TRPV1 epitopes and antibodies

Abstract

The present invention relates to antibodies that bind to TRPV1. The invention also relates to certain epitopes of the protein TRPV1. The invention also relates to immunoconjugates and compositions comprising such antibodies. The invention also provides methods of producing such antibodies. The invention further provides the use of such antibodies for therapeutic purposes, such as in the treatment of pain.

Description

[0001] This application is a divisional application of the patent application filed on December 10, 2020, with application number 202080096086.6 and invention title "TRPV1 epitope and antibody". Technical Field

[0002] This invention generally relates to the fields of epitopes and antibodies, particularly epitopes of the protein TRPV1 and antibodies that bind to TRPV1. Such anti-TRPV1 antibodies have therapeutic uses, such as for treating pain. The antibody-based compositions and methods of this invention, as well as their uses, also extend to the uses of conjugates and other therapeutic combinations, kits, and methods. Background Technology

[0003] TRPV1 ( t ransient r eceptor p otential v anilloid type 1， Transient receptor potential (TRPV1) is an ion channel sensitive to harmful stimuli such as low pH, high temperature (T ≥ 42°C), capsaicin, and inflammatory mediators. Because TRPV1 is associated with pain sensation, it has been studied for nearly 20 years. Several attempts have been made to block receptor activity as a novel mechanism of action for pain treatment, but these attempts have been unsuccessful.

[0004] As is well known in the art, capsaicin is an activator of TRPV1 and can induce pain. Capsaicin is routinely used in the art to assess TRPV1 activation and pain in models. Assessing the inhibition of capsaicin-induced TRPV1 activation is a well-known model system for evaluating the potential of agents to treat pain. Such a model system is described, for example, by Chen et al. (2011).

[0005] Due to the complexity of its activation mechanism (as mentioned above, it can be activated by several stimuli, including low pH, high temperature (T ≥42°C), capsaicin, and inflammatory mediators), most compounds targeting TRPV1 produce adverse effects, such as hyperthermia or loss of thermal sensation.

[0006] For example, compound AMG 517 is a potent small-molecule antagonist of TRPV1 developed by Amgen, which inhibits the capsaicin, pH, and temperature activation of TRPV1. Its study was terminated after a Phase 1 trial in which it caused significant hyperthermia in subjects undergoing molar extraction (Gavva, NR et al. Pain [Pain] (2008), 136 (1-2), 202-210).

[0007] Another small-molecule TRPV1 antagonist developed by Johnson & Johnson, Mavatrep, showed efficacy in a phase 1b study of chronic pain, including subjects with knee osteoarthritis, although some subjects reported side effects of feeling heat and some minor thermal burns (Manitpisitkul P, et al. Scand. J. Pain [Scand. J. Pain] (2018), 18(2):151-164).

[0008] Antibodies that bind to TRPV1 have been previously generated (Klionsky et al., The Journal of Pharmacology and Experimental Therapeutics (2006), Vol. 319(1), pp. 192-198), but these antibodies either do not inhibit capsaicin-induced TRPV1 activity at all, or, when antibodies are reported to inhibit capsaicin-induced TRPV1 activity, they are also reported to inhibit heat-induced TRPV1 activity to the same extent.

[0009] Therefore, improved pain management is needed. TRPV1 is a clinically and genetically validated target. Successful targeting of TRPV1 could provide a long-term, appealing solution to alleviate pain at its source.

[0010] In particular, identifying epitopes on TRPV1 whose targeting would induce preferential inhibition of capsaicin activation of TRPV1, rather than heat-induced TRPV1 activation, would be especially beneficial. This would guide the identification and development of agents, such as antibodies, that can bind to TRPV1 and reduce its capsaicin activation without or with reduced heat-related side effects previously observed with small-molecule TRPV1 antagonists, such as AMG 517 and Mavatrep as described above. Summary of the Invention

[0011] The inventors have addressed this need by identifying specific epitopes (or regions) in the extracellular region of TRPV1 that are particularly useful for targeting, for example, with antibodies to preferentially inhibit capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation. The extracellular region of TRPV1 is, of course, a region (or portion) of TRPV1 that is exposed (or accessible, e.g., accessible by antibodies) on the extracellular side of the cell when TRPV1 is expressed on the cell surface. The inventors have identified and generated isolated peptides corresponding to (or substantially corresponding to) such epitopes. The inventors have also used these isolated peptides to generate antibodies that preferentially inhibit capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation.

[0012] Therefore, in one aspect, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 2 (OTV3) or substantially homologous thereto, SEQ ID NO: 3 (OTV4) or substantially homologous thereto, SEQ ID NO: 4 (OTV5) or substantially homologous thereto, SEQ ID NO: 5 (OTV6) or substantially homologous thereto, SEQ ID NO: 6 (OTV7) or substantially homologous thereto, SEQ ID NO: 7 (OTV8) or substantially homologous thereto, SEQ ID NO: 8 (OTV9) or substantially homologous thereto, SEQ ID NO: 9 (OTV10) or substantially homologous thereto, SEQ ID NO: 10 (OTV11) or substantially homologous thereto, SEQ ID NO: 11 (OTV12) or substantially homologous thereto, SEQ ID NO: 12 (OTV13) or substantially homologous thereto, SEQ ID NO: 2 (OTV3) (or substantially homologous thereto), ...4) (or substantially homologous thereto), SEQ ID NO: 4 (OTV5) (or substantially homologous thereto), SEQ ID NO: 5 (OTV6) (or substantially homologous thereto), SEQ ID NO: 6 (OTV7) (or substantially homologous thereto), SEQ ID NO: 7 (OTV8) (or substantially homologous thereto), SEQ ID NO: 8 (OTV9) (or substantially homologous thereto), SEQ ID NO: 9 (OTV10) (or substantially homologous thereto), SEQ ID NO: 10 (OTV11) (or substantially homologous thereto), SEQ ID NO: 11 (OTV12) (or substantially homologous thereto NO: 13 (OTV14) or a sequence substantially homologous thereto and SEQ ID NO: 14 (OTV15) or a sequence substantially homologous thereto.

[0013] As discussed elsewhere in this article, these isolated peptides can be used as antigenic peptides to generate antibodies that inhibit TRPV1 activation. Typically, these antibodies inhibit capsaicin-induced TRPV1 activation, usually in contrast to heat-induced TRPV1 activation.

[0014] Unless the context clearly indicates otherwise, references to “isolated peptide” or “peptide” in this invention may be regarded as references to “isolated epitope” or “isolated antigenic epitope”.

[0015] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 3 (OTV4) or substantially homologous thereto, SEQ ID NO: 4 (OTV5) or substantially homologous thereto, SEQ ID NO: 6 (OTV7) or substantially homologous thereto, SEQ ID NO: 8 (OTV9), SEQ ID NO: 11 (OTV12) or substantially homologous thereto, and SEQ ID NO: 12 (OTV13) or substantially homologous thereto.

[0016] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 3 (OTV4) or substantially homologous thereto, SEQ ID NO: 4 (OTV5) or substantially homologous thereto, and SEQ ID NO: 11 (OTV12) or substantially homologous thereto.

[0017] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 2 (OTV3) or substantially homologous thereto, SEQ ID NO: 3 (OTV4) or substantially homologous thereto, and SEQ ID NO: 4 (OTV5) or substantially homologous thereto.

[0018] In some embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 2 (OTV3), SEQ ID NO: 3 (OTV4), SEQ ID NO: 4 (OTV5), SEQ ID NO: 5 (OTV6), SEQ ID NO: 6 (OTV7), SEQ ID NO: 7 (OTV8), SEQ ID NO: 8 (OTV9), SEQ ID NO: 9 (OTV10), SEQ ID NO: 10 (OTV11), SEQ ID NO: 11 (OTV12), SEQ ID NO: 12 (OTV13), SEQ ID NO: 13 (OTV14), and SEQ ID NO: 14 (OTV15).

[0019] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 3 (OTV4), SEQ ID NO: 4 (OTV5), SEQ ID NO: 6 (OTV7), SEQ ID NO: 8 (OTV9), SEQ ID NO: 11 (OTV12), and SEQ ID NO: 12 (OTV13).

[0020] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 3 (OTV4), SEQ ID NO: 4 (OTV5), and SEQ ID NO: 11 (OTV12).

[0021] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 2 (OTV3), SEQ ID NO: 3 (OTV4), and SEQ ID NO: 4 (OTV5).

[0022] In some embodiments, the present invention provides isolated peptides composed of amino acid sequences selected from the group consisting of: SEQ ID NO: 2 (OTV3) or substantially homologous to it, SEQ ID NO: 3 (OTV4) or substantially homologous to it, SEQ ID NO: 4 (OTV5) or substantially homologous to it, SEQ ID NO: 5 (OTV6) or substantially homologous to it, SEQ ID NO: 6 (OTV7) or substantially homologous to it, SEQ ID NO: 7 (OTV8) or substantially homologous to it, SEQ ID NO: 8 (OTV9) or substantially homologous to it, SEQ ID NO: 9 (OTV10) or substantially homologous to it, SEQ ID NO: 10 (OTV11) or substantially homologous to it, SEQ ID NO: 11 (OTV12) or substantially homologous to it, SEQ ID NO: 12 (OTV13) or substantially homologous to it, SEQ ID NO: SEQ ID NO: 13 (OTV14) or a sequence substantially homologous thereto, and SEQ ID NO: 14 (OTV15) or a sequence substantially homologous thereto. Preferred isolated peptides (and isolated peptide groups) are disclosed elsewhere herein.

[0023] In some embodiments, the present invention provides isolated peptides composed of amino acid sequences selected from the group consisting of: SEQ ID NO: 2 (OTV3), SEQ ID NO: 3 (OTV4), SEQ ID NO: 4 (OTV5), SEQ ID NO: 5 (OTV6), SEQ ID NO: 6 (OTV7), SEQ ID NO: 7 (OTV8), SEQ ID NO: 8 (OTV9), SEQ ID NO: 9 (OTV10), SEQ ID NO: 10 (OTV11), SEQ ID NO: 11 (OTV12), SEQ ID NO: 12 (OTV13), SEQ ID NO: 13 (OTV14), and SEQ ID NO: 14 (OTV15). Preferred isolated peptides (and groups of isolated peptides) are disclosed elsewhere herein.

[0024] In some embodiments, the isolated peptide may contain one or more additional amino acids at its N-terminus and / or C-terminus. In some preferred embodiments, the isolated peptide may contain one or more additional amino acids at its N-terminus. In some preferred embodiments, the isolated peptide may contain one or more additional amino acids at its C-terminus. In some preferred embodiments, the isolated peptide may contain one or more additional amino acids at both its N-terminus and C-terminus. In some preferred embodiments, the isolated peptide may contain a cysteine ​​(C) residue at its N-terminus and / or C-terminus (or contain additional cysteine ​​(C) residues at its N-terminus). In some embodiments, the isolated peptide may contain a cysteine ​​(C) residue at its N-terminus. In some embodiments, the isolated peptide may contain a cysteine ​​(C) residue at its C-terminus. In some preferred embodiments, the isolated peptide may contain cysteine ​​(C) residues at both its N-terminus and C-terminus. Providing a cysteine ​​residue at the end of the isolated peptide allows for convenient attachment to a peptide carrier, such as as discussed elsewhere herein. If desired, providing cysteine ​​residues at both the N-terminus and C-terminus provides a convenient method for peptide cyclization.

[0025] In some embodiments, the isolated peptide may contain one or more additional modifications at its N-terminus and / or C-terminus. For example, in some embodiments, the isolated peptide may be C-terminally amidated. In some embodiments, the isolated peptide may have modifications (chemical groups or connectors) that can be used to attach (or link or connect) the peptide to a peptide carrier. In some embodiments, the modification (chemical group or connector) that can be used to attach (or link or connect) the peptide to the peptide carrier is a propargyl (Pra) group. The modification (chemical group or connector) that can be used to attach (or link or connect) the peptide to the peptide carrier may be at its N-terminus and / or C-terminus. In some embodiments, the modification (chemical group or connector, such as a propargyl group) that can be used to attach (or link or connect) the peptide to the peptide carrier is at the N-terminus of the isolated peptide.

[0026] In some embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 16 (OTV3) or substantially homologous thereto, SEQ ID NO: 17 (OTV4) or substantially homologous thereto, SEQ ID NO: 18 (OTV5) or substantially homologous thereto, SEQ ID NO: 19 (OTV6) or substantially homologous thereto, SEQ ID NO: 20 (OTV7) or substantially homologous thereto, SEQ ID NO: 21 (OTV8) or substantially homologous thereto, SEQ ID NO: 22 (OTV9) or substantially homologous thereto, SEQ ID NO: 23 (OTV10) or substantially homologous thereto, SEQ ID NO: 24 (OTV11) or substantially homologous thereto, SEQ ID NO: 25 (OTV12) or substantially homologous thereto, SEQ ID NO: SEQ ID NO: 26 (OTV13) or a sequence substantially homologous thereto, SEQ ID NO: 27 (OTV14) or a sequence substantially homologous thereto, and SEQ ID NO: 28 (OTV15) or a sequence substantially homologous thereto.

[0027] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 17 (OTV4) or substantially homologous thereto, SEQ ID NO: 18 (OTV5) or substantially homologous thereto, SEQ ID NO: 20 (OTV7) or substantially homologous thereto, SEQ ID NO: 22 (OTV9) or substantially homologous thereto, SEQ ID NO: 25 (OTV12) or substantially homologous thereto, and SEQ ID NO: 26 (OTV13) or substantially homologous thereto.

[0028] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 17 (OTV4) or substantially homologous thereto, SEQ ID NO: 18 (OTV5) or substantially homologous thereto, and SEQ ID NO: 25 (OTV12) or substantially homologous thereto.

[0029] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 16 (OTV3) or substantially homologous thereto, SEQ ID NO: 17 (OTV4) or substantially homologous thereto, and SEQ ID NO: 18 (OTV5) or substantially homologous thereto.

[0030] In some embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 16 (OTV3), SEQ ID NO: 17 (OTV4), SEQ ID NO: 18 (OTV5), SEQ ID NO: 19 (OTV6), SEQ ID NO: 20 (OTV7), SEQ ID NO: 21 (OTV8), SEQ ID NO: 22 (OTV9), SEQ ID NO: 23 (OTV10), SEQ ID NO: 24 (OTV11), SEQ ID NO: 25 (OTV12), SEQ ID NO: 26 (OTV13), SEQ ID NO: 27 (OTV14), and SEQ ID NO: 28 (OTV15).

[0031] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 17 (OTV4), SEQ ID NO: 18 (OTV5), SEQ ID NO: 20 (OTV7), SEQ ID NO: 22 (OTV9), SEQ ID NO: 25 (OTV12), and SEQ ID NO: 26 (OTV13).

[0032] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 17 (OTV4), SEQ ID NO: 18 (OTV5), and SEQ ID NO: 25 (OTV12).

[0033] In some preferred embodiments, the present invention provides isolated peptides comprising (or comprising) amino acid sequences selected from the group consisting of: SEQ ID NO: 16 (OTV3), SEQ ID NO: 17 (OTV4), and SEQ ID NO: 18 (OTV5).

[0034] In some embodiments, the present invention provides isolated peptides composed of amino acid sequences selected from the group consisting of: SEQ ID NO: 16 (OTV3) or substantially homologous to it, SEQ ID NO: 17 (OTV4) or substantially homologous to it, SEQ ID NO: 18 (OTV5) or substantially homologous to it, SEQ ID NO: 19 (OTV6) or substantially homologous to it, SEQ ID NO: 20 (OTV7) or substantially homologous to it, SEQ ID NO: 21 (OTV8) or substantially homologous to it, SEQ ID NO: 22 (OTV9) or substantially homologous to it, SEQ ID NO: 23 (OTV10) or substantially homologous to it, SEQ ID NO: 24 (OTV11) or substantially homologous to it, SEQ ID NO: 25 (OTV12) or substantially homologous to it, SEQ ID NO: SEQ ID NO: 26 (OTV13) or a sequence substantially homologous thereto, SEQ ID NO: 27 (OTV14) or a sequence substantially homologous thereto, and SEQ ID NO: 28 (OTV15) or a sequence substantially homologous thereto. Preferred isolated peptides (and isolated peptide groups) are disclosed elsewhere herein.

[0035] In some embodiments, the present invention provides isolated peptides comprising amino acid sequences selected from the group consisting of: SEQ ID NO: 16 (OTV3), SEQ ID NO: 17 (OTV4), SEQ ID NO: 18 (OTV5), SEQ ID NO: 19 (OTV6), SEQ ID NO: 20 (OTV7), SEQ ID NO: 21 (OTV8), SEQ ID NO: 22 (OTV9), SEQ ID NO: 23 (OTV10), SEQ ID NO: 24 (OTV11), SEQ ID NO: 25 (OTV12), SEQ ID NO: 26 (OTV13), SEQ ID NO: 27 (OTV14), and SEQ ID NO: 28 (OTV15). Preferred isolated peptides (and groups of isolated peptides) are disclosed elsewhere herein.

[0036] In some embodiments, the present invention provides isolated peptides composed of amino acid sequences selected from the group consisting of: SEQ ID NO: 16 (OTV3), SEQ ID NO: 17 (OTV4), and SEQ ID NO: 18 (OTV5).

[0037] In some embodiments, isolated peptides containing (or consisting of) the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 18 (OTV5 sequence) or a sequence substantially homologous to it are preferred.

[0038] In some embodiments, isolated peptides containing (or consisting of) the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 16 (OTV3 sequence) or a sequence substantially homologous to it are preferred.

[0039] In some embodiments, isolated peptides containing (or consisting of) the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 17 (OTV4 sequence) or a sequence substantially homologous to it are preferred.

[0040] In the context of the isolated peptide sequences of this invention, a sequence “substantially homologous” to a given amino acid sequence may be a sequence containing 1, 2, 3, 4, 5, or 6 (preferably 1, 2, or 3) amino acid substitutions, deletions, or additions compared to the given amino acid sequence, or a sequence having at least 70% sequence identity to the given amino acid sequence, or a sequence having at least 6 consecutive amino acids of the given amino acid sequence. Other examples of “substantially homologous” sequences are described elsewhere herein, which relate to the amino acid sequences “substantially homologous” to the isolated peptides, and these examples of “substantially homologous” sequences also apply to the specific peptide sequences described above.

[0041] In some preferred embodiments, the amino acid sequence that is “substantially homologous” to the isolated peptide is a sequence having or containing one of the following sequences compared to the amino acid sequence of a given isolated peptide: a sequence having 1, 2, or 3 amino acid substitutions, additions, or deletions (preferably 1 or 2, more preferably 1).

[0042] Amino acid sequences that are "substantially homologous" to the isolated peptide include sequences that contain (or consist of) at least 5 or at least 6 consecutive amino acids of the isolated peptide (or contain, or consist of) at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 15, at least 20, at least 25, or at least 30 consecutive amino acids of the isolated peptide). Six amino acids is a typical length for peptide / protein sequences that antibodies recognize or bind to.

[0043] The amino acid sequence that is "substantially homologous" to the isolated peptide includes sequences having or comprising the following sequences, which have at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity with the given isolated peptide sequence, or the sequence comprising (or consisting of) a sequence identity of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% with the given isolated peptide sequence. At least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity is preferred.

[0044] The change in amino acid sequence can be a change in conserved or non-conserved amino acids. Preferably, the change is a substitution of a conserved amino acid.

[0045] As used herein, "conservative amino acid substitution" is a substitution in which an amino acid residue is replaced by another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., glycine, cysteine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0046] The term "substantially homologous" also includes modifications or chemical equivalents of the amino acid sequence of the present invention that perform substantially the same function as the protein of the present invention in substantially the same manner. For example, any substantially homologous isolated peptide should generally retain the ability to act as a peptide or epitope to (or counteract) antibodies that can generate (or produce) antibodies that bind to TRPV1.

[0047] The methods for performing the above-described amino acid manipulations (e.g., generating "substantially homologous" sequences) are well known to those skilled in the art.

[0048] In some embodiments, the isolated peptide does not contain any internal cysteine ​​residues. An “internal” residue is a residue located at a position other than an N-terminal and / or C-terminal residue. Therefore, in some embodiments, sequences “substantially homologous” to a given amino acid sequence do not have cysteine ​​(C) residues as substitutes or additional amino acids.

[0049] Homology (e.g., sequence identity) can be assessed by any convenient method. However, to determine the degree of homology (e.g., identity) between sequences, computer programs that perform multiple alignments of sequences are useful, such as ClustalW (Thompson, Higgins, Gibson, Nucleic Acids Res. [Nucleic Acid Research], 22:4673-4680, 1994). If desired, the ClustalW algorithm can be used with the BLOSUM 62 scoring matrix (Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences], 89:10915-10919, 1992) along with a 10-space opening penalty and a 0.1-space expansion penalty to obtain a highest-order match between two sequences, where at least 50% of the total length of one of the sequences is involved in the alignment. Another method that can be used for sequence alignment is the alignment method of Needleman and Wunsch (Needleman and Wunsch, J. Mol. Biol., 48:443, 1970), revised by Smith and Waterman (Smith and Waterman, Adv. Appl. Math., 2:482, 1981), in order to obtain the highest-order match between two sequences and determine the number of identical amino acids between the two sequences. Other methods for calculating the percentage of identity between two amino acid sequences are generally accepted in the art and include, for example, those described by Carillo and Lipton (Carillo and Lipton, SIAM J. Applied Math., 48:1073, 1988) and those described in: Computational Molecular Biology, Lesk, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genomics Projects.

[0050] Typically, computer programs are used to perform such calculations. Programs for comparing and aligning sequence pairs, such as ALIGN (Myers and Miller, CABIOS [Computer Applications in the Biosciences], 4:11-17, 1988), FASTA (Pearson and Lipman, Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America], 85:2444-2448, 1988; Pearson, Methods in Enzymology [Enzymological Methods], 183:63-98, 1990), and gap BLAST (Altschul et al., Nucleic Acids Res. [Nucleic Acids Research], 25:3389-3402, 1997), BLASTP, BLASTN, or GCG (Devereux, Haeberli, Smithies, Nucleic Acids Res. [Nucleic Acids Research], 12:387, 1984), can also be used for this purpose. In addition, the Dali server of the European Institute of Bioinformatics provides structure-based protein sequence alignment (Holm, Trends in Biochemical Sciences, 20:478-480, 1995; Holm, J. Mol. Biol., 233:123-38, 1993; Holm, Nucleic Acid Res., 26:316-9, 1998).

[0051] By providing reference points, sequences according to the invention having 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% homology, sequence identity, etc., can be determined using the ALIGN program with default parameters (e.g., on the GENESTREAM web server on the Internet, IGH, Montpellier, France).

[0052] In some embodiments, the present invention provides isolated peptides that comprise (or consist of) elongated, truncated, or cyclic forms of the isolated peptide sequences (or sequences substantially homologous to them) disclosed herein. In some embodiments, the isolated peptides may be elongated and cyclic (i.e., circular). In some embodiments, the isolated peptides may be truncated and cyclic (i.e., cyclic). The elongated, truncated, and cyclic forms of peptides are discussed elsewhere herein.

[0053] The isolated peptides of the present invention may comprise (or consist of) an extended form of the isolated peptide sequence disclosed herein, or an extended form of an amino acid sequence substantially homologous to the isolated peptide sequence disclosed herein. For example, one or more additional amino acids (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 or at least 9, at least 10, at least 15 or at least 20 amino acids, or 1-5 or 1-10 or 1-20 amino acids) may be present at one or both ends of the isolated peptide sequence (or a sequence substantially homologous to it).

[0054] The isolated peptides of the present invention may comprise (or consist of) a truncated form of the isolated peptide sequence disclosed herein, or a truncated form of the isolated peptide sequence disclosed herein. For example, one or more amino acids (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9, at least 10 amino acids, or 1-5 or 1-10 amino acids) may be absent at one or both ends of the isolated peptide sequence (or a sequence substantially homologous to it).

[0055] In some embodiments, the length of the isolated peptide can be at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acids, for example, a length of 6 to 10, 6 to 12, 6 to 15, 6 to 20, 6 to 25, 6 to 30, 6 to 40, 6 to 50, 6 to 60, or 6 to 75 amino acids. The length of the isolated peptide can be, for example, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 15, 5 to 20, 5 to 25, 5 to 30, 5 to 40, 5 to 50, 5 to 60, 5 to 70, or 5 to 75 amino acids. The length of the isolated peptide can be, for example, 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 40, 8 to 50, 8 to 60, 8 to 70, or 8 to 75 amino acids.

[0056] In some implementations, the length of the isolated peptide can be ≤ 50 amino acids, for example, ≤ 45, ≤ 40, ≤ 35, ≤ 30, ≤ 25, ≤ 20, ≤ 15, or ≤ 10 amino acids (e.g., lengths of 5-10, 5-15, 5-20, 5-25, 5-30, 5-35, 5-40, 5-45, 5-50, 6-10, 6-15, 6-20, 6-25, 6-30, 6-35, 6-40, 6-45, 6-50, 8-10, 8-15, 8-20, 8-25, 8-30, 8-35, 8-40, 8-45, 8-50, 10-15, 10-20, 10-25, 10-30, 10-3...). 5, 10-40, 10-45, 10-50, 15-20, 15-25, 15-30, 15-35, 15-40, 15-45, 15-50, 20-25, 20-30, 20-35, 25-30, 25-35 or 25-40, 25-45, 25-50, 30-35, 30-40, 30-45, 30-50, 35-40, 35-45, 35-50, 40-45, 40-50 or 45-50 amino acids).

