Modified receptors and ligands

Abstract

The present disclosure generally relates to a modified receptor and / or a modified ligand and uses thereof. The modified receptor and / or modified ligand can be used to establish molecular signalling between two biological components, rendering the modified receptor and / or modified ligand suitable in a broad array of applications.

Description

[0001] “Modified Receptors and Ligands”

[0002] Cross-reference to related applications

[0003] This application claims the right of priority to Australian Provisional No. 2024904310, filed 24 December 2024, the complete contents of which is incorporated by reference herein in its entirety.

[0004] Technical field

[0005] The present disclosure generally relates to a modified receptor and / or a modified ligand and uses thereof. The modified receptor and / or modified ligand can be used to establish molecular signalling between two biological components, rendering the modified receptor and / or modified ligand suitable in a broad array of applications.

[0006] Background

[0007] Safety and efficacy constitute the major criteria governing regulatory approval of any new therapeutic drug. One way to maximise safety and efficacy is to attempt to enable site specific delivery of a therapeutic agent whilst limiting off-target effects (e.g., little or no affinity towards healthy or normal cells and high affinity to target or diseased cells). Various attempted mechanisms to facilitate site specific delivery of therapeutics are known (e.g., antibody-drug conjugates, nanoparticle platforms, liposome platforms, and others), yet successful, targeted therapeutic delivery remains challenging. Accordingly, there is a need for the development of improved targeting strategies for therapeutic agents.

[0008] Summary

[0009] In work leading up to the present disclosure, the inventors recognised that there is a need for inter alia the development of improved strategies for site-specific delivery of therapeutic agents to targets and / or for reducing off-target effects. This can be particularly challenging in the context of cell-based therapies, such as those used for treatment of cancers, due to, inter alia, the heterogeneity of the tumour microenvironment (both cellular and molecular), immunosuppressive qualities of the tumour microenvironment, tumour resistance through antigen escape, and on-target off-tumour effects due to the expression of tumour antigens on normal tissues. However, the inventors postulated that it may be possible to accelerate recruitment of immune cells and drive convergence of those immune cells to diseased tissue (e.g., tumour) by augmenting chemotactic signalling. This possibility was explored by modulating binding interactions between secreted signalling ligands and receptors known to initiate paracrine signalling. Specifically, a strategy for establishing targeted paracrine signalling was developed via modulation of ligand-receptor binding interactions between C-C Chemokine Ligand 3 (CCL3) and the cell-surface receptors CCR1, CCR4 and / or CCR5. CCL3 is a proinflammatory cytokine belonging to the CC chemokine family, and playsa key role in the immune system by regulating the trafficking of immune cells and the formation of the immune landscape through its binding with CCR1, CCR4 and / or CCR5. Chemokines like CCL3 have been shown to influence the migration and maintenance of relevant immune cells (e.g., dendritic cells, Natural Killer (NK) cells, macrophages and T cells) with infected tissues and the tumour microenvironment through their binding interaction with CCR5. The ability to augment paracrine signalling via modulation of the binding interaction between CCL3 and CCR5 therefore presents an attractive treatment strategy where targeted and enhanced inflammatory response is desired (e.g., cancer), but may equally present an attractive therapeutic strategy for diseases where a reduction in inflammatory response is desirable e.g., autoimmune diseases and graft versus host disease (GVHD). Accordingly, the inventors explored means of modulating the receptor-ligand binding interaction between CCR5 and CCL3 (and its isoforms) and, in doing so, identified particular amino acid positions within the native CCR5 receptor and the native CCL3 ligand (and its isoform LD78P) which can be substituted to modify the binding interaction and affinity between cognate binding partners. This includes the identification of specific residue positions within the native CCR5 receptor which, when substituted, increase and / or decrease binding affinity for the cognate native ligand (i.e., CCL3 and isoforms thereof), including specific amino acid substitutions which increase binding affinity for the cognate native ligand and specific amino acid substitutions which decrease binding affinity for the cognate native ligand. Similarly, the inventors have identified specific residue positions within the native CCL3 ligand (and its isoform LD78P), which increase and / or decrease binding affinity for the cognate native receptor CCR5, including specific amino acid substitutions which increase binding affinity for the cognate native receptor CCR5 and specific amino acid substitutions which decrease binding affinity for the cognate native receptor CCR5. Furthermore, by introducing site-specific amino acid changes to the native receptor CCR5 and native ligand CCL3 (and its isoforms) respectively, the inventors have produced synthetic receptor-ligand binding pairs having a synthetic CCL3 (or CCL3 isoform) ligand and a cognate synthetic CCR5 receptor. In certain instances, the synthetic CCL3 (or CCL3 isoform) ligand or synthetic CCR5 receptor may have a greater affinity for binding their synthetic receptor-ligand binding partner relative to their affinity for binding the corresponding native counterpart. Collectively, these findings provide evidence for being able to modify binding interactions between native binding partners involved in paracrine signalling (e.g., CCL3-CCR5) through the introduction of site-specific amino acid substitutions within the respective ligand and / or its cognate receptor, and in doing so establish and / or modulate paracrine signalling in a controlled manner. These findings provide evidence for modified or synthetic CCR5 receptors and / or modified or synthetic CCL3 (or CCL3 isoform) ligands which may be used in a variety of therapies (e g., including, but not limited to, cell therapies for treatment of cancers). In one example, the present disclosure provides a receptor comprising a binding domain corresponding to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1, wherein the receptor comprises:

