Trpv1 epitopes and antibodies

Abstract

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

Description

[0001] The present invention relates generally to the field of epitopes and antibodies, in particular epitopes of the protein TRPV1 and antibodies that bind to TRPV1. Such anti-TRPV1 antibodies have therapeutic uses, such as the treatment of pain. The antibody-based compositions and methods and uses of the present invention also extend to the use of conjugates and other therapeutic combinations, kits and methods.

[0002] TRPV1( t ransient r eceptor p otential v anilloid type 1， Transient receptor potential vanilloid 1 (TRPV1) is an ion channel that is sensitive to noxious stimuli such as low pH, high temperature (T > 42°C), capsaicin and inflammatory mediators. TRPV1 has been studied for almost 20 years because of its association with pain. Several attempts have been made to block the activity of the receptor as a new mode of action for the treatment of pain, but these attempts have not been successful.

[0003] It is well known in the art that capsaicin is an activator of TRPV1 and can cause pain. Capsaicin is routinely used in the art for the evaluation of TRPV1 activation and pain in models. The evaluation of the inhibition of capsaicin-induced TRPV1 activation is a well-known model system for the evaluation of the potential of a pharmaceutical agent to treat pain. For example, Chen et al. (2011) (Chen et al., in TRP Channels, Ed MX, Z., 1-14, CRC Press / Taylor & Francis, 2011) describe such a model system.

[0004] 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 of the compounds targeting TRPV1 have produced adverse effects such as hyperthermia or loss of thermal sensation.

[0005] For example, the compound AMG 517, a potent small molecule antagonist of TRPV1 developed by Amgen, inhibits capsaicin, pH and temperature activation of TRPV1. It was terminated after a phase 1 study in which it caused significant hyperthermia in subjects undergoing molar extraction procedures (Gavva, N.R. et al. Pain (2008), 136(1-2), 202-210).

[0006] Another small molecule TRPV1 antagonist, Mavatrep, developed by Johnson & Johnson, showed efficacy in a phase lb study of chronic pain including subjects with knee osteoarthritis, although some subjects reported side effects of feeling hot and some mild hot burns (Manitpisitkul P, et al. Scand. J. Pain (2018), 18(2): 151-164).

[0007] Antibodies that bind to TRPV1 have been generated previously (Klionsky et al., The Journal of Pharmacology and Experimental Therapeutics (2006), vol. 319(1), pp. 192-198), but these antibodies either completely failed to inhibit capsaicin-induced TRPV1 activity, or when the antibodies were reported to inhibit capsaicin-induced TRPV1 activity, equivalent inhibition of heat-induced TRPV1 activity was also reported.

[0008] Accordingly, improved pain treatments are needed. TRPV1 is a clinically and genetically validated target. Successful targeting of TRPV1 can provide a long sought solution to alleviate pain from the source.

[0009] In particular, it would be particularly beneficial to identify epitopes on TRPV1 that target would facilitate preferential inhibition of capsaicin activation of TRPV1 over heat-induced TRPV1 activation. This would guide the identification and generation of agents, such as antibodies, that can bind to TRPV1 and reduce capsaicin activation of TRPV1 without or with reduced heat-related side effects previously observed with small molecule TRPV1 antagonists (e.g., AMG 517 and Mavatrep, as described above).

[0010] The inventors have met this need by identifying certain epitopes (or regions) in the extracellular region of TRPV1 that are particularly useful for targeting, e.g., with antibodies, in order to preferentially inhibit capsaicin-induced TRPV1 activation over 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 to an antibody) on the extracellular side (or extracellular surface) of a cell when TRPV1 is expressed at (or on) the cell surface of a cell. The inventors have identified and generated isolated peptides corresponding to (or substantially corresponding to) such epitopes. The inventors have also used such isolated peptides to generate antibodies that preferentially inhibit capsaicin activation of TRPV1 over heat-induced TRPV1 activation.

[0011] Thus, in one aspect, the present application provides an isolated peptide comprising an amino acid sequence selected from the group consisting of (or comprising): SEQ ID NO: 2 (OTV3) or a sequence substantially homologous thereto, SEQ ID NO: 3 (OTV4) or a sequence substantially homologous thereto, SEQ ID NO: 4 (OTV5) or a sequence substantially homologous thereto, SEQ ID NO: 5 (OTV6) or a sequence substantially homologous thereto, SEQ ID NO: 6 (OTV7) or a sequence substantially homologous thereto, SEQ ID NO: 7 (OTV8) or a sequence substantially homologous thereto, SEQ ID NO: 8 (OTV9) or a sequence substantially homologous thereto, SEQ ID NO: 9 (OTV10) or a sequence substantially homologous thereto, SEQ ID NO: 10 (OTV11) or a sequence substantially homologous thereto, SEQ ID NO: 11 (OTV12) or a sequence substantially homologous thereto, SEQ ID NO: 12 (OTV13) or a sequence substantially homologous thereto, SEQ ID NO: 13 (OTV14) or a sequence substantially homologous thereto, and SEQ ID NO: 14 (OTV15) or a sequence substantially homologous thereto.

[0012] As discussed elsewhere herein, such isolated peptides can be used as antigenic peptides to generate antibodies that inhibit TRPV1 activation. Typically, such antibodies inhibit capsaicin-induced TRPV1 activation, typically as opposed to heat-induced TRPV1 activation.

[0013] Unless the context clearly dictates otherwise, reference to an "isolated peptide" or "peptide" of the present application can alternatively be taken to refer to an "isolated epitope" or "isolated antigenic epitope".

[0014] In some preferred embodiments, the present application provides an isolated peptide comprising an amino acid sequence selected from the group consisting of (or comprising): SEQ ID NO: 3 (OTV4) or a sequence substantially homologous thereto, SEQ ID NO: 4 (OTV5) or a sequence substantially homologous thereto, SEQ ID NO: 6 (OTV7) or a sequence substantially homologous thereto, SEQ ID NO: 8 (OTV9), SEQ ID NO: 11 (OTV12) or a sequence substantially homologous thereto, and SEQ ID NO: 12 (OTV13) or a sequence substantially homologous thereto.

[0015] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 3 (OTV4) or a sequence substantially homologous thereto, SEQ ID NO: 4 (OTV5) or a sequence substantially homologous thereto, and SEQ ID NO: 11 (OTV12) or a sequence substantially homologous thereto.

[0016] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 2 (OTV3) or a sequence substantially homologous thereto, SEQ ID NO: 3 (OTV4) or a sequence substantially homologous thereto, and SEQ ID NO: 4 (OTV5) or a sequence substantially homologous thereto.

[0017] In some embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence 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).

[0018] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence 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).

[0019] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 3 (OTV4), SEQ ID NO: 4 (OTV5), and SEQ ID NO: 11 (OTV12).

[0020] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 2 (OTV3), SEQ ID NO: 3 (OTV4), and SEQ ID NO: 4 (OTV5).

[0021] In some embodiments, the present application provides an isolated peptide consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 2 (OTV3) or a sequence substantially homologous thereto, SEQ ID NO: 3 (OTV4) or a sequence substantially homologous thereto, SEQ ID NO: 4 (OTV5) or a sequence substantially homologous thereto, SEQ ID NO: 5 (OTV6) or a sequence substantially homologous thereto, SEQ ID NO: 6 (OTV7) or a sequence substantially homologous thereto, SEQ ID NO: 7 (OTV8) or a sequence substantially homologous thereto, SEQ ID NO: 8 (OTV9) or a sequence substantially homologous thereto, SEQ ID NO: 9 (OTV10) or a sequence substantially homologous thereto, SEQ ID NO: 10 (OTV11) or a sequence substantially homologous thereto, SEQ ID NO: 11 (OTV12) or a sequence substantially homologous thereto, SEQ ID NO: 12 (OTV13) or a sequence substantially homologous thereto, 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 groups of isolated peptides) are disclosed elsewhere herein.

[0022] In some embodiments, the present application provides an isolated peptide consisting of an amino acid sequence 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.

[0023] In some embodiments, the isolated peptide can comprise one or more additional amino acids at the N-terminus and / or C-terminus. In some preferred embodiments, the isolated peptide can comprise one or more additional amino acids at the N-terminus. In some preferred embodiments, the isolated peptide can comprise one or more additional amino acids at the C-terminus. In some preferred embodiments, the isolated peptide can comprise one or more additional amino acids at the N-terminus and C-terminus. In some preferred embodiments, the isolated peptide can comprise a cysteine (C) residue at the N-terminus and / or C-terminus (or comprise an additional cysteine (C) residue at the N-terminus and / or C-terminus). In some embodiments, the isolated peptide can comprise a cysteine (C) residue at the N-terminus. In some embodiments, the isolated peptide can comprise a cysteine (C) residue at the C-terminus. In some preferred embodiments, the isolated peptide can comprise a cysteine (C) residue at the N-terminus and C-terminus. Providing a cysteine residue at the terminus of the isolated peptide can allow for convenient attachment to a peptide carrier, e.g., as discussed elsewhere herein. If desired, providing a cysteine residue at both the N-terminus and C-terminus provides a convenient method for cyclization of the peptide.

[0024] In some embodiments, the isolated peptide can comprise one or more additional modifications at the N-terminus and / or C-terminus. For example, in some embodiments, the isolated peptide can be C-terminally amidated. In some embodiments, the isolated peptide can have a modification (chemical group or linker) that can be used to attach (or link or connect) the peptide to a peptide carrier. In some embodiments, the modification (chemical group or linker) that can be used to attach (or link or connect) the peptide to a peptide carrier is a propargyl (Pra) group. The modification (chemical group or linker) that can be used to attach (or link or connect) the peptide to a peptide carrier can be at the N-terminus and / or C-terminus. In some embodiments, the modification (chemical group or linker, such as a propargyl group) that can be used to attach (or link or connect) the peptide to a peptide carrier is at the N-terminus of the isolated peptide.

[0025] In some embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 16 (OTV3) or a sequence substantially homologous thereto, SEQ ID NO: 17 (OTV4) or a sequence substantially homologous thereto, SEQ ID NO: 18 (OTV5) or a sequence substantially homologous thereto, SEQ ID NO: 19 (OTV6) or a sequence substantially homologous thereto, SEQ ID NO: 20 (OTV7) or a sequence substantially homologous thereto, SEQ ID NO: 21 (OTV8) or a sequence substantially homologous thereto, SEQ ID NO: 22 (OTV9) or a sequence substantially homologous thereto, SEQ ID NO: 23 (OTV10) or a sequence substantially homologous thereto, SEQ ID NO: 24 (OTV11) or a sequence substantially homologous thereto, SEQ ID NO: 25 (OTV12) or a sequence substantially homologous thereto, 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.

[0026] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 17 (OTV4) or a sequence substantially homologous thereto, SEQ ID NO: 18 (OTV5) or a sequence substantially homologous thereto, SEQ ID NO: 20 (OTV7) or a sequence substantially homologous thereto, SEQ ID NO: 22 (OTV9) or a sequence substantially homologous thereto, SEQ ID NO: 25 (OTV12) or a sequence substantially homologous thereto, and SEQ ID NO: 26 (OTV13) or a sequence substantially homologous thereto.

[0027] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 17 (OTV4) or a sequence substantially homologous thereto, SEQ ID NO: 18 (OTV5) or a sequence substantially homologous thereto, and SEQ ID NO: 25 (OTV12) or a sequence substantially homologous thereto.

[0028] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 16 (OTV3) or a sequence substantially homologous thereto, SEQ ID NO: 17 (OTV4) or a sequence substantially homologous thereto, and SEQ ID NO: 18 (OTV5) or a sequence substantially homologous thereto.

[0029] In some embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence 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).

[0030] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence 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).

[0031] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 17 (OTV4), SEQ ID NO: 18 (OTV5), and SEQ ID NO: 25 (OTV12).

[0032] In some preferred embodiments, the present application provides an isolated peptide comprising (or including) an amino acid sequence selected from the group consisting of: SEQ ID NO: 16 (OTV3), SEQ ID NO: 17 (OTV4), and SEQ ID NO: 18 (OTV5).

[0033] In some embodiments, the present application provides an isolated peptide consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 16 (OTV3) or a sequence substantially homologous thereto, SEQ ID NO: 17 (OTV4) or a sequence substantially homologous thereto, SEQ ID NO: 18 (OTV5) or a sequence substantially homologous thereto, SEQ ID NO: 19 (OTV6) or a sequence substantially homologous thereto, SEQ ID NO: 20 (OTV7) or a sequence substantially homologous thereto, SEQ ID NO: 21 (OTV8) or a sequence substantially homologous thereto, SEQ ID NO: 22 (OTV9) or a sequence substantially homologous thereto, SEQ ID NO: 23 (OTV10) or a sequence substantially homologous thereto, SEQ ID NO: 24 (OTV11) or a sequence substantially homologous thereto, SEQ ID NO: 25 (OTV12) or a sequence substantially homologous thereto, 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.

[0034] In some embodiments, the present application provides an isolated peptide consisting of an amino acid sequence 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 isolated peptide groups) are disclosed elsewhere herein.

[0035] In some embodiments, the present application provides an isolated peptide consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 16 (OTV3), SEQ ID NO: 17 (OTV4), and SEQ ID NO: 18 (OTV5).

[0036] In some embodiments, an isolated peptide comprising (or consisting of) the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 18 (OTV5 sequence) or a sequence substantially homologous thereto is preferred.

[0037] In some embodiments, an isolated peptide comprising (or consisting of) the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 16 (OTV3 sequence) or a sequence substantially homologous thereto is preferred.

[0038] In some embodiments, an isolated peptide comprising (or consisting of) the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 17 (OTV4 sequence) or a sequence substantially homologous thereto is preferred.

[0039] In the context of the isolated peptide sequences of the present application, a sequence "substantially homologous" to a given amino acid sequence can be a sequence containing 1, 2, 3, 4, 5 or 6 (preferably 1, 2 or 3) amino acid substitutions or 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 in relation to amino acid sequences "substantially homologous" to the isolated peptides, and these examples of "substantially homologous" sequences are also applicable to the specific peptide sequences described above.

[0040] In some preferred embodiments, an amino acid sequence "substantially homologous" to an isolated peptide is a sequence having or comprising 1, 2 or 3 amino acid substitutions or additions or deletions (preferably 1 or 2, more preferably 1) compared to the amino acid sequence of the given isolated peptide.

[0041] An amino acid sequence "substantially homologous" to an isolated peptide includes a sequence comprising (or consisting of) at least 5 or at least 6 consecutive amino acids of the isolated peptide (or comprising (or consisting 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 of a peptide / protein sequence recognised or bound by an antibody.

[0042] An amino acid sequence that is "substantially homologous" to an isolated peptide includes sequences having or comprising 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 to a given isolated peptide sequence, or that comprise (or consist 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% sequence identity to a 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.

[0043] Changes in an amino acid sequence can be changes in either conserved or non-conserved amino acids. Preferably, the changes are conservative amino acid substitutions.

[0044] As used herein, a "conservative amino acid substitution" is one in which the amino acid residue is replaced with another amino acid residue having a side chain of similar charge and / or size. Families of amino acid residues having similar side chains have been defined in the art, and include 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), beta- branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0045] The term "substantially homologous" also includes modifications or chemical equivalents of the amino acid sequences of the application that function in substantially the same manner as the proteins of the application to perform substantially the same function. For example, any substantially homologous isolated peptide should generally retain the ability to act as (or against) an antibody that can be generated (or produced) that binds to TRPV1 as a peptide or epitope.

[0046] Methods for making the above-described amino acid alterations (e.g., to generate "substantially homologous" sequences) are well known to those of skill in the art.

[0047] In some embodiments, the isolated peptide does not comprise any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. Thus, in some embodiments, a sequence that is "substantially homologous" to a given amino acid sequence does not have a cysteine (C) residue as a substitution or additional amino acid.

[0048] 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 Clustal W (Thompson, Higgins, Gibson, Nucleic Acids Res., 22:4673-4680, 1994). If desired, the Clustal W algorithm can be used with the BLOSUM 62 scoring matrix (Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA, 89:10915-10919, 1992) and a gap opening penalty of 10 and a gap extension penalty of 0.1 in order to obtain a highest order match between two sequences, with at least 50% of the total length of one of the sequences involved in the alignment. Other methods useful for aligning sequences are the alignment methods of Needleman and Wunsch (Needleman and Wunsch, J. Mol. Biol., 48:443, 1970) as revised by Smith and Waterman (Smith and Waterman, Adv. Appl. Math., 2:482, 1981) in order to obtain a highest order match between two sequences and to determine the number of identical amino acids between the two sequences. Other methods for calculating the percent 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.

[0049] Typically, such calculations will be performed using a computer program. Programs for comparing and aligning sequences of 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, 85: 2444-2448, 1988; Pearson, Methods in Enzymology, 183: 63-98, 1990) and gapped BLAST (Altschul et al., Nucleic Acids Res., 25: 3389-3402, 1997), BLASTP, BLASTN, or GCG (Devereux, Haeberli, Smithies, Nucleic Acids Res., 12: 387, 1984) can also be used for this purpose. In addition, the Dali server of the European Bioinformatics Institute 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).

[0050] By providing a reference point, sequences having 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homology, sequence identity, etc. according to the present application can be determined using the ALIGN program with default parameters (e.g. on the GENESTREAM web server, IGH, Montpellier, France).

[0051] In some embodiments, the present application provides an isolated peptide comprising (or consisting of) an elongation, truncation or cyclic form of an isolated peptide sequence disclosed herein (or a sequence substantially homologous thereto). In some embodiments, the isolated peptide can be elongated and cyclic (i.e. annular). In some embodiments, the isolated peptide can be truncated and cyclic (i.e. annular). Elongated, truncated and cyclic forms of peptides are discussed elsewhere herein.

[0052] An isolated peptide of the application can comprise (or consist of) an extension of an isolated peptide sequence disclosed herein, or an extension of an amino acid sequence substantially homologous to an 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) can be present at one or both ends of an isolated peptide sequence (or a sequence substantially homologous thereto).

[0053] An isolated peptide of the application can comprise (or consist of) a truncation of an isolated peptide sequence disclosed herein, or a truncation of an 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) can be absent at one or both ends of an isolated peptide sequence (or a sequence substantially homologous thereto).

[0054] In some embodiments, an 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 in length, e.g., 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 in length. An isolated peptide can be, e.g., 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, 5 to 75 amino acids in length. An isolated peptide can be, e.g., 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, 8 to 75 amino acids in length.

[0055] In some embodiments, the length of the isolated peptide can be < 50 amino acids, e.g., the length is < 45, < 40, < 35, < 30, < 25, < 20, < 15, or < 10 amino acids (e.g., the length is 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, 10-35, 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).

[0056] In some embodiments, the length of the isolated peptide can be < 39 amino acids, e.g., the length is < 38, < 35, < 30, < 25, < 20, < 15, < 10 amino acids (e.g., the length is 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 embodiments, the length of the isolated peptide can 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.

[0057] In some embodiments, the isolated peptide can be < 24 amino acids in length, e.g., be < 23, < 20, < 15, < 10 amino acids in length (e.g., be 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 in length).

[0058] In some embodiments, the isolated peptide can be a linear peptide (or a linear epitope).

[0059] In some embodiments, the isolated peptide can be a conformational peptide (or a conformational epitope).

[0060] In some embodiments, the isolated peptide can be a cyclic (or looped) peptide (or a cyclic or looped epitope).

[0061] In some preferred embodiments, the isolated peptide 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: 26 (or a sequence substantially homologous thereto) is a linear peptide.

