CN116178540A - anti-ANG 2 antibodies and uses thereof - Google Patents
anti-ANG 2 antibodies and uses thereof Download PDFInfo
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- CN116178540A CN116178540A CN202111422308.1A CN202111422308A CN116178540A CN 116178540 A CN116178540 A CN 116178540A CN 202111422308 A CN202111422308 A CN 202111422308A CN 116178540 A CN116178540 A CN 116178540A
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Abstract
The invention relates to the field of biological medicine. In particular, the invention provides anti-ANG 2 heavy chain variable region polypeptides, antibodies or antigen-binding fragments thereof, particularly fully human anti-ANG 2 heavy chain variable region polypeptides, antibodies or antigen-binding fragments thereof. The invention also provides polynucleotides encoding the anti-ANG 2 heavy chain variable region polypeptides, antibodies, or antigen-binding fragments thereof, as well as expression vectors and host cells for expressing the anti-ANG 2 heavy chain variable region polypeptides, antibodies, or antigen-binding fragments thereof. The invention further provides methods of producing the anti-ANG 2 heavy chain variable region polypeptides, antibodies, or antigen-binding fragments thereof, and uses thereof.
Description
Technical Field
The invention relates to the field of biological medicine. In particular, the invention provides anti-ANG 2 heavy chain variable region polypeptides, antibodies or antigen-binding fragments thereof, particularly fully human anti-ANG 2 heavy chain variable region polypeptides, antibodies or antigen-binding fragments thereof.
Background
Angiogenin (angiogenin) is part of the vascular growth factor family. As a member of the Angiopoietin family, angiopoietin-2 (also known as ANG2 or ANGPT 2) is a secreted glycoprotein whose overexpression promotes neovascularization. The direct receptor of ANG2 is TIE2, the TIE2 can be combined with angiopoietin ANG1, ANG2 and ANG4, the TIE1 as an orphan receptor can not be directly combined with ANG to be activated, after ANG-TIE2 is combined, the TIE1 and the TIE2 form a complex to be activated, and the ANG-TIE signal channel after ligand combination can regulate vascular permeability, inflammation and pathological remodeling of blood vessels in tumors.
ANG proteins are capable of stimulating the transport and localization of TIE receptors expressed on endothelial cells to cell-cell, cell-matrix junctions. ANG1 and ANG2 function in reverse to regulate angiogenesis. ANG1 is expressed by mesenchymal cells and acts as an agonist to activate TIE2 function, promoting the survival of vascular endothelial cells, tight junctions and stability of blood vessels; ANG2 is expressed by endothelial cells and is usually stored in endothelial cells Wei Boxiao (Weibel-Palade body), and when hypoxia, inflammation and the like are involved in promoting neovascularization, ANG2 is released from Wei Boxiao and competes with ANG1, and acts as an antagonist of TIE2 to inhibit vascular stability, and VEGF and the like together promote neovascularization. Meanwhile, many studies indicate that the overexpression of ANG2 plays a key role in promoting lymph node metastasis of tumors, and thus ANG2 is an important target for pathological angiogenesis-related diseases and tumor treatment.
Antibodies that first neutralized ANG2 interactions with its receptor TIE2 by 2004 demonstrated that blocking ANG2 activity was effective in inhibiting tumor neovascularization and tumor growth (Oliner, j., et al (2004) Cancer Cell 6 (5): 507-516). Therefore, the monoclonal antibody for developing the ANG2 target has great application value in the fields of solid tumor treatment and eye disease treatment related to pathological angiogenesis.
anti-ANG 2 antibodies exist in the prior art (see, e.g., WO2015179166A1 and WO2011014469 A1), including the clinically fully human antibody neva Su Shan anti (nesvacumab) targeting ANG 2. There remains a need in the art to develop new and improved anti-ANG 2 fully human antibodies.
Disclosure of Invention
In one aspect, the present invention provides a heavy chain variable region polypeptide that specifically binds ANG2 comprising HCDR1, HCDR2 and HCDR3 sequences wherein
(a) The HCDR1 sequence is shown as SEQ ID NO. 110
GFTFX 1 X 2 YX 3 MX 4 (SEQ ID NO:110)
Wherein X is 1 Is S or N; x is X 2 S or V; x is X 3 S or G; x is X 4 Is N or H;
(b) The HCDR2 sequence is shown as VISYDGSNKY (SEQ ID NO: 5);
(c) The HCDR3 sequence is shown as SEQ ID NO. 111
X 5 TLDGYTAGYYYGMDV (SEQ ID NO:111)
Wherein X is 5 Is A or E.
In another aspect, the invention provides an anti-ANG 2 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region polypeptide comprising HCDR1, HCDR2 and HCDR3 sequences and a light chain variable region polypeptide comprising LCDR1, LCDR2 and LCDR3 sequences wherein the HCDR1, HCDR2 and HCDR3 sequences are as set forth above and the LCDR1, LCDR2 and LCDR3 sequences are selected from any of (1) - (21):
(1) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 68; (2) the LCDR1 sequence shown in SEQ ID NO. 82; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 83; (3) the LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 84; (4) the LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 85; (5) the LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 86; (6) the LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 80; (7) the LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 39; (8) the LCDR1 sequence shown in SEQ ID NO. 17; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 19; (9) the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO 59; (10) the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 36; (11) the LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 28; and the LCDR3 sequence shown in SEQ ID NO. 29; (12) the LCDR1 sequence shown in SEQ ID NO. 7; the LCDR2 sequence shown in SEQ ID NO. 13; and the LCDR3 sequence shown in SEQ ID NO. 14; (13) the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 26; (14) the LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 9; (15) the LCDR1 sequence shown in SEQ ID NO. 63; the LCDR2 sequence shown in SEQ ID NO. 64; and the LCDR3 sequence shown in SEQ ID NO. 65; (16) the LCDR1 sequence of SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 32; and the LCDR3 sequence shown in SEQ ID NO. 33; (17) the LCDR1 sequence of SEQ ID NO. 42; the LCDR2 sequence shown in SEQ ID NO. 43; and the LCDR3 sequence shown in SEQ ID NO. 44; (18) the LCDR1 sequence shown in SEQ ID NO. 50; the LCDR2 sequence shown in SEQ ID NO. 51; and the LCDR3 sequence shown in SEQ ID NO. 52; (19) the LCDR1 sequence of SEQ ID NO. 46; the LCDR2 sequence shown in SEQ ID NO. 47; and the LCDR3 sequence shown in SEQ ID NO. 48; (20) the LCDR1 sequence shown in SEQ ID NO. 21; the LCDR2 sequence shown in SEQ ID NO. 22; and the LCDR3 sequence shown in SEQ ID NO. 23; (21) the LCDR1 sequence shown in SEQ ID NO. 54; the LCDR2 sequence shown in SEQ ID NO. 55; and the LCDR3 sequence shown in SEQ ID NO. 56.
In yet another aspect, the present invention provides an anti-ANG 2 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region polypeptide comprising HCDR1, HCDR2 and HCDR3 sequences and a light chain variable region polypeptide comprising LCDR1, LCDR2 and LCDR3 sequences, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 sequences are selected from any one of (1) - (3): (1) the HCDR1 sequence shown in SEQ ID NO. 87; the HCDR2 sequence shown in SEQ ID NO. 88; the HCDR3 sequence shown in SEQ ID NO. 89; the LCDR1 sequence shown in SEQ ID NO. 90; the LCDR2 sequence shown in SEQ ID NO. 91; and the LCDR3 sequence shown in SEQ ID NO. 92; (2) the HCDR1 sequence shown in SEQ ID NO. 95; the HCDR2 sequence shown in SEQ ID NO. 96; an HCDR3 sequence shown in SEQ ID NO. 97; the LCDR1 sequence shown in SEQ ID NO. 98; the LCDR2 sequence shown in SEQ ID NO. 99; and the LCDR3 sequence shown in SEQ ID NO. 100; (3) the HCDR1 sequence shown in SEQ ID NO. 103; the HCDR2 sequence shown in SEQ ID NO. 104; the HCDR3 sequence shown in SEQ ID NO. 105; the LCDR1 sequence shown in SEQ ID NO. 106; the LCDR2 sequence shown in SEQ ID NO. 91; and the LCDR3 sequence shown in SEQ ID NO. 107.
The invention further provides a multispecific antibody comprising a first antigen-binding portion which specifically binds ANG2 and a second antigen-binding portion which specifically binds a second antigen, wherein the first antigen-binding portion comprises a heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof of the invention.
The invention also provides a polynucleotide encoding a heavy chain variable region polypeptide, antibody or antigen binding fragment thereof or a multispecific antibody of the invention.
The invention also provides an expression vector comprising a polynucleotide of the invention.
The invention also provides a host cell comprising a polynucleotide or expression vector of the invention.
The invention also provides a pharmaceutical composition comprising a heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof or multispecific antibody of the invention, and a pharmaceutically acceptable carrier.
The invention also relates to the use of a heavy chain variable region polypeptide, antibody or antigen binding fragment thereof, multispecific antibody or pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of: (1) angiogenesis-related eye diseases; or (2) cancer. In one embodiment, the angiogenesis-related eye disease is macular degeneration, retinal vein occlusion, retinopathy of prematurity, diabetic retinopathy, neovascular glaucoma, pathologic myopia, macular edema, retinal edema, diabetic macular edema, or choroidal neovascularization disease. In another embodiment, the cancer is lung cancer, liver cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, ovarian cancer, colorectal cancer, gastric cancer, breast cancer, prostate cancer, uterine cancer, hodgkin's lymphoma, esophageal cancer, anal cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, renal cancer, soft tissue sarcoma, bladder cancer, central Nervous System (CNS) tumors, mesothelioma, glioma, meningioma, or pituitary adenoma.
Drawings
FIGS. 1A-1C show the binding activity of candidate monoclonal supernatants to antigen ANG2 as determined based on ELISA methods.
FIGS. 2A-2C show the blocking activity of candidate monoclonal supernatants based on ELISA to block binding of ANG2 to receptor TIE 2.
FIGS. 3A-3B show the binding activity of a candidate antibody to the antigen ANG2 as determined based on ELISA methods.
FIG. 4 shows the binding activity of a candidate antibody to antigen ANG1 as determined based on ELISA method.
FIGS. 5A-5B show the blocking activity of candidate antibodies based on ELISA to block binding of ANG2 to the receptor TIE 2.
FIG. 6 shows the blocking activity of candidate antibodies based on FACS assays to block binding of ANG2 and hTIE2-HEK293 cells.
FIG. 7 shows the inhibitory activity of candidate antibodies against ANG 2-mediated phosphorylation of TIE 2.
FIGS. 8A-8C show the inhibition of tumor growth by candidate antibodies in a mouse subcutaneous engraftment tumor model; ns, not significant; * P <0.05; * P <0.01; * P <0.001; * P <0.0001.
FIG. 9 shows in vivo plasma concentration versus time profiles of candidate antibodies in Balb/C mice.
Detailed Description
Definition of the definition
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Also, protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, immunology-related terms and laboratory procedures as used herein are terms and conventional procedures that are widely used in the corresponding arts. Meanwhile, in order to better understand the present invention, definitions and explanations of related terms are provided below.
As used herein, the terms "comprises," "comprising," "includes," "including," "having" and "containing" are open-ended, meaning the inclusion of the stated elements, steps or components, but not the exclusion of other non-recited elements, steps or components. The expression "consisting of … …" does not include any elements, steps or components not specified. The expression "consisting essentially of … …" means that the scope is limited to the specified elements, steps, or components, plus any optional elements, steps, or components that do not significantly affect the basic and novel properties of the claimed subject matter. It should be understood that the expressions "consisting essentially of … …" and "consisting of … …" are encompassed within the meaning of the expression "comprising".
As used herein, "antibody" refers to an immunoglobulin or fragment thereof that specifically binds an epitope through at least one antigen binding site. The term "antibody" includes multispecific antibodies (e.g., bispecific antibodies), fully human antibodies, non-human antibodies, humanized antibodies, chimeric antibodies, single domain antibodies, and antigen-binding fragments. Antibodies may be synthetic (e.g., produced by chemical or biological coupling), enzymatically treated, or recombinantly produced. Antibodies provided herein include any immunoglobulin type (e.g., igG, igM, igD, igE, igA and IgY), any class (e.g., igG1, igG2, igG3, igG4, igA1, and IgA 2), or subclass (e.g., igG2a and IgG2 b).
As used herein, a molecule, antibody or product number is used only to distinguish or identify a molecule or product and is not intended to represent such identification as a feature of the molecule or product of the invention. It will be appreciated by those skilled in the art that other molecules, antibodies or products may use such labels, for example for the purpose of distinguishing or identifying, but do not refer to the same or equivalent molecules, antibodies or products. Similarly, like numbering or identification used in the examples is also for convenience of illustration only, and the molecular antibodies or products of the invention are defined by the features described in the appended claims.
As used herein, an "antigen binding fragment" refers to a portion of a full-length antibody that is less than full length, but that comprises at least a portion of the variable region of the full-length antibody (e.g., comprises one or more CDRs and/or one or more antigen binding sites), and thus retains at least a portion of the ability of the full-length antibody to specifically bind an antigen. Examples of antigen binding fragments include, but are not limited to, sdabs (e.g., variable domains of heavy chain antibodies), fv, scFv, dsFv, scdsFv, fab, scFab, fab ', F (ab') 2 Diabodies, fd and Fd' fragments, and other fragments (e.g., fragments comprising modifications).
