WO2024127277A1

WO2024127277A1 - Method of treating pain with an anti-ccl17 antibody

Info

Publication number: WO2024127277A1
Application number: PCT/IB2023/062635
Authority: WO
Inventors: Christian Dean ELLSON; Jagtar Singh NIJJAR; Julia E. SMITH; Louise Kelly MODIS
Original assignee: GlaxoSmithKline Intellectual Property Development Ltd
Current assignee: GlaxoSmithKline Intellectual Property Development Ltd
Priority date: 2022-12-16
Filing date: 2023-12-13
Publication date: 2024-06-20
Anticipated expiration: 2025-06-16

Abstract

A method for treating chronic pain in a human subject, comprising administering a therapeutically effective amount of an antagonistic anti-CCL17 antibody.

Description

METHOD OF TREATING PAIN WITH AN ANTI-CCL17 ANTIBODY

CROSS REFERENCE

This application claims the benefit of U.S. provisional application 63/387,724 filed on December 16, 2022, which is incorporated by reference herein by its entity.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on December 7, 2023, is named “70251W001 SEQ LISTING 7-Dec- 2023” and is 10.7 Kb in size.

FIELD OF THE INVENTION

The present invention relates generally to methods of treatment in a human having chronic pain, through administration of an anti-CCL17 antibody.

BACKGROUND TO THE INVENTION

CCL17, previously known as thymus and activation regulated chemokine (TARC), is a member of the CC-family of chemokines that binds and signals through the G-protein coupled CC-chemokine receptor, CCR4. CCL17 is produced by numerous immune and non-immune cell types. CCR4 is predominantly expressed on Th2 cells but is also present on other immune cell types.

Antibodies to CCL17 have shown early signs of efficacy in inflammatory respiratory conditions such as asthma in mouse models. However, there has been no demonstration of efficacy of anti-CCL17 antibodies in human subjects.

Pain is a notoriously difficult condition to treat, with existing analgesics failing to provide adequate relief from pain in many, if not most, patients. Pain medication typically comes with side effects that are not tolerable to patients, especially central nervous system side effects including addiction, with some medications such as serotonin reuptake inhibitors (SRIs) and opioids. In addition, pre-clinical models of pain have many limitations and thus treatment success in these pain models does not always correlate with success in patients. As such there is a high attrition rate in the pain medication regulatory space. In particular, chronic pain is pain that persists or recurs for longer than three months and includes for example, chronic primary pain, chronic cancer pain, chronic postsurgical or posttraumatic pain, chronic neuropathic pain, chronic headache or orofacial pain, chronic visceral pain and chronic musculoskeletal pain (Treede et al, 2015: A dassjficatign of g fgjgg.ggjg.for There is a very high unmet patient need for

safe, tolerable, and efficacious treatment for management of chronic pain.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a method for treating chronic pain in a human subject, comprising administering to said subject a therapeutically effective amount of an antagonistic anti-CCL17 antibody. In another aspect, the invention provides an antagonistic anti-CCL17 antibody for use in the treatment of chronic pain.

In some embodiments, the anti-CCL17 antibody has decreased Fc-associated engagement of immune effector function and complement mediated cytotoxicity.

In some embodiments, the anti-CCL17 antibody comprises CDHR1, CDHR2, CDHR3, CDLR1, CDLR2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively.

In some embodiments, the anti-CCL17 antibody comprises the heavy chain variable region (VH) of SEQ ID NO: 3 and/or the light chain variable region (VL) of SEQ ID NO: 4.

In some embodiments, the anti-CCL17 antibody comprises a heavy chain comprising SEQ ID NO: 1 and/or a light chain comprising of SEQ ID NO: 2.

In some embodiments, the chronic pain is chronic musculoskeletal pain or chronic neuropathic pain.

In some embodiments, the chronic musculoskeletal pain comprises osteoarthritic pain or lower back pain. In some embodiments, the osteoarthritic pain comprises pain in a hip and/or a knee joint.

In some embodiments, the chronic neuropathic pain comprises chronic peripheral neuropathic pain.

In some embodiments, the chronic peripheral neuropathic pain comprises diabetic peripheral neuropathic pain, trigeminal neuralgia or postherpetic neuralgia.

In some embodiments, the chronic pain comprises moderate to severe pain, optionally wherein the subject has an average daily pain score of >4 and <9 on the 11-point Numerical Rating Scale.

In some embodiments, treatment results in at least a 1 point reduction in the subject’s average daily pain and/or worst daily pain score on the an 11-point Numerical Rating Scale.

In some embodiments, treatment results in at least a 1 point reduction in the subject’s WOMAC pain score and/or WOMAC function score on an 11-point Numerical Rating Scale.

In some embodiments, the subject receiving treatment experiences no central nervous system effects, no adverse events, no clinically significant changes from baseline in key laboratory parameters and/or no NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) grade >3 hematological/clinical chemistry abnormalities.

In some embodiments, the antibody is comprised in a composition which is administered subcutaneously.

In some embodiments, the composition is administered at least once at a dose of 30mg, 60mg, 240mg, 360mg or 480mg.

In some embodiments, the composition is administered more than once, wherein the administration is about weekly or every two weeks. In some embodiments, the composition is administered about weekly at a dose of 60mg, about weekly at a dose of 240mg, about every two weeks at a dose of 240mg, or about weekly at a dose of 360mg.

In some embodiments, the composition is administered using an autoinjector.

In some embodiments, the subject is non-responsive, refractory to, contraindicated for and/or otherwise unwilling to use opioid treatment for their pain.

DESCRIPTION OF DRAWINGS/FIGURES

FIG. 1 - Absolute (FIG. 1A) and change from baseline (FIG. IB) in average knee pain score. Posterior Median and 95% Credible Intervals of Change from Baseline are obtained from a Bayesian repeated measures model adjusting for treatment, week, baseline, and the treatment by week and baseline by week interactions using vague priors. Each day the subject is asked to rate their average pain intensity over the last 24 hours and the subject’s mean is then taken over the 7 days preceding the visit. Scores range from 0-10 and a decrease from baseline is considered to be an improvement.

FIG. 2 - Absolute (FIG. 2A) and change from baseline (FIG. 2B) in worst knee pain score. Posterior Median and 95% Credible Intervals of Change from Baseline are obtained from a Bayesian repeated measures model adjusting for treatment, week, baseline, and the treatment by week and baseline by week interactions using vague priors. Each day the subject is asked to rate their worst pain intensity over the last 24 hours and the subject’s mean is then taken over the 7 days preceding the visit. Scores range from 0-10 and a decrease from baseline is considered to be an improvement.

FIG. 3 - Absolute (FIG. 3A) and change from baseline (FIG. 3B) in WOMAC pain score. Posterior Median and 95% Credible Intervals of Change from Baseline are obtained from a Bayesian repeated measures model adjusting for treatment, week, baseline, and the treatment by week and baseline by week interactions using vague priors. Scores range from 0-10 and a decrease from baseline is considered to be an improvement. FIG. 4 - Absolute (FIG. 4A) and change from baseline (FIG. 4B) in WOMAC stiffness score. Posterior Median and 95% Credible Intervals of Change from Baseline are obtained from a Bayesian repeated measures model adjusting for treatment, week, baseline, and the treatment by week and baseline by week interactions using vague priors. Scores range from 0-10 and a decrease from baseline is considered to be an improvement.

FIG. 5 - Absolute (FIG. 5A) and change from baseline (FIG. 5B) in WOMAC function score. Posterior Median and 95% Credible Intervals of Change from Baseline are obtained from a Bayesian repeated measures model adjusting for treatment, week, baseline, and the treatment by week and baseline by week interactions using vague priors. Scores range from 0-10 and a decrease from baseline is considered to be an improvement.

FIG. 6 - Absolute (FIG. 6A) and change from baseline (FIG. 6B) in Patient Global Assessment of Disease Activity (PtGA) score. Posterior Median and 95% Credible Intervals of Change from Baseline are obtained from a Bayesian repeated measures model adjusting for treatment, week, baseline, and the treatment by week and baseline by week interactions using vague priors. Scores range from 1-5 and a decrease from baseline is considered to be an improvement.

FIG. 7 - Geometric mean free CCL17 in serum (FIG. 7A) and percent reduction from baseline (target engagement) (FIG. 7B) from Day 1 through 12-week follow up period. Large percentage reductions in free CCL17 relative to baseline were observed (based on the semi-quantitative free target assay) and maintained over the dosing intervals following weekly SC administration of the lead anti-CCL17 antibody. Dashed lines in FIG. 7A represent the lower (2.93pg/mL) and upper (3600pg/mL) limits of quantification, and in FIG. 7B represent 90% and 95% target engagement. Error bars in FIG. 7B are 95% confidence intervals.

FIG. 8 - Geometric mean lead anti-CCL17 serum concentration (FIG. 8A) and immunogenicity (FIG. 8B) from Day 1 through 12-week follow up period. The lead anti- CCL17 antibody was rapidly absorbed after SC administration (median tmax ~2 days), with steady state level predicted by Week 8 (Day 57). There were no discernible differences in adverse events (AEs) or efficacy, and PK profiles were consistent for participants with versus without anti -drug antibodies to the lead anti-CCL17 antibody. The dashed line in FIG. 8A represents the lower limit of quantification (lOOng/mL).

FIG. 9 - CCR4 in satellite glial cells of the human DRG donor 5. Scale bars = 50pm.

Top: Note the perinuclear, eccentrically located, intracellular staining in cells surrounding many neuron cell bodies. Bottom: IHC chromogenic triplex. Black arrows show examples of GS+CCR+ satellite glial cells, grey arrows show examples of CD163+ macrophages.

FIG. 10 - CCR4 in satellite glial cells of the human DRG all donors. Scale bars = 50pm.

FIG. 11 - CCR4 ISH with PPIB positive control. Scale bar = 20pm, circles highlight cells with CCR4 ISH signal.

FIG. 12 - Diagram demonstrating proposed mechanism for effective treatment of a broad range of chronic pain indications through targeting CCL17.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification.

It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. As used herein, the conjunctive term "and/or" between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by "and/or," a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. For the avoidance of doubt, the term “comprises” also captures the term “consists”, i.e. where no further integer or group of integers to steps are included.

Any sub-titles herein are included for convenience only, and are not to be construed as limiting the disclosure in any way. The invention will now be further described with reference to the following non-limiting Figures and Examples. Other embodiments of the invention will occur to those skilled in the art in the light of these.

The target

CCL17 (CC chemokine ligand 17), also known as TARC (thymus and activation regulated chemokine) is a chemokine, which is a family of secreted proteins involved in immunoregulatory and inflammatory processes. "Human CCL17" or "CCL17" as used interchangeably herein may refer to the human CCL17 protein having the amino acid sequence shown in SEQ ID NO: 11. The sequence of the full length CCL17 including the signal sequence is available at GenBank; Accession Number NP_002978. As described herein, without being bound by theory, it is thought that the antibody of the invention binding to CCL17 can treat chronic pain by disrupting the action of CCL17 both at the tissue site at the nerve endings as well as the dorsal root ganglion (summarized in FIG. 12).

The antibody

The invention provides herein a method for treating chronic pain, comprising administering to a human subject suffering from chronic pain a therapeutically effective amount of an antagonistic anti-CCL17 antibody.

The term “antibody” is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136).

The term, full, whole or intact antibody, used interchangeably herein, refers to a heterotetrameric glycoprotein with an approximate molecular weight of 150,000 daltons. An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds. This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment. The Fab fragment is composed of the variable domain at the amino-terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CHI (heavy) and CL (light). The Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions. The Fc may elicit effector functions by binding to receptors on immune cells or by binding Clq, the first component of the classical complement pathway. The five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called p, a, y, a and 5 respectively, each heavy chain can pair with either a K or /, light chain. The majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG (IgGl, IgG2, IgG3 and IgG4), the sequences of which differ mainly in their hinge region.

Fully human antibodies can be obtained using a variety of methods, for example using yeast-based libraries or transgenic animals (e.g. mice) that are capable of producing repertoires of human antibodies. Yeast presenting human antibodies on their surface that bind to an antigen of interest can be selected using FACS (Fluorescence-Activated Cell Sorting) based methods or by capture on beads using labelled antigens. Transgenic animals that have been modified to express human immunoglobulin genes can be immunised with an antigen of interest and antigen-specific human antibodies isolated using B-cell sorting techniques. Human antibodies produced using these techniques can then be characterised for desired properties such as affinity, developability and selectivity.

