mu.l per well, and then an equal volume of 100TCID was added to each well 50 Virus, 37 ℃,5% CO 2 Incubator action for 1.5h;
(2) After 1.5h, the cell culture medium was added to 96-well plates at a concentration of 1X 10 in 100. Mu.l per well 5 Individual cells/mL Vero cell suspension;
(3) Simultaneously setting up cell control and virus drip-back control;
cell control: 100. Mu.L of MEM medium (containing 1% diabody) per well was added to 100. Mu.L of Vero cell suspension in 96 well plates for a total of 4 multiplex wells;
virus drip control: will be 100TCID 50 The virus was serially diluted 3 times 10 times with MEM medium (containing 1% diabody) to give 10TCID 50 ,1TCID 50 ,0.1TCID 50 . mu.L of MEM medium (containing 1% diabodies) was added to each well of a 96-well plate, and then an equal volume of 100TCID was added to each well 50 ,10TCID 50 ,1TCID 50 ,0.1TCID 50 Virus, 4 duplicate wells per dilution, 37 ℃,5% CO 2 After 1.5h of incubator action, 1.5h of incubation, 100. Mu.L of 1X 10 concentration was added to each well 5 Individual cells/mL Vero cell suspension. The virus drip-back control results are in the range of 32-320TCID50/50 μl, and the experiment is effective.
(4) Cell 37 ℃,5% CO 2 Incubating the incubator for 3-5 days;
(5) Cytopathy (CPE) was observed under an optical microscope, and changes in CPE in cells were noted as "+", changes in CPE in cells were not observed or normal cell morphology was noted as "-".
And (3) calculating the inhibition effect: half-maximal effective concentration of inhibitory virus (EC 50 )
Wherein A: percentage of inhibition greater than 50%, B: percent less than 50% inhibition, C: log (dilution factor), D: log (sample concentration corresponding to less than 50% inhibition). If the sample does not inhibit viral action, the EC50 will not be measured. The results are shown in Table 4.
TABLE 4 Table 4
Clone number | IC 50 (μg/ml) |
9E12 | 0.03 |
9D11 | 0.3 |
5B2 | 0.3 |
13A12 | 0.03 |
2G1 | 0.003 |
3A4 | 0.03 |
10D4 | 0.03 |
9A6 | 3.16 |
8G9 | 31.6 |
The results in Table 4 demonstrate that the antibodies described above achieve effective neutralization of SARS-CoV-2 real virus. Neutralization IC of SARS-CoV-2 true virus 50 As a result, 9E12 was 0.03. Mu.g/mL, 9D11 was 0.3. Mu.g/mL, 5B2 was 0.3. Mu.g/mL, 13A12 was 0.03. Mu.g/mL, 2G1 was 0.003. Mu.g/mL, 3A4 was 0.03. Mu.g/mL, 10D4 was 0.03. Mu.g/mL, 9A6 was 3.16. Mu.g/mL, and 8G9 was 31.6. Mu.g/mL. The said antibody can neutralize SARS-CoV-2 virus.
Therefore, the candidate antibodies have good neutralizing activity on the real SARS-CoV-2 virus, and can effectively inhibit the continuous amplification of the SARS-CoV-2 virus.
EXAMPLE 5 determination of neutralizing Activity of candidate antibodies against SARS-CoV-2 Virus in animals
The candidate antibody prepared in example 1 was applied to an animal model infected with SARS-CoV-2 virus. The neutralizing activity of the candidate antibody against SARS-CoV-2 virus after administration was determined by quantitative PCR assay of the viral content. As a result, it was found that the candidate antibodies had good neutralizing activity against the candidate antibodies in the animal body.
EXAMPLE 6 detection of SARS-CoV-2 binding kinetics by candidate antibodies
The binding kinetics of monoclonal antibodies were examined using CM5 chip (Cytiva 29149603) using WA-1 S1-His or S protein trimer (Spike primer) as antigen.
1. Antigen conjugation
Buffer solution: PBS (Cytiva BR 100672)
Flow rate: 10 mu L/min
Antigen dilution: acetate pH 5.0 (Cytiva BR 100351)
Antigen concentration: 1 μg/mL
Amino coupling kit (cytova BR 100050): mixing activator EDC and NHS 1:1, and blocking agent ethanolamine
The chip was activated for 700s, the diluted antigen was coupled to a level of about 70RU, and the excess unreacted sites were blocked.
2. Antibody binding
Buffer solution: HBS-EP (Cytiva BR 100669)
Flow rate: 30 mu L/min
Antibody concentration: 2-fold dilution of 0.2. Mu.g/mL to 0.0125. Mu.g/mL
Regeneration buffer: glycine pH 1.5 (Cytiva BR 100354)
According to the set concentration arrangement, the diluted antibodies with each concentration are respectively added into the corresponding 96-well holes to be combined for 120s, dissociated for 120s and regenerated and eluted for 30s as a cycle, and the samples are sequentially loaded from low concentration to high concentration.
The affinity results are shown in Table 5, and the IgG type monoclonal antibodies can be combined with S protein trimer with high efficiency, and the affinity reaches-10 to-15M.
TABLE 5
EXAMPLE 7 affinity studies of candidate antibodies against Spike protein
To avoid the effects of "chorea", monoclonal antibody 2G1 WAs subjected to papain cleavage to obtain Fab fragments, and the binding kinetics of monovalent Fab to the S protein trimers (Spike trimers) of WA1/2020, alpha, beta, gamma, kappa, and Delta were examined.
The binding kinetics of monoclonal antibodies were tested using the CM5 chip (Cytiva 29149603) using the S protein trimers of WA1/2020, alpha, beta, gamma, kappa, and Delta as antigens.
1. Antigen conjugation
Buffer solution: PBS (Cytiva BR 100672)
Flow rate: 10 mu L/min
Antigen dilution: acetate pH 5.0 (Cytiva BR 100351)
Antigen concentration: 1 μg/mL
Amino coupling kit (cytova BR 100050): mixing activator EDC and NHS 1:1, and blocking agent ethanolamine
The chip was activated for 700s, the diluted antigen was coupled to a level of about 70RU, and the excess unreacted sites were blocked.