As used herein, a "full length antibody" generally comprises four polypeptides: two Heavy Chains (HC) and two Light Chains (LC). Each light chain comprises a light chain variable region (VL) and a light chain constant region (CL). Each heavy chain comprises a heavy chain variable region (VH) and a heavy chain constant region (CH).
The light chain variable region and the heavy chain variable region may each comprise three highly variable "Complementarity Determining Regions (CDRs)" and four relatively conserved "Framework Regions (FR)", and are connected from the N-terminus to the C-terminus in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR 4. Herein, CDRs of the light chain variable region (CDRL or LCDR) may be referred to as LCDR1, LCDR2 and LCDR3, and CDRs of the heavy chain variable region (CDRH or HCDR) may be referred to as HCDR1, HCDR2 and HCDR3.
In the present invention, the amino acid sequences of the CDRs are all shown according to the AbM definition rules (the sequences shown according to the AbM definition rules are also in the claims of the present invention). However, it is well known to those skilled in the art that CDRs of an antibody can be defined in a variety of ways, such as Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loops (see, e.g., chothia, c.et Al, nature,342,877-883 (1989); and Al-Lazikani, B.et Al, J.mol.biol.,273,927-948 (1997)), kabat based on antibody sequence variability (see, e.g., kabat, E.A.et Al. (1991) Sequences of Proteins of Immunological Interest, fifthEdition, U.S.Department of Health and Human Services, NIH Publication No. 91-3242), abM (Martin, A.C.R.and J.Allen (2007) "Bioinformatics tools for antibody engineering," in S.Dubel (ed.), handbook of Therapeutic antibodies.Weinheim: wiley-VCH Verlag, pp.95-118), contact (MacCallum, R.M.et Al., (1996) J.mol.biol.262:732-745), IMGT (Lefranc, M.—P.; 2011 (6), IMGT, the International ImMunoGeneTics Information System Cold Spring Harb Protoc.; and Lefranc, M.—P.et Al., dev.Comp. Immunol.; 27,55)), and a large number of crystal structures (37-77)), and a large number of clusters based on the use of the crystal structure. It will be appreciated by those skilled in the art that unless otherwise specified, the terms "CDR" and "complementarity determining region" of a given antibody or region thereof (e.g., variable region) are to be understood as encompassing complementarity determining regions defined in any of the above known schemes as described by the present invention. Although the scope of the claimed invention is based on the sequences shown by the AbM definition rules, the amino acid sequences corresponding to the definition rules according to other CDRs should also fall within the scope of the claimed invention.
Thus, when referring to defining antibodies with a particular CDR sequence as defined herein, the scope of the antibodies also encompasses antibodies whose variable region sequences comprise the particular CDR sequence, but whose purported CDR boundaries differ from the particular CDR boundaries defined herein by the application of different protocols (e.g., different assignment system rules or combinations).
As used herein, the terms "framework region" and "framework region" are used interchangeably. As used herein, the term "framework region", "framework region" or "FR" residues refer to those amino acid residues in the variable region of an antibody other than the CDR sequences as defined above.
Generally, an "Fv" fragment consisting of one VH and one VL by non-covalent interactions is considered to be the smallest antigen-binding fragment that contains an antigen-binding site. But single variable domains (single domain antibodies) also have antigen binding capacity. "Single chain Fv (scFv)" may be obtained by linking VH and VL via a peptide linker. "disulfide stabilized Fv (dsFv)" or "single chain disulfide stabilized Fv (scdsFv or dsscFv)", respectively, can be obtained by introducing disulfide bonds into Fv or scFv.
As used herein, "Fab" comprises one complete antibody light chain (VL-CL) and antibody heavy chain variable region and one heavy chain constant region (VH-CH 1, also known as Fd). A single chain "Fab (scFab)" can be obtained by ligating CL and CH1 in "Fab" with a peptide linker. "F (ab') 2 "essentially comprising two Fab fragments linked by a disulfide bridge of the hinge region. "Fab '" is F (ab') 2 Is capable of reducing F (ab') 2 Disulfide bonds of the hinge region are obtained.
As used herein, the terms "fully human antibody," "fully human antibody," and "human antibody" are used interchangeably and refer to antibodies produced by humans or antibodies having an amino acid sequence corresponding to an antibody produced by humans prepared using any technique known in the art. Fully human antibodies are defined to encompass whole or full length antibodies, fragments thereof, and/or antibodies comprising at least one human heavy and/or light chain polypeptide. Fully human antibodies have a low immunogenicity in humans. In some embodiments, the anti-ANG 2 antibodies or antigen-binding fragments thereof of the invention are fully human antibodies.
As used herein, an "affinity matured" antibody comprises one or more modifications (e.g., substitutions of amino acid residues) in one or more CDRs such that the affinity of the affinity matured antibody for the antigen is improved as compared to a parent antibody that does not comprise such modifications. Methods of affinity maturation of antibodies are known in the art, see, e.g., marks et al, bio/Technology 10:779-783 (1992); barbas et al, proc.Nat.Acad.Sci.USA 91:3809-3813 (1994); scier et al, gene 169:147-155 (1995); and Hawkins et al, J.mol. Biol.226:889-896 (1992).
As used herein, "percent (%) sequence identity" of amino acid sequences, sequence identity "has art-recognized definitions that refer to the percentage of identity between two polypeptide sequences as determined by sequence alignment (e.g., by manual inspection or by a known algorithm). The determination may be made using methods known to those skilled in the art, for example, using publicly available computer software such as BLAST, BLAST-2, clustal Omega and FASTA software.
Polypeptides (e.g., CDR regions, framework regions, and constant regions of antibodies) may be modified, e.g., by substitution, addition, and/or deletion of one or more amino acids, without altering the function of the polypeptide. Substitutions are preferably conservative substitutions of amino acids. Suitable conservative substitutions are well known to those skilled in the art. In addition, antibodies can be modified to alter their properties using methods known in the art, such as altering the type of antibody glycosylation modification, altering the ability to form interchain disulfide bonds, or providing reactive groups for the preparation of antibody conjugates. Such modified antibodies are also encompassed within the scope of the antibodies of the invention.
"affinity" or "binding affinity" is used to measure the strength of the interaction between an antibody and an antigen through non-covalent interactions. The magnitude of the "affinity" can be reported as the equilibrium dissociation constant, K D Or EC (EC) 50 。K D It can be calculated by measuring the equilibrium association constant (ka) and equilibrium dissociation constant (kd): k (K) D =kd/ka. Affinity can be determined using conventional techniques known in the art, such as biofilm interference techniques (e.g., forteBio Octet or gate detection systems can be employed), surface plasmon resonance, enzyme-linked immunosorbent assay (ELISA) or flow cytometry (FACS), and the like.
In this context, an antibody and an antigen "specifically bind" refers to the binding of an antibody to an antigen with a relatively high affinity. Typically, K between a specifically bound antibody and antigen D The value may be at least about 10 -7 M to at least about 10 -10 M or less, e.g. at least about 10 -7 M, at least about 10 -8 M, at least about 10 -9 M, at least about 10 -10 M or lower, as determined, for example, by biofilm interferometry. In some embodiments, an anti-ANG 2 antibody or antigen-binding fragment thereof of the invention has a K of 5nM, 2nM, 1nM or less D The values bind ANG2.
As used herein, the expression "isolated" means that a substance (e.g., a polynucleotide or polypeptide) is isolated from the source or environment in which it is present, i.e., does not substantially comprise any other components. The anti-ANG 2 heavy chain variable region polypeptide, antibody or antigen-binding fragment of the invention, or polynucleotide encoding the same, may be isolated.
The terms "polynucleotide" and "nucleic acid" are used interchangeably herein to refer to an oligomer or polymer comprising at least two linked nucleotides or nucleotide derivatives. Polynucleotides may include deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
Herein, a "vector" is a vector used to introduce an exogenous polynucleotide into a host cell, which is amplified or expressed when the vector is transformed into an appropriate host cell. As used herein, the definition of vector encompasses plasmids, linearized plasmids, viral vectors, cosmids, phage vectors, phagemids, artificial chromosomes (e.g., yeast artificial chromosomes and mammalian artificial chromosomes), and the like. Viral vectors include, but are not limited to, retroviral vectors (including lentiviral vectors), adenoviral vectors, adeno-associated viral vectors, herpes viral vectors, poxviral vectors, and baculovirus vectors, among others. As used herein, an "expression vector" refers to a vector capable of expressing a polypeptide of interest. Expression vectors may generally comprise a polynucleotide sequence encoding a polypeptide of interest and regulatory sequences (e.g., promoters and ribosome binding sites) operably linked thereto.
As used herein, a "host cell" is a cell that is used to receive, hold, replicate, or amplify a vector. Host cells may also be used to express polypeptides encoded by polynucleotides or vectors. The host cell may be a eukaryotic cell or a prokaryotic cell. Prokaryotic cells such as E.coli (E.coli) or B.subtilis (Bacillus subtilis), fungal cells such as yeast cells or Aspergillus, insect cells such as S2 drosophila cells or Sf9, and animal cells such as fibroblasts, CHO cells, COS cells, heLa cells, NSO cells or HEK293 cells.
As used herein, the term "treatment" refers to an improvement in a disease/symptom, e.g., alleviation or disappearance of a disease/symptom, prevention or slowing of the occurrence, progression, and/or worsening of a disease/symptom.
As used herein, "effective amount" means an amount of an active substance (e.g., an antibody or pharmaceutical composition of the invention) that induces a biological or medical response or desired therapeutic effect against a tissue, system, animal, mammal, or human. Thus, an "effective amount" may be that amount required to prevent, cure, ameliorate, block or partially block a disease or condition (e.g., cancer). The effective amount can be determined by one skilled in the art based on factors such as the age, physical condition, sex, severity of symptoms, particular composition or route of administration of the subject, and the like.
As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier that is pharmacologically and/or physiologically compatible with the subject and the active ingredient, as is well known in the art (see, e.g., remington's Pharmaceutical sciences. Mediated by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995).
Examples of mammals, as used herein, include, but are not limited to, humans, non-human primates, rats, mice, cows, horses, pigs, sheep, alpacas, dogs, cats, and the like. As used herein, the term "subject" refers to a mammal, such as a human. In some embodiments, the subject is a patient, e.g., a cancer patient.
anti-ANG 2 polypeptides, antibodies or antigen-binding fragments thereof
In one aspect, the present invention provides a heavy chain variable region polypeptide that specifically binds ANG2 comprising HCDR1, HCDR2 and HCDR3 sequences wherein
(a) The HCDR1 sequence is shown as SEQ ID NO. 110
GFTFX 1 X 2 YX 3 MX 4 (SEQ ID NO:110)
Wherein X is 1 Is S or N; x is X 2 S or V; x is X 3 S or G; x is X 4 Is N or H;
(b) The HCDR2 sequence is shown as VISYDGSNKY (SEQ ID NO: 5);
(c) The HCDR3 sequence is shown as SEQ ID NO. 111
X 5 TLDGYTAGYYYGMDV (SEQ ID NO:111)
Wherein X is 5 Is A or E.
In a specific embodiment, the HCDR1, HCDR2 and HCDR3 sequences are selected from any one of (1) - (4):
(1) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; and an HCDR3 sequence shown in SEQ ID NO. 6;
(2) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; and an HCDR3 sequence shown in SEQ ID NO. 81;
(3) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; and an HCDR3 sequence shown in SEQ ID NO. 6;
(4) An HCDR1 sequence shown in SEQ ID NO. 12; an HCDR2 sequence shown in SEQ ID NO. 5; and the HCDR3 sequence shown in SEQ ID NO. 6.
In another embodiment, the anti-ANG 2 antibody or antigen-binding fragment thereof further comprises a light chain variable region polypeptide comprising LCDR1, LCDR2, and LCDR3 sequences wherein the LCDR1, LCDR2, and LCDR3 sequences are selected from any one of (1) - (21):
(1) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 68;
(2) The LCDR1 sequence shown in SEQ ID NO. 82; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 83;
(3) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 84;
(4) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 85;
(5) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 86;
(6) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 80;
(7) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 39;
(8) An LCDR1 sequence shown in SEQ ID NO. 17; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 19;
(9) The LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO 59;
(10) The LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 36;
(11) The LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 28; and the LCDR3 sequence shown in SEQ ID NO. 29;
(12) An LCDR1 sequence shown in SEQ ID NO. 7; the LCDR2 sequence shown in SEQ ID NO. 13; and the LCDR3 sequence shown in SEQ ID NO. 14;
(13) The LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 26;
(14) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 9;
(15) The LCDR1 sequence shown in SEQ ID NO. 63; the LCDR2 sequence shown in SEQ ID NO. 64; and the LCDR3 sequence shown in SEQ ID NO. 65;
(16) The LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 32; and the LCDR3 sequence shown in SEQ ID NO. 33;
(17) The LCDR1 sequence shown in SEQ ID NO. 42; the LCDR2 sequence shown in SEQ ID NO. 43; and the LCDR3 sequence shown in SEQ ID NO. 44;
(18) The LCDR1 sequence shown in SEQ ID NO. 50; the LCDR2 sequence shown in SEQ ID NO. 51; and the LCDR3 sequence shown in SEQ ID NO. 52;
(19) The LCDR1 sequence shown in SEQ ID NO. 46; the LCDR2 sequence shown in SEQ ID NO. 47; and the LCDR3 sequence shown in SEQ ID NO. 48;
(20) An LCDR1 sequence shown in SEQ ID NO. 21; the LCDR2 sequence shown in SEQ ID NO. 22; and the LCDR3 sequence shown in SEQ ID NO. 23;
(21) The LCDR1 sequence shown in SEQ ID NO. 54; the LCDR2 sequence shown in SEQ ID NO. 55; and the LCDR3 sequence shown in SEQ ID NO. 56.