Alternative antibody formats include alternative scaffolds in which the one or more CDRs of the antibody can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301) or an EGF domain.

Antibodies include antibody fragments. Antibodies also include, but are not limited to, polyclonal monoclonal, chimeric dAb (domain antibody), single chain, Fab , Fab' , F(ab')2 fragments, scFvs, and Fab expression libraries. An antibody may be a whole antibody, or immunoglobulin, or an antibody fragment. An "antagonistic” or “neutralizing” CCL17 antibody refers to an antibody or antibody fragment that partially or completely inhibits, by any mechanism, CCL17 biological activity. This may be through blockade of the interaction between CCL17 and its cognate receptor CCR4. Such antibodies can be identified using assays for CCL17 biological activity as described below. Such antibodies may inhibit measured CCL17 biological activity by 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%.

In some embodiments, the anti-CCL17 antibody comprises any one or a combination of the following CDRs (complementarity determining regions): CDRH1 of SEQ ID NO: 5, CDRH2 of SEQ ID NO: 6, CDRH3 of SEQ ID NO: 7, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9, and CDRL3 of SEQ ID NO: 10. In some embodiments, the anti-CCL17 antibody comprises CDHR1, CDHR2, CDHR3, CDLR1, CDRL2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively. Thus, the invention also provides herein a method for treating chronic pain, comprising administering to a subject suffering from chronic pain a therapeutically effective amount of an antagonistic anti- CCL17 antibody, wherein the anti-CCL17 antibody comprises CDHR1, CDHR2, CDHR3, CDLR1, CDRL2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively.

In some aspects of the invention there is provided an isolated polynucleotide encoding an antagonistic anti-CCL17 antibody, wherein the polynucleotide encodes a CDHR1, CDHR2, CDHR3, CDLR1, CDRL2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively. In some aspects, there is a vector comprising said polynucleotide. In some aspects, there is a host cell comprising said vector. The term "polynucleotide" means a molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. Double and singlestranded DNAs and RNAs are typical examples of polynucleotides. The term "vector" means a non-natural polynucleotide capable of being duplicated within a biological system or that can be moved between such systems. Vector polynucleotides typically contain a cDNA encoding a protein of interest and additional elements, such as origins of replication, polyadenylation signal or selection markers, that function to facilitate the duplication or maintenance of these polynucleotides in a biological system. Examples of such biological systems may include a cell, virus, animal, plant, and reconstituted biological systems utilizing biological components capable of duplicating a vector. The polynucleotide comprising a vector may be DNA or RNA molecules or a hybrid of these.

“CDRs” are defined as the complementarity determining region amino acid sequences of an antigen binding protein (including an antibody). These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, "CDRs" as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.

Throughout this specification, amino acid residues in variable domain sequences and variable domain regions within full-length antigen binding sequences, e.g. within an antibody heavy chain sequence or antibody light chain sequence, are numbered according to the Kabat numbering convention. Similarly, the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used in the Examples follow the Kabat numbering convention. For further information, see Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987).

It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. There are also alternative numbering conventions for CDR sequences, for example those set out in Chothia et al. (1989) Nature 342: 877-883. The structure and protein folding of the antigen binding protein may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person. Other numbering conventions for CDR sequences available to a skilled person include “AbM” (University of Bath) and “contact” (University College London) methods. CDRs may be modified by at least one amino acid substitution, deletion or addition, wherein the variant antigen binding protein substantially retains the biological characteristics of the unmodified protein, such as antagonism of the target CCL17 including ability to block CCL17/CCR4 interaction (e.g. by standard flow cytometry).

It will be appreciated that each of CDRH1, H2, H3, LI, L2, L3 may be modified alone or in combination with any other CDR, in any permutation or combination. In one embodiment, a CDR is modified by the substitution, deletion or addition of up to 3 amino acids, for example 1 or 2 amino acids, for example 1 amino acid. Typically, the modification is a substitution, particularly a conservative substitution, for example as shown in Table 1 below.

Table 1

For example, in a variant CDR, the flanking residues that comprise the CDR as part of alternative defmition(s) e.g. Kabat or Chothia, may be substituted with a conservative amino acid residue.

Such antibodies comprising variant CDRs as described above may be referred to herein as “functional CDR variants”.

In some aspects, there is provided an isolated polynucleotide encoding an antagonistic anti- CCL17 antibody, wherein the polynucleotide encodes a heavy chain variable region (VH) of SEQ ID NO: 3 and/or the light chain variable region (VL) of SEQ ID NO: 4. In some embodiments, the anti-CCL17 antibody comprises a heavy chain comprising SEQ ID NO: 1 and/or a light chain comprising of SEQ ID NO: 2.

In some aspects, there is provided an isolated polynucleotide encoding an antagonistic anti- CCL17 antibody, wherein the polynucleotide encodes a heavy chain comprising SEQ ID NO: 1 and/or a light chain comprising of SEQ ID NO: 2.

By “lead anti-CCL17 antibody” is meant the antibody investigated in Examples 1, 2, 3, and 5. This is an antagonistic anti-CCL17 IgG2o antibody having the heavy chain of SEQ ID NO: 1 and the light chain of SEQ ID NO: 2, including the heavy chain variable region (VH) of SEQ ID NO: 3 and the light chain variable region (VL) of SEQ ID NO: 4, and CDHR1, CDHR2, CDHR3, CDLR1, CDLR2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively. This antibody also comprises seven Fc- disabling mutations V234A, G237A, P238S, H268A, V309L, A330S and P331S according the EU numbering.

Again, it will be clear to the skilled person that all described embodiments further defining the antibody, pharmaceutical composition, production methods, indication, treatment, and administration will all equally apply to these aspects.

In some examples of the invention, the anti-CCL17 antibody is an isolated antibody specifically binding human CCL17 having the sequence of SEQ ID NO: 11, wherein the antibody binds human CCL17 at least within CCL17 amino acid residues 21-23, 44-45 and 60-68. "At least within human CCL17 amino acid residues 21-23, 44-45 and 60-68" means that the anti-CCL17 antibody binds at least one residue residing within the amino acid stretch of residues 21-23 of SEQ ID NO: 11, and at least one residue residing within the amino acid stretch of residues 44-45 of SEQ ID NO: 11, and at least one residue residing within the amino acid stretch of residues 60-68 of SEQ ID NO: 11. The antibody may bind more than one residue within the residues 21-23, 44-45 and 60-68, and additional residues outside of residues 21-23, 44-45 and 60-68 of SEQ ID NO: 11. In some examples, the antibody binds human CCL17 at least at residues R22 and K23 of SEQ ID NO: 11. In some embodiments described herein, the antibody binds human CCL17 at least at residues L21, R22, K23, V44, Q45, N60, Y64, S67 and L68 of SEQ ID NO: 11. “Percent identity” or “% identity” between a query nucleic acid sequence and a subject nucleic acid sequence is the “Identities” value, expressed as a percentage, that is calculated using a suitable algorithm (e.g. BLASTN, FASTA, Needleman-Wunsch, Smith-Waterman, LALIGN, or GenePAST/KERR) or software (e.g. DNASTAR Lasergene, GenomeQuest, EMBOSS needle or EMBOSS infoalign), over the entire length of the query sequence after a pair-wise global sequence alignment has been performed using a suitable algorithm (e.g. Needleman-Wunsch or GenePAST/KERR) or software (e.g. DNASTAR Lasergene or GenePAST/KERR). Importantly, a query nucleic acid sequence may be described by a nucleic acid sequence disclosed herein.

“Percent identity” or “% identity” between a query amino acid sequence and a subject amino acid sequence is the “Identities” value, expressed as a percentage, that is calculated using a suitable algorithm (e.g. BLASTP, FASTA, Needleman-Wunsch, Smith-Waterman, LALIGN, or GenePAST/KERR) or software (e.g. DNASTAR Lasergene, GenomeQuest, EMBOSS needle or EMBOSS infoalign), over the entire length of the query sequence after a pair-wise global sequence alignment has been performed using a suitable algorithm (e.g. Needleman-Wunsch or GenePAST/KERR) or software (e.g. DNASTAR Lasergene or GenePAST/KERR). Importantly, a query amino acid sequence may be described by an amino acid sequence disclosed herein, in particular in one or more of the claims.

The query sequence may be 100% identical to the subject sequence, or it may include up to a certain integer number of amino acid or nucleotide alterations as compared to the subject sequence such that the % identity is less than 100%. For example, the query sequence is at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the subject sequence. In the case of nucleic acid sequences, such alterations include at least one nucleotide residue deletion, substitution or insertion, wherein said alterations may occur at the 5’- or 3’- terminal positions of the query sequence or anywhere between those terminal positions, interspersed either individually among the nucleotide residues in the query sequence or in one or more contiguous groups within the query sequence. In the case of amino acid sequences, such alterations include at least one amino acid residue deletion, substitution (including conservative and non-conservative substitutions), or insertion, wherein said alterations may occur at the amino- or carboxy-terminal positions of the query sequence or anywhere between those terminal positions, interspersed either individually among the amino acid residues in the query sequence or in one or more contiguous groups within the query sequence. For antibody sequences, the % identity may be determined across the entire length of the query sequence, including the CDRs. Alternatively, the % identity may exclude one or more or all of the CDRs, for example all of the CDRs are 100% identical to the subject sequence and the % identity variation is in the remaining portion of the query sequence, e.g. the framework sequence, so that the CDR sequences are fixed and intact. The variant sequence substantially retains the biological characteristics of the unmodified protein, such as antagonism of the CCL17 target including ability to block CCL17/CCR4 interaction (e.g. by standard flow cytometry).

Thus, in some examples the antibody comprises a heavy chain variable region (VH) having a sequence with at least 90%, 95%, 97%, 98% or 99% to SEQ ID NO: 3 and/or the light chain variable region (VL) having a sequence with at least 90%, 95%, 97%, 98% or 99% to SEQ ID NO: 4. In some embodiments, this antibody comprises a CDHR1, CDHR2, CDHR3, CDLR1, CDRL2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively (i.e. the % identity excludes all of the CDRs).

In some examples, the antibody is of IgG2 isotype, optionally IgG2o isotype. In some examples, the antibody may be IgG2o Fc-silenced, optionally wherein the antibody comprises a V234A, G237A, P238S, H268A, V309L, A330S and/or P331S substitution on IgG2, wherein residue numbering is according to the EU Index. In other examples, the antibody is of IgG4 isotype. In some examples, the anti-CCL17 antibody is of IgG4 isotype, and wherein the antibody comprises a S228P, L234A or L235A substitution on IgG4, wherein residue numbering is according to the EU Index.

Competition between the anti-CCL17 antibody of the invention and a reference anti- CCL17 may be determined by one or more techniques known to the skilled person such as ELISA, FMAT, Surface Plasmon Resonance (SPR) or ForteBio Octet Bio-Layer Interferometry (BLI). Such techniques may also be referred to as epitope binning. There are several possible reasons for this competition: the two proteins may bind to the same or overlapping epitopes, there may be steric inhibition of binding, or binding of the first protein may induce a conformational change in the antigen that prevents or reduces binding of the second protein. The reduction or inhibition in biological activity may be partial or total. In some aspects, the anti-CCL17 antibody may neutralise the activity of CCL17 by at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, 99% or 100% relative to CCL17 activity in the absence of the anti- CCL17 antibody. Neutralisation may be determined or measured using one or more assays known to the skilled person or as described herein.

The skilled person will appreciate that, upon production of an antibody in a host cell, post- translational modifications may occur. For example, this may include the cleavage of certain leader sequences, the addition of various sugar moieties in various glycosylation patterns, non-enzymatic glycation, deamidation, oxidation, disulfide bond scrambling and other cysteine variants such as free sulfhydryls, racemized disulfides, thioethers and trisulfide bonds, isomerisation, C-terminal lysine clipping, and N-terminal glutamine cyclisation. The present invention encompasses the use of antigen binding proteins that have been subjected to, or have undergone, one or more post-translational modifications. Thus an “antibody” of the invention includes an “antibody”, as defined earlier that has undergone a post-translational modification such as described herein.