2. Antibody binding
Buffer solution: HBS-EP (Cytiva BR 100669)
Flow rate: 30 mu L/min
Antibody concentration: 2-fold dilution of 0.2. Mu.g/mL to 0.0125. Mu.g/mL
Regeneration buffer: glycine pH 1.5 (Cytiva BR 100354)
According to the set concentration arrangement, the diluted antibodies with each concentration are respectively added into the corresponding 96-well holes to be combined for 120s, dissociated for 120s and regenerated and eluted for 30s as a cycle, and the samples are sequentially loaded from low concentration to high concentration.
The results are shown in Table 6.
TABLE 6
Example 8 detection of neutralizing Capacity of candidate antibodies against pseudoviruses
The pseudovirus contains Spike protein on the surface of SARS-CoV-2, can specifically infect ACE2 positive cells, selects the pseudovirus prepared by Spike proteins of WA1/2020, D614G, cluster 5, alpha, beta, gamma and Delta, and performs a pseudovirus neutralization assay according to the following steps.
1. ACE2-293T cells in logarithmic growth phase were grown at 1X 10 4 Well plated into white transparent 96-well plates (Corning, 3903);
2. the next day, different concentrations of neutralizing antibodies (20,2,0.2,0.02,0.002,0.0002,0.00002. Mu.g/mL) were diluted with DMEM medium (Gibco, C11995500 BT) +10% FBS (Gibco, 10270-106); and an appropriate volume of 0.2. Mu.L/100. Mu.L of COV2-S protein pseudovirus (Yeasen, 11903ES 50) was diluted in the P2 laboratory.
3. Respectively sucking 55 mu L of antibodies with different concentrations and 55 mu L of diluted pseudoviruses, uniformly mixing, setting negative control holes and positive control holes, and incubating at 37 ℃ for 30min;
4. the medium in the 96-well plate was aspirated, 100. Mu.L of medium containing the corresponding antibody-virus mixture was added to the plate, and the plate was incubated with CO 2 Continuously culturing in an incubator;
after 5.6 hours, the culture medium containing the virus is sucked into a waste liquid cylinder containing 84 disinfectant, and the proportion of 84 disinfectant is not less than 30 percent. Then 100. Mu.L of fresh medium was added and CO continued 2 Culturing in an incubator for 48 hours;
6. the outer surface of the 96-well plate was sterilized with 75% alcohol by sealing the 96-well plate with a sealing film in a biosafety cabinet, then taken out, 90. Mu.L of luciferase substrate (Promega, E6120) was added to each well, and after incubation for 3-5min, the fluorescence value of each well was read using an enzyme-labeled instrument.
7. The inhibition ratio at each concentration was calculated from the fluorescence values.
The results are shown in FIG. 3, and the results of FIG. 3 demonstrate that monoclonal antibody 2G1 can effectively neutralize various pseudoviruses. The neutralization IC50 WAs WA 1/2020.0032. Mu.g/mL, D614G 0.0038. Mu.g/mL, cluster 5.0002. Mu.g/mL, alpha 0.0013. Mu.g/mL, beta 0.0028. Mu.g/mL, gamma 0.0005. Mu.g/mL, delta 0.0082. Mu.g/mL.
Example 9 detection of neutralizing Capacity of candidate antibodies against real Virus
2G1 study of the neutralizing ability of mutant true viruses.
Virus neutralization experiments were performed using SARS-CoV-2WA1/2020 (US_WA-1/2020 isolate), alpha (B.1.1.7/UK, strain: SARS-CoV-2/human/USA/CA_CDC_5574/2020), beta (B.1.351/SA, stress: hCoV-19/USA/MD-HP 01542/2021), gamma (P.1/Brazil, stress: SARS-CoV-2/human/USA/MD-MDH-0841/2021) and Delta variants (B.1.617.2/Indian, strain: GNL-751) mutant true viruses. The brief method comprises the following steps: antibodies were serially diluted 3-fold in MEM medium (Gibco) at a concentration of 20. Mu.g/mL to prepare working solutions. Dilutions were added to an equal volume of 100TCID50 virus and incubated for 1 hour at room temperature. The mixture was added to 96-well plates with pooled Vero cells. Cell blank control and virus infection control were set simultaneously. 37 ℃ and 5% CO 2 After 3 days of culture, cytopathic effect (CPE) was observed under a microscope, and plaque was counted for efficacy evaluation. Holes with CPE change were recorded as "+", otherwise as "-".
The IC50 value is calculated according to the following equation: iC50=Antilog (D-C× (50-B)/(A-B)). Wherein A represents an inhibition ratio of more than 50%, B represents an inhibition ratio of less than 50%, C is lg (dilution factor), and D is lg (sample concentration at which the inhibition ratio is less than 50%). All experiments were performed in a biosafety class 3 laboratory. As shown in Table 7, 2G1 has high virus neutralization capacity for WA1/2020, alpha, beta, gamma, delta.
TABLE 7
True virus neutralization ability | IC 50 (μg/ml) | IC 100 (μg/ml) |
WA1/2020 | 0.0240 | 0.0411 |
Alpha | 0.0138 | 0.0411 |
Beta | 0.0046 | 0.0137 |
Gamma | 0.0079 | 0.0137 |
Delta | 0.0079 | 0.0411 |
EXAMPLE 10 in vivo biological Activity Studies of candidate antibodies
10.1 mouse model
AC70 was human ACE2 transgenic mice (Taconic Biosciences, cat# 18222), and AC70 mice were divided into three groups, a control group (PBS), a medium dose group (6.7 mg/mL monoclonal antibody 2G 1) at a low dose (2.2 mg/mL monoclonal antibody 2G 1), and a high dose (20 mg/kg monoclonal antibody 2G 1), each group of 14 mice. All mice were infected with a 100LD50 schedule. Administering a first dose of monoclonal antibody 2G1 and PBS 4 hours after infection; the second and third were administered on days 2 and 4, respectively, after infection. Mice were observed clinically at least once daily and described in terms of clinical health. Scoring on a scale of 1 to 4, a score of 1 being healthy in a standardized scale of 1 to 4 scoring system; score 2 is with standing fur and drowsiness; score 3 is an additional clinical symptom such as humpback posture, orbit tightening, increased respiratory rate and/or weight loss > 15%; score 4 indicates dyspnea and/or cyanosis, unwilling to move when stimulated, or immediate euthanasia is required for weight loss of > 20%. Four mice in each group were euthanized on day 4 post infection to assess viral load and histopathology of the lung and brain. The incidence and motility of the remaining mice was continued to be monitored up to 14 days after infection.