In a further embodiment, the anti-ANG 2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region polypeptide comprising HCDR1, HCDR2 and HCDR3 sequences and a light chain variable region polypeptide comprising LCDR1, LCDR2 and LCDR3 sequences wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 sequences are selected from any one of (1) - (21):
(1) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 68;
(2) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 80;
(3) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 84;
(4) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 85;
(5) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 86;
(6) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 63; the LCDR2 sequence shown in SEQ ID NO. 64; and the LCDR3 sequence shown in SEQ ID NO. 65;
(7) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; the HCDR3 sequence shown in SEQ ID NO. 81; the LCDR1 sequence shown in SEQ ID NO. 82; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 83;
(8) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 9;
(9) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 17; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 19;
(10) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 21; the LCDR2 sequence shown in SEQ ID NO. 22; and the LCDR3 sequence shown in SEQ ID NO. 23;
(11) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 26;
(12) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 28; and the LCDR3 sequence shown in SEQ ID NO. 29;
(13) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 32; and the LCDR3 sequence shown in SEQ ID NO. 33;
(14) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 36;
(15) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 39;
(16) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 42; the LCDR2 sequence shown in SEQ ID NO. 43; and the LCDR3 sequence shown in SEQ ID NO. 44;
(17) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 46; the LCDR2 sequence shown in SEQ ID NO. 47; and the LCDR3 sequence shown in SEQ ID NO. 48;
(18) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 50; the LCDR2 sequence shown in SEQ ID NO. 51; and the LCDR3 sequence shown in SEQ ID NO. 52;
(19) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 54; the LCDR2 sequence shown in SEQ ID NO. 55; and the LCDR3 sequence shown in SEQ ID NO. 56;
(20) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO 59;
(21) An HCDR1 sequence shown in SEQ ID NO. 12; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; the LCDR2 sequence shown in SEQ ID NO. 13; and the LCDR3 sequence shown in SEQ ID NO. 14.
In some embodiments, the heavy chain variable region polypeptide comprises the amino acid sequence of SEQ ID NO:69, SEQ ID NO:10, SEQ ID NO:40, SEQ ID NO:75, SEQ ID NO:15, SEQ ID NO:30, SEQ ID NO:34, SEQ ID NO:37, SEQ ID NO:57, SEQ ID NO:60, or SEQ ID NO: 66. In some embodiments, the heavy chain variable region polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity to SEQ ID NO:69, SEQ ID NO:10, SEQ ID NO:40, SEQ ID NO:75, SEQ ID NO:15, SEQ ID NO:30, SEQ ID NO:34, SEQ ID NO:37, SEQ ID NO:57, SEQ ID NO:60, or SEQ ID NO: 66. In some embodiments, the heavy chain variable region polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions, additions, and/or deletions compared to SEQ ID NO:69, 10, 40, 75, 15, 30, 34, 37, 57, 60, or 66. Preferably, the amino acid substitutions, additions and/or deletions do not occur in the CDR regions.
In some embodiments, the light chain variable region polypeptide comprises the amino acid sequence of SEQ ID NO. 70, SEQ ID NO. 74, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 79, SEQ ID NO. 11, SEQ ID NO. 20, SEQ ID NO. 24, SEQ ID NO. 27, SEQ ID NO. 41, SEQ ID NO. 45, SEQ ID NO. 49, SEQ ID NO. 53, SEQ ID NO. 76, SEQ ID NO. 16, SEQ ID NO. 31, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 58, SEQ ID NO. 61, or SEQ ID NO. 67. In some embodiments, the light chain variable region polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity to SEQ ID NO 70, SEQ ID NO 74, SEQ ID NO 77, SEQ ID NO 78, SEQ ID NO 79, SEQ ID NO 11, SEQ ID NO 20, SEQ ID NO 24, SEQ ID NO 27, SEQ ID NO 41, SEQ ID NO 45, SEQ ID NO 49, SEQ ID NO 53, SEQ ID NO 76, SEQ ID NO 16, SEQ ID NO 31, SEQ ID NO 35, SEQ ID NO 38, SEQ ID NO 58, SEQ ID NO 61, or SEQ ID NO 67. In some embodiments, the light chain variable region polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions, additions, and/or deletions compared to SEQ ID NO 70, 74, 77, 78, 79, 11, 20, 24, 27, 41, 45, 49, 53, 76, 16, 31, 35, 38, 58, 61, or 67. Preferably, the amino acid substitutions, additions and/or deletions do not occur in the CDR regions.
In some embodiments, the heavy chain variable region polypeptide comprises the amino acid sequence of SEQ ID NO:69, SEQ ID NO:10, SEQ ID NO:40, SEQ ID NO:75, SEQ ID NO:15, SEQ ID NO:30, SEQ ID NO:34, SEQ ID NO:37, SEQ ID NO:57, SEQ ID NO:60, or SEQ ID NO: 66; the light chain variable region polypeptide comprises the amino acid sequence of SEQ ID NO. 70, SEQ ID NO. 74, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 79, SEQ ID NO. 11, SEQ ID NO. 20, SEQ ID NO. 24, SEQ ID NO. 27, SEQ ID NO. 41, SEQ ID NO. 45, SEQ ID NO. 49, SEQ ID NO. 53, SEQ ID NO. 76, SEQ ID NO. 16, SEQ ID NO. 31, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 58, SEQ ID NO. 61 or SEQ ID NO. 67.
In a specific embodiment, the heavy chain variable region polypeptide and the light chain variable region polypeptide are selected from any one of (1) - (21):
(1) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 70;
(2) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 74;
(3) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 77;
(4) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 78;
(5) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 79;
(6) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 10; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 11;
(7) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 10; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 20;
(8) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 10; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 24;
(9) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 10; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 27;
(10) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 40; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID NO. 41;
(11) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 40; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 45;
(12) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 40; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 49;
(13) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 40; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 53;
(14) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 75; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 76;
(15) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 15; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 16;
(16) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 30; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 31;
(17) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 34; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 35;
(18) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 37; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 38;
(19) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 57; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 58;
(20) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 60; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 61;
(21) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 66; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 67.
In another aspect, the present invention also provides an anti-ANG 2 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region polypeptide comprising HCDR1, HCDR2 and HCDR3 sequences and a light chain variable region polypeptide comprising LCDR1, LCDR2 and LCDR3 sequences, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 sequences are selected from any one of (1) - (3):
(1) The HCDR1 sequence shown in SEQ ID NO. 87; the HCDR2 sequence shown in SEQ ID NO. 88; the HCDR3 sequence shown in SEQ ID NO. 89; the LCDR1 sequence shown in SEQ ID NO. 90; the LCDR2 sequence shown in SEQ ID NO. 91; and the LCDR3 sequence shown in SEQ ID NO. 92;
(2) The HCDR1 sequence shown in SEQ ID NO. 95; the HCDR2 sequence shown in SEQ ID NO. 96; an HCDR3 sequence shown in SEQ ID NO. 97; the LCDR1 sequence shown in SEQ ID NO. 98; the LCDR2 sequence shown in SEQ ID NO. 99; and the LCDR3 sequence shown in SEQ ID NO. 100;
(3) The HCDR1 sequence shown in SEQ ID NO. 103; the HCDR2 sequence shown in SEQ ID NO. 104; the HCDR3 sequence shown in SEQ ID NO. 105; the LCDR1 sequence shown in SEQ ID NO. 106; the LCDR2 sequence shown in SEQ ID NO. 91; and the LCDR3 sequence shown in SEQ ID NO. 107.
In some embodiments, the heavy chain variable region polypeptide comprises the amino acid sequence of SEQ ID NO. 93, SEQ ID NO. 101 or SEQ ID NO. 108. In some embodiments, the heavy chain variable region polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity to SEQ ID NO. 93, SEQ ID NO. 101 or SEQ ID NO. 108. In some embodiments, the heavy chain variable region polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions, additions, and/or deletions compared to SEQ ID No. 93, SEQ ID No. 101, or SEQ ID No. 108. Preferably, the amino acid substitutions, additions and/or deletions do not occur in the CDR regions.
In some embodiments, the light chain variable region polypeptide comprises the amino acid sequence of SEQ ID NO. 94, SEQ ID NO. 102 or SEQ ID NO. 109. In some embodiments, the light chain variable region polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity to SEQ ID NO. 94, SEQ ID NO. 102 or SEQ ID NO. 109. In some embodiments, the light chain variable region polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions, additions, and/or deletions compared to SEQ ID No. 94, SEQ ID No. 102, or SEQ ID No. 109. Preferably, the amino acid substitutions, additions and/or deletions do not occur in the CDR regions.
In some embodiments, the heavy chain variable region polypeptide comprises the amino acid sequence of SEQ ID NO. 93, SEQ ID NO. 101 or SEQ ID NO. 108; the light chain variable region polypeptide comprises the amino acid sequence of SEQ ID NO. 94, SEQ ID NO. 102 or SEQ ID NO. 109.
In a specific embodiment, the heavy chain variable region polypeptide and the light chain variable region polypeptide are selected from any one of (1) - (3):
(1) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 93; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 94;
(2) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 101; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 102;
(3) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 108; a light chain variable region polypeptide comprising the amino acid sequence of seq id No. 109.
In some embodiments, the anti-ANG 2 antibodies or antigen-binding fragments thereof of the invention are scFv, fab, fab ', F (ab') 2 Fv fragments, disulfide stabilized Fv (dsFv) or diabodies.
In some embodiments, the anti-ANG 2 antibodies or antigen-binding fragments thereof of the invention further comprise a heavy chain constant region and/or a light chain constant region.
The heavy chain constant region and the light chain constant region may each be independently derived from the heavy chain constant region and the light chain constant region of an immunoglobulin of any species. The heavy chain constant region may be derived from the heavy chain constant region of immunoglobulins of any subclass (e.g., igA, igD, igE, igG and IgM), class (e.g., igG1, igG2, igG3, igG4, igA1 and IgA 2) or subclass (e.g., igG2a and IgG2 b), or a combination thereof. The light chain constant region may be derived from a Lambda (Lambda) light chain or a Kappa (Kappa) light chain constant region.
Suitable immunoglobulin constant regions (e.g., CH1 and light chain constant regions, hinge region-CH 2-CH3, CH 1-hinge region-CH 2-CH3 and light chain constant regions, or Fc regions), and types (e.g., igG, e.g., igG1, igG2, igG3, and IgG 4) can be selected and optionally modified to obtain antibodies having the desired properties.
In some embodiments, the heavy chain constant region is a heavy chain constant region (e.g., an Fc region or a CH 1-hinge region-CH 2-CH 3) of a human IgG (e.g., igG1, igG2a, igG2b, igG3, or IgG 4). In one embodiment, the heavy chain constant region is the heavy chain constant region of human IgG1 (exemplary amino acid sequences are shown in SEQ ID NO: 71). In one embodiment, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO. 71.
In a preferred embodiment, the light chain constant region is a human kappa light chain constant region (exemplary amino acid sequence set forth in SEQ ID NO: 72) or a human lambda light chain constant region (exemplary amino acid sequence set forth in SEQ ID NO: 73). In one embodiment, the light chain constant region comprises the amino acid sequence of SEQ ID NO:72 or SEQ ID NO: 73.
In some embodiments, an anti-ANG 2 heavy chain variable region polypeptide, antibody, or antigen-binding fragment thereof of the invention specifically binds ANG2, but does not bind or does not substantially bind ANG1. The expression "unbound" or "substantially unbound" as used herein means that the binding capacity of the polypeptide, antibody or antigen binding fragment thereof of the invention to ANG1 is significantly lower than to ANG 2. For example, as shown in fig. 4, the molecules of the present invention show weak or no binding to ANG1.
Antibodies or antigen binding fragments thereof may be prepared and produced using methods known in the art. Such methods may include, for example, preparing and isolating nucleic acids encoding antibodies or antigen binding fragments from phage display libraries, yeast display libraries, immortalized B cells (e.g., mouse B cell hybridoma cells or EBV immortalized B cells). It is also possible to immunize an animal, for example, an animal (e.g., a humanized mouse) with an antigen or a DNA encoding the antigen, and then isolate B cells expressing the antibody from the immunized animal. Polynucleotides encoding antibodies or antigen-binding fragments thereof may also be isolated from immunized animals or humans or prepared by chemical synthesis, and then used to construct expression vectors for expressing the antibodies or antigen-binding fragments.
Multispecific antibodies
In another aspect, the invention provides a multispecific antibody comprising a first antigen-binding portion which specifically binds ANG2 and a second antigen-binding portion which specifically binds a second antigen, wherein the first antigen-binding portion comprises an anti-ANG 2 heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof of the invention.
As used herein, the term "multispecific antibody" refers to an antibody that is capable of specifically binding to two or more (e.g., 2, 3, 4, 5, or 6) different epitopes. The multispecific antibody may be, for example, a bispecific, trispecific or tetraspecific antibody, which is capable of specifically binding 2, 3 or 4 epitopes, respectively. As used herein, the term "epitope" or "antigenic determinant" refers to a region of an antigen that specifically binds to an antigen binding site of an antibody. Epitopes are typically composed of chemically active surface groups of antigensGroups (such as amino acids or sugar side chains) and generally have specific three-dimensional structural properties as well as specific charge properties. The multispecific antibody may be a multivalent (e.g., 2, 3, 4 valent) antibody, i.e., it has multiple antigen binding sites. The multispecific antibody may be, for example, a chimeric antibody, humanized antibody, fully human antibody, scFab, F (ab') 2 Or diabodies.
