Polypeptides

Abstract

In particular, polypeptides such as antibodies or fragments thereof that bind to LPAR1 are provided.

Description

[Technical field]

[0001] The present invention relates to polypeptides that bind to lysophosphatidic acid receptor 1 ("LPAR1"), as well as constructs and compositions comprising such polypeptides. The present invention also relates to nucleic acids encoding such polypeptides, methods for preparing such polypeptides, vectors comprising nucleic acids encoding such polypeptides, host cells expressing or capable of expressing such polypeptides, and uses of such polypeptides, compositions or constructs. [Background technology]

[0002] LPAR1 is involved in several biological axes that are important in diseases such as inflammatory and / or fibrotic diseases. A previously potent small molecule drug against LPAR1 (BMS-986020) failed in Phase II clinical trials due to insufficient drug selectivity. Therefore, there is a need for new LPAR1 inhibitors. Summary of the Invention [Means for solving the problem]

[0003] Summary of the Invention In a first aspect of the present invention, there is provided a polypeptide that binds to lysophosphatidic acid receptor 1 (LPAR1 or LPA1). Preferably, the polypeptide is an antibody or a fragment thereof, and more preferably, the polypeptide binds to functionally active LPAR1 on the surface of a living cell.

[0004] This is a significant advancement in the field.To the best of the author's knowledge, the polypeptide that binds to functionally active LPAR1 on the surface of living cells, especially the inhibitor polypeptide that binds to functionally active LPAR1 on the surface of living cells, has not been disclosed in the art.Surprisingly, the present inventors have been able to produce such a polypeptide.

[0005] Also provided is a polypeptide (such as an antibody or a fragment thereof) that binds to LPAR1, the polypeptide comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity with SEQ ID NO: 1, 7 or 107, HCDR2 comprises or consists of a sequence having at least 80% identity with SEQ ID NO: 2, 8 to 11, 100 or 108, HCDR3 comprises or consists of a sequence having at least 80% identity with SEQ ID NO: 3, 12 to 15, 101 or 109, LCDR1 comprises or consists of a sequence having at least 80% identity with SEQ ID NO: 4, 16 to 18, 103 or 110, LCDR2 comprises or consists of a sequence having at least 80% identity with SEQ ID NO: 5, 19, 98 or 111, and LCDR3 comprises or consists of a sequence having at least 80% identity with SEQ ID NO: 6, 20 to 22 or 112.

[0006] Also provided is a polypeptide (such as an antibody or fragment thereof) that binds to LPAR1, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:2, HCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:3, LCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:4, LCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:5, and LCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:6.

[0007] Also provided is a polypeptide (such as an antibody or fragment thereof) that binds to LPAR1, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:2, HCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:15, LCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:4, LCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:5, and LCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:6.

[0008] Also provided is a polypeptide (such as an antibody or fragment thereof) that binds to LPAR1, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:2, HCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:3, LCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:4, LCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:98, and LCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:6.

[0009] Also provided is a polypeptide (such as an antibody or fragment thereof) that binds to LPAR1, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:100, HCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:101, LCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:4, LCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:98, and LCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:6.

[0010] Also provided is a polypeptide (such as an antibody or fragment thereof) that binds to LPAR1, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:100, HCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:101, LCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:103, LCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:98, and LCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:6.

[0011] Also provided is a polypeptide (such as an antibody or fragment thereof) that binds to LPAR1, comprising a VH region comprising or consisting of a sequence having at least 80% identity to SEQ ID NO: 36, 37 or SEQ ID NO: 102, and a VL region comprising or consisting of a sequence having at least 80% identity to SEQ ID NO: 38, 99 or 104.

[0012] Also provided is a polypeptide (such as an antibody) that binds to LPAR1, comprising or consisting of a heavy chain comprising or consisting of SEQ ID NO:58, SEQ ID NO:60 or SEQ ID NO:1220, and a light chain comprising or consisting of SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:1219 or SEQ ID NO:1221.

[0013] Constructs comprising the polypeptides of the invention are also provided.

[0014] Compositions comprising the polypeptides or constructs of the invention are also provided.

[0015] Also provided is a pharmaceutical composition comprising a polypeptide or construct of the invention together with a pharma- ceutically acceptable diluent or carrier.

[0016] There is also provided a polypeptide, construct or composition of the invention for use as a medicament.

[0017] There is also provided a polypeptide, construct or composition of the invention for use in the treatment of an inflammatory and / or fibrotic disease.

[0018] There is also provided a polypeptide, construct or composition of the invention for use in the treatment of a disease selected from the list consisting of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, systemic sclerosis and osteoarthritis.

[0019] Polynucleotides encoding the polypeptides or constructs of the invention are also provided.

[0020] Also provided is an expression vector comprising a polynucleotide sequence of the invention.

[0021] Cells comprising the polynucleotide sequences or expression vectors of the invention are also provided.

[0022] In certain embodiments, the polypeptides of the present invention can be expected to benefit from one or more of the following advantages over the prior art: (a) Binding of functional LPAR1 on the surface of living cells. (b) allosteric inhibition of LPAR1; (c) Reverse operation of LPAR1, (d) reduction of Gi / o and / or G13 and / or Gq signaling by LPAR1; (e) reducing or preventing LPA-induced or constitutive cAMP signaling; (f) reducing or preventing LPA-induced calcium mobilization; (g) binding to a novel epitope; (h) reduced toxicity; (i) increased potency, (j) increased binding affinity, (k) increased half-life, (l) reduced medication; (m) Binding to the extracellular domain of LPAR1. [Brief description of the drawings]

[0023] [Figure 1-1] Expression levels of antibody 12 compared to adalimumab biosimilar, its ability to bind to huLPAR1-HA cells, its ability to increase cAMP signaling, its ability to inhibit calcium signaling, and its ability to decrease cell proliferation. [Figure 1-2] Expression levels of antibody 12 compared to adalimumab biosimilar, its ability to bind to huLPAR1-HA cells, its ability to increase cAMP signaling, its ability to inhibit calcium signaling, and its ability to decrease cell proliferation. [Figure 1-3] Expression levels of antibody 12 compared to adalimumab biosimilar, its ability to bind to huLPAR1-HA cells, its ability to increase cAMP signaling, its ability to inhibit calcium signaling, and its ability to decrease cell proliferation. [Figure 2-1] Expression levels, ability to increase cAMP signaling, ability to inhibit calcium signaling, and ability to decrease cell proliferation of antibody 13 compared to adalimumab biosimilar. [Figure 2-2]Expression levels, ability to increase cAMP signaling, ability to inhibit calcium signaling, and ability to decrease cell proliferation of antibody 13 compared to adalimumab biosimilar. [Figure 3-1] Epitope prediction for antibody 7b. [Figure 3-2] Epitope prediction for antibody 7b. [Figure 4] Paratope prediction for antibody 7b. [Figure 5-1] In vitro epitope analysis. [Figure 5-2] In vitro epitope analysis. [Figure 5-3] In vitro epitope analysis. [Figure 6] Epitope delineation on LPAR1. [Figure 7-1] Expression levels of antibody 15 compared to palivizumab biosimilar, ability to increase cAMP signaling, ability to decrease cell proliferation, and ability to bind to huLPAR1-HA cells. [Figure 7-2] Expression levels of antibody 15 compared to palivizumab biosimilar, ability to increase cAMP signaling, ability to decrease cell proliferation, and ability to bind to huLPAR1-HA cells. [Figure 8-1] Expression levels, ability to increase cAMP signaling, and ability to decrease cell proliferation of antibody 16 compared to palivizumab biosimilar. [Figure 8-2] Expression levels, ability to increase cAMP signaling, and ability to decrease cell proliferation of antibody 16 compared to palivizumab biosimilar. [Figure 9-1] Expression levels of antibody 17 compared to palivizumab biosimilar, ability to increase cAMP signaling, ability to decrease cell proliferation, and ability to bind to huLPAR1-HA cells. [Figure 9-2] Expression levels of antibody 17 compared to palivizumab biosimilar, ability to increase cAMP signaling, ability to decrease cell proliferation, and ability to bind to huLPAR1-HA cells. [Figure 10-1] Expression levels of antibody 18 compared to palivizumab biosimilar, ability to increase cAMP signaling, ability to decrease cell proliferation, and ability to bind to huLPAR1-HA cells. [Figure 10-2] Expression levels of antibody 18 compared to palivizumab biosimilar, ability to increase cAMP signaling, ability to decrease cell proliferation, and ability to bind to huLPAR1-HA cells. [Figure 11-1] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 5ug / ml concentration). [Figure 11-2] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 5ug / ml concentration). [Figure 11-3] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 5ug / ml concentration). [Figure 11-4] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 5ug / ml concentration). [Figure 12-1] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 20ug / ml concentration). [Figure 12-2] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 20ug / ml concentration). [Figure 12-3] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 20ug / ml concentration). [Figure 12-4] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 20ug / ml concentration). [Figure 12-5] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 20ug / ml concentration). [Figure 12-6] CIFAT assay microscopy results for antibodies of the invention and prior art (with live cells at 20ug / ml concentration). [Figure 13] BRET testing of antibody 12 compared to prior art small molecule inhibitors. [Figure 14-1] Ability of antibodies 12, 15, 17 and 18 to bind to human, guinea pig, rabbit and mouse LPAR1. [Figure 14-2] Ability of antibodies 12, 15, 17 and 18 to bind to human, guinea pig, rabbit and mouse LPAR1. [Figure 15-1] Ability of antibodies 12, 15, 17 and 18 to bind to human LPAR1, LPAR2 and LPAR3. [Figure 15-2] Ability of antibodies 12, 15, 17 and 18 to bind to human LPAR1, LPAR2 and LPAR3. [Figure 16-1] Pharmacokinetics of antibodies 12, 15, 17 and 18 in rats. [Figure 16-2] Pharmacokinetics of antibodies 12, 15, 17 and 18 in rats. [Figure 17-1] SEC-MALS of antibodies 12, 13, 15, 16, 17 and 18. [Figure 17-2] SEC-MALS of antibodies 12, 13, 15, 16, 17 and 18. [Figure 17-3] SEC-MALS of antibodies 12, 13, 15, 16, 17 and 18. [Figure 18] Efficacy analysis of unilateral ureteral obstruction in guinea pigs using Antibody 13 and Antibody 17. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] [Table 1] TIFF2024535662000002.tif239169TIFF2024535662000003.tif240169TIFF2024535 662000004.tif241169TIFF2024535662000005.tif244169TIFF2024535662000006.t if244169TIFF2024535662000007.tif244169TIFF2024535662000008.tif244169TIF F2024535662000009.tif244169TIFF2024535662000010.tif244169TIFF20245356620 00011.tif244169TIFF2024535662000012.tif244169TIFF2024535662000013.tif24 4169TIFF2024535662000014.tif244169TIFF2024535662000015.tif244169TIFF202 4535662000016.tif244169TIFF2024535662000017.tif244169TIFF20245356620000 18.tif244169TIFF2024535662000019.tif244169TIFF2024535662000020.tif253166

[0025] [Table 2]

[0026] Detailed Description of the Invention definition Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms have the meanings ascribed to them below.

[0027] A polypeptide is an organic polymer consisting of many amino acid residues linked together in a chain. As used herein, "polypeptide" is used interchangeably with "protein" and "peptide."

[0028] The term "antibody" includes any antibody protein construct that contains at least one antibody variable domain that contains at least one antigen binding site (ABS). Antibodies include, but are not limited to, immunoglobulins of the IgA, IgG, IgE, IgD, IgM types (as well as their subtypes). The overall structure of the immunoglobulin G (IgG) antibody, assembled from two identical heavy (H) chains and two identical light (L) chain polypeptides, is well established and highly conserved in mammals (Padlan 1994).

[0029] "Specificity" refers to the number of different types of antigens or antigenic determinants to which a particular antibody or fragment thereof can bind. Antibody specificity is the ability of an antibody to recognize a particular antigen as a unique molecular entity and distinguish it from another. An antibody that "specifically binds" to an antigen or epitope is a term well understood in the art. A molecule is said to exhibit "specific binding" if it reacts with a particular target antigen or epitope more frequently, more rapidly, with greater duration, and / or with greater affinity than it reacts with alternative targets. An antibody "specifically binds" to a target antigen or epitope if it binds with greater affinity, avidity, more easily, and / or with greater duration than it binds to other substances. An antibody (or fragment thereof) may be considered to specifically bind to a target if the binding is statistically significant compared to an unrelated binder. Specific binding of an antibody or fragment thereof to an antigen or antigenic determinant can be determined in any suitable manner known in the art, including, for example, Scatchard analysis and / or competitive binding assays, such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, equilibrium dialysis, equilibrium binding, gel filtration, ELISA or spectroscopy (e.g., using fluorescence assays), as well as different variants thereof known in the art.

[0030] The equilibrium constant for dissociation of the antigen-binding polypeptide from the antigen (K D"Affinity", expressed by K ), is a measure of the binding strength between an antigenic determinant and an antigen-binding site in an antibody (or fragment thereof): K D The smaller the value of K, the stronger the binding strength between the antigenic determinant and the antigen-binding polypeptide. Alternatively, affinity can be expressed as 1 / K D Affinity can also be expressed as an affinity constant (KA), which is a function of the specific antigen of interest. Affinity can be determined by known methods, for example, K D can be determined by the methods listed in Method 1.14 of the Examples section. -6 Any K less than D Values ​​are also considered to indicate binding. -6 M or less, more preferably 10 -7 M or less, more preferably 10 -8 M or less, more preferably 10 -9 It binds with a dissociation constant of less than M.

[0031] "Avidity" is a measure of the strength of binding between a polypeptide, an antibody or a fragment thereof and a relevant antigen. Avidity is related to both the affinity between an antigenic determinant and its antigen-binding site on the antibody and the number of relevant binding sites present on the antibody.

[0032] Suitably, the polypeptide of the present invention is isolated. An "isolated" polypeptide is a polypeptide that has been removed from its native environment. For example, a naturally occurring polypeptide of the present invention is isolated if it has been separated from some or all of the coexisting materials in the natural system. The term "isolated" can also be used to refer to a preparation in which the isolated polypeptide, when formulated as an active ingredient in a pharmaceutical composition, is sufficiently pure to be administered for therapeutic purposes, or is at least 70-80% (w / w) pure, more preferably at least 80-90% (w / w) pure, even more preferably 90-95% pure; most preferably at least 95%, 96%, 97%, 98%, 99% or 100% (w / w) pure.

[0033] Preferably, the polynucleotide used in the present invention is isolated. An "isolated" polynucleotide is a polynucleotide that is removed from its original environment. For example, a naturally occurring polynucleotide is isolated when it is separated from some or all of the coexisting materials in the natural system. A polynucleotide is considered to be isolated, for example, when it is cloned into a vector that is not part of its natural environment or when it is contained within a cDNA.

[0034] For purposes of comparing two closely related polypeptide sequences, the "% sequence identity" between a first polypeptide sequence and a second polypeptide sequence can be calculated using NCBI BLAST v2.0 (BLASTP) using standard settings for polypeptide sequences. For purposes of comparing two closely related polynucleotide sequences, the "% sequence identity" between a first nucleotide sequence and a second nucleotide sequence can be calculated using NCBI BLAST v2.0 (BLASTN) using standard settings for nucleotide sequences.

[0035] A polypeptide or polynucleotide sequence is said to be the same as, or "identical to," another polypeptide or polynucleotide sequence if they share 100% sequence identity over their entire length. Residues in a sequence are numbered from left to right, i.e., from N-terminus to C-terminus for polypeptides; from 5' to 3' for polynucleotides.

[0036] A "difference" between polypeptide sequences refers to an insertion, deletion, or substitution of a single amino acid residue at a position of the second sequence compared to the first sequence. Two polypeptide sequences can contain one, two, or more such amino acid differences. An insertion, deletion, or substitution in a second sequence that is otherwise identical (100% sequence identity) to a first sequence results in a reduced % sequence identity. For example, if an identical sequence is 9 amino acid residues long, a single substitution in the second sequence results in 88.9% sequence identity. If a first and second polypeptide sequence are 9 amino acid residues long and share 6 identical residues, the first and second polypeptide sequences share more than 66% identity (the first and second polypeptide sequences share 66.7% identity).

[0037] Instead, for the purpose of comparing a first reference polypeptide sequence with a second comparative polypeptide sequence, one can ascertain the number of additions, substitutions and / or deletions made to the first sequence to produce the second sequence. An "addition" is the addition of one amino acid residue to the sequence of the first polypeptide (including additions at either end of the first polypeptide). A "substitution" is the replacement of one amino acid residue in the sequence of the first polypeptide with one different amino acid residue. The substitution may be conservative or non-conservative. A "deletion" is the removal of one amino acid residue from the sequence of the first polypeptide (including deletions at either end of the first polypeptide).

[0038] Using the three-letter and one-letter codes, naturally occurring amino acids can be designated as follows: glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (L or Leu), isoleucine (I or Ile), proline (P or Pro), phenylalanine (F or Phe), tyrosine (Y or Tyr), tryptophan (W or Trp), lysine (K or Lys), arginine (R or Arg), histidine (H or His), aspartic acid (D or Asp), glutamic acid (E or Glu), asparagine (N or Asn), glutamine (Q or Gln), cysteine ​​(C or Cys), methionine (M or Met), serine (S or Ser), and threonine (T or Thr). When the residue can be aspartic acid or asparagine, the symbols Asx or B can be used. Where the residue may be glutamic acid or glutamine, the symbols Glx or Z may be used. Unless the context dictates otherwise, reference to aspartic acid includes aspartate and reference to glutamic acid includes glutamate.

[0039] "Conservative" amino acid substitutions are those in which an amino acid residue is replaced with another amino acid residue of similar chemical structure, which is predicted to have little effect on the function, activity, or other biological properties of a polypeptide. Such conservative substitutions are preferably those in which an amino acid within the following group is replaced by another amino acid residue from the same group, as shown in Table 1 below:

[0040] [Table 3]

[0041] Preferably, the hydrophobic amino acid residue is a non-polar amino acid. More preferably, the hydrophobic amino acid residue is selected from V, I, L, M, F, W or C. In some embodiments, the hydrophobic amino acid residue is selected from glycine, alanine, valine, methionine, leucine, isoleucine, phenylalanine, tyrosine or tryptophan. Preferably, any residue in the sequence that does not correspond to a residue provided in the reference sequence is a conservative substitution for the residue in the reference sequence.

[0042] As used herein, the numbering of polypeptide sequences and the definitions of CDRs and FRs (i.e., HCDR1, HCDR2, HCDR3, HFR1, HFR2, HFR3, HFR4, LCDR1, LCDR2, LCDR3, LFR1, LFR2, LFR3 and LFR4) are as defined according to the Kabat system (Kabat et al., 1991, incorporated herein by reference in its entirety) unless otherwise stated. In a limited number of specific embodiments disclosed herein (derived from residue replacement studies performed in Example 7), a non-Kabat numbering system has been applied for CDR definitions, which will be specified when used. "Corresponding" amino acid residues between a first and a second polypeptide sequence are those amino acid residues in the first sequence that share the same position as an amino acid residue in the second sequence according to the Kabat system, although the amino acid residue in the second sequence may differ in identity from the first sequence. Suitably, when the framework and CDRs are the same length according to the Kabat definition, corresponding residues share the same number (and letter). Alignment can be accomplished manually or by using known computer algorithms for sequence alignment, such as, for example, NCBI BLAST v2.0 (BLASTP or BLASTN) using standard settings.

[0043] References to "epitope" herein refer to the portion of a target to which a polypeptide, antibody or fragment thereof binds. An epitope may also be referred to as an "antigenic determinant." An antibody binds to "essentially the same epitope" as another antibody if both recognize the same or sterically overlapping epitopes. A commonly used method for determining whether two antibodies bind to the same or overlapping epitopes is a competition assay using either labeled antigen or labeled antibody, which can be configured in a number of different formats (e.g., well plates using radioactive or enzyme labels, or flow cytometry on antigen-expressing cells). An antibody binds to the "same epitope" as another antibody if both recognize the same epitope (i.e., all contact points between the antigen and antibody are the same). For example, an antibody can bind to the same epitope as another antibody if all contact points across a specified region of the antigen are identified as the same with the aid of characterization methods such as antibody / antigen cross-linking coupling MS, HDX, X-ray crystallography, cryo-EM, or mutagenesis.

[0044] Moreover, with the aid of such characterization methods, it is also possible to characterize antibodies that bind to essentially the same epitope by recognizing some, but not all, of the same contact points. Specifically, such antibodies may share a sufficient number of identical contact points in a specified antigenic region to provide a broadly equivalent technical effect and / or equivalent antigen interaction selectivity. Moreover, in some cases where antibodies recognize essentially the same epitope and confer a broadly equivalent technical effect and / or interaction selectivity, it may be useful to define the epitope binding footprint by the totality of antigen contacts, including from the most N-terminal antigen contact point to the most C-terminal antigen contact point.

[0045] Epitopes found in protein targets can be defined as "linear epitopes" or "conformational epitopes." Linear epitopes are formed by contiguous sequences of amino acids in the protein antigen. Conformational epitopes are formed from amino acids that are discontinuous in the protein sequence but brought together upon folding of the protein into its three-dimensional structure.

[0046] The term "vector", as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, in which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian and yeast vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell after introduction into the host cell, and thereby are replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors"). In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably, since the plasmid is the most commonly used form of vector. However, the invention is intended to include other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions, as well as bacteriophage and phagemid systems. The term "recombinant host cell" (or simply "host cell"), as used herein, is intended to refer to a cell into which a recombinant expression vector has been introduced. Such terms are intended to refer not only to the particular subject cell, but to the progeny of such a cell, for example, which are used to generate cell lines or cell banks that are then optionally stored, donated, sold, transferred, or used to produce the polypeptides, antibodies, or fragments thereof described herein.

[0047] Reference to a "subject," "patient," or "individual" refers to a subject to be treated, particularly a mammalian subject. Mammalian subjects include humans, non-human primates, farm animals (such as cows), sports animals, or pet animals, such as dogs, cats, guinea pigs, rabbits, rats, or mice. In some embodiments, the subject is a human or mouse. Most preferably, the subject is a human.

[0048] The term "sufficient amount" means an amount sufficient to produce a desired effect. The term "therapeutically effective amount" is an amount effective to ameliorate symptoms of a disease or disorder. Since prophylaxis can be considered a treatment, a therapeutically effective amount can be a "prophylactically effective amount."

[0049] A disease or disorder is "ameliorated" if the severity of a sign or symptom of the disease or disorder, the frequency with which such signs or symptoms are experienced by a subject, or both, are reduced.

[0050] As used herein, "treating a disease or disorder" means reducing the frequency and / or severity of at least one sign or symptom of the disease or disorder experienced by a subject.

[0051] "Inflammation" refers to the chronic or acute triggering of the immune system resulting in an inflamed cell, cell type, tissue, or organ.

[0052] "Fibrosis" refers to pathological wound healing in which connective tissue replaces normal tissue, causing tissue remodeling and the formation of scar tissue.

[0053] As used herein, the term "about" includes values ​​within 10% greater and less than the specified value, preferably within 5% greater and less than the specified value, particularly the specified value. The term "between" includes the boundary values ​​specified.

[0054] "Potency" is a measure of the activity of a therapeutic agent expressed in terms of the amount required to produce an effect of a given strength. A highly potent agent will induce a greater response at a lower concentration compared to a less potent agent which will induce a smaller response at a lower concentration. Potency is a function of affinity and efficacy. Efficacy refers to the ability of a therapeutic agent to produce a biological response after binding to a target and the quantitative magnitude of this response. The term half-maximal effective concentration (EC50) refers to the concentration of a therapeutic agent that induces a response that is halfway between the baseline and maximum after a specified exposure time. A therapeutic agent can cause inhibition or stimulation. It is commonly used as a measure of potency and is used herein.

[0055] Polypeptides that bind to LPAR1 Polypeptides are those that contain one or more stretches of amino acid residues that form an antigen-binding site and bind to an epitope on a target antigen with a certain affinity (K, as further described herein). D A polypeptide is said to be a binding polypeptide if it can bind to LPAR1 with a binding affinity (preferably expressed as a K value, Ka value, on-rate (kon-rate) and / or off-rate (koff-rate). "Binding polypeptide" and "antigen-binding polypeptide" are used interchangeably herein, as are the terms "binding to LPAR1" and "anti-LPAR1". A binding polypeptide is preferably capable of exerting a beneficial pharmacological effect upon administration to a subject. Preferably, the polypeptide agonizes, inverse agonizes, antagonizes, or neutralizes LPAR1. In some embodiments, the polypeptide can exert an inverse agonistic effect on LPAR1. In some embodiments, the polypeptide can bind to the outer surface of LPAR1, i.e., the extracellular domain of LPAR1.

[0056] LPAR1 binding polypeptides may include antibodies (described further below), antibodies modified to contain additional binding regions, antibody mimetics, and antigen-binding antibody fragments (described further below). Additional binding polypeptides may include, for example, DARPins (Binz et al., 2003), Affimer™, Fynomer™, Centyrin, Nanofitin®, and cyclic peptides.

[0057] Antibodies and their fragments The polypeptide is preferably an antibody or a fragment thereof.

[0058] A conventional antibody or immunoglobulin (Ig) is a protein that comprises four polypeptide chains: two heavy (H, or HC) and two light (L, or LC) chains. Each chain is divided into a constant region and a variable region. The heavy (H) chain variable region is abbreviated herein as the VH region, and the light (L) chain variable region is abbreviated herein as the VL region. These domains, their associated domains, and domains derived therefrom are referred to herein as variable domains. The VH and VL regions (or "domains") can be further subdivided into regions of hypervariability called "complementarity determining regions" ("CDRs"), which are interposed between more conserved regions called "framework regions" ("FRs"). The framework and complementarity determining regions have been clearly defined (Kabat et al., 1991, which is incorporated herein by reference in its entirety). In conventional antibodies, each VH and VL region is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The CDRs and FRs of the VH region are designated HCDR1, HCDR2, HCDR3, HFR1, HFR2, HFR2, HFR3, and HFR4. The CDRs and FRs of the VL region are designated LCDR1, LCDR2, LCDR3, LFR1, LFR2, LFR3, and LFR4. A conventional antibody tetramer having two immunoglobulin heavy chains and two immunoglobulin light chains is formed, for example, by the immunoglobulin heavy and light chains interconnected by disulfide bonds, and the heavy chains similarly connected. The heavy chain constant region contains three domains, CH1, CH2, and CH3. The light chain constant region consists of one domain, CL. The variable domains of the heavy chain and the variable domains of the light chain are binding domains that interact with an antigen. The constant regions of the antibody typically mediate the binding of the antibody to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0059] A fragment of an antibody (which may also be referred to as an "antibody fragment," "immunoglobulin fragment," "antigen-binding fragment," or "antigen-binding polypeptide"), as used herein, refers to a portion of an antibody that specifically binds to a target (e.g., a molecule in which one or more immunoglobulin chains are not full length, but which specifically binds to a target). Examples of binding fragments that fall within the scope of the term antibody fragment include: (i) Fab fragment (a monovalent fragment consisting of the VL, VH, CL and CH1 domains); (ii) F(ab')2 fragment (a bivalent fragment consisting of two Fab fragments linked by a disulfide bridge at the hinge region); (iii) Fd fragment (consisting of the VH and CH1 domains); (iv) Fv fragment (consisting of the VL and VH domains of a single arm of an antibody); (v) single chain variable fragments, scFv, which consist of VL and VH domains joined by a synthetic linker that allows them to be produced using recombinant methods as a single protein chain in which the VL and VH regions pair to form a monovalent molecule; (vi) VH (a variable domain consisting of a VH domain), (vii) VL (a variable domain consisting of a VL domain), (viii) Domain antibodies (dAbs, consisting of either a VH or VL domain); (ix) a minibody (consisting of a pair of scFv fragments linked via a CH3 domain); and (x) diabodies, which consist of a noncovalent dimer of scFv fragments consisting of the VH domain from one antibody connected by a small peptide linker to the VL domain from another antibody.

[0060] "Human antibody" refers to an antibody having variable and constant regions derived from human germline immunoglobulin sequences. A human subject administered said human antibody does not mount a cross-species antibody response (e.g., HAMA response - what is called human-anti-mouse antibody) against primary amino acids contained within said antibody. Said human antibody may contain amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis or somatic mutation) not encoded by human germline immunoglobulin sequences, for example in the CDRs, particularly CDR3. However, this term is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, e.g., mouse, have been grafted onto human framework sequences. Human antibodies prepared, expressed, created or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant combinatorial human antibody library, antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes, or antibodies prepared, expressed, created or isolated by any other means involving splicing of human immunoglobulin gene sequences into other DNA sequences, may also be referred to as "recombinant human antibodies."

[0061] The replacement of at least one amino acid residue in a framework region of a non-human immunoglobulin variable domain with the corresponding residue from a human variable domain is referred to as "humanization." Humanization of the variable domain may reduce immunogenicity in humans.

[0062] In one embodiment, the antibody or fragment thereof is an scFv, Fab, Fab', F(ab')2, Fv, a variable domain (e.g., VH or VL), a diabody, a minibody, or a full-length antibody. In certain embodiments, the antibody or fragment thereof is an scFv or a full-length antibody.