The method of constructing a mouse infection model is shown in FIG. 4.
Body weight of mice after infection was measured and the results are shown in fig. 5. The results in FIG. 5 demonstrate that there is no significant weight loss at all three doses, high, medium and low, for WA1/2020 and Beta infected mice, indicating that even a low dose of 2.2mg/mL monoclonal antibody 2G1 is sufficient to neutralize the virus. In the Delta infected group, the weight of animals in the 20mg/kg high dose group is not obviously reduced, and the weight reduction phenomenon occurs at the doses of 6.7mg/kg and 2.2 mg/kg.
The WA1/2020, beta and Delta mouse infection models were observed and scored clinically and the results are shown in FIG. 6. The results in FIG. 6 demonstrate that even the 2.2mg/kg low dose monoclonal antibody 2G1, WA1/2020, beta model has no significant clinical condition. Whereas in the Delta model, no clinical symptoms appear at the high dose of 20mg/kg, and clinical reactions appear at the medium and low doses.
According to the euthanasia principle of mice, the mice are considered to die and are not expected to move when dyspnea and/or cyanosis occur or weight loss is more than or equal to 20 percent, and living curves are drawn. Survival curves for WA1/2020, beta and Delta mice infection models were observed and plotted, with the results shown in FIG. 7. The results in FIG. 7 demonstrate that both high, medium and low doses in WA1/2020 and Beta infection models can treat mice without death, with 100% survival, and recovery from health. In the Delta infection model, mice with a survival rate of 10% recovered to a healthy state in the low dose mice, mice with a medium dose of 55.6% survived to a healthy state, and mice with a high dose of 100% survived to a healthy state.
10.2 rhesus monkey model
Rhesus monkeys aged 6-7 were randomized into control groups, low dose (10 mg/kg) and high dose (50 mg/kg), one male and one female for each group. 4mL of 1X 10 for each animal 5 The TCID50 virus infects animals through tracheal intubation. Antibody 2G1 antibody and PBS were administered intravenously 24 hours post infection. The rhesus monkeys were continuously monitored for disease-related changes, body weight and body temperature were measured daily, and samples of pharyngeal swabs and anal swabs were collected for virus titration. The method of construction of rhesus infection model is shown in figure 8.
On day 7 post-infection, animals were euthanized and tissue samples were collected. Viral RNA was extracted using QIAamp Viral RNA Mini Kit (Qiagen). According to the specification of the supplierII One Step qRT-PCR/>Green Kit, vazyme Biotech co., ltd) quantitated viral RNA using one-step real-time quantitative PCR and primers for RBD gene using the quantitive primers: RBD-qF1:5'-CAATGGTTAAGGCAGG-3' (SEQ ID NO. 101); RBD-qR1:5'-CTCAAGGTCTGGATCACG-3' (SEQ ID NO. 102).
The content of viral RNA in rhesus infection model was measured with pharyngeal swabs and the results are shown in fig. 9. The results in FIG. 9 demonstrate that control animals only detected viral RNA loading on days 3,4 and 5 post challenge, with viral RNA loading ranging between 10e3-10e7 copies/mL, with peak viral replication at day 2 post challenge, with slight fluctuations. Overall, the viral load change law shows the proliferation process of the virus in vivo. The RNA load of the high-dose group 2 experimental animals is always in a descending trend, the virus cannot be detected after the virus is reduced from 10e6 copy/mL to 10e3 copy/mL and the virus is detected after the virus is removed from 3 rd and 4 th days, the RNA load of the low-dose group 2 experimental animals is always in a descending trend, the virus is reduced from 10e6 copy/mL to 10e3 copy/mL, and the virus cannot be detected after the virus is removed from 4 th day after the virus is removed.
The anal swab was tested for viral RNA content in the rhesus model and the results are shown in fig. 10. The results in FIG. 10 demonstrate that the control animals can detect viral RNA between 10e3-10e5 copies/mL on days 4,5 and 7, whereas no virus is detected at both the high and low doses.
To further understand the distribution of virus in different tissues of the upper respiratory tract and the lung, tissues of different parts of the trachea, bronchi and lung of animals of a control group and a low and high dose group were collected on the 7 th day after virus challenge, and the viral loads in different organs and tissues were determined. The results are shown in fig. 11, and the results of fig. 11 indicate that: on day 7 post-infection, about 1×10e5 to 1×10e7 copies/g of viral RNA were detected in both the trachea and left and right bronchi of the control animals. The virus was detected in the right middle lung, left lower lung and left bronchi in the high dose group, and only in the trachea in the low dose group.
EXAMPLE 11 in vivo biological Activity Studies of candidate antibodies
In order to analyze the antigen-antibody interaction pattern and binding site of Spike (S) protein and 2G1 antibody, a novel coronavirus (SARS-CoV-2) WA-1 strain trimer S protein extracellular domain and 2G1 antibody complex three-dimensional structure WAs analyzed using a single particle reconstitution technique of a cryo-electron microscope, and the site of antibody binding on S protein WAs confirmed.