[0057] In some implementations, the length of the isolated peptide can be < 39 amino acids, for example, ≤ 38, ≤ 35, ≤ 30, ≤ 25, ≤ 20, ≤ 15, ≤ 10 amino acids (e.g., lengths of 5-10, 5-15, 5-20, 5-25, 5-30, 5-35, 5-38, 6-10, 6-15, 6-20, 6-25, 6-30, 6-35, 6-38, 8-10, 8-15, 8-20, 8-25, 8-30, 8-32, 8-35, 8-38, 10-15, 10-20, 10-25, 10-30, 10-32, 10-35, 10-38, 15-20, 15-25, 15-30, 15-32, 15-35, 15-38, 20-25, 20-30, 20-35, 25-30, 25-35, or 25-38 amino acids). In some implementations, the isolated peptide may be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38 amino acids long.

[0058] In some embodiments, the length of the isolated peptide can be < 24 amino acids, for example, ≤ 23, ≤ 20, ≤ 15, or ≤ 10 amino acids (e.g., lengths of 5-10, 5-15, 5-20, 5-23, 6-10, 6-15, 6-20, 6-23, 8-10, 8-15, 8-20, 8-23, 10-15, 10-20, 10-23, 15-20, 15-23, or 20-23 amino acids).

[0059] In some implementations, the isolated peptide may be a linear peptide (or a linear epitope).

[0060] In some implementations, the isolated peptide may be a conformational peptide (or conformational epitope).

[0061] In some implementations, the isolated peptide may be a cyclic (or ring-shaped) peptide (or a cyclic or ring-shaped epitope).

[0062] In some preferred embodiments, the sequence is based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 6 or SEQ ID NO: 20 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 7 or SEQ ID NO: 21 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 8 or SEQ ID NO: 22 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 9 or SEQ ID NO: 23 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 10 or SEQ ID NO: 24 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 11 or SEQ ID NO: 25 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 12 or SEQ ID NO: The isolated peptide of 26 (or a sequence substantially homologous to it) is a linear peptide.

[0063] In some preferred embodiments, the peptide isolated based on SEQ ID NO: 4 or SEQ ID NO: 18 (or sequences substantially homologous thereto), or based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous thereto), or based on SEQ ID NO: 14 or SEQ ID NO: 28 (or sequences substantially homologous thereto), is a cyclic peptide.

[0064] Methods for synthesizing peptides are well known in the art. A common technique for preparing linear peptides (e.g., for immunization and antibody generation) is Fmoc SPPS (solid-phase peptide synthesis). In SPPS, small porous beads are treated with functional linkers, and peptide chains are built on them using repeated wash-coupling-wash cycles. The synthesized peptide is then released from the beads using chemical cleavage. For the synthesis of cyclic peptides, common methods utilize cyclization, either by forming disulfide bridges (where the bridge is formed by the two cysteine ​​residues of the peptide, for example, one at the N-terminus and one at the C-terminus) or by forming “head-to-tail” bridges, where the bridge consists of typical peptide bonds. Cyclic peptides can be formed on solid supports.

[0065] Other methods for synthesizing peptides include using other chemical synthesis procedures, in vitro translation, or introducing them into cells via a suitable expression vector.

[0066] In some embodiments, the isolated peptide does not contain (or is not composed of) the amino acid sequence EDGKNNSLPMESTPHKCRGSACKP (SEQ ID NO: 30).

[0067] In some embodiments, the isolated peptide does not contain (or is not composed of) the amino acid sequence TLIEDGKNDSLPSESTSHRWRGPACRPPDSSYNSLYSTC (SEQ ID NO: 31).

[0068] In some embodiments, the isolated peptide does not contain (or is not composed of) the amino acid sequence SLPSESTSH (SEQ ID NO: 32).

[0069] The peptides isolated according to the present invention certainly do not include full-length TRPV1 protein (i.e., wild-type TRPV1 protein) or any other full-length (wild-type) protein in the TRPV superfamily, or any other full-length (wild-type) protein. Therefore, the peptides isolated according to the present invention do not include full-length SEQ ID NO: 1.

[0070] The peptides isolated in this invention, although corresponding to (or substantially corresponding to) regions (or epitopes) of the full-length TRPV1 protein (as described elsewhere herein), do not exist naturally (i.e., they do not have naturally occurring counterparts or do not occur independently in nature). Therefore, the peptides isolated in this invention can be considered artificial peptides, or synthetic peptides, or man-made peptides, or non-natural peptides.

[0071] Another aspect of the invention provides conjugates. Typically, the conjugates are configured for generating antibodies. The conjugates may comprise at least one isolated peptide as defined above, which is conjugated (i.e., linked to / connected to) or bonded to a peptide carrier.

[0072] Therefore, in one aspect, the present invention provides conjugates comprising the isolated peptides of the present invention. The conjugates typically comprise the isolated peptides of the present invention and a peptide carrier, wherein the isolated peptides are conjugated or mixed with the peptide carrier. The peptide carriers typically enhance immunogenicity. This can be useful because, in some cases, short peptides that provide (or represent or correspond to) antigenic epitopes are too small to induce an immune response.

[0073] Peptide carriers are typically macromolecules, such as proteins, polysaccharides, or polymeric amino acids. In some embodiments, the peptide carrier is selected from the group consisting of: keyhole cyanin (KLH), ovalbumin (OVA), serum albumin (e.g., bovine serum albumin, BSA), polylysine, etc. KLH is generally preferred.

[0074] The coupling of the isolated peptide to the peptide carrier of the present invention can be, for example, covalent coupling or disulfide bridging. In some embodiments, the isolated peptide of the present invention may have (additional) cysteine ​​residues at its N-terminus or C-terminus (e.g., as described elsewhere herein). Such cysteine ​​residues generally facilitate the coupling of the isolated peptide to the peptide carrier (e.g., KLH). In some embodiments, the isolated peptide may have modifications (e.g., chemical groups, such as propargyl groups) that allow the isolated peptide to couple with the peptide carrier. In some embodiments, the isolated peptide is coupled to the peptide carrier via a standard crosslinking agent (e.g., glutaraldehyde). Methods for linking the isolated peptide to the peptide carrier are well known in the art.

[0075] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 2 (OTV3) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0076] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 2 (OTV3).

[0077] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 2 (OTV3) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0078] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence (OTV3) of SEQ ID NO: 2.

[0079] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 16 (OTV3) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0080] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 16 (OTV3).

[0081] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 16 (OTV3) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0082] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 16 (OTV3).

[0083] In some embodiments, the peptide isolated based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto) is at least 25 amino acids long, or at least 30 amino acids long, or at least 32 amino acids long (e.g., 25-35, 25-38, 25-45, 25-55, 25-65, or 25 to 75 amino acids long). In some embodiments, the peptide isolated based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto) is less than 39 amino acids long, less than 38 amino acids long, less than 37 amino acids long, less than 36 amino acids long, less than 35 amino acids long, less than 34 amino acids long, or less than 33 amino acids long (e.g., 20-25, 20-30, 20-32, 20-38, 25-30, 25-32, 25-38, or 30-38 amino acids long). In some embodiments, the peptide isolated based on SEQ ID NO: 2 or SEQ ID NO: 16 (or sequences substantially homologous thereto) is 29-35 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 2 or SEQ ID NO: 16 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 2 or SEQ ID NO: 16 (or sequences substantially homologous thereto) has an N-terminal cysteine ​​residue.

[0084] In some embodiments, the isolated peptides that are substantially homologous to SEQ ID NO: 2 or SEQ ID NO: 16 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 2 or SEQ ID NO: 16 itself.

[0085] Preferably, the peptide isolated based on SEQ ID NO: 2 or SEQ ID NO: 16 (or sequences substantially homologous to them) is a linear peptide.

[0086] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, the isolated peptide comprising (or consisting of) SEQ ID NO: 2 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 16 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 16 (preferably via the N-terminal cysteine ​​residue of SEQ ID NO: 16) conjugated to the peptide carrier KLH.

[0087] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 3 (OTV4) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0088] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 3 (OTV4).

[0089] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 3 (OTV4) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0090] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV4) of SEQ ID NO: 3.

[0091] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 17 (OTV4) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0092] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 17 (OTV4).

[0093] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 17 (OTV4) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0094] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV4) of SEQ ID NO: 17.

[0095] In some embodiments, the peptide isolated based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) is at least 25 amino acids long, or at least 30 amino acids long, or at least 32 amino acids long (e.g., 25-35, 25-38, 25-45, 25-55, 25-65, or 25 to 75 amino acids long). In some embodiments, the peptide isolated based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) is less than 39 amino acids long, less than 38 amino acids long, or less than 37 amino acids long, or less than 36 amino acids long, or less than 35 amino acids long, or less than 34 amino acids long, or less than 33 amino acids long (e.g., 20-25, 20-30, 20-32, 20-38, 25-30, 25-32, 25-38, or 30-38 amino acids long). In some embodiments, the peptide isolated based on SEQ ID NO: 3 or SEQ ID NO: 17 (or sequences substantially homologous thereto) is 29-35 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 3 or SEQ ID NO: 17 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. An “internal” residue refers to a residue at a position other than an N-terminal and / or C-terminal residue. In some embodiments, the cysteine ​​at position 23 of SEQ ID NO: 3 or position 24 of SEQ ID NO: 17 is substituted with a different amino acid residue. In other embodiments, the peptide isolated based on SEQ ID NO: 3 or SEQ ID NO: 17 (or sequences substantially homologous thereto) contains at least one (e.g., 1) internal cysteine ​​residue (e.g., at position 23 of SEQ ID NO: 3 or position 24 of SEQ ID NO: 17). In some embodiments, the peptide isolated based on SEQ ID NO: 3 or SEQ ID NO: 17 (or sequences substantially homologous to them) has an N-terminal cysteine ​​residue.

[0096] In some embodiments, the isolated peptides that are substantially homologous to SEQ ID NO: 3 or SEQ ID NO: 17 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 3 or SEQ ID NO: 17 itself.

[0097] Preferably, the peptide isolated based on SEQ ID NO: 3 or SEQ ID NO: 17 (or sequences substantially homologous to them) is a linear peptide.

[0098] In one aspect, the present invention provides a conjugate comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 3 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 17 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 17 (preferably via the N-terminal cysteine ​​residue of SEQ ID NO: 17) conjugated to the peptide carrier KLH.

[0099] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 4 (OTV5) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0100] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 4 (OTV5).

[0101] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 4 (OTV5) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0102] In one embodiment, the present invention provides a isolated peptide consisting of the amino acid sequence (OTV5) of SEQ ID NO: 4.

[0103] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 18 (OTV5) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0104] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 18 (OTV5).

[0105] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 18 (OTV5) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0106] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence (OTV5) of SEQ ID NO: 18.

[0107] In some embodiments, the peptide isolated based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto) is at least 25 amino acids long, or at least 30 amino acids long, or at least 32 amino acids long (e.g., 25-35, 25-45, 25-55, 25-65, or 25 to 75 amino acids long). In some embodiments, the peptide isolated based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto) is less than 39 amino acids long, less than 38 amino acids long, or less than 37 amino acids long, or less than 36 amino acids long, or less than 35 amino acids long, or less than 34 amino acids long, or less than 33 amino acids long (e.g., 20-25, 20-30, 20-31, 25-30, 25-32, 20-38, 25-38, or 30-38 amino acids long). In some embodiments, the peptide isolated based on SEQ ID NO: 4 or SEQ ID NO: 18 (or sequences substantially homologous thereto) is 29-35 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 4 or SEQ ID NO: 18 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than the N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 4 or SEQ ID NO: 18 (or sequences substantially homologous thereto) has both N-terminal and C-terminal cysteine ​​residues. In some embodiments, additional modifications may be present at the N-terminus and / or C-terminus (e.g., an acetylacetic group at the N-terminus and / or an amide group at the C-terminus).

[0108] In some embodiments, the isolated peptides that are substantially homologous to SEQ ID NO: 4 or SEQ ID NO: 18 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 4 or SEQ ID NO: 18 itself.

[0109] Preferably, the peptide isolated based on SEQ ID NO: 4 or SEQ ID NO: 18 (or sequences substantially homologous to them) is a cyclic peptide. Preferably, such peptides are cyclized via disulfide bonds between N-terminal and C-terminal cysteine ​​residues.

[0110] In one aspect, the present invention provides a conjugate comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, the isolated peptide comprising (or consisting of) SEQ ID NO: 4 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 18 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 18 (preferably via the propargyl group of SEQ ID NO: 18) conjugated to the peptide carrier KLH.

[0111] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 5 (OTV6) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0112] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 5 (OTV6).

[0113] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 5 (OTV6) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0114] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence (OTV6) of SEQ ID NO: 5.

[0115] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 19 (OTV6) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0116] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 19 (OTV6).

[0117] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 19 (OTV6) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0118] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence (OTV6) of SEQ ID NO: 19.

[0119] In some embodiments, the peptide isolated based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous to it) has a length of < 24 amino acids, or a length of < 20 amino acids, < 15 amino acids, or < 10 amino acids (e.g., lengths of 5-10, 5-12, 5-15, 5-20, 5-23, 8-23, 10-23, 15-23, 20-23, 5-10, 8-10, 10-15, 5-15, 8-15, 10-15, 5-20, 8-20, or 10-20 amino acids). In some embodiments, the peptide isolated based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous to it) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 5-10, 5-15, 5-20, 5-25, or 5-30, or 5-32, or 5-38, or 8-10, 8-15, 8-20, 8-25, or 8-30, or 8-32, or 8-38, or 10-38, or 15-38, or 20-38, or 20-25, or 20-30, or 20-32, or 25-30, or 25-32, or 25-38, or 30-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 5 or SEQ ID NO: 19 (or sequences substantially homologous thereto) is 5-11 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 5 or SEQ ID NO: 19 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 5 or SEQ ID NO: 19 (or sequences substantially homologous thereto) has an N-terminal cysteine ​​residue.

[0120] In some embodiments, isolated peptides substantially homologous to SEQ ID NO: 5 or SEQ ID NO: 19 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 5 or SEQ ID NO: 19 itself.

[0121] Preferably, the peptide isolated based on SEQ ID NO: 5 or SEQ ID NO: 19 (or sequences substantially homologous to them) is a linear peptide.

[0122] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, the isolated peptide comprising (or consisting of) SEQ ID NO: 5 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 19 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 19 (preferably via the N-terminal cysteine ​​residue of SEQ ID NO: 19) conjugated to the peptide carrier KLH.

[0123] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 6 (OTV7) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0124] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 6 (OTV7).

[0125] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 6 (OTV7) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0126] In one embodiment, the present invention provides a isolated peptide consisting of the amino acid sequence (OTV7) of SEQ ID NO: 6.

[0127] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 20 (OTV7) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0128] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 20 (OTV7).

[0129] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 20 (OTV7) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0130] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV7) of SEQ ID NO: 20.

[0131] In some embodiments, the peptide isolated based on SEQ ID NO: 6 or SEQ ID NO: 20 (or a sequence substantially homologous thereto) has a length of < 24 amino acids, or a length of < 20 amino acids, a length of < 15 amino acids, or a length of < 10 amino acids (e.g., a length of 5-23 or 8-23 or 10-23 or 15-23 or 16-23 or 20-23 or 5-10 or 8-10 or 10-15 or 5-15 or 8-15 or 10-15 or 5-20 or 8-20 or 16-20 or 10-20 amino acids). In some embodiments, the peptide isolated based on SEQ ID NO: 6 or SEQ ID NO: 20 (or sequences substantially homologous to them) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 12-20, 12-25, 12-30, 12-32, 12-38, 16-20, 16-25, 16-30, 16-32, 16-38, 20-25, 20-30, 20-32, 25-30, 25-32, 25-38, or 30-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 6 or SEQ ID NO: 20 (or sequences substantially homologous to them) is 13-19 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 6 or SEQ ID NO: 20 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 6 or SEQ ID NO: 20 (or sequences substantially homologous thereto) has an N-terminal cysteine ​​residue.

[0132] In some embodiments, isolated peptides that are substantially homologous to SEQ ID NO: 6 or SEQ ID NO: 20 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 6 or SEQ ID NO: 20 itself.

[0133] Preferably, the peptide isolated based on SEQ ID NO: 6 or SEQ ID NO: 20 (or sequences substantially homologous to them) is a linear peptide.

[0134] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 6 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 20 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 20 (preferably via the N-terminal cysteine ​​residue of SEQ ID NO: 20) conjugated to the peptide carrier KLH.

[0135] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 7 (OTV8) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0136] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 7 (OTV8).

[0137] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 7 (OTV8) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0138] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence (OTV8) of SEQ ID NO: 7.

[0139] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 21 (OTV8) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0140] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 21 (OTV8).

[0141] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 21 (OTV8) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0142] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV8) of SEQ ID NO: 21.

[0143] In some embodiments, the peptide isolated based on SEQ ID NO: 7 or SEQ ID NO: 21 (or sequences substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 20-25, 20-30, 20-32, 20-38, 25-30, 25-32, 25-38, 30-38, 24-30, or 24-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 7 or SEQ ID NO: 21 (or sequences substantially homologous thereto) is 21-27 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 7 or SEQ ID NO: 21 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 7 or SEQ ID NO: 21 (or sequences substantially homologous to them) has an N-terminal cysteine ​​residue.

[0144] In some embodiments, isolated peptides that are substantially homologous to SEQ ID NO: 7 or SEQ ID NO: 21 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 7 or SEQ ID NO: 21 itself.

[0145] Preferably, the peptide isolated based on SEQ ID NO: 7 or SEQ ID NO: 21 (or sequences substantially homologous to them) is a linear peptide.

[0146] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 7 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 21 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 21 (preferably via the N-terminal cysteine ​​residue of SEQ ID NO: 21) conjugated to the peptide carrier KLH.

[0147] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 8 (OTV9) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0148] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 8 (OTV9).

[0149] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 8 (OTV9) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0150] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence (OTV9) of SEQ ID NO: 8.

[0151] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 22 (OTV9) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0152] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 22 (OTV9).

[0153] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 22 (OTV9) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0154] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV9) of SEQ ID NO: 22.

[0155] In some embodiments, the peptide isolated based on SEQ ID NO: 8 or SEQ ID NO: 22 (or sequences substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 20-25, 20-30, 20-32, 20-38, 25-30, 25-32, 25-38, 30-38, 24-30, or 24-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 8 or SEQ ID NO: 22 (or sequences substantially homologous thereto) is 21-27 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 8 or SEQ ID NO: 22 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 8 or SEQ ID NO: 22 (or sequences substantially homologous to them) has a C-terminal cysteine ​​residue.

[0156] In some embodiments, the isolated peptides that are substantially homologous to SEQ ID NO: 8 or SEQ ID NO: 22 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 8 or SEQ ID NO: 22 itself.

[0157] Preferably, the peptide isolated based on SEQ ID NO: 8 or SEQ ID NO: 22 (or sequences substantially homologous to them) is a linear peptide.

[0158] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 8 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 22 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 22 (preferably via the N-terminal cysteine ​​residue of SEQ ID NO: 22) conjugated to the peptide carrier KLH.

[0159] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 9 (OTV10) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0160] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 9 (OTV10).

[0161] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 9 (OTV10) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0162] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV10) of SEQ ID NO: 9.

[0163] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 9 (OTV10) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0164] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 23 (OTV10).

[0165] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 23 (OTV10) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0166] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV10) of SEQ ID NO: 23.

[0167] In some embodiments, the peptide isolated based on SEQ ID NO: 9 or SEQ ID NO: 23 (or sequences substantially homologous to them) has a length of < 24 amino acids, or a length of < 20 amino acids, a length of < 15 amino acids, or a length of < 10 amino acids (e.g., lengths of 5-23 or 8-23 or 10 to 23 or 15 to 23 or 16-23 or 20-23 or 5-10 or 8-10 or 10-15 or 5-15 or 8-15 or 10-15 or 5-20 or 8-20 or 10-20 or 16-20 amino acids). In some embodiments, the peptide isolated based on SEQ ID NO: 9 or SEQ ID NO: 23 (or a sequence substantially homologous to it) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 12-20 or 12-25 or 12-30 or 12-32 or 12-38 or 16-20 or 16-25 or 16-30 or 16-32 or 16-38 or 20-25 or 20-30 or 20-32 or 20-38 or 25-30 or 25-32 or 25-38 or 30-38 or 16-30 or 16-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 9 or SEQ ID NO: 23 (or sequences substantially homologous thereto) is 13-19 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 9 or SEQ ID NO: 23 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 9 or SEQ ID NO: 23 (or sequences substantially homologous thereto) has a C-terminal cysteine ​​residue.

[0168] In some embodiments, isolated peptides that are substantially homologous to SEQ ID NO: 9 or SEQ ID NO: 23 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 9 or SEQ ID NO: 23 itself.

[0169] Preferably, the peptide isolated based on SEQ ID NO: 9 or SEQ ID NO: 23 (or sequences substantially homologous to them) is a linear peptide.

[0170] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 9 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 23 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 23 (preferably via the C-terminal cysteine ​​residue of SEQ ID NO: 23) conjugated to the peptide carrier KLH.

[0171] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 10 (OTV11) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0172] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 10 (OTV11).

[0173] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 10 (OTV11) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0174] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV11) of SEQ ID NO: 10.

[0175] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 24 (OTV11) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0176] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 24 (OTV11).

[0177] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 24 (OTV11) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0178] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV11) of SEQ ID NO: 24.

[0179] In some embodiments, the peptide isolated based on SEQ ID NO: 10 or SEQ ID NO: 24 (or sequences substantially homologous to them) is < 24 amino acids in length, or < 20 amino acids in length, < 15 amino acids in length, or < 10 amino acids in length (e.g., 5-23 or 8-23 or 10 to 23 or 15 to 23 or 20-23 or 5-10 or 8-10 or 10-15 or 5-15 or 8-15 or 10-15 or 5-20 or 8-20 or 10-20 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 10 or SEQ ID NO: 24 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 10-10, 5-15, 5-20, 5-25, or 5-30, or 5-32, or 5-30, or 8-10, 8-15, 8-20, 8-25, or 8-30, or 8-32, or 8-38, or 10-38, or 15-38, or 20-38, or 20-25, or 20-30, or 20-32, or 25-30, or 25-32, or 25-38, or 30-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 10 or SEQ ID NO: 24 (or sequences substantially homologous thereto) is 5-11 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 10 or SEQ ID NO: 24 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 10 or SEQ ID NO: 24 (or sequences substantially homologous thereto) has a C-terminal cysteine ​​residue.

[0180] In some embodiments, isolated peptides that are substantially homologous to SEQ ID NO: 10 or SEQ ID NO: 24 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 10 or SEQ ID NO: 24 itself.

[0181] Preferably, the peptide isolated based on SEQ ID NO: 10 or SEQ ID NO: 24 (or sequences substantially homologous to them) is a linear peptide.

[0182] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 10 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 24 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 24 (preferably via the C-terminal cysteine ​​residue of SEQ ID NO: 24) conjugated to the peptide carrier KLH.

[0183] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 11 (OTV12) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0184] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 11 (OTV12).

[0185] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 11 (OTV12) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0186] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV12) of SEQ ID NO: 11.

[0187] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 25 (OTV12) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0188] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 25 (OTV12).

[0189] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 25 (OTV12) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0190] In one embodiment, the present invention provides a isolated peptide consisting of the amino acid sequence (OTV12) of SEQ ID NO: 25.

[0191] In some embodiments, the peptide isolated based on SEQ ID NO: 11 or SEQ ID NO: 25 (or sequences substantially homologous to them) has a length of < 24 amino acids, or a length of < 20 amino acids, a length of < 15 amino acids, or a length of < 10 amino acids (e.g., a length of 5-23 or 8-23 or 10-23 or 15-23 or 20-23 or 5-10 or 8-10 or 10-15 or 5-13 or 8-13 or 10-13 or 5-15 or 8-15 or 5-20 or 8-20 or 10-20 or 13-15 or 13-20 amino acids). In some embodiments, the peptide isolated based on SEQ ID NO: 11 or SEQ ID NO: 25 (or a sequence substantially homologous to it) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 5-10 or 5-15 or 5-25 or 5-30 or 5-32 or 5-30 or 5-38 or 8-32 or 8-38 or 10-38 or 13-15 or 13-20 or 13-25 or 13-30 or 13-32 or 13-38 or 15-38 or 20-38 or 20-25 or 20-30 or 20-32 or 25-30 or 25-32 or 25-38 or 30-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 11 or SEQ ID NO: 25 (or sequences substantially homologous thereto) is 10-16 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 11 or SEQ ID NO: 25 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 11 or SEQ ID NO: 25 (or sequences substantially homologous thereto) has a C-terminal cysteine ​​residue.

[0192] In some embodiments, isolated peptides that are substantially homologous to SEQ ID NO: 11 or SEQ ID NO: 25 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 11 or SEQ ID NO: 25 itself.