Methods for constructing multispecific antibodies using an antibody or antigen-binding fragment of interest are well known to those skilled in the art (see, e.g., WO 93/08829;Suresh et al, (1986) Methods in Enzymology,121:210; and Traunecker et al, (1991) EMBO, 10:3655-3659).
As used herein, "first antigen binding portion" and "second antigen binding portion" refer to an amino acid sequence comprising an antigen binding site that is capable of binding to an epitope of an antigen, which definition falls within the meaning of an antibody or antigen binding fragment. The first antigen-binding portion and the second antigen-binding portion may be any form of antibody or antigen-binding fragment, including but not limited to Fv, scFv, dsFv, scdsFv, fab, scFab, fab 'and F (ab') 2 。
The first antigen binding portion and the second antigen binding portion may optionally be connected by a linker. In some embodiments, the first antigen binding portion and the second antigen binding portion are not connected by a linker. In other embodiments, the first antigen binding portion and the second antigen binding portion are linked by a linker, such as a peptide linker or a chemical bond. Preferably, the first antigen binding portion and the second antigen binding portion are linked by a peptide linker. Exemplary peptide linkers may include, but are not limited to, poly glycine (G), poly alanine (a), poly serine (S), or combinations thereof, such as GGAS, GGGS, GGGSG or (G) 4 S) n Wherein n is an integer of 1 to 20.
Polynucleotides, vectors and host cells
In another aspect, the invention provides a polynucleotide encoding an anti-ANG 2 heavy chain variable region polypeptide, an antibody or antigen-binding fragment thereof, or a multispecific antibody of the invention.
Polynucleotides of the invention may be obtained using methods known in the art. For example, polynucleotides of the invention may be isolated from humans, phage display libraries, yeast display libraries, immunized animals, immortalized cells (e.g., mouse B cell hybridoma cells, EBV-mediated immortalized B cells), or chemically synthesized. The polynucleotide may be codon optimized for the host cell used for expression.
In yet another aspect, the invention also provides an expression vector comprising a polynucleotide of the invention. The expression vector may further comprise additional polynucleotide sequences, such as transcriptional regulatory sequences and antibiotic resistance genes.
The invention also provides a host cell comprising a polynucleotide or expression vector of the invention. The polynucleotides or expression vectors of the invention may be introduced into a suitable host cell using a variety of methods known in the art. Such methods include, but are not limited to, viral transduction, liposome transfection, electroporation, and calcium phosphate transfection, among others. In a preferred embodiment, the host cell is used to express an anti-ANG 2 heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof, or multispecific antibody of the invention. Examples of host cells include, but are not limited to, prokaryotic cells (e.g., bacteria, e.g., E.coli) and eukaryotic cells (e.g., yeast, insect cells, mammalian cells). Mammalian host cells suitable for antibody expression include, but are not limited to, myeloma cells, heLa cells, HEK cells, chinese Hamster Ovary (CHO) cells, and other mammalian cells suitable for expression of antibodies.
The invention also provides a method of producing an anti-ANG 2 heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof or multispecific antibody of the invention, comprising:
culturing a host cell of the invention under suitable conditions to express an anti-ANG 2 heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof or multispecific antibody of the invention, an
(ii) isolating the heavy chain variable region polypeptide, antibody or antigen binding fragment thereof or multispecific antibody from the host cell or culture thereof.
MedicamentComposition and method for producing the same
The invention also provides a pharmaceutical composition comprising an anti-ANG 2 heavy chain variable region polypeptide, an antibody or antigen-binding fragment thereof or a multispecific antibody of the invention, and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers can include, but are not limited to: diluents, binders and adhesives, lubricants, disintegrants, preservatives, vehicles, dispersants, glidants, sweeteners, coatings, excipients, preservatives, antioxidants (such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated Hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like), solubilizing agents, gelling agents, softeners, solvents (such as water, alcohols, acetic acid, and syrups), buffers (such as phosphate buffers, histidine buffers, and acetate buffers), surfactants (such as nonionic surfactants, such as polysorbate 80, polysorbate 20, poloxamer, or polyethylene glycol), antibacterial agents, antifungal agents, isotonic agents (such as trehalose, sucrose, mannitol, sorbitol, lactose, glucose), absorption retarders, chelating agents, and emulsifiers. For compositions comprising an antibody or antibody conjugate, a suitable carrier may be selected from buffers (e.g., citrate buffer, acetate buffer, phosphate buffer, histidine salt buffer), isotonic agents (e.g., trehalose, sucrose, mannitol, sorbitol, lactose, glucose), nonionic surfactants (e.g., polysorbate 80, polysorbate 20, poloxamers), or combinations thereof.
The pharmaceutical compositions provided herein may be in a variety of dosage forms including, but not limited to, solid, semi-solid, liquid, powder, or lyophilized forms. Preferably, the pharmaceutical composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
The pharmaceutical compositions provided herein may be administered by a variety of routes. Routes of administration include, but are not limited to, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, or intracavity), topical (e.g., intratumoral), epidural, or mucosal (e.g., intranasal, oral, vaginal, rectal, sublingual, or topical). The method of administration may be, for example, injection or infusion.
As a general guidance, the anti-ANG 2 antibodies or antigen-binding fragments thereof of the invention may be administered in a dosage range of about 0.0001 to 100mg/kg, more typically 0.01 to 20mg/kg of subject body weight. For example, the dosage may be 0.3mg/kg body weight, 1mg/kg body weight, 3mg/kg body weight, 5mg/kg body weight, 10mg/kg body weight or 20mg/kg body weight, or in the range of 1-20 mg/kg. Exemplary treatment regimens require weekly dosing, biweekly dosing, tricyclically dosing, weekly dosing, monthly dosing, 3 months dosing, 3-6 months dosing, or slightly shorter initial dosing intervals followed by longer post dosing intervals.
Treatment of
The anti-ANG 2 heavy chain variable region polypeptides, antibodies, or antigen-binding fragments thereof, or multispecific antibodies of the invention inhibit ANG2 activity-related angiogenesis by binding to human ANG2 to block binding of human ANG2 to the human TIE2 receptor and inhibit TIE2 phosphorylation. As used herein, "angiogenesis" refers to the formation of new blood vessels. Studies have shown that angiogenesis is associated with a variety of diseases, such as cancer and angiogenesis-related eye diseases.
The anti-ANG 2 heavy chain variable region polypeptides, antibodies or antigen-binding fragments thereof, multispecific antibodies, or pharmaceutical compositions of the invention may be used to treat cancer or angiogenesis-related eye diseases. The invention also provides the use of an anti-ANG 2 heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof, multispecific antibody or pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of cancer or angiogenesis-related eye diseases. The invention also provides a method of treating cancer or angiogenesis-related eye diseases in a subject comprising administering to the subject an effective amount of an anti-ANG 2 heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof, multispecific antibody, or pharmaceutical composition of the invention.
The angiogenesis-related eye disease may be an eye disease associated with choroidal and retinal vascular diseases, including but not limited to choroidal neovascularization, retinal neovascularization, and diseases associated with vascular leakage. In one embodiment, the angiogenesis-related eye disease is macular degeneration (e.g., dry or wet age-related macular degeneration (AMD)), retinal vein occlusion, retinopathy of prematurity (ROP), diabetic retinopathy, neovascular glaucoma, pathological myopia, macular edema, retinal edema, diabetic Macular Edema (DME), or choroidal neovascularization disease.
As used herein, the term "cancer" or "tumor" refers to or describes a physiological condition in an individual that is generally characterized by unregulated cell growth. Preferably, the cancer is a solid tumor associated with angiogenesis. Cancers may include primary and metastatic cancers. Non-limiting examples of cancers include lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer, skin cancer, head and neck cancer, melanoma, ovarian cancer, colorectal cancer, gastric cancer, breast cancer, prostate cancer, uterine cancer, hodgkin's lymphoma, esophageal cancer, anal cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, renal cancer (e.g., renal cell carcinoma, renal pelvis cancer, and adrenal cancer), soft tissue sarcoma, bladder cancer, central Nervous System (CNS) tumors, mesothelioma, glioma, meningioma, and pituitary adenoma. In a preferred embodiment, the cancer is colorectal cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer or hepatocellular carcinoma.
For the treatment of cancer, the anti-ANG 2 heavy chain variable region polypeptides, antibodies or antigen-binding fragments thereof, multispecific antibodies, or pharmaceutical compositions of the invention may be used in combination with one or more therapeutic agents selected from the group consisting of: chemotherapeutic agents, immune checkpoint inhibitors and angiogenesis inhibitors. Examples of chemotherapeutic agents include, but are not limited to: cyclophosphamide, ifosfamide, melphalan, busulfan, nitrogen mustard, chlorambucil, cyclohexanides, carmustine (BCNU), lomustine (CCNU), cisplatin (DDP), carboplatin (CBP), oxaliplatin (OXA), methotrexate (MTX), 6-mercaptopurine (6-MP), 5-fluorouracil (5-FU), cytarabine, gemcitabine, vincristine, vindesine, camptothecine, irinotecan, topotecan, lubitecan, etoposide, teniposide, paclitaxel, taxane, docetaxel, paclitaxel liposomes, actinomycin D, idarubicin, doxorubicin, epirubicin, mitomycin, bleomycin and doxorubicin. Immune checkpoint inhibitors include, but are not limited to, antibodies that target PD-1, PD-L1, CTLA4, LAG-3, or TIM-3. Angiogenesis inhibitors include, but are not limited to: a variety of receptor tyrosine kinase inhibitors, anti-VEGF antibodies (e.g., bevacizumab), anti-VEGFR antibodies (e.g., ramucirumab), small molecule inhibitors of VEGFR, and VEGF inhibitory fusion proteins (e.g., aflibercept).
Kit for detecting a substance in a sample
The invention also provides a kit comprising an anti-ANG 2 heavy chain variable region polypeptide, an antibody or antigen-binding fragment thereof, a multispecific antibody, or pharmaceutical composition of the invention, and instructions for use. The kit may also comprise a suitable container, such as an ampoule. In some embodiments, the kit further comprises a device for administering the drug. The kit may also comprise a label for indicating the intended use and/or method of use of the kit contents. The term "label" includes any written or recorded material provided on or with or otherwise with the kit.
Advantageous effects
The anti-ANG 2 heavy chain variable region polypeptide, antibody or antigen-binding fragment thereof or multispecific antibody of the present invention can achieve at least the following beneficial effects:
(1) Specifically binds ANG2, but does not bind or does not substantially bind ANG1;
(2) Blocking binding of ANG2 to TIE2 and inhibiting TIE2 phosphorylation;
(3) Inhibiting angiogenesis associated with ANG2 activity; and/or
(4) Inhibit tumor growth.
The anti-ANG 2 antibody or antigen-binding fragment thereof of the invention may be a fully human antibody and thus have low immunogenicity.
Examples
The invention generally described herein will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to limit the invention. The experimental procedures, which are not specified in the following examples, were carried out according to conventional methods and conditions, or according to the commercial specifications.
Example 1 preparation of raw materials
1.1 preparation of antigen proteins ANG2, ANG1 and receptor protein TIE2
The coding sequences for the extracellular domains of human ANG2 (hANG 2, uniprot ID: O15123-1), monkey ANG2 (cANG 2, uniprot ID: A0A2K5VNX 6), murine ANG2 sequence (mANG 2, uniprot ID: O35608-1), human ANG1 (hANG 1, uniprot ID: Q15389-1) and human TIE2 (hTIE 2 ECD, uniprot ID: Q02763-1) were synthesized by general biotechnology Co., ltd. The C end of the gene sequence is respectively connected with the gene sequence of human IgG1 Fc segment (SEQ ID NO: 1) and His tag through PCR amplification, then the gene sequence is constructed to eukaryotic expression vector pcDNA3.4-TOPO (Invitrogen) through a homologous recombination method, the constructed recombinant protein expression vector is respectively transformed into escherichia coli DH5 alpha, the escherichia coli DH5 alpha is cultured overnight at 37 ℃, then plasmid extraction is carried out by using an endotoxin-free plasmid extraction kit (OMEGA, D6950-01), the expression is carried out through an Expi293 transient expression system (thermo Fisher, A14635), and the transient method is seen in Expi293 TM Expression System USER GUIDE。
After 7 days of transfection, the cell expression supernatant was centrifuged at 15000g for 10min at high speed, and the obtained Fc tagged protein expression supernatant was affinity purified with MabSelect SuRe LX (GE, 17547403), and then the target protein was eluted with 100mM sodium acetate (pH 3.0), followed by neutralization with 1M Tris-HCl; the resulting His tag protein expression supernatant was affinity purified with Ni Smart Beads 6FF (Hemsl and Biotechnology Co., ltd., SA 036050) and then the target protein was eluted with a gradient concentration of imidazole. The eluted proteins are respectively changed into PBS buffer solution through ultrafiltration concentration tube (Millipore, UFC 901096), and are frozen at-80 ℃ for standby after being qualified by SDS-PAGE identification and activity identification. Each protein is hereinafter abbreviated as hANG2-Fc, hANG2-His, cANG2-His, mANG2-Fc, hANG1-Fc and hTIE2 ECD-Fc, respectively.
1.2 preparation of positive control antibodies
The positive control antibody used in this application was the anti-ANG 2 antibody nesvacumab synthesized according to the sequences disclosed in US2011027286 A1. Plasmids containing the nesvacumab heavy chain (SEQ ID NO: 2) gene and the nesvacumab light chain (SEQ ID NO: 3) gene were constructed separately by molecular cloning. The remaining steps are described in example 1.1.