[0062] In some preferred embodiments, the isolated peptide based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto), or based on SEQ ID NO: 14 or SEQ ID NO: 28 (or a sequence substantially homologous thereto) is a cyclic peptide.

[0063] 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 a functional linker, on which a peptide chain can be built using repeated wash-couple-wash cycles. The synthesized peptide is then released from the beads using chemical cleavage. For the synthesis of cyclic peptides, a common approach utilizes cyclization, either by forming a disulfide bridge (where the bridge is formed by two cysteines of the peptide, e.g. one at the N-terminus and one at the C-terminus) or by forming a “head-to-tail” bridge, where the bridge is composed of typical peptide bonds. Cyclic peptides can be formed on a solid support.

[0064] Other methods of synthesizing peptides include using other chemical synthesis procedures, in vitro translation, or by introducing a suitable expression vector into a cell.

[0065] In some embodiments, the isolated peptide does not comprise (or consist of) the amino acid sequence EDGKNNSLPMESTPHKCRGSACKP (SEQ ID NO: 30).

[0066] In some embodiments, the isolated peptide does not comprise (or consist of) the amino acid sequence TLIEDGKNDSLPSESTSHRWRGPACRPPDSSYNSLYSTC (SEQ ID NO: 31).

[0067] In some embodiments, the isolated peptide does not comprise (or consist of) the amino acid sequence SLPSESTSH (SEQ ID NO: 32).

[0068] The isolated peptides according to the present application do not of course include the full-length TRPV1 protein (i.e. the wild-type TRPV1 protein) or any other full-length (wild-type) protein in the TRPV superfamily, or any other full-length (wild-type) protein. The isolated peptides according to the present application thus do not include the full-length SEQ ID NO: 1.

[0069] The isolated peptides of the present application, while corresponding to (or substantially corresponding to) a region (or epitope) of the full-length TRPV1 protein (e.g. as described elsewhere herein), do not themselves occur naturally (i.e. they do not have a naturally occurring counterpart or occur independently in nature). The isolated peptides of the present application can thus be considered artificial peptides, or synthetic peptides, or man-made peptides, or non-natural peptides.

[0070] Another aspect of the application provides conjugates. Typically, the conjugates are configured for use in generating antibodies. The conjugates can comprise at least one isolated peptide as defined above, coupled (i.e. linked to or bonded to) or mixed with a peptide carrier.

[0071] Thus, in one aspect, the application provides a conjugate comprising an isolated peptide of the application. The conjugate typically comprises an isolated peptide of the application and a peptide carrier, wherein the isolated peptide is coupled or mixed with the peptide carrier. The peptide carrier typically enhances immunogenicity. This can be useful because, in some cases, short peptides providing (or representing or corresponding to) an epitope of an antigen are too small to induce an immune response by themselves.

[0072] The peptide carrier is typically a macromolecule, such as a protein, a polysaccharide or a polymeric amino acid. In some embodiments, the peptide carrier is selected from the group consisting of keyhole limpet hemocyanin (KLH), ovalbumin (OVA), serum albumin (e.g. bovine serum albumin, BSA), polylysine and the like. KLH is typically preferred.

[0073] Coupling of the isolated peptide of the application to the peptide carrier can for example be covalent coupling or a disulfide bridge. In some embodiments, the isolated peptide of the application can have an (additional) cysteine residue at its N- or C-terminus (e.g. as described elsewhere herein). Such a cysteine residue typically facilitates coupling of the isolated peptide to the peptide carrier (e.g. KLH). In some embodiments, the isolated peptide can have a modification (e.g. a chemical group such as a propargyl group) that allows coupling of the isolated peptide to the peptide carrier. In some embodiments, the isolated peptide is coupled to the peptide carrier via a standard cross-linking agent (e.g. glutaraldehyde). Ways of linking the isolated peptide to the peptide carrier are well known in the art.

[0074] In one embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 2 (OTV3) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0075] In a preferred embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 2 (OTV3).

[0076] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 2 (OTV3) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0077] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 2 (OTV3).

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

[0079] In a preferred embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 16 (OTV3).

[0080] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 2 (OTV3).

[0081] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 2 (OTV3).

[0082] In some embodiments, the length of the isolated peptide based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto) is at least 25 amino acids, or the length is at least 30 amino acids, or the length is at least 32 amino acids (e.g., the length is 25-35, 25-38, 25-45, 25-55, 25-65, or 25 to 75 amino acids). In some embodiments, the length of the isolated peptide based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto) is less than 39 amino acids, the length is less than 38 amino acids, or the length is less than 37 amino acids, or the length is less than 36 amino acids, or the length is less than 35 amino acids, or the length is less than 34 amino acids, or the length is less than 33 amino acids (e.g., the length is 20-25 or 20-30 or 20-32 or 20-38 or 25-30 or 25-32 or 25-38 or 30-38 amino acids). In some embodiments, the length of the isolated peptide based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto) is 29-35 amino acids. In some embodiments, the isolated peptide based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue.

[0083] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 2 or SEQ ID NO: 16 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 2 or SEQ ID NO: 16 itself.

[0084] Preferably, the isolated peptide based on SEQ ID NO: 2 or SEQ ID NO: 16 (or a sequence substantially homologous thereto) is a linear peptide.

[0085] In one aspect, the present application provides a conjugate comprising an 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) and a peptide carrier (e.g., conjugated thereto). Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 16 conjugated to the peptide carrier KLH (preferably via the N-terminal cysteine residue of SEQ ID NO: 16).

[0086] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 3 (OTV4) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0087] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 3 (OTV4).

[0088] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 3 (OTV4) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0089] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 3 (OTV4).

[0090] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 17 (OTV4) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0091] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 17 (OTV4).

[0092] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 17 (OTV4) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0093] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 17 (OTV4).

[0094] In some embodiments, the length of the isolated peptide based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) is at least 25 amino acids, or the length is at least 30 amino acids, or the length is at least 32 amino acids (e.g., the length is 25-35, 25-38, 25-45, 25-55, 25-65, or 25 to 75 amino acids). In some embodiments, the length of the isolated peptide based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) is less than 39 amino acids, the length is less than 38 amino acids, or the length is less than 37 amino acids, or the length is less than 36 amino acids, or the length is less than 35 amino acids, or the length is less than 34 amino acids, or the length is less than 33 amino acids (e.g., the length is 20-25 or 20-30 or 20-32 or 20-38 or 25-30 or 25-32 or 25-38 or 30-38 amino acids). In some embodiments, the length of the isolated peptide based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) is 29-35 amino acids. In some embodiments, the isolated peptide based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the 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 isolated peptide based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) contains at least one (e.g., 1) internal cysteine residue (e.g., at position 23 of SEQ ID NO: 3 or at position 24 of SEQ ID NO: 17). In some embodiments, the isolated peptide based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue.

[0095] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 3 or SEQ ID NO: 17 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 3 or SEQ ID NO: 17 itself.

[0096] Preferably, the isolated peptide based on SEQ ID NO: 3 or SEQ ID NO: 17 (or a sequence substantially homologous thereto) is a linear peptide.

[0097] In one aspect, the present application provides a conjugate comprising an 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) and a peptide carrier (e.g., conjugated thereto). Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 17 conjugated to the peptide carrier KLH (preferably via the N-terminal cysteine residue of SEQ ID NO: 17).

[0098] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 4 (OTV5) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0099] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 4 (OTV5).

[0100] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 4 (OTV5) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0101] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 4 (OTV5).

[0102] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 18 (OTV5) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0103] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 18 (OTV5).

[0104] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 18 (OTV5) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0105] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 18 (OTV5).

[0106] In some embodiments, the length of the isolated peptide based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto) is at least 25 amino acids, or the length is at least 30 amino acids, or the length is at least 32 amino acids (e.g., the length is 25-35, 25-45, 25-55, 25-65, or 25 to 75 amino acids). In some embodiments, the length of the isolated peptide based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto) is less than 39 amino acids, the length is less than 38 amino acids, or the length is less than 37 amino acids, or the length is less than 36 amino acids, or the length is less than 35 amino acids, or the length is less than 34 amino acids, or the length is less than 33 amino acids (e.g., the length is 20-25 or 20-30 or 20-31 or 25-30 or 25-32 or 20-38 or 25-38 or 30-38 amino acids). In some embodiments, the length of the isolated peptide based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto) is 29-35 amino acids. In some embodiments, the isolated peptide based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue and a C-terminal cysteine residue. In some embodiments, additional modifications can be present at the N-terminus and / or C-terminus (e.g., a propargyl group at the N-terminus and / or a carboxamide group at the C-terminus).

[0107] In some embodiments, an isolated peptide substantially homologous to SEQ ID NO: 4 or SEQ ID NO: 18 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 4 or SEQ ID NO: 18 itself.

[0108] Preferably, the isolated peptide based on SEQ ID NO: 4 or SEQ ID NO: 18 (or a sequence substantially homologous thereto) is a cyclic peptide. Preferably, such a peptide is cyclized via a disulfide bond between the N-terminal and C-terminal cysteine residues.

[0109] In one aspect, the present application provides a conjugate comprising an 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) and (e.g., coupled to) a peptide carrier. Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 18 coupled to the peptide carrier KLH (preferably, via the propargyl group of SEQ ID NO: 18).

[0110] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 5 (OTV6) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0111] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 5 (OTV6).

[0112] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 5 (OTV6) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0113] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 5 (OTV6).

[0114] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 19 (OTV6) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0115] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 19 (OTV6).

[0116] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 19 (OTV6) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0117] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 19 (OTV6).

[0118] In some embodiments, the isolated peptide based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous thereto) is <24 amino acids in length, or <20 amino acids in length, <15 amino acids in length, <10 amino acids in length (e.g., 5-10, 5-12, 5-15, 5-20, 5-23, or 8-23, or 10-23, or 15-23, or 20-23, or 5-10, or 8-10, or 10-15, or 5-15, or 8-15, or 10-15, or 5-20, or 8-20, or 10-20 amino acids in length). In some embodiments, the isolated peptide based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or 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 isolated peptide based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous thereto) is 5-11 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue.

[0119] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 5 or SEQ ID NO: 19 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 5 or SEQ ID NO: 19 itself.

[0120] Preferably, the isolated peptide based on SEQ ID NO: 5 or SEQ ID NO: 19 (or a sequence substantially homologous thereto) is a linear peptide.

[0121] In one aspect, the present application provides a conjugate comprising an 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) and a peptide carrier (e.g., conjugated thereto). Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 19 conjugated to the peptide carrier KLH (preferably via the N-terminal cysteine residue of SEQ ID NO: 19).

[0122] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 6 (OTV7) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0123] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 6 (OTV7).

[0124] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 6 (OTV7) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0125] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 6 (OTV7).

[0126] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 20 (OTV7) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0127] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 20 (OTV7).

[0128] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 20 (OTV7) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0129] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 20 (OTV7).

[0130] In some embodiments, the isolated peptide based on SEQ ID NO: 6 or SEQ ID NO: 20 (or a sequence substantially homologous thereto) is <24 amino acids in length, or <20 amino acids in length, <15 amino acids in length, <10 amino acids in length (e.g., 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 length). In some embodiments, the isolated peptide based on SEQ ID NO: 6 or SEQ ID NO: 20 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or 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 25-30 or 25-32 or 25-38 or 30-38 amino acids in length). In some embodiments, the isolated peptide based on SEQ ID NO: 6 or SEQ ID NO: 20 (or a sequence substantially homologous thereto) is 13-19 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 6 or SEQ ID NO: 20 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 6 or SEQ ID NO: 20 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue.

[0131] In some embodiments, an isolated peptide substantially homologous to SEQ ID NO: 6 or SEQ ID NO: 20 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 6 or SEQ ID NO: 20 itself.

[0132] Preferably, the isolated peptide based on SEQ ID NO: 6 or SEQ ID NO: 20 (or a sequence substantially homologous thereto) is a linear peptide.

[0133] In one aspect, the present application provides a conjugate comprising an 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) and a peptide carrier (e.g., conjugated thereto). Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 20 conjugated to the peptide carrier KLH (preferably via the N-terminal cysteine residue of SEQ ID NO: 20).

[0134] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 7 (OTV8) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0135] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 7 (OTV8).

[0136] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 7 (OTV8) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0137] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 7 (OTV8).

[0138] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 21 (OTV8) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0139] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 21 (OTV8).

[0140] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 21 (OTV8) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0141] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 21 (OTV8).

[0142] In some embodiments, the isolated peptide based on SEQ ID NO: 7 or SEQ ID NO: 21 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 20-25 or 20-30 or 20-32 or 20-38 or 25-30 or 25-32 or 25-38 or 30-38 or 24-30 or 24-38 amino acids in length). In some embodiments, the isolated peptide based on SEQ ID NO: 7 or SEQ ID NO: 21 (or a sequence substantially homologous thereto) is 21-27 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 7 or SEQ ID NO: 21 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. By "internal" residues is meant residues at positions other than the N-terminal and / or C-terminal residues. In some embodiments, the isolated peptide based on SEQ ID NO: 7 or SEQ ID NO: 21 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue.

[0143] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 7 or SEQ ID NO: 21 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 7 or SEQ ID NO: 21 itself.

[0144] Preferably, the isolated peptide based on SEQ ID NO: 7 or SEQ ID NO: 21 (or a sequence substantially homologous thereto) is a linear peptide.

[0145] In one aspect, the present application provides a conjugate comprising an 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) and (e.g., coupled to) a peptide carrier. Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 21 coupled to the peptide carrier KLH (preferably via the N-terminal cysteine residue of SEQ ID NO: 21).

[0146] In one embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 8 (OTV9) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0147] In a preferred embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 8 (OTV9).

[0148] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 8 (OTV9) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0149] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 8 (OTV9).

[0150] In one embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 22 (OTV9) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0151] In a preferred embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 22 (OTV9).

[0152] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 22 (OTV9) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0153] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 22 (OTV9).

[0154] In some embodiments, the isolated peptide based on SEQ ID NO: 8 or SEQ ID NO: 22 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 20-25 or 20-30 or 20-32 or 20-38 or 25-30 or 25-32 or 25-38 or 30-38 or 24-30 or 24-38 amino acids in length). In some embodiments, the isolated peptide based on SEQ ID NO: 8 or SEQ ID NO: 22 (or a sequence substantially homologous thereto) is 21-27 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 8 or SEQ ID NO: 22 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. By "internal" residues is meant residues at positions other than the N-terminal and / or C-terminal residues. In some embodiments, the isolated peptide based on SEQ ID NO: 8 or SEQ ID NO: 22 (or a sequence substantially homologous thereto) has a C-terminal cysteine residue.

[0155] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 8 or SEQ ID NO: 22 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 8 or SEQ ID NO: 22 itself.

[0156] Preferably, the isolated peptide based on SEQ ID NO: 8 or SEQ ID NO: 22 (or a sequence substantially homologous thereto) is a linear peptide.

[0157] In one aspect, the present application provides a conjugate comprising an 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) and (e.g., coupled to) a peptide carrier. Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 22 coupled to the peptide carrier KLH (preferably via the N-terminal cysteine residue of SEQ ID NO: 22).

[0158] In one embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 9 (OTV10), or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0159] In a preferred embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 9 (OTV10).

[0160] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 9 (OTV10), or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0161] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 9 (OTV10).

[0162] In one embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 9 (OTV10), or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0163] In a preferred embodiment, the application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 23 (OTV10).

[0164] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 23 (OTV10), or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0165] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 23 (OTV10).

[0166] In some embodiments, the isolated peptide based on SEQ ID NO: 9 or SEQ ID NO: 23 (or a sequence substantially homologous thereto) is <24 amino acids in length, or <20 amino acids in length, <15 amino acids in length, <10 amino acids in length (e.g., 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 length). In some embodiments, the isolated peptide based on SEQ ID NO: 9 or SEQ ID NO: 23 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or 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 isolated peptide based on SEQ ID NO: 9 or SEQ ID NO: 23 (or a sequence substantially homologous thereto) is 13-19 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 9 or SEQ ID NO: 23 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 9 or SEQ ID NO: 23 (or a sequence substantially homologous thereto) has a C-terminal cysteine residue.

[0167] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 9 or SEQ ID NO: 23 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 9 or SEQ ID NO: 23 itself.

[0168] Preferably, the isolated peptide based on SEQ ID NO: 9 or SEQ ID NO: 23 (or a sequence substantially homologous thereto) is a linear peptide.

[0169] In one aspect, the present application provides a conjugate comprising an 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) and (e.g., coupled to) a peptide carrier. Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 23 coupled to the peptide carrier KLH (preferably via the C-terminal cysteine residue of SEQ ID NO: 23).

[0170] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 10 (OTV11) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0171] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 10 (OTV11).

[0172] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 10 (OTV11) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0173] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 10 (OTV11).

[0174] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 24 (OTV11) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0175] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 24 (OTV11).

[0176] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 24 (OTV11) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0177] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 24 (OTV11).

[0178] In some embodiments, the isolated peptide based on SEQ ID NO: 10 or SEQ ID NO: 24 (or a sequence substantially homologous thereto) is <24 amino acids in length, or <20 amino acids in length, <15 amino acids in length, <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 isolated peptide 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, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or 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 isolated peptide based on SEQ ID NO: 10 or SEQ ID NO: 24 (or a sequence substantially homologous thereto) is 5-11 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 10 or SEQ ID NO: 24 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 10 or SEQ ID NO: 24 (or a sequence substantially homologous thereto) has a C-terminal cysteine residue.

[0179] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 10 or SEQ ID NO: 24 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 10 or SEQ ID NO: 24 itself.

[0180] Preferably, the isolated peptide based on SEQ ID NO: 10 or SEQ ID NO: 24 (or a sequence substantially homologous thereto) is a linear peptide.

[0181] In one aspect, the present application provides a conjugate comprising an 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) and a peptide carrier (e.g., conjugated thereto). Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 24 conjugated to the peptide carrier KLH (preferably via the C-terminal cysteine residue of SEQ ID NO: 24).

[0182] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 11 (OTV12) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0183] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 11 (OTV12).

[0184] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 11 (OTV12) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0185] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 11 (OTV12).

[0186] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 25 (OTV12) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0187] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 25 (OTV12).

[0188] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 25 (OTV12) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0189] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 25 (OTV12).

[0190] In some embodiments, the isolated peptide based on SEQ ID NO: 11 or SEQ ID NO: 25 (or a sequence substantially homologous thereto) is <24 amino acids in length, or <20 amino acids in length, <15 amino acids in length, <10 amino acids in length (e.g., 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 length). In some embodiments, the isolated peptide based on SEQ ID NO: 11 or SEQ ID NO: 25 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or 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 isolated peptide based on SEQ ID NO: 11 or SEQ ID NO: 25 (or a sequence substantially homologous thereto) is 10-16 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 11 or SEQ ID NO: 25 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 11 or SEQ ID NO: 25 (or a sequence substantially homologous thereto) has a C-terminal cysteine residue.

[0191] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 11 or SEQ ID NO: 25 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 11 or SEQ ID NO: 25 itself.

[0192] Preferably, the isolated peptide based on SEQ ID NO: 11 or SEQ ID NO: 25 (or a sequence substantially homologous thereto) is a linear peptide.

[0193] In one aspect, the present application provides a conjugate comprising an 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) and (e.g., coupled to) a peptide carrier. Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 25 coupled to the peptide carrier KLH (preferably via the C-terminal cysteine residue of SEQ ID NO: 25).

[0194] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 12 (OTV13) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0195] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 12 (OTV13).

[0196] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 12 (OTV13) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0197] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 12 (OTV13).

[0198] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 26 (OTV13) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0199] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 26 (OTV13).