[0193] Preferably, the peptide isolated based on SEQ ID NO: 11 or SEQ ID NO: 25 (or sequences substantially homologous to them) is a linear peptide.

[0194] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 11 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 25 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 25 (preferably via the C-terminal cysteine ​​residue of SEQ ID NO: 25) conjugated to the peptide carrier KLH.

[0195] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 12 (OTV13) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0196] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 12 (OTV13).

[0197] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 12 (OTV13) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0198] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV13) of SEQ ID NO: 12.

[0199] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 26 (OTV13) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0200] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 26 (OTV13).

[0201] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 26 (OTV13) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0202] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV13) of SEQ ID NO: 26.

[0203] In some embodiments, the peptide isolated based on SEQ ID NO: 12 or SEQ ID NO: 26 (or sequences substantially homologous to them) has a length of < 24 amino acids, or a length of < 20 amino acids, a length of < 15 amino acids, or a length of < 10 amino acids (e.g., a length of 5-23 or 8-23 or 10-23 or 15-23 or 20-23 or 5-10 or 8-10 or 10-15 or 5-13 or 8-13 or 10-13 or 5-15 or 8-15 or 5-20 or 8-20 or 10-20 or 13-15 or 13-20 amino acids). In some embodiments, the peptide isolated based on SEQ ID NO: 12 or SEQ ID NO: 26 (or sequences substantially homologous to them) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 5-10 or 5-15 or 5-25 or 5-30 or 5-32 or 5-30 or 5-38 or 8-32 or 8-38 or 10-38, 13-15 or 13-20 or 13-25 or 13-30 or 13-32 or 13-38 or 15-38 or 20-38 or 20-25 or 20-30 or 20-32 or 25-30 or 25-32 or 25-38 or 30-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 12 or SEQ ID NO: 26 (or sequences substantially homologous thereto) is less than 39 amino acids in length, or 10-16 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 12 or SEQ ID NO: 26 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 12 or SEQ ID NO: 26 (or sequences substantially homologous thereto) has an N-terminal cysteine ​​residue.

[0204] In some embodiments, isolated peptides that are substantially homologous to SEQ ID NO: 12 or SEQ ID NO: 26 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 12 or SEQ ID NO: 26 itself.

[0205] Preferably, the peptide isolated based on SEQ ID NO: 12 or SEQ ID NO: 26 (or sequences substantially homologous to them) is a linear peptide.

[0206] In one aspect, the present invention provides conjugates comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 12 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 26 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides conjugates comprising an isolated peptide consisting of SEQ ID NO: 26 (preferably via the N-terminal cysteine ​​residue of SEQ ID NO: 26) conjugated to the peptide carrier KLH.

[0207] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 13 (OTV14) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0208] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 13 (OTV14).

[0209] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 13 (OTV14) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0210] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV14) of SEQ ID NO: 13.

[0211] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 27 (OTV14) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0212] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 27 (OTV14).

[0213] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 27 (OTV14) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0214] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV14) of SEQ ID NO: 27.

[0215] Preferably, the peptide isolated based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous thereto) comprises an amino sequence (or motif) IED and / or (preferably "and") NYD. The amino acid sequence IED is located at positions 11-13 of SEQ ID NO: 13 and positions 12-14 of SEQ ID NO: 27. The amino acid sequence NYD is located at positions 4-6 of SEQ ID NO: 13 and positions 5-7 of SEQ ID NO: 27.

[0216] Preferably, the peptide isolated based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous thereto) has no more than one (preferably none) amino acid substitution or deletion in the IED motif and / or no more than one (preferably none) amino acid substitution or deletion in the NYD motif.

[0217] The OTV14 peptides (represented by SEQ ID NO: 13 and 27) are conformational epitopes. The IED motif in these sequences corresponds to amino acid positions 599-601 of TRPV1 (SEQ ID NO: 1), and the NYD motif in these sequences corresponds to amino acid positions 653-655 of TRPV1 (SEQ ID NO: 1). Not wishing to be bound by theory, other residues (i.e., residues other than the IED and NYD motifs) act as spacers, believed to force the side chains of the IED and NYD motifs into specific conformations that mimic the actual conformation in a structural model of the complete TRPV1 sequence.

[0218] In some embodiments, the peptide isolated based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous to them) has a length of < 24 amino acids, or a length of < 20 amino acids, or a length of < 15 amino acids (e.g., a length of 5-23 or 8-23 or 10 to 23 or 15 to 23 or 20-23 or 5-10 or 8-10 or 5-11 or 8-11 or 10-15 or 11-15 or 5-15 or 8-15 or 5-20 or 8-20 or 10-20 or 11-20 amino acids). In some embodiments, the peptide isolated based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous to them) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 5-15, 10-15, 10-20, 10-30, 10-35, 10-38, 20-25, 20-30, 20-32, 25-30, 25-32, 25-38, or 30-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous to them) is 12-18 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. "Internal" residues refer to residues located at positions other than N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous thereto) has both N-terminal and C-terminal cysteine ​​residues. In some embodiments, additional modifications may be present at the N-terminus and / or C-terminus (e.g., a propargyl group at the N-terminus and / or an amide group at the C-terminus).

[0219] In some embodiments, isolated peptides that are substantially homologous to SEQ ID NO: 13 or SEQ ID NO: 27 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 13 or SEQ ID NO: 27 itself.

[0220] Preferably, the peptide isolated based on SEQ ID NO: 13 or SEQ ID NO: 27 (or sequences substantially homologous to them) is a cyclic peptide. Preferably, such peptides are cyclized via disulfide bonds between N-terminal and C-terminal cysteine ​​residues.

[0221] In one aspect, the present invention provides a conjugate comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, said isolated peptide comprising (or consisting of) SEQ ID NO: 13 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 27 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides a conjugate comprising an isolated peptide composed of SEQ ID NO: 28 conjugated to the peptide carrier KLH (preferably via the propargyl group of SEQ ID NO: 27).

[0222] In one aspect, the present invention provides isolated peptides comprising an amino acid sequence (or motif) NYD and an amino acid sequence (or motif) IED, wherein the amino acid sequence NYD is located at the N-terminus relative to the amino acid sequence IED, and preferably the NYD and IED sequences are separated by one or more amino acid residues (e.g., separated by 3, 4, or 5 amino acid residues, preferably separated by 4 amino acid residues, for example separated by the amino acid sequence PDGS (SEQ ID NO: 38)). Such isolated peptides may further comprise one or more (e.g., 1, 2, or 3) amino acid residues located at the N-terminus relative to the NYD sequence and / or (preferably "and") one or more (e.g., 1, 2, or 3) amino acid residues located at the C-terminus relative to the IED sequence. Discussions elsewhere herein regarding preferred features and properties (e.g., preferred lengths and modifications) of the isolated peptides of the present invention may be applied, with necessary modifications, to the aspects described herein. In another aspect, the present invention provides a conjugate comprising (i) an isolated peptide comprising an amino acid sequence (or motif) NYD and an amino acid sequence (or motif) IED, wherein the amino acid sequence NYD is located at the N-terminus relative to the amino acid sequence IED, and (ii) a peptide carrier. In a preferred embodiment, the isolated peptide is as described elsewhere herein.

[0223] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 14 (OTV15) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0224] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 14 (OTV15).

[0225] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 14 (OTV15) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0226] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV15) of SEQ ID NO: 14.

[0227] In one embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 28 (OTV15) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0228] In a preferred embodiment, the present invention provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 28 (OTV15).

[0229] In one embodiment, the present invention provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 28 (OTV15) or a substantially homologous sequence thereof. The substantially homologous sequence is described elsewhere herein.

[0230] In one embodiment, the present invention provides a separated peptide consisting of the amino acid sequence (OTV15) of SEQ ID NO: 28.

[0231] In some embodiments, the peptide isolated based on SEQ ID NO: 14 or SEQ ID NO: 28 (or sequences substantially homologous thereto) comprises the amino sequence ESTSH. In some embodiments, the peptide isolated based on SEQ ID NO: 14 or SEQ ID NO: 28 (or sequences substantially homologous thereto) is < 24 amino acids in length, or < 20 amino acids in length, < 15 amino acids in length, or < 10 amino acids in length (e.g., 5-23 or 8-23 or 10 to 23 or 15 to 23 or 20-23 or 5-10 or 8-10 or 5-11 or 8-11 or 10-15 or 11-15 or 5-15 or 8-15 or 5-20 or 8-20 or 10-20 or 11-20 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 14 or SEQ ID NO: 28 (or sequences substantially homologous to them) is less than 39 amino acids in length, less than 38 amino acids in length, less than 37 amino acids in length, less than 36 amino acids in length, less than 35 amino acids in length, less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 5-15, 10-15, 10-20, 10-30, 10-35, 10-38, 20-25, 20-30, 20-32, 25-30, 25-32, 25-38, or 30-38 amino acids in length). In some embodiments, the peptide isolated based on SEQ ID NO: 14 or SEQ ID NO: 28 (or sequences substantially homologous to them) is 8-14 amino acids in length. In some embodiments, the peptide isolated based on SEQ ID NO: 14 or SEQ ID NO: 28 (or sequences substantially homologous thereto) does not contain any internal cysteine ​​residues. “Internal” residues refer to residues located at positions other than the N-terminal and / or C-terminal residues. In some embodiments, the peptide isolated based on SEQ ID NO: 14 or SEQ ID NO: 28 (or sequences substantially homologous thereto) has both N-terminal and C-terminal cysteine ​​residues. In some embodiments, additional modifications may be present at the N-terminus and / or C-terminus (e.g., an N-terminal propargyl group and / or a C-terminal amide group).

[0232] In some embodiments, isolated peptides that are substantially homologous to SEQ ID NO: 14 or SEQ ID NO: 28 have one, two, or three amino acid substitutions, deletions, or additions compared to SEQ ID NO: 14 or SEQ ID NO: 28 itself.

[0233] Preferably, the peptide isolated based on SEQ ID NO: 14 or SEQ ID NO: 28 (or sequences substantially homologous to them) is a cyclic peptide. Preferably, such peptides are cyclized via disulfide bonds between N-terminal and C-terminal cysteine ​​residues.

[0234] In one aspect, the present invention provides a conjugate comprising an isolated peptide and (e.g., conjugated thereto) a peptide carrier, the isolated peptide comprising (or consisting of) SEQ ID NO: 14 (or a sequence substantially homologous thereto) or comprising (or consisting of) SEQ ID NO: 28 (or a sequence substantially homologous thereto). The peptide carrier is described elsewhere herein. In a preferred embodiment, the peptide carrier is KLH. In a preferred embodiment, the present invention provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 28 conjugated to the peptide carrier KLH (preferably via the propargyl group of SEQ ID NO: 28).

[0235] In some embodiments, the isolated peptide (or conjugate) according to the invention may be present in a solution or suspension. Therefore, in one aspect, the invention provides compositions comprising the isolated peptide of the invention, and optionally acceptable (e.g., pharmaceutically acceptable) diluents, buffers, preservatives, and / or excipients.

[0236] In some embodiments, the isolated peptide (or conjugate) may be present (i.e., attached or bound to) a solid support (e.g., beads or microbeads or plates or microtiter plates). Therefore, in one aspect, the present invention provides a solid support attached (directly or indirectly) to the isolated peptide or conjugate of the present invention.

[0237] The isolated peptides (and conjugates) of this invention are generally suitable for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1). For example, the isolated peptides of this invention are generally suitable as antigenic epitopes for identifying (or generating or producing) antibodies. The identification (or generation or production) of antibodies using the isolated peptides of this invention can be carried out in any suitable manner, and suitable techniques are familiar to those skilled in the art (e.g., as discussed elsewhere herein). For example, the isolated peptides (and conjugates) of this invention are generally suitable for identifying (or generating or producing) polyclonal antibodies that bind to TRPV1 (e.g., polyclonal antibodies generated in animals such as rabbits that have been immunized with the isolated peptides (or conjugates) of this invention), or for identifying (or generating or producing) monoclonal antibodies using standard hybridoma techniques or phage display. In other words, the isolated peptides (and conjugates) of this invention generally represent (or correspond to or substantially correspond to) useful epitopes of TRPV1 for targeting with anti-TRPV1 antibodies.

[0238] In some embodiments, the isolated peptides (and conjugates) of the present invention are suitable for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1) and inhibit capsaicin-induced TRPV1 activation.

[0239] In some embodiments, the isolated peptides (and conjugates) of the present invention are suitable for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1) and do not significantly inhibit heat-induced TRPV1 activation.

[0240] In some embodiments, the isolated peptides (and conjugates) of the present invention are suitable for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1) and preferentially inhibit capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation. In some such embodiments, isolated peptides OTV4, OTV5, and OTV12 are preferred. In some such embodiments, isolated peptides OTV3, OTV4, and OTV5 are preferred. In some embodiments, OTV5 is preferred. In some embodiments, OTV4 is preferred. In some embodiments, OTV3 is preferred.

[0241] The isolated peptides (and conjugates) of the present invention correspond (or substantially correspond) to an epitope (or region or portion) of TRPV1 (preferably human TRPV1, SEQ ID NO: 1), which is located in a region of TRPV1 (preferably human TRPV1, SEQ ID NO: 1) from amino acid residue 599 to amino acid residue 656.

[0242] In some embodiments, the isolated peptide of the present invention has an amino acid residue other than cysteine ​​(C) (preferably serine (S)) at position C621 corresponding to human TRPV1 (SEQ ID NO: 1).

[0243] In some embodiments, the isolated peptide of the present invention comprises the amino acid sequence IEDGKN (SEQ ID NO: 33) or a sequence containing 1, 2 or 3 amino acid substitutions, deletions or additions compared to SEQ ID NO: 33.

[0244] In some embodiments, the isolated peptide of the present invention comprises the amino acid sequence LPSEST (SEQ ID NO: 34) or a sequence containing 1, 2 or 3 amino acid substitutions, deletions or additions compared to SEQ ID NO: 34.

[0245] In some embodiments, the isolated peptide of the present invention comprises the amino acid sequence PPDSSYNS (SEQ ID NO:35) or a sequence containing 1, 2 or 3 amino acid substitutions, deletions or additions compared to SEQ ID NO:35.

[0246] In some embodiments, the isolated peptide of the present invention comprises the amino acid sequence RWRGPA (SEQ ID NO: 36) or a sequence containing 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 36.

[0247] In some embodiments, the isolated peptide of the present invention comprises the amino acid sequence RGPASR (SEQ ID NO: 37) or a sequence containing 1, 2 or 3 amino acid substitutions, deletions or additions compared to SEQ ID NO: 37.

[0248] Nucleic acid molecules that contain (or consist of) nucleotide sequences encoding isolated peptides of the present invention as defined herein, or nucleic acid molecules substantially homologous to them, form yet another aspect of the present invention.

[0249] As used herein, the term “substantially homologous” in relation to nucleic acid sequences includes sequences that have at least 65%, 70%, or 75%, preferably at least 80%, and even more preferably at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the starting nucleic acid sequence.

[0250] As used herein, the term "nucleic acid sequence" or "nucleic acid molecule" refers to a sequence of nucleoside or nucleotide monomers composed of naturally occurring bases, sugars, and inter-sugar (backbone) bonds. The term also includes modified or substituted sequences that contain non-naturally occurring monomers or portions thereof. The nucleic acid sequences of this invention can be deoxyribonucleic acid (DNA) sequences or ribonucleic acid (RNA) sequences and can include naturally occurring bases (including adenine, guanine, cytosine, thymidine, and uracil). The sequences can also contain modified bases. Examples of such modified bases include aza- and deazoadenine, guanine, cytosine, thymidine, and uracil; and xanthine and hypoxanthine. Nucleic acid molecules can be double-stranded or single-stranded. Nucleic acid molecules can be wholly or partially synthetic or recombinant.

[0251] In another aspect, the present invention provides compositions comprising the isolated peptides (or conjugates) of the present invention. Such compositions may further comprise (e.g., mixed therewith) suitable diluents, carriers, excipients, and / or preservatives (e.g., pharmaceutically acceptable diluents, carriers, excipients, and / or preservatives).

[0252] As described above, the isolated peptides (and conjugates) of the present invention are generally suitable for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1) and preferentially inhibit capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation.

[0253] Therefore, in one aspect, the present invention provides antibodies, such as isolated antibodies, that bind (or specifically recognize or specifically bind) TRPV1, wherein the antibodies preferentially inhibit capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation.

[0254] In a preferred embodiment, TRPV1 (transient receptor potential vanillic acid type 1) is human TRPV1 (hTRPV1). The amino acid sequence of human TRPV1 is shown in SEQ ID NO: 1 herein.

[0255] In some embodiments, the antibody of the present invention binds to an epitope of TRPV1 located in the extracellular region of the TRPV1 protein. In some embodiments, the antibody binds to an epitope of TRPV1 in the region of TRPV1 defined by amino acid residues 599-656 of TRPV1 (SEQ ID NO: 1). In some embodiments, the entire epitope bound is located within this region of TRPV1. In some embodiments, at least one amino acid of the bound epitope is located within this region of TRPV1.

[0256] In a preferred embodiment, the antibody of the present invention binds to (or is able to bind to) the isolated peptide or conjugate of the present invention. Preferred isolated peptides and conjugates, and preferred groups of isolated peptides and conjugates, are defined elsewhere herein. In a preferred embodiment, the antibody of the present invention binds to the preferred isolated peptide or conjugate as described elsewhere herein. The ability of the antibody to bind to the isolated peptide can be assessed by any suitable means, and suitable methods are familiar to those skilled in the art (e.g., ELISA assays to assess whether a given isolated peptide can competitively bind to a full-length TRPV1 antibody).

[0257] Although the preferred antibodies of the present invention bind (or are able to bind) the isolated peptides or conjugates of the present invention, they generally also bind full-length (or wild-type or natural) TRPV1 (preferably human TRPV1).

[0258] In some embodiments, full-length (or wild-type or natural) TRPV1 (preferably human TRPV1) is TRPV1 expressed on cells, preferably on mammalian cells (e.g., adherent Chinese hamster ovary (CHO) cells). In some embodiments, the antibodies of the present invention are capable of binding to TRPV1 heterologously expressed on cells (e.g., CHO cells). In some embodiments, the antibodies of the present invention are capable of binding to TRPV1 expressed on cells, wherein TRPV1 is expressed from an inducible expression system (e.g., a tetracycline-regulated expression system, as described in the Examples section herein). TRPV1 is typically expressed at the cell surface. The binding of the antibodies of the present invention to TRPV1 can be assessed by any suitable means, and those skilled in the art will be familiar with suitable methods (e.g., flow cytometry (e.g., FACS) or immunocytochemistry or using functional assays, as described elsewhere herein).

[0259] The isolated peptides of the present invention correspond to or substantially correspond to certain regions or epitopes of the full-length TRPV1 (preferably human TRPV1, SEQ ID NO: 1).

[0260] More specifically, the isolated peptides of SEQ ID NO: 2 and SEQ ID NO: 16 (OTV3 peptide) generally correspond to residues 599-630 of human TRPV1 (SEQ ID NO: 1).

[0261] The isolated peptide SEQ ID NO: 3 (OTV4 peptide) corresponds to residues 599-630 of human TRPV1 (SEQ ID NO: 1). The isolated peptide SEQ ID NO: 17 (OTV4 peptide) generally corresponds to residues 599-630 of human TRPV1 (SEQ ID NO: 1).

[0262] The isolated peptides of SEQ ID NO: 4 and SEQ ID NO: 18 (OTV5 peptide) generally correspond to residues 599-630 of human TRPV1 (SEQ ID NO: 1).

[0263] The isolated peptide of SEQ ID NO: 5 (OTV6 peptide) corresponds to residues 599-606 of human TRPV1 (SEQ ID NO: 1). The isolated peptide of SEQ ID NO: 19 (OTV6 peptide) generally corresponds to residues 599-606 of human TRPV1 (SEQ ID NO: 1).

[0264] The isolated peptide SEQ ID NO: 6 (OTV7 peptide) corresponds to residues 599-614 of human TRPV1 (SEQ ID NO: 1). The isolated peptide SEQ ID NO: 20 (OTV7 peptide) generally corresponds to residues 599-614 of human TRPV1 (SEQ ID NO: 1).

[0265] The isolated peptides of SEQ ID NO: 7 and SEQ ID NO: 21 (OTV8 peptide) generally correspond to residues 599-622 of human TRPV1 (SEQ ID NO: 1).

[0266] The isolated peptides of SEQ ID NO: 8 and SEQ ID NO: 22 (OTV9 peptide) generally correspond to residues 607-630 of human TRPV1 (SEQ ID NO: 1).

[0267] The isolated peptides of SEQ ID NO: 9 and SEQ ID NO: 23 (OTV10 peptide) generally correspond to residues 615-630 of human TRPV1 (SEQ ID NO: 1).

[0268] The isolated peptide of SEQ ID NO: 10 (OTV11 peptide) corresponds to residues 623-630 of human TRPV1 (SEQ ID NO: 1). The isolated peptide of SEQ ID NO: 24 (OTV11 peptide) generally corresponds to residues 623-630 of human TRPV1 (SEQ ID NO: 1).

[0269] The isolated peptides of SEQ ID NO: 11 and SEQ ID NO: 25 (OTV12 peptide) generally correspond to residues 631-643 of human TRPV1 (SEQ ID NO: 1).

[0270] The isolated peptide of SEQ ID NO: 12 (OTV13 peptide) corresponds to residues 644-656 of human TRPV1 (SEQ ID NO: 1). The isolated peptide of SEQ ID NO: 26 (OTV13 peptide) generally corresponds to residues 644-656 of human TRPV1 (SEQ ID NO: 1).

[0271] The isolated peptides of SEQ ID NO: 13 and 27 (OTV14 peptide) contain amino acid sequences (or motifs) IED and NYD, which correspond to residues in TRPV1 (SEQ ID NO: 1). More specifically, the IED sequence in SEQ ID NO: 13 and 27 corresponds to residues 599-601 of TRPV1 (SEQ ID NO: 1), and the NYD sequence in SEQ ID NO: 13 and 27 corresponds to residues 653-655 of TRPV1 (SEQ ID NO: 1).

[0272] The isolated peptide of SEQ ID NO: 14 (OTV15 peptide) corresponds to residues 610-620 of human TRPV1 (SEQ ID NO: 1). The isolated peptide of SEQ ID NO: 28 (OTV15 peptide) generally corresponds to residues 610-620 of human TRPV1 (SEQ ID NO: 1).

[0273] "Corresponds to" means that the amino acid sequence (SEQ ID NO:) of the isolated peptide matches the amino acid sequence of the region or epitope of human TRPV1 (SEQ ID NO: 1). "Substantially corresponds to" means that the amino acid sequence (SEQ ID NO:) of the isolated peptide is identifiable as a sequence based on (or derived from) the region or epitope of human TRPV1 (SEQ ID NO: 1) or a modified form thereof. For example, an isolated peptide having a sequence that "substantially corresponds to" the region or epitope of human TRPV1 (SEQ ID NO: 1) typically has one or more (e.g., 1, 2, 3, 4, or 5, preferably 1, 2, or 3) amino acid substitutions, additions, or deletions compared to an isolated peptide having a sequence that corresponds (i.e., precisely corresponds to) the region or epitope of human TRPV1 (SEQ ID NO: 1). Therefore, an isolated peptide having a sequence that "substantially corresponds to" the region or epitope of human TRPV1 (SEQ ID NO: 1) can be considered a "substantially homologous" isolated peptide sequence as defined elsewhere herein.

[0274] In some embodiments, the antibody of the present invention binds to an epitope in the region defined by amino acid residues 599-630, 599-606, 599-614, 599-622, 607-630, 615-630, 623-630, 631-643, 644-656, or 610-620 of TRPV1 (SEQ ID NO: 1), or to an epitope in the region defined by amino acid residues 599-601 and 653-655 of TRPV1 (SEQ ID NO: 1). In some embodiments, the entire bound epitope is located within one of these regions of TRPV1. In some embodiments, at least one amino acid of the bound epitope is located within one of these regions of TRPV1.

[0275] In some embodiments, the antibody of the present invention binds to the epitope of TRPV1 in the region defined by amino acid residues 599-630, 599-614, 607-630, 631-643, or 644-656 of TRPV1 (SEQ ID NO: 1).

[0276] In some embodiments, the antibody of the present invention binds to the epitope of TRPV1 in the region defined by amino acid residues 599-630 or 631-643 of TRPV1 (SEQ ID NO: 1).

[0277] In some embodiments, the antibody of the present invention that binds to TRPV1 at an epitope of TRPV1 in the region defined by amino acid residues 599-630 of TRPV1 (SEQ ID NO: 1) is preferred.

[0278] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0279] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41 or SEQ ID NO: 77, or a sequence substantially homologous to it.

[0280] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42 or SEQ ID NO: 78, or a sequence substantially homologous to it, and

[0281] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43 or SEQ ID NO: 79, or a sequence substantially homologous thereto; and / or (preferably "and")

[0282] The light chain variable region comprises:

[0283] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 91 or preferably SEQ ID NO: 92, or a sequence substantially homologous thereto.