Test procedure
1. Expression and purification of trimeric S proteins
1.1 construction of recombinant expression plasmid for trimeric S protein
An engineered S protein is used to improve the stability of the protein, and the specific scheme is as follows: proline mutations were introduced at positions 817, 892, 899, 942, 986 and 987 of the extracellular region of the S protein (amino acids 1-1208, genbank ID: QHD 43416.1); meanwhile, the furin enzyme cutting sites 'RRAR' of the mutation 682 to 685 are 'GSAS'; fusion of T4 fibritin foldon at the C end of the extracellular region of the S protein assists the extracellular region of the S protein to form a trimer; finally, the C-terminal fragment carrying the 1xFlag tag was cloned into the pCAG vector.
1.2 Expression and purification of S protein
The recombinant expression plasmid was transiently transfected with HEK 293F cells to secrete expressed S protein. When the density of HEK 293F cells in suspension culture reaches 2.0X10 6 Transfection was performed at/mL. In 1L HEK 293F cells, 1mg S plasmid was mixed with 3mg PEI4000 and incubated for 15min before addition to the cells, and after further culture for 60h, cell supernatants were collected for purification.
The supernatant obtained by transfection was filtered, and the cell culture medium was removed by concentration and displacement using a buffer (25 mM Tris-HCl,150mM NaCl,pH8.0). Purification was performed using Anti-Fag M2 resin, and 60mL of buffer (25 mM Tris-HCl,150mM NaCl,pH8.0) was used to wash off the contaminating proteins, followed by elution with 1XFlag peptide. The eluate was concentrated to 2mL and further purified using a molecular sieve chromatography column (Superose 6 Increate 10/300GL, GE company) to obtain a trimeric S protein.
Incubating the obtained S protein and the 2G1 antibody for 1h at a molar ratio of 1:5, concentrating, further purifying by using molecular sieve column chromatography, and removing excessive 2G1 antibody to obtain an S-2G1 complex for preparing a frozen electron microscope sample.
2. Preparation of frozen samples, data collection and single particle method three-dimensional reconstruction
S-2G1 complex was concentrated to 2.5mg/mL, 3.3. Mu.L was added dropwise to hydrophilized carrier mesh (Quantifoil Au R1.2/1.3), and a sample preparation robot was used by Vitrobot (Mark IV, thermo Scientific) to prepare a frozen electron microscope sample through three steps of sample adsorption, suction of excess sample, and quick freezing in sample liquid ethane.
Data collection was performed using a Titan Krios (FEI) 300kV electron microscope equipped with a Gatan K3 camera. Transferring the prepared frozen electron microscope sample into an electron microscope lens cone, and debugging the electron microscope to an optimal stateThe Movie stacks data were collected automatically using automation software. Setting the defocusing range to be 1.2-2.2 μm, and setting the magnification of the K3 camera to be 81000 times, wherein the size of the corresponding pixel isEach picture collected had 32 frames, each frame exposed for 0.08s and total exposure time for 2.56s. The total electron dose of the photograph is about +.>
And (3) carrying out drift correction on the collected original pictures by using MotionCor2, then manually screening the corrected pictures, manually selecting uniform and clear electron microscope pictures, and removing pictures with poor quality or serious pollution. Particles of the S protein and 2G1 complex were automatically selected using Relion 3.0.6. And after carrying out two-dimensional classification on all the particles, selecting matched particles for three-dimensional model reconstruction. Firstly, carrying out two-round three-dimensional classification through crySPARC, then selecting proper particles to carry out 3D remodeling, and then correcting by utilizing Relion to obtain a three-dimensional model of the S protein and 2G1 complex. In order to further improve the resolution of the interaction interface of the S protein and the 2G1, model correction and optimization are performed on the local area, and a three-dimensional model of RBD and 2G1 parts is obtained. The resolution was determined using the fourier shell correlation function curve of the gold standard, and the threshold for the determination was set to 0.143. The detailed procedures of the complex purification, data collection and three-dimensional reconstruction by the single particle method and various parameters are shown in fig. 12-13 and fig. 14. Wherein FIG. 12a shows the purification of 2G1 and S protein complexes by molecular sieve chromatography; FIG. 12b shows E.mu.Ler angle distribution of the S-2G1 complex final 3D model; FIGS. 12c-12d show the local resolution of the S-2G1 complex overall structure (c) and the local RBD-2G1 structure (d); FIG. 12e shows FSC plots of S-2G1 (blue) and RBD-2G1 (orange) complex resolution; FIGS. 12f,12G show the FSC curves of the optimized S-2G1 complex model. FIG. 13a shows a representative cryo-electron microscope micrograph of the S-2G1 complex and the 2D classification, scale in 2D classification being 10nm; fig. 13b shows the data processing steps.
And G, the FSC curve of the RBD-2G1 complex finishing model is identical to f.
In order to build an atomic model of an S protein and 2G1 complex of SARS-CoV-2, 4A8 (PDB ID:7C 2L) is taken as a template, and the corresponding atomic model is superimposed into a refrigeration electron microscope density file of the whole S-2G1 and the local RBD-2G1 obtained by the single particle reconstruction method in the last step by using molecular dynamics flexible matching. Firstly, taking an antibody 4A8 as a template to obtain a 2G1 Chainsaw model; taking a locally optimized RBD-2G1 density file as a standard, and further manually adjusting an atomic model by using Coot software, wherein the principle is to compound chemical characteristics of each amino acid residue into a surrounding density cloud; and finally, optimizing the whole atomic model by using Phenix software, and correcting by using a secondary structure and geometric constraint to prevent overfitting. The detailed data of data collection, 3D model reconstruction and atomic model construction are shown in fig. 14.
Test results
In order to study the binding pattern of the 2G1 antibody to the S protein, the epitope of the 2G1 antibody was revealed and the S-2G1 complex was resolved by a method using a cryoelectron microscopeResolution structure (fig. 15a, fig. 15-16). FIG. 15a is a graph showing the cryoelectron density of S-2G1 complex in orthogonal directions. The heavy and light chains of 2G1 are blue and cyan, respectively. Each monomer structure of the trimeric S protein is grey, orange and pink, respectively. Fig. 15b-e show interactions between 2G1 and RBD and adjacent RBD'. RBD and 2G1 interact primarily through hydrophobic interactions (fig. 15c and 15 d). The 2G1 heavy chains (CDRH 3 and CDRH 1) are located above adjacent RBDs' (fig. 15 e).