[0200] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 26 (OTV13) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0201] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 26 (OTV13).

[0202] In some embodiments, the isolated peptide based on SEQ ID NO: 12 or SEQ ID NO: 26 (or a sequence substantially homologous thereto) is <24 amino acids in length, or <20 amino acids in length, <15 amino acids in length, <10 amino acids in length (e.g., 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 length). In some embodiments, the isolated peptide based on SEQ ID NO: 12 or SEQ ID NO: 26 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or 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 isolated peptide based on SEQ ID NO: 12 or SEQ ID NO: 26 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, 10-16 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 12 or SEQ ID NO: 26 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 12 or SEQ ID NO: 26 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue.

[0203] In some embodiments, the isolated peptide substantially homologous to SEQ ID NO: 12 or SEQ ID NO: 26 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 12 or SEQ ID NO: 26 itself.

[0204] Preferably, the isolated peptide based on SEQ ID NO: 12 or SEQ ID NO: 26 (or a sequence substantially homologous thereto) is a linear peptide.

[0205] In one aspect, the present application provides a conjugate comprising an 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) and (e.g., coupled to) a peptide carrier. Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 26 coupled to the peptide carrier KLH (preferably via the N-terminal cysteine residue of SEQ ID NO: 26).

[0206] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 13 (OTV14) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0207] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 13 (OTV14).

[0208] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 13 (OTV14) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0209] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 13 (OTV14).

[0210] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 27 (OTV14) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0211] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 27 (OTV14).

[0212] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 27 (OTV14) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0213] In one embodiment, the present application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 27 (OTV14).

[0214] Preferably, the isolated peptide based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto) comprises the 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.

[0215] Preferably, in the isolated peptide based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto), there is no more than one (preferably none) amino acid substitution or deletion within the IED motif and / or no more than one (preferably none) amino acid substitution or deletion within the NYD motif.

[0216] The OTV14 peptide (represented by SEQ ID NO: 13 and 27) is a conformational epitope. 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). Without wishing to be bound by theory, the other residues (i.e., the residues other than the IED and NYD motifs) act as spacers, believed to force the side chains of the IED and NYD motifs into a particular conformation that mimics the actual conformation in a structural model of the full TRPV1 sequence.

[0217] In some embodiments, the isolated peptide based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto) is <24 amino acids in length, or <20 amino acids in length, or <15 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 isolated peptide based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 5-15 or 10-15 or 10-20 or 10-30 or 10-35 or 10-38 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 isolated peptide based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto) is 12-18 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An "internal" residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue and a C-terminal cysteine residue. In some embodiments, additional modifications can be present at the N-terminus and / or C-terminus (e.g., a propargyl group at the N-terminus and / or a carboxamide group at the C-terminus).

[0218] In some embodiments, an isolated peptide substantially homologous to SEQ ID NO: 13 or SEQ ID NO: 27 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 13 or SEQ ID NO: 27 itself.

[0219] Preferably, the isolated peptide based on SEQ ID NO: 13 or SEQ ID NO: 27 (or a sequence substantially homologous thereto) is a cyclic peptide. Preferably, such a peptide is cyclized via a disulfide bond between the N-terminal and C-terminal cysteine residues.

[0220] In one aspect, the present application provides a conjugate comprising an 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) and (e.g., coupled to) a peptide carrier. Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application provides a conjugate comprising an isolated peptide consisting of SEQ ID NO: 28 coupled to the peptide carrier KLH (preferably, via the propargyl group of SEQ ID NO: 27).

[0221] In one aspect, the present application provides an isolated peptide comprising the amino acid sequence (or motif) NYD and the amino acid sequence (or motif) IED, wherein the amino acid sequence NYD is located N-terminal 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., 3, 4, or 5 amino acid residues, preferably 4 amino acid residues, e.g., the amino acid sequence PDGS (SEQ ID NO: 38)). Such an isolated peptide can further comprise one or more (e.g., 1, 2, or 3) amino acid residues located N-terminal relative to the NYD sequence and / or (preferably “and”) one or more (e.g., 1, 2, or 3) amino acid residues located C-terminal relative to the IED sequence. The discussion herein elsewhere regarding preferred features and properties (e.g., preferred length and modifications) of the isolated peptides of the present application mutatis mutandis apply to said aspect of the present application. In another aspect, the present application provides a conjugate comprising (i) an isolated peptide comprising the amino acid sequence (or motif) NYD and the amino acid sequence (or motif) IED, wherein the amino acid sequence NYD is located N-terminal relative to the amino acid sequence IED, and (ii) a peptide carrier. In preferred embodiments, the isolated peptide is as described elsewhere herein.

[0222] In one embodiment, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 14 (OTV15) or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0223] In preferred embodiments, the present application provides an isolated peptide comprising the amino acid sequence of SEQ ID NO: 14 (OTV15).

[0224] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 14 (OTV15), or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0225] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 14 (OTV15).

[0226] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 14 (OTV15), or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0227] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 14 (OTV15).

[0228] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 14 (OTV15), or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein.

[0229] In one embodiment, the application provides an isolated peptide consisting of the amino acid sequence of SEQ ID NO: 14 (OTV15).

[0230] In some embodiments, the isolated peptide based on SEQ ID NO: 14 or SEQ ID NO: 28 (or a sequence substantially homologous thereto) comprises the amino sequence ESTSH. In some embodiments, the isolated peptide based on SEQ ID NO: 14 or SEQ ID NO: 28 (or a sequence substantially homologous thereto) is <24 amino acids in length, or <20 amino acids in length, <15 amino acids in length, <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 isolated peptide based on SEQ ID NO: 14 or SEQ ID NO: 28 (or a sequence substantially homologous thereto) is less than 39 amino acids in length, less than 38 amino acids in length, or less than 37 amino acids in length, or less than 36 amino acids in length, or less than 35 amino acids in length, or less than 34 amino acids in length, or less than 33 amino acids in length (e.g., 5-15 or 10-15 or 10-20 or 10-30 or 10-35 or 10-38 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 isolated peptide based on SEQ ID NO: 14 or SEQ ID NO: 28 (or a sequence substantially homologous thereto) is 8-14 amino acids in length. In some embodiments, the isolated peptide based on SEQ ID NO: 14 or SEQ ID NO: 28 (or a sequence substantially homologous thereto) does not contain any internal cysteine residues. An “internal” residue refers to a residue at a position other than the N-terminal and / or C-terminal residue. In some embodiments, the isolated peptide based on SEQ ID NO: 14 or SEQ ID NO: 28 (or a sequence substantially homologous thereto) has an N-terminal cysteine residue and a C-terminal cysteine residue. In some embodiments, additional modifications can be present at the N-terminus and / or C-terminus (e.g., a propargyl group at the N-terminus and / or a carboxamide group at the C-terminus).

[0231] In some embodiments, an isolated peptide substantially homologous to SEQ ID NO: 14 or SEQ ID NO: 28 has 1, 2, or 3 amino acid substitutions, deletions, or additions compared to SEQ ID NO: 14 or SEQ ID NO: 28 itself.

[0232] Preferably, the isolated peptide based on SEQ ID NO: 14 or SEQ ID NO: 28 (or a sequence substantially homologous thereto) is a cyclic peptide. Preferably, such a peptide is cyclised via a disulphide bond between the N-terminal and C-terminal cysteine residues.

[0233] In one aspect, the present application provides a conjugate comprising an 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) and (e.g. conjugated to the same) a peptide carrier. Peptide carriers are described elsewhere herein. In preferred embodiments, the peptide carrier is KLH. In preferred embodiments, the present application 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).

[0234] In some embodiments, the isolated peptide (or conjugate) according to the present application can be present in solution or suspension. Thus, in one aspect, the present application provides a composition comprising an isolated peptide of the present application, and optionally an acceptable (e.g. pharmaceutically acceptable) diluent, buffer, preservative and / or excipient.

[0235] In some embodiments, the isolated peptide (or conjugate) can be present on (i.e. attached or bound to) a solid support (e.g. a bead or microbead or plate or microtitre plate). Thus, in one aspect, the present application provides a solid support attached (directly or indirectly attached) to an isolated peptide or conjugate of the present application.

[0236] The isolated peptides (and conjugates) of the present application are generally useful for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1). For example, the isolated peptides of the present application are generally suitable for use as an antigenic epitope for identifying (or generating or producing) antibodies. Identifying (or generating or producing) antibodies using the isolated peptides of the present application can be performed by any suitable means, and the skilled person is familiar with suitable techniques (e.g. as discussed elsewhere herein). For example, the isolated peptides (and conjugates) of the present application are generally useful for identifying (or generating or producing) polyclonal antibodies that bind to TRPV1 (e.g. polyclonal antibodies generated in an animal such as a rabbit that has been immunised with an isolated peptide (or conjugate) of the present application), 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 the present application generally represent (or correspond to or substantially correspond to) useful epitopes of TRPV1 for targeting with anti-TRPV1 antibodies.

[0237] In some embodiments, the isolated peptides (and conjugates) of the application are useful for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1) and inhibit capsaicin-induced activation of TRPV1.

[0238] In some embodiments, the isolated peptides (and conjugates) of the application are useful for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1) and do not significantly inhibit heat-induced activation of TRPV1.

[0239] In some embodiments, the isolated peptides (and conjugates) of the application are useful for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1) and preferentially inhibit capsaicin-induced activation of TRPV1 over heat-induced activation of TRPV1. In some such embodiments, the isolated peptides OTV4, OTV5 and OTV12 are preferred. In some such embodiments, the 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.

[0240] The isolated peptides (and conjugates) of the application correspond to (or substantially correspond to) an epitope (or region or portion) of TRPV1 (preferably human TRPV1, SEQ ID NO: 1) that is located in the region of TRPV1 (preferably human TRPV1, SEQ ID NO: 1) from amino acid residue 599 to amino acid residue 656.

[0241] In some embodiments, the isolated peptides of the application have an amino acid residue (preferably serine (S)) other than cysteine (C) at the position corresponding to C621 of human TRPV1 (SEQ ID NO: 1).

[0242] In some embodiments, the isolated peptides of the application comprise the amino acid sequence IEDGKN (SEQ ID NO: 33) or a sequence containing 1, 2 or 3 amino acid substitutions or deletions or additions compared to SEQ ID NO: 33.

[0243] In some embodiments, the isolated peptides of the application comprise the amino acid sequence LPSEST (SEQ ID NO: 34) or a sequence containing 1, 2 or 3 amino acid substitutions or deletions or additions compared to SEQ ID NO: 34.

[0244] In some embodiments, the isolated peptides of the application comprise the amino acid sequence PPDSSYNS (SEQ ID NO: 35) or a sequence containing 1, 2 or 3 amino acid substitutions or deletions or additions compared to SEQ ID NO: 35.

[0245] In some embodiments, the isolated peptide of the application comprises the amino acid sequence RWRGPA (SEQ ID NO: 36) or a sequence containing 1, 2 or 3 amino acid substitutions or deletions or additions compared to SEQ ID NO: 36.

[0246] In some embodiments, the isolated peptide of the application comprises the amino acid sequence RGPASR (SEQ ID NO: 37) or a sequence containing 1, 2 or 3 amino acid substitutions or deletions or additions compared to SEQ ID NO: 37.

[0247] Nucleic acid molecules comprising (or consisting of) a nucleotide sequence encoding an isolated peptide of the application as defined herein, or a nucleic acid molecule substantially homologous thereto, form yet further aspects of the application.

[0248] As used herein, the term "substantially homologous" in relation to a nucleic acid sequence includes a sequence having at least 65%, 70% or 75%, preferably at least 80%, even more preferably at least 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the starting nucleic acid sequence.

[0249] As used herein, the term "nucleic acid sequence" or "nucleic acid molecule" refers to a sequence of nucleosides or nucleotides composed of naturally occurring bases, sugars and internucleosidic (backbone) linkages. The term also includes modified or substituted sequences comprising non-naturally occurring monomers or portions thereof. The nucleic acid sequences of the application can be deoxyribonucleic acid sequences (DNA) or ribonucleic acid sequences (RNA) and can include naturally occurring bases (including adenine, guanine, cytosine, thymidine and uracil). Sequences can also contain modified bases. Examples of such modified bases include aza and deaza adenine, guanine, cytosine, thymidine and uracil; and xanthine and hypoxanthine. The nucleic acid molecule can be double-stranded or single-stranded. The nucleic acid molecule can be wholly or partially synthetic or recombinant.

[0250] In another aspect, the application provides a composition comprising an isolated peptide (or conjugate) of the application. Such a composition can further comprise (e.g. be admixed with) a suitable diluent, carrier, excipient and / or preservative (e.g. a pharmaceutically acceptable diluent, carrier, excipient and / or preservative).

[0251] As mentioned above, the isolated peptides (and conjugates) of the application are generally useful for identifying (or generating or producing) antibodies that bind to TRPV1 (preferably human TRPV1) and preferentially inhibit capsaicin-induced TRPV1 activation over heat-induced TRPV1 activation.

[0252] Accordingly, in one aspect, the present application provides antibodies, e.g., isolated antibodies, that bind to (or specifically recognize or specifically bind to) TRPV1, wherein the antibodies preferentially inhibit capsaicin-induced TRPV1 activation, but not heat-induced TRPV1 activation.

[0253] In preferred embodiments, TRPV1 (transient receptor potential vanilloid 1) is human TRPV1 (hTRPV1). The amino acid sequence of human TRPV1 is set forth herein as SEQ ID NO: 1.

[0254] In some embodiments, the antibodies of the present application bind to an epitope of TRPV1 that is located in the extracellular region of the TRPV1 protein. In some embodiments, the antibodies bind 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 epitope bound is located within this region of TRPV1.

[0255] In preferred embodiments, the antibodies of the present application bind to (or are capable of binding to) an isolated peptide or conjugate of the present application. Preferred isolated peptides and conjugates and preferred groups of isolated peptides and conjugates are defined elsewhere herein. In preferred embodiments, the antibodies of the present application bind to preferred isolated peptides or conjugates as described elsewhere herein. The ability of an antibody to bind to an isolated peptide can be assessed by any suitable means, and the skilled person is familiar with suitable methods (e.g., an ELISA assay to assess whether a given isolated peptide can compete with full-length TRPV1 for antibody binding).

[0256] While preferred antibodies of the present application bind to (or are capable of binding to) an isolated peptide or conjugate of the present application, of course they will also typically bind to full-length (or wild-type or native) TRPV1 (preferably human TRPV1).

[0257] In some embodiments, the full-length (or wild-type or native) TRPV1 (preferably human TRPV1) is TRPV1 expressed on a cell, preferably on a mammalian cell, e.g. adherent Chinese hamster ovary (CHO) cell. In some embodiments, the antibodies of the application are capable of binding to TRPV1 heterologously expressed on a cell, e.g. a CHO cell. In some embodiments, the antibodies of the application are capable of binding to TRPV1 expressed on a cell, wherein the TRPV1 is expressed from an inducible expression system, such as a tetracycline-regulated expression system, e.g. as described in the Examples section herein. TRPV1 is typically expressed at (on) the cell surface. Binding of the antibodies of the application to TRPV1 can be assessed by any suitable means, and the skilled person will be familiar with suitable methods (e.g. flow cytometry (such as FACS) or immunocytochemistry or using functional assays, e.g. as described elsewhere herein).

[0258] The isolated peptides of the application correspond to or substantially correspond to certain regions or epitopes of full-length TRPV1 (preferably human TRPV1, SEQ ID NO: 1).

[0259] More particularly, the isolated peptide of SEQ ID NO: 2 and SEQ ID NO: 16 (OTV3 peptide) substantially corresponds to residues 599-630 of human TRPV1 (SEQ ID NO: 1).

[0260] 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) substantially corresponds to residues 599-630 of human TRPV1 (SEQ ID NO: 1).

[0261] The isolated peptide of SEQ ID NO: 4 and SEQ ID NO: 18 (OTV5 peptide) substantially corresponds to residues 599-630 of human TRPV1 (SEQ ID NO: 1).

[0262] 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) substantially corresponds to residues 599-606 of human TRPV1 (SEQ ID NO: 1).

[0263] The isolated peptide of SEQ ID NO: 6 (OTV7 peptide) corresponds to residues 599-614 of human TRPV1 (SEQ ID NO: 1). The isolated peptide of SEQ ID NO: 20 (OTV7 peptide) generally corresponds to residues 599-614 of human TRPV1 (SEQ ID NO: 1).

[0264] The isolated peptide of SEQ ID NO: 7 and SEQ ID NO: 21 (OTV8 peptide) generally corresponds to residues 599-622 of human TRPV1 (SEQ ID NO: 1).

[0265] The isolated peptide of SEQ ID NO: 8 and SEQ ID NO: 22 (OTV9 peptide) generally corresponds to residues 607-630 of human TRPV1 (SEQ ID NO: 1).

[0266] The isolated peptide of SEQ ID NO: 9 and SEQ ID NO: 23 (OTV10 peptide) generally corresponds to residues 615-630 of human TRPV1 (SEQ ID NO: 1).

[0267] 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).

[0268] The isolated peptide of SEQ ID NO: 11 and SEQ ID NO: 25 (OTV12 peptide) generally corresponds to residues 631-643 of human TRPV1 (SEQ ID NO: 1).

[0269] 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).

[0270] The isolated peptide of SEQ ID NO: 13 and 27 (OTV14 peptide) comprises the amino acid sequence (or motif) IED and NYD, which corresponds to residues in TRPV1 (SEQ ID NO: 1). More particularly, the IED sequence within SEQ ID NO: 13 and 27 corresponds to residues 599-601 of TRPV1 (SEQ ID NO: 1), and the NYD sequence within SEQ ID NO: 13 and 27 corresponds to residues 653-655 of TRPV1 (SEQ ID NO: 1).

[0271] 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) substantially corresponds to residues 610-620 of human TRPV1 (SEQ ID NO: 1).

[0272] “Corresponds to” means that the amino acid sequence of the isolated peptide (SEQ ID NO:) matches the amino acid sequence of the specified region or epitope of human TRPV1 (SEQ ID NO: 1). “Substantially corresponds to” means that the amino acid sequence of the isolated peptide (SEQ ID NO:) can be recognized as being based on (or derived from or a modified version of) the sequence of the specified region or epitope of human TRPV1 (SEQ ID NO: 1). For example, an isolated peptide having a sequence that “substantially corresponds to” the sequence of the specified 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 that corresponds to (i.e., exactly matches) the sequence of the specified region or epitope of human TRPV1 (SEQ ID NO: 1). Thus, an isolated peptide having a sequence that “substantially corresponds to” the sequence of the specified region or epitope of human TRPV1 (SEQ ID NO: 1) can be considered to be an “essentially homologous” isolated peptide sequence as defined elsewhere herein.

[0273] In some embodiments, the antibodies of the application bind to TRPV1 at an epitope in a region defined by amino acid residues 599-630, amino acid residues 599-606, amino acid residues 599-614, amino acid residues 599-622, amino acid residues 607-630, amino acid residues 615-630, amino acid residues 623-630, amino acid residues 631-643, amino acid residues 644-656, or amino acid residues 610-620 of TRPV1 (SEQ ID NO: 1), or at an epitope in a region defined by amino acid residues 599-601 and residues 653-655 of TRPV1 (SEQ ID NO: 1). In some embodiments, the entire epitope bound is located within one of these regions of TRPV1. In some embodiments, at least one amino acid of the epitope bound is located within one of these regions of TRPV1.

[0274] In some embodiments, the antibodies of the application bind to TRPV1 at an epitope of TRPV1 in a region defined by amino acid residues 599-630, amino acid residues 599-614, amino acid residues 607-630, amino acid residues 631-643, or amino acid residues 644-656 of TRPV1 (SEQ ID NO: 1).