[0063] The antibody of the present invention may be of any class, e.g., IgG, IgA, IgM, IgE, IgD, or subclasses thereof, and may comprise a kappa or lambda light chain. In one embodiment, the antibody is an IgG, e.g., at least one of the subclasses IgG1, IgG2, IgG3, or IgG4. In one embodiment, the antibody is an IgG1. In a further embodiment, the antibody may be in a format, e.g., an IgG format, with an Fc that has been modified to confer desired properties, e.g., mutated to reduce effector function, extend half-life, alter ADCC, or improve hinge stability. Such modifications are well known in the art, and exemplary embodiments are described herein. For example, the antibody or fragment thereof of the present invention may comprise an IgG1 heavy chain constant region comprising or consisting of an amino acid sequence according to SEQ ID NO:56. Suitably, the heavy chain constant region is selected from the group consisting of Booth et al., 2018, Borrok et al., 2017, Dall'Acqua et al., 2006, Dall'Acqua et al., 2002, Datta-Mannan et al., 2012, Hinton et al., 2004, Igawa et al., 2013, Ko et al., 2021, Lee CH et al., 2019, Lie et al., 2020, Mackness et al., 2019, Petkova et al., 2006, Robbie et al., 2013, Saunders et al., 2016, 2019, Shields et al., 2001, Vaccaro et al., 2006, Vaccaro et al., 2005, Zalevsky et al., 2010, US Patent Publication No. 2014 / 056879, US Patent No. 8,088,376, WO 2006053301, WO 2009086320, and WO 2018035107 (all of which are incorporated by reference herein for purposes of the Fc mutations disclosed herein), including mutations to extend antibody half-life in vivo. Preferably, the heavy chain constant region comprises Fc effector enhancing mutations as described in WO2004029207, WO2004099249 and WO2006019447 (all of which are incorporated by reference herein for purposes of the Fc mutations disclosed herein).

[0064] Suitably, the heavy chain constant region comprises one or more of the following residues: Residue at position 250 is Q, residue at position 252 is Y, residue at position 252 is F, residue at position 252 is W, residue at position 252 is T, residue at position 253 is A, residue at position 254 is T, residue at position 256 is E, residue at position 256 is S, residue at position 256 is R, residue at position 256 is Q, residue at position 256 is D, residue at position 259 is I, residue at position 285 is D, residue at position 285 is N, residue at position 286 is D, residue at position 294 is deleted, residue at position 307 is A, residue at position 307 is Q ,residue at position 307 is P,residue at position 307 is R,residue at position 307 is W,residue at position 308 is P,residue at position 308 is F,residue at position 309 is P,residue at position 309 is D,residue at position 309 is N,residue at position 310 is A,residue at position 311 is S,residue at position 311 is I,residue at position 311 is V,residue at position 311 is H,residue at position 315 is D,residue at position 378 is V,residue at position 380 is A,residue at position 385 is R,residue at position 385 is D,residue at position 385 is S, Residue at position 385 is T, residue at position 385 is H, residue at position 385 is K, residue at position 385 is A, residue at position 385 is G, residue at position 386 is T, residue at position 386 is P, residue at position 386 is D, residue at position 386 is S, residue at position 386 is K, residue at position 386 is R, residue at position 386 is I, residue at position 386 is M, residue at position 387 is R, residue at position 387 is P, residue at position 387 is H, residue at position 387 is S, residue at position 387 is T, residue at position 387 is A, P residue at position 389 is A, residue at position 389 is S, residue at position 389 is N, residue at position 428 is L, residue at position 433 is K, residue at position 433 is R, residue at position 433 is S, residue at position 433 is I, residue at position 433 is P, residue at position 433 is Q, residue at position 434 is F, residue at position 434 is H, residue at position 434 is Y, residue at position 434 is A, residue at position 434 is S, residue at position 435 is A, residue at position 436 is H, residue at position 436 is I, or residue at position 436 is V.

[0065] More preferably, the heavy chain constant region comprises mutations or functional variants at positions 252, 254 and 256, 428 and 434, 433, 434 and 436, 428, 434 and 436, 252, 254, 256 and 322, and 309, 311 and 434. More preferably, the heavy chain constant region comprises mutations at positions 252, 254 and 256, 428 and 434, 433, 434 and 436, 428, 434 and 436, 252, 254, 256 and 322, and 309, 311 and 434. Most preferably, the heavy chain constant region comprises the mutations M252Y, S254T and T256E, or the mutations M428L and N434S. Alternatively, the antibodies could be PEGylated to increase their half-life.

[0066] Alternatively or additionally, the heavy chain constant region may comprise Fc silencing mutations. Preferably, the heavy chain constant region comprises the mutations L234A and L235A. More preferably, the heavy chain constant region comprises the mutations L234A, L235A and P331S (LALAPS). Alternatively, the heavy chain constant region comprises the mutations L234A, L235A and P239G (LALA PG). Alternatively, the heavy chain constant region comprises the mutations L235A and G237A (LAGA).

[0067] Thus, in certain embodiments, the antibody may comprise the following combined heavy chain constant, heavy chain variable (VH), light chain constant and light chain variable (VL) polypeptide sequences in antibody combinations 1 to 680 shown in Table 2. Suitably, the antibody comprises two heavy chains and two light chains, each heavy chain comprising (e.g. consisting of) the heavy chain constant and heavy chain variable (VH) sequences of one antibody combination in Table 2, and each light chain comprising (e.g. consisting of) the light chain constant and light chain variable (VL) sequences of said antibody combination in Table 2.

[0068] [Table 4] TIFF2024535662000024.tif244169TIFF2024535662000025.tif244169TIFF2024535662000026.tif244169TIFF20245356620 00027.tif244169TIFF2024535662000028.tif244169TIFF2024535662000029.tif244169TIFF2024535662000030.tif244169 TIFF2024535662000031.tif236169TIFF2024535662000032.tif244169TIFF2024535662000033.tif244169TIFF20245356620 00034.tif244169TIFF2024535662000035.tif244169TIFF2024535662000036.tif244169TIFF2024535662000037.tif206169

[0069] In further embodiments, the antibody may comprise the combined heavy chain constant, heavy chain variable (VH), light chain constant and light chain variable (VL) polypeptide sequences in combinations 1-25 shown in Table 2 above, wherein the heavy chain constant region comprises one or more of the following residues: Residue at position 250 is Q, residue at position 252 is Y, residue at position 252 is F, residue at position 252 is W, residue at position 252 is T, residue at position 253 is A, residue at position 254 is T, residue at position 256 is E, residue at position 256 is S, residue at position 256 is R, residue at position 256 is Q, residue at position 256 is D, residue at position 259 is I, residue at position 285 is D, residue at position 285 is N, residue at position 286 is D, residue at position 294 is deleted, residue at position 307 is A, residue at position 307 is Q ,residue at position 307 is P,residue at position 307 is R,residue at position 307 is W,residue at position 308 is P,residue at position 308 is F,residue at position 309 is P,residue at position 309 is D,residue at position 309 is N,residue at position 310 is A,residue at position 311 is S,residue at position 311 is I,residue at position 311 is V,residue at position 311 is H,residue at position 315 is D,residue at position 378 is V,residue at position 380 is A,residue at position 385 is R,residue at position 385 is D,residue at position 385 is S, Residue at position 385 is T, residue at position 385 is H, residue at position 385 is K, residue at position 385 is A, residue at position 385 is G, residue at position 386 is T, residue at position 386 is P, residue at position 386 is D, residue at position 386 is S, residue at position 386 is K, residue at position 386 is R, residue at position 386 is I, residue at position 386 is M, residue at position 387 is R, residue at position 387 is P, residue at position 387 is H, residue at position 387 is S, residue at position 387 is T, residue at position 387 is A, P residue at position 389 is, residue at position 389 is S, residue at position 389 is N, residue at position 428 is L, residue at position 433 is K, residue at position 433 is R, residue at position 433 is S, residue at position 433 is I, residue at position 433 is P, residue at position 433 is Q, residue at position 434 is F, residue at position 434 is H, residue at position 434 is Y, residue at position 434 is A, residue at position 434 is S, residue at position 435 is A, residue at position 436 is H, residue at position 436 is I, or residue at position 436 is V.

[0070] In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:37, followed by SEQ ID NO:1239, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:38, followed by SEQ ID NO:57. In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:36, followed by SEQ ID NO:1239, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:38, followed by SEQ ID NO:57. In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:102, followed by SEQ ID NO:1239, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:99, followed by SEQ ID NO:57. In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:102, followed by SEQ ID NO:1239, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:104, followed by SEQ ID NO:57. In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:36 followed by SEQ ID NO:1239, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:99 followed by SEQ ID NO:57.

[0071] In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:37, followed by SEQ ID NO:1264, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:38, followed by SEQ ID NO:57. In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:36, followed by SEQ ID NO:1264, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:38, followed by SEQ ID NO:57. In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:102, followed by SEQ ID NO:1264, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:99, followed by SEQ ID NO:57. In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:102, followed by SEQ ID NO:1264, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:104, followed by SEQ ID NO:57. In one embodiment, the antibody or fragment thereof comprises a heavy chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:36 followed by SEQ ID NO:1264, and a light chain polypeptide sequence from the N-terminus to the C-terminus of SEQ ID NO:99 followed by SEQ ID NO:57.

[0072] The anti-LPAR1 antibodies described herein, in some embodiments, can comprise a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with higher affinity than the native human Fc constant region from which the variant human Fc constant region is derived. For example, the Fc constant region can comprise one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions compared to the native human Fc constant region from which the variant human Fc constant region is derived. The substitutions can increase the binding affinity of an IgG antibody comprising the variant Fc constant region to FcRn at pH 6.0 while maintaining the pH-dependence of the interaction. See, e.g., Hinton et al. (2004) J Biol Chem 279:6213-6216 and Datta-Mannan et al. (2007) Drug Metab Dispos 35:1-9. Methods for testing whether one or more substitutions in an antibody's Fc constant region increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining the pH-dependence of the interaction) are known in the art and are illustrated in the Examples. See, e.g., Datta-Mannan et al. (2007) J Biol Chem 282(3):1709-1717, WO 98 / 23289, WO 97 / 34631, and U.S. Patent No. 6,277,375, the disclosures of each of which are incorporated herein by reference in their entirety.

[0073] Substitutions that enhance the binding affinity of an antibody Fc constant region to FcRn are known in the art and include, for example, (1) the M252Y / S254T / T256E triple substitution described by Dall'Acqua et al. (2006) J Biol Chem 281:23514-23524, (2) the M428L or T250Q / M428L substitutions described in Hinton et al. (2004) J Biol Chem 279:6213-6216 and Hinton et al. (2006) J Immunol 176:346-356, and (3) the N434A or T307 / E380A / N434A substitutions described in Petkova et al. (2006) Int Immunol 18(12):1759-69. Additional substitution pairs: P257I / Q311I, P257I / N434H, and D376V / N434H are described, for example, in Datta-Mannan et al. (2007) J Biol Chem 282(3):1709-1717, the disclosures of which are incorporated herein by reference in their entireties.

[0074] In some embodiments, the variant constant region has a substitution of valine at EU amino acid residue 255. In some embodiments, the variant constant region has a substitution of asparagine at EU amino acid residue 309. In some embodiments, the variant constant region has a substitution of isoleucine at EU amino acid residue 312. In some embodiments, the variant constant region has a substitution at EU amino acid residue 386.

[0075] In some embodiments, the variant Fc constant region comprises 30 or less amino acid substitutions, insertions, or deletions relative to the native constant region from which it is derived (e.g., 29 or less, 28 or less, 27 or less, 26 or less, 25 or less, 24 or less, 23 or less, 22 or less, 21 or less, 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less). In some embodiments, the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of: M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V308F. In some embodiments, the variant human Fc constant region comprises a methionine at position 428 and an asparagine at position 434, each according to EU numbering. In some embodiments, the variant Fc constant region comprises a 428L / 434S double substitution, e.g., as described in U.S. Pat. No. 8,088,376.

[0076] In some embodiments, the variant constant region has the following amino acid positions relative to the native human Fc constant region: 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 306, 307, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 3 Contains substitutions at positions 7, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, ​​384, 385, 386, 387, 389, 424, 428, 433, 434, or 436 (EU numbering). In some embodiments, the substitutions are selected from the group consisting of: glycine to methionine at position 237, proline to alanine at position 238, serine to lysine at position 239, lysine to isoleucine at position 248, threonine to alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine at position 250, methionine to phenylalanine, tryptophan, or tyrosine at position 252, serine to threonine at position 254, arginine to glutamic acid at position 255, threonine to aspartic acid, glutamic acid, or glutamine at position 256, proline to alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine at position 257, and glutamic acid to histidine at position 258, all based on EU numbering. sine, aspartic acid at position 265 to alanine, aspartic acid at position 270 to phenylalanine, asparagine at position 286 to alanine or glutamic acid, threonine at position 289 to histidine, asparagine at position 297 to alanine, serine at position 298 to glycine, valine at position 303 to alanine, valine at position 305 to alanine, threonine at position 307 to alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan, or tyrosine; valine at position 308 is replaced with alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine; leucine or valine at position 309 is replaced with alanine, aspartic acid,glutamic acid, proline, or arginine, glutamine at position 311 to alanine, histidine, or isoleucine, aspartic acid at position 312 to alanine or histidine, leucine at position 314 to lysine or arginine, asparagine at position 315 to alanine or histidine, lysine at position 317 to alanine, asparagine at position 325 to glycine, isoleucine at position 332 to valine, lysine at position 334 to leucine, lysine at position 360 to histidine, aspartic acid at position 376 to alanine, glutamic acid at position 380 to alanine, glutamic acid at position 382 to alanine, asparagine or serine at position 384 to alanine, glycine at position 385 to aspartic acid or histidine, glutamine at position 386 to proline, proline at position 387 to glutamic acid, asparagine at position 389 to alanine or serine, serine at position 424 to alanine, methionine at position 428 to alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine, histidine at position 433 to lysine, asparagine at position 434 to alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine, and tyrosine or phenylalanine at position 436 to histidine.

[0077] In one embodiment, the antibody or fragment thereof is a human antibody or fragment thereof. Thus, the antibody or fragment thereof may be derived from a human immunoglobulin (Ig) sequence. The CDRs, framework and / or constant regions of the antibody (or fragment thereof) may be derived from a human Ig sequence, in particular a human IgG sequence. The CDRs, framework and / or constant regions may be substantially identical to a human Ig sequence, in particular a human IgG sequence. The advantage of using human antibodies is that they are less or not at all immunogenic in humans.

[0078] The antibody or fragment thereof can also be chimeric, for example a mouse-human antibody chimera.

[0079] Alternatively, the antibody or fragment thereof is derived from a non-human species, such as mouse. Such non-human antibodies can be modified to become more similar to antibody variants naturally produced in humans, and thus the antibody or fragment thereof can be partially or fully humanized. Thus, in one embodiment, the antibody or fragment thereof is humanized. Suitably, the antibody or fragment thereof is a human antibody or fragment thereof.

[0080] In one embodiment, the antibody or fragment thereof may be a "functionally active variant", which includes naturally occurring allelic variants as well as mutants or any other non-naturally occurring variants. As known in the art, allelic variants are alternative forms of (poly)peptides, characterized by one or more amino acid substitutions, deletions or additions that do not essentially alter the biological function of the polypeptide. As non-limiting examples, said functionally active variants may still function when the framework containing the CDRs is modified, when the CDRs themselves are modified, when said CDRs are grafted onto another framework, or when N- or C-terminal extensions are incorporated. Furthermore, the binding domains containing the CDRs may also be paired with different partner chains, e.g. those shared by another antibody. When shared by a so-called "common" light chain or a "common" heavy chain, said binding domains may still function. Furthermore, said binding domains may also function when multimerized.

[0081] Polypeptides targeted to epitopes Provided herein is a polypeptide that binds to an epitope on LPAR1. In certain embodiments, binding to an epitope on LPAR1 can have an effect on LPAR1 activity, for example, blocking or reducing the rate of G protein interacting with LPAR1, thereby affecting cell inflammation, fibrosis, proliferation and migration. The polypeptide can have a blocking effect by blocking the binding or interaction of another antibody or molecule (e.g., LPA), or by stabilizing the structure of LPAR1 to block downstream signal transduction (i.e., the blocking effect does not necessarily have to be by blocking the interaction of another molecule). Advantageously, the polypeptide of the present invention is specific to LPAR1 and does not significantly bind to other antigens.

[0082] The present invention provides polypeptides capable of binding to one or more of regions 30 to 44, 106 to 120, 190 to 204, and 280 to 294 of full-length LPAR1 when the UniProt Q92633 numbering is used (SEQ ID NOs: 65 to 68, Example 6).

[0083] In one embodiment, the polypeptide can bind to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid residues within the described region.

[0084] A polypeptide need not necessarily bind to all amino acids within a defined range. For example, an antibody that binds to an epitope that includes amino acid residues within amino acid region 30-44 of SEQ ID NO: 62 (UniProt Q92633) may bind to only one or more of the amino acid residues within said range, such as the amino acid residues at each end of that range (i.e., amino acids 30 and 44), and optionally only those amino acids within that range (i.e., amino acids 32, 34, 36, 38, and 40).

[0085] Suitably, the polypeptide binds to an epitope of LPAR1 comprising at least one of amino acids 30 to 44 of full-length LPAR1 (SEQ ID NO: 62), for example, amino acids 35 and 36 of full-length LPAR1 (SEQ ID NO: 62), and / or amino acids 37 and 38 of full-length LPAR1 (SEQ ID NO: 62), and / or amino acids 32, 39, 40 and 41 of full-length LPAR1 (SEQ ID NO: 62). Suitably, the polypeptide binds to an epitope of LPAR1 comprising at least two, for example, at least three, for example, at least four, for example, at least five, for example, at least ten, for example, all of amino acids 30 to 44 of full-length LPAR1 (SEQ ID NO: 62).

[0086] Suitably, the polypeptide binds to an epitope of LPAR1 including at least one of amino acids 106-120 of full-length LPAR1 (SEQ ID NO: 62), for example, amino acid 114 of full-length LPAR1 (SEQ ID NO: 62). Suitably, the polypeptide binds to an epitope of LPAR1 including at least two, for example, at least three, for example, at least four, for example, at least five, for example, at least ten, for example, all, of amino acids 106-120 of full-length LPAR1 (SEQ ID NO: 62).

[0087] Suitably, the polypeptide binds to an epitope of LPAR1 including at least one of amino acids 190 to 204 of full-length LPAR1 (SEQ ID NO: 62), for example, amino acid 193 of full-length LPAR1 (SEQ ID NO: 62), and / or amino acids 191, 192, 194 and 197 of full-length LPAR1 (SEQ ID NO: 62), and / or amino acid 190 of full-length LPAR1 (SEQ ID NO: 62). Suitably, the polypeptide binds to an epitope of LPAR1 including at least two, for example, at least three, for example, at least four, for example, at least five, for example, at least ten, for example, all of amino acids 190 to 204 of full-length LPAR1 (SEQ ID NO: 62).

[0088] Suitably, the polypeptide binds to an epitope of LPAR1 including at least one of amino acids 280 to 294 of full-length LPAR1 (SEQ ID NO: 62), for example, amino acid 286 of full-length LPAR1 (SEQ ID NO: 62) and / or amino acid 285 of full-length LPAR1 (SEQ ID NO: 62). Suitably, the polypeptide binds to an epitope of LPAR1 including at least two, for example, at least three, for example, at least four, for example, at least five, for example, at least ten, for example, all, of amino acids 280 to 294 of full-length LPAR1 (SEQ ID NO: 62).

[0089] More preferably, the polypeptide binds to an epitope of LPAR1 comprising or consisting of amino acids 30 to 44, 106 to 120, 190 to 204, and 280 to 294 of full-length LPAR1 (SEQ ID NO: 62).

[0090] Suitably, the polypeptide binds to an epitope of LPAR1 comprising residue 36 of full length LPAR1 (SEQ ID NO:62). Suitably, the polypeptide binds to an epitope of LPAR1 comprising residue 193 of full length LPAR1 (SEQ ID NO:62). Suitably, the polypeptide binds to an epitope of LPAR1 comprising residue 35 of full length LPAR1 (SEQ ID NO:62). Suitably, the polypeptide binds to an epitope of LPAR1 comprising residue 35 of full length LPAR1 (SEQ ID NO:62). Suitably, the polypeptide binds to an epitope of LPAR1 comprising residue 286 of LPAR1 (SEQ ID NO:62). Suitably, the polypeptide binds to an epitope of LPAR1 comprising one or more of residues 36, 35, 193 or 286 of full length LPAR1 (SEQ ID NO:62).

[0091] Preferably, the polypeptide binds to a conformational epitope of human LPAR1 that includes one or more residues located within the N-terminal capping helix and one or more residues located within extracellular domain 2. More preferably, the polypeptide binds to an epitope of LPAR1 that includes residues 36 and 193 of full-length LPAR1 (SEQ ID NO:62).

[0092] In one embodiment, polypeptides are provided which bind to the same, or essentially the same, epitope as the polypeptides defined herein.

[0093] In a further embodiment, there is provided a polypeptide that competes with a polypeptide defined herein for binding to LPAR1.

[0094] Polypeptide sequence The polypeptides of the invention can be described by reference to their CDR sequences.

[0095] Specific polypeptides and their CDRs provided by the present invention include:

[0096] [Table 5]

[0097] [Table 6]

[0098] [Table 7] TIFF2024535662000041.tif198168

[0099] The polypeptide may comprise three heavy chain CDRs (HCDR1-3). The polypeptide may comprise three light chain CDRs (LCDR1-3). Preferably, the polypeptide comprises three heavy chain CDRs (HCDR1-3) and three light chain CDRs (LCDR1-3).

[0100] The polypeptide may comprise an HCDR1 comprising a sequence having at least 40%, such as at least 60%, such as at least 80% identity with SEQ ID NO:1 or SEQ ID NO:7. The polypeptide may comprise an HCDR1 consisting of a sequence having at least 40%, such as at least 60%, such as at least 80% identity with SEQ ID NO:1 or SEQ ID NO:7. Suitably, the polypeptide comprises an HCDR1 comprising SEQ ID NO:1 or SEQ ID NO:7. More suitably, the polypeptide comprises an HCDR1 consisting of SEQ ID NO:1 or SEQ ID NO:7. More suitably, the polypeptide comprises an HCDR1 comprising SEQ ID NO:1, or more suitably an HCDR1 consisting of SEQ ID NO:1.

[0101] The polypeptide may comprise an HCDR2 comprising a sequence having at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 85%, for example, at least 90% identity to any one of SEQ ID NOs: 2, 8-11 or 100. The polypeptide may comprise an HCDR2 consisting of a sequence having at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 85%, for example, at least 90% identity to any one of SEQ ID NOs: 2, 8-11 or 100. Preferably, the polypeptide comprises an HCDR2 comprising any one of SEQ ID NOs: 2, 8-11 or 100. More preferably, the polypeptide comprises an HCDR2 comprising any one of SEQ ID NOs: 2, 8-11 or 100, for example, an HCDR2 comprising SEQ ID NO: 2, or more preferably an HCDR2 consisting of SEQ ID NO: 2.

[0102] The polypeptide may comprise an HCDR3 comprising a sequence having at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 90% identity to any one of SEQ ID NOs: 3, 12-15, or 101. The polypeptide may comprise an HCDR3 consisting of a sequence having at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 90% identity to any one of SEQ ID NOs: 3, 12-15, or 101. Preferably, the polypeptide comprises an HCDR3 comprising any one of SEQ ID NOs: 3, 12-15, or 101. More preferably, the polypeptide comprises an HCDR3 consisting of any one of SEQ ID NOs: 3, 12-15, or 101. More preferably, the polypeptide comprises an HCDR3 comprising SEQ ID NO: 3, for example, an HCDR3 consisting of SEQ ID NO: 3. Alternatively, the polypeptide comprises an HCDR3 comprising SEQ ID NO: 15, for example, an HCDR3 consisting of SEQ ID NO: 15. Alternatively, the polypeptide comprises an HCDR3 that comprises, for example, consists of, SEQ ID NO:101.

[0103] The polypeptide may comprise an LCDR1 comprising a sequence having at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 90% identity to any one of SEQ ID NOs: 4, 16-18 or 103. The polypeptide may comprise an LCDR1 consisting of a sequence having at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 90% identity to any one of SEQ ID NOs: 4, 16-18 or 103. Preferably, the polypeptide comprises an LCDR1 comprising any one of SEQ ID NOs: 4, 16-18 or 103. More preferably, the polypeptide comprises an LCDR1 consisting of any one of SEQ ID NOs: 4, 16-18 or 103. More preferably, the polypeptide comprises an LCDR1 comprising SEQ ID NO: 4, or more preferably an LCDR1 consisting of SEQ ID NO: 4. More preferably, the polypeptide comprises an LCDR1 comprising SEQ ID NO: 103, or more preferably an LCDR1 consisting of SEQ ID NO: 103.

[0104] The polypeptide may comprise an LCDR2 comprising a sequence having at least 50% identity, such as at least 60%, such as at least 70%, such as at least 80% identity, to SEQ ID NO: 5, 19 or 98. The polypeptide may comprise an LCDR2 consisting of a sequence having at least 50% identity, such as at least 60%, such as at least 70%, such as at least 80% identity, to SEQ ID NO: 5, 19 or 98. Suitably, the polypeptide comprises an LCDR2 comprising SEQ ID NO: 5, 19 or 98. More suitably, the polypeptide comprises an LCDR2 consisting of SEQ ID NO: 5, 19 or 98. More suitably, the polypeptide comprises an LCDR2 comprising SEQ ID NO: 5, more suitably an LCDR2 consisting of SEQ ID NO: 5.

[0105] The polypeptide may comprise an LCDR3 comprising a sequence having at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80% identity to any one of SEQ ID NOs: 6 or 20 to 22. The polypeptide may comprise an LCDR3 consisting of a sequence having at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80% identity to any one of SEQ ID NOs: 6 or 20 to 22. More preferably, the polypeptide comprises an LCDR3 consisting of any one of SEQ ID NOs: 6 or 20 to 22, more preferably, the polypeptide comprises an LCDR3 consisting of SEQ ID NO: 6, more preferably, the polypeptide comprises an LCDR3 consisting of SEQ ID NO: 6.

[0106] Alternatively, the polypeptide may comprise an HCDR1 comprising, e.g. consisting of, a sequence having at least 40%, such as at least 60%, such as at least 80%, such as at least 100% identity to SEQ ID NO: 107. Suitably, the polypeptide comprises an HCDR2 comprising, e.g. consisting of, a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 100% identity to SEQ ID NO: 108. Suitably, the polypeptide comprises an HCDR3 comprising, e.g. consisting of, a sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 100% identity to SEQ ID NO: 109. Suitably, the polypeptide comprises an LCDR1 comprising, e.g. consisting of, a sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 100% identity to SEQ ID NO: 110. Suitably, the polypeptide comprises an LCDR2 which comprises, e.g. consists of, a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example 100% identity to SEQ ID NO: 111. Suitably, the polypeptide comprises an LCDR3 which comprises, e.g. consists of, a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example 100% identity to SEQ ID NO: 112.

[0107] In one embodiment, the polypeptide comprises: (a) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:3, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO:6; (b) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:8, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:16, LCDR2 comprising SEQ ID NO:19 and LCDR3 comprising SEQ ID NO:20; (c) HCDR1 comprising SEQ ID NO:7, HCDR2 comprising SEQ ID NO:9, HCDR3 comprising SEQ ID NO:13, LCDR1 comprising SEQ ID NO:17, LCDR2 comprising SEQ ID NO:19 and LCDR3 comprising SEQ ID NO:21; (d) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:10, HCDR3 comprising SEQ ID NO:14, LCDR1 comprising SEQ ID NO:18, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (e) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:8, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:16, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:22; (f) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:8, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:16, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (g) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:11, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:20; (h) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:11, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (i) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (j) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:3, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (k) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:15, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (l) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:15, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO:6; (m) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:3, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:98, and LCDR3 comprising SEQ ID NO:6; (n) HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 100, HCDR3 comprising SEQ ID NO: 101, LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 98 and LCDR3 comprising SEQ ID NO: 6, or (o) comprises an HCDR1 comprising SEQ ID NO:1, an HCDR2 comprising SEQ ID NO:100, an HCDR3 comprising SEQ ID NO:101, an LCDR1 comprising SEQ ID NO:103, an LCDR2 comprising SEQ ID NO:98, and an LCDR3 comprising SEQ ID NO:6.

[0108] More preferably, the polypeptide comprises (a) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 3, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 5, and LCDR3 consisting of SEQ ID NO: 6; (b) an HCDR1 consisting of SEQ ID NO: 1, an HCDR2 consisting of SEQ ID NO: 8, an HCDR3 consisting of SEQ ID NO: 12, an LCDR1 consisting of SEQ ID NO: 16, an LCDR2 consisting of SEQ ID NO: 19, and an LCDR3 consisting of SEQ ID NO: 20; (c) an HCDR1 consisting of SEQ ID NO: 7, an HCDR2 consisting of SEQ ID NO: 9, an HCDR3 consisting of SEQ ID NO: 13, an LCDR1 consisting of SEQ ID NO: 17, an LCDR2 consisting of SEQ ID NO: 19, and an LCDR3 consisting of SEQ ID NO: 21; (d) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 10, HCDR3 consisting of SEQ ID NO: 14, LCDR1 consisting of SEQ ID NO: 18, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (e) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 8, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 16, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 22; (f) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 8, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 16, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (g) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 11, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 20; (h) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 11, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (i) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (j) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 3, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (k) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 15, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (l) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 15, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 5, and LCDR3 consisting of SEQ ID NO: 6; (m) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 3, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 98, and LCDR3 consisting of SEQ ID NO: 6; (n) an HCDR1 consisting of SEQ ID NO: 1, an HCDR2 consisting of SEQ ID NO: 100, an HCDR3 consisting of SEQ ID NO: 101, an LCDR1 consisting of SEQ ID NO: 4, an LCDR2 consisting of SEQ ID NO: 98, and an LCDR3 consisting of SEQ ID NO: 6, or (o) comprises an HCDR1 consisting of SEQ ID NO: 1, an HCDR2 consisting of SEQ ID NO: 100, an HCDR3 consisting of SEQ ID NO: 101, an LCDR1 consisting of SEQ ID NO: 103, an LCDR2 consisting of SEQ ID NO: 98, and an LCDR3 consisting of SEQ ID NO: 6.