Glycation is a post-translational non-enzymatic chemical reaction between a reducing sugar, such as glucose, and a free amine group in the protein, and is typically observed at the epsilon amine of lysine side chains or at the N-Terminus of the protein. Glycation can occur during production and storage only in the presence of reducing sugars.

Deamidation can occur during production and storage, is an enzymatic reaction primarily converting asparagine (N) to iso-aspartic acid (iso-aspartate) and aspartic acid (aspartate) (D) at approximately 3: 1 ratio. This deamidation reaction is therefore related to isomerization of aspartate (D) to iso-aspartate. The deamidation of asparagine and the isomerisation of aspartate, both involve the intermediate succinimide. To a much lesser degree, deamidation can occur with glutamine residues in a similar manner. Deamidation can occur in a CDR, in a Fab (non-CDR region), or in the Fc region.

Oxidation can occur during production and storage (i.e. in the presence of oxidizing conditions) and results in a covalent modification of a protein, induced either directly by reactive oxygen species or indirectly by reaction with secondary by-products of oxidative stress. Oxidation happens primarily with methionine residues, but may occur at tryptophan and free cysteine residues. Oxidation can occur in a CDR, in a Fab (non-CDR) region, or in the Fc region.

Disulfide bond scrambling can occur during production and basic storage conditions. Under certain circumstances, disulfide bonds can break or form incorrectly, resulting in unpaired cysteine residues (-SH). These free (unpaired) sulfhydryls (-SH) can promote shuffling.

The formation of a thioether and racemization of a disulphide bond can occur under basic conditions, in production or storage, through a beta elimination of disulphide bridges back to cysteine residues via a dehydroalanine and persulfide intermediate. Subsequent crosslinking of dehydroalanine and cysteine results in the formation of a thioether bond or the free cysteine residues can reform a disulphide bond with a mixture of D- and L- cysteine.

Trisulfides result from insertion of a sulfur atom into a disulphide bond (Cys-S-S-S-Cys ) and are formed due to the presence of hydrogen sulphide in production cell culture.

N-terminal glutamine (Q) and glutamate (glutamic acid) (E) in the heavy chain and/or light chain is likely to form pyroglutamate (pGlu) via cyclization. Most pGlu formation happens in the production bioreactor, but it can be formed non-enzymatically, depending on pH and temperature of processing and storage conditions. Cyclization of N-terminal Q or E is commonly observed in natural human antibodies.

C-terminal lysine clipping is an enzymatic reaction catalyzed by carboxypeptidases, and is commonly observed in recombinant and natural human antibodies. Variants of this process include removal of lysine from one or both heavy chains due to cellular enzymes from the recombinant host cell. Upon administration to the human subject/patient is likely to result in the removal of any remaining C-terminal lysines.

It will be clear to the skilled person that all the described embodiments herein apply to the methods of treatment of chronic pain as well as the described antibody for use in the treatment of chronic pain. As such, the present invention also provides in one aspect for an antagonistic anti-CCL17 antibody for use in the treatment of chronic pain. As such, the present invention also provides in one aspect for an antagonistic anti-CCL17 antibody comprising CDHR1, CDHR2, CDHR3, CDLR1, CDRL2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively, for use in the treatment of chronic pain.

As such, the present invention also provides for in one aspect the use of an antagonistic anti-CCL17 antibody in the manufacture of a medicament for use in the treatment of chronic pain. As such, the present invention also provides for in one aspect the use of an antagonistic anti-CCL17 antibody comprising CDHR1, CDHR2, CDHR3, CDLR1, CDRL2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively, in the manufacture of a medicament for use in the treatment of chronic pain.

For the avoidance of doubt, all described embodiments further defining the antibody, pharmaceutical composition, production methods, indication, treatment, and administration will all equally apply to these aspects.

On the basis of the results presented herein, we would expect that other antagonist anti- CCL17 antibodies, such as those described in WO99/15666 or Ishida, T., et al (2004) Clin Cancer Res 10:7529-7539, any of the other CCL17 antibodies disclosed in WO 2015/069865, or indeed CCL17 antibodies having a high level of sequence identity (e.g. at least 95% sequence identity across the VH and/or VL) with the antibody of the invention, comprising sequences according to SEQ ID NOs: 3 and 4, or SEQ ID NOs: 1 and 2, could also be used in the methods and uses of the invention. Equally, antibodies against the cognate receptor for CCL17, CCR4 could be used to the same effect.

Fc engineering methods can be applied to modify the functional or pharmacokinetics properties of an antibody. Effector function may be altered by making mutations in the Fc region that increase or decrease binding to Clq or Fey receptors and modify CDC or ADCC activity respectively. Modifications to the glycosylation pattern of an antibody can also be made to change the effector function. The in vivo half-life of an antibody can be altered by making mutations that affect binding of the Fc to the FcRn (Neonatal Fc Receptor). Thus, in some embodiments, the anti-CCL17 antibody is Fc-silenced. In some embodiments, the anti-CCL17 antibody has decreased Fc-associated engagement of immune effector function and complement mediated cytotoxicity.

In some embodiments, the anti-CCL17 antibody where half-life is conserved through interactions with FcRn, while potential toxicity derived from activation of FcyRs associated with immune and effector functions such as i) antibody dependent cytotoxicity (ADCC), ii) complement dependent cytotoxicity (CDC), iii) antibody dependent cellular phagocytosis (ADCP), iv) FcR-mediated cellular activation (e.g. cytokine release through FcR cross-linking), and v) FcR-mediated platelet activation/depletion is minimized or eliminated.

In some embodiments, the anti-CCL17 antibody having decreased affinity for at least one Fey receptor as compared to a wildtype Fc.

In some embodiments, the anti-CCL17 antibody having decreased affinity for at least FcyRI and FcyRIIa as compared to an Fc-containing molecule with a wildtype Fc domain.

In some embodiments, the anti-CCL17 antibody that is capable of specifically binding FcRn.

In some embodiments, the anti-CCL17 antibody is an IgG2 antibody wherein binding of the antibody to at least one Fey receptor is reduced as compared to a wildtype IgG2 based Fc region.

In some embodiments, the anti-CCL17 IgG2 antibody comprises V234A, G237A, P238S according to the EU numbering system. In some embodiments, the anti-CCL17 IgG2 antibody comprises V234A, G237A, H268Q or H268A, V309L, A330S, P331S according to the EU numbering system. In some embodiments, the anti-CCL17 IgG2 antibody comprises V234A, G237A, P238S, H268A, V309L, A330S, P331S, and, optionally, P233S according to the EU numbering system. The term “Effector Function” as used herein refers to one or more of antibody-mediated effects including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody- mediated complement activation including complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated phagocytosis (CDCP), antibody dependent complement-mediated cell lysis (ADCML), and Fc-mediated phagocytosis or antibodydependent cellular phagocytosis (ADCP).

The interaction between the Fc region of an antigen binding protein or antibody and various Fc receptors (FcR), including FcyRI (CD64), FcyRII (CD32), FcyRIII (CD 16), FcRn, Clq, and type II Fc receptors is believed to mediate the effector functions of the antigen binding protein or antibody. Significant biological effects can be a consequence of effector functionality. Usually, the ability to mediate effector function requires binding of the antigen binding protein or antibody to an antigen and not all antigen binding proteins or antibodies will mediate every effector function.

Effector function can be assessed in a number of ways including, for example, evaluating ADCC effector function of antibody coated to target cells mediated by Natural Killer (NK) cells via FcyRIII, or monocytes/macrophages via FcyRI, or evaluating CDC effector function of antibody coated to target cells mediated by complement cascade via Clq. For example, an antigen binding protein of the present invention can be assessed for ADCC effector function in a Natural Killer cell assay.

Examples of such assays can be found in Shields et al, 2001, The Journal of Biological Chemistry, Vol. 276, p. 6591-6604; Chappel et al, 1993, The Journal of Biological Chemistry, Vol 268, p. 25124-25131; Lazar et al, 2006, PNAS, 103; 4005-4010. Examples of assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38.

The effects of mutations on effector functions (e.g., FcRn binding, FcyRs and Clq binding, CDC, ADCML, ADCC, ADCP) can be assessed, e.g., as described in Grevys et al., J Immunol. 2015 Jun 1; 194(11): 5497-5508, or Tam et al., Antibodies 2017, 6(3); Monnet et al., 2014 mAbs, 6:2, 422-436. Throughout this specification, amino acid residues in Fc regions, in antibody sequences or full-length antigen binding protein sequences, are numbered according to the EU index numbering convention. Some isotypes of human constant regions, in particular IgG4 and IgG2 isotypes, essentially lack the functions of a) activation of complement by the classical pathway; and b) ADCC. Various modifications to the heavy chain constant region of antibodies may be carried out to alter effector function depending on the desired effector property. IgGl constant regions containing specific mutations that reduce binding to Fc receptors and reduce an effector function, such as ADCC and CDC, have been described (Duncan et al. Nature 1988, 332; 563-564; Lund et al. J. Immunol. 1991, 147; 2657-2662; Chappel et al. PNAS 1991, 88; 9036-9040; Burton and Woof, Adv. Immunol. 1992, 51; 1-84; Morgan et al., Immunology 1995, 86; 319-324; Hezareh et al., J. Virol. 2001, 75 (24); 12161- 12168).

In one embodiment of the present invention the anti-CCL17 antibody comprises a constant region such that the antibody has reduced effector function, such as reduced ADCC and/or CDC. In one such embodiment, the heavy chain constant region may comprise a naturally disabled constant region of an IgG2 or IgG4 isotype or a mutated IgGl constant region. Examples of suitable modifications are described in EP0307434. One example comprises substitution with alanine at positions 235 and 237 (EU index numbering), i.e. L235A and G237A (commonly referred to as “LAGA” mutations). Another example comprises substitution with alanine at positions 234 and 235 (EU index numbering), i.e. L234A and L235A (commonly referred to as “LALA” mutations). Further examples, described in EP2691417 and US8969526, comprise P329G or P329R, in combination with the LALA mutations (EU index numbering) for IgGl Fes and P329G or P329R in combination with S228P and L235E for IgG4 Fes (EU index numbering).

Additional alterations and mutations to decrease effector function include: (with reference to IgGl unless otherwise noted): aglycosylated N297A or N297Q or N297G; L235E; IgG4:F234A/L235A; and chimeric IgG2/IgG4. IgG2: H268Q/V309L/A330S/P331S, and IgG2: V234A/G237A/P238S/H268A/V309L/A330S/P331S can reduce FcyR and Clq binding (Wang et al. 2018 and US8961967).

Other mutations that decrease effector function include L234F/L235E/P33 IS; a chimeric antibody created using the CHI and hinge region from human IgG2 and the CH2 and CH3 regions from human IgG4; IgG2m4, based on the IgG2 isotype with four key amino acid residue changes derived from IgG4 (H268Q, V309L, A330S and P33 IS); IgG2o that contains V234A/G237A/P238S/H268A/V309L/A330S/P331S substitutions to eliminate affinity for Fey receptors and C lq complem ent protei n ; IgG2m4 (H268Q/V309L/A330S/P331S, changes to IgG4); IgG4 (S228P/L234A/L235A); huIgGl L234A/L235A (AA); hu!gG4 S228P/L234A/L235A; IgGls (L234A/L235A/G237A/P238S/H268A/A330S/P33 IS); IgG4sl (S228P/F234A/L235A/G237A/P238S); and IgG4s2 (S228P/F234A/L235A/DG236/G237A/P238S, wherein D denotes a deletion) (Tam et al., Antibodies 2017, 6(3)).

Pharmaceutical composition

In some embodiments, the anti-CCL17 antibody of the invention is comprised in a pharmaceutical composition. The antibody as described herein may be incorporated into pharmaceutical compositions for use in the treatment of chronic pain as described herein.

In one embodiment, the pharmaceutical composition comprises an anti-CCL17 antibody according to the invention in combination with one or more pharmaceutically acceptable carriers and/or excipients. Such compositions comprise a pharmaceutically acceptable carrier as known and called for by acceptable pharmaceutical practice.