1.3 Preparation of hTIE2-HEK293 cell line
The DNA sequence of full-length human TIE2 (NCBI Gene ID: 7010) was constructed onto the pLVX-puro plasmid (Clontech, cat# 632164). Then, the resulting plasmid was transformed into HEK293 cells by electrotransformationCRL-1573 TM ) Is a kind of medium. The grown single cell clones were successfully obtained by 2 μg/mL puromycin pressure screening using the antibody nesvacumab identification (conventional FACS method) to obtain HEK293 cell lines, also referred to herein as "h TIE2-HEK293 cell lines", which express human TIE 2.
EXAMPLE 2 construction and screening of a Natural human antibody phage display library
In this example, an antibody gene phage display library was constructed and screened using the antigen proteins ANG2 (including both harg 2-Fc and harg 2-His) prepared in example 1.1 as screening antigens to obtain a plurality of antibody molecules having specific binding to ANG 2.
2.1 construction of Gene libraries of human antibodies
Peripheral blood mononuclear cells (Peripheral Blood Mononuclear Cell, PBMC) of normal human blood were isolated from Ficoll-Paque density gradient isolate (available from GE company under accession number 17144003S), total RNA was extracted from the isolated PBMC cells by a conventional method, and the extracted total RNA was reverse transcribed into cDNA using a reverse transcription kit (available from TaKaRa company under accession number 6210A). Based on the sequence similarity of the heavy and light chain germline genes, degenerate primers were designed at the front of the V region and the rear of the first constant region of the heavy and light chains, respectively (Li Xiaolin, high capacity non-identicalConstruction of immune humanized Fab phage antibody library and preliminary screening, and obtaining heavy chain variable region gene fragment and light chain variable region gene fragment of antibody after PCR. Fragments containing the light chain and heavy chain variable regions of the antibody were amplified by fusion PCR, and the PCR product and phage display vector were digested, recovered and ligated, and the ligation product was recovered by a recovery kit (Omega, catalog number: D6492-02). Finally, transformation into competent E.coli SS320 (Lucigen, MC 1061F) was performed by electrotransfer (Bio-Rad, micropulser) and the transformed E.coli SS320 bacterial solution was applied to ampicillin-resistant 2-YT solid plates. The library capacity was determined to be 3X 10 by gradient dilution plating 11 cfu, i.e. 3X 10 11 Antibody gene libraries of individual antibody genes (stock-keeping methods refer to example 2.2 in CN 112250763B). Packaging with VSCM13 helper phage (from Stratagene) resulted in an antibody gene phage display library (preparation of antibody gene phage display library is referred to in example 2.3 of CN 112250763B).
2.2 screening of antibody Gene phage display libraries
2.2.1 screening of antibody Gene phage display library by magnetic bead method
The magnetic bead screening is based on the steps of labeling hANG2-Fc with biotin, then combining with streptavidin-coupled magnetic beads, and incubating, washing and eluting the antigen-coupled magnetic beads and antibody gene phage display library. Typically, 3-4 rounds of panning are experienced, whereby specific monoclonal antibodies directed against the antigen can be enriched in large amounts. In this example, biotin-labeled hANG2-Fc was used for phage display library screening, and after 3 rounds of panning, monoclonal antibody primary screening against ANG2 was performed, for specific procedures as described in example 2.4.1 of CN 112250763B.
2.2.2 screening of antibody Gene phage display library by Immunotube method
The aim of the immune tube method and the magnetic bead method is to enrich specific antibodies against antigens, and the method is two mutually complementary and verified experimental methods. The principle of the immune tube screening is that hANG2-Fc is coated on the surface of an immune tube with high adsorption capacity, and a phage display antibody library is added into the immune tube and subjected to a panning process of incubation, washing and elution with antigen proteins adsorbed on the surface of the immune tube, and then subjected to 2-4 rounds of panning, so that the specific monoclonal antibodies aiming at the antigens are finally enriched. In this example, monoclonal antibody primary screening against ANG2 was performed after 3 rounds of panning, for specific procedures with reference to example 2.4.2 in CN 112250763B.
2.3 selection of monoclonal
ELISA detection is carried out on phage pools eluted in each round to evaluate enrichment effect, 10 clones are randomly selected from phage pools screened in each round to carry out sequence analysis, comprehensive analysis is combined with enrichment effect and the proportion of repeatability of the sequenced sequences, and proper rounds are selected to carry out monoclonal selection.
ELISA monoclonal screening Using hANG2-His, positive antibodies binding to hANG2-His obtained from the screening were retested with cANG2-His and mANG2-Fc, and exemplary monoclonal ELISA assay data (OD 450 values binding to human, monkey and murine ANG2 proteins) are shown in Table 1. The candidate fully human antibodies were named by clone number, the variable region amino acid sequences of the candidate fully human antibodies are shown in Table 2, and the complementarity determining region sequences were determined by AbM defining CDRs.
Table 1 screening of exemplary monoclonal antibodies and antigen binding OD450 (ELISA)
TABLE 2 variable region amino acid sequences of candidate antibodies
EXAMPLE 3 preliminary characterization of antigen binding Activity and blocking Activity of candidate monoclonal supernatants
3.1 specific binding of candidate monoclonal supernatant to hANG2-Fc
hANG2-Fc (2. Mu.g/mL, 30. Mu.L/well) was coated on 96-well ELISA plates overnight at 4 ℃. The next day, the well plate was blocked with 5% skim milk for 2h after 3 washes with PBST, and after 3 washes with PBST, a gradient dilution of candidate monoclonal supernatant (obtained after overnight expression of e.coli SS320 containing the monoclonal Fab fragment plasmid) was added and incubated for 1h. After 3 washes with PBST, anti-human Kappa HRP and anti-human Lambda HRP secondary antibody mixtures (Millipore, AP502P, AP 506P) were added and incubated for 1h. After incubation, PBST was washed six times, TMB was added for color development, 2M HCl was added according to the color development result to terminate the reaction, and OD450 value was read by an ELISA reader.
The detection results are shown in FIGS. 1A-1C: both candidate monoclonal supernatants specifically bound to hANG2-Fc and were comparable in binding capacity.
3.2 blocking activity of candidate monoclonal supernatant blocking ANG2 binding to receptor TIE 2.
Coated hTIE2 ECD-Fc (4. Mu.g/mL, 30. Mu.L/well) was incubated overnight at 4 ℃. The next day, the well plates were blocked with 5% skim milk for 2h after 3 washes with PBST. The candidate monoclonal supernatants were then each diluted in gradient and pre-mixed with biotin-labeled hANG2-Fc (4. Mu.g/mL) for 0.5h, and added to 96-well ELISA plates for 1h after blocking was complete and plate washing was completed. Neutravidin-HRP (Therofisther, 31001) was then added after 3 washes with PBST and incubated for 1h. After incubation, PBST plates were washed six times, developed with TMB (SurModics, TMBS-1000-01), and the reaction was stopped by adding 2M HCl based on the developed results, and OD450 values were read by a microplate reader (Molecular Devices, specterMax 190).
The results are shown in FIGS. 2A-2C: the candidate monoclonal supernatant has better ability to block the binding of ANG2 and receptor TIE2 and has equivalent ability.
EXAMPLE 4 construction, expression and purification of candidate antibodies
4.1 plasmid construction
The VH in the Fab sequences of the monoclonal 7, 78A46, 78A74, 78A14, 78A51, 78A5, 17 and 35 obtained by screening is connected with the coding sequence of the constant region (SEQ ID NO: 71) of the human IgG1 to construct a heavy chain coding sequence of the fully human antibody, and the VL in the Fab sequence is connected with the Kappa type (SEQ ID NO: 72) coding sequence of the constant region (CL) of the human light chain or the Lambda type (SEQ ID NO: 73) coding sequence of the human CL to construct a light chain coding sequence of the fully human antibody. The coding sequences of the heavy chain and the light chain of the antibody are respectively inserted into eukaryotic expression vector plasmids pcDNA3.4-TOPO (Invitrogen), and are transformed into escherichia coli DH5 alpha, and are cultured at 37 ℃ overnight. Plasmid extraction was performed using an endotoxin-free plasmid extraction kit (OMEGA, D6950-01) to obtain endotoxin-free antibody plasmids for eukaryotic expression.
4.2 expression and purification of antibodies
The candidate antibody was expressed by the expcho transient expression system (Thermo Fisher, a 29133) as follows: on the day of transfection, cell density was confirmed to be 7×10 6 Up to 1X 10 7 Cell viability about living cells/mL>98% at this time, the cells were adjusted to a final concentration of 6X 10 using fresh ExpiCHO expression medium pre-warmed at 37 ℃ 6 Individual cells/mL. OptiPRO pre-cooled at 4deg.C TM SFM dilution of plasmid of interest (1. Mu.g plasmid was added to 1mL of the medium) with OptiPRO TM SFM dilution of Expifectamine TM CHO, mixing the two materials in equal volume, and gently stirring to obtain the product TM The CHO/plasmid DNA mixture was incubated at room temperature for 1-5min, slowly added to the prepared cell suspension while gently shaking, and finally placed in a cell culture shaker at 37℃and 8% CO 2 Culturing under the condition.
18-22h after transfection, expiCHO was added to the culture broth TM Enhance and ExpiCHO TM Feed, shake flask placed on a shaker at 32℃and 5% CO 2 Culturing was continued under the conditions. On day 5 post transfection, the same volume of ExpiCHO was added TM Feed, slowly add while gently mix the cell suspension. After 7 days of transfection, the cell culture supernatant expressing the protein of interest was centrifuged at 15000g for 10min at high speed, the resulting supernatant was affinity purified with MabSelect SuRe LX (GE, 17547403), the protein of interest was eluted with 100mM sodium acetate (pH 3.0), then neutralized with 1M Tris-HCl, and finally the resulting protein was exchanged into PBS buffer by ultrafiltration concentration tube (Millipore, UFC 901096).
Example 5 determination of antigen binding Activity and blocking Activity of candidate antibodies based on ELISA method
In this example, the binding activity of 8 candidate antibodies 7, 78A46, 78A74, 78A14, 78A51, 78A5, 17 and 35 to hANG2-His and hANG1-Fc was examined based on the ELISA method, and the activity of the candidate antibodies blocking the binding of ANG2 to the receptor TIE2 was examined based on the ELISA method.
5.1 detection of candidate antibody binding Activity to hANG2-His based on ELISA
hANG2-His (2. Mu.g/mL, 30. Mu.L/well) was coated on 96-well ELISA plates overnight at 4 ℃. The next day, the well plate was blocked with 5% skim milk for 2h after 3 washes with PBST, and after 3 washes with PBST, gradient diluted candidate antibody and positive control antibody nesvacumab were added and incubated for 1h. Anti-human Fc HRP secondary antibody (Jackson Immuno Research, 109-035-008) was then added after 3 washes with PBST and incubated for 1h. After incubation, the plates were washed 6 times with PBST and developed with TMB (SurModics, TMBS-1000-01). Based on the color development, the reaction was stopped by adding 2M HCl and the OD450 value was read by a microplate reader (Molecular Devices, specterMax 190).
The results are shown in FIGS. 3A-3B and Table 3: all candidate antibodies had higher antigen binding activity to the hANG2-His and all were significantly better than the positive control antibody nesvacumab.
5.2 detection of candidate antibody binding Activity to hANG1-Fc based on ELISA
hANG1-Fc (2. Mu.g/mL, 30. Mu.L/well) was coated on 96-well ELISA plates overnight at 4 ℃. The next day, the well plate was blocked with 5% skim milk for 2h after 3 washes with PBST, and after 3 washes with PBST, gradient diluted candidate antibody and positive control antibody nesvacumab were added and incubated for 1h. After 3 washes with PBST, anti-human Kappa HRP and anti-human Lambda HRP secondary antibody mixtures (Millipore, AP502P, AP 506P) were added and incubated for 1h. After incubation, PBST was washed six times, TMB was added for color development, 2M HCl was added according to the color development result to terminate the reaction, and OD450 value was read by an ELISA reader.
The results are shown in fig. 4: except for the weak binding of antibody 78A5 to hANG1-Fc, none of the remaining 7 antibodies, nor the positive control antibody, bound to hANG 1.
5.3 detection of blocking Activity of candidate antibodies to block binding of ANG2 and receptor TIE2 based on ELISA
Coated hTIE2 ECD-Fc (4. Mu.g/mL, 30. Mu.L/well) was incubated overnight at 4 ℃. The next day, the well plates were blocked with 5% skim milk for 2h after 3 washes with PBST. Candidate or positive control antibodies nesvacumab were then serially diluted and pre-mixed with biotin-labeled hANG2-Fc (4. Mu.g/mL) for 0.5h, respectively, and added to 96-well ELISA plates for 1h after blocking was complete and plate washing was completed. After 3 washes with PBST, secondary antibody Neutravidin-HRP (Therofisther, 31001) was added and incubated for 1h. After incubation, PBST plates were washed six times, developed with TMB (SurModics, TMBS-1000-01), and the reaction was stopped by adding 2M HCl based on the developed results, and OD450 values were read by a microplate reader (Molecular Devices, specterMax 190).
The results are shown in FIGS. 5A-5B and Table 3: the candidate antibodies all have better ability to block ANG2 and receptor TIE2 binding, and all exhibit blocking activity superior to that of the control antibody nesvacumab.