[0275] In some embodiments, the antibodies of the application bind to TRPV1 at an epitope of TRPV1 in a region defined by amino acid residues 599-630, or 631-643 of TRPV1 (SEQ ID NO: 1).

[0276] In some embodiments, antibodies of the application that bind to TRPV1 at an epitope of TRPV1 in a region defined by amino acid residues 599-630 of TRPV1 (SEQ ID NO: 1) are preferred.

[0277] In some embodiments, the application provides an antibody, e.g., an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0278] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 41 or SEQ ID NO: 77, or a sequence substantially homologous thereto,

[0279] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 42 or SEQ ID NO: 78, or a sequence substantially homologous thereto, and

[0280] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO:43 or SEQ ID NO:79 or a sequence substantially homologous thereto; and / or (preferably "and")

[0281] wherein the light chain variable region comprises:

[0282] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO:91 or preferably SEQ ID NO:92,

[0283] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO:45 or SEQ ID NO:81, and

[0284] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:46 or SEQ ID NO:82. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0285] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0286] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO:41 or SEQ ID NO:77,

[0287] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO:42 or SEQ ID NO:78, and

[0288] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO:43 or SEQ ID NO:79, and / or (preferably "and")

[0289] wherein the light chain variable region comprises:

[0290] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO:91 or preferably SEQ ID NO:92,

[0291] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO:45 or SEQ ID NO:81, and

[0292] (f) a VL CDR3 having or comprising an amino acid sequence of SEQ ID NO: 46 or SEQ ID NO: 82.

[0293] In some embodiments of the application, the VL CDR1 has or comprises an amino acid sequence of SEQ ID NO: 91 (KSSQSL LX8S X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 ). In these embodiments, X8, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 and X 16 may be any amino acid, and X 17 may be any amino acid or not an amino acid. Preferably, one or more, most preferably all of these X residues are selected from the following group: X8is D or Y; X 10 is A or S; X 11 is G or N; X 12 is K or Q; X 13 is T or K; X 14 is Y or N; X 15 is L or C, X 16 is N or L; X 17 is A or not an amino acid. Thus, a preferred VL CDR1 has or comprises an amino acid sequence of SEQ ID NO: 92. For example, a preferred VL CDR1 sequence of the present embodiments has or comprises SEQ ID NO: 44, 62 or 80.

[0294] In embodiments of the application, where one or more CDR sequences contain an X X residue, CDRs having sequences substantially homologous thereto (containing 1, 2 or 3, preferably 1 or 2 (more preferably 1) altered amino acids or amino acid substitutions compared to the given CDR sequence) are also encompassed by the present application. In some such embodiments, the alteration or substitution of the amino acid residue(s) can include one or more X X residues or can be at residues other than X X residues. In other such embodiments, the alteration is in a mixture of X X residues and non-X X residues.

[0295] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0296] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 41 or a sequence substantially homologous thereto,

[0297] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 42 or a sequence substantially homologous thereto, and

[0298] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 43 or a sequence substantially homologous thereto; and / or (preferably "and")

[0299] wherein the light chain variable region comprises:

[0300] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 91 or preferably SEQ ID NO: 92 or a sequence substantially homologous thereto,

[0301] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 45 or a sequence substantially homologous thereto, and

[0302] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 46 or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0303] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0304] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 77 or a sequence substantially homologous thereto,

[0305] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 78 or a sequence substantially homologous thereto, and

[0306] (c) a VH CDR3 that has the amino acid sequence of SEQ ID NO: 79 or a sequence substantially identical thereto; and / or (preferably "and")

[0307] wherein the light chain variable region comprises:

[0308] (d) a variable light (VL) CDR1 that has the amino acid sequence of SEQ ID NO: 91 or preferably SEQ ID NO: 92, or a sequence substantially identical thereto,

[0309] (e) a VL CDR2 that has the amino acid sequence of SEQ ID NO: 81 or a sequence substantially identical thereto, and

[0310] (f) a VL CDR3 that has the amino acid sequence of SEQ ID NO: 82 or a sequence substantially identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0311] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0312] (a) a variable heavy (VH) CDR1 that has the amino acid sequence of SEQ ID NO: 440 or preferably SEQ ID NO: 441, or a sequence substantially identical thereto,

[0313] (b) a VH CDR2 that has the amino acid sequence of SEQ ID NO: 442 or preferably SEQ ID NO: 443, or a sequence substantially identical thereto, and

[0314] (c) a VH CDR3 that has the amino acid sequence of SEQ ID NO: 444 or preferably SEQ ID NO: 445, or a sequence substantially identical thereto; and / or (preferably "and")

[0315] wherein the light chain variable region comprises:

[0316] (d) a variable light (VL) CDR1 that has the amino acid sequence of SEQ ID NO: 446 or preferably SEQ ID NO: 447, or a sequence substantially identical thereto,

[0317] (e) a VL CDR2 having or comprising an 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 thereto, and

[0318] (f) a VL CDR3 having or comprising 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, or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0319] In some embodiments of the application, the VH CDR1 has or comprises an amino acid sequence of SEQ ID NO: 440 (SD X3 A W N). In these embodiments, X3 can be any amino acid. Preferably, the X3 residue is F or Y. Thus, a preferred VH CDR1 has or comprises an amino acid sequence of SEQ ID NO: 441. For example, a preferred VH CDR1 sequence of the present embodiments has or comprises SEQ ID NO: 103, 123, 143, 163, 183, 203, 223, 243, or 263.

[0320] In some embodiments of the application, the VH CDR2 has or comprises an amino acid sequence of SEQ ID NO: 442 (X1 I T Y S X6 X7 T N X 10 N P S L X 15 S). In these embodiments, X1, X6, X7, X 10 , X 15 , and X 10 may be any amino acid. Preferably, one or more, most preferably all of these X residues are selected from the following group: X1 is Y or F; X6 is G or D; X7 is Y or H or N; X 15is K or I or R. Thus, a preferred VH CDR2 has or comprises the amino acid sequence of SEQ ID NO: 443. For example, a preferred VH CDR2 sequence of the present embodiments has or comprises SEQ ID NO: 104, 124, 144, 164, 184, 204, 224, 244, or 264.

[0321] In some embodiments of the application, the VH CDR3 has or comprises the amino acid sequence of SEQ ID NO: 444 (SX2X3X4F D Y). In these embodiments, X2, X3, and X4 can be any amino acid. Preferably, one or more, most preferably all of these X residues are selected from the following group: X2 is T or G; X3 is T or A or N; X4 is Y or F. Thus, a preferred VH CDR3 has or comprises the amino acid sequence of SEQ ID NO: 445. For example, a preferred VH CDR3 sequence of the present embodiments has or comprises SEQ ID NO: 105, 125, 145, 165, 185, 205, 225, 245, or 265.

[0322] In some embodiments of the application, the VL CDR1 has or comprises the amino acid sequence of SEQ ID NO: 446 (RSS Q X5X6X7HS D GN T Y L E). In these embodiments, X5, X6, and X7 can be any amino acid. Preferably, one or more, most preferably all of these X residues are selected from the following group: X5 is S or T; X6 is I or V; X7 is L or V or I. Thus, a preferred VL CDR1 has or comprises the amino acid sequence of SEQ ID NO: 447. For example, a preferred VL CDR1 sequence of the present embodiments has or comprises SEQ ID NO: 106, 126, 146, 166, 186, 206, 226, 246, or 266.

[0323] Certain preferred combinations of VH CDR sequences and VL CDR sequences are listed in Table W, one row for each of numbers 1-45:

[0324] Table W

[0325]

[0326]

[0327] In embodiments of the application illustrated in Table W, preferably the consensus sequence as shown in SEQ ID NO: 440 is the sequence as shown in SEQ ID NO: 441. In embodiments of the application illustrated in Table W, preferably the consensus sequence as shown in SEQ ID NO: 442 is the sequence as shown in SEQ ID NO: 443. In embodiments of the application illustrated in Table W, preferably the consensus sequence as shown in SEQ ID NO: 444 is the sequence as shown in SEQ ID NO: 445. In embodiments of the application illustrated in Table W, preferably the consensus sequence as shown in SEQ ID NO: 446 is the sequence as shown in SEQ ID NO: 447. In some embodiments of the application illustrated in Table W, combinations of CDR sequences shown in rows 37-45 are preferred. In some embodiments, sequences substantially homologous to the specific sequences recited in Table W can be used instead of the specific sequences themselves.

[0328] In some embodiments, the antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 440 or preferably of SEQ ID NO: 441, a VH CDR2 having the amino acid sequence of SEQ ID NO: 442 or preferably of SEQ ID NO: 443, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 444 or preferably of SEQ ID NO: 445, and / or (preferably "and") wherein the light chain variable region comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 446 or preferably of SEQ ID NO: 447. In some such embodiments, preferably the light chain variable region comprises 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 the light chain variable region comprises 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 the light chain variable region comprises 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 the light chain variable region comprises a VL CDR2 having the amino acid sequence of SEQ ID NO: 167 and a VL CDR3 having the amino acid sequence of SEQ ID NO: 168, or the light chain variable region comprises 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 the light chain variable region comprises 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 the light chain variable region comprises 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 the light chain variable region comprises a VL CDR2 having the amino acid sequence of SEQ ID NO: 247 and a VL CDR3 having the amino acid sequence of SEQ ID NO: 248, or the light chain variable region comprises a VL CDR2 having the amino acid sequence of SEQ ID NO: 267 and a 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 can be used instead of the specific sequences themselves.

[0329] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0330] (a) a variable heavy (VH) CDR1 having an 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, 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 a sequence substantially homologous thereto,

[0331] (b) a VH CDR2 having an amino acid sequence 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 a sequence substantially homologous thereto, and

[0332] (c) a VH CDR3 having an 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 identical thereto; and / or (preferably“and”) (d) a VL CDR1 having an amino acid sequence of SEQ ID NO: 448, or preferably SEQ ID NO: 449, or a sequence substantially identical thereto,

[0333] wherein the light chain variable region comprises:

[0334] (d) a VL CDR1 having an amino acid sequence of SEQ ID NO: 448, or preferably SEQ ID NO: 449, or a sequence substantially identical thereto,

[0335] (e) a VL CDR2 having an 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, 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 a sequence substantially identical thereto, and

[0336] (f) a VL CDR3 having or comprising 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. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0337] In some embodiments of the application, the VL CDR1 has or comprises an amino acid sequence of SEQ ID NO: 448 (X1 S S Q X5 X6 X7 X8 S X 10 X 11 X 12 X 13 X 14 X 15 L X 17 ). In these embodiments, X1, X5, X6, X7, X 10 , X 11 , X 13 , X 14 , X 15 , and X 17 can be any amino acid, and X 12 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 following groups: 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 is S or A or D; X 11 is G or N; X 13 is K or N; X 14 is T or N; X 15 is Y or C; X 17 is A or N or E; X 12is Q or is not an amino acid. Thus, a preferred VL CDR1 has or comprises the amino acid sequence of SEQ ID NO: 449. For example, a preferred VL CDR1 sequence of the present embodiments has or comprises SEQ ID NO: 106, 126, 146, 166, 186, 206, 226, 246, 266, 286, 306, 326, 366, 386, 406, 44, 62, or 80.

[0338] Certain preferred combinations of VH CDR sequences and VL CDR sequences are listed in Table Y, below, in each row numbered 1-18:

[0339] Table Y

[0340]

[0341] In the embodiments of the application shown in Table Y, preferably the consensus sequence shown as SEQ ID NO: 448 is the sequence shown as SEQ ID NO: 449. In some embodiments, sequences substantially homologous to the particular sequences listed in Table Y can be used instead of the particular sequences themselves.

[0342] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 448 or, preferably, SEQ ID NO: 449 (or a sequence substantially homologous thereto). In some such embodiments, preferably, the light chain variable region comprises a VL CDR2 and a VL CDR3, and the heavy chain variable region comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the CDRs have the amino acid sequences listed as given in a row selected from row numbers 1-18 of Table Y, above (or sequences substantially homologous thereto). In other words, in some such embodiments, in addition to a VL CDR1 having the amino acid sequence of SEQ ID NO: 448 or, preferably, SEQ ID NO: 449 (or a sequence substantially homologous thereto), preferably the light chain variable region comprises a combination of a VL CDR2, a VL CDR3 and the heavy chain variable region comprises a combination of a VH CDR1, a VH CDR2, and a VH CDR3, 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 a row of Table Y, above.

[0343] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0344] (a) a variable heavy (VH) CDR1 having an 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 thereto,

[0345] (b) a VH CDR2 having an 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 thereto, and

[0346] (c) a VH CDR3 having an 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")

[0347] wherein the light chain variable region comprises:

[0348] (d) a VL CDR1 having an 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 thereto,

[0349] (e) a VL CDR2 having an 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 thereto, and

[0350] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:450 or preferably SEQ ID NO:451, or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0351] In some embodiments of the application, the VL CDR3 has or comprises the amino acid sequence of SEQ ID NO: 450 (X1QGX4HX6PX8T). 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 following group: X1 is W or F or S; X4 is T or S; X6 is F or V; X8 is P or Y or is not an amino acid. Thus, a preferred VL CDR3 has or comprises the amino acid sequence of SEQ ID NO: 451. For example, preferred VL CDR3 sequences of this embodiment have or comprise the sequence of 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.

[0352] Certain preferred combinations of VH CDR sequences and VL CDR sequences are listed in Table AA, one row for each of numbers 1-14:

[0353] Table AA

[0354]

[0355]

[0356] In the embodiments of the application shown in Table AA, preferably the consensus sequence shown as SEQ ID NO: 450 is the sequence shown as SEQ ID NO: 451. In some embodiments, sequences substantially homologous to the particular sequences listed in Table AA can be used instead of the particular sequences themselves.

[0357] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises a VL CDR3 having an amino acid sequence of SEQ ID NO: 450, or preferably SEQ ID NO: 451 (or a sequence substantially homologous thereto). In some such embodiments, preferably the light chain variable region comprises a VL CDR1 and a VL CDR2, and the heavy chain variable region comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the CDRs have the amino acid sequences (or sequences substantially homologous thereto) as set forth in a given row of CDRs selected from rows 1-14 of Table AA above. In other words, in some such embodiments, in addition to the VL CDR3 having an amino acid sequence of SEQ ID NO: 450, or preferably SEQ ID NO: 451 (or a sequence substantially homologous thereto), the preferred light chain variable region comprises a combination of VL CDR1, VL CDR2 and the heavy chain variable region comprises a combination of VH CDR1, VH CDR2, and VH CDR3, wherein the VL CDR1, VL CDR2, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences set forth in combination (i.e., together) in a row of Table AA above.

[0358] In some embodiments, the application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0359] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 77, SEQ ID NO: 363, or SEQ ID NO: 383, or a sequence substantially homologous thereto,

[0360] (b) a VH CDR2 having an 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 thereto, and

[0361] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 79, SEQ ID NO: 365, or 385, or a sequence substantially homologous thereto; and / or (preferably "and")

[0362] wherein the light chain variable region comprises:

[0363] (d) a VL CDR1 having an amino acid sequence of SEQ ID NO: 80, SEQ ID NO: 366, SEQ ID NO: 386, or a sequence substantially homologous thereto,

[0364] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 81, SEQ ID NO: 367, SEQ ID NO: 387, or a sequence substantially homologous thereto, and

[0365] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 452, or preferably SEQ ID NO: 439, or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0366] In some embodiments of the application, the VL CDR3 has or comprises an amino acid sequence of SEQ ID NO: 452 (QQ Y Y X5 Y P 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 following group: X5 is Y or S; X8 is P or T; X9 is T or is not an amino acid. Thus, a preferred VL CDR3 has or comprises an amino acid sequence of SEQ ID NO: 439. For example, a preferred VL CDR3 sequence of the present embodiments has or comprises SEQ ID NO: 82, SEQ ID NO: 368, or SEQ ID NO: 388.

[0367] Certain preferred combinations of VH CDR sequences and VL CDR sequences are listed in Table CC, each row numbered 1-3:

[0368] Table CC

[0369]

[0370] In the embodiments of the application shown in Table CC, preferably the consensus sequence as shown in SEQ ID NO: 452 is the sequence as shown in SEQ ID NO: 439. In some embodiments, sequences substantially homologous to the particular sequences listed in Table CC can be used instead of the particular sequences themselves.

[0371] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises a VL CDR3 having an amino acid sequence of SEQ ID NO: 452, or preferably SEQ ID NO: 439 (or a sequence substantially homologous thereto). In some such embodiments, preferably the light chain variable region comprises a VL CDR1 and a VL CDR2, and the heavy chain variable region comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the CDRs have the amino acid sequences (or sequences substantially homologous thereto) as set forth in a given row of Column CDR of Table CC selected from row numbers 1-3 of the above Table CC. In other words, in some such embodiments, in addition to the VL CDR3 having an amino acid sequence of SEQ ID NO: 452, or preferably SEQ ID NO: 439 (or a sequence substantially homologous thereto), preferably the light chain variable region comprises a combination of VL CDR1, VL CDR2 and the heavy chain variable region comprises a combination of VH CDR1, VH CDR2, and VH CDR3, wherein the VL CDR1, VL CDR2, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences set forth in combination (i.e., together) in a row of the above Table CC.

[0372] In some embodiments, the application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0373] (a) a variable heavy (VH) CDR1 having an 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 thereto,

[0374] (b) a VH CDR2 having an amino acid sequence 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 a sequence substantially homologous thereto, and

[0375] (c) a VH CDR3 having an 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")

[0376] wherein the light chain variable region comprises:

[0377] (d) a VL CDR1 having an amino acid sequence 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, SEQ ID NO: 306, or a sequence substantially homologous thereto,

[0378] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 107, or a sequence substantially homologous thereto, and

[0379] (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, SEQ ID NO: 268, SEQ ID NO: 308, or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0380] Certain preferred combinations of VH CDR sequences and VL CDR sequences are listed in Table DD below in each row numbered 1-10:

[0381] Table DD

[0382]

[0383] In some embodiments, sequences substantially homologous to the particular sequences listed in Table DD can be used instead of the particular sequences themselves.

[0384] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a VL CDR2 having an 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 a VL CDR1 and a VL CDR3, and the heavy chain variable region comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the CDRs have the amino acid sequences (or sequences substantially homologous thereto) as listed in a given row of Column 1-10 of Table DD above. In other words, in some such embodiments, in addition to a VL CDR2 having an amino acid sequence of SEQ ID NO: 107 (or a sequence substantially homologous thereto), preferably the light chain variable region comprises a combination of VL CDR1, VL CDR3 and the heavy chain variable region comprises a combination of VH CDR1, VH CDR2, and VH CDR3, wherein the VL CDR1, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences listed in combination (i.e., together) in a row of Table DD above.

[0385] In some embodiments, the application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0386] (a) a variable heavy (VH) CDR1 having an 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 thereto,

[0387] (b) a VH CDR2 having an 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 thereto, and

[0388] (c) a VH CDR3 having an 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")

[0389] wherein the light chain variable region comprises:

[0390] (d) a VL CDR1 having an 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 identical thereto,

[0391] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 81, or a sequence substantially identical thereto, and

[0392] (f) a VL CDR3 having an 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 identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0393] Certain preferred combinations of VH CDR sequences and VL CDR sequences are listed in Table EE, each row numbered 1-4:

[0394] Table EE

[0395]

[0396] In some embodiments, sequences substantially identical to the particular sequences listed in Table EE can be used instead of the particular sequences themselves.