[0109] A polypeptide can include four heavy chain framework regions (HFR1-HFR4).

[0110] The polypeptide may comprise HFR1 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 40, HFR2 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 41, HFR3 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 42, and / or HFR4 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 43. Suitably, the polypeptide comprises HFR1 comprising SEQ ID NO: 40, HFR2 comprising SEQ ID NO: 41, HFR3 comprising SEQ ID NO: 42 and / or HFR4 comprising SEQ ID NO: 43. More preferably, the polypeptide comprises an HFR1 consisting of SEQ ID NO:40, an HFR2 consisting of SEQ ID NO:41, an HFR3 consisting of SEQ ID NO:42 and / or an HFR4 consisting of SEQ ID NO:43.

[0111] Alternatively, the polypeptide may comprise an HFR1 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 48, an HFR2 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 49, an HFR3 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 50, and / or an HFR4 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 51. Suitably, the polypeptide comprises an HFR1 comprising SEQ ID NO: 48, an HFR2 comprising SEQ ID NO: 49, an HFR3 comprising SEQ ID NO: 50 and / or an HFR4 comprising SEQ ID NO: 51. More preferably, the polypeptide comprises an HFR1 consisting of SEQ ID NO:48, an HFR2 consisting of SEQ ID NO:49, an HFR3 consisting of SEQ ID NO:50 and / or an HFR4 consisting of SEQ ID NO:51.

[0112] The polypeptide can include four light chain framework regions (LFR1-LFR4).

[0113] The polypeptide may comprise an LFR1 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 44, an LFR2 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 45, an LFR3 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 46, and / or an LFR4 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 47. Suitably, the polypeptide comprises an LFR1 comprising SEQ ID NO: 44, an LFR2 comprising SEQ ID NO: 45, an LFR3 comprising SEQ ID NO: 46 and / or an LFR4 comprising SEQ ID NO: 47. More preferably, the polypeptide comprises an LFR1 consisting of SEQ ID NO:44, an LFR2 consisting of SEQ ID NO:45, an LFR3 consisting of SEQ ID NO:46 and / or an LFR4 consisting of SEQ ID NO:47.

[0114] Alternatively, the polypeptide may comprise an LFR1 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 52, an LFR2 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 53, an LFR3 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 54, and / or an LFR4 comprising or consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 55. Suitably, the polypeptide comprises an LFR1 comprising SEQ ID NO: 52, an LFR2 comprising SEQ ID NO: 53, an LFR3 comprising SEQ ID NO: 54 and / or an LFR4 comprising SEQ ID NO: 55. More preferably, the polypeptide comprises an LFR1 consisting of SEQ ID NO:52, an LFR2 consisting of SEQ ID NO:53, an LFR3 consisting of SEQ ID NO:54 and / or an LFR4 consisting of SEQ ID NO:55.

[0115] A polypeptide of the invention may be described by reference to its VH and VL domain sequences. A polypeptide may comprise a VH domain and / or a VL domain, most preferably a VH domain and a VL domain.

[0116] Specific polypeptides and their VH and VL domain sequences provided by the present invention include the following:

[0117] [Table 8]

[0118] The VH region may comprise an amino acid sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 98%, such as at least 99% sequence identity to any one of SEQ ID NOs: 23, 25, 27, 29, 33, 35, 36, 37, 96 or 102. Suitably, the VH region consists of an amino acid sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 98%, such as at least 99% sequence identity to any one of SEQ ID NOs: 23, 25, 27, 29, 33, 35, 36, 37, 96 or 102.

[0119] Suitably, the VH region comprises the amino acid sequence of SEQ ID NO: 23, 25, 27, 29, 33, 35, 36, 37, 96 or 102, more suitably, the VH region comprises the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37. Alternatively, the VH region comprises the amino acid sequence of SEQ ID NO: 102. Suitably, the VH region consists of the amino acid sequence of SEQ ID NO: 23, 25, 27, 29, 33, 35, 36, 37, 96 or 102, more suitably, the VH region consists of the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37. Alternatively, the VH region consists of the amino acid sequence of SEQ ID NO: 102.

[0120] The VL region may comprise an amino acid sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 98%, such as at least 99% sequence identity to any one of SEQ ID NOs: 24, 26, 28, 30, 31, 32, 34, 38, 39, 97, 99 or 104. Suitably, the VL region consists of an amino acid sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 98%, such as at least 99% sequence identity to any one of SEQ ID NOs: 24, 26, 28, 30, 31, 32, 34, 38, 39, 97, 99 or 104.

[0121] Suitably, the VL region comprises the amino acid sequence of SEQ ID NO: 24, 26, 28, 30, 31, 32, 34, 38, 39, 97, 99 or 104. More suitably, the VL region comprises the amino acid sequence of SEQ ID NO: 38 or SEQ ID NO: 39. Alternatively, the VL region comprises the amino acid sequence of SEQ ID NO: 99 or SEQ ID NO: 104.

[0122] Suitably, the VL region consists of the amino acid sequence of SEQ ID NO: 24, 26, 28, 30, 31, 32, 34, 38, 39, 97, 99 or 104. More suitably, the VL region consists of the amino acid sequence of SEQ ID NO: 38 or SEQ ID NO: 39. Alternatively, the VL region consists of the amino acid sequence of SEQ ID NO: 99 or SEQ ID NO: 104.

[0123] In one embodiment, the polypeptide comprises: (a) a VH region comprising SEQ ID NO:23 and a VL region comprising SEQ ID NO:24; (b) a VH region comprising SEQ ID NO:25 and a VL region comprising SEQ ID NO:26; (c) a VH region comprising SEQ ID NO:27 and a VL region comprising SEQ ID NO:28; (d) a VH region comprising SEQ ID NO:29 and a VL region comprising SEQ ID NO:30; (e) a VH region comprising SEQ ID NO:27 and a VL region comprising SEQ ID NO:31; (f) a VH region comprising SEQ ID NO:27 and a VL region comprising SEQ ID NO:32; (g) a VH region comprising SEQ ID NO: 33 and a VL region comprising SEQ ID NO: 34; (h) a VH region comprising SEQ ID NO: 33 and a VL region comprising SEQ ID NO: 39; (i) a VH region comprising SEQ ID NO: 35 and a VL region comprising SEQ ID NO: 39; (j) a VH region comprising SEQ ID NO: 36 and a VL region comprising SEQ ID NO: 39; (k) a VH region comprising SEQ ID NO: 37 and a VL region comprising SEQ ID NO: 39; (l) a VH region comprising SEQ ID NO: 36 and a VL region comprising SEQ ID NO: 38; (m) a VH region comprising SEQ ID NO: 37 and a VL region comprising SEQ ID NO: 38; (n) a VH region comprising SEQ ID NO: 96 and a VL region comprising SEQ ID NO: 97; (o) a VH region comprising SEQ ID NO: 36 and a VL region comprising SEQ ID NO: 99; (p) a VH region comprising SEQ ID NO: 102 and a VL region comprising SEQ ID NO: 99; or (q) comprises a VH region comprising SEQ ID NO: 102 and a VL region comprising SEQ ID NO: 104.

[0124] More preferably, the polypeptide comprises (a) a VH region consisting of SEQ ID NO: 23 and a VL region consisting of SEQ ID NO: 24; (b) a VH region consisting of SEQ ID NO: 25 and a VL region consisting of SEQ ID NO: 26; (c) a VH region consisting of SEQ ID NO:27 and a VL region consisting of SEQ ID NO:28; (d) a VH region consisting of SEQ ID NO:29 and a VL region consisting of SEQ ID NO:30; (e) a VH region consisting of SEQ ID NO: 27 and a VL region consisting of SEQ ID NO: 31; (f) a VH region consisting of SEQ ID NO: 27 and a VL region consisting of SEQ ID NO: 32; (g) a VH region consisting of SEQ ID NO: 33 and a VL region consisting of SEQ ID NO: 34; (h) a VH region consisting of SEQ ID NO: 33 and a VL region consisting of SEQ ID NO: 39; (i) a VH region consisting of SEQ ID NO: 35 and a VL region consisting of SEQ ID NO: 39; (j) a VH region consisting of SEQ ID NO: 36 and a VL region consisting of SEQ ID NO: 39; (k) a VH region consisting of SEQ ID NO: 37 and a VL region consisting of SEQ ID NO: 39; (l) a VH region consisting of SEQ ID NO: 36 and a VL region consisting of SEQ ID NO: 38; (m) a VH region consisting of SEQ ID NO: 37 and a VL region consisting of SEQ ID NO: 38; (n) a VH region consisting of SEQ ID NO: 96 and a VL region consisting of SEQ ID NO: 97; (o) a VH region consisting of SEQ ID NO: 36 and a VL region consisting of SEQ ID NO: 99; (p) a VH region consisting of SEQ ID NO: 102 and a VL region consisting of SEQ ID NO: 99; or (q) comprising a VH region consisting of SEQ ID NO: 102 and a VL region consisting of SEQ ID NO: 104.

[0125] The inventors have identified several residues in the polypeptides of the invention that can be substituted without significant loss of function, without loss of function, or that result in enhanced function (see, e.g., Example 7 and Table 10).

[0126] Thus, in one embodiment, the polypeptide comprises three heavy chain CDRs (HCDR1 to HCDR3) and three light chain CDRs (LCDR1 to LCDR3) (wherein the CDRs in this embodiment are defined according to the non-Kabat numbering system), wherein HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 72) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:76), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 DY (SEQ ID NO: 80), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 84), and LCDR2 comprises (e.g., consists of) X 41 AX 42 X 43 X 44 X 45 X46 (SEQ ID NO: 88), and LCDR3 comprises (e.g., consists of) X 47 X 48 X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO:92): The amino acid of X1 is selected from the group consisting of S, Y, T, G, R, E, K, D and N; The amino acid of X2 is selected from the group consisting of K, R, L, T, G, V, A, S, F, W, Q, M, Y, I, E, H, N, D and P; the amino acid of X3 is selected from the group consisting of R, K, H, T, S, F, G, V, A, L, N, Q, E, M, P, W, and I; the amino acid of X4 is selected from the group consisting of A and G; the amino acid of X5 is selected from the group consisting of M and I; the amino acid of X6 is selected from the group consisting of S, E, G, D, L, T, N, Q, I, V, A, K, M, H and Y; The amino acid of X7 is selected from the group consisting of E; the amino acid of X8 is selected from the group consisting of L, Q and D; the amino acid of X9 is selected from the group consisting of P, A, G, F, S, T and W; X 10 is selected from the group consisting of R; X 11 is selected from the group consisting of S, T and D; X 12 are selected from the group consisting of G, R, S, Y, A, T, D, E and W; X 13 is selected from the group consisting of Y; X 14 is selected from the group consisting of T; X 15 is selected from the group consisting of N, H and S; X 16are selected from the group consisting of R, N, F, K, Q, V, D, E, Y, G, M, P, W, H, L, I, S, T and A; X 17 is selected from the group consisting of Q, A, I, S, P, T, N, V, G, H, L, M, W, K, R, F, D, Y and E; X 18 are selected from the group consisting of G, D, E, H, L, V, Y, A, F, I, K, Q, W, R, M, P, S and N; X 19 is selected from the group consisting of T, K, Q, E, R and M; X 20 is selected from the group consisting of R, F, K, I, A, L, V, W, Y, M, P, Q, G and S; X 21 is absent or selected from the group consisting of K and R; X 22 are selected from the group consisting of K, R, A, H, S, Q, T, P, M, W, Y, G, L, F, V, E and N; X 23 is absent or selected from the group consisting of K and R; X 24 is selected from the group consisting of R, Y, A, H, P, L, K, G, Q, N, I, F, W, S, T, M, E, V and D; X 25 is selected from the group consisting of A, Q, T, S, G, V, R, I, H, K, P, L, M and F; X 26 is selected from the group consisting of R and S; X 27 is selected from the group consisting of Y, H, Q and A; X 28 is selected from the group consisting of A, T, S, D and E; X 29 is selected from the group consisting of M and L; X 30 is selected from the group consisting of Q, K, R, S and T; X 31is selected from the group consisting of A, S and T; X 32 is selected from the group consisting of S, T and D; X 33 are selected from the group consisting of Q, G, R, K, L, M, P, Y, S, A, N, H, W, D, E, F, T and I; X 34 is selected from the group consisting of S, G, H, N, T, Y and D; X 35 is selected from the group consisting of V, A and I; X 36 is selected from the group consisting of R, K, S, G and A; X 37 are selected from the group consisting of Y, F, L, Q, S, H, T, G, I, M, V, W, K, N, R, D and P; X 38 is selected from the group consisting of N, A, G, H, Q, S, Y, F and W; X 39 is selected from the group consisting of V, I, M and L; X 40 is selected from the group consisting of A, G and D; X 41 are selected from the group consisting of Y, H, R, T, A, D, K, L, N, Q, M, W, E, F and S; X 42 are selected from the group consisting of S, K, M, Q, R, V, Y, G, E, D, T, A, F, I, N, W, H and L; X 43 is selected from the group consisting of N, K, R, Q, T, Y, A, S, D and E; X 44 is selected from the group consisting of R, L, K and A; X 45 is selected from the group consisting of Y, I, K, M, Q, R, V, A, N, S, W, H, L, T, P, D, F, G and E; X 46are selected from the group consisting of T, A, D, E, Q, R, S, H, K, P, L, F, G, I, M, V, W, Y and N; X 47 is selected from the group consisting of Q, S and L; X 48 is selected from the group consisting of H, N, S, T, A, Q and V; X 49 is selected from the group consisting of H, A, D and F; X 50 is selected from the group consisting of Y and L; X 51 are selected from the group consisting of S, K, V, D, N, R, H, T, A, G, Q, I, M, F, W, Y and L; X 52 is selected from the group consisting of S, A, T, G, V, W and Y; X 53 is selected from the group consisting of T and Y.

[0127] Thus, in a further embodiment, the polypeptide comprises three heavy chain CDRs (HCDR1 to HCDR3) and three light chain CDRs (LCDR1 to LCDR3) (wherein the CDRs in this embodiment are defined according to the non-Kabat numbering system), wherein HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 73) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:77), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29DY (SEQ ID NO: 81), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 85), and LCDR2 comprises (e.g., consists of) X 41 AX 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 89), and LCDR3 comprises (e.g., consists of) X 47 X 48 X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO:93): The amino acid of X1 is selected from the group consisting of S, Y, T, G, R, E and K; The amino acid of X2 is selected from the group consisting of K, R, L, T, G, V, A, S, F, W, Q, M, Y, I, E, H and N; the amino acid of X3 is selected from the group consisting of R, K, H, T, S, F, G, V, A, L, N, Q, E, M, P and W; the amino acid of X4 is selected from the group consisting of A and G; the amino acid of X5 is selected from the group consisting of M and I; the amino acid of X6 is selected from the group consisting of S, E, G, D, L, T, N, Q, I, V, A, K and M; The amino acid of X7 is selected from the group consisting of E; the amino acid at X8 is selected from the group consisting of L and Q; the amino acid of X9 is selected from the group consisting of P, A, G, F, S and T; X 10 is selected from the group consisting of R; X 11 is selected from the group consisting of S, T and D; X 12 are selected from the group consisting of G, R, S, Y, A, T, D, E and W; X 13 is selected from the group consisting of Y; X 14 is selected from the group consisting of T; X 15 is selected from the group consisting of N, H and S; X 16 is selected from the group consisting of R, N, F, K, Q, V, D, E, Y, G, M, P, W, H and L; X 17 is selected from the group consisting of Q, A, I, S, P, T, N, V, G, H, L, M, W, K, R, F, D, Y and E; X 18 are selected from the group consisting of G, D, E, H, L, V, Y, A, F, I, K, Q, W, R, M, P and S; X 19 is selected from the group consisting of T, K, Q, E, R and M; X 20 are selected from the group consisting of R, F, K, I, A, L, V, W, Y and M; X 21 is absent or selected from the group consisting of K and R; X 22 are selected from the group consisting of K, R, A, H, S, Q, T, P, M, W, Y, G, L, F and V; X 23 is absent or selected from the group consisting of K and R; X 24 is selected from the group consisting of R, Y, A, H, P, L, K, G, Q, N, I, F, W, S, T, M, E, V and D; X 25 is selected from the group consisting of A, Q, T, S, G, V, R and I; X 26 is selected from the group consisting of R and S; X 27is selected from the group consisting of Y; X 28 is selected from the group consisting of A, T, S and D; X 29 is selected from the group consisting of M and L; X 30 is selected from the group consisting of Q, K, R, S and T; X 31 is selected from the group consisting of A, S and T; X 32 is selected from the group consisting of S, T and D; X 33 are selected from the group consisting of Q, G, R, K, L, M, P, Y, S, A, N, H, W, D and E; X 34 is selected from the group consisting of S, G, H, N, T and Y; X 35 is selected from the group consisting of V, A and I; X 36 is selected from the group consisting of R, K, S and G; X 37 are selected from the group consisting of Y, F, L, Q, S, H, T, G, I, M, V, W, K, N and R; X 38 is selected from the group consisting of N, A, G, H, Q and S; X 39 is selected from the group consisting of V, I, M and L; X 40 is selected from the group consisting of A, G and D; X 41 is selected from the group consisting of Y, H, R, T, A, D, K, L, N and Q; X 42 are selected from the group consisting of S, K, M, Q, R, V, Y, G, E, D, T, A, F, I, N, W and H; X 43 is selected from the group consisting of N, K, R, Q, T, Y, A, S, D and E; X 44is selected from the group consisting of R, L and K; X 45 is selected from the group consisting of Y, I, K, M, Q, R, V, A, N, S, W, H, L, T, P, D, F and G; X 46 are selected from the group consisting of T, A, D, E, Q, R, S, H, K, P, L, F, G, I, M, V, W, Y and N; X 47 is selected from the group consisting of Q, S and L; X 48 is selected from the group consisting of H, N, S, T, A and Q; X 49 is selected from the group consisting of H; X 50 is selected from the group consisting of Y and L; X 51 are selected from the group consisting of S, K, V, D, N, R, H, T, A, G, Q, I, M, F, W and Y; X 52 is selected from the group consisting of S, A, T and G; X 53 is selected from the group consisting of T and Y.

[0128] Thus, in a further embodiment, the polypeptide comprises three heavy chain CDRs (HCDR1 to HCDR3) and three light chain CDRs (LCDR1 to LCDR3) (wherein the CDRs in this embodiment are defined according to the non-Kabat numbering system), wherein HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 74) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:78), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 DY (SEQ ID NO: 82), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 86), and LCDR2 comprises (e.g., consists of) X 41 AX 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 90), and LCDR3 comprises (e.g., consists of) X 47 X 48 X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO:94) comprising (e.g. consisting of): The amino acid of X1 is selected from the group consisting of S, Y, T, G and R; The amino acid of X2 is selected from the group consisting of K, R, L, T, G, V, A, S, F, W, Q, M, Y, I, and E; the amino acid of X3 is selected from the group consisting of R, K, H, T, S, F, G, V, A, L, N, and Q; the amino acid of X4 is selected from the group consisting of A and G; the amino acid of X5 is selected from the group consisting of M and I; the amino acid of X6 is selected from the group consisting of S, E, G, D, L, T, N, Q, I, V and A; The amino acid of X7 is selected from the group consisting of E; the amino acid at X8 is selected from the group consisting of L and Q; the amino acid of X9 is selected from the group consisting of P, A, G, F and S; X10 is selected from the group consisting of R; X 11 is selected from the group consisting of S and T; X 12 is selected from the group consisting of G, R, S, Y, A and T; X 13 is selected from the group consisting of Y; X 14 is selected from the group consisting of T; X 15 is selected from the group consisting of N, H and S; X 16 is selected from the group consisting of R, N, F, K, Q, V, D, E, Y, G, M and P; X 17 are selected from the group consisting of Q, A, I, S, P, T, N, V, G, H, L, M, W, K, R and F; X 18 are selected from the group consisting of G, D, E, H, L, V, Y, A, F, I, K, Q, W, R, M, P and S; X 19 is selected from the group consisting of T, K, Q, E, R and M; X 20 is selected from the group consisting of R, F, K, I, A, L, V, W and Y; X 21 is absent or selected from the group consisting of K and R; X 22 are selected from the group consisting of K, R, A, H, S, Q, T, P, M, W, G and Y; X 23 is absent or selected from the group consisting of K and R; X 24 is selected from the group consisting of R, Y, A, H, P, L, K, G, Q, N, I, F, W, S, T, M, E and V; X 25 is selected from the group consisting of A, Q, T, S, G and V; X 26is selected from the group consisting of R; X 27 is selected from the group consisting of Y; X 28 is selected from the group consisting of A, T, S and D; X 29 is selected from the group consisting of M; X 30 is selected from the group consisting of Q, K, R, S and T; X 31 is selected from the group consisting of A, S and T; X 32 is selected from the group consisting of S, T and D; X 33 are selected from the group consisting of Q, G, R, K, L, M, P, Y, S, A, N, H and W; X 34 is selected from the group consisting of S, G, H, N, T and Y; X 35 is selected from the group consisting of V, A and I; X 36 is selected from the group consisting of R, K and S; X 37 are selected from the group consisting of Y, F, L, Q, S, H, T, G, I, M, V, W, K, N and R; X 38 is selected from the group consisting of N, A, G, H, Q and S; X 39 is selected from the group consisting of V, I, M and L; X 40 is selected from the group consisting of A, G and D; X 41 is selected from the group consisting of Y, H, R and T; X 42 are selected from the group consisting of S, K, M, Q, R, V, Y, G, E, D, T, A, F, I, N and W; X 43 is selected from the group consisting of N, K, R, Q, T, Y, A and S; X 44 is selected from the group consisting of R, L and K; X 45 are selected from the group consisting of Y, I, K, M, Q, R, V, A, N, S, W, H, L, T, P, D and F; X 46 are selected from the group consisting of T, A, D, E, Q, R, S, H, K, P, L, F, G, I, M, V, W, Y and N; X 47 is selected from the group consisting of Q and S; X 48 is selected from the group consisting of H, N, S, T, A and Q; X 49 is selected from the group consisting of H; X 50 is selected from the group consisting of Y; X 51 is selected from the group consisting of S, K, V, D, N, R, H, T, A and G; X 52 is selected from the group consisting of S and A; X 53 is selected from the group consisting of T and Y.

[0129] Thus, in a further embodiment, the polypeptide comprises three heavy chain CDRs (HCDR1 to HCDR3) and three light chain CDRs (LCDR1 to LCDR3) (wherein the CDRs in this embodiment are defined according to the non-Kabat numbering system), wherein HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 75) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:79), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 DY (SEQ ID NO: 83), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 87), and LCDR2 comprises (e.g., consists of) X 41 AX 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 91), and LCDR3 comprises (e.g., consists of) X 47 X 48 X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO:95) The amino acid of X1 is selected from the group consisting of S, Y, T and G; The amino acid of X2 is selected from the group consisting of K, R, L, T, G, V, A, S, F, W, Q, M and Y; the amino acid of X3 is selected from the group consisting of R, K, H, T, S, F, G and V; the amino acid of X4 is selected from the group consisting of A and G; the amino acid of X5 is selected from the group consisting of M and I; the amino acid of X6 is selected from the group consisting of S, E, G, D, L and T; The amino acid of X7 is selected from the group consisting of E; the amino acid at X8 is selected from the group consisting of L and Q; the amino acid of X9 is selected from the group consisting of P, A and G; X 10 is selected from the group consisting of R; X 11 is selected from the group consisting of S and T; X 12 is selected from the group consisting of G and R; X 13 is selected from the group consisting of Y; X 14 is selected from the group consisting of T; X 15 is selected from the group consisting of N, H and S; X 16 is selected from the group consisting of R, N, F, K, Q, V, D and E; X 17 is selected from the group consisting of Q, A, I, S, P, T, N and V; X 18 are selected from the group consisting of G, D, E, H, L, V, Y, A, F, I, K, Q, W and R; X 19 is selected from the group consisting of T and K; X 20 is selected from the group consisting of R, F, K and I; X 21 is absent or selected from the group consisting of K and R; X 22 is selected from the group consisting of K, G and R; X 23 is absent or selected from the group consisting of K and R; X 24 are selected from the group consisting of R, Y, A, H, P, L, K, G, Q, N, I, F and W; X 25 is selected from the group consisting of A, Q, T, S and G; X 26 is selected from the group consisting of R; X 27 is selected from the group consisting of Y; X 28 is selected from the group consisting of A, T and S; X 29 is selected from the group consisting of M; X 30 is selected from the group consisting of Q, K, R, S and T; X 31 is selected from the group consisting of A and S; X 32 is selected from the group consisting of S and T; X 33 is selected from the group consisting of Q, G, R, K, L, M, P, Y and S; X 34 is selected from the group consisting of S, G, H and N; X 35 is selected from the group consisting of V, A and I; X 36 is selected from the group consisting of R; X 37 are selected from the group consisting of Y, F, L, Q, S, H, T, G, I, M, V and W; X 38 is selected from the group consisting of N, A, G, H, Q and S; X 39 is selected from the group consisting of V, I, M and L; X 40 is selected from the group consisting of A and G; X 41 is selected from the group consisting of Y and H; X 42 is selected from the group consisting of S, K, M, Q, R, V, Y, G and E; X 43 is selected from the group consisting of N, K and R; X 44 is selected from the group consisting of R, L and K; X 45 is selected from the group consisting of Y, I, K, M, Q, R, V, A, N, S, W and H; X 46are selected from the group consisting of T, A, D, E, Q, R, S, H, K, P, L, F, G, I, M and V; X 47 is selected from the group consisting of Q; X 48 is selected from the group consisting of H, N, S and T; X 49 is selected from the group consisting of H; X 50 is selected from the group consisting of Y; X 51 is selected from the group consisting of S, K and V; X 52 is selected from the group consisting of S and A; X 53 is selected from the group consisting of T.

[0130] In one embodiment, the polypeptide comprises three heavy chain CDRs (HCDR1-HCDR3) and three light chain CDRs (LCDR1-LCDR3) (wherein the CDRs in this embodiment are defined by the non-Kabat numbering system), wherein HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 72) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:76), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 DY (SEQ ID NO: 80), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 84), and LCDR2 comprises (e.g., consists of) X 41 AX 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 88), and LCDR3 comprises (e.g., consists of) X 47 X 48 X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO: 92), comprising amino acids X1 to X 53 are X1 to X listed in the "CDR numbering" column of Table 10. 53 and each is selected from the amino acids listed in the corresponding row in the "Tested Residues" column of Table 10. More preferably, amino acids X1 to X 53 are each selected from the amino acids listed in the corresponding rows of Table 10 under the columns "20-40% Functionality of Best Residues", "40-60% Functionality of Best Residues", "60-80% Functionality of Best Residues" and "Best Residue(s)". More preferably, the amino acids X1 to X 53 are each selected from the amino acids listed in the corresponding rows of Table 10 under the columns "40-60% functional of best residues", "60-80% functional of best residues" and "Best residue(s)". More preferably, the amino acids X1 to X 53 are each selected from the amino acids listed in the corresponding rows in the "60-80% Functionality of Best Residues" and "Best Residue(s)" columns of Table 10. Most preferably, amino acids X1 to X 53 are each selected from the amino acids listed in the corresponding row in the "Best Residue(s)" column of Table 10.

[0131] In one embodiment, the polypeptide comprises a VH domain and a VL domain, the VH domain having the polypeptide sequence QVQLVQSGSELKKPGASVKVSCKASGYTFX1X2X3X4X5X6WVRQAPGQGLEWX7GX8IX9X 10 X 11 X 12 X 13 X 14 X 15 X 16 YX 17 X 18 X 19 FX 20 GRFX 21 X 22 SADKSX 23 STAYLQISSLKAEDTAVYX 24 CARDX 25 X 26 X 27 X 28 X 29 X 30 X 31 X 32 DYWX 33 QGTTVTVSS (SEQ ID NO: 70) and the VL region comprises (e.g., consists of) the polypeptide sequence X 34 IQMTQSPSSLSASVGDRVTITCX 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 WYQQKPGKAPKLLIYX 46 AX 47 X 48 X 49 X 50 X 51 GVPSRFSGSGSGTTDFTFTISSLQPEDIATYX 52 CX 53 X 54 X 55 X 56 X 57 X 58 PLX 59 FGGGTKLEIK (SEQ ID NO:71) and amino acids X1 to X59 is X1 to X listed in the "Full Length Numbering" column of Table 10. 59 and each is selected from the amino acids listed in the corresponding row in the "Tested Residues" column of Table 10 (in this embodiment, the CDRs are defined by the non-Kabat numbering system). More preferably, amino acids X1 to X 59 are each selected from the amino acids listed in the corresponding rows of Table 10 under the columns "20-40% Functionality of Best Residues", "40-60% Functionality of Best Residues", "60-80% Functionality of Best Residues" and "Best Residue(s)". More preferably, the amino acids X1 to X 59 are each selected from the amino acids listed in the corresponding rows of Table 10 under the columns "40-60% functional of best residues", "60-80% functional of best residues" and "Best residue(s)". More preferably, the amino acids X1 to X 59 are each selected from the amino acids listed in the corresponding rows in the "60-80% Functionality of Best Residues" and "Best Residue(s)" columns of Table 10. Most preferably, amino acids X1 to X 59 are each selected from the amino acids listed in the corresponding row in the "Best Residue(s)" column of Table 10.