Table 3 binding Activity and blocking Activity of candidate antibodies based on ELISA method
Antibody name | Binding Activity EC 50 (μg/mL) | Blocking active IC 50 (μg/mL) |
nesvacumab | 0.442 | 1.578 |
78A46 | 0.049 | 0.367 |
78A74 | 0.097 | 0.626 |
78A51 | 0.136 | 0.566 |
7 | 0.128 | 0.611 |
78A14 | 0.122 | 0.631 |
78A5 | 0.166 | 0.648 |
17 | 0.120 | 0.547 |
35 | 0.173 | 0.676 |
Example 6 detection of blocking Activity of candidate antibodies based on FACS method
In this example, candidate antibodies were evaluated for their activity to block binding of ANG2 to the cell surface expression receptor TIE2 based on FACS methods.
Candidate antibody and control antibody nesvacumab were gradient diluted using FACS buffer (1×pbs+2% fbs) and antibody dilutions were added to 96-well round bottom plates at 100 μl per well. hANG2-Fc-biotin protein was diluted to 2. Mu.g/mL using the same FACS buffer, 100. Mu.L was added to the corresponding 96-well plate, mixed well and the 96-well plate was incubated at 4℃for 1h. hTIE2-HEK293 cell Density was adjusted to 1X 10 6 Individual cells/mL were added at 100. Mu.L per well to a new 96-well round bottom plate, centrifuged at 4℃at 300g and the supernatant removed. 180. Mu.L of a mixture of the antibody to be detected and hANG2-Fc-biotin, which had been incubated beforehand, was added to the corresponding wells, mixed well and incubated at 4℃for 30min. After washing the incubated cell mixture 3 times, 200. Mu.L 1 was added: 200 dilutions of PE-labeled strepitavidins (Invitrogen, 12-4317-87) were incubated at 4℃for 30min in the absence of light, and after 3 washes the amount of hANG2-Fc-biotin bound to the cells (expressed as mean fluorescence intensity, MFI) was detected by flow cytometry (Beckman, cytoFLEX AOO-1-1102).
The experimental results are shown in fig. 6 and table 4: the blocking activity of antibodies 78a46, 78a74, 78a51, 78a14 was superior to the control antibody nesvacumab.
Table 4 blocking activity of candidate antibodies based on FACS method
Antibody name | Blocking IC 50 Value (μg/mL) |
nesvacumab | 0.362 |
78A46 | 0.234 |
78A74 | 0.298 |
78A51 | 0.227 |
7 | 0.377 |
78A14 | 0.265 |
78A5 | 0.480 |
17 | 0.323 |
35 | 0.424 |
Example 7 candidate antibody inhibition of TIE2 phosphorylation Activity assay
hTIE2-HEK293 cells were plated into polylysine coated 96-well plates (WHB, WHB-96-LC), 1X 10 per well 4 The individual cells were incubated at 37℃for 24h. After the completion of the culture, the cell culture supernatant was discarded, rinsed once with serum-free DMEM medium, and 50 μl of mixed DMEM medium containing hANG2-Fc and a gradient of the antibody to be tested was added to each well, followed by incubation at 37 ℃ for 30min. The supernatant was then removed and the cell plates were rinsed once with 4℃pre-chilled PBS, and 100. Mu.L of 1 Xcell lysate (CST, 9803) and 1 Xprotease inhibitor (Thermo, 78430) were added to each well and lysed on ice for 30min. Collecting lysate, quantitatively detecting phosphorylated TIE2 in protein lysate, and detecting by using a detection kit of Human Phospho-Tie-2 DuoSet IC ELISA (R&D, DYC 2720-2), the detailed detection method and the operation steps are shown in the instruction book of the kit.
The detection results are shown in fig. 7 and table 5: most candidate antibodies were shown to have superior or equivalent activity in inhibiting ANG 2-mediated TIE2 phosphorylation to the positive control antibody nesvacumab, with antibodies 78a46, 78a74 and 17 being significantly superior to nesvacumab.
TABLE 5 inhibitory Activity of candidate antibodies against TIE2 phosphorylation
Antibody name | IC 50 (μg/mL) |
Nesvacumab | 8.308 |
78A74 | 5.467 |
7 | 9.761 |
78A51 | 8.052 |
78A14 | 7.311 |
78A46 | 3.568 |
78A5 | 7.089 |
17 | 6.357 |
35 | 11.93 |
EXAMPLE 8 evaluation of in vivo efficacy of candidate antibodies
In the embodiment, the tumor inhibition effect of 6 candidate antibodies and a positive control antibody nesvacuumab in animals is verified, and the tumor cells are colon cancer cells Colo205 #CCL-222 TM ). Male BALB/c nude mice (Peking Violet laboratory animal technologies Co., ltd.) of about 20g were used 6-8 weeks old and each was subcutaneously injected 5X 10 6 Colo205 cells with tumor volume up to 150mm 3 When the medicine is left and right, the operation of dividing the medicine into component cages and administering medicine is carried out. 8 tumor-bearing nude mice per group, 8 groups: including 6 candidate antibody groups, 1 negative control group, and 1 positive control antibody nesvacumab group. The administration mode is intraperitoneal injection, the dosage is 5mg/kg, the administration is carried out once every 3-4 days, the administration is carried out 2 times a week, the tumor volume is measured 2 times, and the administration is carried out 6 times/3 weeks. Tumor volume (V) calculation mode: v=l×w 2 2 (where L is the longest of the tumor diameters and W is the shortest of the tumor diameters). Mice were euthanized 1 week after dosing was completed, tumors were removed and tumor weights were measured. Tumor volume, tumor weight and mouse weight change data were analyzed, and tumor inhibition rate, tumor inhibition rate TGI (%) = (1-experimental group tumor average volume/PBS control group tumor average volume) ×100% was calculated.
The results are shown in FIGS. 8A-8C and Table 6, respectively. As can be seen from fig. 8C, there was no significant difference between the weights of the mice in each group, and there was no significant change in the weights of the mice in each group during the treatment period, indicating that the mice were well tolerated by the antibody. As can be seen from fig. 8A, 8B and table 6, the PBS negative control mice developed the most rapidly tumor, and all antibody groups had significant tumor-inhibiting effect compared to the PBS group; wherein, the tumor volume and tumor weight of the mice in the groups 17, 35, 78A14, 78A46 and 78A74 are lower than those of the positive control antibody nesvacumab group, and the mice show better tumor inhibition effect.
TABLE 6 tumor rejection Rate of candidate antibodies TGI (%)
Example 9 detection of drug metabolism Rate of candidate antibodies in Balb/C mice
In this example, the drug metabolism rate of 6 candidate antibodies in Balb/C mice (Experimental animal technologies Co., ltd. In Beijing Vitre) was measured, while using the positive control antibody nesvacumab as a control. The experimental animals are divided into 7 groups, each group comprises 6 Balb/C mice, and each mouse is injected into the abdominal cavity with the dosage of 40mg/kg; the dosing volume was 10mL/kg. Blood samples collected at time points 2h, 4h, 8h, 1d, 2d, 3d, 4d, 5d, 9d, 14d of each group were left at room temperature for 2 hours, 3 mice were selected for each time point of each group to collect blood samples, mice within the group were alternately bled, and then centrifuged at 10000g for 5 minutes at 4 ℃. The supernatant was collected and immediately subjected to experiments or samples aliquoted for storage at-80 ℃.
ELISA was used to quantitatively determine the drug concentration in mouse serum. hANG2-Fc (2. Mu.g/mL) was coated on 96 Kong Bankong ELISA plates, and coated overnight at 4 ℃; after 3 washes of PBST plates, blocking was performed for 1h using 2% BSA, 160. Mu.L/Kong Shiwen; after PBST is washed for 3 times, the serum to be tested of the mice is diluted to different concentrations by 2% BSA, 30 mu L of the serum to be tested of the mice is added into each hole, and the mice are incubated for 1h at room temperature; after washing the plate 3 times, a 1:5000 dilution of a mixture of anti-human IgG kappa HRP secondary antibody (Millipore, AP 502P) and anti-human Lambda HRP secondary antibody (Millipore, AP 506P) was added and incubated for 1h at room temperature; after incubation, the plates were washed 6 times with PBST and developed with TMB (SurModics, TMBS-1000-01). Based on the color development, the reaction was stopped by adding 2M HCl and the OD450 value was read by a microplate reader (Molecular Devices, specterMax 190).
The results are shown in fig. 9 and table 7: the drug metabolism rate of antibodies 78a74, 78a14, 7 and 17 is lower than that of the control antibody nesvacumab, and thus the bioavailability of antibodies 78a74, 78a14, 7 and 17 is higher than that of the control antibody nesvacumab.
TABLE 7 blood concentration values (μg/mL) at various time points for candidate antibodies
Antibody name | 2h | 4h | 8h | 24h | 48h | 72h | 96h | 120h | 216h | 336h |
Nesvacumab | 693 | 819 | 877 | 419 | 225 | 159 | 150 | 164 | 45 | 17 |
78A46 | 232 | 264 | 216 | 173 | 203 | 158 | 138 | 105 | 63 | 29 |
78A14 | 473 | 492 | 628 | 560 | 516 | 488 | 500 | 301 | 273 | 38 |
78A74 | 1135 | 1811 | 1272 | 1351 | 1461 | 1257 | 1194 | 906 | 507 | 252 |
7 | 531 | 726 | 569 | 477 | 428 | 431 | 371 | 366 | 88 | 25 |
17 | 441 | 586 | 537 | 413 | 432 | 387 | 396 | 353 | 274 | 127 |
35 | 303 | 316 | 323 | 244 | 248 | 168 | 156 | 158 | 61 | 8 |
Example 10 engineering of candidate antibodies
In the previous example data, antibody 78A74 showed better rates of drug metabolism in mice, blocking ANG2-TIE2 phosphorylating activity, etc. Affinity maturation transformation is based on an M13 phage display technology, a codon-based primer (in the primer synthesis process, a single codon is composed of NNK) is adopted to introduce CDR region mutation, 4 phage display libraries are constructed by each parent molecule, library 1 and library 2 are single-point combined mutation, library 1 is CDRL1+CDRL3+CDRH3 combined mutation, and library 2 is CDRL2+CDRH1+CDRH2 combined mutation; library 3 and library 4 are double point saturation mutations, library 3 is a double point saturation mutation of CDRL3, and library 4 is a double point saturation mutation of CDRH 3.
The single CDR region mutant fragment is obtained by taking an antibody 78A74 as a template through a PCR mode, then a Fab fragment (VL-CL-linker-VH-CH 1) is obtained through an overlay PCR mode, point mutant antibodies are connected into phage display vectors through double digestion (HindIII and NotI) and double sticky end connection, and finally an antibody sequence with mutation sites is transferred into escherichia coli SS320 through electrotransformation.
After packaging 4 libraries of the construction into phage, the library was subjected to sea selection, preliminary screening and affinity sequencing and sequence analysis (see example 2 for methods), the 28 positive clonotype expression Fab supernatants were selected for affinity sequencing and sequence analysis, and finally the 5 preferred Fab fragments were selected for sample preparation and affinity evaluation. Fully human antibodies were prepared based on these 5 Fab fragments (see example 4 for methods) whose variable region amino acid sequences are shown in table 8.
TABLE 8 variable region amino acid sequence of anti-ANG 2 fully human antibody obtained by affinity maturation (SEQ ID NO:)
Antibody name | HCDR1 | HCDR2 | HCDR3 | LCDR1 | LCDR2 | LCDR3 | VH | VL |
78A74-7 | 62 | 5 | 6 | 7 | 8 | 80 | 69 | 74 |
78A74-21 | 62 | 5 | 81 | 82 | 8 | 83 | 75 | 76 |
78A74-25 | 62 | 5 | 6 | 7 | 8 | 84 | 69 | 77 |
78A74-35 | 62 | 5 | 6 | 7 | 8 | 85 | 69 | 78 |
78A74-36 | 62 | 5 | 6 | 7 | 8 | 86 | 69 | 79 |
Example 11 affinity kinetic assessment of anti-ANG 2 antibodies
In this example, neovacumab was used as a positive control based on the detection of the binding affinity of candidate antibodies to the antigen ANG2 by the Gator device.
The antibody to be tested was diluted to 20nM in 10 XKB (10 XPBS buffer containing 1% BSA, 0.5% Tween 20), and hANG2-His as an antigen was diluted 2-fold in 10 XKB buffer at concentrations of 100nM, 50nM, 25nM and 0nM, respectively. Under the condition of avoiding light, a sensor (Gator, 20-5006) is prewetted by using 10 XKB buffer solution, a sample plate (Gator, 06-0153) is tested after at least 10 minutes, and the test is carried out according to a preset program after the test is completed. Firstly, binding an antibody and a sensor for 120s, after the binding is completed and balanced for 30s in 10 XKB buffer, transferring the sensor combined with the antibody into antigen diluents with different concentrations to bind for 120s, after signals are stabilized, transferring the sensor into the 10 XKB buffer, wherein the dissociation time is 120s, and finally obtaining K through the binding dissociation data fitting of antigen with different concentrations D (affinity kinetic constant), kon (binding constant), and Koff (dissociation constant), kon can be written as Ka, koff can be written as Kd.
The results of the assay are shown in Table 9 and show that antibodies 78A74-7, 78A74-21 and 78A74-25 have a higher affinity than antibody 78A74 and about 2-fold greater than the control antibody nesvacumab. Antibodies 7, 35, 78a46, 78a14, 78a74-35 and 78a74-36 have similar affinity for human ANG2 as the control antibodies.