FIG. 16a shows the epitope boundaries of three similar antibodies (S2E 12, B1-182.1 and REGN 10933) respectively in different colors, with the epitopes of S2E12, B1-182.1 and REGN10933 being red, orange and green, respectively. FIG. 16B shows a comparison of the binding angles of 2G1, S2E12, B1-182.1 and REGN 10933. The 2G1 epitope border is blue. The epitope boundaries of ACE2 binding sites, 2G1, S2E12, B1-182.1 and REGN10933 are superimposed on RBD and shown in black, blue, red, orange and green, respectively. The connection line of the Fab center point and the RBD center of the 2G1 antibody is taken as a central axis, the angles of S2E12, B1-182.1 and the central axis are about 6 degrees, and the angle of REGN10933 and the main axis is about 13 degrees. FIG. 16c shows amino acid position statistics for epitopes on RBD of 2G1, ACE2, S2E12, B1-182.1 and REGN 10933.
However, in this overall structure, the structural density at the interface between RBD and 2G1 is not clear, so that the sub-complex of the 2G1 antibody and the RBD binding domain is resolved by a locally optimized computational methodThe resolution structure provides a structural basis for accurately analyzing the interaction of 2G1 with RBD (fig. 15 b). In the S-2G1 complex structure, three soluble 2G1 antibody Fab domains bind to the three RBD domains of trimeric S spike protein, respectively. Also in this configuration, all RBDs are in a "down" conformation, with the trimeric S protein as a whole in a locked conformation (FIG. 15 a). In addition, an additional density of the fatty acid Linoleic Acid (LA) was found in the S protein, consistent with the location of the LA binding pocket in the locked conformation S trimer structure reported in the literature.
Through detailed analysis of the 2G1 and RBD binding interface, it was found that antibody 2G1 binds to the loop region at the RBD tip, which partially overlaps with the ACE2 receptor binding site and does not belong to the mutant hot spot region of VOCs. The heavy chain of 2G1 participates in RBD interactions primarily through three Complementarity Determining Regions (CDRs) CDRH1 (amino acid residues 30 to 35), CDRH2 (amino acid residues 50 to 65) and CDRH3 (amino acid residues 98 to 111); the light chain is involved in interactions mainly through the two CDR regions of CDRL1 (amino acid residues 23 to 36) and CDRL3 (amino acid residues 91 to 100) (fig. 15 b-e). The binding interface between RBD and 2G1 is mainly stabilized by a broad hydrophobic interaction network, of which the more important interactions are: phe486 of the RBD top loop region binds to Tyr33, tyr52 on the heavy chain and Tyr34, tyr93, trp99 on the light chain via hydrophobic and/or-interactions (FIG. 15 c). CDRH1 and CDRH3 of the 2G1 heavy chain are directly above the LA binding pocket in the adjacent RBD' (fig. 15b and 15 e). The 2G1 was compared with three antibodies with similar epitopes (S2E 12, B1-182.1 and REGN 10933) (FIGS. 16 a-c). Structural comparison analysis showed that the epitope of 2G1 partially overlapped with the three antibodies (S2E 12, B1-182.1 and REGN 10933), but they had different binding directions (fig. 16B). In addition, 2G1 has a relatively narrow binding epitope (F456, a475, G476, S477, T478, E484, G485, F486, N487, Y489), which may have the advantage of being less susceptible to viral mutation, thus achieving broad-spectrum virus neutralization capability (fig. 16 c).
By resolving the complex cryoelectron microscope structure of the S protein and 2G1, 2G1 was revealed to be able to bind the S protein in a locked conformation, in which the RBD domain is in a "down" conformation in each monomer of the S trimer. No other antibodies in the structural database have been found to bind this locked conformation. Although the epitopes of 2G1, S2E12 and B1-182.1 are relatively similar and partially overlapping, it is reported that S2E12 and B1-182.1 bind in structure to RBD in the "up" conformation, whereas 2G1 is able to bind S protein in the locked conformation, probably due to the specific angle of 2G1 antibody binding. In the current stage of research, it is speculated that the reason for the neutralizing activity of 2G1 is not only to block ACE2 binding to RBD, but also to prevent conformational changes in the fusion state S by binding to the locked conformation S protein. In addition, amino acids of the 2G1 antibody epitope located at a specific position at the RBD tip deviate from the mutant hot spot of VOCs, potentially increasing the broad-spectrum neutralization activity of this antibody. Thus, the complex structure of S-2G1 may provide a good reference for developing vaccines and optimizing optimal combination therapies.
The embodiments of the present application have been described in detail above, but the present application is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solutions of the present application within the scope of the technical concept of the present application, and all the simple modifications belong to the protection scope of the present application. In addition, the specific features described in the foregoing embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described in detail. Moreover, any combination of the various embodiments of the present application may be made without departing from the spirit of the present application, which should also be considered as disclosed herein.
Sequence listing
<110> Jie Ke (Tianjin) biomedical Co., ltd., american Jie Ke laboratory Co., ltd., jie ku (Shanghai) biomedical research Co., ltd.)