Pharmaceutical compositions may be administered by injection or continuous infusion (examples include, but are not limited to, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intraocular, and intraportal). In one embodiment, the composition is suitable for subcutaneous administration. Pharmaceutical compositions may be suitable for topical administration (which includes, but is not limited to, epicutaneous, inhaled, intranasal or ocular administration) or enteral administration (which includes, but is not limited to, oral, vaginal, or rectal administration).

The pharmaceutical composition may be included in a kit containing the antibody together with other medicaments, and/or with instructions for use. For convenience, the kit may comprise the reagents in predetermined amounts with instructions for use. The kit may also include devices used for administration of the pharmaceutical composition.

The terms “individual”, “subject” and “patient” are used herein interchangeably. The antibody described herein may also be used in methods of treatment. It will be appreciated by those skilled in the art that references herein to treatment refer to the treatment of established conditions. However, compounds of the invention may, depending on the condition, also be useful in the prevention of certain diseases. The anti- CCL17 antibody described herein is used in an effective amount for therapeutic, prophylactic or preventative treatment. A therapeutically effective amount of the anti- CCL17 antibody described herein is an amount effective to ameliorate or reduce one or more symptoms of, or to prevent or cure, the disease.

Production methods

Antigen binding proteins, including antibodies, may be prepared by any of a number of conventional techniques. For example, antigen binding proteins may be purified from cells that naturally express them (e.g., an antibody can be purified from a hybridoma that produces it), or produced in recombinant expression systems.

A number of different expression systems and purification regimes can be used to generate the anti-CCL17 antibody of the invention. Generally, host cells are transformed with a recombinant expression vector encoding the desired antigen binding protein. The expression vector may be maintained by the host as a separate genetic element or integrated into the host chromosome depending on the expression system. A wide range of host cells can be employed, including Prokaryotes (including Gram negative or Gram positive bacteria, for example Escherichia coli, Bacilli sp., Pseudomonas sp., Corynebacterium sp.), Eukaryotes including yeast (for example Saccharomyces cerevisiae, Pichia pastoris), fungi (for example Aspergilus sp.), or higher Eukaryotes including insect cells and cell lines of mammalian origin (for example, CHO, NSO, , PER.C6, HEK293, HeLa).

The host cell may be an isolated host cell. The host cell is usually not part of a multicellular organism (e.g., plant or animal). The host cell may be a non-human host cell.

Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian host cells are known in the art. The cells can be cultured under conditions that promote expression of the antigen binding protein using a variety of equipment such as shake flasks, spinner flasks, and bioreactors. The polypeptide is recovered by conventional protein purification procedures. Protein purification procedures typically consist of a series of unit operations comprised of various filtration and chromatographic processes developed to selectively concentrate and isolate the antigen binding protein. The purified antibody may be formulated in a pharmaceutically acceptable composition.

The indication

Chronic pain is a notoriously difficult indication to treat, with existing analgesics failing to provide adequate relief from pain in many, if not most, patients. In particular, pain medication typically comes with side effects (including central nervous system effects) that are not tolerable to patients. In addition, pre-clinical models of pain have many limitations and thus treatment success in these pain models does not always correlate with success in patients. As such there is a high attrition rate in the pain medication regulatory space.

In particular, chronic pain is pain that persists or recurs for longer than three months and includes for example, chronic primary pain, chronic cancer pain, chronic postsurgical or posttraumatic pain, chronic neuropathic pain, chronic headache or orofacial pain, chronic visceral pain and chronic musculoskeletal pain (Treede et al, 2015: A classification of chronic pain for ICD-11 : PAIN (lww.com)). Thus, in some embodiments, the subject has been suffering with the pain persisting or recurring for at least three months prior to the treatment method of the invention. In some embodiments, the subject has been suffering with the pain persisting or recurring for at least six months prior to the treatment method of the invention.

There is a very high unmet patient need for safe and efficacious treatment for management of chronic pain. In some embodiments, the chronic pain is chronic musculoskeletal pain or chronic neuropathic pain. All chronic pain, including for example osteoarthritic pain, can be of varying severity from mild through moderate to severe. However, the biggest burden of this disease lies in patients who suffer from pain that is described as moderate or severe, which can be in terms of pain intensity, pain-related distress and/or functional impairment. Thus, in some embodiments, the chronic pain is moderate to severe pain. In particular, in chronic pain, patients experiencing this type of moderate to severe pain are likely to have had an inadequate response to existing treatments including but not limited to non-steroidal anti-inflammatory drugs (NSAIDs), serotonin-uptake inhibitors (SRIs) and opioids, some which may also be associated with tolerability and safety issues such as dependence and central nervous system (CNS) side effects. There is a clear need for new treatment options that offer meaningful pain relief with a more benign safety profile better suited to longterm use.

Chronic musculoskeletal pain

In some embodiments, the chronic pain is chronic musculoskeletal pain. Chronic musculoskeletal pain (also sometimes referred to as chronic nociceptive pain) is defined as chronic pain arising from musculoskeletal structures such as bones or joints. In the most recent edition of the International Classification of Diseases, ICD-10, chronic musculoskeletal pain can be categorized as primary chronic musculoskeletal pain, where there is unknown etiology in a particular location such as back pain or periarticular pain, or secondary chronic musculoskeletal pain where the pain is related to known pathological conditions affecting the muscles, bones or joints such as osteoarthritis, inflammatory arthritis and disease of connective tissue (Serge et al, 2019: The IASP cj assificafion of chronicjiain for^^

Examples of chronic musculoskeletal pain include such pain from persistent inflammation (e.g. due to infection, crystal deposition, auto-immune and auto-inflammatory disorders), such pain associated with structural changes (e.g. associated with osteoarthritis, spondylosis or injury), and such pain associated with disease of the central nervous systems (e.g. associated with Parkinson’s Disease, multiple sclerosis or peripheral neurological disease) (Perrot et al, 2019 PAIN: The IASP classification of chronic pain for ICD-11: chronic . : PAIN (lww.com)) .

In some embodiments, the chronic musculoskeletal pain comprises osteoarthritic pain. Osteoarthritic pain (often referred to as OA pain) is caused when the cartilage cushioning the joint between two or more bones wears away and there is direct contact and rubbing of opposing bones. This type of pain can affect many joints in the body, but typically occurs in the joints of the hand, the hip or the knee. Clearly, osteoarthritic pain in the large joints of the hip and knee in particular can cause significant disability for patients in that they are not able to have normal walking function. Thus, in some embodiments, the osteoarthritic pain is in a hip or a knee joint. Alternatively, the osteoarthritic pain is in a hip joint and a knee joint. Alternatively, the osteoarthritic pain is in a hip joint and a hand joint. Alternatively, the osteoarthritic pain is in a knee joint and a hand joint. Alternatively, the osteoarthritic pain is in a hip joint and a knee joint and a hand joint. For pain in the hands and knees, as well as for many other chronic musculoskeletal pains, topical NSAIDs are first line treatment. For hip OA and more severe chronic musculoskeletal pain more generally, systemic NSAIDs such ibuprofen and COX-2 inhibitors are used. Intraarticular glucocorticoid injections may also be used for hip and knee OA. If these prove to be insufficient or poorly tolerated, further options for chronic musculoskeletal pain including OA pain include paracetamol, antidepressants, topical capsaicin (knee), intra-articular hyaluronic acid (knee) and opioids. For OA of the hip and knee associated with severe pain, significant functional impairment and diminished quality of life, joint replacement surgery can provide benefit.

In some embodiments, the chronic musculoskeletal pain comprises lower back pain, (or chronic low back pain). Lower back pain (often referred to as LBP) has been defined by the Global Burden of Disease studies as pain in the area on the posterior aspect of the body from the lower margin of the twelfth ribs to the lower gluteal folds with or without pain referred into one or both lower limbs that lasts for at least one day. The cause of lower back pain can be multifactorial and can sometimes be challenging to diagnose, but can range from mechanistic in nature, caused by a disruption in the way components of the back (including spine, muscle, intervertebral discs and nerves) fit together and move, to inflammatory, degenerative, or involve other reasons such as osteoporosis, infection, tumors, or autoimmune diseases

Chronic neuropathic pain

In some embodiments, the chronic pain is chronic neuropathic pain. Chronic neuropathic pain is defined as chronic pain caused by a lesion or disease of the somatosensory nervous system, may be spontaneous or evoked, as an increased response to a painful stimulus (hyperalgesia) or a painful response to a normally nonpainful stimulus (allodynia) (Scholz et al, 2019: Tire .I SP.cias ifi.cafion.of chronic .pain for .ICO- 1.1.: .chro c neuropathic pa - Neuropathic pain is often treated with a multi-pronged approach,

including physical therapy, but typical pharmaceutical options include anti-seizure drugs such as Gabapentin, Pregabalin, Topiramate, Carbamazepine, or Lamotrigine; or antidepressants such as Amitriptyline, Nortriptyline, Venlafaxine or Duloxetine. These medications are often reported to cause side effects which may be worse than the neuropathic pain. Generally, neuropathic pain responds poorly to standard pain treatments and can often get worse instead of better over time. In addition, with an ageing population it is expected that the burden of chronic pain will continue to rise.

Chronic neuropathic pain can be categorized as chronic central neuropathic pain or chronic peripheral neuropathic pain. Examples of chronic central neuropathic pain include chronic central neuropathic pain associated with spinal cord injury, chronic central neuropathic pain associated with brain injury, chronic central post-stroke pain and chronic central neuropathic pain associated with multiple sclerosis. In some embodiments, the chronic neuropathic pain comprises chronic peripheral neuropathic pain. Examples of chronic peripheral neuropathic pain include trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy (such as diabetic peripheral neuropathic pain), postherpetic neuralgia and painful radiculopathy.

In some embodiments, the chronic peripheral neuropathic pain comprises diabetic peripheral neuropathic pain. Diabetic peripheral neuropathic pain (often referred to as DPNP) is a long-term complication of both type 1 and type 2 diabetes mellitus that afflicts a large proportion of diabetic patients. Approximately half of DPNP patients experience ongoing pain despite treatment and a similar proportion experience burning pain all the time. First line treatments include anticonvulsants such as gabapentin and pregabalin and SNRIs such as duloxetine. Tricyclic antidepressants may also be used. If these prove to be insufficient or poorly tolerated, opioids may be considered although their use is discouraged, especially as their long-term use is hampered by safety and tolerability issues.

In some embodiments, the chronic peripheral neuropathic pain comprises trigeminal neuralgia. Trigeminal neuralgia (often referred to as TGN) is a manifestation of orofacial neuropathic pain restricted to one or more divisions of the trigeminal nerve. The pain is recurrent, abrupt in onset and termination, triggered by innocuous stimuli and typically compared to an electric shock or described as shooting or stabbing. Some patients experience continuous pain between these painful paroxysms. In some embodiments, the chronic peripheral neuropathic pain comprises postherpetic neuralgia. Postherpetic neuralgia (often referred to as PTN) is defined as pain persisting for > 3 months following the onset or healing of herpes zoster (also known as shingles). The innervation territory of the first (ophthalmic) branch of the trigeminal nerve and thoracic dermatomes are the locations most frequently affected by chronic pain after herpes zoster. Postherpetic neuralgia may emerge in continuation of the acute pain associated with the skin rash or develop after a painless interval.

Treatment

As disclosed herein, it was found that administration of the antibody of the invention provided osteoarthritic pain patients with efficacious and safe treatment, and this can be applied to many other chronic pain conditions including chronic musculoskeletal pain and other chronic pain indications. Thus, in some embodiments, the method for treating chronic pain is treating chronic pain associated with chronic musculoskeletal pain or chronic peripheral neuropathic pain. Further, in some embodiments, the method for treating chronic pain is treating chronic pain associated with osteoarthritic pain, diabetic peripheral neuropathic pain, lower back pain, trigeminal neuralgia or postherpetic neuralgia.

It will be appreciated by those skilled in the art that references herein to treatment refer to the treatment of established chronic pain. However, treatment may also include prevention of recurrence of chronic pain. A therapeutically effective amount of the antibody described herein is an amount effective to ameliorate or reduce or prevent chronic pain.