TABLE 9 evaluation of affinity kinetics of candidate antibodies
Antibody name | K D (M) | ka(1/Ms) | kd(1/s) |
nesvacumab | 1.17E-09 | 1.80E+05 | 2.11E-04 |
7 | 1.56E-09 | 1.97E+05 | 3.07E-04 |
35 | 2.36E-09 | 2.04E+05 | 4.82E-04 |
78A46 | 9.08E-10 | 1.99E+05 | 1.81E-04 |
78A14 | 1.62E-09 | 1.79E+05 | 2.89E-04 |
78A74 | 1.22E-09 | 1.95E+05 | 2.38E-04 |
78A74-7 | 5.44E-10 | 1.89E+05 | 1.03E-04 |
78A74-21 | 6.87E-10 | 1.92E+05 | 1.32E-04 |
78A74-25 | 8.28E-10 | 1.94E+05 | 1.61E-04 |
78A74-35 | 1.52E-09 | 1.87E+05 | 2.84E-04 |
78A74-36 | 1.32E-09 | 2.00E+05 | 2.63E-04 |
Those skilled in the art will further recognize that the invention may be embodied in other specific forms without departing from the spirit or central characteristics thereof. Since the foregoing description of the present disclosure discloses only exemplary embodiments thereof, it should be understood that other variations are considered to be within the scope of the invention. Therefore, the present invention is not limited to the specific embodiments described in detail herein. Rather, reference should be made to the appended claims for indicating the scope and content of the invention.
Sequence listing
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Pro Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Val Ser Gln His
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 17
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 1JIU LCDR1
<400> 17
Arg Ala Ser Gln Ser Val Ala Ser Ser Tyr Leu Ala
1 5 10
<210> 18
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 1JIU LCDR2
<400> 18
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 19
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 1JIU LCDR3
<400> 19
Gln Gln Tyr Gly Ser Ser Pro Pro Trp Thr
1 5 10
<210> 20
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 1JIU VL
<400> 20
Glu Ile Val Met Thr Gln Ser Pro Gly Thr Gln Ser Leu Ser Pro Gly
1 5 10 15
Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ala Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Lys Lys Pro Asp Gln Ala Pro Arg Leu Ile
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 21
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A51 LCDR1
<400> 21
Thr Gly Thr Thr Ser Asp Val Gly Gly Phe Asn Tyr Val Ser
1 5 10
<210> 22
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A51 LCDR2
<400> 22
Asp Val Thr Asn Arg Pro Ser
1 5
<210> 23
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A51 LCDR3
<400> 23
Thr Ser Tyr Thr Ser Arg Asn Thr Leu Tyr Val
1 5 10
<210> 24
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A51 VL
<400> 24
Gln Ser Ala 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 Thr Ser Asp Val Gly Gly Phe
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Ile Ile Phe Asp Val Thr Asn Arg Pro Ser Gly Val Ser Asp 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 Asp Asp Glu Ala Asp Tyr Tyr Cys Thr Ser Tyr Thr Ser Arg
85 90 95
Asn Thr Leu Tyr Val Phe Gly Thr Ala Thr Lys Val Thr Val Leu
100 105 110
<210> 25
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 7 LCDR1
<400> 25
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 26
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 7 LCDR3
<400> 26
Gln Gln Arg Ser Asn Ser Leu Thr
1 5
<210> 27
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 7 VL
<400> 27
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Ser Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 28
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A42 LCDR2
<400> 28
Gly Ala Ser Asn Arg Ala Thr
1 5
<210> 29
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A42 LCDR3
<400> 29
Gln His Tyr Gly Ser Ser Leu Phe Thr
1 5
<210> 30
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A42 VH
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Arg Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ala
115 120 125
<210> 31
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A42 VL
<400> 31
Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Phe Tyr Cys Gln His Tyr Gly Ser Ser Leu
85 90 95
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 32
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 9 LCDR2
<400> 32
Gly Ala Thr Ser Arg Ala Ile
1 5
<210> 33
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 9 LCDR3
<400> 33
Glu Gln Tyr Asp Asn Ser Pro Tyr Thr
1 5
<210> 34
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 9 VH
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ala
115 120 125
<210> 35
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> 9 VL
<400> 35
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Asp Thr Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Thr Ser Arg Ala Ile Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Thr Ile Ser Gly Leu Glu
65 70 75 80
Pro Glu Asp Ile Ala Val Tyr Tyr Cys Glu Gln Tyr Asp Asn Ser Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 36
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 2 LCDR3
<400> 36
Gln Gln Tyr Gly Ser Ser Pro Tyr Thr
1 5
<210> 37
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 2 VH
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Met Val Thr Val Ser Ala
115 120 125
<210> 38
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> 2 VL
<400> 38
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 39
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 21 LCDR3
<400> 39
Gln Gln Arg Ser Asn Trp Pro Pro Ser Tyr Thr
1 5 10
<210> 40
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 21 VH
<400> 40
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ala
115 120 125
<210> 41
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 21 VL
<400> 41
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Ser Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 42
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A27 LCDR1
<400> 42
Arg Ala Ser Gln Gly Ile Ser Ser Gly Leu Val
1 5 10
<210> 43
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A27 LCDR2
<400> 43
Asp Ala Ser Ser Val Gln Ser
1 5
<210> 44
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A27 LCDR3
<400> 44
Gln Gln Gly Asn Ser Phe Pro Pro Thr
1 5
<210> 45
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A27 VL
<400> 45
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Gly
20 25 30
Leu Val Trp Tyr Gln Val Lys Pro Gly Lys Ala Pro Gln Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Val Gln Ser Gly Val Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A40 LCDR1
<400> 46
Arg Ala Ser Gln Asp Ile Arg Asn Glu Leu Ser
1 5 10
<210> 47
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A40 LCDR2
<400> 47
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 48
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A40 LCDR3
<400> 48
Leu Gln Asp Asn Asn Tyr Pro Arg Thr
1 5
<210> 49
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A40 VL
<400> 49
Asn Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Val Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Glu
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Leu Gln Asp Asn Asn Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Asp Ile Arg
100 105
<210> 50
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A45 LCDR1
<400> 50
Arg Ala Ser Gln Val Ile Asn Ser Asp Leu Asn
1 5 10
<210> 51
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A45 LCDR2
<400> 51
Asp Ala Ser Thr Leu Lys Ser
1 5
<210> 52
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A45 LCDR3
<400> 52
Gln Gln Asn Tyr Arg Thr Leu Ser Tyr Thr
1 5 10
<210> 53
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A45 VL
<400> 53
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Asn Ser Asp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Thr Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Arg Thr Leu Ser
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 54
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A46 LCDR1
<400> 54
Gly Gly Asn Ile Leu Gly Ser Asn Thr Val His
1 5 10
<210> 55
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A46 LCDR2
<400> 55
Tyr Asp Asn Asp Arg Pro Ser
1 5
<210> 56
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A46 LCDR3
<400> 56
His Val Trp Asp Arg Val Ala Thr Gln Tyr Val
1 5 10
<210> 57
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A46 VH
<400> 57
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 58
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A46 VL
<400> 58
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Leu Gly Ser Asn Thr Val
20 25 30
His Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Val Thr Val Ile Tyr
35 40 45
Tyr Asp Asn Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asp Thr Ala Thr Leu Thr Ile Ser Gly Val Glu Ala Gly
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys His Val Trp Asp Arg Val Ala Thr Gln
85 90 95
Tyr Val Phe Gly Ser Gly Thr Lys Val Thr Val Leu
100 105
<210> 59
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 8 LCDR3
<400> 59
Gln Gln Tyr Gly Ser Ser Pro Ser Tyr Thr
1 5 10
<210> 60
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 8 VH
<400> 60
Glu Val Gln Leu Leu 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 Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 61
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 8 VL
<400> 61
Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Ser Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 62
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 6 HCDR1
<400> 62
Gly Phe Thr Phe Ser Ser Tyr Ser Met Asn
1 5 10
<210> 63
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 6 LCDR1
<400> 63
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 64
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 6 LCDR2
<400> 64
Asp Val Ser Asn Arg Ala Thr
1 5
<210> 65
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 6 LCDR3
<400> 65
Gln Gln Arg Ala Ser Trp Pro Leu Thr
1 5
<210> 66
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 6 VH
<400> 66
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ala
115 120 125
<210> 67
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 6 VL
<400> 67
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Val Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Phe Tyr Tyr Cys Gln Gln Arg Ala Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 68
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74 LCDR3
<400> 68
Gln Gln Arg Ser Asn Trp Pro Pro Glu Trp Thr
1 5 10
<210> 69
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74 VH
<400> 69
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 70
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74 VL
<400> 70
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Glu Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 71
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> hIgG1 heavy chain constant region
<400> 71
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 72
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> hIgG1 CL (Kappa)
<400> 72
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 73
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> hIgG1 CL (Lambda)
<400> 73
Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210> 74
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-7 VL
<400> 74
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Leu Met Ser Asn Trp Pro Pro
85 90 95
Glu Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 75
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-21 VH
<400> 75
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Glu Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 76
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-21 VL
<400> 76
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Gly Pro Pro
85 90 95
Glu Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 77
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-25 VL
<400> 77
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Glu Leu Tyr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 78
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-35 VL
<400> 78
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Ala Met Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 79
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-36 VL
<400> 79
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Thr Met Trp Pro Pro
85 90 95
Glu Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 80
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-7 LCDR3
<400> 80
Gln Leu Met Ser Asn Trp Pro Pro Glu Trp Thr
1 5 10
<210> 81
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-21 HCDR3
<400> 81
Glu Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 82
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-21 LCDR1
<400> 82
Arg Ala Ser Gln Ser Val Gly Ser Tyr Leu Ala
1 5 10
<210> 83
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-21 LCDR3
<400> 83
Gln Gln Arg Ser Asn Gly Pro Pro Glu Trp Thr
1 5 10
<210> 84
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-25 LCDR3
<400> 84
Gln Gln Arg Ser Asn Trp Pro Pro Glu Leu Tyr
1 5 10
<210> 85
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-35 LCDR3
<400> 85
Gln Gln Arg Ser Asn Trp Pro Pro Ala Met Thr
1 5 10
<210> 86
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A74-36 LCDR3
<400> 86
Gln Gln Arg Thr Met Trp Pro Pro Glu Trp Thr
1 5 10
<210> 87
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A5 HCDR1
<400> 87
Gly Tyr Thr Phe Thr Asn Tyr Asp Phe Ser
1 5 10
<210> 88
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A5 HCDR2
<400> 88
Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn
1 5 10
<210> 89
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A5 HCDR3
<400> 89
Asp Val Ile Pro Tyr Gly Tyr Pro Ala Phe Asp Ile
1 5 10
<210> 90
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A5 LCDR1
<400> 90
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 91
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A5 LCDR2
<400> 91
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 92
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A5 LCDR3
<400> 92
Gln Gln Ala Asn Ser Phe Pro Ile Thr
1 5
<210> 93
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A5 VH
<400> 93
Gln Val Gln Leu Val Gln 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 Asn Tyr
20 25 30
Asp Phe Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser 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
Gly Arg Asp Val Ile Pro Tyr Gly Tyr Pro Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 94
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 78A5 VL
<400> 94
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 95
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 17 HCDR1
<400> 95
Gly Phe Thr Phe Asn Lys Tyr Thr Ile Asn
1 5 10
<210> 96
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 17 HCDR2
<400> 96
Asp Ile Ser Ser Gly Gly Asp Tyr Val Asn
1 5 10
<210> 97
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 17 HCDR3
<400> 97
Asp Ala Leu Thr Tyr Ser Asn Asn Trp Leu Asp Ser
1 5 10
<210> 98
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 17 LCDR1
<400> 98
Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala
1 5 10
<210> 99
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 17 LCDR2
<400> 99
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 100
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 17 LCDR3
<400> 100
Gln Gln Phe Glu Ser Tyr Pro Leu Thr
1 5
<210> 101
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 17 VH
<400> 101
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Thr Ile Asn Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Leu Val
35 40 45
Ala Asp Ile Ser Ser Gly Gly Asp Tyr Val Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Ser Val Tyr
65 70 75 80
Leu Leu Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Leu Thr Tyr Ser Asn Asn Trp Leu Asp Ser Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 102
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 17 VL
<400> 102
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Glu Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 103
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 35 HCDR1
<400> 103
Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5 10
<210> 104
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 35 HCDR2
<400> 104
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr
1 5 10
<210> 105
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> 35 HCDR3
<400> 105
Asp Leu Leu Asp Phe Trp Ser Gly Pro Gly Ala Phe Asp Ile
1 5 10
<210> 106
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 35 LCDR1
<400> 106
Arg Ala Ser Gln His Ile Ser Ser Trp Leu Ala
1 5 10
<210> 107
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 35 LCDR3
<400> 107
Gln Gln Phe Asn Ser Tyr Pro Leu Thr
1 5
<210> 108
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> 35 VH
<400> 108
Glu Val Gln Leu Leu 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 Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu Leu Asp Phe Trp Ser Gly Pro Gly Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 109
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 35 VL
<400> 109
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln His Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 110
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR1
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa is S or N
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa is S or V
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa is S or G
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa is N or H
<400> 110
Gly Phe Thr Phe Xaa Xaa Tyr Xaa Met Xaa
1 5 10
<210> 111
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR3
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa is A or E
<400> 111
Xaa Thr Leu Asp Gly Tyr Thr Ala Gly Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
Claims (20)
1. A heavy chain variable region polypeptide that specifically binds ANG2 comprising HCDR1, HCDR2 and HCDR3 sequences wherein
(a) The HCDR1 sequence is shown as SEQ ID NO. 110
GFTFX 1 X 2 YX 3 MX 4 (SEQ ID NO:110)
Wherein X is 1 Is S or N; x is X 2 S or V; x is X 3 S or G; x is X 4 Is N or H;
(b) The HCDR2 sequence is shown as VISYDGSNKY (SEQ ID NO: 5);
(c) The HCDR3 sequence is shown as SEQ ID NO. 111
X 5 TLDGYTAGYYYGMDV(SEQ ID NO:111)
Wherein X is 5 Is A or E.