<120> antigen binding proteins that specifically bind SARS-CoV-2
<130> 0093-PA-017CN
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1 5 10
<210> 32
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR2-8G4
<400> 32
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Ala
1 5 10
<210> 33
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR2-6F12
<400> 33
Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 34
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR2-8G9
<400> 34
Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 35
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR3-13H8
<400> 35
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Met Phe Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Val Arg
20 25 30
<210> 36
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR3-2G1
<400> 36
Arg Phe Thr Ile Ser Arg Asp Lys Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Phe Tyr Tyr Cys Ala Arg
20 25 30
<210> 37
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR3-5H10
<400> 37
Gln Val Thr Ile Ser Val Asp Lys Ser Ile Asn Thr Ala Tyr Leu Gln
1 5 10 15
Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg
20 25 30
<210> 38
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR3-7G10
<400> 38
Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 39
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR3-8G4
<400> 39
Arg Leu Thr Met Thr Thr Asp Thr Pro Thr Thr Thr Ala Tyr Met Glu
1 5 10 15
Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 40
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR3-6F12
<400> 40
Leu Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Tyr Leu Lys
1 5 10 15
Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 41
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR3-8G9
<400> 41
Gln Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 42
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR4-13H8;5H10;7G10;8G9
<400> 42
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 43
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR4-8G4;6F12
<400> 43
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 44
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> HFR4-2G1
<400> 44
Trp Asp Glu Gly Thr Met Val Thr Val Ser Ser
1 5 10
<210> 45
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1-13H8
<400> 45
Thr Gly Ser Ser Ser Asp Val Gly Ser Tyr Asp Leu Val Ser
1 5 10
<210> 46
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1-2G1
<400> 46
Thr Gly Thr Ser Ser Asp Val Gly Gly Ser Asn Tyr Val Ser
1 5 10
<210> 47
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1-5H10
<400> 47
Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser
1 5 10
<210> 48
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1-7G10;8G4
<400> 48
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His
1 5 10
<210> 49
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1-8G9
<400> 49
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Phe Asp Val His
1 5 10
<210> 50
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1-6F12
<400> 50
Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Asn Leu Val Ser
1 5 10
<210> 51
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR2-13H8;2G1;6F12
<400> 51
Glu Val Ser Lys Arg Pro Ser
1 5
<210> 52
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR2-5H10
<400> 52
Asp Val Ser Asp Arg Pro Ser
1 5
<210> 53
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR2-7G10;8G4
<400> 53
Gly Asn Ser Asn Arg Pro Ser
1 5
<210> 54
<211> 7
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR2-8G9
<400> 54
Gly Asp Ser Asn Arg Pro Ser
1 5
<210> 55
<211> 9
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR3-13H8
<400> 55
Cys Ser Tyr Val Gly Ser Phe Trp Leu
1 5
<210> 56
<211> 10
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR3-2G1
<400> 56
Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val
1 5 10
<210> 57
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR3-5H10
<400> 57
Ser Ser Tyr Thr Ser Ser Asn Thr Arg Val Val
1 5 10
<210> 58
<211> 13
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR3-7G10
<400> 58
Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser Pro Tyr Val
1 5 10
<210> 59
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR3-8G4
<400> 59
Gln Ser Tyr Asp Ser Ser Leu Ser Gly Tyr Val
1 5 10
<210> 60
<211> 12
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR3-8G9
<400> 60
Gln Ser Tyr Asp Asn Ser Leu Ser Ala Pro Tyr Val
1 5 10
<210> 61
<211> 11
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR3-6F12
<400> 61
Cys Ser Tyr Ala Gly Ser Ser Thr Pro Tyr Val
1 5 10
<210> 62
<211> 22
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR1-13H8;5H10;7G10;6F12
<400> 62
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys
20
<210> 63
<211> 22
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR1-2G1
<400> 63
Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys
20
<210> 64
<211> 22
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR1-8G4;8G9
<400> 64
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys
20
<210> 65
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR2-13H8
<400> 65
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Phe Met Ile Tyr
1 5 10 15
<210> 66
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR2-2G1
<400> 66
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Ser
1 5 10 15
<210> 67
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR2-5H10
<400> 67
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr
1 5 10 15
<210> 68
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR2-7G10
<400> 68
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Pro Leu Ile Tyr
1 5 10 15
<210> 69
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR2-8G4
<400> 69
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Val Leu Ile Tyr
1 5 10 15
<210> 70
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR2-8G9
<400> 70
Trp Tyr Gln Gln Leu Pro Glu Thr Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 71
<211> 15
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR2-6F12
<400> 71
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Ile Ile Ser
1 5 10 15
<210> 72
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR3-13H8
<400> 72
Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
1 5 10 15
Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 73
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR3-2G1
<400> 73
Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
1 5 10 15
Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 74
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR3-5H10
<400> 74
Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
1 5 10 15
Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asn Tyr Tyr Cys
20 25 30
<210> 75
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR3-7G10
<400> 75
Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser
1 5 10 15
Leu Ala Ile Ala Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 76
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR3-8G4
<400> 76
Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser
1 5 10 15
Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Thr Asp Tyr Tyr Cys
20 25 30
<210> 77
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR3-8G9
<400> 77
Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser
1 5 10 15
Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 78
<211> 32
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR3-6F12
<400> 78
Gly Val Ser Thr Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
1 5 10 15
Leu Thr Ile Ser Gly Leu Gln Ala Gly Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 79
<211> 13
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR4-13H8;2G1;7G10;8G4;8G9;5H10
<400> 79
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
1 5 10
<210> 80
<211> 13
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LFR4-6F12