[0284] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45 or SEQ ID NO: 81, or a sequence substantially homologous to it, and

[0285] (f) A VL CDR3 having the amino acid sequence of SEQ ID NO: 46 or SEQ ID NO: 82, or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0286] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0287] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41 or SEQ ID NO: 77,

[0288] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42 or SEQ ID NO: 78, and

[0289] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43 or SEQ ID NO: 79, and / or (preferably "and")

[0290] The light chain variable region comprises:

[0291] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 91 or preferably SEQ ID NO: 92,

[0292] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45 or SEQ ID NO: 81, and

[0293] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 46 or SEQ ID NO: 82.

[0294] In some embodiments of the present invention, VL CDR1 has or includes the amino acid sequence of SEQ ID NO: 91 (KS SQSLL X8S X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 In these implementation schemes, X8, X 10 X 11 X 12 X 13 X 14 X 15 and X 16 It can be any amino acid, and X 17 It can be any amino acid or not an amino acid. Preferably, one or more of these X residues, most preferably all of them, are selected from the group consisting of: X8 being D or Y; X 10 Is it A or S; X 11 Is it G or N; X 12 It is K or Q; X 13 Is it T or K; X 14 It is Y or N; X 15 Is it L or C, X 16 It is N or L; X 17 It may or may not be an amino acid. Therefore, the preferred VL CDR1 has or contains the amino acid sequence of SEQ ID NO: 92. For example, the preferred VL CDR1 sequence of this embodiment has or contains SEQ ID NO: 44, 62 or 80.

[0295] In an embodiment of the present invention, when one or more CDR sequences contain X X Residues having a substantially homologous sequence to which the CDR (containing 1, 2, or 3, preferably 1 or 2 (more preferably 1) altered amino acids or amino acid substitutions compared to a given CDR sequence) are also covered in this invention. In some such embodiments, the alteration or substitution of the amino acid residues may include one or more X residues. X Residues may be present except for X X At residues other than the specified residues. In other such embodiments, the change is at X.X residues and non-X X In a mixture of residues.

[0296] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0297] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41 or a sequence substantially homologous to it,

[0298] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42 or a sequence substantially homologous to it, and

[0299] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43 or a sequence substantially homologous to it; and / or (preferably "and")

[0300] The light chain variable region comprises:

[0301] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 91 or preferably SEQ ID NO: 92, or a sequence substantially homologous thereto.

[0302] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45 or a sequence substantially homologous to it, and

[0303] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 46 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0304] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0305] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77 or a sequence substantially homologous to it,

[0306] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 78 or a sequence substantially homologous to it, and

[0307] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 79 or a sequence substantially homologous to it; and / or (preferably "and")

[0308] The light chain variable region comprises:

[0309] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 91 or preferably SEQ ID NO: 92, or a sequence substantially homologous thereto.

[0310] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 81 or a sequence substantially homologous to it, and

[0311] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 82 or a sequence substantially homologous to it. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0312] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0313] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 440 or preferably SEQ ID NO: 441, or a sequence substantially homologous to it.

[0314] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 442 or preferably SEQ ID NO: 443, or a sequence substantially homologous to it, and

[0315] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 444 or preferably SEQ ID NO: 445 or a sequence substantially homologous thereto; and / or (preferably "and")

[0316] The light chain variable region comprises:

[0317] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 446 or preferably SEQ ID NO: 447, or a sequence substantially homologous to it.

[0318] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 107, SEQ ID NO: 127, SEQ ID NO: 147, SEQ ID NO: 167, SEQ ID NO: 187, SEQ ID NO: 207, SEQ ID NO: 227, SEQ ID NO: 247 or SEQ ID NO: 267, or a sequence substantially homologous to therewith, and

[0319] (f) A VL CDR3 having the amino acid sequence of SEQ ID NO: 108, SEQ ID NO: 128, SEQ ID NO: 148, SEQ ID NO: 168, SEQ ID NO: 188, SEQ ID NO: 208, SEQ ID NO: 228, SEQ ID NO: 248, or SEQ ID NO: 268, or a sequence substantially homologous thereto. The substantially homologous sequences are described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0320] In some embodiments of the invention, VH CDR1 has or contains the amino acid sequence of SEQ ID NO: 440 (SD X3 AWN). In these embodiments, X3 can be any amino acid. Preferably, the X3 residue is F or Y. Therefore, preferred VH CDR1 has or contains the amino acid sequence of SEQ ID NO: 441. For example, preferred VHCDR1 sequences of this embodiment have or contain SEQ ID NO: 103, 123, 143, 163, 183, 203, 223, 243, or 263.

[0321] In some embodiments of the present invention, VH CDR2 has or includes the amino acid sequence of SEQ ID NO: 442 (X1I TYS X6 X7 TNX). 10 NPSLX 15 S). In these implementation schemes, X1, X6, X7, X 10 and X 15It can be any amino acid. Preferably, one or more of these X residues, most preferably all of them, are selected from the group consisting of: X1 is Y or F; X6 is G or D; X7 is Y or H or N; X 10 Is it Y or F; X 15 It is K, I, or R. Therefore, the preferred VH CDR2 has or contains the amino acid sequence of SEQ ID NO:443. For example, the preferred VH CDR2 sequence of this embodiment has or contains SEQ ID NO: 104, 124, 144, 164, 184, 204, 224, 244, or 264.

[0322] In some embodiments of the invention, VH CDR3 has or comprises the amino acid sequence of SEQ ID NO: 444 (S X2X3 X4 FDY). In these embodiments, X2, X3, and X4 can be any amino acid. Preferably, one or more of these X residues, most preferably all of them, are selected from the group consisting of: X2 being T or G; X3 being T or A or N; and X4 being Y or F. Therefore, a preferred VH CDR3 has or comprises the amino acid sequence of SEQ ID NO: 445. For example, a preferred VH CDR3 sequence of this embodiment has or comprises SEQ ID NO: 105, 125, 145, 165, 185, 205, 225, 245, or 265.

[0323] In some embodiments of the invention, VL CDR1 has or comprises the amino acid sequence of SEQ ID NO: 446 (RSSQ X5 X6 X7H SDGNTYLE). In these embodiments, X5, X6, and X7 can be any amino acid. Preferably, one or more of these X residues, most preferably all, are selected from the group consisting of: X5 being S or T; X6 being I or V; and X7 being L or V or I. Therefore, a preferred VL CDR1 has or comprises the amino acid sequence of SEQ ID NO: 447. For example, a preferred VL CDR1 sequence of this embodiment has or comprises SEQ ID NO: 106, 126, 146, 166, 186, 206, 226, 246, or 266.

[0324] Preferred combinations of VH CDR sequences and VL CDR sequences are listed in each row of Table W below, numbered 1-45:

[0325] Table W

[0326]

[0327]

[0328] In the embodiments of the invention shown in Table W, the common sequence as shown in SEQ ID NO: 440 is preferably the sequence shown in SEQ ID NO: 441. In the embodiments of the invention shown in Table W, the common sequence as shown in SEQ ID NO: 442 is preferably the sequence shown in SEQ ID NO: 443. In the embodiments of the invention shown in Table W, the common sequence as shown in SEQ ID NO: 444 is preferably the sequence shown in SEQ ID NO: 445. In the embodiments of the invention shown in Table W, the common sequence as shown in SEQ ID NO: 446 is preferably the sequence shown in SEQ ID NO: 447. In some embodiments of the invention shown in Table W, the combination of CDR sequences shown in rows 37-45 is preferred. In some embodiments, sequences substantially homologous to the specific sequences listed in Table W may be used instead of the specific sequences themselves.

[0329] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VH CDR1 having the amino acid sequence of SEQ ID NO: 440 or preferably SEQ ID NO: 441, VH CDR2 having the amino acid sequence of SEQ ID NO: 442 or preferably SEQ ID NO: 443, and VH CDR3 having the amino acid sequence of SEQ ID NO: 444 or preferably SEQ ID NO: 445, and / or (preferably "and") wherein the light chain variable region comprises VL CDR1 having the amino acid sequence of SEQ ID NO: 446 or preferably SEQ ID NO: 447. In some such embodiments, preferably, the light chain variable region comprises VL CDR2 having the amino acid sequence of SEQ ID NO: 107 and VLCDR3 having the amino acid sequence of SEQ ID NO: 108; or the light chain variable region comprises VL CDR2 having the amino acid sequence of SEQ ID NO: 127 and VL CDR3 having the amino acid sequence of SEQ ID NO: 128; or the light chain variable region comprises VLCDR2 having the amino acid sequence of SEQ ID NO: 147 and VL CDR3 having the amino acid sequence of SEQ ID NO: 148; or the light chain variable region comprises VL CDR2 having the amino acid sequence of SEQ ID NO: 167 and VL CDR3 having the amino acid sequence of SEQ ID NO: 168; or the light chain variable region comprises VL CDR2 having the amino acid sequence of SEQ ID NO: 187 and VL CDR3 having the amino acid sequence of SEQ ID NO: 188; or the light chain variable region comprises VL CDR2 having the amino acid sequence of SEQ ID NO: 207 and VL CDR3 having the amino acid sequence of SEQ ID NO: 188. CDR2 and VL CDR3 having the amino acid sequence of SEQ ID NO: 208, or the light chain variable region comprising VL CDR2 having the amino acid sequence of SEQ ID NO: 227 and VL CDR3 having the amino acid sequence of SEQ ID NO: 228, or the light chain variable region comprising VL CDR2 having the amino acid sequence of SEQ ID NO: 247 and VL CDR3 having the amino acid sequence of SEQ ID NO: 248, or the light chain variable region comprising VL CDR2 having the amino acid sequence of SEQ ID NO: 267 and VL CDR3 having the amino acid sequence of SEQ ID NO: 268. In some embodiments, sequences substantially homologous to the specific sequences listed in this paragraph may be used instead of the specific sequences themselves.

[0330] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0331] (a) A variable-weight (VH) CDR1 having the amino acid sequences of SEQ ID NO: 103, SEQ ID NO: 123, SEQ ID NO: 143, SEQ ID NO: 163, SEQ ID NO: 183, SEQ ID NO: 203, SEQ ID NO: 223, SEQ ID NO: 243, SEQ ID NO: 263, SEQ ID NO: 283, SEQ ID NO: 303, SEQ ID NO: 323, SEQ ID NO: 363, SEQ ID NO: 383, SEQ ID NO: 403, SEQ ID NO: 41, SEQ ID NO: 59, or SEQ ID NO: 77, or sequences substantially homologous to them.

[0332] (b) VH CDR2 having the amino acid sequences of SEQ ID NO: 104, SEQ ID NO: 124, SEQ ID NO: 144, SEQ ID NO: 164, SEQ ID NO: 184, SEQ ID NO: 204, SEQ ID NO: 224, SEQ ID NO: 244, SEQ ID NO: 264, SEQ ID NO: 284, SEQ ID NO: 304, SEQ ID NO: 324, SEQ ID NO: 364, SEQ ID NO: 384, SEQ ID NO: 404, SEQ ID NO: 42, SEQ ID NO: 60, or SEQ ID NO: 78, or sequences substantially homologous to them.

[0333] (c) A VH CDR3 having the amino acid sequence of SEQ ID NO: 105, SEQ ID NO: 125, SEQ ID NO: 145, SEQ ID NO: 165, SEQ ID NO: 185, SEQ ID NO: 205, SEQ ID NO: 225, SEQ ID NO: 245, SEQ ID NO: 265, SEQ ID NO: 285, SEQ ID NO: 305, SEQ ID NO: 325, SEQ ID NO: 365, SEQ ID NO: 385, SEQ ID NO: 405, SEQ ID NO: 43, SEQ ID NO: 61, or SEQ ID NO: 79, or a sequence substantially homologous thereto; and / or (preferably "and")

[0334] The light chain variable region comprises:

[0335] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 448 or preferably SEQ ID NO: 449, or a sequence substantially homologous thereto.

[0336] (e) VL CDR2 having the amino acid sequences of SEQ ID NO: 107, SEQ ID NO: 127, SEQ ID NO: 147, SEQ ID NO: 167, SEQ ID NO: 187, SEQ ID NO: 207, SEQ ID NO: 227, SEQ ID NO: 247, SEQ ID NO: 267, SEQ ID NO: 287, SEQ ID NO: 307, SEQ ID NO: 327, SEQ ID NO: 367, SEQ ID NO: 387, SEQ ID NO: 407, SEQ ID NO: 45, SEQ ID NO: 63, or SEQ ID NO: 81, or sequences substantially homologous to them.

[0337] (f) A VL CDR3 having an amino acid sequence of SEQ ID NO: 108, SEQ ID NO: 128, SEQ ID NO: 148, SEQ ID NO: 168, SEQ ID NO: 188, SEQ ID NO: 208, SEQ ID NO: 228, SEQ ID NO: 248 or SEQ ID NO: 268, SEQ ID NO: 288, 308, SEQ ID NO: 328, SEQ ID NO: 368, SEQ ID NO: 388, SEQ ID NO: 408, SEQ ID NO: 46, SEQ ID NO: 64 or SEQ ID NO: 82, or a sequence substantially homologous thereto. The substantially homologous sequences are described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0338] In some embodiments of the present invention, VL CDR1 has or includes the amino acid sequence of SEQ ID NO: 448 (X1 SSQ X5 X6 X7 X8S X 10 X 11 X 12 X 13 X 14 X 15 LX 17 In these implementation schemes, X1, X5, X6, X7, X8, X... 10 X 11 X 13 X 14 X 15 and X 17 It can be any amino acid, and X 12 It can be any amino acid or not an amino acid. Preferably, one or more of these X residues, most preferably all of them, are selected from the group consisting of: X1 is R or K; X5 is S or T; X6 is L or V or I; X7 is L or V or I; X8 is H or D or Y; X 10 It is S, A, or D; X 11 Is it G or N; X 13 It is K or N; X 14 Is it T or N; X 15 It is Y or C; X 17 It is A, N, or E; X 12It may or may not be an amino acid. Therefore, the preferred VL CDR1 has or contains the amino acid sequence of SEQ ID NO: 449. For example, the preferred VL CDR1 sequence of this embodiment has or contains SEQ ID NO: 106, 126, 146, 166, 186, 206, 226, 246, 266, 286, 306, 326, 366, 386, 406, 44, 62, or 80.

[0339] Preferred combinations of VH CDR sequences and VL CDR sequences are listed in each row of Table Y below, numbered 1-18:

[0340] Table Y

[0341]

[0342]

[0343] In the embodiments of the invention shown in Table Y, the common sequence as shown in SEQ ID NO: 448 is preferably the sequence shown in SEQ ID NO: 449. In some embodiments, a sequence substantially homologous to the specific sequence listed in Table Y may be used instead of the specific sequence itself.

[0344] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VL CDR1 having an amino acid sequence (or substantially homologous to) SEQ ID NO: 448 or preferably SEQ ID NO: 449. In some such embodiments, preferably, the light chain variable region comprises VL CDR2 and VL CDR3, and the heavy chain variable region comprises VH CDR1, VHCDR2, and VH CDR3, wherein the CDRs have an amino acid sequence (or substantially homologous to) as listed in the given rows selected from row numbers 1-18 of Table Y above. In other words, in some such embodiments, in addition to VL CDR1 having the amino acid sequence of SEQ ID NO: 448 or preferably SEQ ID NO: 449 (or a sequence substantially homologous thereto), the light chain variable region preferably contains a combination of VL CDR2 and VL CDR3 and the heavy chain variable region contains a combination of VH CDR1, VH CDR2 and VHCDR3, wherein the VL CDR2, VL CDR3, VH CDR1, VH CDR2 and VH CDR3 have the amino acid sequences listed in combination (i.e. together) in the rows of Table Y above.

[0345] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0346] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41, SEQ ID NO: 59, SEQ ID NO: 103, SEQ ID NO: 123, SEQ ID NO: 143, SEQ ID NO: 163, SEQ ID NO: 183, SEQ ID NO: 203, SEQ ID NO: 223, SEQ ID NO: 243, SEQ ID NO: 263, SEQ ID NO: 283, SEQ ID NO: 303, or SEQ ID NO: 403, or a sequence substantially homologous to therewith.

[0347] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42, SEQ ID NO: 60, SEQ ID NO: 104, SEQ ID NO: 124, SEQ ID NO: 144, SEQ ID NO: 164, SEQ ID NO: 184, SEQ ID NO: 204, SEQ ID NO: 224, SEQ ID NO: 244, SEQ ID NO: 264, SEQ ID NO: 284, SEQ ID NO: 304, or SEQ ID NO: 404, or a sequence substantially homologous to therewith, and

[0348] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43, SEQ ID NO: 61, SEQ ID NO: 105, SEQ ID NO: 125, SEQ ID NO: 145, SEQ ID NO: 165, SEQ ID NO: 185, SEQ ID NO: 205, SEQ ID NO: 225, SEQ ID NO: 245, SEQ ID NO: 265, SEQ ID NO: 285, SEQ ID NO: 305, or SEQ ID NO: 405, or a sequence substantially homologous thereto; and / or (preferably "and")

[0349] The light chain variable region comprises:

[0350] (d) VL CDR1 having the amino acid sequence of SEQ ID NO: 44, SEQ ID NO: 62, SEQ ID NO: 106, SEQ ID NO: 126, SEQ ID NO: 146, SEQ ID NO: 166, SEQ ID NO: 186, SEQ ID NO: 206, SEQ ID NO: 226, SEQ ID NO: 246, SEQ ID NO: 266, SEQ ID NO: 286, SEQ ID NO: 306, or SEQ ID NO: 406, or a sequence substantially homologous to therewith.

[0351] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45, SEQ ID NO: 63, SEQ ID NO: 107, SEQ ID NO: 127, SEQ ID NO: 147, SEQ ID NO: 167, SEQ ID NO: 187, SEQ ID NO: 207, SEQ ID NO: 227, SEQ ID NO: 247, SEQ ID NO: 267, SEQ ID NO: 287, SEQ ID NO: 307, or SEQ ID NO: 407, or a sequence substantially homologous to therewith, and

[0352] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 450 or preferably SEQ ID NO: 451, or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0353] In some embodiments of the invention, VL CDR3 has or comprises the amino acid sequence of SEQ ID NO: 450 (X1Q G X4 H X6 P X8 T). In these embodiments, X1, X4, and X6 can be any amino acid, and X8 can be any amino acid or not an amino acid. Preferably, one or more, most preferably all, of these X residues are selected from the group consisting of: X1 being W or F or S; X4 being T or S; X6 being F or V; and X8 being P or Y or not an amino acid. Therefore, a preferred VL CDR3 has or comprises the amino acid sequence of SEQ ID NO: 451. For example, the preferred VL CDR3 sequence of this embodiment has or includes SEQ ID NO: 46, SEQ ID NO: 64, SEQ ID NO: 108, SEQ ID NO: 128, SEQ ID NO: 148, SEQ ID NO: 168, SEQ ID NO: 188, SEQ ID NO: 208, SEQ ID NO: 228, SEQ ID NO: 248, SEQ ID NO: 268, SEQ ID NO: 288, SEQ ID NO: 308, or SEQ ID NO: 408.

[0354] Preferred combinations of VH CDR sequences and VL CDR sequences are listed in each row of Table AA below, numbered 1-14:

[0355] Table AA

[0356]

[0357]

[0358] In the embodiments of the invention shown in Table AA, the common sequence as shown in SEQ ID NO: 450 is preferably the sequence shown in SEQ ID NO: 451. In some embodiments, a sequence substantially homologous to the specific sequence listed in Table AA may be used instead of the specific sequence itself.

[0359] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VL CDR3 having an amino acid sequence (or substantially homologous to) SEQ ID NO: 450 or preferably SEQ ID NO: 451. In some such embodiments, preferably, the light chain variable region comprises VL CDR1 and VL CDR2, and the heavy chain variable region comprises VH CDR1, VHCDR2, and VH CDR3, wherein the CDRs have an amino acid sequence (or substantially homologous to) as listed in the given rows selected from rows 1-14 of Table AA above. In other words, in some such embodiments, in addition to VL CDR3 having the amino acid sequence of SEQ ID NO: 450 or preferably SEQ ID NO: 451 (or a sequence substantially homologous thereto), the light chain variable region preferably contains a combination of VL CDR1 and VL CDR2 and the heavy chain variable region contains a combination of VH CDR1, VH CDR2 and VHCDR3, wherein said VL CDR1, VL CDR2, VH CDR1, VH CDR2 and VH CDR3 have the amino acid sequences listed in combination (i.e. together) in the rows of Table AA above.

[0360] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0361] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77, SEQ ID NO: 363, or SEQ ID NO: 383, or a sequence substantially homologous to thereto.

[0362] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42, SEQ ID NO: 78, SEQ ID NO: 364, or SEQ ID NO: 384, or a sequence substantially homologous to thereto, and

[0363] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 79, SEQ ID NO: 365, or 385, or a sequence substantially homologous thereto; and / or (preferably "and")

[0364] The light chain variable region comprises:

[0365] (d) VL CDR1 having the amino acid sequences of SEQ ID NO: 80, SEQ ID NO: 366, and SEQ ID NO: 386, or sequences substantially homologous to them.

[0366] (e) VL CDR2 having the amino acid sequences of SEQ ID NO: 81, SEQ ID NO: 367, and SEQ ID NO: 387, or sequences substantially homologous to them, and

[0367] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 452 or preferably SEQ ID NO: 439, or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0368] In some embodiments of the invention, VL CDR3 has or comprises the amino acid sequence of SEQ ID NO: 452 (QQYY X5 YP X8 X9). In these embodiments, X5 and X8 can be any amino acid, and X9 can be any amino acid or not an amino acid. Preferably, one or more, most preferably all, of these X residues are selected from the group consisting of: X5 being Y or S; X8 being P or T; and X9 being T or not an amino acid. Therefore, a preferred VL CDR3 has or comprises the amino acid sequence of SEQ ID NO: 439. For example, a preferred VL CDR3 sequence of this embodiment has or comprises SEQ ID NO: 82, SEQ ID NO: 368, or SEQ ID NO: 388.

[0369] Preferred combinations of VH CDR sequences and VL CDR sequences are listed in each row of Table CC below, numbered 1-3:

[0370] Table CC

[0371]

[0372] In the embodiments of the invention shown in Table CC, the common sequence as shown in SEQ ID NO: 452 is preferably the sequence shown in SEQ ID NO: 439. In some embodiments, a sequence substantially homologous to the specific sequence listed in Table CC may be used instead of the specific sequence itself.

[0373] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VL CDR3 having an amino acid sequence (or substantially homologous to) SEQ ID NO: 452 or preferably SEQ ID NO: 439. In some such embodiments, preferably, the light chain variable region comprises VL CDR1 and VL CDR2, and the heavy chain variable region comprises VH CDR1, VHCDR2, and VH CDR3, wherein the CDRs have an amino acid sequence (or substantially homologous to) as listed in the given rows selected from rows 1-3 of Table CC above. In other words, in some such embodiments, in addition to VL CDR3 having the amino acid sequence of SEQ ID NO: 452 or preferably SEQ ID NO: 439 (or a sequence substantially homologous thereto), the light chain variable region preferably contains a combination of VL CDR1 and VL CDR2 and the heavy chain variable region contains a combination of VH CDR1, VH CDR2 and VHCDR3, wherein said VL CDR1, VL CDR2, VH CDR1, VH CDR2 and VH CDR3 have the amino acid sequences listed in combination (i.e. together) in the rows of Table CC above.

[0374] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0375] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 103, SEQ ID NO: 123, SEQ ID NO: 143, SEQ ID NO: 163, SEQ ID NO: 183, SEQ ID NO: 203, SEQ ID NO: 223, SEQ ID NO: 243, SEQ ID NO: 263, or SEQ ID NO: 303, or a sequence substantially homologous to thereto.

[0376] (b) VH CDR2 having the amino acid sequences of SEQ ID NO: 104, SEQ ID NO: 124, SEQ ID NO: 144, SEQ ID NO: 164, SEQ ID NO: 184, SEQ ID NO: 204, SEQ ID NO: 224, SEQ ID NO: 244, SEQ ID NO: 264, SEQ ID NO: 304 or sequences substantially homologous to them, and

[0377] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 105, SEQ ID NO: 125, SEQ ID NO: 145, SEQ ID NO: 165, SEQ ID NO: 185, SEQ ID NO: 205, SEQ ID NO: 225, SEQ ID NO: 245, SEQ ID NO: 265, or SEQ ID NO: 305, or a sequence substantially homologous thereto; and / or (preferably "and")

[0378] The light chain variable region comprises:

[0379] (d) VL CDR1 having the amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 126, SEQ ID NO: 146, SEQ ID NO: 166, SEQ ID NO: 186, SEQ ID NO: 206, SEQ ID NO: 226, SEQ ID NO: 246, SEQ ID NO: 266, or SEQ ID NO: 306, or sequences substantially homologous to them.