[0132] In certain embodiments, the residue in HCDR2 corresponding to residue number 5 of SEQ ID NO:2 is arginine, and / or the residue in HCDR3 corresponding to residue number 6 of SEQ ID NO:3 is arginine, and / or the residue in HCDR3 corresponding to residue number 7 of SEQ ID NO:3 is tyrosine, and / or the residue in LCDR2 corresponding to residue number 1 of SEQ ID NO:5 is tyrosine, and / or the residue in LCDR3 corresponding to residue number 3 of SEQ ID NO:6 is histidine.

[0133] In certain embodiments, residue H53 is an arginine, and / or residue H100 is an arginine, and / or residue H100A is a tyrosine, and / or residue L50 is a tyrosine, and / or residue L91 is a histidine, according to the Kabat numbering.

[0134] In certain embodiments, the residue corresponding to position 74 of SEQ ID NO:70 may be selected from lysine or threonine.

[0135] In certain embodiments, the polypeptide comprises the paratope residues selected as highly likely in Figure 4. Suitably, the residue corresponding to position 47 of SEQ ID NO:418 is a tryptophan, the residue corresponding to position 103 of SEQ ID NO:418 is a glycine, the residue corresponding to position 105 of SEQ ID NO:418 is a tyrosine, the residue corresponding to position 31 of SEQ ID NO:39 is a tyrosine, and the residue corresponding to position 92 of SEQ ID NO:39 is a tyrosine.

[0136] In a further embodiment, the polypeptide further comprises paratope residues selected as likely in Figure 4. Suitably, the residue corresponding to position 52 of SEQ ID NO:418 is a leucine, the residue corresponding to position 54 of SEQ ID NO:418 is an arginine, the residue corresponding to position 104 of SEQ ID NO:418 is an arginine, the residue corresponding to position 26 of SEQ ID NO:39 is a serine, the residue corresponding to position 27 of SEQ ID NO:39 is a glutamine, the residue corresponding to position 49 of SEQ ID NO:39 is a tyrosine, and the residue corresponding to position 91 of SEQ ID NO:39 is a histidine.

[0137] In a further embodiment, the polypeptide further comprises paratope residues selected as possible in Figure 4. Suitably, the residue corresponding to position 55 of SEQ ID NO:418 is a serine, the residue corresponding to position 58 of SEQ ID NO:418 is a threonine, the residue corresponding to position 59 of SEQ ID NO:418 is an asparagine, the residue corresponding to position 62 of SEQ ID NO:418 is a glutamine, the residue corresponding to position 100 of SEQ ID NO:418 is a phenylalanine, the residue corresponding to position 1 of SEQ ID NO:39 is a serine, the residue corresponding to position 29 of SEQ ID NO:39 is a valine, the residue corresponding to position 90 of SEQ ID NO:39 is a histidine, and the residue corresponding to position 93 of SEQ ID NO:39 is a serine.

[0138] In a further embodiment, the polypeptide further comprises a paratope residue selected as possible in Figure 4. Suitably, the residue corresponding to position 31 of SEQ ID NO:418 is a serine, the residue corresponding to position 60 of SEQ ID NO:418 is a tyrosine, the residue corresponding to position 61 of SEQ ID NO:418 is an asparagine, the residue corresponding to position 65 of SEQ ID NO:418 is a threonine, the residue corresponding to position 99 of SEQ ID NO:418 is an aspartic acid, the residue corresponding to position 101 of SEQ ID NO:418 is an arginine, the residue corresponding to position 102 of SEQ ID NO:418 is a serine, the residue corresponding to position 25 of SEQ ID NO:39 is an alanine, the residue corresponding to position 30 of SEQ ID NO:39 is an arginine, the residue corresponding to position 67 of SEQ ID NO:39 is a serine, the residue corresponding to position 89 of SEQ ID NO:39 is a glutamine, and the residue corresponding to position 94 of SEQ ID NO:39 is a serine.

[0139] In one embodiment, the VH region comprises, e.g. consists of, an amino acid sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 98%, such as at least 99%, such as 100% sequence identity to SEQ ID NO: 113. Suitably, the VL region comprises, e.g. consists of, an amino acid sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 98%, such as at least 99%, such as 100% sequence identity to SEQ ID NO: 114.

[0140] A polypeptide of the invention may be described by reference to its heavy or light chain constant region sequence. A polypeptide of the invention may alternatively be described by reference to its heavy or light chain sequence. A polypeptide may comprise a heavy chain constant region and / or a light chain constant region, most preferably a heavy chain constant region and a light chain constant region.

[0141] Specific constant regions provided by the present invention include:

[0142] [Table 9]

[0143] Suitably, the heavy chain comprises a polypeptide sequence having at least 50%, such as at least 70%, such as at least 90% identity to SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:1220 or SEQ ID NO:1236. More suitably, the heavy chain comprises SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:1220 or SEQ ID NO:1236. More suitably, the heavy chain consists of SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:1220 or SEQ ID NO:1236.

[0144] Suitably, the heavy chain comprises a polypeptide sequence having at least 50%, such as at least 70%, such as at least 90% identity to SEQ ID NO: 58 or SEQ ID NO: 60. More suitably, the heavy chain comprises SEQ ID NO: 58 or SEQ ID NO: 60. More suitably, the heavy chain consists of SEQ ID NO: 58 or SEQ ID NO: 60.

[0145] Suitably, the light chain comprises a polypeptide sequence having at least 50%, such as at least 70%, such as at least 90% identity to SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:1219 or SEQ ID NO:1221. More suitably, the light chain comprises SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:1219 or SEQ ID NO:1221. More suitably, the light chain consists of SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:1219 or SEQ ID NO:1221.

[0146] Suitably, the light chain comprises a polypeptide sequence having at least 50%, such as at least 70%, such as at least 90% identity to SEQ ID NO: 59 or SEQ ID NO: 61. More suitably, the light chain comprises SEQ ID NO: 59 or SEQ ID NO: 61. More suitably, the light chain consists of SEQ ID NO: 59 or SEQ ID NO: 61.

[0147] A polypeptide of the present invention may be described by reference to multiple combined polypeptide sequences.

[0148] Suitably, the polypeptide (such as an antibody or fragment thereof) comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:2, HCDR3 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:3, LCDR1 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:4, LCDR2 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:5 and LCDR3 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:6.

[0149] Suitably, the polypeptide (such as an antibody or fragment thereof) comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:2, HCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:15, LCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:4, LCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:5 and LCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:6.

[0150] Suitably, the polypeptide (such as an antibody or fragment thereof) comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:2, HCDR3 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:3, LCDR1 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:4, LCDR2 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:98 and LCDR3 comprises or consists of a sequence having at least 80% identity with SEQ ID NO:6.

[0151] Suitably, the polypeptide (such as an antibody or fragment thereof) comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:100, HCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:101, LCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:4, LCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:98 and LCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:6.

[0152] Suitably, the polypeptide (such as an antibody or fragment thereof) comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:1, HCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:100, HCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:101, LCDR1 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:103, LCDR2 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:98 and LCDR3 comprises or consists of a sequence having at least 80% identity to SEQ ID NO:6.

[0153] Suitably, the polypeptide (such as an antibody or fragment thereof) comprises a VH region comprising or consisting of a sequence having at least 80% identity to SEQ ID NO: 36 or SEQ ID NO: 102, and a VL region comprising or consisting of a sequence having at least 80% identity to SEQ ID NO: 99 or 104.

[0154] Suitably, the polypeptide (such as an antibody or fragment thereof) further comprises heavy and light chain constant regions.

[0155] Suitably, the polypeptide (such as an antibody) comprises or consists of a heavy chain comprising or consisting of SEQ ID NO:58 or SEQ ID NO:61, and a light chain comprising or consisting of SEQ ID NO:59 or SEQ ID NO:60.

[0156] In one embodiment, a polypeptide of any one of the sequences disclosed herein is provided. In one embodiment, a polynucleotide encoding any one of the polypeptide sequences disclosed herein is provided.

[0157] It is understood that embodiments referring to "at least 80%" or "80% or more" herein include any value equal to or greater than 80%, for example, 85%, 90%, 95%, 97%, 98%, 99% or 100% sequence identity.

[0158] Instead of percentage sequence identity, equivalent embodiments can also be defined by one or more amino acid changes, such as one or more additions, substitutions and / or deletions. In one embodiment, the sequence can contain up to 5 amino acid changes, such as up to 3 amino acid changes, in particular up to 2 amino acid changes. For example, the sequence can contain up to 5 amino acid substitutions, such as up to 3 amino acid substitutions, in particular up to 1 or 2 amino acid substitutions. For example, the CDR3 of the polypeptide of the invention can comprise or more preferably consist of a sequence having no more than 2, more preferably no more than 1 substitution(s) compared to any one of SEQ ID NO:3.

[0159] For fragments comprising both the VH and VL domains, these may be associated either covalently (e.g., by a disulfide bond or a linker) or non-covalently. The antibody fragments described herein may include scFvs, i.e., fragments comprising the VH and VL domains linked by a linker. In one embodiment, the VH and VL domains are linked by a (e.g., synthetic) polypeptide linker. The polypeptide linker is (Gly4Ser) n A linker may be included, where n=1-8, for example, 2, 3, 4, 5, 6 or 7. In a further embodiment, the linker comprises SEQ ID NO: 69. In a further embodiment, the linker consists of SEQ ID NO: 69.

[0160] In one embodiment there is provided a polypeptide comprising one or more of the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, VH or VL sequences provided in the attached sequence listing, or sharing at least 90%, such as at least 95%, such as at least 99% identity thereto. Most preferably, the polypeptide is an antibody or fragment thereof.

[0161] Antibody sequence modification Antibodies and fragments thereof can be modified using known methods. Sequence modifications to the antibody molecules described herein can be readily incorporated by one of skill in the art. The following examples are non-limiting.

[0162] Upon antibody discovery and sequence recovery from phage libraries, the desired antibody variable domains can be reformatted into full-length IgG by subcloning. To speed up the process, variable domains are often transferred using restriction enzymes. Such restriction sites can be altered from the canonical sequences (such canonical sequences can be found, for example, in the International ImMunoGeneTics [IMGT] information system, see http: / / www.imgt.org) to introduce additional / substitute amino acids. These can be introduced as kappa or lambda light chain sequence modifications.

[0163] join The polypeptide of the present invention is 3.0×10 -7 M (i.e., 300 nM) or less, 2.5 × 10 -7 M (i.e., 250 nM) or less, 2.0 × 10 -7 M (i.e., 200 nM) or less than 1.5 x 10 -7 Binding affinity (K D In a further embodiment, K D is 1.3 x 10 -7 M (i.e., 130 nM) or less, e.g., 1.0×10 -7 In yet a further embodiment, the K D is 6.0 x 10 -8 M (i.e., less than 60 nM), e.g., 5.0×10 -8 M (i.e., less than 50 nM), 4.0 × 10 -8 M (i.e., less than 40 nM), 3.0 × 10 -8 M (i.e., 30 nM) or less than 2.0 x 10 -8 In a further embodiment, the K D is 1.5 x 10 -8M (i.e., 15 nM) or less, e.g., 1.0×10 -8 M (i.e., 10 nM) or less, 9.0 × 10 -9 M (i.e., 9 nM) or less, 8.0 × 10 -9 M (i.e., 8 nM) or less, 7.0 × 10 -9 M (i.e., 7 nM) or less, 6.0 × 10 -9 M (i.e., 6 nM) or less, 5.0 × 10 -9 M (i.e., 5 nM) or less, 4.0 × 10 -9 M (i.e., 4 nM) or less, 3.0 × 10 -9 M (i.e., 3 nM) or less, 2.0 × 10 -9 M (i.e., 2 nM) or less or 1.5 x 10 -9 M (i.e., 1.5 nM) or less or 1.0 x 10 -9 M (i.e., 1 nM) or less. For example, in one embodiment, -7 Binding affinity (K D ) is provided an anti-LPAR1 antibody that binds to LPAR1.

[0164] Suitably, the K of the polypeptide of the present invention D is determined using a kinetic exclusion assay (KinExA; a type of bioassay in which a solution containing the receptor, ligand and receptor-ligand complex is exposed to additional ligand immobilized on a solid phase). Preferably, KinExA uses LPAR1 expressing cells as the titrating binding partner. Preferably, K D is measured from a monovalent antibody, e.g., a Fab. In one embodiment, the K D can be established by method 1.14, which is more fully described in the Examples section below.

[0165] Functional characteristics evaluation The assays described herein can be used to characterize the function of the polypeptide of the present invention.For example, the polypeptide described herein can be assessed by measuring calcium mobilization or cAMP production.LPAR1 predominantly signals through Gi / o to inhibit cAMP production and signals through Gq / 11 to promote calcium mobilization.LPAR1 also signals through G13 to promote Rho signaling.

[0166] The polypeptides described herein can also be assessed by measuring cell proliferation and migration.For example, DNA synthesis, which is a marker of cell proliferation, can be measured after applying the polypeptide to cells, for example, by BrdU incorporation.Cell migration can be assessed by applying the polypeptide to cells and then using a fluorescent microscope to count the percentage of cells that have migrated.

[0167] In functional assays, the output can be measured by calculating the half-maximal concentration, also referred to as "EC50" or "effective concentration at 50 percent". The term "IC50" refers to the inhibitory concentration. Both EC50 and IC50 can be measured using methods known in the art, such as flow cytometry methods. For the avoidance of doubt, EC50 values ​​in this application are provided using an IgG1 format antibody. Such values ​​can be readily converted based on the molecular weight of the antibody format for equivalent values ​​as follows: (μg / ml) / (MW in kDa)=μM Milliliters may be referred to herein as "ml" or "mL", and may be used interchangeably.

[0168] The EC50 for down-regulation after polypeptide binding may be less than 0.5 μg / ml, for example, less than 0.4 μg / ml, 0.3 μg / ml, 0.2 μg / ml, 0.15 μg / ml, 0.1 μg / ml or 0.05 μg / ml. In particular, the EC50 value is the value when the antibody is measured in IgG1 format. For example, the EC50 value may be measured using flow cytometry.

[0169] In one embodiment, the polypeptide of the present invention modulates the function of LPAR1. More preferably, the polypeptide binding to LPAR1 is an inhibitor of LPAR1, such as an inverse agonist of LPAR1. In one embodiment, the polypeptide of the present invention is an allosteric inhibitor of LPAR1.

[0170] Suitably, binding to LPAR1 reduces Gi / o signalling by LPAR1.

[0171] Suitably, binding to LPAR1 reduces or prevents LPA-induced or constitutive reduction in cAMP production (e.g., increases cAMP production in the assay detailed below (and utilized in Example 1.7)). In one embodiment, cAMP production is increased by at least 10%, such as at least 50%, such as at least 70%, such as at least 100%, such as at least 150%, such as at least 200%, such as at least 250%, such as at least 300%.

[0172] Suitably, binding to LPAR1 reduces or prevents LPA-induced calcium mobilization (eg reduces calcium mobilization in the assay detailed in Example 1.8).

[0173] In one embodiment, the polypeptide binding to LPAR1 reduces the activity of LPAR1 by at least 10%, such as at least 20%, such as at least 30%, such as at least 40%, such as at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 98%, such as at least 99%, such as at least 100%. More preferably, the activity of LPAR1 is indicated by the assays detailed in Examples 1.1 to 1.16, such as the assays detailed in Examples 1.7 or 1.11. Most preferably, the activity of LPAR1 is indicated by the HTRF cAMP assay outlined below.

[0174] HTRF cAMP assay CHO-K1 EDG2 Gi / Gq cells are seeded in multi-well plates at 3000 cells per 25 μL of full growth medium and incubated at 37° C. for 24 hours. Cells are serum-starved for 4 hours at 37° C. After serum starvation, medium is discarded and replaced with 5 μL cell assay buffer (HBSS+0.1% (w / v) BSA+20 mM HEPES). Cells are stimulated with various concentrations of human antibodies or human antibody-containing supernatants and incubated for 15 minutes at 37° C. After preincubation, cells are stimulated with LPA (0.5 μM) and forskolin (5 μM) and incubated for 1 hour at 37° C. cAMP-cryptate and anti-cAMP-d2 working solutions are prepared in lysis and detection buffer and added to all wells of the plate. After incubation at room temperature in the dark for 1 hour, the plate is read on a plate reader. cAMP concentrations are determined by applying the 620 / 665 nm fluorescence ratio to a standard curve of known cAMP concentrations.

[0175] Binding of the antibodies of the invention to LPAR1 on the surface of live cells is suitably indicated using the transient transfection CIFAT assay outlined below.

[0176] Transient transfection of CIFAT CHO-K1 cells are seeded in multi-well plates at 20,000 cells per 200 μL of complete growth medium and incubated at 37° C. for 24 hours. In a sterile tube, 0.0309 uL / well of PEI is diluted in 10 uL / well of transfection medium (DMEM supplemented with 2 mM L-glutamine and penicillin-streptomycin). The diluted PEI is added to 100 ng / well of DNA, which is then immediately mixed and the mixture is incubated at room temperature for 10 minutes. 200 μL / well of complete growth medium is added to the PEI-DNA mixture, then the medium in the wells is removed and 200 ul of the complete growth medium / PEI / DNA mixture is added in the wells of the adherent cell plate. The plate is incubated at 37° C. for 24 hours. The medium is discarded and replaced with 200 μL of complete growth medium. The plate is incubated at 37° C. for 24 hours. The medium is removed from the wells and the cells are incubated with various concentrations of primary antibodies for 75 minutes at 37° C. After washing and cell fixation with 4% PFA, antibody binding is detected using a goat anti-human detection antibody incubated for 1 hour at room temperature. Fluorescence at 488 nm is measured.

[0177] multispecific antibody The antibody of the present invention may be monospecific or may bind to additional targets, and thus be bispecific or multispecific. Multispecific antibodies may be specific for different epitopes of one target polypeptide, or may be specific for two or more target polypeptides. Thus, in one embodiment, the polypeptide of the present invention is comprised in a construct that comprises a first binding specificity for LPAR1 and a second binding specificity for a second target epitope.

[0178] The second binding specificity can target an antigen in the same cell as LPAR1 or in a different cell of the same or different tissue type. In certain embodiments, the target epitope can be present on different cells, including different T cells, B cells, tumor cells, autoimmune tissue cells, or virus-infected cells. Alternatively, the target epitope can be present on the same cell.

[0179] In one embodiment, the construct comprises a polypeptide that binds to a target other than LPAR1.

[0180] Immunoconjugates The polypeptides of the present invention (such as antibodies or fragments thereof) may be conjugated to a therapeutic moiety, such as a cytotoxin or a chemotherapeutic agent. Most preferably, the polypeptides are conjugated to a therapeutic moiety that is antifibrotic. Such conjugates may be referred to as immunoconjugates. As used herein, the term "immunoconjugate" refers to an antibody or fragment thereof that is chemically or biologically linked to another moiety, such as a cytotoxin, a radioactive agent, a cytokine, an interferon, a target or reporter moiety, an enzyme, a toxin, a peptide or a protein, or a therapeutic agent. Most preferably, the therapeutic agent is antifibrotic. The antibody or fragment thereof may be linked to a cytotoxin, a radioactive agent, a cytokine, an interferon, a target or reporter moiety, an enzyme, a toxin, a peptide or a therapeutic agent at any position along the molecule, so long as it is capable of binding to its target. Examples of immunoconjugates include antibody-drug conjugates and antibody-toxin fusion proteins. In one embodiment, the drug may be a second, different antibody against LPAR1. In certain embodiments, the antibody may be conjugated to an agent specific for tumor cells or virus-infected cells. The type of therapeutic moiety that may be conjugated to the anti-LPAR1 antibody takes into account the condition to be treated and the desired therapeutic effect to be achieved.

[0181] Polynucleotides and Expression Vectors In one aspect of the invention, there is provided a polynucleotide encoding a polypeptide of the invention.

[0182] In one aspect of the present invention, there is provided a polynucleotide comprising or consisting of a sequence having at least 70%, for example, at least 80%, for example, at least 90%, for example, at least 95%, for example, at least 99% sequence identity to a polynucleotide encoding any one of the parts of SEQ ID NOs: 1 to 22, 40 to 55, 72 to 95, 98, 100, 101, 103, and 107 to 112, which encodes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, HFR1, HFR2, HFR3, HFR4, LFR1, LFR2, LFR3, or LFR4 of the encoded immunoglobulin chain variable domain.

[0183] In one embodiment of the present invention, the polynucleotide comprises any one of SEQ ID NOs:1368-1374.

[0184] To express a polypeptide, the polynucleotides described herein can be inserted into an expression vector (which can be termed an "expression cassette," as is well understood in the art) such that the gene is operably linked to transcriptional and translational control sequences. Thus, in one aspect of the invention, there is provided an expression vector comprising a polynucleotide sequence of the invention as defined herein.

[0185] The present invention also provides polynucleotide sequences and expression vectors and plasmids encoding any of the polypeptide sequences disclosed herein, including any variant polypeptide sequence disclosed herein, optionally containing one or more amino acid substitutions.

[0186] Mutations can be made in the DNA or cDNA encoding the polypeptide that are silent with respect to the amino acid sequence of the polypeptide but provide for codons preferred for translation in a particular host. For example, preferred codons for translation of nucleic acids in E. coli and S. cerevisiae, as well as mammals, particularly humans, are known.

[0187] Mutations in a polypeptide can be achieved, for example, by substitutions, additions, or deletions to the nucleic acid encoding the polypeptide. Substitutions, additions, or deletions to the nucleic acid encoding the polypeptide can be introduced by a number of methods, including, for example, error-prone PCR, shuffling, oligonucleotide-directed mutagenesis, assembly PCR, PCR mutagenesis, in vivo mutagenesis, cassette mutagenesis, recursive ensemble mutagenesis, exponential ensemble mutagenesis, site-directed mutagenesis, gene reassembly, artificial gene synthesis, gene site saturation mutagenesis (GSSM), synthetic ligation reassembly (SLR), or a combination of these methods. Modifications, additions or deletions to nucleic acids can also be introduced by methods including recombination, recursive sequence recombination, phosphothioate-modified DNA mutagenesis, uracil-containing template mutagenesis, gapped duplex mutagenesis, point mismatch repair mutagenesis, repair-deficient host strain mutagenesis, chemical mutagenesis, radiation-induced mutagenesis, deletion mutagenesis, restriction-selection mutagenesis, restriction-purification mutagenesis, ensemble mutagenesis, chimeric nucleic acid multimer creation, or combinations thereof.

[0188] In particular, artificial gene synthesis can be used. The gene encoding the polypeptide of the invention can be synthetically produced, for example, by solid-phase DNA synthesis. The entire gene can be synthesized de novo without the need for a precursor template DNA. To obtain the desired oligonucleotide, the building blocks are sequentially coupled to the growing oligonucleotide chain in the order required by the product sequence. After completion of chain assembly, the product is released from the solid phase into solution, deprotected, and collected. The product can be isolated by high performance liquid chromatography (HPLC) to obtain the desired oligonucleotide in high purity.

[0189] Expression vectors include, for example, plasmids, retroviruses, cosmids, yeast artificial chromosomes (YACs) and episomes derived from Epstein-Barr Virus (EBV). A polynucleotide is ligated into a vector such that transcriptional and translational control sequences within the vector perform their intended function of regulating the transcription and translation of the polynucleotide. Expression and / or control sequences can include promoters, enhancers, transcription terminators, a start codon (i.e., ATG) 5' to the coding sequence, splicing signals for introns, and stop codons. Expression vectors and expression control sequences are selected to be compatible with the expression host cell used. Thus, the present invention further provides a nucleotide sequence encoding a polypeptide of the present invention comprising a VH region and a VL region joined by a synthetic linker (encoding SEQ ID NO:69). It is understood that a polynucleotide or expression vector of the present invention can include a VH region, a VL region, or both (optionally including a linker). Thus, polynucleotides encoding the VH and VL regions can be inserted into separate vectors; alternatively, sequences encoding both regions are inserted into the same expression vector. The polynucleotide(s) are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the polynucleotide and vector, or blunt end ligation if no restriction sites are present).

[0190] A convenient vector is one that encodes a functionally complete CH and / or CL immunoglobulin sequence, with appropriate restriction sites engineered so that any VH or VL sequence can be easily inserted and expressed, as described herein. The expression vector may also encode a signal peptide that facilitates secretion of the polypeptide from the host cell. The polynucleotide may be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the polypeptide. The signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).

[0191] In one aspect of the present invention, a cell (e.g., a host cell) is provided that comprises a polynucleotide or expression vector as defined herein. It is understood that the cell may comprise a first vector encoding a light chain of the polypeptide and a second vector encoding a heavy chain of the polypeptide. Alternatively, both the heavy and light chains may be encoded in the same expression vector that is introduced into the cell.

[0192] In one embodiment, the polynucleotide or expression vector encodes a membrane anchor or transmembrane domain fused to a polypeptide, such that the polypeptide is displayed on the extracellular surface of the cell.

[0193] Transformation can be carried out by any known method for introducing polynucleotides into host cells. Methods for the introduction of heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, electroporation, transduction, encapsulation of polynucleotide(s) in liposomes, biolistic injection of DNA into nuclei, and direct microinjection. In addition, nucleic acid molecules can be introduced into mammalian cells by viral vectors.

[0194] Mammalian cell lines available as hosts for expression are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC). Such cell lines include, among others, Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells, and many other cell lines. Mammalian host cells include human, mouse, rat, dog, monkey, pig, goat, cow, horse, and hamster cells. A cell line of particular preference is selected by determining which cell line has a high expression level. Other cell lines that may be used are insect cell lines, e.g., Sf9 cells, amphibian cells, bacterial cells, plant cells, and fungal cells. Antigen-binding fragments of antibodies, such as scFv and Fv fragments, can be isolated and expressed in E. coli using methods known in the art.

[0195] The polypeptide is produced by culturing the host cells for a period of time sufficient to allow for expression of the polypeptide in the host cells, or more preferably, secretion of the polypeptide into the culture medium that the host cells are grown in. The polypeptide may be recovered from the culture medium using standard protein purification methods.

[0196] The polypeptides of the present invention can be obtained and manipulated using, for example, the techniques disclosed in Green and Sambrook, Molecular Cloning: A Laboratory Manual (2012) 4th Edition Cold Spring Harbour Laboratory Press.

[0197] Monoclonal antibodies can be produced using hybridoma technology by fusing specific antibody-producing B cells with myeloma (B cell cancer) cells, selected for their ability to grow in tissue culture and the absence of antibody chain synthesis.

[0198] Monoclonal antibodies against the determined antigens can be, for example, a) immortalizing lymphocytes obtained from the peripheral blood of an animal previously immunized with a determined antigen with immortal cells, preferably myeloma cells, to form hybridomas; b) culturing the formed immortalized cells (hybridomas) and recovering cells that produce antibodies with the desired specificity; can be obtained by:

[0199] Alternatively, the use of hybridoma cells is not required. Antibodies capable of binding to the target antigens described herein can be routinely isolated from suitable antibody libraries using, for example, phage display, yeast display, ribosome display or mammalian display techniques known in the art. Thus, monoclonal antibodies can be isolated, for example, from a) cloning a DNA or cDNA sequence obtained from lymphocytes, in particular peripheral blood lymphocytes, of an animal (preferably previously immunized with a determined antigen) into a vector, in particular a phage, more particularly a filamentous bacteriophage; b) transforming a prokaryotic cell with the vector described above under conditions allowing the production of the antibody; c) selecting the antibodies by subjecting them to antigen affinity selection; d) recovering antibodies having the desired specificity The composition can be obtained by a process comprising:

[0200] Optionally, isolated polynucleotides encoding the polypeptides described herein that bind to LPAR1 may be easily manufactured to produce sufficient quantities to be used as a medicine to ameliorate signs or symptoms of a disease. When used as a medicine in this manner, typically the polynucleotide of interest is first operably linked to an expression vector or expression cassette designed to express the antibody or fragment thereof in a subject or patient. Such expression cassettes and methods of delivery of polynucleotides, or what are sometimes termed "nucleic acid-based" medicines, are well known in the art. For a recent review, see Hollevoet and Declerck (2017).

[0201] Also provided is a method for the production of a polypeptide, an anti-LPAR1 antibody, or a fragment or variant thereof, comprising culturing a host cell of the present invention in a cell culture medium under conditions for expressing the coding nucleic acid sequence of a plasmid or vector inside the cell. The method can further comprise obtaining the polypeptide, the anti-LPAR1 antibody, or a fragment or variant thereof from the cell culture supernatant. The obtained antigen-binding molecule can then be formulated into a pharmaceutical composition. Further provided is a method for producing a cell expressing a polypeptide, an anti-LPAR1 antibody, or a fragment or variant thereof, comprising transfecting the cell with a plasmid or vector of the present invention. The cell can then be cultured for the production of the polypeptide, the anti-LPAR1 antibody, or a fragment or variant thereof.