Measuring pain levels can be challenging and tends to require on self-reporting of pain levels by patients. For example, average daily pain score or worst daily pain score can be self-reported by patients on a 11 -point numerical score, where scores range from 0 (no pain, stiffness or difficulty) to 10 (worst imaginable pain, stiffness or difficulty), typically when measured over the seven days prior to dosing (also known as weekly average/worst pain score). Average daily pain intensity score can also be self-reported by patients on a 11 -point numerical score, where scores range from 0 (no pain, stiffness or difficulty) to 10 (worst imaginable pain, stiffness or difficulty), typically when measured over the 24 hours at screening. Thus, in some embodiments, moderate to severe pain is wherein the subject has an average daily pain intensity score (measured over the preceding 24 hours) or average daily pain score (measured over preceding 7 days, i.e. taking an average of the average daily intensity pain score over the preceding 7 hours) of >4 and <9 on the 11 -point Numerical Rating Scale. In some embodiments, the subject has an average daily pain or average daily pain intensity score of >7 on the 11 -point Numerical Rating Scale., and in some embodiments the subject has an average daily pain score of <7 on the 11-point Numerical Rating Scale.

In some embodiments, the subject has an average daily pain or average daily pain intensity score of between 4 and 9; between 5 and 9; between 6 and 9; between 7 and 9; or between 8 and 9 on the 11-point Numerical Rating Scale. In some embodiments, the subject has an average daily pain score or average daily pain intensity score of between 4 and 8; between 5 and 8; between 6 and 8; or between 7 and 8; or between 8 and 9 on the 11-point Numerical Rating Scale. In some embodiments, the subject has an average daily pain score or average daily pain intensity score of between 4 and 7; between 5 and 7; or between 6 and 7 on the 11-point Numerical Rating Scale. In some embodiments, the subject has an average daily pain score or average daily pain intensity score of between 4 and 5; or between 4 and 6; or between 5 and 6 on the 11-point Numerical Rating Scale.

Pain levels may also be measured by WOMAC (Western Ontario McMasters Osteoarthritis Index) scores, which is a standardized questionnaire commonly used in the art to assess pain, stiffness and function in patients with a range of pain conditions including osteoarthritic pain, back pain, rheumatoid arthritis pain, juvenile rheumatoid arthritis pain, pain associated with systemic lupus erythematosus and fibromyalgia. Typically, WOMAC scores are made over a 7 day recall period. Higher WOMAC scores indicate worse pain, stiffness, and functional limitations. The WOMAC measures five items for pain, two for stiffness), and 17 for functional limitation which can each be rated on a the 11-point Numerical Rating Scale compared to baseline. Physical functioning questions cover everyday activities such as stair use, standing up from a sitting or lying position, standing, bending, walking, getting in and out of a car, shopping, putting on or taking off socks, lying in bed, getting in or out of a bath, sitting, and heavy and light household duties.

Pain levels may also be measured by a patient global assessment of disease activity (PtGA) and/or a physician global assessment of disease activity (PhGA). This assessment tends to be a single question asking a patient in the case of PtGA, or physician in the case of PhGA, to answer out of 5, out of 10, or out of 100, a question such as “how is your/your patient’s disease?” or “how active is your/your patient’s disease?”, with a higher score indicating a worse disease condition.

Sleep disturbance is also another parameter that can indicate the level of pain in a subject, as generally the worst the pain level is in a chronic pain patient, the more their sleep will be disturbed. Sleep disturbance can be measured in subject using the PROMIS-Sleep Disturbance Short Form which is a patient recorded outcome instrument designed to assess self-reported sleep disturbance for which the recall period is the past seven days, SF-36 which is a 36 item questionnaire assessing health-related quality of life scored on a scale of 0-100 with higher scores indicating a higher quality of life, PGIC which is a patient global impression of overall change in the severity of sleep disturbance, or PGIS which is a patient global impression of the overall severity of overall sleep disturbance severity in the past 7 days.

Pain levels may also be measured using McGill pain questionnaire Short Form is a 22-item questionnaire, which has been developed and validated to evaluate multi-dimensional pain over time. The questionnaire consists of 22 descriptors that are rated on an intensity scale from 0 = none to 10 = worse possible.

Pain levels may also be measured using the Brief Pain Inventory Short Form (BPI-SF). The BPI (SF) allows patients participants to rate the severity of their pain and the degree to which that pain interfered with multiple and common dimensions of feeling and function. The BPI assesses pain severity by measuring pain at its “worst”, “least”, “average”, and “now”. Furthermore, the BPI measures how much pain has interfered with seven daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others and sleep. The BPI pain interference score is scored as the mean of the seven interference items. This mean can be used if at least four of seven items have been completed on a given administration.

Step count (i.e. the number of steps taken by a subject in a day) can also give an indication into a subject’s level of pain, with patients who are in pain tending to move less having decreased physical activity. Thus, patients suffering from chronic pain tend to register lower step counts (e.g. with a device such as a pedometer or accelerometer in a wearable or handheld device). Therefore, in some embodiments, treatment results in at least one of: a) a reduction in the subject’s average daily pain and/or worst daily pain score on the 11 -point Numerical Rating Scale b) a reduction in the subject’s average daily pain intensity and/or worst daily pain intensity on the 11 -point Numerical Rating Scale c) a reduction in the subject’s WOMAC pain score and/or WOMAC function score d) a reduction in the subject’s WOMAC pain subscale score and/or WOMAC function subscale score e) a reduction in the subject’s PtGA and/or PhGA score f) a reduction in the subject’s sleep disturbance g) a reduction in at least one of the subject’s Short-Form McGill Pain Questionnaire scores h) a reduction in the subject’s Brief Inventory Short Form pain severity and/or pain interference scores i) an increase in the subject’s daily step count all compared to baseline (i.e. prior to or without said treatment). Alternatively, these reductions may be as compared to placebo treatment. Optionally, these reductions in pain measurement are recorded after at least 4 weeks of treatment, at least 8 weeks of treatment, or at least 12 weeks of treatment. These reductions in pain measurement may be recorded in subjects in the absence of treatment discontinuations and/or the use of prohibited pain medications.

In some embodiments the treatment may result in a reduction by at least 1, at least 2 points, at least 3 point, at least 4 points or at least 5 point, in the subject’s average daily pain score, and/or worst daily pain score on the 11 -point Numerical Rating Scale compared to baseline. In some embodiments, the subject’s average daily pain score and/or worst daily pain score after treatment may be less than 8, less than 7, less than 6, less than 5, less than 4, or less than 3, on the 11-point Numerical Rating Scale. In some embodiments, the subject’s average daily pain score and/or worst daily pain score on the 11-point Numerical Rating Scale may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of decreasing average daily pain score and/or worst daily pain score in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

In some embodiments the treatment may result in a reduction by at least 1, at least 2 points, at least 3 points, at least 4 points, or at least 5 points in the subject’s average daily pain intensity and/or worst daily pain intensity on the 11 -point Numerical Rating Scale compared to baseline. In some embodiments, the subject’s average daily pain intensity and/or worst daily pain intensity after treatment may be less than 8, less than 7, less than 6, less than 5, less than 4, or less than 3, on the 11-point Numerical Rating Scale. In some embodiments, the subject’s average daily pain intensity and/or worst daily pain intensity on the 11-point Numerical Rating Scale may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of decreasing average daily pain intensity and/or worst daily pain intensity in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

Further, in some embodiments, where WOMAC pain and function scores are measured on a 11-point Numerical Rating Scale, treatment results in at least a 1 point, 2 point, 3 point, 4 point or 5 point reduction in the subject’s WOMAC pain score and/or WOMAC function score compared to baseline. In some embodiments, the subject’s WOMAC pain score and/or WOMAC function score after treatment may be less than 8, less than 7, less than 6, less than 5, less than 4, or less than 3, on the 11-point Numerical Rating Scale. In some embodiments, the subject’s WOMAC pain score and/or WOMAC function score on the 11-point Numerical Rating Scale may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of decreasing WOMAC pain and/or function scores in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

Further, in some embodiments, where WOMAC pain and function subscale scores are measured on a 11-point Numerical Rating Scale treatment results in at least a 1 point, 2 point, 3 point, 4 point or 5 point reduction in the subject’s WOMAC pain subscale score and/or WOMAC function subscale score compared to baseline. In some embodiments, the subject’s WOMAC pain subscale score and/or WOMAC function subscale score after treatment may be less than 8, less than 7, less than 6, less than 5, less than 4, or less than 3, on the 11 -point Numerical Rating Scale. In some embodiments, the subject’s WOMAC pain subscale score and/or WOMAC function subscale score on the 11 -point Numerical Rating Scale may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of decreasing WOMAC pain and/or function subscale scores in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

Further, in some embodiments, where PtGA scores are measured on a 5 -point Numerical Rating Scale treatment results in at least a 0.5 point, 1 point, 1.5 point, 2 point or 2.5 point reduction in the subject’s PtGA score compared to baseline. In some embodiments, the subject’s PtGA score after treatment may be less than 4, less than 3.5, less than 3, less than 2.5, less than 2, or less than 1.5. In some embodiments, the subject’s PtGA score may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of decreasing PtGA scores in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

Further, in some embodiments, where PhGA scores are measured on a 11 -point Numerical Rating Scale treatment results in at least a 1 point, 2 point, 3 point, 4 point or 5 point reduction in the subject’s PhGA score compared to baseline. In some embodiments, the subject’s PhGA score after treatment may be less than 8, less than 7, less than 6, less than 5, less than 4, or less than 3. In some embodiments, the subject’s PhGA score may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of decreasing PhGA scores in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

Further, in some embodiments, the subject’s sleep disturbance score may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of reducing the sleep disturbance score in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

Further, in some embodiments, where Short-Form McGill Questionnaire scores are measured on a 11 -point Numerical Rating Scale treatment results in at least a 1 point, 2 point, 3 point, 4 point or 5 point reduction in at least one of the subject’s Short-Form McGill Questionnaire scores compared to baseline. In some embodiments, at least one of the subject’s Short-Form McGill Questionnaire scores after treatment may be less than 8, less than 7, less than 6, less than 5, less than 4, or less than 3. In some embodiments, at least one of the subject’s Short-Form McGill Questionnaire scores may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of decreasing at least one of the subject’s Short- Form McGill Questionnaire scores in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

Further, in some embodiments, where Brief Inventory Short Form pain severity and/or pain interference scores are measured on a 11 -point Numerical Rating Scale treatment results in at least a 1 point, 2 point, 3 point, 4 point or 5 point reduction in the Brief Inventory Short Form pain severity and/or pain interference scores compared to baseline. In some embodiments, the Brief Inventory Short Form pain severity and/or pain interference scores after treatment may be less than 8, less than 7, less than 6, less than 5, less than 4, or less than 3. In some embodiments, the Brief Inventory Short Form pain severity and/or pain interference scores may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to baseline. As such, the invention also provides for a method of decreasing the Brief Inventory Short Form pain severity and/or pain interference scores in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention.

Optionally, all of these reductions in pain measurements, any of: the subject’s average daily pain and/or worst daily pain on the 11-point Numerical Rating Scale, the subject’s average daily pain intensity and/or worst daily pain intensity on the 11-point Numerical Rating Scale, the subject’s WOMAC pain score and/or WOMAC function score, the subject’s WOMAC pain subscale score and/or WOMAC function subscale score, the subject’s PtGA and/or PhGA score, the subject’s sleep disturbance, at least one of the subject’s Short-Form McGill questionnaire scores or the Brief Inventory Short Form pain severity and/or pain interference scores are recorded after at least 4 weeks of treatment, at least 8 weeks of treatment, or at least 12 weeks of treatment.

Further, in some embodiments, after treatment with the antibody of the invention the subject’s step count may increase by at least 500 steps, 1000 steps, 1500 steps, 2000 steps, 2500 steps, 3000 steps, 3500 steps, 4000 steps, 4500 steps or 5000 steps a day compared to baseline. As such, the invention also provides for a method of increasing step count in a human subject suffering from chronic pain, the method comprising administering to a subject suffering from chronic pain a therapeutically effective amount of the antagonistic anti-CCL17 antibody of the invention. Optionally, this increase in step count is recorded after at least 4 weeks of treatment, at least 8 weeks of treatment or at least 12 weeks of treatment.