[0380] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 107 or a sequence substantially homologous to it, and

[0381] (f) A VL CDR3 having the amino acid sequences of SEQ ID NO: 108, SEQ ID NO: 128, SEQ ID NO: 148, SEQ ID NO: 168, SEQ ID NO: 188, SEQ ID NO: 208, SEQ ID NO: 228, SEQ ID NO: 248, SEQ ID NO: 268, or SEQ ID NO: 308, or sequences substantially homologous to them. Substantially homologous sequences are described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0382] Preferred combinations of VH CDR sequences and VL CDR sequences are listed in each row of Table DD below, numbered 1-10:

[0383] Table DD

[0384]

[0385] In some implementations, a sequence that is substantially homologous to a specific sequence listed in Table DD may be used instead of the specific sequence itself.

[0386] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR2 having the amino acid sequence of SEQ ID NO: 107 (or a sequence substantially homologous thereto). In some such embodiments, preferably, the light chain variable region comprises VL CDR1 and VL CDR3, and the heavy chain variable region comprises VH CDR1, VH CDR2, and VH CDR3, wherein the CDRs have amino acid sequences (or sequences substantially homologous thereto) as listed in the given rows selected from rows 1-10 of Table DD above. In other words, in some such embodiments, in addition to VL CDR2 having the amino acid sequence of SEQ ID NO: 107 (or a sequence substantially homologous to it), the light chain variable region preferably contains a combination of VL CDR1 and VL CDR3 and the heavy chain variable region contains a combination of VH CDR1, VH CDR2 and VH CDR3, wherein VL CDR1, VL CDR3, VH CDR1, VHCDR2 and VH CDR3 have the amino acid sequences listed in combination (i.e. together) in the rows of Table DD above.

[0387] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0388] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77, SEQ ID NO: 323, SEQ ID NO: 363, or SEQ ID NO: 383, or a sequence substantially homologous to thereto.

[0389] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 78, SEQ ID NO: 324, SEQ ID NO: 364, or SEQ ID NO: 384, or a sequence substantially homologous to thereto, and

[0390] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 79, SEQ ID NO: 325, SEQ ID NO: 365, or SEQ ID NO: 385, or a sequence substantially homologous thereto; and / or (preferably "and")

[0391] The light chain variable region comprises:

[0392] (d) VL CDR1 having the amino acid sequence of SEQ ID NO: 80, SEQ ID NO: 326, SEQ ID NO: 366, or SEQ ID NO: 386, or a sequence substantially homologous to it.

[0393] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 81 or a sequence substantially homologous to it, and

[0394] (f) A VL CDR3 having the amino acid sequence of SEQ ID NO: 82, SEQ ID NO: 328, SEQ ID NO: 368, or SEQ ID NO: 388, or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0395] Preferred combinations of VH CDR sequences and VL CDR sequences are listed in each row of Table EE below:

[0396] Table EE

[0397]

[0398] In some implementations, a sequence that is substantially homologous to a specific sequence listed in Table EE may be used instead of the specific sequence itself.

[0399] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR2 having the amino acid sequence of SEQ ID NO: 81 (or a sequence substantially homologous thereto). In some such embodiments, preferably, the light chain variable region comprises VL CDR1 and VL CDR3, and the heavy chain variable region comprises VH CDR1, VH CDR2, and VH CDR3, wherein the CDRs have amino acid sequences (or sequences substantially homologous thereto) as listed in the given rows selected from rows 1-4 of Table EE above. In other words, in some such embodiments, in addition to VL CDR2 having the amino acid sequence of SEQ ID NO: 81 (or a sequence substantially homologous to it), the light chain variable region preferably contains a combination of VL CDR1 and VL CDR3 and the heavy chain variable region contains a combination of VH CDR1, VH CDR2 and VH CDR3, wherein VL CDR1, VL CDR3, VH CDR1, VHCDR2 and VH CDR3 have the amino acid sequences listed in combination (i.e. together) in the rows of Table EE above.

[0400] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0401] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41, SEQ ID NO: 59, SEQ ID NO: 283, or SEQ ID NO: 403, or a sequence substantially homologous to thereto.

[0402] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42, SEQ ID NO: 60, SEQ ID NO: 284, or SEQ ID NO: 404, or a sequence substantially homologous to thereto, and

[0403] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43, SEQ ID NO: 61, SEQ ID NO: 285, or SEQ ID NO: 405, or a sequence substantially homologous thereto; and / or (preferably "and")

[0404] The light chain variable region comprises:

[0405] (d) VL CDR1 having the amino acid sequence of SEQ ID NO: 44, SEQ ID NO: 62, SEQ ID NO: 286, or SEQ ID NO: 406, or a sequence substantially homologous to thereto.

[0406] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45 or a sequence substantially homologous to it, and

[0407] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 46, SEQ ID NO: 64, SEQ ID NO: 288, or SEQ ID NO: 408, or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0408] Preferred combinations of VH CDR sequences and VL CDR sequences are listed in each row of Table FF below, numbered 1-4:

[0409] Table FF

[0410]

[0411] In some implementations, a sequence that is substantially homologous to a specific sequence listed in Table FF may be used instead of the specific sequence itself.

[0412] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR2 having the amino acid sequence of SEQ ID NO: 45 (or a sequence substantially homologous thereto). In some such embodiments, preferably, the light chain variable region comprises VL CDR1 and VL CDR3, and the heavy chain variable region comprises VH CDR1, VH CDR2, and VH CDR3, wherein the CDRs have amino acid sequences (or sequences substantially homologous thereto) as listed in the given rows selected from rows 1-4 of Table FF above. In other words, in some such embodiments, in addition to VL CDR2 having the amino acid sequence of SEQ ID NO: 45 (or a sequence substantially homologous to it), the light chain variable region preferably contains a combination of VL CDR1 and VL CDR3 and the heavy chain variable region contains a combination of VH CDR1, VH CDR2 and VH CDR3, wherein VL CDR1, VL CDR3, VH CDR1, VHCDR2 and VH CDR3 have the amino acid sequences listed in combination (i.e. together) in the rows of Table FF above.

[0413] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR1 having the amino acid sequence of SEQ ID NO: 91 (or preferably SEQ ID NO: 92). In some such embodiments, preferably VL CDR2, VLCDR3, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have amino acid sequences as defined elsewhere herein.

[0414] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VH CDR1 having the amino acid sequence of SEQ ID NO: 440 (or preferably SEQ ID NO: 441). In some such embodiments, preferably VL CDR1, VLCDR2, VL CDR3, VH CDR2, and VH CDR3 (e.g., combinations thereof) have an amino acid sequence as defined elsewhere herein.

[0415] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VH CDR2 having the amino acid sequence of SEQ ID NO: 442 (or preferably SEQ ID NO: 443). In some such embodiments, preferably VL CDR1, VLCDR2, VL CDR3, VH CDR1, and VH CDR3 (e.g., combinations thereof) have an amino acid sequence as defined elsewhere herein.

[0416] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VH CDR3 having the amino acid sequence of SEQ ID NO: 444 (or preferably SEQ ID NO: 445). In some such embodiments, preferably VL CDR1, VLCDR2, VL CDR3, VH CDR1, and VH CDR2 (e.g., combinations thereof) have an amino acid sequence as defined elsewhere herein.

[0417] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR1 having the amino acid sequence of SEQ ID NO: 446 (or preferably SEQ ID NO: 447). In some such embodiments, preferably VL CDR2, VLCDR3, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have the amino acid sequence as defined elsewhere herein.

[0418] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR1 having the amino acid sequence of SEQ ID NO: 448 (or preferably SEQ ID NO: 449). In some such embodiments, preferably VL CDR2, VLCDR3, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have an amino acid sequence as defined elsewhere herein.

[0419] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR3 having the amino acid sequence of SEQ ID NO: 450 (or preferably SEQ ID NO: 451). In some such embodiments, preferably VL CDR1, VLCDR2, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have an amino acid sequence as defined elsewhere herein.

[0420] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR3 having the amino acid sequence of SEQ ID NO: 452 (or preferably SEQ ID NO: 439). In some such embodiments, preferably VL CDR1, VLCDR2, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have the amino acid sequence as defined elsewhere herein.

[0421] In some embodiments, the antibody of the present invention comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises VL CDR2 having an amino acid sequence (or a sequence substantially homologous thereto) of SEQ ID NO: 107, SEQ ID NO: 81, or SEQ ID NO: 45. In some such embodiments, preferably VL CDR1, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have an amino acid sequence as defined elsewhere herein.

[0422] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0423] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41 or a sequence substantially homologous to it,

[0424] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42 or a sequence substantially homologous to it, and

[0425] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43 or a sequence substantially homologous to it; and / or

[0426] The light chain variable region comprises:

[0427] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 44 or a sequence substantially homologous to it,

[0428] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45 or a sequence substantially homologous to it, and

[0429] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 46 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0430] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0431] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41,

[0432] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42, and

[0433] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43; and / or

[0434] The light chain variable region comprises:

[0435] (d) Variable light (VL)CDR1 having the amino acid sequence of SEQ ID NO: 44,

[0436] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45, and

[0437] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 46.

[0438] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0439] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41 or a sequence substantially homologous to it,

[0440] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42 or a sequence substantially homologous to it, and

[0441] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43 or a sequence substantially homologous to it; and

[0442] The light chain variable region comprises:

[0443] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 44 or a sequence substantially homologous to it,

[0444] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45 or a sequence substantially homologous to it, and

[0445] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 46 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0446] In a preferred embodiment, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0447] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41,

[0448] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 42, and

[0449] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 43; and

[0450] The light chain variable region comprises:

[0451] (d) Variable light (VL)CDR1 having the amino acid sequence of SEQ ID NO: 44,

[0452] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 45, and

[0453] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 46.

[0454] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0455] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77 or a sequence substantially homologous to it,

[0456] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 78 or a sequence substantially homologous to it, and

[0457] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 79 or a sequence substantially homologous to it; and / or

[0458] The light chain variable region comprises:

[0459] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 80 or a sequence substantially homologous to it,

[0460] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 81 or a sequence substantially homologous to it, and

[0461] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 82 or a sequence substantially homologous to it. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0462] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0463] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77,

[0464] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 78, and

[0465] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 79; and / or

[0466] The light chain variable region comprises:

[0467] (d) Variable light (VL)CDR1 having the amino acid sequence of SEQ ID NO: 80,

[0468] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 81, and

[0469] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 82.

[0470] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0471] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77 or a sequence substantially homologous to it,

[0472] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 78 or a sequence substantially homologous to it, and

[0473] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 79 or a sequence substantially homologous to it; and

[0474] The light chain variable region comprises:

[0475] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 80 or a sequence substantially homologous to it,

[0476] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 81 or a sequence substantially homologous to it, and

[0477] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 82 or a sequence substantially homologous to it. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0478] In a preferred embodiment, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0479] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77,

[0480] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 78, and

[0481] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 79; and

[0482] The light chain variable region comprises:

[0483] (d) Variable light (VL)CDR1 having the amino acid sequence of SEQ ID NO: 80,

[0484] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 81, and

[0485] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 82.

[0486] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0487] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 103 or a sequence substantially homologous to it,

[0488] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 104 or a sequence substantially homologous to it, and

[0489] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 105 or a sequence substantially homologous to it; and / or (preferably "and")

[0490] The light chain variable region comprises:

[0491] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 106 or a sequence substantially homologous to it,

[0492] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 107 or a sequence substantially homologous to it, and

[0493] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 108 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0494] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 103, VH CDR2 of SEQ ID NO: 104, and VH CDR3 of SEQ ID NO: 105, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 106, VL CDR2 of SEQ ID NO: 107, and VL CDR3 of SEQ ID NO: 108.

[0495] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0496] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 123 or a sequence substantially homologous to it,

[0497] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 124 or a sequence substantially homologous to it, and

[0498] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 125 or a sequence substantially homologous to it; and / or (preferably "and")

[0499] The light chain variable region comprises:

[0500] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 126 or a sequence substantially homologous to it,

[0501] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 127 or a sequence substantially homologous to it, and

[0502] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 128 or a sequence substantially homologous to it. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0503] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 123, VH CDR2 of SEQ ID NO: 124, and VH CDR3 of SEQ ID NO: 125, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 126, VL CDR2 of SEQ ID NO: 127, and VL CDR3 of SEQ ID NO: 128.

[0504] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0505] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 143 or a sequence substantially homologous to it,

[0506] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 144 or a sequence substantially homologous to it, and

[0507] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 145 or a sequence substantially homologous to it; and / or (preferably "and")

[0508] The light chain variable region comprises:

[0509] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 146 or a sequence substantially homologous to it,

[0510] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 147 or a sequence substantially homologous to it, and

[0511] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 148 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0512] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 143, VH CDR2 of SEQ ID NO: 144, and VH CDR3 of SEQ ID NO: 145, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 146, VL CDR2 of SEQ ID NO: 147, and VL CDR3 of SEQ ID NO: 148.

[0513] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0514] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 183 or a sequence substantially homologous to it,

[0515] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 184 or a sequence substantially homologous to it, and

[0516] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 185 or a sequence substantially homologous to it; and / or (preferably "and")

[0517] The light chain variable region comprises:

[0518] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 186 or a sequence substantially homologous to it,

[0519] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 187 or a sequence substantially homologous to it, and

[0520] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 188 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0521] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 183, VH CDR2 of SEQ ID NO: 184, and VH CDR3 of SEQ ID NO: 185, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 186, VL CDR2 of SEQ ID NO: 187, and VL CDR3 of SEQ ID NO: 188.

[0522] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0523] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 203 or a sequence substantially homologous to it,

[0524] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 204 or a sequence substantially homologous to it, and

[0525] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 205 or a sequence substantially homologous to it; and / or (preferably "and")

[0526] The light chain variable region comprises:

[0527] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 206 or a sequence substantially homologous to it,

[0528] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 207 or a sequence substantially homologous to it, and

[0529] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 208 or a sequence substantially homologous to it. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0530] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 203, VH CDR2 of SEQ ID NO: 204, and VH CDR3 of SEQ ID NO: 205, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 206, VL CDR2 of SEQ ID NO: 207, and VL CDR3 of SEQ ID NO: 208.

[0531] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0532] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 223 or a sequence substantially homologous to it,

[0533] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 224 or a sequence substantially homologous to it, and

[0534] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 225 or a sequence substantially homologous to it; and / or (preferably "and")

[0535] The light chain variable region comprises:

[0536] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 226 or a sequence substantially homologous to it,

[0537] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 227 or a sequence substantially homologous to it, and

[0538] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 228 or a sequence substantially homologous to it. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0539] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 223, VH CDR2 of SEQ ID NO: 224, and VH CDR3 of SEQ ID NO: 225, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 226, VL CDR2 of SEQ ID NO: 227, and VL CDR3 of SEQ ID NO: 228.

[0540] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0541] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 283 or a sequence substantially homologous to it,

[0542] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 284 or a sequence substantially homologous to it, and

[0543] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 285 or a sequence substantially homologous to it; and / or (preferably "and")

[0544] The light chain variable region comprises:

[0545] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 286 or a sequence substantially homologous to it,

[0546] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 287 or a sequence substantially homologous to it, and

[0547] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 288 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0548] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 283, VH CDR2 of SEQ ID NO: 284, and VH CDR3 of SEQ ID NO: 285, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 286, VL CDR2 of SEQ ID NO: 287, and VL CDR3 of SEQ ID NO: 288.

[0549] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0550] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 303 or a sequence substantially homologous to it,

[0551] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 304 or a sequence substantially homologous to it, and

[0552] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 305 or a sequence substantially homologous to it; and / or (preferably "and")

[0553] The light chain variable region comprises:

[0554] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 306 or a sequence substantially homologous to it,

[0555] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 307 or a sequence substantially homologous to it, and

[0556] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 308 or a sequence substantially homologous to it. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0557] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 303, VH CDR2 of SEQ ID NO: 304, and VH CDR3 of SEQ ID NO: 305, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 306, VL CDR2 of SEQ ID NO: 307, and VL CDR3 of SEQ ID NO: 308.

[0558] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0559] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 323 or a sequence substantially homologous to it,

[0560] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 324 or a sequence substantially homologous to it, and

[0561] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 325 or a sequence substantially homologous to it; and / or (preferably "and")

[0562] The light chain variable region comprises:

[0563] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 326 or a sequence substantially homologous to it,

[0564] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 327 or a sequence substantially homologous to it, and

[0565] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 328 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0566] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 323, VH CDR2 of SEQ ID NO: 324, and VH CDR3 of SEQ ID NO: 325, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 326, VL CDR2 of SEQ ID NO: 327, and VL CDR3 of SEQ ID NO: 328.

[0567] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0568] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 343 or a sequence substantially homologous to it,

[0569] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 344 or a sequence substantially homologous to it, and

[0570] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 345 or a sequence substantially homologous to it; and / or (preferably "and")

[0571] The light chain variable region comprises:

[0572] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 346 or a sequence substantially homologous to it,

[0573] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 347 or a sequence substantially homologous to it, and

[0574] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 348 or a sequence substantially homologous to it. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0575] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 343, VH CDR2 of SEQ ID NO: 344, and VH CDR3 of SEQ ID NO: 345, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 346, VL CDR2 of SEQ ID NO: 347, and VL CDR3 of SEQ ID NO: 348.

[0576] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0577] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 363 or a sequence substantially homologous to it,

[0578] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 364 or a sequence substantially homologous to it, and

[0579] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 365 or a sequence substantially homologous to it; and / or (preferably "and")

[0580] The light chain variable region comprises:

[0581] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 366 or a sequence substantially homologous to it,

[0582] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 367 or a sequence substantially homologous to it, and

[0583] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 368 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0584] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 363, VH CDR2 of SEQ ID NO: 364, and VH CDR3 of SEQ ID NO: 365, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 366, VL CDR2 of SEQ ID NO: 367, and VL CDR3 of SEQ ID NO: 368.

[0585] In some embodiments, the present invention provides an antibody, such as an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises:

[0586] (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 423 or a sequence substantially homologous to it,

[0587] (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 424 or a sequence substantially homologous to it, and

[0588] (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 425 or a sequence substantially homologous to it; and / or (preferably "and")

[0589] The light chain variable region comprises:

[0590] (d) Variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 426 or a sequence substantially homologous to it,

[0591] (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 427 or a sequence substantially homologous to it, and

[0592] (f) VL CDR3 having the amino acid sequence of SEQ ID NO: 428 or a sequence substantially homologous thereto. The substantially homologous sequence is described elsewhere herein. Preferably, the substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

[0593] In some embodiments, the antibody comprises at least one heavy chain variable region comprising VH CDR1 of SEQ ID NO: 423, VH CDR2 of SEQ ID NO: 424, and VH CDR3 of SEQ ID NO: 425, and / or (preferably "and") at least one light chain variable region comprising VL CDR1 of SEQ ID NO: 426, VL CDR2 of SEQ ID NO: 427, and VL CDR3 of SEQ ID NO: 428.

[0594] Certain preferred embodiments of the present invention provide antibodies comprising a VH domain having an amino acid sequence of SEQ ID NO: 39 or 57 or 75, or a sequence substantially homologous thereto, and / or a VL domain having an amino acid sequence of SEQ ID NO: 40 or 58 or 76, or a sequence substantially homologous thereto.

[0595] A further preferred embodiment provides an antibody comprising a VH domain of the amino acid sequence of SEQ ID NO: 39, 57, or 75 and a VL domain comprising three light chain CDRs. Preferably, the light chain CDRs have SEQ ID NOs 44, 45, and 46; or 80, 81, and 82.

[0596] A further preferred embodiment provides an antibody comprising a VL domain having an amino acid sequence of SEQ ID NO: 40, 58, or 76 and a VH domain comprising three heavy chain CDRs. Preferably, the heavy chain CDRs have SEQ ID NO 41, 42, and 43; or 77, 78, or 79.

[0597] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 39 or a sequence substantially homologous thereto, and / or a VL domain having the amino acid sequence of SEQ ID NO: 40 or a sequence substantially homologous thereto.

[0598] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 40, or a sequence having at least 80% (e.g., at least 85%, 90%, 95% or 98%) sequence identity with it, and / or wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 39, or a sequence having at least 80% (e.g., at least 85%, 90%, 95% or 98%) sequence identity with it.

[0599] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 40, and / or wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 39.

[0600] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 40, and wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 39.

[0601] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 57 or a sequence substantially homologous thereto, and / or a VL domain having the amino acid sequence of SEQ ID NO: 58 or a sequence substantially homologous thereto.

[0602] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 58, or a sequence having at least 80% sequence identity with it (e.g., at least 85%, 90%, 95% or 98%), and / or wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 57, or a sequence having at least 80% sequence identity with it (e.g., at least 85%, 90%, 95% or 98%).

[0603] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 58, and / or wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 57.

[0604] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 58, and wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 57.

[0605] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 75 or a sequence substantially homologous thereto, and / or a VL domain having the amino acid sequence of SEQ ID NO: 76 or a sequence substantially homologous thereto.

[0606] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 76, or a sequence having at least 80% sequence identity with it (e.g., at least 85%, 90%, 95%, or 98%), and / or wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 75, or a sequence having at least 80% sequence identity with it (e.g., at least 85%, 90%, 95%, or 98%).

[0607] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 76, and / or wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 75.

[0608] In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 76, and wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 75.

[0609] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 101 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 102 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 102, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 101.

[0610] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 121 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 122 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 122, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 121.

[0611] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 141 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 142 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 142, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 141.

[0612] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 161 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 162 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 162, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 161.

[0613] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 181 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 182 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 182, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 181.

[0614] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 201 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 202 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 202, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 201.

[0615] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 221 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 222 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 222, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 221.

[0616] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 241 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 242 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 242, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 241.

[0617] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 261 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 262 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 262, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 261.

[0618] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 281 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 282 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 282, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 281.

[0619] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 301 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 302 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 302, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 301.

[0620] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 321 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 322 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 322, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 321.

[0621] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 341 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 342 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 342, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 341.

[0622] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 361 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 362 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 362, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 361.

[0623] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 381 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 382 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 382, ​​and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 381.

[0624] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 401 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 402 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 402, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 401.

[0625] In one embodiment, the present invention provides an antibody comprising a VH domain having the amino acid sequence of SEQ ID NO: 421 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity), and / or (preferably "and") a VL domain having the amino acid sequence of SEQ ID NO: 422 or a sequence substantially homologous thereto (e.g., having at least 80% sequence identity, such as a sequence having at least 85%, 90%, 95%, or 98% sequence identity). In a preferred embodiment, the present invention provides an antibody wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 422, and / or (preferably "and") wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 421.

[0626] Other preferred embodiments are the Ig (e.g., IgG) forms of the antibodies described herein, such as the IgG forms of OT-Ab3, OT-Ab2, and OT-Ab1 antibodies (or antibodies based thereon), preferably in full-length IgG form. Other preferred embodiments are the Ig (e.g., IgG) forms of OT-Ab3, OT-Ab2, OT-Ab1, 32C8-1, 33C9-1, 34C11-1, 40B10-1, 41B5-1, 43D6-1, 44E8-1, 46B7-1, 46D9-1, 12C9-1, 12G6-1, 15D8-1, 16F1-1, 17E11-1, 17E9-1, 18E10-1, and R4P1-C1 antibodies (or antibodies based thereon), preferably in full-length IgG form. In some embodiments, IgG is IgG1 or IgG2 (e.g., IgG... 2b Therefore, in some embodiments, the antibody is an Ig antibody containing the CDR sequence and / or the heavy chain variable region and / or the light chain variable region as described herein. It should be understood, of course, that a complete IgG antibody will typically contain two substantially identical heavy chains and two substantially identical light chains.

[0627] In some embodiments, antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibody sequences listed in Tables A, B, and C are preferred. In some embodiments, antibodies based on the OT-Ab1 antibody sequence listed in Table C are preferred.

[0628] In some implementations, antibodies based on the OT-Ab3, OT-Ab2, OT-Ab1, 32C8-1, 33C9-1, 34C11-1, 40B10-1, 41B5-1, 43D6-1, 44E8-1, 46B7-1, 46D9-1, 12C9-1, 12G6-1, 15D8-1, 16F1-1, 17E11-1, 17E9-1, 18E10-1, and R4P1-C1 antibody sequences listed in Tables AC and EU herein are preferred.

[0629] Some examples of the antibodies of the present invention are the monoclonal antibodies OT-Ab3, OT-Ab2, and OT-Ab1, the sequences of which are shown in Tables A, B, and C herein. The monoclonal antibodies OT-Ab3, OT-Ab2, and OT-Ab1 were identified using hybridoma technology, wherein the OTV5 peptide (SEQ ID NO: 18) serves as the immunogen. The CDR domain, VH domain, and VL domain are shown in Tables A, B, and C herein. Antibodies containing these CDR domains or VH and VL domains (or sequences substantially homologous to them) are a preferred aspect of the present invention.

[0630] Other examples of antibodies of the present invention are monoclonal antibodies 32C8-1, 33C9-1, 34C11-1, 40B10-1, 41B5-1, 43D6-1, 44E8-1, 46B7-1, and 46D9-1, the sequences of which are shown in Table EM herein. Monoclonal antibodies 32C8-1, 33C9-1, 34C11-1, 40B10-1, 41B5-1, 43D6-1, 44E8-1, 46B7-1, and 46D9-1 were identified using hybridoma technology, with the OTV3 peptide (SEQ ID NO: 16) serving as the immunogen. The CDR domain, VH domain, and VL domain are shown in Table EM herein. Antibodies containing these CDR domains or VH and VL domains (or sequences substantially homologous to them) are a preferred aspect of the present invention.