<400> 80
Phe Gly Ser Gly Thr Lys Val Thr Val Leu Gly Gln Pro
1 5 10
<210> 81
<211> 122
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VH-13H8
<400> 81
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Ser His
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Arg Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Met Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Val Arg Gly His Glu Thr Ser Leu Phe Arg Ser Ser Phe Asp Asp Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 82
<211> 122
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VH-2G1
<400> 82
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Gln Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ile Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Lys Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Phe Tyr Tyr Cys Ala
85 90 95
Arg Gly Leu Ile Arg Gly Ile Ile Met Thr Gly Ala Phe Asp Ile Trp
100 105 110
Asp Glu Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 83
<211> 120
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VH-5H10
<400> 83
Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Arg Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Val Asp Lys Ser Ile Asn Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Leu Phe Leu Trp Glu Ala Gly Pro Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 84
<211> 126
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VH-7G10
<400> 84
Glu Val Gln Leu Leu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Val Asn Gly Asn Thr Arg Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Lys Met Ile Pro Val Leu Gly Val Phe Thr Lys Gly Gly
100 105 110
Trp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 85
<211> 131
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VH-8G4
<400> 85
Gln Leu Gln Leu Gln Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Ala Trp Ile Ser Ala Phe Asn Gly Asn Thr Asp Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Leu Thr Met Thr Thr Asp Thr Pro Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Ser Pro Phe Tyr Tyr Asp Arg Ser Gly His Tyr Thr
100 105 110
Arg Asp Tyr Tyr Ala Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
115 120 125
Val Ser Ser
130
<210> 86
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VH-6F12
<400> 86
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Phe Gly Thr Thr His Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Leu Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Tyr
65 70 75 80
Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Arg Arg Gly Gly Asp Val Phe Glu Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 87
<211> 119
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VH-8G9
<400> 87
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Val Asn Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Ser Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Gln Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Arg Thr Val Tyr Tyr Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 88
<211> 112
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VL-13H8
<400> 88
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Ser Ser Ser Asp Val Gly Ser Tyr
20 25 30
Asp Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Phe
35 40 45
Met Ile Tyr Glu Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Val Gly Ser
85 90 95
Phe Trp Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
100 105 110
<210> 89
<211> 113
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VL-2G1
<400> 89
Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Ser
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Ser Glu Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser
85 90 95
Asn Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
100 105 110
Pro
<210> 90
<211> 114
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VL-5H10
<400> 90
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asn Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Asn Thr Arg Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
Gln Pro
<210> 91
<211> 116
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VL-7G10
<400> 91
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Pro
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ala Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Ser Pro Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val
100 105 110
Leu Gly Gln Pro
115
<210> 92
<211> 114
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VL-8G4
<400> 92
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Val
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Thr Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly
100 105 110
Gln Pro
<210> 93
<211> 115
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VL-8G9
<400> 93
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Phe Asp Val His Trp Tyr Gln Gln Leu Pro Glu Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Asn Ser
85 90 95
Leu Ser Ala Pro Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
Gly Gln Pro
115
<210> 94
<211> 114
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> VL-6F12
<400> 94
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Ile Ile Ser Glu Val Ser Lys Arg Pro Ser Gly Val Ser Thr Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95
Ser Thr Pro Tyr Val Phe Gly Ser Gly Thr Lys Val Thr Val Leu Gly
100 105 110
Gln Pro
<210> 95
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1 formula
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa=Ser or Thr
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa=Asp or Asn
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa=Ile or Val
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa=Ala, gly or Ser
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa=Gly, ser or Tyr
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa= Asp, phe, asn or Tyr
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa=Asp, leu or Tyr
<220>
<221> misc_feature
<222> (14)..(14)
<223> Xaa=His or Ser
<400> 95
Thr Gly Xaa Ser Ser Xaa Xaa Gly Xaa Xaa Xaa Xaa Val Xaa
1 5 10
<210> 96
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1 formula 2
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa=Ser or Thr
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa=Gly or Ser
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa=Ser or Tyr
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa=Asp or Asn
<220>
<221> misc_feature
<222> (12)..(12)
<223> xaa=leu or Tyr
<400> 96
Thr Gly Xaa Ser Ser Asp Val Gly Xaa Xaa Xaa Xaa Val Ser
1 5 10
<210> 97
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1 formula 3
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa=Gly or Ser
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa=Ser or Tyr
<220>
<221> misc_feature
<222> (12)..(12)
<223> xaa=leu or Tyr
<400> 97
Thr Gly Thr Ser Ser Asp Val Gly Xaa Xaa Asn Xaa Val Ser
1 5 10
<210> 98
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1 formula 4
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa=Ser or Tyr
<400> 98
Thr Gly Thr Ser Ser Asp Val Gly Gly Xaa Asn Tyr Val Ser
1 5 10
<210> 99
<211> 14
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> LCDR1 formula 5
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa=Phe or Tyr
<400> 99
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Xaa Asp Val His
1 5 10
<210> 100
<211> 846
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> ACE2-Fc
<400> 100
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Glu Pro Lys Ser Ser Asp Lys Thr His
610 615 620
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
625 630 635 640
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
645 650 655
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
660 665 670
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
675 680 685
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
690 695 700
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