In some embodiments, treatment results in a reduction in the use of other analgesic medications (often referred to as “rescue medication”) by the subject during the treatment period. For example, in some cases, there will be a reduction in the use of paracetamol (also known as acetaminophen) by the subject. Such a reduction may comprise a reduction in the number of incidences where paracetamol is used, in the number of days where paracetamol is used, in the number of doses of paracetamol taken each day, or the dosage amount of paracetamol that is used over the treatment period. In some embodiments, treatment also comprises administration of paracetamol at a maximum dose of 3g per day.

It is also a goal of treatment to provide clinically meaningful analgesia coupled with a safety profile devoid of CNS side effects. The invention provides for a treatment that is peripherally restricted, thus no centrally-mediated side effects would be expected (in contrast to centrally acting analgesics such as opioids). Centrally-mediated side effects may also be known as central nervous system effects. For example, central nervous system effects may include effects divided into three groups. The first group includes effects that lower the level of consciousness-sedation, drowsiness and sleep disturbance. The second group affects the thinking process and the ability to react-cognitive impairment, psychomotor impairment, delirium, hallucinations, dreams and nightmares. The third group is of the direct toxic effects of opioids on neurons and includes myoclonus, hyperalgesia and tolerance.

As such, in some embodiments, the subject receiving treatment experiences no central nervous system effects, no adverse events, no changes in baseline in key laboratory parameters and/or no NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) grade >2 hematological/clinical chemistry abnormalities.

An adverse event may be any undesirable experience associated with use of a medicinal product in a patient. An adverse event may be defined as a serious adverse event if the event is death, life-threatening, requires hospitalization, leads to disability or permanent, leads to a congenital anomaly or birth defect, or requires intervention to prevent permanent impairment or damage. Adverse events may be adverse events of special interest if it is a serious infection, an opportunistic infection, TB or TB re-activation, a serious hypersensitivity reaction or an injection site reaction.

The antibody of the invention can be particularly useful in subjects who are non-responsive to, refractory to, and/or contraindicated for, another analgesic drug including non-steroidal anti-inflammatory drugs (NSAIDs), serotonin-uptake inhibitors, and/or opioids. Thus, in some embodiments, the subject is non-responsive to, refractory to, and/or contraindicated for, another analgesic drug including non-steroidal anti-inflammatory drugs (NSAIDs), serotonin-uptake inhibitors, and/or opioids. Opioids may include hydrocodone, oxycodone, percocet, morphine, meperidine, hydromorphone, fentanyl, and methadone

Given the particularly undesirable side effects of opioids (including central nervous system effects), in some embodiments, the subject is non-responsive, refractory to, contraindicated for and/or otherwise unwilling to use opioid treatment for their pain. In some embodiments, the antibody of the invention is used in absence of an opioid to treat chronic pain and/or to avert opioid addiction in the subject. Thus, in another aspect of the invention, there is provided a method for treating chronic pain whilst avoiding opioid side effects and/or addiction, comprising administering to a human subject suffering from chronic pain a therapeutically effective amount of an antagonistic anti-CCL17 antibody. Again, it will be clear to the skilled person that all described embodiments further defining the antibody, pharmaceutical composition, production methods, indication, treatment, and administration will all equally apply to these aspects.

Administration

As is known in the art, antibody treatments are typically administered systemically, including intravenously, subcutaneously or nasally. In some embodiments, the antibody is comprised in a composition which is administered subcutaneously. In some embodiments, the subcutaneous composition is administered to the abdomen and/or the thigh of the subject. The skilled person will understand that the term “dose” in the context of a composition in this invention refers to the therapeutically effective amount of the antagonistic anti-CCL17 antibody.

In some embodiments, the composition is administered at least once at a dose of between 25mg to lOOOmg, between 30mg and 750mg, between 50mg to 500mg, or between 60mg to 480mg. In some embodiments, the composition is administered at least once at a dose of 60mg, 240mg, 360mg or 480mg. As such, the present invention also provides a pharmaceutical composition comprising between 25mg to lOOmg, between 30mg and 750mg, between 50mg to 500mg, between 60mg to 480mg, about 60mg, 240mg, 360mg or 480mg of an antagonistic anti-CCL17 antibody comprising CDHR1, CDHR2, CDHR3, CDLR1, CDRL2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively. In some embodiments, this composition is suitable for subcutaneous administration.

Whilst regular treatment may be needed, patient adherence to treatment can be challenging in some cases and thus it is desirable to avoid the need for e.g. daily dosing. Thus, in some embodiments, wherein the composition is administered more than once, the administration is about weekly or about every two weeks. By “about weekly” is meant every 7 days, +/- 2 days and by about every two weeks is meant every 14 days, +/- 2 days. For the avoidance of doubt, about weekly includes exactly weekly (i.e. every 7 days) and about every two weeks includes exactly every two weeks (i.e. every 14 days). In other embodiments, the dosing may be less frequent then about every two weeks: including, but not limited to, about every three weeks, four weeks, five weeks or six weeks, or about monthly or bimonthly. Again “about” may include a tolerance of +/- 2 days. Thus, in some embodiments, the composition is administered about weekly at a dose of between 25mg to lOOOmg, between 50mg to 500mg, or between 60mg to 480mg. In some embodiments, the composition is administered about weekly at a dose of 60mg, 240mg, 360mg or 480mg. In some embodiments, the composition is administered about every two weeks at a dose of between 25mg to lOOOmg, between 50mg to 500mg, or between 60mg to 480mg. In some embodiments, the composition is administered about every two weeks at a dose of 60mg, 240mg, 360mg or 480mg. In some embodiments, the composition is administered about weekly at a dose of 60mg, about weekly at a dose of 240mg, about every two weeks at a dose of 240mg, or about weekly at a dose of 360mg.

In some embodiments, the treatment period is at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks or at least 24 weeks. In some embodiments, the composition is administered about weekly for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks or at least 24 weeks; or about every two weeks for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks or at least 24 weeks.

To allow for effective delivery of the composition, subcutaneous administration of a fixed dose can be achieved using an autoinjector or prefilled syringe, which are both highly convenient for subjects and for healthcare providers and systems. Thus, in some embodiments the composition is administered using an autoinjector or prefilled syringe. It will be clear to the skilled person that the invention also provides for an autoinjector or prefilled syringe comprising the antibody of the invention for use in treating chronic pain as described herein.

EXAMPLES

EXAMPLE 1 - Acute pain PAINCART study

A double-blind study was conducted between October 2019 and September 2021 to evaluate whether an antibody according to the invention was effective in relieving elicited (acute) pain in healthy participants. The study was split into three treatment periods and two treatment arms where either placebo (normal saline, i.e. 0.9% sodium chloride) or the lead anti-CCL17 antibody (3mg/kg) were administered by IV. As defined above, and for the avoidance of doubt throughout the Examples described herein, this lead anti-CCL17 antibody is an antagonistic anti-CCL17 IgG2o antibody having the heavy chain of SEQ ID NO: 1 and the light chain of SEQ ID NO: 2, including the heavy chain variable region (VH) of SEQ ID NO: 3 and the light chain variable region (VL) of SEQ ID NO: 4, and CDHR1, CDHR2, CDHR3, CDLR1, CDLR2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively. This antibody also comprises seven Fc-disabling mutations V234A, G237A, P238S, H268A, V309L, A33 OS and P33 IS according to the EU numbering.

In the first treatment arm, participants received a single dose of placebo in treatment period 1, followed by the lead anti-CCL17 antibody in treatment period 2, followed by the lead anti-CCL17 antibody in treatment period 3. There was a washout period of at least 4 weeks between dosing (i.e. Day 1) in each of the study periods.

In the second treatment arm, participants received a single dose of the lead anti-CCL17 antibody in treatment period 1, followed by placebo in treatment period 2, followed by placebo in treatment period 3. There was a washout period of at least 4 weeks between dosing (i.e. Day 1) in each of the study periods.

Healthy participants who were receiving either the lead anti-CCL17 antibody or placebo underwent three different types of tests to mimic different types of (acute) pain:

1. Heat/burn pain test: a small heating device was placed on the skin of the upper back. The device heats up slowly. Participants were asked to press a button when the heat became painful. The test was repeated three times on the same skin area. Thermal pain tests were performed first on normal skin contralateral to site of UVB irradiation then on UVB irradiated skin. A 30 x 30 millimeter(mm) thermode was placed on participant’s back. Initial temperature of the thermode was 32 degree Celsius (C) and increased by 0.5 degree C per second until the participant indicated the stimulus as painful (pain detection threshold indicated with pushing a button on a hand-held feedback control or when a temperature of 50 degree C was reached). AUC was derived from temperature versus (vs) time of study period, calculated via trapezoidal method and was normalized. Baseline was mean value of two assessments taken prior to dosing in each session (Day 1). Posterior Median Ratio to Baseline was derived by taking ratio of posterior median of post-Baseline visit value to posterior median of Baseline value.

2. Cold pain test: Participants were asked to place their hand in lukewarm water for about two minutes. The same hand was then placed in freezing cold water. Participants removed their hand after two minutes or when the pain became unbearable. Participants put nondominant hand in water bath at 35+/-0.5degree C. Blood pressure cuff on upper arm inflated to 20mm of Mercury below resting diastolic pressure. Participants then removed hand and directly placed it in similarsized bath (1.0+-0.5degree C). Participants indicated increase in pain intensity by moving electronic Visual Analogue scale (eVAS) slider when pain detection threshold was reached (first change in sensation from cold non-painful to painful). When pain tolerance was reached, Participants removed their hand and blood pressure cuff was deflated. AUC was derived as time to intolerable pain vs time of study period, calculated via trapezoidal method and was normalized. Baseline was mean value of two assessments taken prior to dosing in each session (Dayl). Posterior Median Ratio to Baseline derived by ratio of posterior median of postBaseline visit value to posterior median of Baseline value.

3. Electrical pain test: Two wires were placed on the skin below the knees. Participants received small electric shocks which increased in power. The test was stopped when the pain became unbearable. Two electrodes were placed on clean (scrubbed) skin overlying left tibial bone 100 mm distal from caudal end of patella to detect cutaneous electrical pain. Each stimulus (10-Hertz [Hz] tetanic pulse with duration of 0.2 milliseconds) was controlled by a computer-controlled constant current stimulator. Pain intensity after each stimulation was measured using eVAS, until pain tolerance level was reached, or maximum of 50 milliamper (mA) was reached. AUC was derived from mA versus time of study period, calculated via trapezoidal method and was normalized. Baseline was defined as mean value of two assessments taken prior to dosing in each session (Day 1). Posterior Median Ratio to Baseline derived by ratio of posterior median of post-Baseline visit value to posterior median of Baseline value.

In each part of the study, study doctors measured participants’ elicited pain levels at baseline (on Day 1 before the participants received the study medicine) and on Day 1, Day 2, Day 8, and Day 15 (after the participants received the study medicine). For each pain test, the results recorded on the different days after the participants received the study medicines were combined and averaged at the end of the study. The average result after the participants received the study medicines was divided by the average result recorded at baseline (i.e. the average ratio to baseline) which is summarized below in Table 2. In conclusion, the lead anti-CCL17 antibody was not effective in relieving elicited acute pain caused by the pain tests in healthy participants. The study was terminated due to meeting protocol defined futility.

Table 2

*Number of participants who met the criteria that were considered for the respective pain tests.

EXAMPLE 2 - Phase 1 study in healthy volunteers and osteoarthritic pain patients

This study was a 2-part, phase I, randomized, double blind, placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and target engagement of single ascending intravenous doses and a single subcutaneous (SC) dose of the lead anti-CCL17 antibody in healthy participants (Part A) and to additionally assess the safety and efficacy of repeat SC doses in participants with chronic pain associated with osteoarthritis of the knee (Part B).

In Part A of this study, the lead anti-CCL17 antibody was administered to 6 cohorts of healthy male and female (of non-reproductive potential) participants. The dose range evaluated was 0.1 mg/kg to 10 mg/kg via a 1-hour intravenous infusion (Cohorts 1 to 5) and 3 mg/kg (up to a maximum dose of 240 mg) via SC injection (Cohort 6). No clinically significant change was observed for haematology, clinical chemistry or in urinalysis. No clinically significant safety signal was observed for vital signs. No clinically significant arrhythmia was recorded on telemetry and no clinically significant ECG abnormality or QTcF prolongation was recorded on any 12-lead ECG.