[0631] Other examples of antibodies of the present invention are monoclonal antibodies 12C9-1, 12G6-1, 15D8-1, 16F1-1, 17E11-1, 17E9-1, and 18E10-1, the sequences of which are shown in Table NT herein. Monoclonal antibodies 12C9-1, 12G6-1, 15D8-1, 16F1-1, 17E11-1, 17E9-1, and 18E10-1 were identified using hybridoma technology, with the OTV4 peptide (SEQ ID NO: 17) serving as the immunogen. The CDR domain, VH domain, and VL domain are shown in Table NT herein. Antibodies containing these CDR domains or VH and VL domains (or sequences substantially homologous to them) are a preferred aspect of the present invention.

[0632] Another example of the antibody of the present invention is the monoclonal antibody R4P1-C1, the sequence of which is shown in Table U herein. The monoclonal antibody was identified using phage display technology as described in the Examples section herein. The CDR domain, VH and VL domains are shown in Table U herein. Antibodies containing these CDR domains or VH and VL domains (or sequences substantially homologous to them) are a preferred aspect of the present invention.

[0633] Typically, monoclonal antibodies OT-Ab3, OT-Ab2, OT-Ab1, 32C8-1, 33C9-1, 34C11-1, 40B10-1, 41B5-1, 43D6-1, 44E8-1, 46B7-1, 46D9-1, 12C9-1, 12G6-1, 15D8-1, 16F1-1, 17E11-1, 17E9-1, 18E10-1, and / or R4P1-C1 (or antibodies based thereon, such as those having substantially homologous sequences) bind to (or are able to bind to, e.g., specifically bind to) epitopes of TRPV1 in the region of TRPV1 defined by amino acid residues 599-630 of TRPV1 (SEQ ID NO: 1). In some embodiments, the entire epitope to be bound is located within this region of TRPV1. In some embodiments, at least one amino acid of the epitope to be bound is located within this region of TRPV1.

[0634] Some instances of substantially homologous sequences are sequences having at least 65% identity with the disclosed amino acid sequence. In some embodiments, the antibody of the present invention comprises at least one light chain variable region comprising an amino acid sequence region having at least about 65%, 70%, or 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, and most preferably at least about 97%, 98%, or 99% amino acid sequence identity with the amino acid sequence of SEQ ID NO: 40, 58, 76, 102, 122, 142, 162, 182, 202, 222, 242, 262, 282, 302, 322, 342, 362, 382, ​​402, or 422; and / or at least one heavy chain variable region comprising an amino acid sequence region having at least about 65%, 70%, or 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, or 95%, and most preferably at least about 97%, 98%, or 99% amino acid sequence identity with the amino acid sequence of SEQ ID NO: The amino acid sequences of 39, 57, 75, 101, 121, 141, 161, 181, 201, 221, 241, 261, 281, 301, 321, 341, 361, 381, 401, or 421 have amino acid sequence regions with at least about 65%, 70%, or 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, or 95%, and most preferably at least about 97%, 98%, or 99% amino acid sequence identity.

[0635] Other preferred examples of substantially homologous sequences are sequences containing conserved amino acid substitutions of the disclosed amino acid sequence.

[0636] Other preferred examples of substantially homologous sequences are sequences containing one, two, or three, preferably one or two (more preferably one) altered amino acids in one or more disclosed CDR regions. Such alterations may be conserved or non-conserved amino acid substitutions, or mixtures thereof.

[0637] In some of these implementations, the preferred change is a conserved amino acid substitution.

[0638] In all embodiments, antibodies containing substantially homologous sequences retain the ability to bind to TRPV1. Preferably, antibodies containing substantially homologous sequences retain one or more (preferably all) of the properties described for OT-Ab3 and / or OT-Ab2 and / or OT-Ab1 antibodies. Preferably, antibodies containing substantially homologous sequences retain one or more (preferably all) of the properties described for 32C8-1 and / or 33C9-1 and / or 34C11-1 and / or 40B10-1 and / or 41B5-1 and / or 43D6-1 and / or 44E8-1 and / or 46B7-1 and / or 46D9-1 and / or 12C9-1 and / or 12G6-1 and / or 15D8-1 and / or 16F1-1 and / or 17E11-1 and / or 17E9-1 and / or 18E10-1 and / or R4P1-C1 antibodies.

[0639] Further examples of substantially homologous amino acid sequences according to the invention are described elsewhere herein.

[0640] The CDRs of the antibodies of the present invention are preferably distinguished by a suitable framework, such as those found in naturally occurring antibodies and / or effective engineered antibodies. Therefore, the V of the present invention... H V L Individual CDR sequences are preferably provided in or incorporated into a suitable frame or scaffold to enable antigen binding. Such frame sequences or regions may correspond to naturally occurring frame regions FR1, FR2, FR3, and / or FR4, as appropriate, to form a suitable scaffold, or they may correspond to common frame regions, for example, identified by comparing various naturally occurring frame regions. Alternatively, non-antibody scaffolds or frames (e.g., T-cell receptor frames) may be used.

[0641] Suitable sequences for use in the frame region are well known and documented in the art, and any of them can be used. The preferred sequence for the frame region is the V constituting the present invention. H and / or V LOne or more frame regions of the domain, i.e., one or more frame regions of the OT-Ab3, OT-Ab2, or OT-Ab1 antibodies as disclosed in Tables AC and EU herein, one or more frame regions of the 32C8-1, 33C9-1, 34C11-1, 40B10-1, 41B5-1, 43D6-1, 44E8-1, 46B7-1, 46D9-1, 12C9-1, 12G6-1, 15D8-1, 16F1-1, 17E11-1, 17E9-1, 18E10-1, or R4P1-C1 antibodies, or frame regions substantially homologous to them, and in particular frame regions that allow the maintenance of antigen specificity, such as frame regions that result in substantially the same or identical 3D structure of the antibodies.

[0642] In some preferred embodiments, all four variable light chain (SEQ ID NO: 51, 52, 53 and 54) and / or variable heavy chain (SEQ ID NO: 47, 48, 49 and 50) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0643] In other preferred embodiments, all four variable light chain (SEQ ID NO: 69, 70, 71 and 72) and / or variable heavy chain (SEQ ID NO: 65, 66, 67 and 68) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0644] In other preferred embodiments, all four variable light chain (SEQ ID NO: 87, 88, 89 and 90) and / or variable heavy chain (SEQ ID NO: 83, 84, 85 and 86) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0645] In other preferred embodiments, all four variable light chain (SEQ ID NO: 113, 114, 115 and 116) and / or variable heavy chain (SEQ ID NO: 109, 110, 111 and 112) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0646] In other preferred embodiments, all four variable light chain (SEQ ID NO: 133, 134, 135 and 136) and / or variable heavy chain (SEQ ID NO: 129, 130, 131 and 132) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0647] In other preferred embodiments, all four variable light chain (SEQ ID NO: 153, 154, 155 and 156) and / or variable heavy chain (SEQ ID NO: 149, 150, 151 and 152) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0648] In other preferred embodiments, all four variable light chain (SEQ ID NO: 173, 174, 175 and 176) and / or variable heavy chain (SEQ ID NO: 169, 170, 171 and 172) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0649] In other preferred embodiments, all four variable light chain (SEQ ID NO: 193, 194, 195 and 196) and / or variable heavy chain (SEQ ID NO: 189, 190, 191 and 192) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0650] In other preferred embodiments, all four variable light chain (SEQ ID NO: 213, 214, 215 and 216) and / or variable heavy chain (SEQ ID NO: 209, 210, 211 and 212) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0651] In other preferred embodiments, all four variable light chain (SEQ ID NO: 233, 234, 235 and 236) and / or variable heavy chain (SEQ ID NO: 229, 230, 231 and 232) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0652] In other preferred embodiments, all four variable light chain (SEQ ID NO: 253, 254, 255 and 256) and / or variable heavy chain (SEQ ID NO: 249, 250, 251 and 252) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0653] In other preferred embodiments, all four variable light chain (SEQ ID NO: 273, 274, 275 and 276) and / or variable heavy chain (SEQ ID NO: 269, 270, 271 and 272) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0654] In other preferred embodiments, all four variable light chain (SEQ ID NO: 293, 294, 295 and 296) and / or variable heavy chain (SEQ ID NO: 289, 290, 291 and 292) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0655] In other preferred embodiments, all four variable light chain (SEQ ID NO: 313, 314, 315 and 315) and / or variable heavy chain (SEQ ID NO: 309, 310, 311 and 312) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0656] In other preferred embodiments, all four variable light chain (SEQ ID NO: 333, 334, 335 and 336) and / or variable heavy chain (SEQ ID NO: 329, 330, 331 and 332) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0657] In other preferred embodiments, all four variable light chain (SEQ ID NO: 353, 354, 355 and 356) and / or variable heavy chain (SEQ ID NO: 349, 350, 351 and 352) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0658] In other preferred embodiments, all four variable light chain (SEQ ID NO: 373, 374, 375 and 376) and / or variable heavy chain (SEQ ID NO: 369, 370, 371 and 372) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0659] In other preferred embodiments, all four variable light chain (SEQ ID NO: 393, 394, 395 and 396) and / or variable heavy chain (SEQ ID NO: 389, 390, 391 and 392) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0660] In other preferred embodiments, all four variable light chain (SEQ ID NO: 413, 414, 415 and 416) and / or variable heavy chain (SEQ ID NO: 409, 410, 411 and 412) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0661] In other preferred embodiments, all four variable light chain (SEQ ID NO: 433, 434, 435 and 436) and / or variable heavy chain (SEQ ID NO: 429, 430, 431 and 432) frame regions (FRs), as appropriate, or substantially homologous FR regions, are found in the antibodies of the present invention.

[0662] In some embodiments, the VH and / or VL domains of the present invention may additionally include a signal peptide at their N-terminus (e.g., located directly at the N-terminus relative to the VH or VL domain). However, such signal peptides are typically not present in the antibody itself (e.g., not in mature antibodies or isolated antibody products) because they are usually cleaved away.

[0663] In some embodiments, the VH domain comprising SEQ ID NO: 39 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 93 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 40 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 94 at its N-terminus.

[0664] In some embodiments, the VH domain comprising SEQ ID NO: 57 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 95 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 58 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 96 at its N-terminus.

[0665] In some embodiments, the VH domain comprising SEQ ID NO: 75 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 97 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 76 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 98 at its N-terminus.

[0666] In some embodiments, the VH domain comprising SEQ ID NO: 101 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 117 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 102 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 118 at its N-terminus.

[0667] In some embodiments, the VH domain comprising SEQ ID NO: 121 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 137 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 122 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 138 at its N-terminus.

[0668] In some embodiments, the VH domain comprising SEQ ID NO: 141 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 157 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 142 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 158 at its N-terminus.

[0669] In some embodiments, the VH domain comprising SEQ ID NO: 161 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 177 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 162 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 178 at its N-terminus.

[0670] In some embodiments, the VH domain comprising SEQ ID NO: 181 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 197 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 182 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 198 at its N-terminus.

[0671] In some embodiments, the VH domain comprising SEQ ID NO: 201 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 217 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 202 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 218 at its N-terminus.

[0672] In some embodiments, the VH domain comprising SEQ ID NO: 221 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 237 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 222 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 238 at its N-terminus.

[0673] In some embodiments, the VH domain comprising SEQ ID NO: 241 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 257 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 242 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 258 at its N-terminus.

[0674] In some embodiments, the VH domain comprising SEQ ID NO: 261 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 277 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 262 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 278 at its N-terminus.

[0675] In some embodiments, the VH domain comprising SEQ ID NO: 281 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 297 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 282 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 298 at its N-terminus.

[0676] In some embodiments, the VH domain comprising SEQ ID NO: 301 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 317 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 302 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 318 at its N-terminus.

[0677] In some embodiments, the VH domain comprising SEQ ID NO: 321 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 337 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 322 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 338 at its N-terminus.

[0678] In some embodiments, the VH domain comprising SEQ ID NO: 341 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 357 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 342 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 358 at its N-terminus.

[0679] In some embodiments, the VH domain comprising SEQ ID NO: 361 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 377 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 362 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 378 at its N-terminus.

[0680] In some embodiments, the VH domain comprising SEQ ID NO: 381 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 397 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 382 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 398 at its N-terminus.

[0681] In some embodiments, the VH domain comprising SEQ ID NO: 401 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 417 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 402 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 418 at its N-terminus.

[0682] In some embodiments, the VH domain comprising SEQ ID NO: 421 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 437 at its N-terminus. In some embodiments, the VL domain comprising SEQ ID NO: 422 (or a sequence substantially homologous thereto) further comprises a signal peptide of SEQ ID NO: 438 at its N-terminus.

[0683] As described above, in this aspect of the invention, the antibody inhibits capsaicin-induced TRPV1 activation.

[0684] In some implementations, inhibition of capsaicin-induced TRPV1 activation is any measurable or significant inhibition, more preferably statistically significant inhibition (e.g., compared to a control without antibody or a control with an antibody that does not bind to TRPV1).

[0685] In some embodiments, the level (or amount) of inhibition of capsaicin-induced TRPV1 activation observed (or caused or triggered) by a control (e.g., not binding to (or not specifically binding to) TRPV1) is expressed (or set to) a zero inhibition level (or zero inhibition value or 0% inhibition level or value). Therefore, in some embodiments, the % inhibition (or relative to) of capsaicin-induced TRPV1 activation discussed elsewhere herein is compared with the inhibition observed (or caused or triggered) by a control antibody (e.g., a control antibody not binding to TRPV1).

[0686] In some embodiments, the inhibition of capsaicin-induced TRPV1 activation is at least 5%, at least 10%, at least 15%, preferably at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%.

[0687] In some implementations, the inhibition of capsaicin-induced TRPV1 activation is up to 5%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%.

[0688] Therefore, in some embodiments, the inhibition of capsaicin-induced TRPV1 activation is 5%-100%, 10%-100%, 15%-100%, 20%-100%, 25%-100%, 30%-100%, 35%-100%, 40%-100%, 45%-100%, 50%-100%, 55%-100%, 60%-100%, 65%-100%, 70%-100%, 75%-100%, 80%-100%, 85%-100%, 90%-100%, or 95%-100%.

[0689] In some implementations, the inhibition of capsaicin-induced TRPV1 activation is 5%-75%, 10%-75%, 15%-75%, 20%-75%, 25%-75%, 30%-75%, 35%-75%, 40%-75%, 45%-75%, 50%-75%, 55%-75%, 60%-75%, 65%-75%, or 70%-75%.

[0690] In some implementations, the inhibition of capsaicin-induced TRPV1 activation is 5%-50%, 10%-50%, 15%-50%, 20%-50%, 25%-50%, 30%-50%, 35%-50%, 40%-50%, or 45%-50%.

[0691] In some implementations, the inhibition of capsaicin-induced TRPV1 activation is 5%-25%, 10%-25%, 15%-25%, or 20%-25%.

[0692] In some preferred embodiments, the inhibition of capsaicin-induced TRPV1 activation is at least 20%, or at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%.

[0693] In some embodiments, the antibody of the present invention has an IC50 of ≤ 5 µM, ≤ 1 µM, ≤ 900 nM, ≤ 800 nM, ≤ 700 nM, ≤ 600 nM, ≤ 500 nM, ≤ 400 nM, ≤ 300 nM, ≤ 200 nM, ≤ 100 nM, ≤ 75 nM, ≤ 50 nM, ≤ 25 nM, ≤ 10 nM, ≤ 5 nM, ≤ 2 nM, ≤ 1 nM, ≤ 500 pM, ≤ 400 pM, ≤ 300 pM, ≤ 200 pM, ≤ 100 pM, ≤ 50 pM, ≤ 25 pM, ≤ 10 pM, ≤ 5 pM, ≤ 2 pM, or ≤ 1 pM in terms of inhibiting capsaicin-induced TRPV1 activation. Preferably, IC50 is ≤ 1 µM, for example ≤ 750 nM, ≤ 500 nM, ≤ 400 nM, ≤ 300 nM, ≤ 200 nM, ≤ 100 nM, ≤ 75 nM, ≤ 50 nM, ≤ 25 nM, ≤ 10 nM or ≤ 5 nM. In some implementations, the IC50 value can be in the range of 1 pM to ≤ 5 µM, for example, 1 pM-1 µM, 1 pM-500 nM, 1 pM-100 nM, 1 pM-50 nM, 500 pM-10 µM, 500 pM-1 µM, 500 pM-500 nM, 500 pM-100 nM, 500 pM-50 nM, 1 nM-10 µM, 1 nM-1 µM, 1 nM-500 nM, 1 nM-100 nM, 1 nM-50 nM, 10 nM-10 µM, 10 nM-10 µM, 10 nM-500 nM, 10 nM-100 nM, 10 nM-50 nM, 100 nM-10 µM, 100 nM-1 µM, or 100 nM-500 nM. In some embodiments, the IC50 value can be as high as 5 µM, or as high as 1 µM, or as high as 900 nM, or as high as 800 nM, or as high as 700 nM, or as high as 600 nM, or as high as 500 nM, or as high as 400 nM, or as high as 300 nM, or as high as 200 nM, or as high as 100 nM, or as high as 50 nM, or as high as 10 nM. The IC50 value represents the half-maximal inhibitory concentration (MCMC) of a substance in the biological process under study; in the context of this invention, it represents the MMC of an antibody used to inhibit capsaicin-induced TRPV1 activation. The IC50 value in the context of this invention can alternatively be considered as the value used to inhibit capsaicin-induced cellular TRPV1-mediated Ca2+ activation. 2+The half-maximal inhibitory concentration (IC50) of the influent antibody. The IC50 value can be calculated by any suitable method (and based on any suitable test, method, or assay, such as those described herein). For example, the IC50 value can be established (or calculated) based on the results of the FLIPR method. Particularly preferred FLIPR methods are described in the Examples section of this document.

[0694] As described above, in this aspect of the invention, the antibody preferentially inhibits capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation.

[0695] In some embodiments, the inhibition of heat-induced TRPV1 activation (if any) by the antibodies of the present invention is substantially the same (or not significantly different, similar, or comparable) to the inhibition of heat-induced TRPV1 activation (observed (or caused or triggered by) a control (e.g., a control antibody that does not bind (or does not specifically bind) to TRPV1). In some embodiments, the level (or amount of) inhibition of heat-induced TRPV1 activation observed (or caused or triggered by) a control (e.g., a control antibody that does not bind (or does not specifically bind) to TRPV1) is expressed (or set to) a zero inhibition level (or a zero inhibition value or a 0% inhibition level or value). Therefore, in some embodiments, the % inhibition (or relative to) of heat-induced TRPV1 activation discussed elsewhere herein is compared to the inhibition observed (or caused or triggered by) a control antibody (e.g., a control antibody that does not bind to TRPV1).

[0696] In some embodiments, the antibody of the present invention inhibits heat-induced TRPV1 activation by no more than 25%, or no more than 20%, or no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% or 0%.

[0697] Therefore, in some embodiments, the antibody of the present invention inhibits heat-induced TRPV1 activation by 0%-25%, 0%-20%, 0%-10%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1% or 0%.

[0698] In some preferred embodiments, the antibody of the present invention causes (or triggers) no measurable inhibition of heat-induced TRPV1 activation or no significant inhibition of heat-induced TRPV1 activation (preferably no statistically significant inhibition).

[0699] In some embodiments, the above-mentioned inhibition is determined when the antibody is used at concentrations in the range of micromolar (µM), nanomolar (nM), or picomolar (pM), preferably in the range of nanomolar (nM) or picomolar (pM). Therefore, in some embodiments, the above-mentioned inhibition is determined when the antibody is used at concentrations of ≤ 10 µM, ≤ 5 µM, ≤ 1 µM, ≤ 900 nM, ≤ 800 nM, ≤ 700 nM, ≤ 600 nM, ≤ 500 nM, ≤ 400 nM, ≤ 300 nM, ≤ 200 nM, ≤ 100 nM, ≤ 75 nM, ≤ 50 nM, ≤ 25 nM, ≤ 10 nM, ≤ 5 nM, ≤ 2 nM, ≤ 1 nM, ≤ 500 pM, ≤ 400 pM, ≤ 300 pM, ≤ 200 pM, ≤ 100 pM, ≤ 50 pM, ≤ 25 pM, ≤ 10 pM, ≤ 5 pM, ≤ 2 pM, or ≤ 1 pM. Therefore, in some implementations, when the antibody is at a concentration of 1 pM to ≤ 10 µM, such as 1 pM-1 µM, 1 pM-500 nM, 1 pM-100 nM, 1 pM-50 nM, 500 pM-10 µM, 500 pM-1 µM, 500 pM-500 nM, 500 pM-100 nM, 500 pM-50 nM, 1 nM-10 µM, 1 nM-1 µM, 1 nM-500 nM, 1 nM-100 nM, 1 nM-50 nM, 10 nM-10 µM, 10 nM-1 µM, 10 nM-50 nM, 10 nM-10 µM, 10 nM-50 nM, 100 nM-10 µM, 100 nM-1 µM, or 100 nM-500 nM, the dosage is specified. The above-mentioned inhibition was determined when the antibody was used at a concentration of up to nM. In some embodiments, the above-mentioned inhibition was determined when the antibody was used at a concentration of up to 5 µM, or up to 1 µM, or up to 900 nM, or up to 800 nM, or up to 700 nM, or up to 600 nM, or up to 400 nM, or up to 300 nM, or up to 200 nM, or up to 100 nM, or up to 50 nM or up to 10 nM.

[0700] In some embodiments, when the antibody is a polyclonal antibody (e.g., a rabbit polyclonal antibody), the above-described inhibition (e.g., % inhibition) and concentration are applied. In some embodiments, when the antibody is a monoclonal antibody (e.g., a mouse monoclonal antibody), the above-described inhibition (e.g., % inhibition) and concentration are applied.

[0701] As described above, in this aspect of the invention, the antibody preferentially inhibits capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation. This means that a given antibody inhibits (or is able to inhibit) capsaicin-induced TRPV1 activation to a greater extent than it inhibits (or is able to inhibit) heat-induced TRPV1 activation. Therefore, if a given antibody inhibits capsaicin-induced TRPV1 activation by X%, then the antibody inhibits heat-induced TRPV1 activation by < X%.

[0702] In some embodiments, the percentage inhibition (or percentage inhibition value) of capsaicin-induced TRPV1 activation is at least 5% higher than the percentage inhibition (or percentage inhibition value) of heat-induced TRPV1 activation, but typically at least 10%, preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or even 100% higher.

[0703] In some embodiments, the percentage inhibition (or percentage inhibition value) of capsaicin-induced TRPV1 activation is at least 20%, and the percentage inhibition (or percentage inhibition value) of heat-induced TRPV1 activation is ≤ 10%, ≤ 5%, or 0%. In some embodiments, the percentage inhibition (or percentage inhibition value) of capsaicin-induced TRPV1 activation is at least 40%, and the percentage inhibition (or percentage inhibition value) of heat-induced TRPV1 activation is ≤ 10%, ≤ 5%, or 0%. In some embodiments, the percentage inhibition (or percentage inhibition value) of capsaicin-induced TRPV1 activation is at least 60%, and the percentage inhibition (or percentage inhibition value) of heat-induced TRPV1 activation is ≤ 10%, ≤ 5%, or 0%. In some embodiments, the percentage inhibition (or percentage inhibition value) of capsaicin-induced TRPV1 activation is at least 80%, and the percentage inhibition (or percentage inhibition value) of heat-induced TRPV1 activation is ≤ 10%, ≤ 5%, or 0%. In some embodiments, the percentage inhibition (or percentage inhibition value) of capsaicin-induced TRPV1 activation is at least 40%, and the percentage inhibition (or percentage inhibition value) of heat-induced TRPV1 activation is ≤ 25%, ≤ 20%, 15%, ≤ 10%, ≤ 5%, or 0%. In some embodiments, the percentage inhibition (or percentage inhibition value) of capsaicin-induced TRPV1 activation is at least 60%, and the percentage inhibition (or percentage inhibition value) of heat-induced TRPV1 activation is ≤ 25%, ≤ 20%, 15%, ≤ 10%, ≤ 5%, or 0%. In some embodiments, the percentage inhibition (or percentage inhibition value) of capsaicin-induced TRPV1 activation is at least 80%, and the percentage inhibition (or percentage inhibition value) of heat-induced TRPV1 activation is ≤ 25%, ≤ 20%, 15%, ≤ 10%, ≤ 5%, or 0%.

[0704] In some implementations, the antibody preferentially inhibits capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation, as determined by testing (or assaying) to determine (or quantifying) the level (or amount) of inhibition of capsaicin-induced TRPV1 activation and testing (or assaying) to determine the level (or amount) of inhibition of heat-induced TRPV1 activation. Suitable assays are described elsewhere herein.

[0705] In some implementations, the antibody preferentially inhibits (or is able to inhibit) capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation, as determined when the antibody is used at the same concentration in two such assays (i.e., the same concentration of antibody is used in the test to determine the level of inhibition of capsaicin-induced TRPV1 activation, as in the test to determine the level of inhibition of heat-induced TRPV1 activation).