[0202] Lysophosphatidic acid receptor 1 (LPAR1) Lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA) belongs to a family of endogenous lipid molecules that exert their effects through interaction with the LPA family of G protein-coupled receptors (GPCRs), of which there are currently six identified receptor subtypes. LPAR1-3 receptors belong to the endothelial differentiation gene (EDG) family GPCRs, whereas LPAR4-6 receptors are closely related to the purinergic family GPCRs. LPAR1 receptors predominantly signal through Gi / o to inhibit cAMP production and through Gq / 11 to promote calcium mobilization, but also signal through G12 / 13 to activate Rho GTPase nucleotide exchange factors (GEFs).

[0203] LPAR1 is also called LPA-1, LPA receptor 1, lysophosphatidic acid receptor 1, or lysophosphatidic acid receptor Edg-2.

[0204] The crystal structure of LPAR1 was solved in 2015 (Chrencik et al. 2015). It displays many of the features typical of family A GPCRs, with seven transmembrane helices, with 94 of a total of 364 amino acids facing the extracellular solvent. It includes an N-terminal region 50 amino acids long. Uniquely, however, the N-terminus folds over a seven-helix bundle to form a helical cap on the extracellular side that almost completely occludes the ligand-binding site and buries the ligand. Human LPAR1 shares 99%, 99%, 97% and 97% amino acid identity with its orthologues in cynomolgus monkey, rhesus monkey, mouse and rat, respectively.

[0205] The extracellular region of LPAR1 comprises extracellular domains 0-3 (ECD0-ECD3). In the N-terminal region, ECD0, residues 25-50 of SEQ ID NO:62 form a unique capping helix that is held in place by a disulfide bridge between ECD0 and ECD2. With reference to SEQ ID NO:62, the entire N-terminus is residues 1-50, the N-terminal capping helix is ​​residues 25-50, the entire ECD1 is residues 106-121, the entire ECD2 is residues 185-204, and the entire ECD3 is residues 280-294.

[0206] In one embodiment, LPAR1 is human LPAR1. In one embodiment, LPAR1 is not human LPAR1. LPAR1 can be native LPAR1 and / or full-length LPAR1. Alternatively, LPAR1 is a fragment of LPAR1, for example, a fragment comprising one or more extracellular regions of LPAR1. In certain embodiments, the fragment of LPAR1 is at least 50 amino acids long, for example, at least 100 amino acids long, for example, at least 150 amino acids long, for example, at least 200 amino acids long, for example, at least 250 amino acids long, for example, at least 300 amino acids long, for example, at least 350 amino acids long.

[0207] Suitably, LPAR1 comprises or consists of a sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99% identity to SEQ ID NO: 62, SEQ ID NO: 63 or SEQ ID NO: 64. More suitably, LPAR1 comprises or consists of SEQ ID NO: 62, SEQ ID NO: 63 or SEQ ID NO: 64.

[0208] In one embodiment, LPAR1 is functionally active LPAR1. "Functionally active" means that LPAR1 can signal through downstream signaling pathways (e.g., cAMP, Ca mobilization). Binding of LPA to functionally active LPAR1 results in the transmission of downstream signals, and / or functionally active LPAR1 maintains a constitutive level of downstream signaling. Functionally inactive LPAR1 cannot initiate signaling.

[0209] In a further embodiment, LPAR1 is localized on the extracellular surface.In a further embodiment, LPAR1 is present on the surface of living cells.In a further embodiment, the polypeptide is an antagonist of LPAR1.In a further embodiment, the polypeptide is an antagonist of LPA-mediated signal transduction.

[0210] composition In a further aspect of the present invention, compositions are provided that include the polypeptide or construct as defined herein. In such embodiments, the composition may include the polypeptide or construct, optionally in combination with other excipients. Also included are compositions that include one or more additional active agents, such as active agents suitable for treating the diseases referred to herein.

[0211] In a further aspect of the present invention, a pharmaceutical composition is provided comprising a polypeptide or construct as defined herein together with a pharma- ceutically acceptable diluent or carrier. The polypeptide or construct of the present invention may be incorporated into a pharmaceutical composition suitable for administration to a subject. Typically, a pharmaceutical composition comprises a polypeptide or construct of the present invention and a pharma- ceutically acceptable carrier. As used herein, a "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are physiologically compatible. Examples of pharma- ceutically acceptable carriers include one or more of water, saline, salts, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In many cases, it is preferred to include an isotonic agent, such as a sugar, a polyalcohol, such as mannitol, sorbitol, or sodium chloride, in the composition. Pharmaceutically acceptable substances that enhance the shelf life or effectiveness of the polypeptide may be included, such as wetting agents or minor amounts of auxiliary substances, such as wetting agents or emulsifying agents, preservatives or buffers.

[0212] The compositions of the present invention can be in various forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. A typical preferred composition is in the form of an injectable or infusible solution.

[0213] The preferred mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, administration is by intravenous infusion or injection. In another preferred embodiment, administration is by intramuscular or subcutaneous injection.

[0214] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, dispersion, liposomes, or other ordered structures suitable to high drug concentration.

[0215] It is within the scope of the present invention to use the pharmaceutical compositions of the present invention in therapeutic methods for the treatment of the diseases described herein, as an adjunct or in conjunction with other established therapies commonly used in the treatment of such diseases.

[0216] In a further aspect of the invention, the polypeptide, composition or pharmaceutical composition is administered sequentially, simultaneously or separately with at least one active agent.

[0217] treatment Chronic kidney disease / diabetic kidney disease (CKD / DKD) Chronic kidney disease (CKD) can be caused by many factors, including diabetes, and 25-55% of all dialysis patients worldwide have diabetic kidney disease. CKD is characterized by a gradual loss of kidney function. Clinically, it is initially diagnosed by an estimated glomerular filtration rate (eGRF) of <60 mL / min (eGFR in healthy adults is >90 mL / min). The presence of protein in the urine (proteinuria) is an indicator of kidney damage and a prognostic sign of worsening eGFR.

[0218] LPAR1 inhibitors have not yet been investigated in human renal disease. Three published studies examine the effect of LPAR1 (or LPAR1 and LPAR3) inhibition on renal function in three separate models (Zhang et al. (2017), Li et al. (2017) & Lee JH et al. (2019)). All three studies found a reduction in albuminuria and renal fibrosis and inflammation. Various components of the LPAR1 signaling pathway were found to be upregulated in different forms of renal disease.

[0219] When CKD is accompanied by and caused by diabetes, it is known as diabetic kidney disease (DKD).

[0220] Although LPAR1 inhibitors have not been previously trialed in the treatment of DKD, there is significant evidence linking LPAR1 biology to clinical disease. LPAR1 plays a role in a variety of biological pathways and diseases, including neuropathic pain, bone growth, and cancer, but has special importance in three biological axes that are at the heart of kidney disease; fibrosis, inflammation, and metabolic syndrome. These three axes exert specific and measurable changes to the levels of numerous biochemicals found in blood and urine. These are consistent with molecules found to be modulated by LPAR1 inhibition in phase II studies (Palmer et al. 2018) and various animal studies.

[0221] LPAR1 genetic knockout or pharmacological inhibition was protective in multiple models of mouse renal fibrosis (Zhang et al., 2017; Prader et al., 2007; Swaney et al. 2011). A phase II efficacy trial in idiopathic pulmonary fibrosis (Palmer et al. 2018) showed that a small molecule inhibitor of LPAR1 was effective in preserving forced vital capacity over the study period.

[0222] LPAR1 plays a role in the induction of inflammation. Addition of LPA to whole blood induces LPAR1-mediated histamine release (Swaney et al. 2010). In mice with vasculitis, recruitment of neutrophils to the vessel wall for inflammation depended on LPAR1 expression in neutrophils (Miyabe et al. 2019).

[0223] Increased signaling through the LPA / LPAR1 axis has been implicated in metabolic syndrome and cardiovascular health. Li et al. 2017 found that LPAR1 was selectively upregulated in mouse kidney mesenchymal cell lines after exposure to high glucose concentrations. Rancoule et al. 2013 found that mice treated with an LPAR1 / 3 inhibitor for 3 weeks had improved tolerance to ip injections of glucose. Guo et al. (2013) found that administration of exogenous adiponectin to db / db mice significantly reduced albuminuria and histological evidence of renal fibrosis.

[0224] Three studies have been published examining the effects of LPAR1 (or LPAR1 and LPAR3) inhibition on renal function (Zhang et al. 2017, Li et al. 2017, Lee JH et al. 2019), which are summarized in Table 8.

[0225] [Table 10]

[0226] All three studies found a reduction in albuminuria, renal fibrosis and inflammation.

[0227] Conversely, upregulation of components of the LPAR1 signaling pathway was found in different forms of renal disease. Zhang et al. 2017 observed increased levels of autotaxin and LPAR1 in the kidneys of diabetic patients. Sasagawa et al. 1998 observed a 2.6-fold increase in lysophosphatidic acid levels in the plasma of patients with renal failure compared to controls.

[0228] Peritoneal fibrosis Sakai et al. 2013 showed that genetic deletion or pharmacological inhibition of LPAR1 protected mice from fibrosis in response to CG peritoneal injury.

[0229] Liver fibrosis In a mouse model of NASH, treatment with an LPAR1 antagonist showed a strong reduction in the expression of fibrotic and inflammatory genes (Nishikawa et al. 2016). A correlation between the degree of liver fibrosis and plasma LPA levels was shown in response to chronic liver injury in an in vivo mouse study (Watanabe et al. 2007).

[0230] Idiopathic pulmonary fibrosis (IPF) As previously described, a phase II clinical trial of IPF showed that a small molecule inhibitor of LPAR1 was effective in treating lung fibrosis (Palmer et al. 2018). Furthermore, an in vivo mouse study using LPAR1-deficient mice found that LPAR1 deficiency protected mice from fibrosis and mortality after lung injury (Tager et al. 2007).

[0231] Skin fibrosis Using a mouse model of bleomycin-induced skin fibrosis, LPAR1 knockout mice were found to be resistant to bleomycin-induced increases in skin thickness and collagen (Castelino et al. 2011).

[0232] systemic sclerosis Mass spectrometry analysis of serum from systemic sclerosis patients found elevated levels of 2-arachidonoyl-LPA (Tokumura et al. 2009).

[0233] Osteoarthritis Treatment with an LPAR1 antagonist caused reduced synovial inflammation, cartilage damage and bone erosion in mice (Orosa et al. 2014).

[0234] In a further aspect of the invention there is provided a polypeptide, construct or composition as defined herein for use as a medicament.

[0235] In one embodiment, the polypeptide, construct or composition is for use in therapy, in particular for use in the treatment of inflammatory and / or fibrotic diseases or cancer. Suitably, the polypeptide, construct or composition is for use in the treatment of inflammatory and / or fibrotic diseases. Suitably, the polypeptide, construct or composition is for use in the treatment of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis or osteoarthritis. Suitably, the polypeptide is for use in the treatment of chronic kidney disease, for example diabetic kidney disease. Alternatively, the polypeptide, construct or composition is for use in the treatment of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis, osteoarthritis, NASH, rheumatoid arthritis, neuropathic pain or cancer.

[0236] In a further embodiment, a method is provided for treating a disease in a subject in need thereof, comprising administering a polypeptide, construct or composition as defined herein. In a further embodiment, a method is provided for treating an inflammatory disease and / or a fibrotic disease in a subject in need thereof, comprising administering a polypeptide, construct or composition as defined herein. In a further embodiment, a method is provided for treating chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis or osteoarthritis, comprising administering a polypeptide, construct or composition as defined herein. In a further embodiment, a method is provided for treating chronic kidney disease, e.g. diabetic kidney disease, comprising administering a polypeptide, construct or composition as defined herein. Instead, there is provided a method of treating chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis, osteoarthritis, NASH, rheumatoid arthritis, neuropathic pain or cancer, comprising the step of administering a polypeptide, construct or composition as defined herein.

[0237] In a further aspect of the present invention, there is provided the use of a polypeptide, construct or composition as defined herein for the manufacture of a medicament for the treatment of a disease. In a further aspect of the present invention, there is provided the use of a polypeptide, construct or composition as defined herein for the manufacture of a medicament for the treatment of an inflammatory disease and / or a fibrotic disease. In a further embodiment, there is provided the use of a polypeptide, construct or composition as defined herein for the manufacture of a medicament for the treatment of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis or osteoarthritis. In a further embodiment, there is provided the use of a polypeptide, construct or composition as defined herein for the manufacture of a medicament for the treatment of chronic kidney disease, for example diabetic kidney disease. Alternatively, there is provided the use of a polypeptide, construct or composition as defined herein for the manufacture of a medicament for the treatment of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis, osteoarthritis, NASH, rheumatoid arthritis, neuropathic pain or cancer.

[0238] In one embodiment, the polypeptide, construct or composition is administered in a therapeutically effective amount.

[0239] The present invention will now be further illustrated by the following non-limiting examples. EXAMPLES

[0240] [Example 1] Method 1.1 Immunization Protocol Mice were immunized with LPAR1. After immunization, spleens were dissected and homogenized in DMEM as described by Forbes et al. (2011). After lysis of red blood cells and pelleting of splenocytes, splenocytes were resuspended in 1.5 mL FBS and refrigerated for 10 min, followed by addition of 1.5 mL 20% DMSO in FBS. The suspended cells were then aliquoted into cryovials and frozen at a rate of -1°C / min.

[0241] 1.2 Hybridoma isolation Cryogenically frozen splenocytes from immunized mice were thawed and fused with sp2 / 0 myeloma cells using polyethylene glycol to generate hybridomas. Hybridomas were then plated in methylcellulose medium gels and productive hybridomas were selected using HAT (hypoxanthine-aminopterin-thymidine) reagent. After 5 days, IgG-producing hybridoma colonies were identified using CloneDetect reagent (Molecular Devices) and subsequently picked and seeded into monoclonal cultures. LPAR1-reactive hybridomas were identified by screening culture supernatants for differential binding to LPAR1-expressing cells in a FACS assay. Briefly, CHO cells were transiently transfected with plasmids to express either LPAR1 or an unrelated GPCR, and 2 days after transfection of the CHO cells, hybridoma supernatants were mixed with both populations of CHO cells. Antibody binding to the cells was detected using an anti-mouse IgG secondary antibody. Hybridoma supernatants that bound to CHO-LPAR1 cells but not to CHO-unrelated GPCR cells were defined as LPAR1 binders.

[0242] 1.3 Isolation of Ig genes from hybridomas 10 6 LPAR1-specific hybridoma cells were subjected to total RNA extraction and reverse transcription to generate a total cDNA library. Next-generation sequencing of the total cDNA library was performed on an Illumina HiSeq sequencer. Contig assembly was performed to search for DNA sequences encoding the VH or VL sequences of the antibody.

[0243] 1.4 Construction of recombinant vectors DNA fragments of the VH or VL regions were cloned into human IgG1 heavy chain or human kappa light chain expression vectors using the overhang cloning method. Variable region sequences were optimized for human (Homo Sapiens) and cloned into the vector via 5'BspEI and 3'Bsal or via 5'BssHII and 3'Apal. Mini-scale DNA samples were reconstituted in cell culture grade water to 100ng / μL. Plasmids were stored at -20°C until required for transfection.

[0244] 1.5 Antibody Expression For antibody expression, HEK293 cells were cultured at 37°C in 8% CO2, and 2 × 10 cells were added. 6 Cells were seeded at a density of 100x. Heavy and light chain plasmids were transiently co-transfected into HEK293 cells. Enhancers were added 18-22 hours post-transfection. Supernatants were harvested 5 days post-transfection. Cells were pelleted by centrifugation at 1000g for 10 minutes and the supernatants were aliquoted into appropriate sterile plastic containers.

[0245] 1.6 Antibody purification Recombinantly expressed human antibodies were purified from cell culture supernatants using a Protein A, 5 mL gravity flow column. Prior to loading the sample, the column was equilibrated with Protein A IgG binding buffer, pH 8.0. The cell culture supernatant was clarified using a 0.45 μM filter and mixed 1:1 with Protein A IgG binding buffer, pH 8.0. After passing the sample through the column, the flow-through was collected and then passed through the column five times. The column was washed with PBS and 0.5 M L-arginine buffer, pH 7. The antibodies were eluted from the column into 1 M Tris-HCl, pH 8.0 using IgG elution buffer, pH 2.8. The eluted sample was buffer exchanged into PBS using a centrifugal filter unit and sterile filtered using a 0.2 μM centrifuge tube filter. The purified antibodies were stored in PBS at 4°C.

[0246] 1.7 HTRF cAMP assay cAMP Hunter™ CHO-K1 EDG2 Gi / Gq cells (DiscoverX) were seeded in 384-well white plates at 3000 cells per 25 μL of complete growth medium and incubated at 37° C. for 24 hours. The next day, cells were subjected to serum deprivation for 4 hours at 37° C. After serum deprivation, the medium was discarded and replaced with 5 μL of cell assay buffer (HBSS+0.1% (w / v) BSA+20 mM HEPES). Cells were stimulated with various concentrations of human antibodies or human antibody-containing supernatants and incubated for 15 minutes at 37° C. After preincubation, cells were stimulated with LPA (0.5 μM) and forskolin (5 μM) and incubated for 1 hour at 37° C. cAMP-cryptate and anti-cAMP-d2 working solutions were prepared in lysis and detection buffer according to the manufacturer's protocol and added to all wells of the plate. After incubation in the dark for 1 h at room temperature, the plate was read on a plate reader. cAMP concentrations were measured by applying the 620 / 665 nm fluorescence ratio to a standard curve of known cAMP concentrations using Prism 5 (GraphPad Software, CA, USA).

[0247] 1.8 Calcium mobilization assay Human lung fibroblasts were seeded in 384-well plates at 8000 cells per well in 50 μL of complete growth medium and incubated at 37°C for 24 hours. The next day the medium was changed to serum-free and incubated at 37°C for 24 hours. After serum removal, the medium was replaced with Fluo-4 no wash dye (Molecular Devices) diluted in buffer (HBSS, pH 7.4 supplemented with 20 mM HEPES, 2.5 mM probenecid, 0.1% (w / v) BSA) and equilibrated at 37°C for 45 minutes. The plate was transferred to the FLIPR for calcium mobilization assay. Human antibodies or human antibody-containing supernatants at various concentrations were delivered to the plate for 120 seconds with recording and incubated at 37°C for 20 minutes. After preincubation, an EC80 concentration of ligand (100 nM LPA) was delivered online for 120 seconds with recording. Data were collected in ScreenWorks version 3.2 (Molecular Devices) and relative fluorescence units (RFU) were plotted against the logarithm of compound concentration using nonlinear regression analysis in Prism 5 (GraphPad Software, CA, USA).

[0248] 1.9 HPF BrdU incorporation assay Human lung fibroblasts were seeded in 384-well Blackview plates at 1500 cells / well in 35 μL of assay medium (RPMI 1640 + 2 mM L-glutamine + 0.1% (w / v) HSA + penicillin-streptomycin). Cells were incubated for 24 h at 37°C. The next day cells were stimulated with various concentrations of human antibodies and incubated for 30 min at 37°C. After preincubation cells were stimulated with LPA (10 μM) and incubated for 8 h at 37°C. Reagents from the Perkin Elmer DELFIA cell proliferation kit were used in the following steps. Cells were treated with 10 μM BrdU labeling solution and incubated for 16 h at 37°C. After 16 h of BrdU incorporation the medium was removed and cells were fixed. After washing, anti-BrdU-EU working solution was added to the plates and incubated for an additional 2 h at room temperature. After further washing, DELFIA inducer solution was added to all wells of the plate, followed by shaking incubation at room temperature for 20 min. Time-resolved fluorescence was measured using a BMG LABTECH ClarioStar plate reader. Background levels of RFU were subtracted from the raw RFU values ​​detected in each well, and concentration-response curves were fitted using a four-parameter logistic equation in Prism 5 (GraphPad Software, CA, USA).

[0249] 1.10 HPF / HKF migration assay Human lung or human kidney fibroblasts were grown to 80% confluence in complete growth medium in cell culture flasks. Prior to the experiment, the medium was replaced with serum-free and the cells were incubated at 37°C for 24 h. The lower membrane of the 96-well transwell chambers (5 μM) was coated with 6.6 μg / mL fibronectin (diluted in water supplemented with 20 mM HEPES) and air-dried overnight under sterile conditions. The next day, the opposite side of the chemotaxis membrane was coated with 6.6 μg / mL fibronectin as described above. Assay buffer containing chemoattractant (LPA) was added to the lower chamber of the plate, which was then dried and a fibronectin-coated pore size 5 μM membrane was placed on top. Growth-arrested fibroblasts were detached, washed, and resuspended in RPMI 1640 + 0.1% (w / v) BSA, followed by incubation at 1 × 10 cells. 5 1000 / well were loaded into the upper chamber. Human antibodies were diluted in assay buffer (RPMI 1640 + 0.1% (w / v) BSA) and added to the cell suspension in the upper chamber. After 24 h of incubation at 37 °C, fibroblasts on the upper side of the membrane were removed with a fine-tipped cotton swab so that only cells that had migrated through the membrane remained. The membrane was fixed with 100% methanol for 10 min, stained with DAPI for 10 min, and rinsed with distilled water. The membrane chamber was mounted in a clear plastic fixture and cells on the lower side were counted using a fluorescent microscope at 10x magnification and images were taken.

[0250] 1.11 Transient transfection of CIFAT CHO-K1 cells were seeded in clear 96-well plates at 20,000 cells per 200 μL of complete growth medium and incubated at 37° C. for 24 hours. The next day, 0.0309 μL / well of PEI (Generon, MW 160,000) was diluted in 10 μL / well of transfection medium (DMEM supplemented with 2 mM L-glutamine and penicillin-streptomycin) in a sterile tube. The diluted PEI was added to 100 ng / well of DNA encoding the target protein (human LPAR1 (SEQ ID NO: 62) unless otherwise noted), followed by immediate vortexing and incubation of the mixture at room temperature for 10 minutes. 200 μL / well of complete growth medium was added to the PEI-DNA mixture, followed by removal of the medium in the wells and addition of 200 μL of the complete growth medium / PEI / DNA mixture to the wells of the adherent cell plate. The plate was incubated at 37° C. for 24 hours. The next day the medium was discarded and replaced with 200 μL of complete growth medium. The plates were incubated at 37° C. for 24 hours. The next day the medium was removed from the wells and the cells were incubated with various concentrations of primary antibodies for 75 minutes at 37° C. After washing and cell fixation with 4% PFA, antibody binding was detected using a goat anti-human Alexa Fluor 488 detection antibody (Invitrogen) and incubated for 1 hour at room temperature. Fluorescence at 488 nm was measured using a BMG LABTECH ClarioStar plate reader and microscopic images were taken at 10x magnification.

[0251] 1.12 Stable cell CIFAT CHO-LPAR1 and CHO-CXCR2 cells were seeded in a black 96-well plate at a ratio of 2:23, totaling 50,000 cells / 200 μL complete growth medium. Cells were incubated for 24 hours at 37°C. The next day, medium was removed from the wells and cells were incubated with various concentrations of primary antibodies for 75 minutes at 37°C. After washing and cell fixation with 4% PFA, antibody binding was detected using a goat anti-human Alexa Fluor 488 detection antibody (Invitrogen) and incubated for 1 hour at room temperature. Fluorescence at 488 nm was measured using a BMG LABTECH ClarioStar plate reader and microscopic images were taken at 10x magnification.

[0252] 1.13 Competitive CIFAT CHO-LPAR1 (GenScript) cells were seeded at 50,000 cells / 200 μL complete growth medium into black 96-well plates and incubated at 37°C for 24 hours. The next day, medium was removed from the wells and cells were incubated with 100 μg / mL primary antibody for 20 minutes at 37°C. After preincubation with the antibody, 10 μg / mL biotinylated competing antibody was added followed by incubation at 37°C for 20 minutes. After washing and cell fixation with 4% PFA, antibody binding was detected using Alexa Fluor 488 streptavidin detection antibody (Molecular Probes) and incubated at 4°C for 45 minutes. Fluorescence at 488 nm was measured using a BMG LABTECH ClarioStar plate reader and microscopic images were taken at 10x magnification.

[0253] 1.14K D Measurement Monomeric affinity constant K for antibody interaction with LPAR1 D was measured using the KinExA method, using monomeric Fab derived from the antibody, which measures the concentration of unbound antibody over a range of antigen concentrations. D = ([free antigen][free antibody]) / [antigen-antibody complex], so from these measurements, K DThe value of can be estimated. The source of antigen, CHO-LPAR1 cells, is titrated in a background of a constant binding partner (CBP, e.g., the Fab to be tested). The sample is gently shaken until equilibrium is reached. After incubation, the cells are centrifuged and the free CBP is removed without disturbing the cell pellet. A portion of the free CBP is captured using beads coated with Anti-Species. The captured CBP is detected by fluorescently labeled anti-CBP using KinExA. The fluorescent signal is converted to a voltage signal that is directly proportional to the concentration of free CBP in the equilibrated sample.

[0254] In this application D Values ​​are provided using antibodies in Fab format.

[0255] 1.15 BRET assay HEK293 cells were co-transfected in suspension with hLPAR1 and one of the following biosensors: G protein activation sensors (Gαi2, Gα13, and Gαq) and β-arrestin2-PM recruitment biosensor (+GRK2) using a 3:1 ratio of polyethyleneimine (PEI) transfection agent. Immediately after transfection, cells were seeded directly into 96-well plates at a density of 35,000 cells / well. 48 hours after transfection, BRET experiments were performed in both agonist and allosteric / antagonist modes. Culture medium was aspirated and replaced with 30 μl of Hank's Balanced Salt Solution Buffer (HBSS) using a plate washer. Plates were equilibrated for 60 minutes at room temperature. For agonist testing, serial dilutions of antibodies were made in PBS and subsequently added to each well. Antibodies were assayed at 12 concentrations in technical replicates. Small molecules were added to each relevant well. Small molecules were assayed at 22 concentrations with each biosensor. Cells were then incubated with antibody or small molecule for 60 or 10 minutes, respectively, at room temperature. 10 μL of 10 μM e-coelenterazine Prolume Purple (Nanolight) was then added to each well. Cells were incubated for an additional 10 minutes at room temperature. BRET readings were then collected with a plate reader (filters: 400 nm / 70 nm, 515 nm / 20 nm) with an integration time of 0.4 seconds. For allosteric testing (after agonist testing), the EC75 of the endogenous ligand (oleoyl-LPA) was added to each well already containing antibody or small molecule. Cells were incubated for an additional 10 minutes at room temperature. BRET readings were then collected with a plate reader (filters: 400 nm / 70 nm, 515 nm / 20 nm) with an integration time of 0.4 seconds. The BRET signal was determined by calculating the ratio of the light emitted by the GFP acceptor (515 nm) to the light emitted by the luciferase donor (400 nm). All BRET ratios were normalized using pre-established BRET values ​​for positive and negative controls. The normalized BRET ratio is referred to as universal BRET (uBRET).The resulting dose-response curves were fitted using a three-parameter or four-parameter logistic nonlinear regression model in GraphPad Prism 9.

[0256] 1.16 Pharmacokinetics in rats Pharmacokinetic studies in rats were performed using male Sprague Dawley rats (275-325 g). Rats were administered the test antibody as an IV slow bolus. Blood samples were collected at the following time points: pre-dose, 2 min, 1 h, 3 h, 6 h, 24 h, 48 h, 96 h, 7 days, 14 days, and 21 days after dosing. For each animal and each blood sample collection, 200 μL of venous blood was collected from the sublingual vein under isoflurane anesthesia into a K2EDTA vial. Blood samples were mixed gently, immediately placed on crushed ice, and centrifuged at approximately 1500×g for approximately 10 min at approximately 4°C within 30 min of sample collection. For each blood sample, the resulting plasma was divided into two 30 μL aliquots and transferred using disposable plastic utensils into polypropylene tubes with conical bottoms and stored at −80°C until analysis by capture ELISA. Plates were coated overnight with 1 μg / mL capture IgG, washed, and blocked the next morning with 3% (w / v) milk for 2 h. Plasma dilutions were incubated on the plates for 2 h at room temperature. Plates were washed with PBS+0.05% tween 20 (PBST) and then incubated with anti-human Fc HRP-conjugated secondary detection antibody (1:5000 in PBST) for 1 h at room temperature. After washing, wells were incubated with TMB substrate for 15 min at room temperature, followed by the addition of 1 M sulfuric acid. Absorbance was measured at 450 nm in a plate reader. Antibody concentrations were calculated using interpolation from standard curves constructed for each test IgG in Prism 5 (GraphPad Software, CA, USA). Interpolated data were analyzed using Phoenix WinNonlin® version 8.1 (Certara USA, Inc., Princeton, NJ) to extract relevant PK parameters.

[0257] [Example 2] Identification of anti-LPAR1 antibodies, determination of germline sequences, and identification of clonally related hybridomas Mice were immunized as described in Example 1.1. Hybridomas producing antibodies specific to LPAR1 were isolated as described in Example 1.2. The sequence of the antibody against LPAR1 produced by the hybridoma was determined using the method of Example 1.3 (Antibody 1). The variable domains of Antibody 1 were sequenced. The sequences are shown in SEQ ID NOs: 23 (VH) and 24 (VL).