[0397] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a VL CDR2 having an 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 a VL CDR1 and a VL CDR3, and the heavy chain variable region comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the CDRs have the amino acid sequences (or sequences substantially homologous thereto) as listed in a given row of Column 1-4 of Table EE selected from the above Table EE. In other words, in some such embodiments, in addition to a VL CDR2 having an amino acid sequence of SEQ ID NO: 81 (or a sequence substantially homologous thereto), preferably the light chain variable region comprises a combination of VL CDR1, VL CDR3 and the heavy chain variable region comprises a combination of VH CDR1, VH CDR2, and VH CDR3, wherein the VL CDR1, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences listed in combination (i.e., together) in a row of Table EE above.

[0398] In some embodiments, the application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0399] (a) a variable heavy (VH) CDR1 having an 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 thereto,

[0400] (b) a VH CDR2 having an 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 thereto, and

[0401] (c) a VH CDR3 having an 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")

[0402] wherein the light chain variable region comprises:

[0403] (d) a VL CDR1 having an 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 identical thereto,

[0404] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO:45, or a sequence substantially identical thereto, and

[0405] (f) a VL CDR3 having an 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 identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0406] Certain preferred combinations of VH CDR sequences and VL CDR sequences are listed in Table FF below in each row numbered 1-4:

[0407] Table FF

[0408]

[0409] In some embodiments, sequences substantially identical to the particular sequences listed in Table FF can be used instead of the particular sequences themselves.

[0410] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a 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 a VL CDR1 and a VL CDR3, and the heavy chain variable region comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the CDRs have the amino acid sequences (or sequences substantially homologous thereto) as listed in a given row of Column 1-4 of Table FF selected from above. In other words, in some such embodiments, in addition to a VL CDR2 having the amino acid sequence of SEQ ID NO: 45 (or a sequence substantially homologous thereto), preferably the light chain variable region comprises a combination of VL CDR1, VL CDR3 and the heavy chain variable region comprises a combination of VH CDR1, VH CDR2, and VH CDR3, wherein the VL CDR1, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 have the amino acid sequences listed in combination (i.e., together) in a row of Table FF above.

[0411] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 91 (or preferably SEQ ID NO: 92). In some such embodiments, preferably the VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have the amino acid sequences as defined elsewhere herein.

[0412] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 440 (or preferably SEQ ID NO: 441). In some such embodiments, preferably the VL CDR1, VL CDR2, VL CDR3, VH CDR2, and VH CDR3 (e.g., combinations thereof) have the amino acid sequences as defined elsewhere herein.

[0413] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises a VH CDR2 having the amino acid sequence of SEQ ID NO: 442 (or preferably SEQ ID NO: 443). In some such embodiments, preferably the VL CDR1, VL CDR2, VL CDR3, VH CDR1, and VH CDR3 (e.g., combinations thereof) have the amino acid sequences as defined elsewhere herein.

[0414] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises a VH CDR3 having the amino acid sequence of SEQ ID NO: 444 (or preferably SEQ ID NO: 445). In some such embodiments, preferably the VL CDR1, VL CDR2, VL CDR3, VH CDR1, and VH CDR2 (e.g., combinations thereof) have the amino acid sequences as defined elsewhere herein.

[0415] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 446 (or preferably SEQ ID NO: 447). In some such embodiments, preferably the VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have the amino acid sequences as defined elsewhere herein.

[0416] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 446 (or preferably SEQ ID NO: 447). In some such embodiments, preferably the VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have the amino acid sequences as defined elsewhere herein.

[0417] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a VL CDR3 having an amino acid sequence of SEQ ID NO: 450 (or preferably SEQ ID NO: 451). In some such embodiments, preferably the VL CDR1, VL CDR2, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have amino acid sequences as defined elsewhere herein.

[0418] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a VL CDR3 having an amino acid sequence of SEQ ID NO: 452 (or preferably SEQ ID NO: 439). In some such embodiments, preferably the VL CDR1, VL CDR2, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have amino acid sequences as defined elsewhere herein.

[0419] In some embodiments, an antibody of the application comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the light chain variable region comprises a VL CDR2 having an amino acid sequence of SEQ ID NO: 107 or SEQ ID NO: 81 or SEQ ID NO: 45 (or a sequence substantially homologous thereto). In some such embodiments, preferably the VL CDR1, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 (e.g., combinations thereof) have amino acid sequences as defined elsewhere herein.

[0420] In some embodiments, the application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0421] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 41 or a sequence substantially homologous thereto,

[0422] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 42 or a sequence substantially homologous thereto, and

[0423] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 43 or a sequence substantially homologous thereto; and / or

[0424] wherein the light chain variable region comprises:

[0425] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO:44,

[0426] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO:45, and

[0427] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:46. Substantially similar sequences are described elsewhere herein. Preferably, the substantially similar sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially similar sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0428] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0429] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO:41,

[0430] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO:42, and

[0431] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO:43; and / or

[0432] wherein the light chain variable region comprises:

[0433] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO:44,

[0434] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO:45, and

[0435] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:46.

[0436] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0437] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO:41,

[0438] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO:42, and

[0439] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO:43; and

[0440] wherein the light chain variable region comprises:

[0441] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO:44,

[0442] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO:45, and

[0443] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:46. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0444] In preferred embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0445] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO:41,

[0446] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO:42, and

[0447] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO:43; and

[0448] wherein the light chain variable region comprises:

[0449] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO:44,

[0450] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO:45, and

[0451] (f) a VL CDR3 having the amino acid sequence of SEQ ID NO:46.

[0452] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0453] (a) a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO:77, or a sequence substantially homologous thereto,

[0454] (b) a VH CDR2 having the amino acid sequence of SEQ ID NO:78, or a sequence substantially homologous thereto, and

[0455] (c) a VH CDR3 having the amino acid sequence of SEQ ID NO:79, or a sequence substantially homologous thereto; and / or

[0456] wherein the light chain variable region comprises:

[0457] (d) a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO:80, or a sequence substantially homologous thereto,

[0458] (e) a VL CDR2 having the amino acid sequence of SEQ ID NO:81, or a sequence substantially homologous thereto, and

[0459] (f) a VL CDR3 having the amino acid sequence of SEQ ID NO:82, or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0460] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0461] (a) a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO:77,

[0462] (b) a VH CDR2 having the amino acid sequence of SEQ ID NO:78, and

[0463] (c) a VH CDR3 that has an amino acid sequence of SEQ ID NO: 79; and / or

[0464] wherein the light chain variable region comprises:

[0465] (d) a variable light (VL) CDR1 that has an amino acid sequence of SEQ ID NO: 80,

[0466] (e) a VL CDR2 that has an amino acid sequence of SEQ ID NO: 81, and

[0467] (f) a VL CDR3 that has an amino acid sequence of SEQ ID NO: 82.

[0468] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, that binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0469] (a) a variable heavy (VH) CDR1 that has an amino acid sequence of SEQ ID NO: 77, or a sequence substantially homologous thereto,

[0470] (b) a VH CDR2 that has an amino acid sequence of SEQ ID NO: 78, or a sequence substantially homologous thereto, and

[0471] (c) a VH CDR3 that has an amino acid sequence of SEQ ID NO: 79, or a sequence substantially homologous thereto; and

[0472] wherein the light chain variable region comprises:

[0473] (d) a variable light (VL) CDR1 that has an amino acid sequence of SEQ ID NO: 80, or a sequence substantially homologous thereto,

[0474] (e) a VL CDR2 that has an amino acid sequence of SEQ ID NO: 81, or a sequence substantially homologous thereto, and

[0475] (f) a VL CDR3 that has an amino acid sequence of SEQ ID NO: 82, or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, the substantially homologous sequence is a sequence that contains 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially homologous sequence is a sequence that contains conservative amino acid substitutions of a given CDR sequence.

[0476] In preferred embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0477] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 77,

[0478] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 78, and

[0479] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 79; and

[0480] wherein the light chain variable region comprises:

[0481] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 80,

[0482] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 81, and

[0483] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 82.

[0484] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0485] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 103, or a sequence substantially homologous thereto,

[0486] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 104, or a sequence substantially homologous thereto, and

[0487] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 105, or a sequence substantially homologous thereto; and / or (preferably "and")

[0488] wherein the light chain variable region comprises:

[0489] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 106, or a sequence substantially homologous thereto,

[0490] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 107, or a sequence substantially homologous thereto, and

[0491] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 108, or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0492] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 103, a VH CDR2 of SEQ ID NO: 104, and a VH CDR3 of SEQ ID NO: 105, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 106, a VL CDR2 of SEQ ID NO: 107, and a VL CDR3 of SEQ ID NO: 108.

[0493] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0494] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 123, or a sequence substantially homologous thereto,

[0495] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 124, or a sequence substantially homologous thereto, and

[0496] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 125, or a sequence substantially homologous thereto; and / or (preferably "and")

[0497] wherein the light chain variable region comprises:

[0498] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 126, or a sequence substantially homologous thereto,

[0499] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 127, or a sequence substantially homologous thereto, and

[0500] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 128 or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0501] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 123, a VH CDR2 of SEQ ID NO: 124, and a VH CDR3 of SEQ ID NO: 125, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 126, a VL CDR2 of SEQ ID NO: 127, and a VL CDR3 of SEQ ID NO: 128.

[0502] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0503] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 143 or a sequence substantially homologous thereto,

[0504] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 144 or a sequence substantially homologous thereto, and

[0505] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 145 or a sequence substantially homologous thereto; and / or (preferably "and")

[0506] wherein the light chain variable region comprises:

[0507] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 146 or a sequence substantially homologous thereto,

[0508] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 147 or a sequence substantially homologous thereto, and

[0509] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 148 or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0510] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 143, a VH CDR2 of SEQ ID NO: 144, and a VH CDR3 of SEQ ID NO: 145, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 146, a VL CDR2 of SEQ ID NO: 147, and a VL CDR3 of SEQ ID NO: 148.

[0511] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0512] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 183 or a sequence substantially homologous thereto,

[0513] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 184 or a sequence substantially homologous thereto, and

[0514] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 185 or a sequence substantially homologous thereto; and / or (preferably "and")

[0515] wherein the light chain variable region comprises:

[0516] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 186 or a sequence substantially homologous thereto,

[0517] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 187 or a sequence substantially homologous thereto, and

[0518] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 188, or a sequence substantially identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0519] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 183, a VH CDR2 of SEQ ID NO: 184, and a VH CDR3 of SEQ ID NO: 185, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 186, a VL CDR2 of SEQ ID NO: 187, and a VL CDR3 of SEQ ID NO: 188.

[0520] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0521] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 203, or a sequence substantially identical thereto,

[0522] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 204, or a sequence substantially identical thereto, and

[0523] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 205, or a sequence substantially identical thereto; and / or (preferably "and")

[0524] wherein the light chain variable region comprises:

[0525] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 206, or a sequence substantially identical thereto,

[0526] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 207, or a sequence substantially identical thereto, and

[0527] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 208, or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0528] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 203, a VH CDR2 of SEQ ID NO: 204, and a VH CDR3 of SEQ ID NO: 205, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 206, a VL CDR2 of SEQ ID NO: 207, and a VL CDR3 of SEQ ID NO: 208.

[0529] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0530] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 223, or a sequence substantially homologous thereto,

[0531] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 224, or a sequence substantially homologous thereto, and

[0532] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 225, or a sequence substantially homologous thereto; and / or (preferably "and")

[0533] wherein the light chain variable region comprises:

[0534] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 226, or a sequence substantially homologous thereto,

[0535] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 227, or a sequence substantially homologous thereto, and

[0536] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:228, or a sequence substantially identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0537] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 223, a VH CDR2 of SEQ ID NO: 224, and a VH CDR3 of SEQ ID NO: 225, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 226, a VL CDR2 of SEQ ID NO: 227, and a VL CDR3 of SEQ ID NO: 228.

[0538] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0539] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 283, or a sequence substantially identical thereto,

[0540] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 284, or a sequence substantially identical thereto, and

[0541] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 285, or a sequence substantially identical thereto; and / or (preferably "and")

[0542] wherein the light chain variable region comprises:

[0543] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 286, or a sequence substantially identical thereto,

[0544] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 287, or a sequence substantially identical thereto, and

[0545] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:288, or a sequence substantially identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0546] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 283, a VH CDR2 of SEQ ID NO: 284, and a VH CDR3 of SEQ ID NO: 285, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 286, a VL CDR2 of SEQ ID NO: 287, and a VL CDR3 of SEQ ID NO: 288.

[0547] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0548] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 303, or a sequence substantially identical thereto,

[0549] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 304, or a sequence substantially identical thereto, and

[0550] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 305, or a sequence substantially identical thereto; and / or (preferably "and")

[0551] wherein the light chain variable region comprises:

[0552] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 306, or a sequence substantially identical thereto,

[0553] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 307, or a sequence substantially identical thereto, and

[0554] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:308, or a sequence substantially identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0555] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 303, a VH CDR2 of SEQ ID NO: 304, and a VH CDR3 of SEQ ID NO: 305, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 306, a VL CDR2 of SEQ ID NO: 307, and a VL CDR3 of SEQ ID NO: 308.

[0556] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0557] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 323, or a sequence substantially identical thereto,

[0558] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 324, or a sequence substantially identical thereto, and

[0559] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 325, or a sequence substantially identical thereto; and / or (preferably "and")

[0560] wherein the light chain variable region comprises:

[0561] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 326, or a sequence substantially identical thereto,

[0562] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 327, or a sequence substantially identical thereto, and

[0563] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:328 or a sequence substantially identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0564] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 323, a VH CDR2 of SEQ ID NO: 324, and a VH CDR3 of SEQ ID NO: 325, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 326, a VL CDR2 of SEQ ID NO: 327, and a VL CDR3 of SEQ ID NO: 328.

[0565] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0566] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO:343 or a sequence substantially identical thereto,

[0567] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO:344 or a sequence substantially identical thereto, and

[0568] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO:345 or a sequence substantially identical thereto; and / or (preferably "and")

[0569] wherein the light chain variable region comprises:

[0570] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO:346 or a sequence substantially identical thereto,

[0571] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO:347 or a sequence substantially identical thereto, and

[0572] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:348 or a sequence substantially identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0573] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 343, a VH CDR2 of SEQ ID NO: 344, and a VH CDR3 of SEQ ID NO: 345, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 346, a VL CDR2 of SEQ ID NO: 347, and a VL CDR3 of SEQ ID NO: 348.

[0574] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0575] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 363, or a sequence substantially identical thereto,

[0576] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 364, or a sequence substantially identical thereto, and

[0577] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 365, or a sequence substantially identical thereto; and / or (preferably "and")

[0578] wherein the light chain variable region comprises:

[0579] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 366, or a sequence substantially identical thereto,

[0580] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 367, or a sequence substantially identical thereto, and

[0581] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO: 368 or a sequence substantially identical thereto. Substantially identical sequences are described elsewhere herein. Preferably, the substantially identical sequence is a sequence containing 1, 2, or 3 amino acid substitutions compared to a given CDR sequence, or the substantially identical sequence is a sequence containing conservative amino acid substitutions of a given CDR sequence.

[0582] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 363, a VH CDR2 of SEQ ID NO: 364, and a VH CDR3 of SEQ ID NO: 365, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 366, a VL CDR2 of SEQ ID NO: 367, and a VL CDR3 of SEQ ID NO: 368.

[0583] In some embodiments, the present application provides an antibody, e.g., an isolated antibody, which binds to TRPV1 and comprises at least one heavy chain variable region comprising three CDRs and at least one light chain variable region comprising three CDRs, wherein the heavy chain variable region comprises:

[0584] (a) a variable heavy (VH) CDR1 having an amino acid sequence of SEQ ID NO: 423 or a sequence substantially identical thereto,

[0585] (b) a VH CDR2 having an amino acid sequence of SEQ ID NO: 424 or a sequence substantially identical thereto, and

[0586] (c) a VH CDR3 having an amino acid sequence of SEQ ID NO: 425 or a sequence substantially identical thereto; and / or (preferably "and")

[0587] wherein the light chain variable region comprises:

[0588] (d) a variable light (VL) CDR1 having an amino acid sequence of SEQ ID NO: 426 or a sequence substantially identical thereto,

[0589] (e) a VL CDR2 having an amino acid sequence of SEQ ID NO: 427 or a sequence substantially identical thereto, and

[0590] (f) a VL CDR3 having an amino acid sequence of SEQ ID NO:428 or a sequence substantially homologous thereto. Substantially homologous sequences are described elsewhere herein. Preferably, 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 conservative amino acid substitutions of a given CDR sequence.

[0591] In some embodiments, the antibody comprises at least one heavy chain variable region comprising a VH CDR1 of SEQ ID NO: 423, a VH CDR2 of SEQ ID NO: 424, and a VH CDR3 of SEQ ID NO: 425, and / or (preferably "and") at least one light chain variable region comprising a VL CDR1 of SEQ ID NO: 426, a VL CDR2 of SEQ ID NO: 427, and a VL CDR3 of SEQ ID NO: 428.

[0592] Certain preferred embodiments of the application 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.

[0593] Further preferred embodiments provide antibodies comprising a VH domain of the amino acid sequence of SEQ ID NO: 39 or 57 or 75 and a VL domain comprising 3 light chain CDRs. Preferably, the light chain CDRs have SEQ ID NOs 44, 45, and 46; or 80, 81, and 82.

[0594] Further preferred embodiments provide antibodies comprising a VL domain of the amino acid sequence of SEQ ID NO: 40 or 58 or 76 and a VH domain comprising 3 heavy chain CDRs. Preferably, the heavy chain CDRs have SEQ ID NOs 41, 42, and 43; or 77, 78, or 79.

[0595] In one embodiment, the application provides antibodies comprising a VH domain having an amino acid sequence of SEQ ID NO: 39 or a sequence substantially homologous thereto, and / or a VL domain having an amino acid sequence of SEQ ID NO: 40 or a sequence substantially homologous thereto.

[0596] In preferred embodiments, the application 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 thereto, 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 thereto.

[0597] In preferred embodiments, the application 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.

[0598] In preferred embodiments, the application 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.

[0599] In one embodiment, the application 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.

[0600] In preferred embodiments, the application 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 thereto (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 thereto (e.g. at least 85%, 90%, 95% or 98%).

[0601] In preferred embodiments, the application 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.

[0602] In preferred embodiments, the application 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.

[0603] In one embodiment, the present application 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.

[0604] In preferred embodiments, the present application 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 thereto (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 thereto (e.g. at least 85%, 90%, 95% or 98%).

[0605] In preferred embodiments, the present application 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.

[0606] In preferred embodiments, the present application 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.

[0607] In one embodiment, the present application 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. a sequence having at least 80% sequence identity thereto, for example at least 85%, 90%, 95% or 98% sequence identity thereto), 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. a sequence having at least 80% sequence identity thereto, for example at least 85%, 90%, 95% or 98% sequence identity thereto). In preferred embodiments, the present application 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.

[0608] In one embodiment, the application 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., a sequence having at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto), 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., a sequence having at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0609] In one embodiment, the application 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., a sequence having at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto), 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., a sequence having at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0610] In one embodiment, the application 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., a sequence having at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto), 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., a sequence having at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0611] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0612] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0613] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0614] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0615] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0616] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0617] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0618] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0619] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0620] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto), 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0621] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto), 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0622] In one embodiment, the application 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto), 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., a sequence with at least 80% sequence identity thereto, for example, at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the application 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.

[0623] In one embodiment, the present application 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., a sequence having at least 80% sequence identity thereto, e.g., a sequence having at least 85%, 90%, 95%, or 98% sequence identity thereto) 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., a sequence having at least 80% sequence identity thereto, e.g., a sequence having at least 85%, 90%, 95%, or 98% sequence identity thereto). In preferred embodiments, the present application 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.