[0706] In some implementations, the antibody preferentially inhibits capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation, as in determining the level of inhibition in a test for heat-induced TRPV1 activation when the antibody is used at a concentration at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, preferably at least 5 times (e.g., 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, or 2-5, 3-5, or 4-5 times) higher than the concentration used in a test to determine the level of inhibition of capsaicin-induced TRPV1 activation.

[0707] In some embodiments, the inhibition of capsaicin-induced TRPV1 activation is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% or at least 50% for antibodies that bind to an isolated peptide (or substantially homologous to) the isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (OTV4 peptide) or to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0708] In some embodiments, capsaicin-induced TRPV1 activation is inhibited by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, or up to 50% for antibodies that bind to the isolated peptide (or substantially homologous to) the isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 or for antibodies that bind to the epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0709] In some embodiments, the aforementioned percentage inhibition of capsaicin-induced TRPV1 activation is determined when the antibody (e.g., a polyclonal antibody, such as a rabbit polyclonal antibody) is used at a concentration of 50 nM to 1 µM or 100 nM to 1 µM, for example 400 nM to 500 nM, or about 500 nM (e.g., 533 nM).

[0710] In some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 3 or SEQ ID NO: 17, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, the inhibition of heat-induced TRPV1 activation is no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, and preferably there is no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0711] Therefore, in some embodiments, for antibodies that bind to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 3 or SEQ ID NO: 17, or antibodies that bind to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, the inhibition of heat-induced TRPV1 activation is 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1%, or preferably 0%.

[0712] In some embodiments, the aforementioned percentage inhibition of heat-induced TRPV1 activation is determined as follows for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 3 or SEQ ID NO: 17, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0713] In some embodiments, for antibodies that bind to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 3 or SEQ ID NO: 17, or antibodies that bind to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration approximately 5 times higher than that which inhibits capsaicin-induced TRPV1 activation by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, or at least 50%, heat-induced TRPV1 activation is observed to be no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition.

[0714] In some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 3 or SEQ ID NO: 17, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration of about 3 µM (e.g., 2.7 µM), heat-induced TRPV1 activation of no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition is observed, and when the antibody is used at a concentration of about 500 nM (e.g., 533 nM), capsaicin-induced TRPV1 activation of at least 10%, at least 15%, preferably at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, or at least 50% inhibition is observed.

[0715] In some embodiments, for antibodies that bind to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 3 or SEQ ID NO: 17, or antibodies that bind to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration of about 3 µM (e.g., 2.7 µM), an inhibition of no more than 5% of heat-induced TRPV1 activation is observed, and when the antibody is used at a concentration of about 500 nM (e.g., 533 nM), at least 20% inhibition of capsaicin-induced TRPV1 activation is observed.

[0716] In some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 4 or SEQ ID NO: 18 (OTV5 peptide) or to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, the inhibition of capsaicin-induced TRPV1 activation is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%.

[0717] In some embodiments, the inhibition of capsaicin-induced TRPV1 activation is up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, or up to 75% for antibodies that bind to the isolated peptide (or substantially homologous to) the isolated peptide or to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0718] In some embodiments, the aforementioned percentage inhibition of capsaicin-induced TRPV1 activation is determined as follows for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 4 or SEQ ID NO: 18, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0719] In some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 4 or SEQ ID NO: 18, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, the inhibition of heat-induced TRPV1 activation is no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, and preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0720] Therefore, in some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 4 or SEQ ID NO: 18, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, the inhibition of heat-induced TRPV1 activation is 0%-15%, preferably 0%-10%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1%, or preferably 0%.

[0721] In some embodiments, the aforementioned percentage inhibition of heat-induced TRPV1 activation is determined as follows for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 4 or SEQ ID NO: 18, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0722] In some embodiments, for antibodies that bind to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 4 or SEQ ID NO: 18, or antibodies that bind to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration approximately 5 times higher than that which inhibits capsaicin-induced TRPV1 activation by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, or at least 50%, heat-induced TRPV1 activation is observed to be no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition.

[0723] In some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 4 or SEQ ID NO: 18, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration of about 50 nM (e.g., 67 nM), heat-induced TRPV1 activation of no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition is observed, and when the antibody is used at a concentration of about 10 nM (e.g., 13.3 nM), capsaicin-induced TRPV1 activation inhibition of at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, or at least 50% is observed.

[0724] In some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 4 or SEQ ID NO: 18, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration of about 5 nM (e.g., 6.7 nM), heat-induced TRPV1 activation of no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition is observed, and when the antibody is used at a concentration of about 1 nM (e.g., 1.33 nM), capsaicin-induced TRPV1 activation of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, or at least 50% inhibition is observed.

[0725] In some embodiments, for antibodies that bind to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 4 or SEQ ID NO: 18, or antibodies that bind to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration of about 5 nM (e.g., 6.7 nM), an inhibition of no more than 5% of heat-induced TRPV1 activation is observed, and when the antibody is used at a concentration of about 1 nM (e.g., 1.33 nM), an inhibition of at least 10% of capsaicin-induced TRPV1 activation is observed.

[0726] In some embodiments, the inhibition of capsaicin-induced TRPV1 activation is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% for antibodies that bind to an isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 11 or SEQ ID NO: 25 (OTV12 peptide) or to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0727] In some embodiments, capsaicin-induced TRPV1 activation is inhibited by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, or up to 40% for antibodies that bind to the isolated peptide (or substantially homologous to) the isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 or for antibodies that bind to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0728] In some embodiments, the aforementioned percentage inhibition of capsaicin-induced TRPV1 activation is determined as follows for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 11 or SEQ ID NO: 25, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0729] In some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 3 or SEQ ID NO: 25, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, the inhibition of heat-induced TRPV1 activation is no more than 5%, no more than 4%, no more than 11%, no more than 2%, or no more than 1%, preferably 0%, and preferably there is no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0730] Therefore, in some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 11 or SEQ ID NO: 25, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, the inhibition of heat-induced TRPV1 activation is 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1%, or preferably 0%.

[0731] In some embodiments, the aforementioned percentage inhibition of heat-induced TRPV1 activation is determined as follows for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 11 or SEQ ID NO: 25, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide.

[0732] In some embodiments, for antibodies that bind to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 11 or SEQ ID NO: 25, or antibodies that bind to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration approximately 5 times higher than that which inhibits capsaicin-induced TRPV1 activation by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, or at least 50%, heat-induced TRPV1 activation is observed to be no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition.

[0733] In some embodiments, for antibodies binding to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 11 or SEQ ID NO: 25, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration of about 50 nM (e.g., 67 nM), heat-induced TRPV1 activation of no more than 5%, no more than 4%, no more than 3%, preferably no more than 2% or no more than 1%, preferably no measurable (or no significant) inhibition is observed, and when the antibody is used at a concentration of about 10 nM (e.g., 13.3 nM), capsaicin-induced TRPV1 activation of at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, or at least 50% inhibition is observed.

[0734] In some embodiments, for antibodies that bind to the isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 11 or SEQ ID NO: 25, or antibodies that bind to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, when the antibody is used at a concentration of about 50 nM (e.g., 67 nM), an inhibition of no more than 5% of heat-induced TRPV1 activation is observed, and when the antibody is used at a concentration of about 10 nM (e.g., 13.3 nM), an inhibition of at least 20% of capsaicin-induced TRPV1 activation is observed.

[0735] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of capsaicin-induced TRPV1 activation is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80%.

[0736] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of capsaicin-induced TRPV1 activation is up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, or up to 90%.

[0737] In some embodiments, the aforementioned % inhibition of capsaicin-induced TRPV1 activation by antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto) is determined as when the antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) is used at a concentration of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 243 nM for an OT-Ab1-based antibody, or 166 nM for an OT-Ab2-based antibody, or 326 nM for an OT-Ab3-based antibody).

[0738] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of heat-induced TRPV1 activation is no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, and preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0739] Therefore, in some embodiments, for antibodies (e.g., monoclonal antibodies, such as mouse monoclonal antibodies) based on the OT-Ab3, OT-Ab2 and OT-Ab1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of heat-induced TRPV1 activation is 0%-15%, preferably 0%-10%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1%, or preferably 0%.

[0740] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous to them), the aforementioned % inhibition of heat-induced TRPV1 activation is determined as when the antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) is used at a concentration of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 243 nM for an OT-Ab1-based antibody, or 166 nM for an OT-Ab2-based antibody, or 326 nM for an OT-Ab3-based antibody).

[0741] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), when the antibody is used at a concentration that inhibits capsaicin-induced TRPV1 activation by at least 25%, preferably at least 30%, at least 35%, at least 40%, or at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80%, heat-induced TRPV1 activation is observed to be no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition.

[0742] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), when said antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 243 nM for OT-Ab1-based antibodies, or 166 nM for OT-Ab2-based antibodies, or 326 nM for OT-Ab3-based antibodies), heat-induced TRPV1 activation of no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition is observed, and when said antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 243 nM for OT-Ab1-based antibodies, or 166 nM for OT-Ab2-based antibodies), heat-induced TRPV1 activation of no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition is observed, and when said antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 166 nM for OT-Ab2-based antibodies), heat-induced TRPV1 activation of no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition is When used at a concentration of nM, or for example, 326 nM for an OT-Ab3-based antibody, at least 25%, preferably at least 30%, at least 35%, at least 40%, or at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% inhibition of capsaicin-induced TRPV1 activation was observed.

[0743] In some embodiments, for antibodies based on the 16F1-1, 15D8-1, 17E11-1, or 17E9-1 of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of capsaicin-induced TRPV1 activation is up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, or up to 75%.

[0744] In some embodiments, for antibodies based on the 16F1-1, 15D8-1, 17E11-1, or 17E9-1 of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the aforementioned % inhibition of capsaicin-induced TRPV1 activation is determined as when the antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) is used at a concentration of 50 nM to 1 µM or 100 nM to 1 µM, for example 50 nM to 500 nM or 100 nM to 500 nM (e.g., 253 nM for a 16F1-1-based antibody, or 130 nM for a 15D8-1-based antibody, or 110 nM for a 17E11-1-based antibody, or 83 nM for a 17E9-1-based antibody).

[0745] In some embodiments, for antibodies based on the 15D8-1 or 17E11-1 of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of heat-induced TRPV1 activation is no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, and preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0746] Therefore, in some embodiments, for antibodies (e.g., monoclonal antibodies, such as mouse monoclonal antibodies) based on the 15D8-1 or 17E11-1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of heat-induced TRPV1 activation is 0%-15%, preferably 0%-10%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1%, or preferably 0%.

[0747] In some embodiments, for antibodies based on the 15D8-1 or 17E11-1 of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the aforementioned % inhibition of heat-induced TRPV1 activation is determined as when the antibody is used at a concentration of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 200 nM).

[0748] In some embodiments, for antibodies based on the 15D8-1 or 17E11-1 of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), when the antibody is used at a concentration that inhibits capsaicin-induced TRPV1 activation by at least 25%, preferably at least 30%, at least 35%, at least 40%, or at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%, heat-induced TRPV1 activation is observed to be no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition.

[0749] In some embodiments, for antibodies based on the 15D8-1 or 17E11-1 of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), when said antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 200 nM), heat-induced TRPV1 activation is observed to be no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition, and when said antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM or 100 nM to 200 nM (e.g., 130 nM for 15D8-1-based antibodies, or 110 nM for 17E11-1-based antibodies), heat-induced TRPV1 activation is observed to be significantly reduced. Using a concentration of nM, capsaicin-induced TRPV1 activation was observed to be inhibited by at least 25%, preferably at least 30%, at least 35%, at least 40%, or at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%.

[0750] In some embodiments, for antibodies based on the 41B5-1 antibody of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of heat-induced TRPV1 activation is no more than 15%, preferably no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, and preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0751] Therefore, in some embodiments, for antibodies (e.g., monoclonal antibodies, such as mouse monoclonal antibodies) based on the 41B5-1 antibody of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the inhibition of heat-induced TRPV1 activation is 0%-15%, preferably 0%-10%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1%, or preferably 0%.

[0752] In some embodiments, for antibodies based on the 41B5-1 antibody of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the aforementioned % inhibition of heat-induced TRPV1 activation is determined as when the antibody is used at a concentration of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 300 nM).

[0753] In some embodiments, for antibodies based on the 46B7-1 antibody of the present invention (e.g., those having its CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous to it), the inhibition of heat-induced TRPV1 activation is no more than 25% or no more than 20%.

[0754] Therefore, in some embodiments, for antibodies based on the 46B7-1 antibody of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous to them) (e.g., monoclonal antibodies, such as mouse monoclonal antibodies), the inhibition of heat-induced TRPV1 activation is 0%-25%, 0%-20%, or 0%-15%.

[0755] In some embodiments, for antibodies based on the 46B7-1 antibody of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), the aforementioned % inhibition of heat-induced TRPV1 activation is as determined when the antibody is used at a concentration of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 367 nM).

[0756] In some implementations, the aforementioned inhibition (e.g., % inhibition) of capsaicin-induced TRPV1 activation is determined as in patch-clamp methods (e.g., elsewhere herein).

[0757] In some implementations, the aforementioned inhibition (e.g., % inhibition) of thermally induced TRPV1 activation is determined as described elsewhere herein.

[0758] In some embodiments, antibodies (e.g., monoclonal antibodies, such as mouse monoclonal antibodies) based on the 41B5-1, 15D8-1, 46B7-1, 16F1-1, 17E11-1, or 17E9-1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous to them) may have an IC50 with respect to capsaicin-induced TRPV1 activation ≤ 1 µM, preferably ≤ 750 nM, or ≤ 500 nM. In some such embodiments, the IC50 value can be in the range of 10 nM to 1 µM, for example, 50 nM to 1 µM, or 100 nM to 1 µM, or 200 nM to 1 µM, or 10 nM to 750 nM, or 50 nM to 750 nM, or 100 nM to 750 nM, or 200 nM to 750 nM, or 10 nM to 500 nM, or 50 nM to 500 nM, or 100 nM to 500 nM, or 200 nM to 500 nM. In some such embodiments, the IC50 value can be up to 1 µM, for example, up to 750 nM, or up to 500 nM. The IC50 value can be established (or calculated) based on the results of any suitable determination or test (e.g., the FLIPR method) as described herein. Particularly preferred FLIPR methods are described in the Examples section of this document.

[0759] In some embodiments, for antibodies based on the 41B5-1, 15D8-1, 46B7-1, or 17E11-1 antibodies of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), when the antibody is used at a concentration that inhibits capsaicin-induced TRPV1 activation by about 50%, heat-induced TRPV1 activation is observed to be no more than 25%, no more than 20%, no more than 15%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition.

[0760] In some embodiments, for antibodies based on the 41B5-1, 15D8-1, or 17E11-1 of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), when the antibody is used at a concentration that inhibits capsaicin-induced TRPV1 activation by about 50%, heat-induced TRPV1 activation is observed to be no more than 15%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition.

[0761] In some embodiments, for antibodies based on the 41B5-1, 15D8-1, 46B7-1, or 17E11-1 of the present invention (e.g., those having their CDR sequence and / or VH domain and / or VL domain sequences, or sequences substantially homologous thereto), when said antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 200 nM for antibodies based on 15D8-1 or 17E11-1, or 300 nM for antibodies based on 41B5-1, or 367 nM for antibodies based on 46B7-1), heat-induced TRPV1 activation of no more than 25%, no more than 20%, no more than 15%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition, and when said antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM, ... 17E11-1, or preferably 0%, no more than 1%, preferably no more than 1%, preferably no more than 0%, preferably no more than 1%, preferably no more than 0%, preferably no more than 1%, preferably no more than 0%, preferably no more than 1%, preferably no When used at concentrations of nM or 100 nM to 200 nM (e.g., 170 nM for an antibody based on 41B5-1, or 70 nM for an antibody based on 15D8-1, or 200 nM for an antibody based on 46B7-1, or 230 nM for an antibody based on 17E11-1), approximately 50% inhibition of capsaicin-induced TRPV1 activation was observed.

[0762] In some embodiments, for antibodies of the present invention based on antibodies 41B5-1, 15D8-1, and 17E11-1, when the antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM (e.g., 200 nM for antibodies based on 15D8-1 or 17E11-1, or 300 nM for antibodies based on 41B5-1), heat-induced TRPV1 activation of no more than 15%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition is observed, and when the antibodies are used at concentrations of 100 nM to 1 µM, for example 100 nM to 500 nM or 100 nM to 200 nM (e.g., 170 nM for antibodies based on 41B5-1, or 70 nM for antibodies based on 15D8-1, or 230 nM for antibodies based on 17E11-1), heat-induced TRPV1 activation of no more than 15%, no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%, preferably 0%, preferably no measurable (or no significant) inhibition is observed, heat-induced TRPV1 activation of no more than 15D8-1, or preferably no more than 300 nM for antibodies based on 41B5-1, or 230 nM for antibodies based on 17E11-1), heat-induced TRPV1 activation of no more than 15D8-1, no more than 500 nM, or 200 nM for antibodies based on 17E11-1, no more than 100 nM for 17D8- Using a concentration of nM, approximately 50% inhibition of capsaicin-induced TRPV1 activation was observed.

[0763] In some embodiments, the inhibition of capsaicin-induced TRPV1 activation is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% for antibodies binding to an isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 6 or SEQ ID NO: 20 (OTV7 peptide) or to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide. In some embodiments, these percentage inhibitions (e.g., % inhibitions) of capsaicin-induced TRPV1 activation are determined as by calcium imaging methods (e.g., as described elsewhere herein).

[0764] In some embodiments, capsaicin-induced TRPV1 activation is inhibited by up to 5%, up to 10%, up to 15%, up to 20%, up to 25%, or up to 30% for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 6 or SEQ ID NO: 20, or for antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide. In some embodiments, these percentage inhibitions (e.g., % inhibitions) of capsaicin-induced TRPV1 activation are determined as by calcium imaging methods (e.g., as described elsewhere herein).

[0765] In some embodiments, the aforementioned percentage inhibition of capsaicin-induced TRPV1 activation is determined as follows for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 6 or SEQ ID NO: 20, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide. In some embodiments, these percentage inhibitions (e.g., percentage inhibition) of capsaicin-induced TRPV1 activation are determined as follows by calcium imaging methods (e.g., as described elsewhere herein).

[0766] In some embodiments, the inhibition of capsaicin-induced TRPV1 activation is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% for antibodies binding to an isolated peptide (or a substantially homologous isolated peptide) of SEQ ID NO: 8 or SEQ ID NO: 22 (OTV9 peptide) or to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide. In some embodiments, these percentage inhibitions (e.g., % inhibitions) of capsaicin-induced TRPV1 activation are determined as by calcium imaging methods (e.g., as described elsewhere herein).

[0767] In some embodiments, capsaicin-induced TRPV1 activation is inhibited by up to 5%, up to 10%, up to 15%, up to 20%, up to 25%, or up to 30% for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 8 or SEQ ID NO: 22, or for antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide. In some embodiments, these percentage inhibitions (e.g., % inhibitions) of capsaicin-induced TRPV1 activation are determined as by calcium imaging methods (e.g., as described elsewhere herein).

[0768] In some embodiments, the aforementioned percentage inhibition of capsaicin-induced TRPV1 activation is determined as follows for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 8 or SEQ ID NO: 22, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide. In some embodiments, these percentage inhibitions (e.g., percentage inhibitions) of capsaicin-induced TRPV1 activation are determined as by calcium imaging methods (e.g., as described elsewhere herein).

[0769] In some embodiments, the inhibition of capsaicin-induced TRPV1 activation is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% for antibodies binding to isolated peptides (or substantially homologous to) the isolated peptide of SEQ ID NO: 12 or SEQ ID NO: 26 (OTV13 peptide) or for antibodies binding to TRPV1 epitopes corresponding to (or substantially corresponding to) such isolated peptides. In some embodiments, these percentage inhibitions (e.g., % inhibitions) of capsaicin-induced TRPV1 activation are determined as by calcium imaging methods (e.g., as described elsewhere herein).

[0770] In some embodiments, capsaicin-induced TRPV1 activation is inhibited by up to 5%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, or up to 35% for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 12 or SEQ ID NO: 26, or for antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide. In some embodiments, these percentage inhibitions (e.g., % inhibitions) of capsaicin-induced TRPV1 activation are determined as by calcium imaging methods (e.g., as described elsewhere herein).

[0771] In some embodiments, the aforementioned percentage inhibition of capsaicin-induced TRPV1 activation is determined as follows for antibodies binding to the isolated peptide (or substantially homologous to) of SEQ ID NO: 12 or SEQ ID NO: 26, or antibodies binding to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide. In some embodiments, these percentage inhibitions (e.g., percentage inhibitions) of capsaicin-induced TRPV1 activation are determined as by calcium imaging methods (e.g., as described elsewhere herein).

[0772] In some embodiments, capsaicin-induced TRPV1 activation is TRPV1 activation induced when capsaicin is present (or used or in contact with TRPV1) at a concentration of 10 nM to 10 µM, for example, 100 nM to 1 µM (e.g., a concentration of 100 nM or 1 µM). In some embodiments, capsaicin-induced TRPV1 activation is TRPV1 activation induced when capsaicin is present at 100 nM. In some embodiments, capsaicin-induced TRPV1 activation is TRPV1 activation induced when capsaicin is present at 300 nM.

[0773] Capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed by any suitable method, and a technician will be familiar with the appropriate method.

[0774] In some embodiments, capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed (or evaluated) using electrophysiological methods such as patch-clamp techniques. Patch-clamp techniques are well known in the art and are also described herein. According to the invention, a reduction (or inhibition or decrease) of capsaicin-induced current by the antibodies of the present invention compared to control antibodies (e.g., control antibodies that do not bind to (or do not specifically bind to) TRPV1 generally indicates that the antibody inhibits capsaicin-induced TRPV1 activation.

[0775] In some embodiments, the patch-clamp method includes clamping (e.g., using a pipette) TRPV1-expressing cells (e.g., in a bath) and recording the current (or current signal). Typically, the current (or current signal) is measured (e.g., in parallel tests) in cells stimulated (or incubated) with capsaicin, in cells stimulated with capsaicin and the antibody of the present invention, and preferably also in cells stimulated (or incubated) with capsaicin and a control antibody (e.g., a control antibody that does not bind (or does not specifically bind) to TRPV1). For example, a reduction (or inhibition or decrease) in capsaicin-induced current compared to a control antibody generally indicates that the antibody of the present invention inhibits capsaicin-induced TRPV1 activation.

[0776] In some embodiments, in the patch-clamp method, whole-cell recording is performed using a microfluidic device for patch-clamp recording along with a patch-clamp amplifier. In some embodiments, the cells are Chinese hamster ovary (CHO) cells expressing TRPV1. In some embodiments, the bath and pipette solutions contain buffers F and G, respectively (as defined elsewhere herein). In some embodiments, the cells are clamped (e.g., at -60 mV) and the current signal is recorded at a sampling frequency (e.g., 10 kHz) and low-pass filtered (e.g., 2 kHz). In some embodiments, digital / analog sampling and acquisition software is used to acquire the patch-clamp recordings. In a preferred embodiment, the current amplitude is measured by exposing the cells to capsaicin (e.g., 100 nM capsaicin), with and without the antibody or control antibody of the present invention. In a preferred embodiment, cells are exposed to 100 nM capsaicin in buffer F (or buffer A) for approximately 20 s, followed by approximately 60 s in buffer F (or buffer A), approximately 60 s in antibody in buffer F (or buffer A), and then approximately 20 s in 100 nM capsaicin and antibody together in buffer F (or buffer A). In a preferred embodiment, measurements in which the sealing resistance changes significantly during treatment are excluded from the analysis. In a preferred embodiment, the peak amplitude recorded during antibody + capsaicin stimulation is divided by the peak amplitude recorded during capsaicin stimulation. The resulting value can be multiplied by 100 to obtain the cellular response during antibody + capsaicin stimulation as a percentage of the control response (capsaicin, i.e., capsaicin only). Thus, in some embodiments, the % inhibition of capsaicin-induced TRPV1 stimulation (activation) can be calculated as (1 - (peak amplitude recorded during antibody + capsaicin stimulation divided by peak amplitude recorded during capsaicin-only stimulation) x 100). Measurements are preferably performed on cells from at least two different cell culture dishes. The preferred patch-clamp method is described in the Examples section of this paper.

[0777] In some embodiments, the patch-clamp method involves stimulating (or activating) TRPV1-expressing cells four times with capsaicin (e.g., 100 nM or 300 nM capsaicin). In some such embodiments, hTRPV1-expressing cells are pretreated with the antibody of the present invention before the third activation (or stimulation), and the antibody is incubated with capsaicin during the third activation (or stimulation). In some such embodiments, the first, second, and fourth activations (stimulations) are performed with capsaicin alone. The amplitude of the third current peak in the presence of the antibody can be compared to the average amplitude of the second and fourth current peaks. In some embodiments, cells are treated twice with capsaicin alone to obtain peaks 1 and 2, then treated with the antibody, then treated with the antibody and capsaicin together to obtain peak 3, and subsequently treated with capsaicin alone to obtain peak 4. In some embodiments, % inhibition can be calculated as (1 - ((peak 3) / ((peak 2 + peak 4) / 2)))*100. In some other embodiments, cells are first treated twice with capsaicin alone to obtain peaks 1 and 2, then treated with an antibody or a medium, then treated with an antibody or medium together with capsaicin to obtain peak 3, followed by treatment with capsaicin alone to obtain peak 4. In some such embodiments, % inhibition can be calculated as (1 - (peak 3)). Ab / Peak 2 Ab ) / (peak3 veh / Peak 2 veh )))*100.