[0258] The sequence of Antibody 1 was analyzed to deduce the mouse germline sequence from which the antibody was derived (SEQ ID NO: 25 (VH) and 26 (VL), Antibody 2). Antibody 2 was produced and expressed, and then tested for LPAR1 binding affinity. Antibody 2 had very low binding affinity to LPAR1.

[0259] Subsequently, Antibody 3 was designed, whose variable regions consisted of the CDR regions of Antibody 1 and the framework regions of Antibody 2, as shown in SEQ ID NOs: 27 (VH) and 28 (VL).

[0260] Hybridomas related to Antibody 1 were identified, which were also derived from the mouse germline sequence of Antibody 2. One such hybridoma was Antibody 4 (SEQ ID NOs: 29 (VH) and 30 (VL)), which contains a mutation in LCDR3 (Q90H) that is not present in Antibody 1.

[0261] The VL domain of Antibody 3 was subsequently altered to contain a Q90H mutation (Antibody 5, SEQ ID NOs: 27 (VH) and 31 (VL)). This antibody had improved affinity and expression compared to the original Antibody 1 clone.

[0262] An additional hybridoma was also isolated that produces an antibody specific to LPAR1. The sequence of this additional antibody (63D8) was determined using the method of Example 1.3. The VH and VL sequences of the antibody are shown in SEQ ID NO: 113 (63D8 VH) and 114 (63D8 VL).

[0263] All antibodies referred to herein contained a human kappa light chain constant region and an IgG1 heavy chain constant region (unless otherwise noted). For some antibodies, silencing mutations were introduced within the Fc region and / or IgG2 or IgG4 subtypes were created.

[0264] Example 3: Humanization and affinity maturation Several humanized variants of Antibody 1 were generated, of which Antibody 7 (SEQ ID NO: 33 (VH) and 34 (VL)) was the best in terms of expression, stability and function. The sequence of an alternative variant Antibody 14 (SEQ ID NO: 96 (14 VH) and 97 (14 VL)) is also provided.

[0265] Mutant versions of antibody 5 were generated in which each residue in the CDR predicted to be the product of somatic mutation was reverted to the corresponding mouse germline residue. In most cases, reversion of these residues was found to be detrimental to the high affinity binding properties of antibody 5. The exception was a mutation in LCDR3, where reversion to serine (N93S) resulted in a large affinity gain (antibody 6, SEQ ID NOs: 27 (VH) and 32 (VL)).

[0266] One version of Antibody 7 was generated (Antibody 8, SEQ ID NOs: 33 (VH) and 39 (VL)) that contains two light chain mutations Q90H and N93S.

[0267] Residue E61 in HCDR2 of antibody 8 was diversified to all amino acids except cysteine. Mutation E61Q was found to significantly enhance function (Antibody 9, SEQ ID NOs: 35 (VH) and 39 (VL)).

[0268] In parallel, phage display of antibody 3 was performed to randomize HCDR3. Two HCDR3 sequences were found (antibody 10, SEQ ID NO: 36 (VH) and 39 (VL) and antibody 11, SEQ ID NO: 37 (VH) and 39 (VL)). It was found that the total charge of the heavy chain in antibodies 10 and 11 was increased by 2 compared to antibody 3. To eliminate the risk of non-specific interactions caused by this high positive charge, a mutation in LCDR2 (T56D) was made (antibody 12, SEQ ID NO: 36 (VH) and 38 (VL) and antibody 13, SEQ ID NO: 37 (VH) and 38 (VL)). Antibodies 12 and 13 reduced the tendency for non-specific interactions with minimal impact on affinity.

[0269] [Example 4] Investigation of Antibody 12 Further experiments were performed on antibody 12.

[0270] Antibody 12 was expressed according to method 1.5. Expression levels were compared to adalimumab biosimilar (Figure 1A). The ability of antibody 12 to bind to huLPAR1-HA cells was assessed using a transient transfection CIFAT assay (method 1.11). The results are shown in Figure 1B. The ability of antibody 12 to increase cAMP signaling, inhibit calcium signaling, and decrease cell proliferation was examined using methods 1.7, 1.8, and 1.9. The results are shown in Figure 1C-E. The K D was measured using Method 1.14. Antibody 12 has a K of 1.28 nm D It was found to have the following structure:

[0271] [Example 5] Investigation of Antibody 13 The experiments described in Example 4 were also performed for antibody 13. The results are shown in Figures 2A (expression levels compared to adalimumab biosimilar), 2B (ability to increase cAMP signaling), 2C (ability to inhibit calcium signaling) and 2D (ability to decrease cell proliferation). D Antibody 13 has a K of 993 pM. D It was found to have the following structure:

[0272] [Example 6] Epitope analysis In silico The epitope of the antibody 7 variant (antibody 7b, SEQ ID NOs: 418 (VH) and 39 (VL)) was elucidated in silico using SEQ ID NO: 64 as the sequence for LPAR1. SEQ ID NO: 64 is a modified truncated version of LPAR1 (4Z35 LPAR1 crystal structure). The predicted epitope residues are shown in Figure 3A (for sequence) and Figure 3B (for 3D structure) using numbering based on SEQ ID NO: 64. The predicted epitope interacting regions 1-4 (SEQ ID NOs: 65-68) are shown in Figure 3A and Figure 3C.

[0273] The paratope residues of antibody 7b were also predicted (Figure 4). The CDRs are underlined using the Chothia definitions in Figure 4.

[0274] It was also established by competitive CIFAT (run 1.13) that antibody 1 and 63D8 compete for the same epitope (data not shown).

[0275] In vitro Based on the epitope analysis shown in Figures 3 and 4, constructs were designed to investigate the in silico predicted important residues / interaction regions. Plasmids containing human LPAR1 sequence (obtained from UniProt) with selected single or multiple residue substitutions to alanine were used. CHO-K1 cells were transiently transfected with these plasmids and the binding of anti-LPAR1 mAbs to each of these receptor variants was evaluated using protocol 1.11. The anti-LPAR1 mAbs had a VH of SEQ ID NO: 369 and a VL of SEQ ID NO: 39. The numbering of LPAR1 is based on UniProt Q92633 LPAR1 (SEQ ID NO: 62).

[0276] Figure 5 shows the epitope residues involved, in silico predictions and fluorescence images of cells stained with anti-HA (expression control), anti-LPAR1 mAb and negative control mAb. Table 9 provides an overview of the epitope residues, their location in the extracellular domain, and whether the residue was found to be important for epitope binding.

[0277] [Table 11]

[0278] Figure 6 shows an updated version of Figure 3B, including labeling of identified critical residues involved in epitope binding. This study showed that residues 36R and 193E are involved in antibody binding to LPAR1, with possible contributions from residues 35N and 286Q.

[0279] [Example 7] Residue substitution Key residues in the LPAR1 binding antibodies (produced either in cell supernatants or as purified IgG) derived from Antibody 1 discussed above were substituted individually or in combination and then analyzed for their effect on LPAR1 function. The residues selected to be substituted were those that have X in the following sequence: n where each CDR (the CDRs in this example are defined by the non-Kabat numbering system) is underlined:

[0280] [ka]

[0281] The residues in the CDRs selected to be replaced are n (the CDRs in this example are defined by the non-Kabat numbering system), where residue X 21 and X 23 may or may not be present. If present, X 21 and / or X 23is selected from K and R. These residues were not present in these experiments.

[0282] [ka]

[0283] The results of each substitution are shown in Table 10 below, where "full-length numbering" X n is the equivalent X of SEQ ID NO: 70 or 71 n Corresponds to "CDR numbering" X n (if present) are equivalent Xs in SEQ ID NOs: 72, 76, 80, 84, 88 and 92 n Substitutions were tested using the cAMP assay (Method 1.7) with the exception of residues marked with *, which indicate that these substitutions were tested using the stable cell CIFAT assay (Method 1.12). Throughout this study, residue X was selected for maximum affinity. 20 , X 21 Or X 22 It has been found that it is preferred that one of

[0284] In addition, it was found in a stable cell CIFAT assay (Method 1.12) that the lysine residue at position 74 of SEQ ID NO:70 could be substituted with threonine while still maintaining function, to the extent that both lysine and threonine at position 74 of SEQ ID NO:70 were considered the "best residues" according to the functional categories shown in Table 10.

[0285] The VH and VL sequences of further antibodies generated in this study are provided in the attached sequence listing.

[0286] [Table 12] TIFF2024535662000049.tif240169TIFF2024535662000050.tif240169TIFF2024535662000051.tif240162

[0287] Example 8: Antibody substitution and investigation of antibodies 15-18 Further optimized antibodies were generated containing the "best residue" substitutions from Table 10. These include Antibody 15 (SEQ ID NO: 36 (VH) and 99 (VL)), Antibody 16, Antibody 17 (SEQ ID NO: 102 (VH) and 99 (VL)) and Antibody 18 (SEQ ID NO: 102 (VH) and 104 (VL)).

[0288] A mutation in LCDR2 (T56E) was introduced into antibody 15 to eliminate the risk of non-specific interactions caused by high positive charge. This mutation also eliminates the risk of isomerization caused by the previously identified mutation T56D. Antibody 16 contains the same VH and VL sequences as antibody 15 (SEQ ID NOs: 36 and 99). The heavy chain constant region of antibody 16 contains a different silencing mutation than the heavy chain constant region of antibody 15.

[0289] Antibodies 15, 16, 17 and 18 were each expressed according to method 1.5. Expression levels were compared to Palivizumab biosimilars. The expression level of antibody 15 is presented in Figure 7A, the expression level of antibody 16 is presented in Figure 8A, the expression level of antibody 17 is presented in Figure 9A, and the expression level of antibody 18 is presented in Figure 10A.

[0290] The ability of these antibodies to increase cAMP signaling was tested using method 1.7. Results for Antibody 15 are shown in Figure 7B. Results for Antibody 16 are shown in Figure 8B. Results for Antibody 17 are shown in Figure 9B. Results for Antibody 18 are shown in Figure 10B.

[0291] The ability of these antibodies to reduce cell proliferation was tested using method 1.9. Results for Antibody 15 are shown in Figure 7C. Results for Antibody 16 are shown in Figure 8C. Results for Antibody 17 are shown in Figure 9C. Results for Antibody 18 are shown in Figure 10C.

[0292] The ability of these antibodies to bind to huLPAR1-HA cells was assessed using a transient transfection CIFAT assay (Method 1.11). Results for antibody 15 are shown in Figure 7D. Results for antibody 17 are shown in Figure 9D. Results for antibody 18 are shown in Figure 10D.

[0293] The K of these antibodies D The K of antibody 15 was confirmed. D The KD of antibody 16 was also 824 pM. The KD of antibody 17 was also 824 pM. D is 1 nM, and the K of antibody 18 D was 1.39 nM.

[0294] [Example 9] Comparison with commercially available anti-LPAR1 antibodies using CIFAT assay The anti-LPAR1 antibodies of the present invention were tested together with commercially available anti-LPAR1 antibodies in a transient transfection CIFAT assay for live cells (Method 1.11) and a transient transfection CIFAT assay for fixed cells (Method 1.11). The list of antibodies tested is shown in Table 11.

[0295] [Table 13]

[0296] The results are shown in Figures 11 and 12, where the scale bar represents 100 μm. Figure 11 shows the results of an experiment testing 5 μg / mL of antibody on fixed / permeabilized cells and 5 μg / mL of antibody on live cells. Figure 12 shows the results of an experiment testing 5 μg / mL of antibody on fixed / permeabilized cells and 20 μg / mL of antibody on live cells. These data show that whereas prior art antibodies do not bind to LPAR1 on the surface of live cells, a series of antibodies of the present invention have been generated that bind to LPAR1 on the surface of live cells.

[0297] [Example 10] Allosteric inhibition The inhibitory properties of antibody 12 were investigated by bioluminescence resonance energy transfer (BRET, method 1.15) and compared to a prior art small molecule LPAR1 inhibitor (BMS-986020) (see Figure 13). The top line is the value recorded in the presence of LPA, and the bottom line is the value recorded in the absence of LPA. In the presence of LPA (top line, Figure 13A), even at high concentrations, the antibody does not produce the same inhibition as the system without LPA (in this assay measuring the interaction of the G protein G13 with the GPCR). This can only happen if the ligand (LPA) is also simultaneously interacting with the receptor to allow some signaling. As the top line flattens out at high concentrations, it is likely that the system has reached maximum receptor occupancy and therefore that the ligand is interacting with the receptor even when the antibody has reached maximum occupancy. Therefore, the antibody must be acting allosterically. One contrasting example is the prior art BMS-986020 molecule, which is a competitive inhibitor, resulting in 100% inhibition (in this assay) even in the presence of LPA (top line, FIG. 13B).

[0298] [Example 11] Interspecies cross-reactivity The species cross-reactivity of antibodies 12, 15, 17 and 18 was investigated using transient transfection CIFAT (method 1.11). Cells were transfected with DNA encoding human LPAR1, mouse LPAR1, guinea pig LPAR1 or rabbit LPAR1 according to Table 12. The results are shown in Figure 14A (antibody 12), Figure 14B (antibody 15), Figure 14C (antibody 17) and Figure 14D (antibody 18).

[0299] [Table 14]

[0300] [Example 12] LPAR isoform specificity The specificity of antibodies 12, 15, 17 and 18 for human LPAR isoforms was investigated using transient transfection CIFAT (method 1.11). Cells were transfected with DNA encoding human LPAR1, human LPAR2 or human LPAR3 according to Table 13. The results are shown in Figure 15A (antibody 12), Figure 15B (antibody 15), Figure 15C (antibody 17) and Figure 15D (antibody 18).

[0301] [Table 15]

[0302] [Example 13] Pharmacokinetics in rats The pharmacokinetics of antibodies 12, 15, 17 and 18 in rats was investigated using method 1.16. Palivizumab biosimilars (SEQ ID NOs: 1227 (VH) and 1228 (VL)) were used as control isotypes. The results are shown in FIG.

[0303] By visual inspection, all five antibodies showed the same plasma concentration-time profile after a single intravenous dose of 3 mg / kg. For all antibodies, the median tmax was observed at 0.3 hours, i.e., the first blood draw time after dosing. The mean Cmax observed after intravenous dosing was 143.8 μg / mL and 217.5 μg / mL for Antibody 17 and Antibody 12, respectively. Plasma concentrations declined in a similar manner for all antibodies, i.e., with a first rapid phase and a second slow phase, showing quantifiable plasma concentrations up to 504 hours after dosing for all antibodies and all animals.

[0304] [Example 14] SEC-MALS Size exclusion chromatography using multi-angle light scattering was performed on antibodies 12, 13, 15, 16, 17 and 18. The results are shown in Figure 17A (antibody 12), Figure 17B (antibody 13), Figure 17C (antibody 15), Figure 17D (antibody 16), Figure 17E (antibody 17) and Figure 17F (antibody 18).

[0305] [Example 15] Histological examination of the liver in cynomolgus monkeys The small molecule antagonist BMS-986020 showed efficacy in patients with idiopathic pulmonary fibrosis (IPF) but exhibited off-target hepatobiliary toxicity. The observed toxicity was confirmed to be compound-specific due to off-target binding to several intrahepatic bile acid efflux transporters (e.g., BSEP, MRP3, and MRP4) and not mediated by antagonism of LPAR1.

[0306] A dose-finding study was conducted to determine potential toxicity of antibody 17 administered intravenously (infusion) to cynomolgus monkeys. The test article, antibody 17, was administered to eight monkeys by intravenous infusion (30 min) on day 1 (group 1) or days 1, 8, and 15 (groups 2-4). Monkeys were assigned to four groups based on sex and received antibody 17 at 10, 33, or 100 mg / kg / day.

[0307] [Table 16]

[0308] Six monkeys (Groups 2-4) that received three doses of antibody 17 underwent detailed gross pathology examinations, organ weight recordings, and microscopic evaluations two days after the third dose. No unscheduled deaths occurred during the study.

[0309] Administration of antibody 17 appeared to be well tolerated at the injection site. No adverse effects were observed throughout the study, and no adverse findings were noted on histopathological examination.

[0310] Example 16: Efficacy model of unilateral ureteral obstruction (UUO) in guinea pigs Unilateral ureteral obstruction (UUO) is a well-characterized model of renal fibrosis that induces tubular necrosis and inflammatory cell infiltration in a relatively short period of time, which are key pathophysiological features of chronic kidney disease.

[0311] method Efficacy studies of two unilateral ureteral obstruction (UUO) models were performed using 6-week-old female Hartley guinea pigs. UUO surgery was performed on day 0. BMS-986020 was administered orally at a dose of 30 mg / kg in a volume of 5 mL / kg twice daily from days -1 to 9. Isotype control and anti-LPAR1 antibodies were administered intraperitoneally at a dose of 6 mg / kg (low dose) or 20 mg / kg (high dose) in a volume of 10 mL / kg on days -1, 0, 3, and 6. Survival, clinical signs, behavior, and individual body weights were monitored daily.

[0312] On day 10, the guinea pigs were sacrificed and the weights of the ligated left and right kidneys were measured at the time of sacrifice.

[0313] Hydroxyproline is an amino acid that constitutes about 14% of collagen and serves as an important indicator of the severity of fibrosis. To quantify renal hydroxyproline content, frozen right posterior sections of left kidney samples were processed by alkaline-acid hydrolysis method. After adding AC buffer (2.2 M acetic acid / 0.48 M citric acid) to the samples, they were centrifuged and the supernatants were collected. A standard curve of hydroxyproline was constructed using serial dilutions of trans-4-hydroxy-L-proline (Sigma-Aldrich, USA) starting from 16 μg / mL. The prepared samples and standards were mixed with chloramine T solution (Nacalai Tesque Inc., Japan) and incubated at room temperature for 25 min. Subsequently, the samples were mixed with Ehrlich's solution and heated at 65 °C for 20 min to develop color. After cooling the samples on ice and centrifuging to remove precipitates, the optical density of each supernatant was measured at 560 nm. Hydroxyproline concentrations were calculated from the hydroxyproline standard curve. Protein concentrations in kidney samples were measured using a BCA protein assay kit (Thermo Fisher Scientific, USA) and used to normalize calculated hydroxyproline values. Renal hydroxyproline content was expressed as μg per mg protein.

[0314] The left kidney was fixed in Bouin's solution and embedded in paraffin. For PAS staining, sections were cut from the paraffin blocks and stained with Schiff's reagent (FUJIFILM Wako pure chemical corporation, Japan) according to the manufacturer's instructions. To visualize collagen deposition, kidney sections were stained with picro-sirius red solution (FUJIFILM Wako pure chemical corporation). To quantify the interstitial and medullary fibrosis areas, bright-field images of the corticomedullary regions were acquired at 200x magnification using a digital camera (DFC295), and the positive areas in 5 fields / section were measured using ImageJ software (National Institute of Health, USA).

[0315] result In study 1 (Figure 18A), antibody 13 was used as an anti-LPAR1 antibody at a dose of 20 mg / kg. Each group contained eight guinea pigs. Histological picrosirius staining showed increased fibrotic areas in the cortex after UUO surgery (vehicle in Figure 25A). Treatment with BMS-986020 reduced cortical fibrosis compared to vehicle. Treatment with anti-LPAR1 antibody resulted in a reduction in cortical fibrosis to the same extent as treatment with BMS-986020. No differences in hydroxyproline were observed between groups.

[0316] In study 2 (Figure 18B), antibody 17 was used as the anti-LPAR1 antibody. Each batch contained 20 guinea pigs. Treatment with BMS-986020 showed a trend toward a decrease in hydroxyproline compared to vehicle. Treatment with 20 mg / kg (high dose) of anti-LPAR1 antibody significantly decreased hydroxyproline compared to the isotype antibody. No observable differences were observed between groups in histological picrosirius staining.

[0317] Reductions in histological picrosirius staining or hydroxyproline measurements, markers of fibrosis, were observed in both study arms treated with anti-LPAR1 mAb.