Part B of the study evaluated the efficacy (OA chronic pain), safety, tolerability, pharmacokinetics, target engagement, and immunogenicity of the lead anti-CCL17 antibody in participants with OA of the knee randomized (1: 1) where participants received weekly subcutaneous doses of 240 mg the lead anti-CCL17 antibody or placebo for 8 weeks, with a 12-week follow-up period. The co-primary efficacy endpoints are the change from baseline to Week 8 in average knee pain score and worst knee pain score. Participants completed a daily electronic diary to record pain on a numerical rating scale; and all nonstudy pain medications were prohibited (until Day 71). Exploratory efficacy endpoints include change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores. Data were summarized descriptively and a Bayesian repeated measures model using a non-informative prior was fitted to change from baseline data and 95% credible intervals (CrI) were calculated. Safety data were summarized as adverse events (AEs).

Demographic and clinical characteristics were broadly comparable between treatments; however, more participants in the lead anti-CCL17 antibody group were male (67% vs. 46%) and Kellgren and Lawrence grade 4 (33% vs. 17%), as can be seen in Table 3.

Table 3. Baseline demographic and clinical characteristics of the OA study population

^a Assessed using an 11 -point numerical rating scale, where scores range from 0 (no pain/stiffness/difficulty) to 10 (worst imaginable pain/stiffness/difficulty). BMI, body mass index; OA, osteoarthritis; SC, subcutaneous; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Measurement of pain

All Patient Reported Outcomes (PROs) were administered before laboratory assessments and other procedures or consultations to avoid influencing the participants’ perception of OA pain:

Daily pain scores

Participants recorded pain intensity scores daily (evening time) in a digital tool for the 7 consecutive days preceding dosing (during screening) and then daily from Day 1 to Day 84 (12 weeks). They assessed, over the past 24 hours, both: average knee pain intensity in index knee worst knee pain intensity in index knee using the NRS, scoring pain on an 11 -point scale (0-10), with 0 =no pain, and 10 = pain as bad as you can imagine. Participants were instructed to complete the pain NRS questionnaire at approximately the same time each day. Participants also recorded any rescue paracetamol/acetaminophen (if taken) for knee OA over the past 24 h on a digital tool.

WOMAC osteoarthritis index

WOMAC Index 3.1 was completed by participants on paper questionnaires. The questionnaire covers pain, stiffness and function related to osteoarthritis in the index knee over the past 7 days. Participants were to respond to each question using an 11 -point NRS (0-10), with 0 = no pain/stiffness/difficulty, and 10 = extreme pain/stiffness/difficulty. They were required to take at least 5 minutes to complete the questionnaire. Patient and physician global assessments of disease (PtGA and PhGA)

The PtGA and PhGA were completed on paper questionnaires by participants and physicians.

The patient global assessment asked the study participant: “Considering all the ways in which your knee osteoarthritis affects you, how do you feel your knee osteoarthritis is doing today?” Participants were to respond on a Likert scale ranging from 1-5, where 1 = very good (no symptom and no limitation of normal activities), 2 = good (mild symptoms and no limitation of normal activities), 3 = fair (moderate symptoms and limitation of some normal activities), 4 = poor (severe symptoms and inability to carry out most normal activities), and 5 = very poor (very severe symptoms and inability to carry out all normal activities). Higher scores indicated worse condition.

The physician global assessment asked the physicians: “What is your assessment of the patient’s current disease activity?” Physicians were to respond by using an 11-point NRS scale (0-10), with 0 = none, and 10 = extremely active. Where possible, the same physician performed all disease assessments for a particular individual participant.

Measurement of safety

The safety assessments were the monitoring of AEs, clinical laboratory tests, vital signs, ECGs, physical examinations, echocardiograms and skin reactions. The investigator or site staff were responsible for detecting, documenting and reporting events that met the definition of an AE or SAE. AE information volunteered by the participant, discovered by investigator questioning or detected by other means was collected from the start of study intervention until the follow-up contact. The following information on AEs was obtained:

• Duration (start and stop dates).

• Severity (mild, moderate, severe).

• Causality (reasonable possibility yes/no).

• Actions taken and outcome.

Efficacy results

Participants were recorded their daily pain intensity scores (evening time) in a digital tool for the 7 consecutive days preceding dosing (during screening) and then daily from Day 1 to Day 84 (12 weeks). For each participant, the mean pain score over the 7 days prior to each visit was calculated as the average pain score; similarly the worst value over the 7 days prior to each visit was assigned as the worst pain score. Baseline scores for each participant were assigned based on the 7 days prior to the first dosing visit.

Average Knee Pain Score

Median Average knee pain scores decreased consistently from Baseline throughout the study, with larger decreases observed in participants receiving 240 mg SC lead anti-CCL17 antibody than in participants receiving placebo (FIG. 1). The posterior median difference (95% credible interval [CrI]) between 240 mg SC lead anti-CCL17 antibody and placebo in the change from baseline in Average Knee Pain Intensity at Week 8 (i.e. the average daily pain score) was -1.18 (-2.15, -0.20).

Worst Knee Pain Intensity

Median worst knee pain scores decreased consistently from Baseline throughout the study, with larger decreases in worst pain scores observed in participants receiving 240 mg SC lead anti-CCL17 antibody than in participants receiving placebo (FIG. 2). The posterior median difference (95% CrI) between 240 mg SC lead anti-CCL17 antibody and placebo in the change from baseline in Worst Knee Pain Intensity at Week 8 (i.e. the average worst pain score) was -1.09 (-2.29, 0.12).

WOMAC Osteoarthritis Index

Larger decreases from baseline in median WOMAC pain scores were observed in participants receiving 240 mg SC lead anti-CCL17 antibody than in participants receiving placebo (FIG. 3). The posterior median difference (CrI) between 240 mg SC lead anti- CCL17 antibody and placebo in the change from baseline in WOMAC Pain Score at Day 57 was -1.41 (-2.35, -0.46). Similar results were seen for WOMAC function scores (FIG. 5); the posterior median difference (CrI) between 240 mg SC lead anti-CCL17 antibody and placebo in the change from baseline in WOMAC Function Score at Day 57 was -1.29 (-2.28, -0.29). The effect of 240 mg SC lead anti-CCL17 antibody compared to placebo on WOMAC stiffness (FIG. 4) was smaller than that observed for WOMAC Pain Score and WOMAC Function Score; the posterior median difference (CrI) between 240 mg SC lead anti-CCL17 antibody and placebo in the change from baseline in WOMAC Stiffness Score at Day 57 was -0.57 (-1.71, 0.55). Patient Global Assessment of Disease

Results can be seen in FIG. 6. The posterior median difference (CrI) between 240 mg SC lead anti-CCL17 antibody and placebo in the change from baseline in PtGA was -0.3 (-0.6, 0.0).

Physician Global Assessment of Disease

There was no evidence of a difference between 240 mg SC lead anti-CCL17 antibody and placebo in the change from baseline in PhGA over time. At Day 57 the median change from baseline score was -2 in both treatment groups.

Safety results

Single doses of 0.1, 0.3, 1, 3, 10 mg/kg IV, and 240mg SC lead anti-CCL17 antibody were administered and well tolerated in part la in healthy participants.

Weekly doses of 240mg SC lead anti-CCL17 antibody were administered for eight weeks in part lb in participants with OA knee pain. More subjects reported injection site reactions (ISRs), and there were more total ISRs in the lead anti-CCL17 antibody group compared to the placebo group: 10(42%) & 24 lead anti-CCL17 antibody vs. 3(13%) & 4 placebo. All injection site reactions were non-serious and mild. There was insufficient evidence to determine if this imbalance was causally related to lead anti-CCL17 antibody.

In Part la and lb, no deaths, SAEs, or safety signals were identified. No serious AEs or deaths were reported.

Conclusion

Results from this study suggest that lead anti-CCL17 antibody may help to alleviate pain in patients with OA of the knee with favorable tolerability and safety.

EXAMPLE 3 - Phase 2 study in osteoarthritic (OA) pain

This is a Phase 2, dose-finding, multicentre, randomized, double-blind, parallel group, placebo-controlled study of the lead anti-CCL17 antibody in participants with moderate to severe knee OA pain to investigate the efficacy, safety, PK, TE and dose-exposure-target engagement-efficacy relationship of the lead anti-CCL17 antibody. Approximately 1050 adult subjects (ages 40 to 80 years) with chronic pain associated with knee osteoarthritis will be screened to achieve approximately 420 randomized participants. Screening will take place within a maximum of 35 days before randomisation. After undergoing the screening visit, a washout period for all pain medications is required prior to Day -7, consisting of 3 days or 5 half-lives, whichever is longer.

The total study period is up to 31 weeks which includes, up to a maximum of 5 weeks of screening period, 16 weeks of treatment period and 15 weeks of safety follow-up period (16 weeks from the last treatment dose). The approximate sample size is 420 participants. All participants will be treated for 16 weeks, however the primary efficacy endpoint evaluation will be at Week 12.

Participants will be randomized to one of 5 treatment arms. Specifically, placebo weekly, 360 mg weekly, 240 mg weekly, 240 mg every 2 weeks or 60 mg weekly. For the arm which receives 240 mg every 2 weeks, there will be alternate placebo administration every 2 weeks. Lead anti-CCL17 antibody or placebo will be administered as subcutaneous (SC) injection. Participants will be randomised in a 2: 1 : 1 : 1 : 1 ratio. Randomisation will be stratified by subject region (Japan, China and rest of the world) and average of daily pain score at baseline <7 or >7.

An interim analysis for futility will be performed when approximately 120 participants complete Week 12 or early withdrawal visit. Participants, who complete the 16-week treatment period, will exit the study after 15 weeks safety follow-up (16 weeks from the last treatment dose). Participants who discontinue treatment/withdraw from the study will undergo the assessments for early withdrawal and a follow-up visit approximately 15 weeks from the last dose of study treatment.

The study is designed to examine the efficacy, safety, tolerability, PK and target engagement (TE) of different doses/regimens of lead anti-CCL17 antibody in adult participants with moderate to severe pain due to knee osteoarthritis.

This dose finding study is expands on our existing knowledge on the efficacy and safety of the lead anti-CCL17 antibody, in patients with knee OA pain, including but not limited to validation of clinical activity, durability of efficacy, impact of dosing regimen and dose- exposure-target engagement- response (D-E-TE-R) relationship.

The parallel group design is chosen as the most appropriate one to evaluate effects of a mAh analgesic in a chronic pain indication. Due to the nature of the disease and the outcome measures used, a placebo arm is necessary to establish efficacy.

The primary endpoint is change from baseline in weekly average of average daily pain intensity (i.e. average daily pain score) (in the index knee), assessed on the Numeric Rating Scale (NRS) at Week 12. A 12-week timepoint for primary efficacy analysis is deemed appropriate as it is consistent with assessing efficacy once steady-state reductions in CCL17 are predicted to be achieved and with the regulatory expectation on primary endpoint evaluation in chronic pain trials. However, to account for any uncertainties in achievement of steady state levels in CCL17 and for an indirect relationship between target engagement and efficacy (consistent with CCL17 acting via a secondary mediator), a 16- week treatment period has been chosen to provide data after an additional 4 weeks of treatment to inform the understanding of the longitudinal response of the lead anti-CCL17 antibody.

Average daily pain score on NRS is a validated clinical endpoint widely used in clinical studies of OA pain and is accepted by the regulatory agencies. It is a direct and simple way of measuring pain intensity with clear clinical relevance to patients. The endpoint will be calculated by assessing the average pain intensity in the 7 days prior to each respective time point (ie: baseline and week 12). The average daily pain score on NRS is highly correlated with other commonly used disease specific assessment tool such as WOMAC pain subscale. Since average daily pain on NRS provides more data points, it is conceptually more sensitive to change, which is beneficial in exposure-response characterisation over WOMAC pain subscale. In this study, WOMAC pain and function will be captured as secondary endpoints to inform efficacy for these outcomes.