[0778] In some implementations, capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed (or evaluated) using calcium imaging methods. Capsaicin induces calcium uptake.

[0779] In some embodiments, capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed (or evaluated) by: (i) loading TRPV1-expressing cells with a calcium indicator (e.g., as described elsewhere herein), (ii) contacting (or incubating) the cells with the antibody of the present invention (or a control antibody or a mediator-only (i.e., antibody-free) control), and (iii) contacting (or incubating) the cells (i.e., cells already incubated with the antibody of the present invention or the control in (ii)) with capsaicin and calcium (Ca). 2+ (iv) The ability of the antibody of the present invention to reduce (or decrease or inhibit) capsaicin-induced calcium influx (or uptake) into cells is assessed (or determined or measured) by measuring (or determining) a signal (e.g., a fluorescence signal) from a calcium indicator (e.g., compared to a control antibody or a mediator-only control). Preferred features of such embodiments will be apparent from the discussion elsewhere herein, and these may be applied, with necessary modifications, to the embodiments discussed in this paragraph.

[0780] In some calcium imaging methods used to assess capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation, a calcium indicator (e.g., Fluo-3 AM) is used. In some such methods, cells expressing hTRPV1 (e.g., CHO cells) are incubated with the calcium indicator to "load" the cells, for example, at 37°C for 30 min, and preferably then washed (after which the calcium indicator remains inside the cells), and then incubated, for example, at room temperature for 1 h with the antibody of the present invention or with a control antibody (e.g., dissolved in PBS) or without additional agents. The control antibody is typically an antibody that does not bind to (or does not specifically bind to) TRPV1. Typically, the cells are then incubated with capsaicin (e.g., 1 µM) and Ca... 2+ (e.g., 150 μM) contact (e.g., adding capsaicin and calcium to the antibody solution covering the cells), and monitoring (or measuring) the intracellular calcium content by measuring the fluorescence intensity (of a calcium indicator), for example, using a plate reader. Typically, the fluorescence intensity observed after (or during) incubation with capsaicin and calcium (where cells are pre-incubated with the antibody of the present invention) is relative to the fluorescence intensity observed after incubation with capsaicin and calcium (Ca). 2+ The fluorescence intensity observed after (or during) incubation (where cells were not previously incubated with the antibody of this invention or any additional agents) was normalized. This was compared with the fluorescence intensity observed after incubation with capsaicin and calcium (Ca). 2+ Before incubation, there was no comparison with incubation using the antibody of the present invention (e.g., compared with incubation using capsaicin and calcium (Ca)). 2+ (Compared to the control antibody incubation before incubation), if incubation with capsaicin and calcium (Ca) 2+ If the fluorescence intensity decreases (or is inhibited or reduced) after incubation with the antibody of the present invention before incubation, this generally indicates that the antibody of the present invention inhibits capsaicin-induced TRPV1 activation. Particularly preferred calcium imaging methods are described in the Examples section of this document.

[0781] In some implementations, capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed (or evaluated) using a fluorescence imaging plate reader (FLIPR) method.

[0782] In certain preferred FLIPR methods (which reflect the FLIPR method used in Example 3 of this document), cells expressing TRPV1 (e.g., CHO cells expressing TRPV1) are cultured in black transparent-bottomed microplates (e.g., 96-well microplates). The cells are then loaded with a calcium indicator (e.g., 4 µM Fluo-3 AM) by incubation with a calcium indicator (e.g., 4 µM Fluo-3 AM) in a buffer, such as HEPES buffer (140 nM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM D-glucose, pH 7.4) at room temperature for, for, for, for, for, for, 30 minutes. The cells are then washed with a buffer (e.g., HEPES) to remove the extracellular calcium indicator (e.g., Fluo-3 AM) (the calcium indicator remains intracellular after washing). Subsequently, the antibody of the present invention, diluted in a buffer (e.g., a calcium-containing buffer such as HEPES), is added to the wells. For example, 100 µl of antibody-containing buffer is added to the cells in each well (typically, serially diluted antibodies diluted in a buffer (e.g., a calcium-containing buffer such as HEPES) are added to the wells, i.e., different concentrations of antibody in different wells). The cells are incubated in the presence of the antibody (e.g., for 4 minutes, at, for example, room temperature). Fluorescence measurements are typically performed using a microplate reader, for example, where the excitation wavelength is 483 nm (bandwidth 14 nm) and the emission wavelength is 530 nm (bandwidth 30 nm). First, baseline fluorescence intensity is measured. Then (i.e., subsequently), a fixed amount of capsaicin in a calcium-containing buffer (e.g., in 100 µl buffer) such as HEPES is added to each well (giving a previously determined capsaicin concentration representing the capsaicin EC50 value of the studied cell batch; typically this concentration is in the submicromolar range, e.g., it might be in the lower nM range, such as 10 nM). A second fluorescence intensity measurement is performed after a set time (typically within a few minutes, e.g., 1 to 5, 1 to 10, or 1 to 20 minutes). Fluorescence intensity (of a calcium indicator) provides a report (or reading) of intracellular calcium levels (and capsaicin-induced TRPV1 activation). This FLIPR assay relies on the presence of calcium (Ca) in the buffer at the time capsaicin is added. 2+ (That is, when cells are exposed to capsaicin, it depends on the presence of calcium in the buffer), and any suitable calcium-containing buffer (a suitable buffer will be familiar to a technician), such as the HEPES buffer described above, provides sufficient calcium. The antibody of the present invention can be added to cells (wells) in PBS (phosphate-buffered saline) before being diluted to a buffer (e.g., a calcium-containing buffer such as HEPES). EC50 is the concentration of a substance that gives the half-maximal response of a biological process, in this case, the TRPV1-mediated calcium... 2+Entering (or TRPV1-mediated Ca) 2+ (Uptake) of cells. Data can be presented (or obtained or determined) as fluorescence rate, which is calculated as fluorescence at a set (or specific) time after the addition of capsaicin minus fluorescence measured before the addition of capsaicin (baseline). If a decrease in fluorescence rate is observed (or measured or determined) with increasing antibody (i.e., the given antibody being tested) concentration (e.g., higher (or increased) concentrations in an antibody dilution series), it generally indicates that the antibody of the present invention inhibits capsaicin-induced TRPV1 activation. The IC50 value of the antibody being tested can be calculated (and this can be readily performed by those skilled in the art). The IC50 value is the half-maximal inhibitory concentration of a substance in the biological process under investigation, in this case, capsaicin-induced cellular TRPV1-mediated Ca2+. 2+ Inflow (or ingestion or entry). The particularly preferred FLIPR method is described in the Examples section of this paper.

[0783] As mentioned above, some methods involve the use of calcium indicators (e.g., Fluo3-AM). Those skilled in the art are familiar with such indicators. Calcium indicators can be conveniently used to visualize the levels of calcium ions (Ca) during (or after) exposure to a specific stimulus (e.g., capsaicin or heat). 2+ This indicates whether the intracellular concentration (or amount) of calcium increases (or the extent of the increase). Such calcium indicators can be loaded into cells (before exposure to a stimulus), and their fluorescence is related to the intracellular concentration (or amount) of calcium. 2+ The addition of ions after ion combination increases (i.e., in Ca) 2+ After ions flow into the cell, for example from cells containing Ca... 2+ (The culture medium or buffer solution for ions).

[0784] Thermally induced TRPV1 activation is typically induced (or, as determined) at ≥ 42°C. Therefore, in some embodiments, thermally induced TRPV1 activation is induced at 42°C-45°C, 42°C-50°C, 42°C-60°C, 42°C-70°C, 42°C-80°C, 42°C-90°C, or 42°C-100°C. In a preferred embodiment, thermally induced TRPV1 activation is induced (or, as determined) at 42°C. In another preferred embodiment, thermally induced TRPV1 activation is induced (or, as determined) at 45°C.

[0785] Thermally induced TRPV1 activation (and inhibition of thermally induced TRPV1 activation) can be evaluated by any suitable method, and a person skilled in the art will be familiar with suitable methods. Heat (e.g., ≥ 42°C, preferably 42°C) induces the opening of TRPV1 ion channels and leads to the ionization of calcium (Ca) ions. 2+ Influx of intracellular calcium ions into TRPV1-expressing cells. Therefore, the flow of intracellular calcium ions (Ca) can be determined by measuring intracellular calcium ions (Ca). 2+ The concentration (or amount) of calcium ions (Ca) is assessed to evaluate whether thermally induced TRPV1 activation (and inhibition of thermally induced TRPV1 activation) increases (or to what extent) during (or after) heating. Calcium indicators (such as Fluo-3 or Fluo3-AM) can be conveniently used to visualize the concentration (or amount) of calcium ions (Ca) during (or after) heating. 2+ This indicates whether the intracellular concentration (or amount) of calcium increases (or the extent of the increase). Such calcium indicators can be loaded into cells (before exposure to heat), and their fluorescence is related to the intracellular concentration (or amount) of calcium. 2+ The addition of ions after ion combination increases (i.e., in Ca) 2+ After ions flow into the cell, for example from cells containing Ca... 2+ (The culture medium containing ions). This can be observed by any convenient means, such as by confocal microscopy. Whether the TRPV1-binding antibody can inhibit (or to what extent) heat-induced TRPV1 activation can be assessed by contacting TRPV1-expressing cells with the antibody (e.g., by delivering the antibody to cells using a microfluidic device, such as Biopen as described in the Examples section of this document) and determining whether heat-induced TRPV1 activation is inhibited (or reduced) (or to what extent) compared to heat-induced TRPV1 activation in the absence of the antibody (e.g., compared to heat-induced TRPV1 activation observed in the presence of a control antibody that does not bind (or does not specifically bind) to TRPV1). Heat (42°C) can be provided by any suitable means, such as a laser heating system, as described in the Examples section of this document. A reduction (e.g., a significant reduction) in heat-induced TRPV1 activation in the presence of an anti-TRPV1 antibody indicates that the antibody inhibits heat-induced TRPV1 activation. The fact that heat-induced TRPV1 activation is not reduced (or not significantly reduced) in the presence of an anti-TRPV1 antibody indicates that the antibody does not (or does not significantly) inhibit heat-induced TRPV1 activation. Particularly preferred methods for assessing heat-induced TRPV1 activation (and inhibition of heat-induced TRPV1 activation) are described in the Examples section of this document.

[0786] In some embodiments, heat-induced TRPV1 activation (and its inhibition) can be assessed (or evaluated) using a method in which cells expressing TRPV1 receive two heat pulses. In some such embodiments, cells are first subjected to a heat pulse followed by cooling, followed by combined administration (or contact) of an antibody and a heat pulse, followed by cooling. The effect of an antibody on heat-induced TRPV1 activation can be assessed by determining the effect of the antibody on heat-induced calcium ion influx into cells. Calcium influx into cells (peak amplitude) can be measured using a calcium indicator (e.g., Fluo-3). The ratio of the second (second heat pulse or peak 2) to the first (first heat pulse or peak 1) peak amplitude can be calculated for both the antibody and the mediator. In some embodiments, the percentage of inhibition can be calculated by comparing the ratio of the antibody to the ratio of the mediator. Thus, in some embodiments, %inhibition can be (1-((peak 2)) / (peak 2) / (peak 1) / (peak 2 ... Ab / Peak 1 Ab ) / (peak2 veh / Peak 1 veh )))*100.

[0787] In some embodiments, the antibody of the present invention can inhibit (or is able to inhibit) NADA-induced TRPV1 activation. NADA (N-arachidonic dopamine) is a potential natural TRPV1 agonist.

[0788] In some embodiments, the inhibition of NADA-induced TRPV1 activation by the antibody of the present invention is any measurable or significant inhibition (e.g., compared to a control without the antibody or a control with an antibody that does not bind to TRPV1). In some embodiments, the amount (or level) of inhibition of NADA-induced TRPV1 activation (e.g., % inhibition) is as described elsewhere herein with respect to the inhibition of capsaicin-induced TRPV1 activation.

[0789] In ...

Claims

1. An antibody that binds to TRPV1, wherein the antibody binds to TRPV1 in the extracellular region of TRPV1, and wherein the antibody preferentially inhibits capsaicin-induced TRPV1 activation rather than heat-induced TRPV1 activation.

2. The antibody of claim 1, wherein the antibody binds to an epitope of TRPV1 in the region of TRPV1 defined by amino acid residues 599-656 of TRPV1 (SEQ ID NO: 1).

3. The antibody of claim 1 or claim 2, wherein the antibody binds to an epitope of TRPV1 in the region defined by amino acid residues 599-630, 599-606, 519-614, 599-622, 607-630, 615-630, 623-630, 631-643, 644-656 or 610-620 of TRPV1 (SEQ ID NO: 1), or binds to an epitope of TRPV1 in the region defined by amino acid residues 599-601 and 653-655 of TRPV1.

4. The antibody according to any one of claims 1 to 3, wherein the antibody binds to TRPV1 at an epitope in the region defined by amino acid residues 599-630.

5. The antibody of any one of claims 1 to 4, wherein the antibody binds to an isolated peptide, the isolated peptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 4, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, or comprising a sequence having 1, 2, or 3 amino acid substitutions, additions, or deletions compared to the amino acid sequence.

6. The antibody of any one of claims 1 to 5, wherein the antibody binds to an isolated peptide, the isolated peptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 18, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, or comprising a sequence having 1, 2, or 3 amino acid substitutions, additions, or deletions compared to the amino acid sequence.

7. The antibody of any one of claims 1 to 6, wherein the antibody binds to an isolated peptide, said isolated peptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 18, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, or sequences having 1, 2, or 3 amino acid substitutions, additions, or deletions compared to the amino acid sequence described above.

8. The antibody of any one of claims 1 to 7, wherein the antibody binds to an isolated peptide, said isolated peptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 18, SEQ ID NO: 16 and SEQ ID NO:

17.

9. The antibody according to any one of claims 5 to 8, wherein the isolated peptide is a linear peptide or a cyclic peptide.

10. The antibody according to any one of claims 1 to 9, wherein the antibody comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 448, preferably SEQ ID NO:

449.

11. The antibody of any one of claims 1 to 10, wherein the antibody comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein (i) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77, a VH CDR2 having the amino acid sequence of SEQ ID NO: 78, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 79, or sequences substantially homologous thereto, and / or the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 80, a VL CDR2 having the amino acid sequence of SEQ ID NO: 81, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 82, or sequences substantially homologous thereto; (ii) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 41, a VH CDR2 having the amino acid sequence of SEQ ID NO: 42, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 43, or sequences substantially homologous thereto, and / or the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 44, a VL CDR2 having the amino acid sequence of SEQ ID NO: 45, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 46, or sequences substantially homologous thereto; (iii) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 103, a VH CDR2 having the amino acid sequence of SEQ ID NO: 104, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 105, or sequences substantially homologous thereto, and / or the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 106, a VL CDR2 having the amino acid sequence of SEQ ID NO: 107, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 108, or sequences substantially homologous thereto; (iv) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 123, a VH CDR2 having the amino acid sequence of SEQ ID NO: 124, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 125, or sequences substantially homologous thereto, and / or the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 126, a VL CDR2 having the amino acid sequence of SEQ ID NO: 127, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 128, or sequences substantially homologous thereto; (v) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 143, a VH CDR2 having the amino acid sequence of SEQ ID NO: 144, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 145, or sequences substantially homologous thereto, and / or wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 146, a VL CDR2 having the amino acid sequence of SEQ ID NO: 147, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 148, or sequences substantially homologous thereto; (vi) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 183, a VH CDR2 having the amino acid sequence of SEQ ID NO: 184, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 185, or sequences substantially homologous thereto, and / or the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 186, a VL CDR2 having the amino acid sequence of SEQ ID NO: 187, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 188, or sequences substantially homologous thereto; (vii) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 203, a VH CDR2 having the amino acid sequence of SEQ ID NO: 204, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 205, or sequences substantially homologous thereto, and / or the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 206, a VL CDR2 having the amino acid sequence of SEQ ID NO: 207, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 208, or sequences substantially homologous thereto; (viii) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 223, a VH CDR2 having the amino acid sequence of SEQ ID NO: 224, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 225, or sequences substantially homologous thereto, and / or wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 226, a VL CDR2 having the amino acid sequence of SEQ ID NO: 227, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 228, or sequences substantially homologous thereto; (ix) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 283, a VH CDR2 having the amino acid sequence of SEQ ID NO: 284, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 285, or sequences substantially homologous thereto, and / or wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 286, a VL CDR2 having the amino acid sequence of SEQ ID NO: 287, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 288, or sequences substantially homologous thereto; (x) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 303, a VH CDR2 having the amino acid sequence of SEQ ID NO: 304, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 305, or sequences substantially homologous thereto, and / or wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 306, a VL CDR2 having the amino acid sequence of SEQ ID NO: 307, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 308, or sequences substantially homologous thereto; (xi) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 323, a VH CDR2 having the amino acid sequence of SEQ ID NO: 324, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 325, or sequences substantially homologous thereto, and / or wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 326, a VL CDR2 having the amino acid sequence of SEQ ID NO: 327, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 328, or sequences substantially homologous thereto; or (xii) The heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 363, a VH CDR2 having the amino acid sequence of SEQ ID NO: 364, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 365, or sequences substantially homologous thereto, and / or wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 366, a VL CDR2 having the amino acid sequence of SEQ ID NO: 367, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 368, or sequences substantially homologous thereto. The substantially homologous sequence is a sequence containing one, two, or three amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

12. The antibody of claim 10, wherein the antibody comprises VL CDR2, VL CDR3, VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence defined together in any one of portions (i) to (xii) of claim 11.

13. The antibody of any one of claims 1 to 12, wherein the antibody comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the heavy chain variable region comprises: (a) Variable weight (VH) CDR1 having the amino acid sequence of SEQ ID NO: 77, (b) VH CDR2 having the amino acid sequence of SEQ ID NO: 78, and (c) VH CDR3 having the amino acid sequence of SEQ ID NO: 79; and The light chain variable region comprises: (d) Variable light (VL)CDR1 having the amino acid sequence of SEQ ID NO: 80, (e) VL CDR2 having the amino acid sequence of SEQ ID NO: 81, and (f) VL CDR3 having the amino acid sequence of SEQ ID NO:

82.

14. The antibody of any one of claims 1 to 13, wherein the antibody comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein (i) The light chain variable region has the amino acid sequence of SEQ ID NO: 76 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 75 or a sequence having at least 80% sequence identity with it; (ii) The light chain variable region has the amino acid sequence of SEQ ID NO: 58 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 57 or a sequence having at least 80% sequence identity with it; (iii) The light chain variable region has the amino acid sequence of SEQ ID NO: 40 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 39 or a sequence having at least 80% sequence identity with it; (iv) The light chain variable region has the amino acid sequence of SEQ ID NO: 102 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 101 or a sequence having at least 80% sequence identity with it; (v) The light chain variable region has the amino acid sequence of SEQ ID NO: 122 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 121 or a sequence having at least 80% sequence identity with it; (vi) The light chain variable region has the amino acid sequence of SEQ ID NO: 142 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 141 or a sequence having at least 80% sequence identity with it; (vii) The light chain variable region has the amino acid sequence of SEQ ID NO: 162 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 161 or a sequence having at least 80% sequence identity with it; (viii) The light chain variable region has the amino acid sequence of SEQ ID NO: 182 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 181 or a sequence having at least 80% sequence identity with it; (ix) The light chain variable region has the amino acid sequence of SEQ ID NO: 202 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 201 or a sequence having at least 80% sequence identity with it; (x) The light chain variable region has the amino acid sequence of SEQ ID NO: 222 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 221 or a sequence having at least 80% sequence identity with it; (xi) The light chain variable region has the amino acid sequence of SEQ ID NO: 242 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 241 or a sequence having at least 80% sequence identity with it; (xii) The light chain variable region has the amino acid sequence of SEQ ID NO: 262 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 261 or a sequence having at least 80% sequence identity with it; (xiii) The light chain variable region has the amino acid sequence of SEQ ID NO: 282 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 281 or a sequence having at least 80% sequence identity with it; (xiv) The light chain variable region has the amino acid sequence of SEQ ID NO: 302 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 301 or a sequence having at least 80% sequence identity with it; (xv) The light chain variable region has the amino acid sequence of SEQ ID NO: 322 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 321 or a sequence having at least 80% sequence identity with it; (xvi) The light chain variable region has the amino acid sequence of SEQ ID NO: 362 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 361 or a sequence having at least 80% sequence identity with it; (xvii) The light chain variable region has the amino acid sequence of SEQ ID NO: 382 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 381 or a sequence having at least 80% sequence identity with it; or (xviii) The light chain variable region has the amino acid sequence of SEQ ID NO: 402 or a sequence having at least 80% sequence identity with it, and / or the heavy chain variable region has the amino acid sequence of SEQ ID NO: 401 or a sequence having at least 80% sequence identity with it.

15. The antibody of any one of claims 1 to 9, wherein the antibody comprises at least one heavy chain variable region having three CDRs and at least one light chain variable region having three CDRs, wherein the heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 343, a VH CDR2 having the amino acid sequence of SEQ ID NO: 344, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 345, or sequences substantially homologous thereto, and / or wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 346, a VL CDR2 having the amino acid sequence of SEQ ID NO: 347, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 348, or sequences substantially homologous thereto, wherein the substantially homologous sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

16. The antibody of any one of claims 1 to 9 or claim 15, wherein the antibody comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 342 or a sequence having at least 80% sequence identity therewith, and / or wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 341 or a sequence having at least 80% sequence identity therewith.

17. The antibody of any one of claims 1 to 9, wherein the antibody comprises at least one heavy chain variable region having three CDRs and at least one light chain variable region having three CDRs, wherein the heavy chain variable region comprises a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO: 423, a VH CDR2 having the amino acid sequence of SEQ ID NO: 424, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 425, or sequences substantially homologous thereto, and / or wherein the light chain variable region comprises a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO: 426, a VL CDR2 having the amino acid sequence of SEQ ID NO: 427, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 428, or sequences substantially homologous thereto, wherein the substantially homologous sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence containing conserved amino acid substitutions of a given CDR sequence.

18. The antibody of any one of claims 1 to 9 or claim 17, wherein the antibody comprises at least one heavy chain variable region containing three CDRs and at least one light chain variable region containing three CDRs, wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 422 or a sequence having at least 80% sequence identity therewith, and / or wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO: 421 or a sequence having at least 80% sequence identity therewith.

19. The antibody according to any one of claims 1 to 18, wherein the antibody is a polyclonal antibody or a monoclonal antibody.

20. The antibody of any one of claims 1 to 19, wherein the antibody is a complete antibody containing an antibody constant region.

21. The antibody according to any one of claims 1 to 20, wherein the antibody is an IgG antibody.

22. The antibody according to any one of claims 1 to 19, wherein the antibody is an antigen-binding fragment of an antibody.

23. A composition comprising an antibody as described in any one of claims 1 to 22 and a diluent, carrier, or excipient, preferably a pharmaceutically acceptable diluent, carrier, or excipient.

24. A nucleic acid molecule comprising a nucleotide sequence encoding an antibody as described in any one of claims 1 to 22, or a group of nucleic acid molecules, each comprising a nucleotide sequence, wherein the group of nucleic acid molecules together encodes an antibody as described in any one of claims 1 to 22.

25. A method for producing an antibody as described in any one of claims 1 to 22, the method comprising the following steps: (i) culturing a nucleic acid molecule comprising (i) one or more nucleic acid molecules encoding an antibody as described in any one of claims 1 to 22, or (ii) a group of nucleic acid molecules, each of which comprises a nucleotide sequence, wherein the group of nucleic acid molecules together encodes an antibody as described in any one of claims 1 to 22, or (iii) one or more recombinant expression vectors, under conditions suitable for expression of the encoded antibody, the recombinant expression vectors comprising one or more of the nucleic acid molecules; and (ii) Isolate or obtain the antibody from the host cell or from the growth medium / supernatant.

26. The antibody as defined in any one of claims 1 to 22 is used for therapy.

27. The antibody as defined in any one of claims 1 to 22 is used for pain therapy.

28. A method for treating pain, the method comprising administering to a patient in need a therapeutically effective amount of an antibody as defined in any one of claims 1 to 22.

29. Use of an antibody as defined in any one of claims 1 to 22 in the preparation of a medicament for therapeutic purposes.

30. The use as described in claim 29, wherein the therapy is for treating pain.

31. An isolated peptide, wherein the isolated peptide is defined as in any one of claims 5 to 9.

32. A conjugate comprising a separated peptide as defined in any one of claims 5 to 9, and a peptide carrier.

33. The conjugate of claim 32, wherein the peptide carrier is keyhole hemocyanin (KLH), ovalbumin (OVA), or bovine serum albumin (BSA).

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