[0624] Other preferred embodiments are Ig (e.g., IgG) forms of the antibodies described herein, e.g., IgG forms, preferably full-length IgG forms, of the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies (or antibodies based thereon). Other preferred embodiments are Ig (e.g., IgG) forms, preferably full-length IgG forms, of 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 antibodies (or antibodies based thereon). In some embodiments, the IgG is an IgG1 or IgG2 (e.g., IgG2a) antibody. 2b ) Thus, in some embodiments, the antibody is an Ig antibody comprising CDR sequences and / or a heavy chain variable region and / or a light chain variable region as described herein. It will of course be understood that a full IgG antibody will typically comprise two substantially identical heavy chains and two substantially identical light chains.

[0625] In some embodiments, antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibody sequences listed in Tables A, B, and C herein are preferred. In some embodiments, antibodies based on the OT-Ab1 antibody sequences listed in Table C are preferred.

[0626] In some embodiments, 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 A-C and E-U herein are preferred.

[0627] Some examples of antibodies of the application are monoclonal antibodies OT-Ab3, OT-Ab2, and OT-Ab1, the sequences of which are shown in Tables A, B, and C herein. Monoclonal antibodies OT-Ab3, OT-Ab2, and OT-Ab1 were identified using hybridoma technology, with the OTV5 peptide (SEQ ID NO: 18) as the immunogen. The CDR domains, VH, and VL domains are shown in Tables A, B, and C herein. Antibodies comprising these CDR domains or VH and VL domains (or sequences substantially homologous thereto) are preferred aspects of the application.

[0628] Other examples of antibodies of the application 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 Tables E-M 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) as the immunogen. The CDR domains, VH, and VL domains are shown in Tables E-M herein. Antibodies comprising these CDR domains or VH and VL domains (or sequences substantially homologous thereto) are preferred aspects of the application.

[0629] Other examples of antibodies of the application 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 Tables N-T 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) as the immunogen. The CDR domains, VH, and VL domains are shown in Tables N-T herein. Antibodies comprising these CDR domains or VH and VL domains (or sequences substantially homologous thereto) are preferred aspects of the application.

[0630] Another example of an antibody of the application is 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 domains, VH and VL domains are shown in Table U herein. Antibodies comprising these CDR domains or VH and VL domains (or sequences substantially homologous thereto) are preferred aspects of the application.

[0631] Generally, monoclonal antibody 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, e.g., antibodies having a sequence substantially homologous thereto) bind to (or is capable of binding, e.g., specifically binding) an epitope 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 bound is located within this region of TRPV1. In some embodiments, at least one amino acid of the epitope bound is located within this region of TRPV1.

[0632] Certain examples of sequences substantially homologous are sequences having at least 65% identity to the disclosed amino acid sequences. In certain embodiments, an antibody of the application comprises at least one light chain variable region comprising a region of amino acid sequence 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 to 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 a region of amino acid sequence 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 to the amino acid sequence of SEQ ID NO: 39, 57, 75, 101, 121, 141, 161, 181, 201, 221, 241, 261, 281, 301, 321, 341, 361, 381, 401, or 421.

[0633] Other preferred examples of substantially homologous sequences are sequences containing conservative amino acid substitutions of the disclosed amino acid sequences.

[0634] Other preferred examples of substantially homologous sequences are sequences containing 1, 2 or 3, preferably 1 or 2 (more preferably 1) altered amino acids in one or more of the disclosed CDR regions. Such alterations can be conservative or non-conservative amino acid substitutions, or mixtures thereof.

[0635] In some such embodiments, preferred alterations are conservative amino acid substitutions.

[0636] 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 the 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 the 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.

[0637] Further examples of substantially homologous amino acid sequences according to the application are described elsewhere herein.

[0638] The CDRs of the antibodies of the application are preferably separated by suitable framework regions, such as those found in naturally occurring antibodies and / or effective engineered antibodies. Thus, the V H , V L and individual CDR sequences are preferably provided in or incorporated into a suitable framework or scaffold for antigen binding. Such framework sequences or regions can correspond to naturally occurring framework regions FR1, FR2, FR3 and / or FR4, as appropriate to form a suitable scaffold, or can correspond to consensus framework regions, for example identified by comparing various naturally occurring framework regions. Alternatively, non-antibody scaffolds or frameworks can be used (for example T cell receptor frameworks).

[0639] Suitable sequences that can be used for framework regions are well known in the art and documented in the literature, and any of these can be used. Preferred sequences for framework regions are those that make up the V H and / or V Lone or more framework regions of the OT-Ab3, OT-Ab2, or OT-Ab1 antibodies as disclosed herein in Tables A-C and E-U, 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 a framework region substantially homologous thereto, and in particular a framework region that allows for maintenance of antigen specificity, e.g., a framework region that results in a substantially identical or identical 3D structure of the antibody.

[0640] In certain preferred embodiments, all four variable light chain (SEQ ID NOs: 51, 52, 53, and 54) and / or variable heavy chain (SEQ ID NOs: 47, 48, 49, and 50) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0641] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 69, 70, 71, and 72) and / or variable heavy chain (SEQ ID NOs: 65, 66, 67, and 68) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0642] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 87, 88, 89, and 90) and / or variable heavy chain (SEQ ID NOs: 83, 84, 85, and 86) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0643] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 113, 114, 115, and 116) and / or variable heavy chain (SEQ ID NOs: 109, 110, 111, and 112) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0644] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 133, 134, 135, and 136) and / or variable heavy chain (SEQ ID NOs: 129, 130, 131, and 132) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0645] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 153, 154, 155, and 156) and / or variable heavy chain (SEQ ID NOs: 149, 150, 151, and 152) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0646] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 173, 174, 175, and 176) and / or variable heavy chain (SEQ ID NOs: 169, 170, 171, and 172) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0647] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 193, 194, 195, and 196) and / or variable heavy chain (SEQ ID NOs: 189, 190, 191, and 192) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0648] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 213, 214, 215, and 216) and / or variable heavy chain (SEQ ID NOs: 209, 210, 211, and 212) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0649] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 233, 234, 235, and 236) and / or variable heavy chain (SEQ ID NOs: 229, 230, 231, and 232) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0650] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 253, 254, 255, and 256) and / or variable heavy chain (SEQ ID NOs: 249, 250, 251, and 252) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0651] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 273, 274, 275, and 276) and / or variable heavy chain (SEQ ID NOs: 269, 270, 271, and 272) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0652] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 293, 294, 295, and 296) and / or variable heavy chain (SEQ ID NOs: 289, 290, 291, and 292) framework regions (FRs), as the case can be, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0653] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 313, 314, 315, and 315) and / or variable heavy chain (SEQ ID NOs: 309, 310, 311, and 312) framework regions (FRs), as the case can be, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0654] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 333, 334, 335, and 336) and / or variable heavy chain (SEQ ID NOs: 329, 330, 331, and 332) framework regions (FRs), as the case can be, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0655] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 353, 354, 355, and 356) and / or variable heavy chain (SEQ ID NOs: 349, 350, 351, and 352) framework regions (FRs), as the case can be, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0656] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 373, 374, 375, and 376) and / or variable heavy chain (SEQ ID NOs: 369, 370, 371, and 372) framework regions (FRs), as the case can be, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0657] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 393, 394, 395, and 396) and / or variable heavy chain (SEQ ID NOs: 389, 390, 391, and 392) framework regions (FRs), as the case can be, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0658] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 413, 414, 415, and 416) and / or variable heavy chain (SEQ ID NOs: 409, 410, 411, and 412) framework regions (FRs), as the case can be, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0659] In other preferred embodiments, all four variable light chain (SEQ ID NOs: 433, 434, 435, and 436) and / or variable heavy chain (SEQ ID NOs: 429, 430, 431, and 432) framework regions (FRs), as appropriate, or FR regions substantially homologous thereto, are found in the antibodies of the application.

[0660] In some embodiments, the VH and / or VL domains of the application can additionally comprise a signal peptide at their N-terminal end (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 present in a mature antibody or isolated antibody product), as they are typically cleaved off.

[0661] In some embodiments, the VH domain comprising SEQ ID NO: 39 (or a sequence substantially homologous thereto) further comprises at its N-terminal end a signal peptide of SEQ ID NO: 93. In some embodiments, the VL domain comprising SEQ ID NO: 40 (or a sequence substantially homologous thereto) further comprises at its N-terminal end a signal peptide of SEQ ID NO: 94.

[0662] In some embodiments, the VH domain comprising SEQ ID NO: 57 (or a sequence substantially homologous thereto) further comprises at its N-terminal end a signal peptide of SEQ ID NO: 95. In some embodiments, the VL domain comprising SEQ ID NO: 58 (or a sequence substantially homologous thereto) further comprises at its N-terminal end a signal peptide of SEQ ID NO: 96.

[0663] In some embodiments, the VH domain comprising SEQ ID NO: 75 (or a sequence substantially homologous thereto) further comprises at its N-terminal end a signal peptide of SEQ ID NO: 97. In some embodiments, the VL domain comprising SEQ ID NO: 76 (or a sequence substantially homologous thereto) further comprises at its N-terminal end a signal peptide of SEQ ID NO: 98.

[0664] In some embodiments, the VH domain comprising SEQ ID NO: 101 (or a sequence substantially homologous thereto) further comprises at its N-terminal end a signal peptide of SEQ ID NO: 117. In some embodiments, the VL domain comprising SEQ ID NO: 102 (or a sequence substantially homologous thereto) further comprises at its N-terminal end a signal peptide of SEQ ID NO: 118.

[0665] In some embodiments, the VH domain comprising SEQ ID NO: 121 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 137 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 122 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 138 at its N-terminal end.

[0666] In some embodiments, the VH domain comprising SEQ ID NO: 141 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 157 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 142 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 158 at its N-terminal end.

[0667] In some embodiments, the VH domain comprising SEQ ID NO: 161 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 177 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 162 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 178 at its N-terminal end.

[0668] In some embodiments, the VH domain comprising SEQ ID NO: 181 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 197 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 182 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 198 at its N-terminal end.

[0669] In some embodiments, the VH domain comprising SEQ ID NO: 201 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 217 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 202 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 218 at its N-terminal end.

[0670] In some embodiments, the VH domain comprising SEQ ID NO: 221 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 237 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 222 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 238 at its N-terminal end.

[0671] In some embodiments, the VH domain comprising SEQ ID NO: 241 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 257 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 242 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 258 at its N-terminal end.

[0672] In some embodiments, the VH domain comprising SEQ ID NO: 261 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 277 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 262 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 278 at its N-terminal end.

[0673] In some embodiments, the VH domain comprising SEQ ID NO: 281 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 297 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 282 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 298 at its N-terminal end.

[0674] In some embodiments, the VH domain comprising SEQ ID NO: 301 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 317 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 302 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 318 at its N-terminal end.

[0675] In some embodiments, the VH domain comprising SEQ ID NO: 321 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 337 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 322 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 338 at its N-terminal end.

[0676] In some embodiments, the VH domain comprising SEQ ID NO: 341 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 357 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 342 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 358 at its N-terminal end.

[0677] In some embodiments, the VH domain comprising SEQ ID NO: 361 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 377 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 362 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 378 at its N-terminal end.

[0678] In some embodiments, the VH domain comprising SEQ ID NO: 381 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 397 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 382 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 398 at its N-terminal end.

[0679] In some embodiments, the VH domain comprising SEQ ID NO: 401 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 417 at its N-terminal end. In some embodiments, the VL domain comprising SEQ ID NO: 402 (or a sequence substantially homologous thereto) further comprises the signal peptide of SEQ ID NO: 418 at its N-terminal end.

[0680] In some embodiments, the VH domain comprising SEQ ID NO: 421 (or a sequence substantially homologous thereto) further comprises at the N-terminal end thereof the signal peptide of SEQ ID NO: 437. In some embodiments, the VL domain comprising SEQ ID NO: 422 (or a sequence substantially homologous thereto) further comprises at the N-terminal end thereof the signal peptide of SEQ ID NO: 438.

[0681] As noted above, in this aspect of the application, the antibody inhibits capsaicin-induced activation of TRPV1.

[0682] In some embodiments, the inhibition of capsaicin-induced activation of TRPV1 is any measurable or significant inhibition, more preferably a statistically significant inhibition (e.g., compared to a control without the antibody or compared to a control with an antibody that does not bind to TRPV1).

[0683] In some embodiments, the level of (or amount of) inhibition of capsaicin-induced activation of TRPV1 observed with (or caused or elicited by) a control (e.g., that does not bind to (or does not specifically bind to) TRPV1) is represented (or set as) zero level of inhibition (or zero inhibition value or 0% level or value of inhibition). Thus, in some embodiments, the % inhibition of capsaicin-induced activation of TRPV1 discussed elsewhere herein (or relative to) is compared to the inhibition observed with (or caused or elicited by) a control antibody (e.g., a control antibody that does not bind to TRPV1).

[0684] In some embodiments, the inhibition of capsaicin-induced activation of TRPV1 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% inhibition.

[0685] In some embodiments, the inhibition of capsaicin-induced activation of TRPV1 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% inhibition.

[0686] Thus, in some embodiments, the inhibition of capsaicin-induced activation of TRPV1 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% inhibition.

[0687] In some embodiments, the inhibition of capsaicin-induced activation of TRPV1 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% inhibition.

[0688] In some embodiments, the inhibition of capsaicin-induced activation of TRPV1 is 5-50%, 10-50%, 15-50%, 20-50%, 25-50%, 30-50%, 35-50%, 40-50%, or 45-50% inhibition.

[0689] In some embodiments, the inhibition of capsaicin-induced activation of TRPV1 is 5-25%, 10-25%, 15-25%, or 20-25% inhibition.

[0690] In some preferred embodiments, the inhibition of capsaicin-induced activation of TRPV1 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% inhibition.

[0691] In some embodiments, the antibodies of the application have an IC50 of < 5 mM, < 1 mM, < 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 the inhibition of capsaicin-induced activation of TRPV1. Preferably, the IC50 is < 1 mM, e.g., < 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 embodiments, the IC50 value can be in the range of 1 pM to < 5 mM, e.g., 1 pM to 1 mM, 1 pM to 500 nM, 1 pM to 100 nM, 1 pM to 50 nM, 500 pM to 10 mM, 500 pM to 1 mM, 500 pM to 500 nM, 500 pM to 100 nM, 500 pM to 50 nM, 1 nM to 10 mM, 1 nM to 1 mM, 1 nM to 500 nM, 1 nM to 100 nM, 1 nM to 50 nM, 10 nM to 10 mM, 10 nM to 1 mM, 10 nM to 500 nM, 10 nM to 100 nM, or 10 nM to 50 nM. The IC50 value represents the half maximal inhibitory concentration of a substance in the biological process under study, and in the context of the present application, indicates the half maximal inhibitory concentration of the antibody for inhibiting capsaicin-induced activation of TRPV1. The IC50 value in the context of the present application can alternatively be viewed as the half maximal inhibitory concentration of the antibody for inhibiting capsaicin-induced cellular TRPV1 -mediated Ca2+flux. The IC50 value can be calculated by any suitable means (and based on any suitable test, method, or assay, e.g., the methods 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 herein. 2+ The half maximal inhibitory concentration of the antibody for the influx. The IC50 value can be calculated by any suitable means (and based on any suitable test, method, or assay, e.g., the methods 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 herein.

[0692] As noted above, in this aspect of the application, the antibody preferentially inhibits capsaicin-induced TRPV1 activation over heat-induced TRPV1 activation.

[0693] In some embodiments, the inhibition of heat-induced TRPV1 activation by the antibodies of the application, if any, is substantially the same (or not significantly different or similar or comparable) to the inhibition of heat-induced TRPV1 activation observed (or caused or elicited by) with a control (e.g., a control antibody that does not bind to (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 elicited by) with a control (e.g., a control antibody that does not bind to (or does not specifically bind to) TRPV1) is expressed (or set as) a zero level of inhibition (or a zero inhibition value or a 0% level or value of inhibition). Thus, 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 elicited by) with a control antibody (e.g., a control antibody that does not bind to TRPV1).

[0694] In some embodiments, the antibodies of the application inhibit 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%.

[0695] Thus, in some embodiments, the antibodies of the application inhibit heat-induced TRPV1 activation by 0-25%, 0-20%, 0-10%, 0-5%, 0-4%, 0-3%, 0-2%, 0-1% or 0%.

[0696] In some preferred embodiments, the antibodies of the application cause (or elicit) no measurable inhibition of heat-induced TRPV1 activation or no significant inhibition (preferably no statistically significant inhibition) of heat-induced TRPV1 activation.

[0697] In some embodiments, the above inhibition (e.g., % inhibition) and concentrations apply when the antibody is a polyclonal antibody (e.g., a rabbit polyclonal antibody). In some embodiments, the above inhibition (e.g., % inhibition) and concentrations apply when the antibody is a monoclonal antibody (e.g., a mouse monoclonal antibody).

[0698] In some embodiments, the above inhibition (e.g., % inhibition) and concentrations apply when the antibody is a polyclonal antibody (e.g., a rabbit polyclonal antibody). In some embodiments, the above inhibition (e.g., % inhibition) and concentrations apply when the antibody is a monoclonal antibody (e.g., a mouse monoclonal antibody).

[0699] As noted above, in this aspect of the application, the antibody preferentially inhibits capsaicin-induced TRPVl activation over heat-induced TRPVl activation. This means that a given antibody inhibits (or is capable of inhibiting) capsaicin-induced TRPVl activation to a greater extent than it inhibits (or is capable of inhibiting) heat-induced TRPVl activation. Thus, if a given antibody inhibits capsaicin-induced TRPVl activation by X%, then the antibody inhibits heat-induced TRPVl activation by < X%.

[0700] In some embodiments, the % inhibition (or % inhibition value) of capsaicin-induced TRPV1 activation is at least 5% higher, but typically at least 10% higher, preferably at least 20% higher, at least 30% higher, at least 40% higher, at least 50% higher, at least 60% higher, at least 70% higher, at least 80% higher, at least 90% higher, or even 100% higher than the % inhibition (or % inhibition value) of heat-induced TRPV1 activation.

[0701] In some embodiments, the % inhibition (or % inhibition value) of capsaicin-induced TRPV1 activation is at least 20% and the % inhibition (or % inhibition value) of heat-induced TRPV1 activation is <10% or is <5% or is 0%. In some embodiments, the % inhibition (or % inhibition value) of capsaicin-induced TRPV1 activation is at least 40% and the % inhibition (or % inhibition value) of heat-induced TRPV1 activation is <10% or is <5% or is 0%. In some embodiments, the % inhibition (or % inhibition value) of capsaicin-induced TRPV1 activation is at least 60% and the % inhibition (or % inhibition value) of heat-induced TRPV1 activation is <10% or is <5% or is 0%. In some embodiments, the % inhibition (or % inhibition value) of capsaicin-induced TRPV1 activation is at least 80% and the % inhibition (or % inhibition value) of heat-induced TRPV1 activation is <10% or is <5% or is 0%. In some embodiments, the % inhibition (or % inhibition value) of capsaicin-induced TRPV1 activation is at least 40% and the % inhibition (or % inhibition value) of heat-induced TRPV1 activation is <25% or is <20% or is 15% or is <10% or is <5% or is 0%. In some embodiments, the % inhibition (or % inhibition value) of capsaicin-induced TRPV1 activation is at least 60% and the % inhibition (or % inhibition value) of heat-induced TRPV1 activation is <25% or is <20% or is 15% or is <10% or is <5% or is 0%. In some embodiments, the % inhibition (or % inhibition value) of capsaicin-induced TRPV1 activation is at least 80% and the % inhibition (or % inhibition value) of heat-induced TRPV1 activation is <25% or is <20% or is 15% or is <10% or is <5% or is 0%.