[0318] item The following is a series of headings that define the present invention and preferred aspects thereof: 1. A polypeptide that binds to LPAR1. 2. The polypeptide according to item 1, comprising three heavy chain CDRs (HCDR1 to HCDR3). 3. The polypeptide according to any of items 1 or 2, comprising an HCDR1 comprising a sequence having at least 40%, such as at least 60%, such as at least 80% identity to SEQ ID NO:1 or SEQ ID NO:7. 4. The polypeptide according to item 3, comprising an HCDR1 consisting of a sequence having at least 40%, such as at least 60%, such as at least 80% identity to SEQ ID NO:1 or SEQ ID NO:7. 5. The polypeptide according to item 3, comprising an HCDR1 comprising SEQ ID NO:1. 6. The polypeptide according to item 5, comprising an HCDR1 consisting of SEQ ID NO:1. 7. The polypeptide according to item 3, comprising an HCDR1 comprising SEQ ID NO:7. 8. The polypeptide according to item 7, comprising HCDR1 consisting of SEQ ID NO:7. 9. The polypeptide according to any one of items 1 to 8, comprising an HCDR2 comprising a sequence having at least 50%, such as at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 85%, for example, at least 90% identity to any one of SEQ ID NOs: 2, 8 to 11 or 100. 10. The polypeptide according to item 9, comprising an HCDR2 consisting of a sequence having at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 85%, for example, at least 90% identity to any one of SEQ ID NOs: 2, 8 to 11 or 100. 11. The polypeptide according to item 9, comprising an HCDR2 comprising any one of SEQ ID NOs: 2, 8 to 11, or 100. 12. The polypeptide according to item 10, comprising an HCDR2 consisting of any one of SEQ ID NOs: 2, 8 to 11, or 100. 13. The polypeptide according to item 11, comprising an HCDR2 comprising SEQ ID NO:2 or SEQ ID NO:100. 14. The polypeptide according to item 12, comprising an HCDR2 consisting of SEQ ID NO: 2 or SEQ ID NO: 100. 15. The polypeptide according to any one of items 1 to 14, comprising an HCDR3 comprising a sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 85%, for example at least 90% identity to any one of SEQ ID NOs: 3, 12 to 15 or 101. 16. The polypeptide according to item 15, comprising an HCDR3 consisting of a sequence having at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 85%, for example, at least 90% identity to any one of SEQ ID NOs: 3, 12 to 15, or 101. 17. The polypeptide according to item 15, comprising an HCDR3 comprising any one of SEQ ID NOs: 3, 12 to 15, or 101. 18. The polypeptide according to item 16, comprising an HCDR3 consisting of any one of SEQ ID NOs: 3, 12 to 15, and 101. 19. The polypeptide according to item 17, comprising an HCDR3 comprising SEQ ID NO:3 or SEQ ID NO:101. 20. The polypeptide according to item 18, comprising an HCDR3 consisting of SEQ ID NO: 3 or SEQ ID NO: 101. 21. The polypeptide according to any one of items 1 to 20, comprising three light chain CDRs (LCDR1 to 3). 22. The polypeptide according to item 21, comprising an LCDR1 comprising a sequence having at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 90% identity to any one of SEQ ID NOs: 4, 16-18, or 103. 23. The polypeptide according to item 22, comprising an LCDR1 consisting of a sequence having at least 60%, for example, at least 70%, for example, at least 80%, for example, at least 90% identity to any one of SEQ ID NOs: 4, 16 to 18, or 103. 24. The polypeptide according to item 22, comprising an LCDR1 comprising any one of SEQ ID NOs: 4, 16 to 18, or 103. 25. The polypeptide according to item 23, comprising an LCDR1 consisting of any one of SEQ ID NOs: 4, 16 to 18, and 103. 26. The polypeptide according to item 24, comprising an LCDR1 comprising SEQ ID NO: 4 or SEQ ID NO: 103. 27. The polypeptide according to item 25, comprising an LCDR1 consisting of SEQ ID NO: 4 or SEQ ID NO: 103. 28. The polypeptide according to any one of items 1 to 27, comprising an LCDR2 comprising a sequence having at least 50% identity, such as at least 60%, such as at least 70%, for example at least 80% identity to SEQ ID NO: 5, 19 or 98. 29. The polypeptide according to item 28, comprising an LCDR2 consisting of a sequence having at least 50% identity, such as at least 60%, such as at least 70%, such as at least 80% identity to SEQ ID NO: 5, 19 or 98. 30. The polypeptide according to item 28, comprising an LCDR2 comprising SEQ ID NO: 5, 19 or 98. 31. The polypeptide according to item 29, comprising an LCDR2 consisting of SEQ ID NO: 5, 19 or 98. 32. The polypeptide according to item 30, comprising an LCDR2 comprising SEQ ID NO: 98. 33. The polypeptide according to item 31, comprising an LCDR2 consisting of SEQ ID NO: 98. 34. The polypeptide according to any one of items 1 to 33, comprising an LCDR3 comprising a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80% identity to any one of SEQ ID NOs: 6 or 20 to 22. 35. The polypeptide according to item 34, comprising an LCDR3 consisting of a sequence having at least 50%, for example, at least 60%, for example, at least 70%, for example, at least 80% identity to any one of SEQ ID NOs: 6 or 20 to 22. 36. The polypeptide according to item 34, comprising an LCDR3 comprising any one of SEQ ID NOs: 6 or 20 to 22. 37. The polypeptide according to item 35, comprising an LCDR3 consisting of any one of SEQ ID NOs: 6 and 20 to 22. 38. The polypeptide according to item 36, comprising an LCDR3 comprising SEQ ID NO:6. 39. The polypeptide according to item 37, comprising an LCDR3 consisting of SEQ ID NO:6. 40. The polypeptide according to any one of items 1 to 39, wherein the residue in HCDR2 corresponding to residue number 5 in SEQ ID NO:2 is arginine. 41. The polypeptide according to any one of items 1 to 40, wherein the residue in HCDR3 corresponding to residue number 6 in SEQ ID NO: 3 is arginine. 42. The polypeptide according to any one of items 1 to 41, wherein the residue in HCDR3 corresponding to residue number 7 in SEQ ID NO: 3 is a tyrosine. 43. The polypeptide according to any one of items 1 to 42, wherein the residue in LCDR2 corresponding to residue number 1 in SEQ ID NO:5 is a tyrosine. 44. The polypeptide according to any one of items 1 to 43, wherein the residue in LCDR3 corresponding to residue number 3 in SEQ ID NO: 6 is a histidine. 45. (a) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:3, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO:6; (b) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:8, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:16, LCDR2 comprising SEQ ID NO:19 and LCDR3 comprising SEQ ID NO:20; (c) HCDR1 comprising SEQ ID NO:7, HCDR2 comprising SEQ ID NO:9, HCDR3 comprising SEQ ID NO:13, LCDR1 comprising SEQ ID NO:17, LCDR2 comprising SEQ ID NO:19 and LCDR3 comprising SEQ ID NO:21; (d) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:10, HCDR3 comprising SEQ ID NO:14, LCDR1 comprising SEQ ID NO:18, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (e) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:8, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:16, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:22; (f) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:8, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:16, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (g) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:11, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:20; (h) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:11, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (i) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:12, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (j) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:3, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (k) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:15, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:19, and LCDR3 comprising SEQ ID NO:6; (l) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:15, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO:6; (m) HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, HCDR3 comprising SEQ ID NO:3, LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:98, and LCDR3 comprising SEQ ID NO:6; (n) HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 100, HCDR3 comprising SEQ ID NO: 101, LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 98 and LCDR3 comprising SEQ ID NO: 6, or (o) HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 100, HCDR3 comprising SEQ ID NO: 101, LCDR1 comprising SEQ ID NO: 103, LCDR2 comprising SEQ ID NO: 98, and LCDR3 comprising SEQ ID NO: 6 2. The polypeptide according to item 1, comprising: 46. ​​(a) HCDR1 consisting of SEQ ID NO:1, HCDR2 consisting of SEQ ID NO:2, HCDR3 consisting of SEQ ID NO:3, LCDR1 consisting of SEQ ID NO:4, LCDR2 consisting of SEQ ID NO:5, and LCDR3 consisting of SEQ ID NO:6; (b) an HCDR1 consisting of SEQ ID NO: 1, an HCDR2 consisting of SEQ ID NO: 8, an HCDR3 consisting of SEQ ID NO: 12, an LCDR1 consisting of SEQ ID NO: 16, an LCDR2 consisting of SEQ ID NO: 19, and an LCDR3 consisting of SEQ ID NO: 20; (c) an HCDR1 consisting of SEQ ID NO: 7, an HCDR2 consisting of SEQ ID NO: 9, an HCDR3 consisting of SEQ ID NO: 13, an LCDR1 consisting of SEQ ID NO: 17, an LCDR2 consisting of SEQ ID NO: 19, and an LCDR3 consisting of SEQ ID NO: 21; (d) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 10, HCDR3 consisting of SEQ ID NO: 14, LCDR1 consisting of SEQ ID NO: 18, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (e) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 8, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 16, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 22; (f) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 8, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 16, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (g) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 11, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 20; (h) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 11, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (i) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 12, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (j) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 3, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (k) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 15, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 19, and LCDR3 consisting of SEQ ID NO: 6; (l) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 15, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 5, and LCDR3 consisting of SEQ ID NO: 6; (m) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 2, HCDR3 consisting of SEQ ID NO: 3, LCDR1 consisting of SEQ ID NO: 4, LCDR2 consisting of SEQ ID NO: 98, and LCDR3 consisting of SEQ ID NO: 6; (n) an HCDR1 consisting of SEQ ID NO: 1, an HCDR2 consisting of SEQ ID NO: 100, an HCDR3 consisting of SEQ ID NO: 101, an LCDR1 consisting of SEQ ID NO: 4, an LCDR2 consisting of SEQ ID NO: 98, and an LCDR3 consisting of SEQ ID NO: 6, or (o) HCDR1 consisting of SEQ ID NO: 1, HCDR2 consisting of SEQ ID NO: 100, HCDR3 consisting of SEQ ID NO: 101, LCDR1 consisting of SEQ ID NO: 103, LCDR2 consisting of SEQ ID NO: 98, and LCDR3 consisting of SEQ ID NO: 6 46. ​​The polypeptide according to item 45, comprising: 47. A polypeptide comprising three heavy chain CDRs (HCDR1 to HCDR3) and three light chain CDRs (LCDR1 to LCDR3) (CDRs are defined in this section according to the non-Kabat numbering system), wherein HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 72) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:76), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 DY (SEQ ID NO: 80), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 84), and LCDR2 comprises (e.g. consists of) X 41 AX 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 88), and LCDR3 comprises (e.g., consists of) X 47 X 48 X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO: 92), the amino acid of X1 is selected from the group consisting of S, Y, T, G, R, E, K, D and N; the amino acid of X2 is selected from the group consisting of K, R, L, T, G, V, A, S, F, W, Q, M, Y, I, E, H, N, D and P; the amino acid of X3 is selected from the group consisting of R, K, H, T, S, F, G, V, A, L, N, Q, E, M, P, W and I; the amino acid of X4 is selected from the group consisting of A and G; the amino acid of X5 is selected from the group consisting of M and I; the amino acid of X6 is selected from the group consisting of S, E, G, D, L, T, N, Q, I, V, A, K, M, H and Y; the amino acid at X7 is selected from the group consisting of E; the amino acid at X8 is selected from the group consisting of L, Q and D; the amino acid of X9 is selected from the group consisting of P, A, G, F, S, T and W; X 10 is selected from the group consisting of R; X 11 is selected from the group consisting of S, T and D; X 12 are selected from the group consisting of G, R, S, Y, A, T, D, E and W; X 13 is selected from the group consisting of: Y; X 14 is selected from the group consisting of T; X 15 is selected from the group consisting of N, H and S; X 16 are selected from the group consisting of R, N, F, K, Q, V, D, E, Y, G, M, P, W, H, L, I, S, T and A; X 17 are selected from the group consisting of Q, A, I, S, P, T, N, V, G, H, L, M, W, K, R, F, D, Y and E; X 18 are selected from the group consisting of G, D, E, H, L, V, Y, A, F, I, K, Q, W, R, M, P, S and N; X 19 are selected from the group consisting of T, K, Q, E, R and M; X 20 are selected from the group consisting of R, F, K, I, A, L, V, W, Y, M, P, Q, G and S; X 21 is absent or selected from the group consisting of K and R, X 22 are selected from the group consisting of K, R, A, H, S, Q, T, P, M, W, Y, G, L, F, V, E and N; X 23 is absent or selected from the group consisting of K and R; X 24 are selected from the group consisting of R, Y, A, H, P, L, K, G, Q, N, I, F, W, S, T, M, E, V and D; X 25 are selected from the group consisting of A, Q, T, S, G, V, R, I, H, K, P, L, M and F; X 26 is selected from the group consisting of R and S; X 27 is selected from the group consisting of Y, H, Q and A; X 28 is selected from the group consisting of A, T, S, D and E; X 29 is selected from the group consisting of M and L; X 30 is selected from the group consisting of Q, K, R, S and T; X 31 is selected from the group consisting of A, S and T; X 32 is selected from the group consisting of S, T and D; X 33 are selected from the group consisting of Q, G, R, K, L, M, P, Y, S, A, N, H, W, D, E, F, T and I; X 34 are selected from the group consisting of S, G, H, N, T, Y and D; X 35 is selected from the group consisting of V, A and I; X 36 is selected from the group consisting of R, K, S, G and A; X 37 are selected from the group consisting of Y, F, L, Q, S, H, T, G, I, M, V, W, K, N, R, D and P; X 38 are selected from the group consisting of N, A, G, H, Q, S, Y, F and W; X 39 is selected from the group consisting of V, I, M and L; X 40 is selected from the group consisting of A, G and D; X 41 are selected from the group consisting of Y, H, R, T, A, D, K, L, N, Q, M, W, E, F and S; X 42 are selected from the group consisting of S, K, M, Q, R, V, Y, G, E, D, T, A, F, I, N, W, H and L; X 43 are selected from the group consisting of N, K, R, Q, T, Y, A, S, D and E; X 44 is selected from the group consisting of R, L, K and A; X 45 are selected from the group consisting of Y, I, K, M, Q, R, V, A, N, S, W, H, L, T, P, D, F, G and E; X 46 are selected from the group consisting of T, A, D, E, Q, R, S, H, K, P, L, F, G, I, M, V, W, Y and N; X 47 is selected from the group consisting of Q, S and L; X 48 is selected from the group consisting of H, N, S, T, A, Q and V; X 49 is selected from the group consisting of H, A, D and F; X 50is selected from the group consisting of Y and L; X 51 are selected from the group consisting of S, K, V, D, N, R, H, T, A, G, Q, I, M, F, W, Y and L; X 52 are selected from the group consisting of S, A, T, G, V, W and Y; X 53 is selected from the group consisting of T and Y. 47. The polypeptide according to any one of items 1 to 46. 48. HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 73) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:77), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 DY (SEQ ID NO: 81), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 85), and LCDR2 comprises (e.g. consists of) X 41 AX 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 89), and LCDR3 comprises (e.g., consists of) X 47 X 48X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO: 93) (CDRs are defined in this section according to the non-Kabat numbering system), the amino acid of X1 is selected from the group consisting of S, Y, T, G, R, E and K; the amino acid of X2 is selected from the group consisting of K, R, L, T, G, V, A, S, F, W, Q, M, Y, I, E, H and N; the amino acid of X3 is selected from the group consisting of R, K, H, T, S, F, G, V, A, L, N, Q, E, M, P and W; the amino acid of X4 is selected from the group consisting of A and G; the amino acid of X5 is selected from the group consisting of M and I; the amino acid of X6 is selected from the group consisting of S, E, G, D, L, T, N, Q, I, V, A, K and M; the amino acid at X7 is selected from the group consisting of E; the amino acid at X8 is selected from the group consisting of L and Q; the amino acid of X9 is selected from the group consisting of P, A, G, F, S and T; X 10 is selected from the group consisting of R; X 11 is selected from the group consisting of S, T and D; X 12 are selected from the group consisting of G, R, S, Y, A, T, D, E and W; X 13 is selected from the group consisting of: Y; X 14 is selected from the group consisting of T; X 15 is selected from the group consisting of N, H and S; X 16 are selected from the group consisting of R, N, F, K, Q, V, D, E, Y, G, M, P, W, H and L; X 17are selected from the group consisting of Q, A, I, S, P, T, N, V, G, H, L, M, W, K, R, F, D, Y and E; X 18 are selected from the group consisting of G, D, E, H, L, V, Y, A, F, I, K, Q, W, R, M, P and S; X 19 are selected from the group consisting of T, K, Q, E, R and M; X 20 are selected from the group consisting of R, F, K, I, A, L, V, W, Y and M; X 21 is absent or selected from the group consisting of K and R, X 22 are selected from the group consisting of K, R, A, H, S, Q, T, P, M, W, Y, G, L, F and V; X 23 is absent or selected from the group consisting of K and R, X 24 are selected from the group consisting of R, Y, A, H, P, L, K, G, Q, N, I, F, W, S, T, M, E, V and D; X 25 is selected from the group consisting of A, Q, T, S, G, V, R and I; X 26 is selected from the group consisting of R and S; X 27 is selected from the group consisting of: Y; X 28 is selected from the group consisting of A, T, S and D; X 29 is selected from the group consisting of M and L; X 30 is selected from the group consisting of Q, K, R, S and T; X 31 is selected from the group consisting of A, S and T; X 32 is selected from the group consisting of S, T and D; X 33are selected from the group consisting of Q, G, R, K, L, M, P, Y, S, A, N, H, W, D and E; X 34 are selected from the group consisting of S, G, H, N, T and Y; X 35 is selected from the group consisting of V, A and I; X 36 is selected from the group consisting of R, K, S and G; X 37 are selected from the group consisting of Y, F, L, Q, S, H, T, G, I, M, V, W, K, N and R; X 38 is selected from the group consisting of N, A, G, H, Q and S; X 39 is selected from the group consisting of V, I, M and L; X 40 is selected from the group consisting of A, G and D; X 41 are selected from the group consisting of Y, H, R, T, A, D, K, L, N and Q; X 42 are selected from the group consisting of S, K, M, Q, R, V, Y, G, E, D, T, A, F, I, N, W and H; X 43 are selected from the group consisting of N, K, R, Q, T, Y, A, S, D and E; X 44 is selected from the group consisting of R, L and K; X 45 are selected from the group consisting of Y, I, K, M, Q, R, V, A, N, S, W, H, L, T, P, D, F and G; X 46 are selected from the group consisting of T, A, D, E, Q, R, S, H, K, P, L, F, G, I, M, V, W, Y and N; X 47 is selected from the group consisting of Q, S and L; X 48 is selected from the group consisting of H, N, S, T, A and Q; X 49 is selected from the group consisting of H; X 50 is selected from the group consisting of Y and L; X 51 are selected from the group consisting of S, K, V, D, N, R, H, T, A, G, Q, I, M, F, W and Y; X 52 is selected from the group consisting of S, A, T and G; X 53 is selected from the group consisting of T and Y. Item 48. The polypeptide according to item 47. 49. HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 74) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:78), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 DY (SEQ ID NO: 82), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 86), and LCDR2 comprises (e.g. consists of) X 41 AX 42 X 43 X 44 X 45 X 46(SEQ ID NO: 90), and LCDR3 comprises (e.g., consists of) X 47 X 48 X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO: 94) (CDRs are defined in this section according to the non-Kabat numbering system), the amino acid of X1 is selected from the group consisting of S, Y, T, G and R; the amino acid of X2 is selected from the group consisting of K, R, L, T, G, V, A, S, F, W, Q, M, Y, I and E; the amino acid of X3 is selected from the group consisting of R, K, H, T, S, F, G, V, A, L, N, and Q; the amino acid of X4 is selected from the group consisting of A and G; the amino acid of X5 is selected from the group consisting of M and I; the amino acid of X6 is selected from the group consisting of S, E, G, D, L, T, N, Q, I, V and A; the amino acid at X7 is selected from the group consisting of E; the amino acid at X8 is selected from the group consisting of L and Q; the amino acid of X9 is selected from the group consisting of P, A, G, F and S; X 10 is selected from the group consisting of R; X 11 is selected from the group consisting of S and T; X 12 are selected from the group consisting of G, R, S, Y, A and T; X 13 is selected from the group consisting of: Y; X 14 is selected from the group consisting of T; X 15 is selected from the group consisting of N, H and S; X 16 are selected from the group consisting of R, N, F, K, Q, V, D, E, Y, G, M and P; X17 are selected from the group consisting of Q, A, I, S, P, T, N, V, G, H, L, M, W, K, R and F; X 18 are selected from the group consisting of G, D, E, H, L, V, Y, A, F, I, K, Q, W, R, M, P and S; X 19 are selected from the group consisting of T, K, Q, E, R and M; X 20 are selected from the group consisting of R, F, K, I, A, L, V, W and Y; X 21 is absent or selected from the group consisting of K and R, X 22 are selected from the group consisting of K, R, A, H, S, Q, T, P, M, W, G and Y; X 23 is absent or selected from the group consisting of K and R, X 24 are selected from the group consisting of R, Y, A, H, P, L, K, G, Q, N, I, F, W, S, T, M, E and V; X 25 is selected from the group consisting of A, Q, T, S, G and V; X 26 is selected from the group consisting of R; X 27 is selected from the group consisting of: Y; X 28 is selected from the group consisting of A, T, S and D; X 29 is selected from the group consisting of M; X 30 is selected from the group consisting of Q, K, R, S and T; X 31 is selected from the group consisting of A, S and T; X 32 is selected from the group consisting of S, T and D; X 33are selected from the group consisting of Q, G, R, K, L, M, P, Y, S, A, N, H and W; X 34 are selected from the group consisting of S, G, H, N, T and Y; X 35 is selected from the group consisting of V, A and I; X 36 is selected from the group consisting of R, K and S; X 37 are selected from the group consisting of Y, F, L, Q, S, H, T, G, I, M, V, W, K, N and R; X 38 is selected from the group consisting of N, A, G, H, Q and S; X 39 is selected from the group consisting of V, I, M and L; X 40 is selected from the group consisting of A, G and D; X 41 is selected from the group consisting of Y, H, R and T; X 42 are selected from the group consisting of S, K, M, Q, R, V, Y, G, E, D, T, A, F, I, N and W; X 43 are selected from the group consisting of N, K, R, Q, T, Y, A and S; X 44 is selected from the group consisting of R, L and K; X 45 are selected from the group consisting of Y, I, K, M, Q, R, V, A, N, S, W, H, L, T, P, D and F; X 46 are selected from the group consisting of T, A, D, E, Q, R, S, H, K, P, L, F, G, I, M, V, W, Y and N; X 47 is selected from the group consisting of Q and S; X 48 is selected from the group consisting of H, N, S, T, A and Q; X 49is selected from the group consisting of H; X 50 is selected from the group consisting of: Y; X 51 are selected from the group consisting of S, K, V, D, N, R, H, T, A and G; X 52 is selected from the group consisting of S and A; X 53 is selected from the group consisting of T and Y. Item 49. The polypeptide according to item 48. 50. HCDR1 comprises (e.g. consists of) X1X2X3X4X5X6 (SEQ ID NO: 75) and HCDR2 comprises (e.g. consists of) X7IX8X9X 10 X 11 X 12 X 13 X 14 X 15 YX 16 X 17 X 18 FX 19 G (SEQ ID NO:79), and HCDR3 comprises (e.g., consists of) DX 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 DY (SEQ ID NO: 83), and LCDR1 comprises (e.g., consists of) X 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 (SEQ ID NO: 87), and LCDR2 comprises (e.g. consists of) X 41 AX 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 91), and LCDR3 comprises (e.g., consists of) X 47 X48 X 49 X 50 X 51 X 52 PLX 53 (SEQ ID NO: 95) (CDRs are defined in this section according to the non-Kabat numbering system), the amino acid of X1 is selected from the group consisting of S, Y, T and G; the amino acid of X2 is selected from the group consisting of K, R, L, T, G, V, A, S, F, W, Q, M and Y; the amino acid of X3 is selected from the group consisting of R, K, H, T, S, F, G and V; the amino acid of X4 is selected from the group consisting of A and G; the amino acid of X5 is selected from the group consisting of M and I; the amino acid of X6 is selected from the group consisting of S, E, G, D, L and T; the amino acid at X7 is selected from the group consisting of E; the amino acid at X8 is selected from the group consisting of L and Q; the amino acid of X9 is selected from the group consisting of P, A and G; X 10 is selected from the group consisting of R; X 11 is selected from the group consisting of S and T; X 12 is selected from the group consisting of G and R; X 13 is selected from the group consisting of: Y; X 14 is selected from the group consisting of T; X 15 is selected from the group consisting of N, H and S; X 16 are selected from the group consisting of R, N, F, K, Q, V, D and E; X 17 is selected from the group consisting of Q, A, I, S, P, T, N and V; X 18are selected from the group consisting of G, D, E, H, L, V, Y, A, F, I, K, Q, W and R; X 19 is selected from the group consisting of T and K; X 20 is selected from the group consisting of R, F, K and I; X 21 is absent or selected from the group consisting of K and R, X 22 is selected from the group consisting of K, G and R; X 23 is absent or selected from the group consisting of K and R, X 24 are selected from the group consisting of R, Y, A, H, P, L, K, G, Q, N, I, F and W; X 25 is selected from the group consisting of A, Q, T, S and G; X 26 is selected from the group consisting of R; X 27 is selected from the group consisting of: Y; X 28 is selected from the group consisting of A, T and S; X 29 is selected from the group consisting of M; X 30 is selected from the group consisting of Q, K, R, S and T; X 31 is selected from the group consisting of A and S; X 32 is selected from the group consisting of S and T; X 33 are selected from the group consisting of Q, G, R, K, L, M, P, Y and S; X 34 is selected from the group consisting of S, G, H and N; X 35 is selected from the group consisting of V, A and I; X 36is selected from the group consisting of R; X 37 are selected from the group consisting of Y, F, L, Q, S, H, T, G, I, M, V and W; X 38 is selected from the group consisting of N, A, G, H, Q and S; X 39 is selected from the group consisting of V, I, M and L; X 40 is selected from the group consisting of A and G; X 41 is selected from the group consisting of Y and H; X 42 are selected from the group consisting of S, K, M, Q, R, V, Y, G and E; X 43 is selected from the group consisting of N, K and R; X 44 is selected from the group consisting of R, L and K; X 45 are selected from the group consisting of Y, I, K, M, Q, R, V, A, N, S, W and H; X 46 are selected from the group consisting of T, A, D, E, Q, R, S, H, K, P, L, F, G, I, M and V; X 47 is selected from the group consisting of Q; X 48 is selected from the group consisting of H, N, S and T; X 49 is selected from the group consisting of H; X 50 is selected from the group consisting of: Y; X 51 is selected from the group consisting of S, K and V; X 52 is selected from the group consisting of S and A; X 53 is selected from the group consisting of T 50. The polypeptide according to item 49. 51.X 21 and / or X 23 but not present. 52.X 20 , X 21 and X 22 At least one of X 20 , X 21 , X 22 , X 23 , X 24 and X 25 52. The polypeptide according to any one of Items 47 to 51, wherein at least one of the amino acids is lysine or arginine. 53.X 20 , X 21 , X 22 , X 23 , X 24 and X 25 X 20 , X 21 and X 22 53. The polypeptide according to item 52, wherein one or more of the following is lysine or arginine. 54. The polypeptide according to any one of items 1 to 53, comprising four heavy chain framework regions (HFR1 to HFR4). 55. The polypeptide according to item 54, comprising HFR1 comprising or consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 90% identity to SEQ ID NO: 40, HFR2 comprising or consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, for example at least 80%, for example at least 90% identity to SEQ ID NO: 41, HFR3 comprising or consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, for example at least 80%, for example at least 90% identity to SEQ ID NO: 42, and / or HFR4 comprising or consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, for example at least 80%, for example at least 90% identity to SEQ ID NO: 43. 56. The polypeptide according to item 55, wherein the residue corresponding to residue 13 of SEQ ID NO: 41 is selected from I and M, the residue corresponding to residue 3 of SEQ ID NO: 42 is selected from V and S, the residue corresponding to residue 4 of SEQ ID NO: 42 is selected from L and F, the residue corresponding to residue 10 of SEQ ID NO: 42 is selected from S, A and V, the residue corresponding to residue 29 of SEQ ID NO: 42 is selected from F and Y, and / or the residue corresponding to residue 2 of SEQ ID NO: 43 is selected from G and S. 57. The polypeptide according to any of items 55 or 56, comprising HFR1 comprising SEQ ID NO: 40, HFR2 comprising SEQ ID NO: 41, HFR3 comprising SEQ ID NO: 42 and / or HFR4 comprising SEQ ID NO: 43. 58. The polypeptide according to item 57, comprising HFR1 consisting of SEQ ID NO: 40, HFR2 consisting of SEQ ID NO: 41, HFR3 consisting of SEQ ID NO: 42 and / or HFR4 consisting of SEQ ID NO: 43. 59. The polypeptide according to any one of items 1 to 58, comprising four light chain framework regions (LFR1 to LFR4). 60. The polypeptide according to item 59, comprising an LFR1 comprising or consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 90% identity to SEQ ID NO: 44, an LFR2 comprising or consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 90% identity to SEQ ID NO: 45, an LFR3 comprising or consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 90% identity to SEQ ID NO: 46, and / or an LFR4 comprising or consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 90% identity to SEQ ID NO: 47. 61. The polypeptide according to item 60, wherein the residue corresponding to residue 1 of SEQ ID NO: 44 is selected from S, D, Q, E, N and A, and / or the residue corresponding to residue 31 of SEQ ID NO: 46 is selected from F and Y. 62. The polypeptide according to any of items 60 or 61, comprising an LFR1 comprising SEQ ID NO: 44, an LFR2 comprising SEQ ID NO: 45, an LFR3 comprising SEQ ID NO: 46 and / or an LFR4 comprising SEQ ID NO: 47. 63. The polypeptide according to item 62, comprising an LFR1 consisting of SEQ ID NO: 44, an LFR2 consisting of SEQ ID NO: 45, an LFR3 consisting of SEQ ID NO: 46 and / or an LFR4 consisting of SEQ ID NO: 47. 64. The polypeptide according to any one of items 1 to 63, comprising a VH region. 65. The polypeptide according to item 64, wherein the VH region comprises an amino acid sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 90%, for example at least 95%, such as at least 98%, for example at least 99% sequence identity to any one of SEQ ID NOs: 23, 25, 27, 29, 33, 35, 36, 37, 96 or 102. 66. The polypeptide according to item 65, wherein the VH region consists of an amino acid sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 90%, for example at least 95%, for example at least 98%, for example at least 99% sequence identity to any one of SEQ ID NOs: 23, 25, 27, 29, 33, 35, 36, 37, 96 or 102. 67. The polypeptide according to item 65, wherein the VH region comprises the amino acid sequence of SEQ ID NO: 23, 25, 27, 29, 33, 35, 36, 37, 96 or 102. 68. The polypeptide according to item 67, wherein the VH region comprises the amino acid sequence of SEQ ID NO: 36. 69. The polypeptide according to item 67, wherein the VH region comprises the amino acid sequence of SEQ ID NO: 37. 70. The polypeptide according to item 67, wherein the VH region comprises the amino acid sequence of SEQ ID NO: 102. 71. The polypeptide according to item 66, wherein the VH region consists of the amino acid sequence of SEQ ID NO: 23, 25, 27, 29, 33, 35, 36, 37, 96 or 102. 72. The polypeptide according to item 71, wherein the VH region consists of the amino acid sequence of SEQ ID NO: 36. 73. The polypeptide according to item 71, wherein the VH region consists of the amino acid sequence of SEQ ID NO: 37. 74. The polypeptide according to item 71, wherein the VH region consists of the amino acid sequence of SEQ ID NO: 102. 75. A polypeptide according to any one of items 1 to 74, comprising a VL region. 76. The polypeptide according to item 75, wherein the VL region comprises an amino acid sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 90%, for example at least 95%, for example at least 98%, for example at least 99% sequence identity to any one of SEQ ID NOs: 24, 26, 28, 30, 31, 32, 34, 38, 39, 97, 99 or 104. 77. The polypeptide according to item 76, wherein the VL region consists of an amino acid sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 90%, for example at least 95%, for example at least 98%, for example at least 99% sequence identity to any one of SEQ ID NOs: 24, 26, 28, 30, 31, 32, 34, 38, 39, 97, 99 or 104. 78. The polypeptide according to item 76, wherein the VL region comprises the amino acid sequence of SEQ ID NO: 24, 26, 28, 30, 31, 32, 34, 38, 39, 97, 99 or 104. 79. The polypeptide according to item 78, wherein the VL region comprises the amino acid sequence of SEQ ID NO: 38. 80. The polypeptide according to item 78, wherein the VL region comprises the amino acid sequence of SEQ ID NO: 99. 81. The polypeptide according to item 78, wherein the VL region comprises the amino acid sequence of SEQ ID NO: 104. 82. The polypeptide according to item 77, wherein the VL region consists of the amino acid sequence of SEQ ID NO: 24, 26, 28, 30, 31, 32, 34, 38, 39, 97, 99 or 104. 83. The polypeptide according to item 82, wherein the VL region consists of the amino acid sequence of SEQ ID NO: 38. 84. The polypeptide according to item 82, wherein the VL region consists of the amino acid sequence of SEQ ID NO: 99. 85. The polypeptide according to item 82, wherein the VL region consists of the amino acid sequence of SEQ ID NO: 104. 86. (a) a VH region comprising SEQ ID NO:23 and a VL region comprising SEQ ID NO:24; (b) a VH region comprising SEQ ID NO:25 and a VL region comprising SEQ ID NO:26; (c) a VH region comprising SEQ ID NO:27 and a VL region comprising SEQ ID NO:28; (d) a VH region comprising SEQ ID NO:29 and a VL region comprising SEQ ID NO:30; (e) a VH region comprising SEQ ID NO:27 and a VL region comprising SEQ ID NO:31; (f) a VH region comprising SEQ ID NO:27 and a VL region comprising SEQ ID NO:32; (g) a VH region comprising SEQ ID NO: 33 and a VL region comprising SEQ ID NO: 34; (h) a VH region comprising SEQ ID NO: 33 and a VL region comprising SEQ ID NO: 39; (i) a VH region comprising SEQ ID NO: 35 and a VL region comprising SEQ ID NO: 39; (j) a VH region comprising SEQ ID NO: 36 and a VL region comprising SEQ ID NO: 39; (k) a VH region comprising SEQ ID NO: 37 and a VL region comprising SEQ ID NO: 39; (l) a VH region comprising SEQ ID NO: 36 and a VL region comprising SEQ ID NO: 38; (m) a VH region comprising SEQ ID NO: 37 and a VL region comprising SEQ ID NO: 38; (n) a VH region comprising SEQ ID NO: 96 and a VL region comprising SEQ ID NO: 97; (o) a VH region comprising SEQ ID NO: 36 and a VL region comprising SEQ ID NO: 99; (p) a VH region comprising SEQ ID NO: 102 and a VL region comprising SEQ ID NO: 99; or (q) a VH region comprising SEQ ID NO: 102 and a VL region comprising SEQ ID NO: 104 86. The polypeptide according to any one of items 1 to 85, comprising: 87. (a) a VH region consisting of SEQ ID NO:23 and a VL region consisting of SEQ ID NO:24; (b) a VH region consisting of SEQ ID NO: 25 and a VL region consisting of SEQ ID NO: 26; (c) a VH region consisting of SEQ ID NO:27 and a VL region consisting of SEQ ID NO:28; (d) a VH region consisting of SEQ ID NO:29 and a VL region consisting of SEQ ID NO:30; (e) a VH region consisting of SEQ ID NO: 27 and a VL region consisting of SEQ ID NO: 31; (f) a VH region consisting of SEQ ID NO: 27 and a VL region consisting of SEQ ID NO: 32; (g) a VH region consisting of SEQ ID NO: 33 and a VL region consisting of SEQ ID NO: 34; (h) a VH region consisting of SEQ ID NO: 33 and a VL region consisting of SEQ ID NO: 39; (i) a VH region consisting of SEQ ID NO: 35 and a VL region consisting of SEQ ID NO: 39; (j) a VH region consisting of SEQ ID NO: 36 and a VL region consisting of SEQ ID NO: 39; (k) a VH region consisting of SEQ ID NO: 37 and a VL region consisting of SEQ ID NO: 39; (l) a VH region consisting of SEQ ID NO: 36 and a VL region consisting of SEQ ID NO: 38; (m) a VH region consisting of SEQ ID NO: 37 and a VL region consisting of SEQ ID NO: 38; (n) a VH region consisting of SEQ ID NO: 96 and a VL region consisting of SEQ ID NO: 97; (o) a VH region consisting of SEQ ID NO: 36 and a VL region consisting of SEQ ID NO: 99; (p) a VH region consisting of SEQ ID NO: 102 and a VL region consisting of SEQ ID NO: 99; or (q) a VH region consisting of SEQ ID NO: 102 and a VL region consisting of SEQ ID NO: 104 87. The polypeptide according to item 86, comprising: 88. The polypeptide according to any one of items 1 to 87, wherein residue H53 is arginine. 89. The polypeptide according to any one of items 1 to 88, wherein residue H100 is arginine. 90. The polypeptide according to any one of items 1 to 89, wherein residue H100A is a tyrosine. 91. The polypeptide according to any one of items 1 to 90, wherein residue L50 is a tyrosine. 92. The polypeptide according to any one of items 1 to 91, wherein residue L91 is a histidine. 93. The polypeptide according to any one of items 1 to 92, wherein the residue corresponding to position 74 of SEQ ID NO: 70 is a lysine or threonine. 94. The polypeptide according to any one of items 1 to 93, wherein the residue corresponding to position 47 of SEQ ID NO: 418 is tryptophan, the residue corresponding to position 103 of SEQ ID NO: 418 is glycine, the residue corresponding to position 105 of SEQ ID NO: 418 is tyrosine, the residue corresponding to position 31 of SEQ ID NO: 39 is tyrosine, and the residue corresponding to position 92 of SEQ ID NO: 39 is tyrosine. 95. The polypeptide according to item 94, wherein the residue corresponding to position 52 of SEQ ID NO: 418 is leucine, the residue corresponding to position 54 of SEQ ID NO: 418 is arginine, the residue corresponding to position 104 of SEQ ID NO: 418 is arginine, the residue corresponding to position 26 of SEQ ID NO: 39 is serine, the residue corresponding to position 27 of SEQ ID NO: 39 is glutamine, the residue corresponding to position 49 of SEQ ID NO: 39 is tyrosine, and the residue corresponding to position 91 of SEQ ID NO: 39 is histidine. 96. The polypeptide according to item 95, wherein the residue corresponding to position 55 of SEQ ID NO: 418 is a serine, the residue corresponding to position 58 of SEQ ID NO: 418 is a threonine, the residue corresponding to position 59 of SEQ ID NO: 418 is an asparagine, the residue corresponding to position 62 of SEQ ID NO: 418 is a glutamine, the residue corresponding to position 100 of SEQ ID NO: 418 is a phenylalanine, the residue corresponding to position 1 of SEQ ID NO: 39 is a serine, the residue corresponding to position 29 of SEQ ID NO: 39 is a valine, the residue corresponding to position 90 of SEQ ID NO: 39 is a histidine, and the residue corresponding to position 93 of SEQ ID NO: 39 is a serine. 97. The polypeptide according to item 96, wherein the residue corresponding to position 31 of SEQ ID NO: 418 is serine, the residue corresponding to position 60 of SEQ ID NO: 418 is tyrosine, the residue corresponding to position 61 of SEQ ID NO: 418 is asparagine, the residue corresponding to position 65 of SEQ ID NO: 418 is threonine, the residue corresponding to position 99 of SEQ ID NO: 418 is aspartic acid, the residue corresponding to position 101 of SEQ ID NO: 418 is arginine, the residue corresponding to position 102 of SEQ ID NO: 418 is serine, the residue corresponding to position 25 of SEQ ID NO: 39 is alanine, the residue corresponding to position 30 of SEQ ID NO: 39 is arginine, the residue corresponding to position 67 of SEQ ID NO: 39 is serine, the residue corresponding to position 89 of SEQ ID NO: 39 is glutamine, and the residue corresponding to position 94 of SEQ ID NO: 39 is serine. 98. The polypeptide according to item 1, comprising an HCDR1 comprising a sequence having at least 40%, such as at least 60%, such as at least 80% identity to SEQ ID NO: 107. 99. The polypeptide according to item 98, comprising an HCDR1 consisting of a sequence having at least 40%, such as at least 60%, such as at least 80% identity to SEQ ID NO: 107. 100. The polypeptide according to item 99, comprising an HCDR1 comprising SEQ ID NO: 107. 101. The polypeptide according to any one of items 100, comprising HCDR1 consisting of SEQ ID NO: 107. 102. The polypeptide according to any one of items 1 or 98 to 101, comprising an HCDR2 comprising a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 85%, for example at least 90% identity to SEQ ID NO: 108. 103. The polypeptide according to item 102, comprising an HCDR2 consisting of a sequence having at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 85%, for example at least 90% identity with SEQ ID NO: 108. 104. The polypeptide according to item 103, comprising an HCDR2 comprising SEQ ID NO: 108. 105. The polypeptide according to item 104, comprising an HCDR2 consisting of SEQ ID NO: 108. 106. The polypeptide according to any one of items 1 or 98 to 105, comprising an HCDR3 comprising a sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 109. 107. The polypeptide according to item 106, comprising an HCDR3 consisting of a sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 109. 108. The polypeptide according to item 107, comprising an HCDR3 comprising SEQ ID NO: 109. 109. The polypeptide according to item 108, comprising an HCDR3 consisting of SEQ ID NO: 109. 110. The polypeptide according to any one of items 1 or 98 to 109, comprising an LCDR1 comprising a sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 110. 111. The polypeptide according to item 110, comprising an LCDR1 consisting of a sequence having at least 60%, such as at least 70%, such as at least 80%, such as at least 90% identity to SEQ ID NO: 110. 112. The polypeptide according to item 111, comprising LCDR1 comprising SEQ ID NO: 110. 113. The polypeptide according to item 112, comprising LCDR1 consisting of SEQ ID NO: 110. 114. The polypeptide according to any one of items 1 or 98 to 113, comprising an LCDR2 comprising a sequence having at least 50% identity, such as at least 60%, such as at least 70%, such as at least 80% identity to SEQ ID NO: 111. 115. The polypeptide according to item 114, comprising an LCDR2 consisting of a sequence having at least 50% identity, such as at least 60%, such as at least 70%, such as at least 80% identity, to SEQ ID NO: 111. 116. The polypeptide according to item 115, comprising an LCDR2 comprising SEQ ID NO: 111. 117. The polypeptide according to item 116, comprising an LCDR2 consisting of SEQ ID NO: 111. 118. The polypeptide according to any one of items 1 or 98 to 117, comprising an LCDR3 comprising a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80% identity to SEQ ID NO: 112. 119. The polypeptide according to item 118, comprising an LCDR3 consisting of a sequence having at least 50%, such as at least 60%, such as at least 70%, such as at least 80% identity to SEQ ID NO: 112. 120. The polypeptide according to item 119, comprising an LCDR3 comprising SEQ ID NO: 112. 121. The polypeptide according to item 120, comprising an LCDR3 consisting of SEQ ID NO: 112. 122. The polypeptide according to item 1, comprising a VH region comprising an amino acid sequence having at least 60%, such as at least 70%, for example at least 80%, for example at least 90%, for example at least 95%, for example at least 98%, for example at least 99% sequence identity to SEQ ID NO: 113. 123. The polypeptide according to item 122, wherein the VH region consists of an amino acid sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 90%, for example at least 95%, for example at least 98%, for example at least 99% sequence identity with SEQ ID NO: 113. 124. The polypeptide according to item 123, wherein the VH region comprises the amino acid sequence of SEQ ID NO: 113. 125. The polypeptide according to item 124, wherein the VH region consists of the amino acid sequence of SEQ ID NO: 113. 126. The polypeptide according to any one of items 1 or 122 to 125, comprising a VL region comprising an amino acid sequence having at least 60%, such as at least 70%, for example at least 80%, for example at least 90%, for example at least 95%, for example at least 98%, for example at least 99% sequence identity to SEQ ID NO: 114. 127. The polypeptide according to item 126, wherein the VL region consists of an amino acid sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 90%, for example at least 95%, for example at least 98%, for example at least 99% sequence identity with SEQ ID NO: 114. 128. The polypeptide according to item 127, wherein the VL region comprises the amino acid sequence of SEQ ID NO: 114. 129. The polypeptide according to item 128, wherein the VL region consists of the amino acid sequence of SEQ ID NO: 114. 130. The polypeptide according to any one of items 1 to 129, comprising a heavy chain constant region. 131. The polypeptide according to item 130, wherein the heavy chain constant region comprises a polypeptide sequence having at least 50%, such as at least 70%, such as at least 90% identity to SEQ ID NO: 1375. 132. The polypeptide according to item 131, wherein the heavy chain constant region comprises SEQ ID NO: 1375. 133. The polypeptide according to item 132, wherein the heavy chain constant region consists of SEQ ID NO: 1375. 134. The polypeptide according to any one of items 130 to 133, wherein the heavy chain region comprises a polypeptide sequence having at least 50%, such as at least 70%, such as at least 90% identity to SEQ ID NO: 58, SEQ ID NO: 60 or SEQ ID NO: 1220. 135. The polypeptide according to item 134, wherein the heavy chain region comprises SEQ ID NO: 58, SEQ ID NO: 60 or SEQ ID NO: 1220. 136. The polypeptide according to item 135, wherein the heavy chain region consists of SEQ ID NO: 58, SEQ ID NO: 60 or SEQ ID NO: 1220. 137. The polypeptide according to any one of items 130 to 136, wherein the heavy chain constant region comprises or consists of an IgG1 heavy chain constant region, such as a human IgG1. 138. The polypeptide according to any one of items 1 to 137, comprising a light chain constant region. 139. The polypeptide according to item 138, wherein the light chain constant region comprises a polypeptide sequence having at least 50%, such as at least 70%, such as at least 90% identity to SEQ ID NO: 57. 140. The polypeptide according to item 139, wherein the light chain constant region comprises SEQ ID NO:57. 141. The polypeptide according to item 140, wherein the light chain constant region consists of SEQ ID NO:57. 142. The polypeptide according to any one of items 138 to 141, wherein the light chain region comprises a polypeptide sequence having at least 50%, such as at least 70%, such as at least 90% identity to SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 1219 or SEQ ID NO: 1221. 143. The polypeptide according to item 142, wherein the light chain region comprises SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:1219 or SEQ ID NO:1221. 144. The polypeptide according to item 143, wherein the light chain region consists of SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 1219 or SEQ ID NO: 1221. 145. The polypeptide according to any one of items 138 to 144, wherein the light chain constant region comprises or consists of a kappa light chain constant region, such as a human kappa light chain. 146. The polypeptide according to any one of items 1 to 145, wherein the polypeptide comprises a VH and a VL domain, and the VH and VL domains are linked by a linker, such as a polypeptide linker. 147. The linker is (Gly4Ser) n 147. The polypeptide according to item 146, comprising the format (SEQ ID NO: 69), wherein n = 1 to 8. 148. The polypeptide according to any one of items 1 to 147, wherein LPAR1 is human LPAR1. 149. The polypeptide according to any one of items 1 to 148, wherein LPAR1 is native LPAR1. 150. The polypeptide according to any one of items 1 to 149, wherein LPAR1 is full-length LPAR1. 151. The polypeptide according to any one of items 1 to 148, wherein LPAR1 is a fragment of LPAR1. 152. The polypeptide according to item 151, wherein the fragment of LPAR1 comprises the extracellular domain of LPAR1. 153. The polypeptide according to any of items 151 or 152, wherein the fragment of LPAR1 is at least 50 amino acids long, such as at least 100 amino acids long, such as at least 150 amino acids long, such as at least 200 amino acids long, such as at least 250 amino acids long, such as at least 300 amino acids long, such as at least 350 amino acids long. 154. The polypeptide according to any one of items 1 to 153, wherein LPAR1 comprises a sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 90%, for example at least 95%, for example at least 99% identity to SEQ ID NO: 62, SEQ ID NO: 63 or SEQ ID NO: 64. 155. The polypeptide according to item 154, wherein LPAR1 consists of a sequence having at least 60%, such as at least 70%, for example at least 80%, such as at least 90%, for example at least 95%, for example at least 99% identity to SEQ ID NO: 62, SEQ ID NO: 63 or SEQ ID NO: 64. 156. The polypeptide according to item 155, wherein LPAR1 comprises SEQ ID NO: 62, SEQ ID NO: 63 or SEQ ID NO: 64. 157. The polypeptide according to item 156, wherein LPAR1 consists of SEQ ID NO: 62, SEQ ID NO: 63 or SEQ ID NO: 64. 158. The polypeptide according to any one of items 1 to 157, which binds to functionally active LPAR1. 159. The polypeptide according to any one of items 1 to 158, wherein LPAR1 is on the surface of the cell. 160. The polypeptide according to item 159, wherein the cell is a living cell. 161. The polypeptide according to any one of items 1 to 160, which modulates the function of LPAR1. 162. The polypeptide according to item 161, which is an inhibitor of LPAR1. 163. The polypeptide according to item 162, which is an allosteric inhibitor of LPAR1. 164. The polypeptide according to any one of items 161 to 163, which is an inverse agonist of LPAR1. 165. The polypeptide according to any one of items 1 to 164, wherein binding to LPAR1 reduces Gi / o signaling by LPAR1. 166. The polypeptide according to any of items 1 to 165, wherein binding to LPAR1 reduces or prevents LPA-induced or constitutive reduction in cAMP production. 167. The polypeptide according to item 166, wherein binding to LPAR1 increases cAMP production in an HTRF cAMP assay. 168. The polypeptide according to any one of items 1 to 167, wherein binding to LPAR1 reduces or prevents LPA-induced calcium mobilization. 169. The polypeptide according to item 168, wherein binding to LPAR1 reduces calcium mobilization in the assay detailed in example 1.8. 170. The polypeptide according to any one of items 1 to 169, wherein the polypeptide, upon binding to LPAR1, reduces the activity of LPAR1 by at least 10%, such as at least 20%, for example at least 30%, such as at least 40%, for example at least 50%, such as at least 60%, for example at least 70%, such as at least 80%, for example at least 90%, such as at least 95%, for example at least 98%, such as at least 99%, for example at least 100%. 171. The polypeptide according to item 170, wherein the activity of LPAR1 is indicated by HTRF cAMP assay. 172. A K of less than 150 nM, for example less than 30 nM, for example less than 15 nM, in particular less than 1.5 nM D 172. The polypeptide according to any one of items 1 to 171, which binds to LPAR1 at 173.K D 173. The polypeptide according to claim 172, wherein is measured using a kinetic exclusion assay. 174. The polypeptide according to any one of items 1 to 173, which binds to an epitope of human LPAR1 comprising at least one of amino acids 30 to 44 of full-length LPAR1 (SEQ ID NO: 62). 175. The polypeptide according to item 174, which binds to an epitope of human LPAR1 comprising amino acids 35 and 36 of full-length LPAR1 (SEQ ID NO: 62). 176. The polypeptide according to any of items 174 or 175, which binds to an epitope of human LPAR1 comprising amino acids 37 and 38 of full-length LPAR1 (SEQ ID NO: 62). 177. The polypeptide according to any one of items 174 to 176, which binds to an epitope of human LPAR1 comprising amino acids 32, 39, 40 and 41 of full-length LPAR1 (SEQ ID NO: 62). 178. The polypeptide according to any one of items 174 to 177, which binds to an epitope of human LPAR1 comprising at least five of amino acids 30 to 44 of full-length LPAR1 (SEQ ID NO: 62). 179. The polypeptide according to item 178, which binds to an epitope of human LPAR1 comprising at least 10 of amino acids 30 to 44 of full-length LPAR1 (SEQ ID NO: 62). 180. The polypeptide according to item 179, which binds to an epitope of human LPAR1 comprising amino acids 30 to 44 of full-length LPAR1 (SEQ ID NO: 62). 181. The polypeptide according to any one of items 1 to 180, which binds to an epitope of human LPAR1 comprising at least one of amino acids 106 to 120 of full-length LPAR1 (SEQ ID NO: 62). 182. The polypeptide according to item 181, which binds to an epitope of human LPAR1 comprising amino acid 114 of full-length LPAR1 (SEQ ID NO: 62). 183. The polypeptide according to any of items 181 or 182, which binds to an epitope of human LPAR1 comprising at least five of amino acids 106 to 120 of full-length LPAR1 (SEQ ID NO: 62). 184. The polypeptide according to item 183, which binds to an epitope of human LPAR1 comprising at least 10 of amino acids 106 to 120 of full-length LPAR1 (SEQ ID NO: 62). 185. The polypeptide according to item 184, which binds to an epitope of human LPAR1 comprising amino acids 106 to 120 of full-length LPAR1 (SEQ ID NO: 62). 186. The polypeptide according to any one of items 1 to 185, which binds to an epitope of human LPAR1 comprising at least one of amino acids 190 to 204 of full-length LPAR1 (SEQ ID NO: 62). 187. The polypeptide according to item 186, which binds to an epitope of human LPAR1 comprising amino acid 193 of full-length LPAR1 (SEQ ID NO: 62). 188. The polypeptide according to any of items 186 or 187, which binds to an epitope of human LPAR1 comprising amino acids 191, 192, 194 and 197 of full-length LPAR1 (SEQ ID NO: 62). 189. The polypeptide according to any one of items 186 to 188, which binds to an epitope of human LPAR1 comprising amino acid 190 of full-length LPAR1 (SEQ ID NO: 62). 190. The polypeptide according to any one of items 186 to 189, which binds to an epitope of human LPAR1 comprising at least five of amino acids 190 to 204 of full-length LPAR1 (SEQ ID NO: 62). 191. The polypeptide according to item 190, which binds to an epitope of human LPAR1 comprising at least 10 of amino acids 190 to 204 of full-length LPAR1 (SEQ ID NO: 62). 192. The polypeptide according to item 191, which binds to an epitope of human LPAR1 comprising amino acids 190 to 204 of full-length LPAR1 (SEQ ID NO: 62). 193. The polypeptide according to any one of items 1 to 192, which binds to an epitope of human LPAR1 comprising at least one of amino acids 280 to 294 of full-length LPAR1 (SEQ ID NO: 62). 194. The polypeptide according to item 193, which binds to an epitope of human LPAR1 comprising amino acid 286 of full-length LPAR1 (SEQ ID NO: 62). 195. The polypeptide according to any of items 193 or 194, which binds to an epitope of human LPAR1 comprising amino acid 285 of full-length LPAR1 (SEQ ID NO: 62). 196. The polypeptide according to any one of items 193 to 195, which binds to an epitope of human LPAR1 comprising at least five of amino acids 280 to 294 of full-length LPAR1 (SEQ ID NO: 62). 197. The polypeptide according to item 196, which binds to an epitope of human LPAR1 comprising at least 10 of amino acids 280 to 294 of full-length LPAR1 (SEQ ID NO: 62). 198. The polypeptide according to item 197, which binds to an epitope of human LPAR1 comprising amino acids 280 to 294 of full-length LPAR1 (SEQ ID NO: 62). 199. The polypeptide according to any one of items 1 to 198, which binds to an epitope of human LPAR1 comprising amino acids 30 to 44, 106 to 120, 190 to 204 and 280 to 294 of full-length LPAR1 (SEQ ID NO: 62). 200. The polypeptide according to item 199, which binds to an epitope of human LPAR1 consisting of amino acids 30 to 44, 106 to 120, 190 to 204, and 280 to 294 of full-length LPAR1 (SEQ ID NO: 62). 201. The polypeptide according to any one of items 1 to 173, which binds to an epitope of LPAR1 comprising one or more of residues 35, 36, 193 or 286 of full-length LPAR1 (SEQ ID NO: 62). 202. The polypeptide according to item 201, which binds to an epitope of LPAR1 comprising residue 35 of full-length LPAR1 (SEQ ID NO: 62). 203. The polypeptide according to item 201, which binds to an epitope of LPAR1 comprising residue 36 of full-length LPAR1 (SEQ ID NO: 62). 204. The polypeptide according to item 201, which binds to an epitope of LPAR1 comprising residue 193 of full-length LPAR1 (SEQ ID NO: 62). 205. The polypeptide according to item 201, which binds to an epitope of LPAR1 comprising residue 286 of full-length LPAR1 (SEQ ID NO: 62). 206. The polypeptide according to any one of items 1 to 205, which binds to a conformational epitope of human LPAR1 comprising one or more residues located within the N-terminal capping helix and one or more residues located within extracellular domain 2. 207. The polypeptide according to item 206, which binds to an epitope of LPAR1 comprising residues 36 and 193 of full-length LPAR1 (SEQ ID NO: 62). 208. A polypeptide which binds to the same or essentially the same epitope as a polypeptide defined in any one of items 1 to 207. 209. A polypeptide that competes with a polypeptide defined in any one of items 1 to 208 for binding to LPAR1. 210. The polypeptide according to any one of items 1 to 209, which is an antibody or a fragment thereof. 211. The polypeptide according to item 210, wherein the antibody or fragment thereof is selected from the list consisting of an scFv, Fab, Fab', F(ab')2, Fv, a variable domain (e.g., VH or VL), a diabody, a minibody or a full-length antibody. 212. The polypeptide according to item 211, wherein the antibody or fragment thereof is selected from the list consisting of an scFv, a Fab or a full length antibody. 213. The polypeptide according to item 212, wherein the antibody or fragment thereof is a full-length antibody or a Fab. 214. The polypeptide according to item 213, wherein the full-length antibody is an IgG1 antibody. 215. The polypeptide according to any one of items 210 to 214, wherein the antibody heavy chain constant region comprises one or more mutations to reduce effector function, extend half-life, alter ADCC, or improve hinge stability. 216. The polypeptide according to item 215, wherein the heavy chain constant region comprises any one of SEQ ID NOs: 56, 1235, 1376 and 1377. 217. The heavy chain constant region of an antibody comprising the following residues: Residue at position 250 is Q, residue at position 252 is Y, residue at position 252 is F, residue at position 252 is W, residue at position 252 is T, residue at position 253 is A, residue at position 254 is T, residue at position 256 is E, residue at position 256 is S, residue at position 256 is R, residue at position 256 is Q, residue at position 256 is D, residue at position 259 is I, residue at position 285 is D, residue at position 285 is N, residue at position 286 is D, residue at position 287 is N, residue at position 288 is N, residue at position 289 is N, residue at position 290 is N, residue at position 291 is N, residue at position 292 is N, residue at position 293 is N, residue at position 294 is N, residue at position 295 is N, residue at position 296 is N, residue at position 297 is N, residue at position 298 is N, residue at position 299 is N, residue at position 300 is N, residue at position 301 is N, residue at position 302 is N, residue at position 303 is N, residue at position 304 is N, residue at position 305 is N, residue at position 306 is N, residue at position 307 is N, residue at position 308 is N, residue at position 309 is N, residue at position 310 is N, residue at position 311 is N, residue at position 312 is N, residue at position 313 is N, residue at position 314 is N, residue at position 315 is N, residue at position 316 is N, residue at position 317 is N, residue at position 318 is N, residue at position 319 is N, residue at position 320 is N, residue at position 321 is N Residue at position 94, residue at position 307 which is A, residue at position 307 which is Q, residue at position 307 which is P, residue at position 307 which is R, residue at position 307 which is W, residue at position 308 which is P, residue at position 308 which is F, residue at position 309 which is P, residue at position 309 which is D, residue at position 309 which is N, residue at position 310 which is A, residue at position 311 which is S, residue at position 311 which is I, residue at position 311 which is V, residue at position 311 which is H, residue at position 315 which is D Group, residue at position 378 which is V, residue at position 380 which is A, residue at position 385 which is R, residue at position 385 which is D, residue at position 385 which is S, residue at position 385 which is T, residue at position 385 which is H, residue at position 385 which is K, residue at position 385 which is A, residue at position 385 which is G, residue at position 386 which is T, residue at position 386 which is P, residue at position 386 which is D, residue at position 386 which is S, residue at position 386 which is K, residue at position 386 which is R, residue at position 386 which is I residue at position 6, residue at position 386 which is M, residue at position 387 which is R, residue at position 387 which is P, residue at position 387 which is H, residue at position 387 which is S, residue at position 387 which is T, residue at position 387 which is A, residue at position 389 which is P, residue at position 389 which is S, residue at position 389 which is N, residue at position 428 which is L, residue at position 433 which is K, residue at position 433 which is R, residue at position 433 which is S, residue at position 433 which is I, residue at position 433 which is P,a residue at position 433 which is Q, a residue at position 434 which is F, a residue at position 434 which is H, a residue at position 434 which is Y, a residue at position 434 which is A, a residue at position 434 which is S, a residue at position 435 which is A, a residue at position 436 which is H, a residue at position 436 which is I or a residue at position 436 which is V, 217. The polypeptide according to any one of Items 210 to 214 or 216, comprising one or more of the following: 218. The polypeptide according to item 215, wherein the mutation is selected from the mutations listed in Table 2. 219. The polypeptide according to item 218, wherein the heavy chain constant region comprises the mutations M252Y, S254T and T256E or M428L and N434S. 220. The polypeptide according to any one of items 217 to 219, wherein the heavy chain constant region comprises any one of SEQ ID NOs: 1237 to 1367. 221. The polypeptide according to item 220, wherein the heavy chain constant region consists of any one of SEQ ID NOs: 1237 to 1367. 222. The polypeptide according to any one of items 210 to 221, wherein the antibody or fragment thereof is a human antibody or fragment thereof. 223. A construct comprising a polypeptide according to any one of items 1 to 222. 224. The construct according to item 223, comprising a polypeptide that binds to a target other than LPAR1. 225. A composition comprising a polypeptide or construct according to any one of items 1 to 224. 226. A pharmaceutical composition comprising a polypeptide or construct according to any one of items 1 to 225 together with a pharma- ceutically acceptable diluent or carrier. 227. A polypeptide, construct or composition according to any one of items 1 to 226 for use as a medicament. 228. A polypeptide, construct or composition according to any one of items 1 to 227 for use in the treatment of an inflammatory and / or fibrotic disease. 229. The polypeptide, construct or composition according to item 228 for use in the treatment of a disease selected from the list consisting of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, systemic sclerosis and osteoarthritis. 230. The polypeptide, construct or composition according to item 227 for use in the treatment of a disease selected from the list consisting of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis, osteoarthritis, NASH, rheumatoid arthritis, neuropathic pain or cancer. 231. A method for treating an inflammatory and / or fibrotic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polypeptide, construct or composition according to any one of items 1 to 226. 232. A method for treating a disease selected from the list consisting of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, systemic sclerosis and osteoarthritis in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a polypeptide, construct or composition according to any one of items 1 to 226. 233. A method for treating a disease selected from the list consisting of chronic kidney disease, renal fibrosis, peritoneal fibrosis, hepatic fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis, osteoarthritis, NASH, rheumatoid arthritis, neuropathic pain or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polypeptide, construct or composition according to any one of items 1 to 226. 234. Use of a polypeptide, construct or composition according to any of items 1 to 226 in the manufacture of a medicament for the treatment of an inflammatory and / or fibrotic disease. 235. Use of a polypeptide, construct or composition according to any one of items 1 to 226 in the manufacture of a medicament for the treatment of a disease selected from the list consisting of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, systemic sclerosis and osteoarthritis. 236. Use of a polypeptide, construct or composition according to any one of items 1 to 226 in the manufacture of a medicament for the treatment of a disease selected from the list consisting of chronic kidney disease, renal fibrosis, peritoneal fibrosis, liver fibrosis, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), skin fibrosis, systemic sclerosis, osteoarthritis, NASH, rheumatoid arthritis, neuropathic pain or cancer. 237. A polynucleotide sequence encoding a polypeptide or construct according to any one of items 1 to 224. 238. The polynucleotide according to item 237, comprising any one of SEQ ID NOs: 1368 to 1374. 239. The polynucleotide according to item 238, consisting of any one of SEQ ID NOs: 1368 to 1374. 240. An expression vector comprising a polynucleotide sequence according to any one of items 237 to 239. 241. A cell comprising the polynucleotide sequence according to any one of items 237 to 239 or the expression vector according to item 240.