705 710 715 720
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
725 730 735
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
740 745 750
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
755 760 765
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
770 775 780
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
785 790 795 800
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
805 810 815
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
820 825 830
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
835 840 845
<210> 101
<211> 16
<212> DNA
<213> Artificial sequence (Artificial Sequence)
<220>
<223> RBD-qF1
<400> 101
caatggttaa ggcagg 16
<210> 102
<211> 18
<212> DNA
<213> Artificial sequence (Artificial Sequence)
<220>
<223> RBD-qR1
<400> 102
ctcaaggtct ggatcacg 18
Claims (16)
1. An isolated antigen binding protein that specifically binds SARS-CoV-2 comprising an LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3 selected from any one of the following groups:
(1) The amino acid sequence of LCDR1 is shown as SEQ ID NO. 45, the amino acid sequence of LCDR2 is shown as SEQ ID NO. 51, the amino acid sequence of LCDR3 is shown as SEQ ID NO. 55, the amino acid sequence of HCDR1 is shown as SEQ ID NO. 2, the amino acid sequence of HCDR2 is shown as SEQ ID NO. 8, and the amino acid sequence of HCDR3 is shown as SEQ ID NO. 15;
(2) The amino acid sequence of LCDR1 is shown as SEQ ID NO. 46, the amino acid sequence of LCDR2 is shown as SEQ ID NO. 51, the amino acid sequence of LCDR3 is shown as SEQ ID NO. 56, the amino acid sequence of HCDR1 is shown as SEQ ID NO. 1, the amino acid sequence of HCDR2 is shown as SEQ ID NO. 9, and the amino acid sequence of HCDR3 is shown as SEQ ID NO. 16;
(3) The amino acid sequence of LCDR1 is shown as SEQ ID NO. 47, the amino acid sequence of LCDR2 is shown as SEQ ID NO. 52, the amino acid sequence of LCDR3 is shown as SEQ ID NO. 57, the amino acid sequence of HCDR1 is shown as SEQ ID NO. 3, the amino acid sequence of HCDR2 is shown as SEQ ID NO. 10, and the amino acid sequence of HCDR3 is shown as SEQ ID NO. 17;
(4) The amino acid sequence of LCDR1 is shown as SEQ ID NO. 48, the amino acid sequence of LCDR2 is shown as SEQ ID NO. 53, the amino acid sequence of LCDR3 is shown as SEQ ID NO. 58, the amino acid sequence of HCDR1 is shown as SEQ ID NO. 4, the amino acid sequence of HCDR2 is shown as SEQ ID NO. 11, and the amino acid sequence of HCDR3 is shown as SEQ ID NO. 18;
(5) The amino acid sequence of LCDR1 is shown as SEQ ID NO. 48, the amino acid sequence of LCDR2 is shown as SEQ ID NO. 53, the amino acid sequence of LCDR3 is shown as SEQ ID NO. 59, the amino acid sequence of HCDR1 is shown as SEQ ID NO. 5, the amino acid sequence of HCDR2 is shown as SEQ ID NO. 12, and the amino acid sequence of HCDR3 is shown as SEQ ID NO. 19;
(6) The amino acid sequence of LCDR1 is shown as SEQ ID NO. 49, the amino acid sequence of LCDR2 is shown as SEQ ID NO. 54, the amino acid sequence of LCDR3 is shown as SEQ ID NO. 60, the amino acid sequence of HCDR1 is shown as SEQ ID NO. 7, the amino acid sequence of HCDR2 is shown as SEQ ID NO. 14, and the amino acid sequence of HCDR3 is shown as SEQ ID NO. 21; and, a step of, in the first embodiment,
(7) The amino acid sequence of LCDR1 is shown as SEQ ID NO. 50, the amino acid sequence of LCDR2 is shown as SEQ ID NO. 51, the amino acid sequence of LCDR3 is shown as SEQ ID NO. 61, the amino acid sequence of HCDR1 is shown as SEQ ID NO. 6, the amino acid sequence of HCDR2 is shown as SEQ ID NO. 13, and the amino acid sequence of HCDR3 is shown as SEQ ID NO. 20.
2. The isolated antigen binding protein of claim 1, comprising a light chain variable region VL and a heavy chain variable region VH, wherein the VL and VH are selected from any one of the group consisting of:
(1) VL comprises the amino acid sequence shown in SEQ ID NO. 88, and VH comprises the amino acid sequence shown in SEQ ID NO. 81;
(2) VL comprises the amino acid sequence shown in SEQ ID NO. 89, and VH comprises the amino acid sequence shown in SEQ ID NO. 82;
(3) VL comprises the amino acid sequence shown in SEQ ID NO. 90, and VH comprises the amino acid sequence shown in SEQ ID NO. 83;
(4) VL comprises the amino acid sequence shown in SEQ ID NO. 91, and VH comprises the amino acid sequence shown in SEQ ID NO. 84;
(5) VL comprises the amino acid sequence shown in SEQ ID NO. 92, and VH comprises the amino acid sequence shown in SEQ ID NO. 85;
(6) VL comprises the amino acid sequence shown in SEQ ID NO. 93, and VH comprises the amino acid sequence shown in SEQ ID NO. 87; and, a step of, in the first embodiment,
(7) VL comprises the amino acid sequence shown in SEQ ID NO. 94, and VH comprises the amino acid sequence shown in SEQ ID NO. 86.
3. The isolated antigen binding protein of claim 1, comprising an antibody light chain constant region.
4. The isolated antigen binding protein of claim 1, comprising an antibody heavy chain constant region.
5. The isolated antigen binding protein of claim 1, which has activity in neutralizing SARS-CoV-2.
6. The isolated antigen binding protein of claim 1, comprising an antibody or antigen binding fragment thereof.
7. The isolated antigen binding protein of claim 6, wherein the antigen binding fragment comprises a Fab, fab ', F (ab) 2, fv fragment, F (ab') 2, scFv, di-scFv, and/or dAb.
8. The isolated antigen binding protein of claim 6, wherein the antibody is a fully human antibody.
9. An isolated nucleic acid molecule encoding the isolated antigen binding protein of any one of claims 1-8.
10. A vector comprising the nucleic acid molecule of claim 9.
11. A cell comprising the nucleic acid molecule of claim 9 or the vector of claim 10.
12. The cell of claim 11, which expresses the isolated antigen binding protein of any one of claims 1-8.
13. A method of making the isolated antigen binding protein of any one of claims 1-8, the method comprising culturing the cell of claim 11 under conditions such that the isolated antigen binding protein of any one of claims 1-8 is expressed.
14. A pharmaceutical composition comprising the isolated antigen binding protein of any one of claims 1-8, the nucleic acid molecule of claim 9, the vector of claim 10 and/or the cell of claim 11, and optionally a pharmaceutically acceptable adjuvant.
15. Use of the isolated antigen binding protein of any one of claims 1-8, the nucleic acid molecule of claim 9, the vector of claim 10, the cell of claim 11 and/or the pharmaceutical composition of claim 14 in the manufacture of a medicament for preventing, alleviating and/or treating an infection with novel coronavirus covd-19.
16. A method of detecting SARS-CoV-2 comprising the step of administering the isolated antigen binding protein of any one of claims 1-8 and said method is a non-disease diagnostic method.
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CN111423508A (en) * | 2020-03-31 | 2020-07-17 | 江苏省疾病预防控制中心(江苏省公共卫生研究院) | Separated SARS-CoV-2 protein binding molecule for resisting virus infection |
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WO2008060331A2 (en) * | 2006-05-19 | 2008-05-22 | Amgen Inc. | Antibodies to sars coronavirus |
CN111592595B (en) * | 2020-04-27 | 2021-02-19 | 南京医科大学 | Neutralizing antibody against novel coronavirus SARS-Cov-2 and application thereof |
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CN111560070B (en) * | 2020-05-27 | 2021-10-01 | 江苏省疾病预防控制中心(江苏省公共卫生研究院) | Antibody aiming at novel coronavirus NP protein and detection application thereof |
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CN111423508A (en) * | 2020-03-31 | 2020-07-17 | 江苏省疾病预防控制中心(江苏省公共卫生研究院) | Separated SARS-CoV-2 protein binding molecule for resisting virus infection |
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