2. The heavy chain variable region polypeptide of claim 1 wherein the HCDR1, HCDR2 and HCDR3 sequences are selected from any one of (1) - (4):
(1) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; and an HCDR3 sequence shown in SEQ ID NO. 6;
(2) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; and an HCDR3 sequence shown in SEQ ID NO. 81;
(3) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; and an HCDR3 sequence shown in SEQ ID NO. 6;
(4) An HCDR1 sequence shown in SEQ ID NO. 12; an HCDR2 sequence shown in SEQ ID NO. 5; and the HCDR3 sequence shown in SEQ ID NO. 6.
3. An anti-ANG 2 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region polypeptide comprising HCDR1, HCDR2 and HCDR3 sequences and a light chain variable region polypeptide comprising LCDR1, LCDR2 and LCDR3 sequences wherein the HCDR1, HCDR2 and HCDR3 sequences are as defined in claim 1 or 2 wherein the LCDR1, LCDR2 and LCDR3 sequences are selected from any one of (1) - (21):
(1) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 68;
(2) The LCDR1 sequence shown in SEQ ID NO. 82; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 83;
(3) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 84;
(4) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 85;
(5) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 86;
(6) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 80;
(7) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 39;
(8) An LCDR1 sequence shown in SEQ ID NO. 17; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 19;
(9) The LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO 59;
(10) The LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 36;
(11) The LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 28; and the LCDR3 sequence shown in SEQ ID NO. 29;
(12) An LCDR1 sequence shown in SEQ ID NO. 7; the LCDR2 sequence shown in SEQ ID NO. 13; and the LCDR3 sequence shown in SEQ ID NO. 14;
(13) The LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 26;
(14) An LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 9;
(15) The LCDR1 sequence shown in SEQ ID NO. 63; the LCDR2 sequence shown in SEQ ID NO. 64; and the LCDR3 sequence shown in SEQ ID NO. 65;
(16) The LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 32; and the LCDR3 sequence shown in SEQ ID NO. 33;
(17) The LCDR1 sequence shown in SEQ ID NO. 42; the LCDR2 sequence shown in SEQ ID NO. 43; and the LCDR3 sequence shown in SEQ ID NO. 44;
(18) The LCDR1 sequence shown in SEQ ID NO. 50; the LCDR2 sequence shown in SEQ ID NO. 51; and the LCDR3 sequence shown in SEQ ID NO. 52;
(19) The LCDR1 sequence shown in SEQ ID NO. 46; the LCDR2 sequence shown in SEQ ID NO. 47; and the LCDR3 sequence shown in SEQ ID NO. 48;
(20) An LCDR1 sequence shown in SEQ ID NO. 21; the LCDR2 sequence shown in SEQ ID NO. 22; and the LCDR3 sequence shown in SEQ ID NO. 23;
(21) The LCDR1 sequence shown in SEQ ID NO. 54; the LCDR2 sequence shown in SEQ ID NO. 55; and the LCDR3 sequence shown in SEQ ID NO. 56.
4. The anti-ANG 2 antibody or antigen-binding fragment thereof of claim 3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences are selected from any one of (1) - (21):
(1) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 68;
(2) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 80;
(3) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 84;
(4) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 85;
(5) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 86;
(6) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 63; the LCDR2 sequence shown in SEQ ID NO. 64; and the LCDR3 sequence shown in SEQ ID NO. 65;
(7) The HCDR1 sequence shown in SEQ ID NO. 62; an HCDR2 sequence shown in SEQ ID NO. 5; the HCDR3 sequence shown in SEQ ID NO. 81; the LCDR1 sequence shown in SEQ ID NO. 82; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 83;
(8) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 9;
(9) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 17; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 19;
(10) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 21; the LCDR2 sequence shown in SEQ ID NO. 22; and the LCDR3 sequence shown in SEQ ID NO. 23;
(11) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 26;
(12) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 28; and the LCDR3 sequence shown in SEQ ID NO. 29;
(13) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; the LCDR2 sequence shown in SEQ ID NO. 32; and the LCDR3 sequence shown in SEQ ID NO. 33;
(14) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO. 36;
(15) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; an LCDR2 sequence shown in SEQ ID NO. 8; and the LCDR3 sequence shown in SEQ ID NO. 39;
(16) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 42; the LCDR2 sequence shown in SEQ ID NO. 43; and the LCDR3 sequence shown in SEQ ID NO. 44;
(17) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 46; the LCDR2 sequence shown in SEQ ID NO. 47; and the LCDR3 sequence shown in SEQ ID NO. 48;
(18) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 50; the LCDR2 sequence shown in SEQ ID NO. 51; and the LCDR3 sequence shown in SEQ ID NO. 52;
(19) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 54; the LCDR2 sequence shown in SEQ ID NO. 55; and the LCDR3 sequence shown in SEQ ID NO. 56;
(20) An HCDR1 sequence shown in SEQ ID NO. 4; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; the LCDR1 sequence shown in SEQ ID NO. 25; an LCDR2 sequence shown in SEQ ID NO. 18; and the LCDR3 sequence shown in SEQ ID NO 59;
(21) An HCDR1 sequence shown in SEQ ID NO. 12; an HCDR2 sequence shown in SEQ ID NO. 5; an HCDR3 sequence shown in SEQ ID NO. 6; an LCDR1 sequence shown in SEQ ID NO. 7; the LCDR2 sequence shown in SEQ ID NO. 13; and the LCDR3 sequence shown in SEQ ID NO. 14.
5. The anti-ANG 2 antibody or antigen-binding fragment thereof of claim 3 or 4, wherein the heavy chain variable region polypeptide comprises:
(1) The amino acid sequence of SEQ ID NO. 69, SEQ ID NO. 10, SEQ ID NO. 40, SEQ ID NO. 75, SEQ ID NO. 15, SEQ ID NO. 30, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 57, SEQ ID NO. 60 or SEQ ID NO. 66; or alternatively
(2) Amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity to SEQ ID NO:69, SEQ ID NO:10, SEQ ID NO:40, SEQ ID NO:75, SEQ ID NO:15, SEQ ID NO:30, SEQ ID NO:34, SEQ ID NO:37, SEQ ID NO:57, SEQ ID NO:60 or SEQ ID NO: 66.
6. The anti-ANG 2 antibody or antigen-binding fragment thereof of any one of claims 3-5, wherein the light chain variable region polypeptide comprises:
(1) An amino acid sequence of SEQ ID NO. 70, SEQ ID NO. 74, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 79, SEQ ID NO. 11, SEQ ID NO. 20, SEQ ID NO. 24, SEQ ID NO. 27, SEQ ID NO. 41, SEQ ID NO. 45, SEQ ID NO. 49, SEQ ID NO. 53, SEQ ID NO. 76, SEQ ID NO. 16, SEQ ID NO. 31, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 58, SEQ ID NO. 61 or SEQ ID NO. 67; or alternatively
(2) Amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity to the amino acid sequence of SEQ ID NO 70, SEQ ID NO 74, SEQ ID NO 77, SEQ ID NO 78, SEQ ID NO 79, SEQ ID NO 11, SEQ ID NO 20, SEQ ID NO 24, SEQ ID NO 27, SEQ ID NO 41, SEQ ID NO 45, SEQ ID NO 49, SEQ ID NO 53, SEQ ID NO 76, SEQ ID NO 16, SEQ ID NO 31, SEQ ID NO 35, SEQ ID NO 38, SEQ ID NO 58, SEQ ID NO 61, or SEQ ID NO 67.
7. The anti-ANG 2 antibody or antigen-binding fragment thereof of claim 3 or 4, wherein the heavy chain variable region polypeptide and light chain variable region polypeptide are selected from any one of (1) - (21):
(1) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 70;
(2) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 74;
(3) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 77;
(4) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 78;
(5) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 69; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 79;
(6) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 10; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 11;
(7) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 10; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 20;
(8) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 10; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 24;
(9) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 10; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 27;
(10) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 40; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 41;
(11) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 40; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 45;
(12) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 40; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 49;
(13) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 40; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 53;
(14) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 75; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 76;
(15) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 15; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 16;
(16) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 30; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 31;
(17) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 34; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 35;
(18) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 37; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 38;
(19) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 57; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 58;
(20) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 60; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 61;
(21) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 66; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 67.
8. An anti-ANG 2 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region polypeptide comprising HCDR1, HCDR2 and HCDR3 sequences and a light chain variable region polypeptide comprising LCDR1, LCDR2 and LCDR3 sequences, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 sequences are selected from any one of (1) - (3):
(1) The HCDR1 sequence shown in SEQ ID NO. 87; the HCDR2 sequence shown in SEQ ID NO. 88; the HCDR3 sequence shown in SEQ ID NO. 89; the LCDR1 sequence shown in SEQ ID NO. 90; the LCDR2 sequence shown in SEQ ID NO. 91; and the LCDR3 sequence shown in SEQ ID NO. 92;
(2) The HCDR1 sequence shown in SEQ ID NO. 95; the HCDR2 sequence shown in SEQ ID NO. 96; an HCDR3 sequence shown in SEQ ID NO. 97; the LCDR1 sequence shown in SEQ ID NO. 98; the LCDR2 sequence shown in SEQ ID NO. 99; and the LCDR3 sequence shown in SEQ ID NO. 100;
(3) The HCDR1 sequence shown in SEQ ID NO. 103; the HCDR2 sequence shown in SEQ ID NO. 104; the HCDR3 sequence shown in SEQ ID NO. 105; the LCDR1 sequence shown in SEQ ID NO. 106; the LCDR2 sequence shown in SEQ ID NO. 91; and the LCDR3 sequence shown in SEQ ID NO. 107.
9. The anti-ANG 2 antibody or antigen-binding fragment thereof of claim 8, wherein the heavy chain variable region polypeptide comprises:
(1) The amino acid sequence of SEQ ID NO. 93, SEQ ID NO. 101 or SEQ ID NO. 108; or alternatively
(2) An amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity to SEQ ID No. 93, SEQ ID No. 101 or SEQ ID No. 108.
10. anti-ANG 2 antibody or antigen-binding fragment thereof according to claim 8 or 9, wherein the light chain variable region polypeptide comprises:
(1) The amino acid sequence of SEQ ID NO. 94, SEQ ID NO. 102 or SEQ ID NO. 109; or alternatively
(2) An amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity to SEQ ID No. 94, SEQ ID No. 102 or SEQ ID No. 109.
11. The anti-ANG 2 antibody or antigen-binding fragment thereof of claim 8, wherein the heavy chain variable region polypeptide and light chain variable region polypeptide are selected from any one of (1) - (3):
(1) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 93; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 94;
(2) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 101; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 102;
(3) A heavy chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 108; a light chain variable region polypeptide comprising the amino acid sequence of SEQ ID No. 109.
12. anti-ANG 2 antibody or antigen-binding fragment thereof according to any one of claims 3-11, which is a fully human antibody, scFv, fab, fab ', F (ab') 2 Fv fragments, disulfide stabilized Fv (dsFv) or diabodies.
13. The anti-ANG 2 antibody or antigen-binding fragment thereof of any one of claims 3-12, further comprising a heavy chain constant region and/or a light chain constant region;
preferably, the heavy chain constant region is a human IgG1 heavy chain constant region and/or the light chain constant region is a human kappa or lambda light chain constant region;
more preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO. 71; and/or
The light chain constant region comprises the amino acid sequence of SEQ ID NO:72 or SEQ ID NO: 73.
14. anti-ANG 2 antibody or antigen-binding fragment thereof according to any one of claims 3-13, which specifically binds ANG2 but does not bind or does not substantially bind ANG1.
15. A multispecific antibody comprising a first antigen-binding portion that specifically binds ANG2 and a second antigen-binding portion that specifically binds a second antigen, wherein the first antigen-binding portion comprises a heavy chain variable region polypeptide as defined in claim 1 or 2 or an anti-ANG 2 antibody or antigen-binding fragment thereof as defined in any one of claims 3-14.
16. A polynucleotide encoding the heavy chain variable region polypeptide of claim 1 or 2, the anti-ANG 2 antibody or antigen-binding fragment thereof of any one of claims 3-14, or the multispecific antibody of claim 15.
17. An expression vector comprising the polynucleotide of claim 16.
18. A host cell comprising the polynucleotide of claim 16 or the expression vector of claim 17.
19. A pharmaceutical composition comprising a heavy chain variable region polypeptide according to claim 1 or 2, an anti-ANG 2 antibody or antigen-binding fragment thereof according to any one of claims 3-14, or a multispecific antibody according to claim 15, and a pharmaceutically acceptable carrier.
20. Use of a heavy chain variable region polypeptide according to claim 1 or 2, an anti-ANG 2 antibody or antigen-binding fragment thereof according to any one of claims 3-14, a multispecific antibody according to claim 15, or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for the treatment of:
(1) Angiogenesis-related eye diseases; or (b)
(2) Cancer;
preferably, the method comprises the steps of,
the angiogenesis-related eye disease is macular degeneration, retinal vein occlusion, retinopathy of prematurity, diabetic retinopathy, neovascular glaucoma, pathological myopia, macular edema, retinal edema, diabetic macular edema or choroidal neovascularization disease;
the cancer is lung cancer, liver cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, ovarian cancer, colorectal cancer, gastric cancer, breast cancer, prostate cancer, uterine cancer, hodgkin's lymphoma, esophageal cancer, anal cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, renal cancer, soft tissue sarcoma, bladder cancer, central Nervous System (CNS) tumor, mesothelioma, glioma, meningioma or pituitary adenoma.
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