[0702] In some embodiments, the antibody preferentially inhibits capsaicin-induced TRPV1 activation over heat-induced TRPV1 activation as determined by performing a test (or assay) to determine (or quantify) the level (or amount) of inhibition of capsaicin-induced TRPV1 activation and performing a test (or assay) to determine the level (or amount) of inhibition of heat-induced TRPV1 activation. Suitable assays are described elsewhere herein.

[0703] In some embodiments, the antibody preferentially inhibits (or is capable of inhibiting) capsaicin-induced TRPV1 activation but not heat-induced TRPV1 activation, as determined when the antibody is used at the same concentration in both 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).

[0704] In some embodiments, the antibody preferentially inhibits capsaicin-induced TRPV1 activation but not heat-induced TRPV1 activation, as determined when the antibody is used at a concentration that is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, preferably at least 5-fold (e.g., 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold or 2-5, 3-5, or 4-5-fold) higher than the concentration used in the test to determine the level of inhibition of capsaicin-induced TRPV1 activation.

[0705] In some embodiments, the antibody or antibodies that bind to the isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (OTV4 peptide) (or an isolated peptide substantially homologous thereto) or that bind to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such isolated peptide, 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% inhibition.

[0706] In some embodiments, the antibody or antibodies that bind to the isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (OTV4 peptide) (or an isolated peptide substantially homologous thereto) or that bind to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such isolated peptide, 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%, or up to 50% inhibition.

[0707] In some embodiments, the % inhibition of capsaicin-induced TRPV1 activation for the antibody or antibodies that bind to the isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (OTV4 peptide) (or an isolated peptide substantially homologous thereto) or that bind to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such isolated peptide 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 mM or 100 nM to 1 mM, e.g., 400 nM to 500 nM, or about 500 nM (e.g., 533 nM).

[0708] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an 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%, preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0709] Thus, in some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, the inhibition of heat-induced TRPV1 activation is 0-5%, 0-4%, 0-3%, 0-2%, 0-1%, or preferably 0%.

[0710] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, the above % inhibition of heat-induced TRPV1 activation is as 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 mM or 100 nM to 10 mM, e.g., 200 nM to 3 mM, or about 300 nM (e.g., 270 nM) or about 3 mM (e.g., 2.7 mM).

[0711] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, 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 of heat-induced TRPV1 activation is observed when the antibody is used at a concentration that is about 5-fold higher than a concentration that 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%.

[0712] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, 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 of heat-induced TRPV1 activation is observed when the antibody is used at a concentration of about 3 mM (e.g., 2.7 mM), and 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 of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of about 500 nM (e.g., 533 nM).

[0713] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 17 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, no more than 5% inhibition of heat-induced TRPV1 activation is observed when the antibody is used at a concentration of about 3 mM (e.g., 2.7 mM), and at least 20% inhibition of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of about 500 nM (e.g., 533 nM).

[0714] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (OTV5 peptide) (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, 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%.

[0715] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, 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% inhibition.

[0716] In some embodiments, the above % inhibition of capsaicin-induced TRPV1 activation for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide is as determined when the antibody (e.g., a polyclonal antibody, such as a rabbit polyclonal antibody) is used at a concentration of 100 pM to 100 nM, e.g., 1 nM to 20 nM, or about 10 nM (e.g., 13.3 nM).

[0717] In some embodiments, the inhibition of heat-induced TRPV1 activation for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide 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%, preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0718] Thus, in some embodiments, the inhibition of heat-induced TRPV1 activation for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide is 0% to 15%, preferably 0% to 10%, 0% to 5%, 0% to 4%, 0% to 3%, 0% to 2%, 0% to 1%, or preferably 0%.

[0719] In some embodiments, the above % inhibition of heat-induced TRPV1 activation for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide is as determined when the antibody (e.g., a polyclonal antibody, such as a rabbit polyclonal antibody) is used at a concentration of 1 nM to 100 nM, e.g., 5 nM to 75 nM, or about 5 nM (e.g., 6.7 nM) or about 50 nM (e.g., 67 nM).

[0720] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, 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 of heat-induced TRPV1 activation is observed when the antibody is used at a concentration that is about 5-fold higher than a concentration that 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%.

[0721] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, 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 of heat-induced TRPV1 activation is observed when the antibody is used at a concentration of about 50 nM (e.g., 67 nM), and at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% or at least 50% inhibition of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of about 10 nM (e.g., 13.3 nM).

[0722] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 corresponding to (or substantially corresponding to) such an isolated peptide, 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 of heat-induced TRPV1 activation is observed when the antibody is used at a concentration of about 5 nM (e.g., 6.7 nM), and 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 of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of about 1 nM (e.g., 1.33 nM).

[0723] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 4 or SEQ ID NO: 18 (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide, no more than 5% inhibition of heat-induced TRPV1 activation is observed when the antibody is used at a concentration of about 5 nM (e.g., 6.7 nM), and at least 10% inhibition of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of about 1 nM (e.g., 1.33 nM).

[0724] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 (OTV12 peptide) (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide, 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% inhibition.

[0725] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 (OTV12 peptide) (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide, 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%, or up to 40% inhibition.

[0726] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 (OTV12 peptide) (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide, the % inhibition of capsaicin-induced TRPV1 activation described above is as determined when the antibody (e.g., a polyclonal antibody, such as a rabbit polyclonal antibody) is used at a concentration of 10 pM to 100 nM, e.g., 100 pM to 20 nM, or about 10 nM (e.g., 13.3 nM).

[0727] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 3 or SEQ ID NO: 25 (OTV12 peptide) (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an 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%, preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0728] Thus, in some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide, the inhibition of heat-induced TRPV1 activation is 0-5%, 0-4%, 0-3%, 0-2%, 0-1%, or preferably 0%.

[0729] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide, the above % inhibition of heat-induced TRPV1 activation is as determined when the antibody (e.g., a polyclonal antibody, such as a rabbit polyclonal antibody) is used at a concentration of 100 pM to 500 nM, e.g., 500 pM to 100 nM, or about 1 nM (e.g., 0.67 nM) or about 50 nM (e.g., 67 nM).

[0730] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide, 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 of heat-induced TRPV1 activation is observed when the antibody is used at a concentration that is about 5-fold higher than the concentration that 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%.

[0731] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide, 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 of heat-induced TRPV1 activation is observed when the antibody is used at a concentration of about 50 nM (e.g., 67 nM), and at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% or at least 50% inhibition of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of about 10 nM (e.g., 13.3 nM).

[0732] In some embodiments, for an antibody that binds to an isolated peptide of SEQ ID NO: 11 or SEQ ID NO: 25 (or to an isolated peptide substantially homologous thereto) or to an epitope of TRPV1 corresponding to (or substantially corresponding to) such isolated peptide, no more than 5% inhibition of heat-induced TRPV1 activation is observed when the antibody is used at a concentration of about 50 nM (e.g., 67 nM), and at least 20% inhibition of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of about 10 nM (e.g., 13.3 nM).

[0733] In some embodiments, for an antibody based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), 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%.

[0734] In some embodiments, for an antibody based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), 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% inhibition.

[0735] In some embodiments, the above % inhibition of capsaicin-induced TRPV1 activation for an antibody based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) is as determined when the antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) is used at a concentration of 100 nM to 1 mM, e.g., 100 nM to 500 nM (e.g., 243 nM for an OT-Ab1 -based antibody, or e.g., 166 nM for an OT-Ab2-based antibody, or e.g., 326 nM for an OT-Ab3-based antibody).

[0736] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2 and OT-Ab1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, 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%, preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0737] Thus, in some embodiments, for antibodies based on the OT-Ab3, OT-Ab2 and OT-Ab1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) (e.g., monoclonal antibodies, such as mouse monoclonal antibodies), 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%.

[0738] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2 and OT-Ab1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), the above % inhibition of heat-induced TRPV1 activation is as determined when the antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) is used at a concentration of 100 nM to 1 mM, e.g., 100 nM to 500 nM (e.g., 243 nM for an OT-Ab1 -based antibody, or e.g., 166 nM for an OT-Ab2-based antibody, or e.g., 326 nM for an OT-Ab3-based antibody).

[0739] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2 and OT-Ab1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), 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 of heat-induced TRPV1 activation is observed 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%.

[0740] In some embodiments, for antibodies based on the OT-Ab3, OT-Ab2 and OT-Ab1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), when the antibody is used at a concentration of 100 nM to 1 mM, e.g., 100 nM to 500 nM (e.g., 243 nM for antibodies based on OT-Ab1, or e.g., 166 nM for antibodies based on OT-Ab2, or e.g., 326 nM for antibodies based on OT-Ab3), 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 of heat-induced TRPV1 activation is observed, and 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 is observed.

[0741] In some embodiments, for antibodies based on the 16F1-1, 15D8-1, 17E11-1 or 17E9-1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), 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% inhibition.

[0742] In some embodiments, for an antibody based on the 16F1-1, 15D8-1, 17E11-1 or 17E9-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), the above % inhibition of capsaicin-induced TRPV1 activation is as determined when the antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) is used at a concentration of 50 nM to 1 μΜ or 100 nM to 1 μΜ, e.g., 50 nM to 500 nM or 100 nM to 500 nM (e.g., 253 nM for an antibody based on 16F1-1, or e.g., 130 nM for an antibody based on 15D8-1, or e.g., 110 nM for an antibody based on 17E11-1, or e.g., 83 nM for an antibody based on 17E9-1).

[0743] In some embodiments, for an antibody based on the 15D8-1 or 17E11-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, 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%, preferably no measurable (or no significant) inhibition of heat-induced TRPV1 activation.

[0744] Thus, in some embodiments, for an antibody based on the 15D8-1 or 17E11-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) (e.g., a monoclonal antibody, such as a mouse monoclonal antibody), the inhibition of heat-induced TRPV1 activation is 0% to 15%, preferably 0% to 10%, 0% to 5%, 0% to 4%, 0% to 3%, 0% to 2%, 0% to 1%, or preferably 0%.

[0745] In some embodiments, for an antibody based on the 15D8-1 or 17E11-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), the above % inhibition of heat-induced TRPV1 activation is as determined when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM (e.g., 200 nM).

[0746] In some embodiments, for an antibody based on the 15D8-1 or 17E11-1 antibody of the application (e.g., those having the CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), 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 of heat-induced TRPV1 activation is observed 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%.

[0747] In some embodiments, for an antibody based on the 15D8-1 or 17E11-1 antibody of the application (e.g., those having the CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), 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 of heat-induced TRPV1 activation is observed when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM (e.g., 200 nM), and 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% inhibition of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM, or 100 nM to 200 nM (e.g., 130 nM for an antibody based on 15D8-1, or e.g., 110 nM for an antibody based on 17E11-1).

[0748] In some embodiments, for an antibody based on the 41B5-1 antibody of the application (e.g., those having the CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), 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 of heat-induced TRPV1 activation is observed.

[0749] Thus, in some embodiments, the inhibition of heat-induced TRPV1 activation for an antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) based on the 41B5-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) is 0-15%, preferably 0-10%, 0-5%, 0-4%, 0-3%, 0-2%, 0-1%, or preferably 0%.

[0750] In some embodiments, the above % inhibition of heat-induced TRPV1 activation for an antibody based on the 41B5-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) is as determined when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM (e.g., 300 nM).

[0751] In some embodiments, the inhibition of heat-induced TRPV1 activation for an antibody based on the 46B7-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) is no more than 25% or no more than 20%.

[0752] Thus, in some embodiments, the inhibition of heat-induced TRPV1 activation for an antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) based on the 46B7-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) is 0-25%, 0-20%, or 0-15%.

[0753] In some embodiments, the above % inhibition of heat-induced TRPV1 activation for an antibody based on the 46B7-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) is as determined when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM (e.g., 367 nM).

[0754] In some embodiments, the above inhibition (e.g., % inhibition) of capsaicin-induced TRPV1 activation is as determined in a patch clamp assay (e.g., as described elsewhere herein).

[0755] In some embodiments, the above inhibition (e.g., % inhibition) of heat-induced TRPV1 activation is as determined as described elsewhere herein.

[0756] In some embodiments, an antibody (e.g., a monoclonal antibody, such as a mouse monoclonal antibody) based on the 41B5-1, 15D8-1, 46B7-1, 16F1-1, 17E11-1, or 17E9-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto) can have an IC50 of < 1 μΜ, preferably < 750 nM, or < 500 nM, with respect to inhibition of capsaicin-induced TRPV1 activation. In some such embodiments, the IC50 value can be in the range of 10 nM to 1 μΜ, e.g., 50 nM to 1 μΜ, or 100 nM to 1 μΜ, or 200 nM to 1 μΜ, 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 μΜ, e.g., up to 750 nM, or up to 500 nM. The IC50 value can be established (or calculated) based on the results of, e.g., any suitable assay or test as described herein (e.g., the FLIPR method). Particularly preferred FLIPR methods are described in the Examples section herein.

[0757] In some embodiments, for an antibody based on the 41B5-1, 15D8-1, 46B7-1, or 17E11-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), when the antibody is used at a concentration that inhibits capsaicin-induced TRPV1 activation by about 50%, 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 of heat-induced TRPV1 activation is observed.

[0758] In some embodiments, for an antibody based on the 41B5-1, 15D8-1, or 17E11-1 antibody of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), when the antibody is used at a concentration that inhibits capsaicin-induced TRPV1 activation by about 50%, 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 of heat-induced TRPV1 activation is observed.

[0759] In some embodiments, for antibodies based on the 41B5-1, 15D8-1, 46B7-1, or 17E11-1 antibodies of the application (e.g., those having CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto), when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM (e.g., 200 nM for 15D8-1 or 17E11-1 based antibodies, or e.g., 300 nM for 41B5-1 based antibodies, or e.g., 367 nM for 46B7-1 based antibodies), 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 of heat-induced TRPV1 activation is observed, and about 50% inhibition of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM, or 100 nM to 200 nM (e.g., 170 nM for 41B5-1 based antibodies, or e.g., 70 nM for 15D8-1 based antibodies, or e.g., 200 nM for 46B7-1 based antibodies, or e.g., 230 nM for 17E11-1 based antibodies).

[0760] In some embodiments, for antibodies based on the 41B5-1, 15D8-1, 17E11-1 antibodies of the application, when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM (e.g., 200 nM for 15D8-1 or 17E11-1 based antibodies, or e.g., 300 nM for 41B5-1 based antibodies), 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 of heat-induced TRPV1 activation is observed, and about 50% inhibition of capsaicin-induced TRPV1 activation is observed when the antibody is used at a concentration of 100 nM to 1 μΜ, e.g., 100 nM to 500 nM, or 100 nM to 200 nM (e.g., 170 nM for 41B5-1 based antibodies, or e.g., 70 nM for 15D8-1 based antibodies, or e.g., 230 nM for 17E11-1 based antibodies).

[0761] 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% inhibition for an antibody that binds to an isolated peptide of SEQ ID NO: 6 or SEQ ID NO: 20 (OTV7 peptide) (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide. In some embodiments, these % inhibition (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0762] 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% inhibition for an antibody that binds to an isolated peptide of SEQ ID NO: 6 or SEQ ID NO: 20 (OTV7 peptide) (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide. In some embodiments, these % inhibition (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0763] In some embodiments, the above % inhibition of capsaicin-induced TRPV1 activation is as determined when the antibody (e.g., a polyclonal antibody, such as a rabbit polyclonal antibody) is used at a concentration of 1 nM to 100 nM (e.g., 40 nM) for an antibody that binds to an isolated peptide of SEQ ID NO: 6 or SEQ ID NO: 20 (OTV7 peptide) (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide. In some embodiments, these % inhibition (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0764] 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% inhibition for an antibody that binds to an isolated peptide of SEQ ID NO: 6 or SEQ ID NO: 20 (OTV7 peptide) (or an isolated peptide substantially homologous thereto) or an antibody that binds to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide. In some embodiments, these % inhibition (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0765] In some embodiments, the % inhibition of capsaicin-induced TRPV1 activation for an antibody that binds to (or is substantially homologous to) an isolated peptide of SEQ ID NO: 8 or SEQ ID NO: 22 (or an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% inhibition. In some embodiments, these % inhibitions (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0766] In some embodiments, the % inhibition of capsaicin-induced TRPV1 activation for an antibody that binds to (or is substantially homologous to) an isolated peptide of SEQ ID NO: 8 or SEQ ID NO: 22 (or an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide is as determined when the antibody (e.g., a polyclonal antibody, such as a rabbit polyclonal antibody) is used at a concentration of 1 nM to 100 nM (e.g., 8 nM). In some embodiments, these % inhibitions (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0767] In some embodiments, the % inhibition of capsaicin-induced TRPV1 activation for an antibody that binds to (or is substantially homologous to) an isolated peptide of SEQ ID NO: 12 or SEQ ID NO: 26 (OTV13 peptide) (or an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% inhibition. In some embodiments, these % inhibitions (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0768] In some embodiments, the % inhibition of capsaicin-induced TRPV1 activation for an antibody that binds to (or is substantially homologous to) an isolated peptide of SEQ ID NO: 12 or SEQ ID NO: 26 (OTV13 peptide) (or an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% inhibition. In some embodiments, these % inhibitions (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0769] In some embodiments, the above % inhibition of capsaicin-induced TRPV1 activation for an antibody that binds to (or is substantially homologous to) an isolated peptide of SEQ ID NO: 12 or SEQ ID NO: 26 (or to an epitope of TRPV1 that corresponds to (or substantially corresponds to) such an isolated peptide) is as determined when the antibody (e.g., a polyclonal antibody, such as a rabbit polyclonal antibody) is used at a concentration of 1 nM to 100 nM (e.g., 40 nM). In some embodiments, these % inhibitions (e.g., % inhibition) of capsaicin-induced TRPV1 activation are as determined by a calcium imaging method (e.g., as described elsewhere herein).

[0770] In some embodiments, capsaicin-induced TRPV1 activation is TRPV1 activation induced when capsaicin is present (or used or contacted with TRPV1) at a concentration of 10 nM to 10 μΜ, e.g., 100 nM to 1 μΜ (e.g., at a concentration of 100 nM or 1 μΜ). 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.

[0771] Capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed by any suitable method, and the skilled person will be familiar with suitable methods.

[0772] In some embodiments, capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed (or are assessed) using electrophysiological methods (such as patch clamp techniques). Patch clamp methods are well known in the art and are also described herein. Typically, a reduction (or inhibition or decrease) in capsaicin-induced current in cells stimulated (or incubated) with capsaicin compared to cells stimulated (or incubated) with capsaicin and an antibody of the application, and also preferably compared to cells stimulated (or incubated) with capsaicin and a control antibody (e.g., a control antibody that does not bind to (or does not specifically bind to) TRPV1), indicates that the antibody of the application inhibits capsaicin-induced TRPV1 activation.

[0773] In some embodiments, patch clamp methods comprise the step of clamping (e.g., with a pipette) an expressed TRPV1 cell (e.g., in a bath) and recording the current (or current signal). Typically, the current (or current signal) is measured (e.g., tested in parallel) in cells stimulated (or incubated) with capsaicin and in cells stimulated with capsaicin and an antibody of the application, and also preferably in cells stimulated (or incubated) with capsaicin and a control antibody (e.g., a control antibody that does not bind to (or does not specifically bind to) TRPV1). For example, a reduction (or inhibition or decrease) in capsaicin-induced current compared to a control antibody typically indicates that the antibody of the application inhibits capsaicin-induced TRPV1 activation.