All participants will have 3 off treatment follow-up visits, with the last one occurring approximately 15 weeks after their last treatment visit (16 weeks after lost dose). This equates to a follow-up period over approximately 5 x the observed terminal elimination half-life for total lead anti-CCL17 antibody. The purpose of this Phase 2 study is to investigate the efficacy, safety, PK, TE and dose-exposure- -efficacy (D-E-TE-R) relationship of the lead anti-CCL17 antibody using approximately 420 participants and to provide the data necessary to select the optimal effective and safe dose(s) of lead anti- CCL17 antibody to be carried forward into Phase 3 studies in subjects with knee/hip OA.

The proposed dose levels and regimens have been selected based on an integration of model predicted target engagement (reductions from baseline in free CCL17) and free CCL17 concentration-time data. The target-mediated drug disposition (TMDD) model uses the Quasi Steady-State (QSS) approximation, and is fitted to the time-matched total lead anti-CCL17 antibody and total CCL17 data in healthy and OA participants.

Table 4: Model Predicted Steady-State Reductions in Free CCL17 (maximum, trough, % of the dosing interval and average) by Dose Level and Frequency

From this modelling, the following doses were selected for testing as compared to placebo over a period of at least 12 weeks, but up to 16 weeks, with a safety follow-up period until week 31 :

• 360mg weekly

• 240mg weekly

• 240mg every two weeks (with alternate placebo administration every two weeks)

• 60mg weekly EXAMPLE 4 - CCL17 treatment in neuropathic pain

Immunohistochemistry (IHC) and in-situ hybridization (ISH) was carried out to characterize the distribution of CCR4 (the receptor for CCL17) in human dorsal root ganglia (DRG) tissue.

Thoracolumbar human DRGs were prospectively collected from cadavers using selection criteria to maximise RNA preservation and minimise confounding variables (drug use, neurodegenerative disease etc). Sections of formalin-fixed paraffin embedded DRG from 5 unrelated donors were stained for macrophage markers (CD 163, CD68, CD206), a satellite glial cell marker (Glutamine Synthetase, GS) and CCR4 by immunohistochemistry and ISH. Tissue quality was evaluated using H&E stained sections and a positive control RNAScope probe (PPIB). The block with the most DRG tissue of good RNA quality from each of the 5 selected donors was used for the final staining runs. Donor 3 was excluded as the tissue did not meet the inclusion criteria, due to the small DRG sample and the 24-hour delay prior to fixation.

Chromogenic multiplexes of CD 163, GS and CCR4 IHC demonstrated specific, strong positive staining for CCR4 restricted to perinuclear, eccentrically located, intracytoplasmic compartments (e.g. golgi/endoplasmic reticulum) ofGS+ CD163- cells surrounding neuronal cell bodies (satellite glial cells) (FIG. 9). This pattern was seen across all donors (FIG. 10). Low but consistent expression of CCR4 was also seen by ISH in cells in a similar location and cell type (FIG. 11).

This evidence supports the hypothesis that CCL17 drives a pain mechanism at the dorsal root ganglia (FIG. 12) allowing for effective treatment of neuropathic pain using the antibody of the invention.

EXAMPLE 5 - Phase 2 study in diabetic peripheral neuropathic pain (DPNP)

This is a Phase 2, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy, safety, tolerability, PK and TE of the lead anti-CCL17 antibody vs placebo when administered with repeated weekly SC injection in approximately 240 (up to a maximum of 300) enrolled participants with DPNP. Participants will undergo a screening visit, after which they will go into a washout period of all of their DPNP pain medications, consisting of at least 3 days or 5 half-lives, whichever is longer. This is followed by a further 7 days of run-in period to establish an accurate baseline; after which they will be randomized at 1 : 1 : 1 ratio to either lead anti- CCL17 antibody at 60 mg SC weekly or lead anti-CCL17 antibody at 360 mg SC weekly or placebo.

Total study duration will be approximately 32 weeks. Screening will take place within 5 weeks before randomization. Treatment period is up to 12 weeks. Primary endpoint is at Week 12 to determine the efficacy of 60 and 360 mg SC lead anti-CCL17 antibody on pain compared to placebo in participants with DPNP. Participants will be followed for additional 15 weeks in the off-treatment follow-up period. There will be 2 visits during the off-treatment follow-up period in addition to end of study visit at Week 27, where bloods for PK, TE, safety and some efficacy endpoints will be collected. Any rescue medication use will be reported by the participant in an electronic diary.

Approximately 240 participants (up to a maximum of 300 participants) will be randomized to one of the treatment arms (lead anti-CCL17 antibody or placebo) based on 1: 1: 1 allocation. All participants will be treated for 12 weeks with the primary efficacy endpoint evaluation at that time point.

An Interim Analysis for futility will be performed when approximately 90 participants qualify for Week 12 assessment (by either attending the Week 12 assessment or through missing data imputation strategy, for example in the case that a participant withdraws from the study).

The overall study design is well established to assess the efficacy of a novel therapeutic agent in participants with DPNP after they have been unable to sufficiently manage pain despite trying standard of care therapies. The double-blind, placebo-controlled, randomized study design is considered the gold standard for the safety and efficacy assessment of a new therapy in DPNP both by clinicians and regulatory authorities.

The primary endpoint is change from baseline in average daily pain (ADP) score at Week

12, assessed on a Numeric Rating Scale (NRS). ADP on NRS is a validated clinical endpoint widely used in clinical studies of DPNP and is accepted by the regulatory agencies. It is a direct and simple way of measuring pain intensity with clear clinical relevance to participants. Pain intensity is the regulator requested key measure of efficacy of an analgesic drug and should always be reported. In long-term studies the weekly averages of the daily measurement compared to baseline (i.e. average daily pain score), are commonly used as the primary efficacy variable. Change in ADP intensity is further supported by other endpoints such as the change from baseline in the Short-Form McGill Pain Questionnaire and change from baseline in Brief Pain Inventory Short Form (BPI-SF) questionnaire domains that will generate additional evidence to inform how a participant feels and functions.

All participants will have a final follow-up visit 15 weeks after their last visit at Week 12 (16 weeks after their last dose of study intervention at week 11). This equates to a followup period over approximately 5x the apparent terminal elimination half-life for total lead anti-CCL17 antibody.

The proposed dose levels and regimens have been selected based on an integration of model predicted target engagement (reductions from baseline in free CCL17) and free CCL17 concentration-time data (Table 4). The target-mediated drug disposition (TMDD) model uses the Quasi Steady-State (QSS) approximation and is fitted to the time-matched total lead anti-CCL17 antibody and total CCL17 data in healthy and OA participants. As there is no rationale for a population effect, translation to DPNP has been assumed. From this modelling, a 6-fold dose range (60mg and 360mg weekly) was selected fortesting compared to placebo in this study.

SEQUENCE LISTINGS

SEQ ID NO: 1: Amino acid sequence of the heavy chain (CB302 HC as per WO 2015/069865)

EVOLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVROMPGKGLEWMGIIDPSD SDTRYSPSFOGOVTISADKSISTAYLQWSSLKASDTAMYYCARVGPADVWDAFDY WGOGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA

LTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERK

CCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWY

VDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK

SEQ ID NO: 2: Amino acid sequence of the light chain (CB302 LC as per WO 2015/069865)

DIVMTOSPDSLAVSLGERATINCKSSOSVLLSFDNINKLAWYOQKPGOPPKLLIYD ASTRESGVPDRFSGSGSGTDFTLTISSLOAEDVAVYYCOQFYSVPSTFGOGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES

VTEQDSKD STYSLS STLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC

SEQ ID NO: 3: Amino acid sequence of heavy chain variable region (VH of C17M293 as per WO 2015/069865)

EVOLVOSGAEVKKPGESLKISCKGSGYSFTSYWIGWVROMPGKGLEWMGIIDPSD SDTRYSPSFQGOVTISADKSISTAYLOWSSLKASDTAMYYCARVGPADVWDAFDY WGQGTLVTVSS

SEQ ID NO: 4: Amino acid sequence of light chain variable region (VL of C17B258 as per WO 2015/069865)

DIVMTQSPDSLAVSLGERATINCKSSOSVLLSFDNINKLAWYQQKPGQPPKLLIYD ASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQFYSVPSTFGQGTKVEIK

SEQ ID NO: 5: Amino acid sequence of CDHR1 (HCDR1 of C17F25 as per WO 2015/069865) SYWIG

SEQ ID NO: 6: Amino acid sequence of CDHR2 (HCDR2 of C17F24 as per WO 2015/069865)

IIDPSDSDTRYSPSFQG

SEQ ID NO: 7: Amino acid sequence of CDHR3 (HCDR3 of C17B293 as per WO 2015/069865)

VGPADVWDAFDY

SEQ ID NO: 8: Amino acid sequence of CDLR1 (LCDR1 of C17B234 as per WO 2015/069865)

KSSQSVLLSFDNINKLA

SEQ ID NO: 9: Amino acid sequence of CDLR2 (LCDR2 of C17B238 as per WO 2015/069865)

DASTRES

SEQ ID NO: 10: Amino acid sequence of CDLR3 (LCDR3 of C17B234 as per WO 2015/069865)

QQFYSVPST

SEQ ID NO: 11: Human CCL17 amino acid sequence

ARGTNVGRECCLEYFKGAIPLRKLKTWYQTSEDCSRDAIVFVTVQGRAICSDPNN

KRVKNA VKYLQ SLERS

Claims

1. A method for treating chronic pain in a human subject, comprising administering to said subject a therapeutically effective amount of an antagonistic anti-CCL17 antibody.

2. The method of claim 1, wherein the anti-CCL17 antibody has decreased Fc- associated engagement of immune effector function and complement mediated cytotoxicity.

3. The method of any preceding claim, wherein the anti-CCL17 antibody comprises CDHR1, CDHR2, CDHR3, CDLR1, CDLR2, CDLR3 which comprise the sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 respectively.

4. The method of any preceding claim, wherein the anti-CCL17 antibody comprises the heavy chain variable region (VH) of SEQ ID NO: 3 and/or the light chain variable region (VL) of SEQ ID NO: 4.

5. The method of any preceding claim, wherein the anti-CCL17 antibody comprises a heavy chain comprising SEQ ID NO: 1 and/or a light chain comprising of SEQ ID NO: 2.

6. The method of any preceding claim, wherein the chronic pain is chronic musculoskeletal pain or chronic neuropathic pain.

7. The method of claim 6, wherein the chronic musculoskeletal pain comprises osteoarthritic pain or lower back pain.

8. The method of claim 7, wherein the osteoarthritic pain comprises pain in a hip and/or a knee joint.

9. The method of claim 6, wherein the chronic neuropathic pain comprises chronic peripherical neuropathic pain.

10. The method of claim 9, wherein the chronic peripheral neuropathic pain comprises diabetic peripheral neuropathic pain, trigeminal neuralgia or postherpetic neuralgia.

11. The method of any preceding claim, wherein the chronic pain comprises moderate to severe pain, optionally wherein the subject has an average daily pain score of >4 and <9 on the 11 -point Numerical Rating Scale. The method of any preceding claim, wherein treatment results in at least a 1 point reduction in the subject’s average daily pain and/or worst daily pain score on an 11- point Numerical Rating Scale. The method of any preceding claim, wherein treatment results in at least a 1 point reduction in the subject’s WOMAC pain score and/or WOMAC function score on an 11 -point Numerical Rating Scale. The method of any preceding claim, wherein the subject receiving treatment experiences no central nervous system effects, no adverse events, no clinically significant changes from baseline in key laboratory parameters and/or no NCI- CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) grade >3 hematological/clinical chemistry abnormalities. The method of any preceding claim wherein the antibody is comprised in a composition which is administered subcutaneously. The method of claim 15 wherein the composition is administered at least once at a dose of 30mg, 60mg, 240mg, 360mg or 480mg. The method of any one of claims 15 or 16 wherein the composition is administered more than once, wherein the administration is about weekly or every two weeks. The method of any one of claims 15 to 17 wherein the composition is administered about weekly at a dose of 60mg, about weekly at a dose of 240mg, about every two weeks at a dose of 240mg, or about weekly at a dose of 360mg. The method of any one of claims 15 to 18, wherein the composition is administered using an autoinjector. The method of any preceding claim, wherein the subject is non-responsive, refractory to, contraindicated for and/or otherwise unwilling to use opioid treatment for their pain. An antagonistic anti-CCL17 antibody for use in the treatment of chronic pain.