[0319] Miscellaneous All references referred to in this application, including patents and patent applications, are incorporated by reference to the maximum extent possible.

[0320] Throughout this specification and the claims which follow, unless the context requires otherwise, it is understood that the word "comprise" and variations such as "comprises" and "comprising" imply the inclusion of a stated integer, step, group of integers or group of steps, but not the exclusion of any other integer, step, group of integers or group of steps.

[0321] This application of which this specification and claims form part may be used as a basis for priority in respect of any later application. The claims of such later application may be directed to any feature or combination of features described herein. These may take the form of product, composition, process, or use claims and may include, by way of example and not limitation, the following claims:

[0322] [Table 17] TIFF2024535662000057.tif241169TIFF2024535662000058.tif240169TIFF2024535662000059.tif108169

Claims

1. An antibody that binds to lysophosphatidic acid receptor 1 ("LPAR1"), wherein the antibody is an inhibitor of LPAR1, and the antibody comprises three heavy chain CDRs (HCDR1-3) and three light chain CDRs (LCDR1-3), wherein the antibody comprises HCDR1 having the amino acid sequence shown in SEQ ID NO: 1, HCDR2 having the amino acid sequence shown in SEQ ID NO: 100, HCDR3 having the amino acid sequence shown in SEQ ID NO: 101, LCDR1 having the amino acid sequence shown in SEQ ID NO: 4, LCDR2 having the amino acid sequence shown in SEQ ID NO: 98, and LCDR3 having the amino acid sequence shown in SEQ ID NO:

6.

2. The antibody according to claim 1, wherein the antibody comprises a heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 102 and a light chain variable region containing the amino acid sequence shown in SEQ ID NO:

99.

3. The antibody according to claim 1, wherein the antibody is a full-length IgG1 antibody.

4. The antibody according to claim 1, wherein the antibody comprises an Fc region into which a mutation has been introduced for the purpose of reducing effector function, extending half-life, altering ADCC, or improving hinge stability.

5. A pharmaceutical composition comprising the antibody described in Claim 1 and a pharmaceutically acceptable diluent or carrier.

6. The antibody according to claim 2, wherein the antibody comprises a heavy chain including a heavy chain variable region including the amino acid sequence shown in SEQ ID NO: 102 and a heavy chain constant region including the amino acid sequence shown in SEQ ID NO: 1239, and a light chain including a light chain variable region including the amino acid sequence shown in SEQ ID NO: 99 and a light chain constant region including the amino acid sequence shown in SEQ ID NO:

57.

7. An antibody that binds to LPAR1, The aforementioned antibody a. Two heavy chain polypeptides, each heavy chain polypeptide comprising a heavy chain variable region containing three heavy chain CDRs (HCDR1-3), wherein HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 100, and HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 101, and b. Two light chain polypeptides, each light chain polypeptide comprising a light chain variable region containing three light chain CDRs (LCDR1-3), wherein LCDR1 comprises SEQ ID NO: 4, LCDR2 comprises SEQ ID NO: 98, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO:

6. Includes, The aforementioned antibody is an IgG1 antibody.

8. An antibody that binds to LPAR1, The aforementioned antibody a. Two heavy chain polypeptides, wherein each heavy chain polypeptide includes a heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 102, and b. Two light chain polypeptides, each of which includes a light chain variable region containing the amino acid sequence shown in Sequence ID No.

99. Includes, The aforementioned antibody is an IgG1 antibody.

9. An antibody that binds to LPAR1, The antibody comprises two heavy chain polypeptides and two light chain polypeptides, each heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1220, and each light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1219, wherein the residue corresponding to position 255 in SEQ ID NO: 1220 is "Y", the residue corresponding to position 257 in SEQ ID NO: 1220 is "T", and the residue corresponding to position 259 in SEQ ID NO: 1220 is "E".

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