[0774] In some embodiments, in a patch clamp method, whole cell recording is performed using a microfluidic device for patch clamp recording together 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 buffer 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 / analogue sampling and acquisition software is used to acquire the patch clamp recordings. In preferred embodiments, the current amplitude is measured by exposing the cells to capsaicin (e.g. 100 nM capsaicin) with and without the antibody of the application or a control antibody. In preferred embodiments, the cells are exposed to 100 nM capsaicin in buffer F (or buffer A) for about 20 s, followed by buffer F (or buffer A) for about 60 s, the antibody in buffer F (or buffer A) for about 60 s, and then 100 nM capsaicin and the antibody together in buffer F (or buffer A) for about 20 s. In preferred embodiments, measurements in which the seal resistance changed greatly during the treatment are excluded from the analysis. In preferred embodiments, the peak amplitude recorded during the antibody + capsaicin stimulation is divided by the peak amplitude recorded during the capsaicin stimulation. The value obtained can be multiplied by 100 to obtain the cell response during the 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 the antibody + capsaicin stimulation divided by the peak amplitude recorded during the capsaicin only stimulation)) x 100). The measurements are preferably performed on cells from at least two different cell culture dishes. A particularly preferred patch clamp method is described in the Examples section herein.

[0775] In some embodiments, the patch clamp method comprises stimulating (or activating) TRPV1 expressing cells four times with capsaicin (e.g., 100 nM capsaicin or 300 nM capsaicin). In some such embodiments, the hTRPV1 expressing cells are pre-treated with an antibody of the application prior to the third activation (or stimulation) and the antibody is incubated with the capsaicin during the third activation (or stimulation). In some such embodiments, the first, second, and fourth activations (stimulations) are with capsaicin only. The amplitude of the third current peak in the presence of the antibody can be compared to the average of the amplitudes of the second and fourth current peaks. In some embodiments, the cells are treated twice with capsaicin alone to obtain peaks 1 and 2, then treated with the antibody, then treated with the antibody with capsaicin to obtain peak 3, followed by treatment with capsaicin alone to obtain peak 4. In some embodiments, the % inhibition can be calculated as (1 - ((peak 3) / ((peak 2 + peak 4) / 2))) * 100. In some other embodiments, the cells are first treated twice with capsaicin alone to obtain peaks 1 and 2, then treated with the antibody or vehicle, then treated with the antibody or vehicle with capsaicin to obtain peak 3, followed by treatment with capsaicin alone to obtain peak 4. In some such embodiments, the % inhibition can be calculated as (1 - ((peak 3 Ab / peak 2 Ab ) / (peak 3 veh / peak 2 ve h)) * 100.

[0776] In some embodiments, capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed (or assessed) using a calcium imaging method. Capsaicin causes calcium uptake.

[0777] In some embodiments, capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed (or assessed) by: (i) loading TRPV1 expressing cells with a calcium indicator (e.g., as described elsewhere herein), (ii) contacting (or incubating) the cells with an antibody of the application (or a control antibody or a vehicle only (i.e., no antibody) control), and (iii) contacting (or exposing the cells (i.e., cells have been incubated with an antibody of the application or a control in (ii)) with capsaicin and calcium (Ca 2+ ) and (iv) assessing (or determining or measuring) the ability of an antibody of the application to reduce (or decrease or inhibit) capsaicin-induced calcium influx (or uptake) into the cells by measuring (or determining) the signal (e.g., fluorescent signal) from the calcium indicator (e.g., compared to a control antibody or a vehicle only control). Preferred features of such embodiments will be apparent from the discussion elsewhere herein and these can be applied mutatis mutandis to the embodiments discussed in this paragraph.

[0778] In some calcium imaging methods for assessing 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 a calcium indicator to "load" the cells with the calcium indicator (e.g., Fluo-3 AM, e.g., at 4.4 mM) for example 30 min at, e.g., 37°C, and preferably then washed (the calcium indicator remains inside the cells after washing), and then incubated with an antibody of the application or with a control antibody (e.g., dissolved in PBS) or without additional agents for example 1 h at, e.g., room temperature. The control antibody is typically an antibody that does not bind to (or does not specifically bind to) TRPV1. Typically, the cells are then contacted with capsaicin (e.g., 1 mM) and Ca 2+ (e.g., 150 mM) (e.g., the capsaicin and calcium are added to the antibody solution covering the cells), and the intracellular calcium levels are monitored (or measured) by measuring the fluorescence intensity (of the calcium indicator), e.g., with a plate reader. Typically, the fluorescence intensity observed after (or during) incubation with capsaicin and calcium, where the cells were pre-incubated with an antibody of the application, is normalized to the fluorescence intensity observed after (or during) incubation with capsaicin and calcium (Ca 2+ ) where the cells were not pre-incubated with an antibody of the application or any additional agents. If the fluorescence intensity is reduced (or inhibited or decreased) when pre-incubated with an antibody of the application prior to incubation with capsaicin and calcium (Ca 2+ ) compared to when not pre-incubated with an antibody of the application prior to incubation with capsaicin and calcium (Ca 2+ ) (e.g., compared to pre-incubation with a control antibody prior to incubation with capsaicin and calcium (Ca 2+ ) this typically indicates that the antibody of the application inhibits capsaicin-induced TRPV1 activation. Particularly preferred calcium imaging methods are described in the Examples section herein.

[0779] In some embodiments, capsaicin-induced TRPV1 activation and inhibition of capsaicin-induced TRPV1 activation can be assessed (or assessed) using a fluorescent imaging plate reader (FLIPR) method.

[0780] In certain preferred FLIPR methods (which reflect the FLIPR method used in Example 3 herein) TRPV1 expressing cells (e.g. TRPV1 expressing CHO cells) are cultured in a black clear bottom microplate (e.g. 96 well microplate). The cells are then loaded with a calcium indicator (e.g. Fluo-3 AM, e.g. 4 μΜ) by incubation with the calcium indicator (e.g. Fluo-3 AM) in a buffer, e.g. HEPES buffer (140 nM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM D-glucose, pH 7.4) for e.g. 30 minutes at e.g. room temperature. The cells are then washed with buffer (e.g. HEPES) to remove extracellular calcium indicator (e.g. Fluo-3 AM) (the calcium indicator remains intracellular after washing). Subsequently, an antibody of the application diluted into a buffer (e.g. calcium containing buffer, such as HEPES) is added to the wells, e.g. 100 μΐ of antibody containing buffer is added to the cells in each well (typically serially diluted antibodies diluted into a buffer (e.g. 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 e.g. room temperature). Fluorescence measurements are typically made by a microplate reader, e.g. with an excitation wavelength of 483 nm (bandwidth 14 nm) and an emission wavelength of 530 (bandwidth 30 nm). Baseline fluorescence intensity is first measured, then (i.e. subsequently) a fixed amount of capsaicin in calcium containing buffer (e.g. in 100 μΐ buffer) such as HEPES is added to each well (giving a capsaicin concentration that has been previously determined to represent the capsaicin EC50value for the batch of cells under study, typically such a concentration is in the sub-micromolar range, e.g. such a concentration can be in the lower nM range, e.g. 10 nM) and a second fluorescence intensity measurement is made after a set time (typically within a few minutes, e.g. 1 to 5 or 1 to 10 or 1 to 20 minutes). The fluorescence intensity (of the calcium indicator) provides a report (or readout) of the amount of calcium within the cell (and capsaicin induced TRPV1 activation). This FLIPR assay relies on the presence of calcium in the buffer upon addition of capsaicin (i.e. relies on the presence of calcium in the buffer when the cells are exposed to capsaicin) and any suitable calcium containing buffer can be used (the skilled person will be familiar with suitable buffers), e.g. the HEPES buffer described above provides sufficient calcium). Antibodies of the application can be in PBS (phosphate buffered saline) prior to dilution into a buffer (e.g. calcium containing buffer, such as HEPES) (i.e. prior to being diluted) for addition to the cells (wells). The EC50is the concentration of a substance which gives half maximal response of a biological process, in this case TRPV1 mediated Ca 2+ ). The EC50value is determined by fitting a dose response curve to the data (typically using a non-linear regression curve fitting program, e.g. GraphPad Prism). The EC50value is the concentration of the antibody which gives 50% of the maximal response (i.e. the response of the antibody at its highest concentration). The EC50value is a measure of the potency of the antibody. The EC50value is determined by fitting a dose response curve to the data (typically using a non-linear regression curve fitting program, e.g. GraphPad Prism). The EC50value is the concentration of the antibody which gives 50% of the maximal response (i.e. the response of the antibody at its highest concentration). The EC50value is a measure of the potency of the antibody. 2+into (or TRPV1 -mediated Ca 2+ uptake) into cells. The data can be presented (or obtained or determined) as a rate of fluorescence, which is calculated as the fluorescence at a set (or specified) time after addition of capsaicin minus the fluorescence measured before addition of capsaicin (baseline). If a decrease in the rate of fluorescence is observed (or measured or determined) as the concentration of the antibody (i.e. the given antibody being tested) is increased (e.g. at a higher (or increased) concentration in a dilution series of the antibody), this is generally indicative of the antibody of the application inhibiting capsaicin-induced activation of TRPV1. An IC50value for the antibody being tested can be calculated (and this can readily be done by the skilled person). The IC50value is the half maximal inhibitory concentration of a substance in a biological context, in this case capsaicin-induced TRPV1 -mediated Ca 2+ uptake (or uptake or entry) into cells. A particularly preferred FLIPR method is described in the Examples section herein.

[0781] As mentioned above, certain methods comprise the use of a calcium indicator (e.g. Fluo3-AM). The skilled person will be familiar with such indicators. Calcium indicators can be used to conveniently visualise whether (or the extent to which) the intracellular concentration (or amount) of calcium ions (Ca 2+ ) increases during (or after) exposure to a particular stimulus (e.g. capsaicin or heat). Such calcium indicators can be loaded into cells (prior to exposure to the stimulus), and their fluorescence increases upon binding to Ca 2+ ) ions (i.e. upon Ca 2+ ) ions entering the cell, e.g. from a culture medium or buffer containing Ca 2+ ) ions.

[0782] Heat-induced TRPV1 activation is generally TRPV1 activation induced at > 42°C (or as determined). Thus, in some embodiments, heat-induced TRPV1 activation is TRPV1 activation 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 preferred embodiments, heat-induced TRPV1 activation is TRPV1 activation induced at 42°C - 45°C. In preferred embodiments, heat-induced TRPV1 activation is TRPV1 activation induced at 42°C. In another preferred embodiment, heat-induced TRPV1 activation is TRPV1 activation induced at 45°C.

[0783] Heat-induced TRPV1 activation (and inhibition of heat-induced TRPV1 activation) can be assessed by any suitable method, and the skilled person will be familiar with suitable methods. Heat (e.g. > 42°C, preferably 42°C) induces opening of the TRPV1 ion channel and leads to an influx of calcium ions (Ca2+ ) into the expressed TRPV1 cells. Thus, heat-induced TRPV1 activation (and inhibition of heat-induced TRPV1 activation) can be assessed by determining whether the concentration (or amount) of intracellular calcium ions (Ca 2+ ) is increased (or the degree of increase) during (or after) heating. Calcium indicators (e.g., Fluo-3 or Fluo3-AM) can be conveniently used to visualize whether the intracellular concentration (or amount) of calcium ions (Ca 2+ ) is increased (or the degree of increase) during (or after) heating. Such calcium indicators can be loaded into the cells (prior to exposure to heat), and their fluorescence increases upon binding to Ca 2+ ions (i.e., upon influx of Ca 2+ ions into the cells, e.g., from a culture medium containing Ca 2+ ions). This can be observed by any convenient means, e.g., by confocal microscopy. Whether a TRPV1 -binding antibody is able to inhibit (or the degree of inhibition) heat-induced TRPV1 activation can be assessed by contacting TRPV1 -expressing cells with the antibody (e.g., by delivering the antibody to the cells using a microfluidic device (e.g., a Biopen, described in the Examples section herein)) and determining whether heat-induced TRPV1 activation is inhibited (or reduced) (or the degree of inhibition (or reduction)) 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 to (or does not specifically bind to) TRPV1 ). Heat (42°C) can be provided using any suitable means, e.g., a laser heating system, e.g., as described in the Examples section herein. 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 absence of a reduction (or a significant reduction) in heat-induced TRPV1 activation in the presence of an anti-TRPV1 antibody indicates that the antibody does not (or does not significantly) inhibit heat-induced TRPV1 activation. A particularly preferred method of assessing heat-induced TRPV1 activation (and inhibition of heat-induced TRPV1 activation) is described in the Examples section herein.

[0784] In some embodiments, heat-induced TRPV1 activation (and inhibition thereof) can be assessed (or assessed) using a method in which cells expressing TRPV1 receive two heat pulses. In some such embodiments, the cells are first subjected to a heat pulse, followed by cooling, followed by combined administration (or exposure) of an antibody and a heat pulse, followed by cooling. The effect of the antibody on heat-induced TRPV1 activation can be assessed by determining the effect of the antibody on heat-induced calcium influx into the cells. Calcium influx into the 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 the antibody and vehicle. In some embodiments, the percent inhibition can be calculated by comparing the ratio for the antibody to the ratio for the vehicle. Thus, in some embodiments, the % inhibition can be (1 - ((peak 2 / peak 1) antibody / (peak 2 / peak 1) vehicle)) * 100. Ab / peak 1 Ab / peak 1 veh / peak 1 veh .

[0785] In some embodiments, the antibodies of the application can inhibit (or are capable of inhibiting) NADA-induced TRPV1 activation. NADA (N-arachidonyl dopamine) is a potential natural TRPV1 agonist.

[0786] In some embodiments, the inhibition of NADA-induced TRPV1 activation by the antibodies of the application is any measurable or significant inhibition (e.g., compared to a control without the antibody or compared to 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 inhibition of capsaicin-induced TRPV1 activation.

[0787] In some embodiments, NADA-induced TRPV1 activation is TRPV1 activation induced when NADA is present (or used or contacted with TRPV1) at a concentration of 10 nM to 10 mM, e.g., 100 nM to 1 mM (e.g., a concentration of 100 nM or 1 mM). In some embodiments, NADA-induced TRPV1 activation is TRPV1 activation induced when NADA is present at 1 mM.

[0788] In some embodiments, NADA-induced TRPV1 activation (or inhibition thereof) is determined in a patch clamp method as described elsewhere herein, e.g., using NADA in place of capsaicin.

[0789] In some embodiments, the inhibition of NADA-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%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% for antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the application, preferably OT-Ab1 (e.g., those having the CDR sequences and / or VH and / or VL domain sequences thereof, or sequences substantially homologous thereto).

[0790] In some embodiments, the inhibition of NADA-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% for antibodies based on the OT-Ab3, OT-Ab2, and OT-Ab1 antibodies of the application, preferably OT-Ab1 (e.g., those having the CDR sequences and / or VH and / or VL domain sequ...

Claims

1. A monoclonal 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. The antibody comprises a heavy chain variable region containing three CDRs and a light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VHCDR1 consisting of an amino acid sequence as shown in SEQ ID NO:363, VHCDR2 consisting of an amino acid sequence as shown in SEQ ID NO:364, and VHCDR3 consisting of an amino acid sequence as shown in SEQ ID NO:365, and wherein the light chain variable region comprises VLCDR1 consisting of an amino acid sequence as shown in SEQ ID NO:366, VL CDR2 consisting of an amino acid sequence as shown in SEQ ID NO:367, and VL CDR3 consisting of an amino acid sequence as shown in SEQ ID NO:

368.

2. The antibody as claimed in claim 1, wherein... (i) The light chain variable region has an amino acid sequence as shown in SEQ ID NO:362 or a sequence having at least 80% sequence identity with it, and the heavy chain variable region has an amino acid sequence as shown in SEQ ID NO:361 or a sequence having at least 80% sequence identity with it; or (ii) The light chain variable region has an amino acid sequence as shown in SEQ ID NO:382 or a sequence having at least 80% sequence identity with it, and the heavy chain variable region has an amino acid sequence as shown in SEQ ID NO:381 or a sequence having at least 80% sequence identity with it.

3. A monoclonal antibody that binds to TRPV1, wherein the antibody inhibits capsaicin-induced TRPV1 activation, wherein the antibody binds to an epitope of TRPV1 in the TRPV1 region defined by amino acid residues 599-656 of TRPV1 as shown in SEQ ID NO:

1. The antibody comprises a heavy chain variable region containing three CDRs and a light chain variable region containing three CDRs, wherein the heavy chain variable region comprises VHCDR1 consisting of an amino acid sequence as shown in SEQ ID NO:363, VHCDR2 consisting of an amino acid sequence as shown in SEQ ID NO:364, and VHCDR3 consisting of an amino acid sequence as shown in SEQ ID NO:365, and wherein the light chain variable region comprises VLCDR1 consisting of an amino acid sequence as shown in SEQ ID NO:366, VL CDR2 consisting of an amino acid sequence as shown in SEQ ID NO:367, and VL CDR3 consisting of an amino acid sequence as shown in SEQ ID NO:

368.

4. The monoclonal antibody as described in claim 3, wherein (i) The light chain variable region has an amino acid sequence as shown in SEQ ID NO:362 or a sequence having at least 80% sequence identity with it, and the heavy chain variable region has an amino acid sequence as shown in SEQ ID NO:361 or a sequence having at least 80% sequence identity with it; or (ii) The light chain variable region has an amino acid sequence as shown in SEQ ID NO:382 or a sequence having at least 80% sequence identity with it, and the heavy chain variable region has an amino acid sequence as shown in SEQ ID NO:381 or a sequence having at least 80% sequence identity with it.

5. The antibody according to any one of claims 1 to 4, wherein the antibody is a complete antibody containing an antibody constant region.

6. The antibody of claim 5, wherein the antibody is an IgG antibody.

7. The antibody according to any one of claims 1 to 4, wherein the antibody is an antigen-binding fragment of an antibody.

8. A composition comprising an antibody and an excipient as described in any one of claims 1 to 7.

9. The composition of claim 8, wherein the excipient is a pharmaceutically acceptable excipient.

10. The composition of claim 8, wherein the excipient is a diluent or a carrier.

11. The composition of claim 10, wherein the diluent or carrier is a pharmaceutically acceptable diluent or carrier.

12. A nucleic acid molecule comprising a nucleotide sequence encoding an antibody as described in any one of claims 1 to 7.

13. A set of nucleic acid molecules, each of the set of nucleic acid molecules comprising a nucleotide sequence, wherein the set of nucleic acid molecules together encodes an antibody as described in any one of claims 1 to 7.

14. A method for producing an antibody as described in any one of claims 1 to 7, the method comprising the following steps: (i) culturing host cells, said host cells comprising (a) one or more nucleic acid molecules encoding an antibody as described in any one of claims 1 to 7, or (b) a group of nucleic acid molecules, each of said nucleic acid molecules comprising a nucleotide sequence, wherein said group of nucleic acid molecules together encode an antibody as described in any one of claims 1 to 7, or (c) one or more recombinant expression vectors, under conditions suitable for expression of the encoded antibody, said recombinant expression vectors comprising one or more of said nucleic acid molecules; and (ii) Isolate or obtain the antibody from the host cell or from the growth medium / supernatant.

15. Use of the antibody as described in any one of claims 1 to 7 in the preparation of a medicament for therapeutic purposes; The therapy described therein is for treating pain.

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