[0010] (a) aspartic acid at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;

[0011] (b) leucine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;

[0012] (c) arginine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;

[0013] (d) lysine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;

[0014] (e) aspartic acid at a position corresponding to amino acid 32 in the amino acid sequence set forth in SEQ ID NO: 1;

[0015] (f) serine at a position corresponding to amino acid 89 in the amino acid sequence set forth in SEQ ID NO: 1;

[0016] (g) alanine at a position corresponding to amino acid 94 in the amino acid sequence set forth in SEQ ID NO: 1;

[0017] (h) phenylalanine at a position corresponding to amino acid 104 in the amino acid sequence set forth in SEQ ID NO: 1;

[0018] (i) asparagine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1;

[0019] (j) leucine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1;

[0020] (k) aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0021] (l) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0022] (m) leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0023] (n) asparagine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0024] (o) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0025] (p) serine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0026] (q) methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0027] (r) serine at a position corresponding to amino acid 172 in the amino acid sequence set forth in SEQ ID NO: 1;(s) glutamic acid at a position corresponding to amino acid 179 in the amino acid sequence set forth in SEQ ID NO: 1;

[0028] (t) glutamic acid at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1;

[0029] (u) glutamine at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1;

[0030] (v) glutamic acid at a position corresponding to amino acid 181 in the amino acid sequence set forth in SEQ ID NO: 1;

[0031] (w) aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;

[0032] (x) glutamic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;

[0033] (y) glycine at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;

[0034] (z) serine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0035] (aa) glutamic acid at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0036] (bb) arginine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0037] (cc) histidine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0038] (dd) glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0039] (ee) leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0040] (ff) histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0041] (gg) aspartic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0042] (hh) tryptophan at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0043] (ii) serine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0044] (jj) cysteine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0045] (kk) methionine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(11) histidine at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;

[0046] (mm) glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;

[0047] (nn) arginine at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;

[0048] (oo) aspartic acid at a position corresponding to amino acid 262 in the amino acid sequence set forth in SEQ ID NO: 1;

[0049] (pp) threonine at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1;

[0050] (qq) glutamic acid at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1;

[0051] (rr) arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1;

[0052] (ss) arginine at a position corresponding to amino acid 291 in the amino acid sequence set forth in SEQ ID NO: 1; or

[0053] (tt) any combination thereof with the exception of combinations of different amino acids at the same position relative to the sequence set forth in SEQ ID NO: 1.

[0054] In one example, the receptor comprises:

[0055] (a) lysine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;

[0056] (b) arginine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1, aspartic acid at a position corresponding to amino acid 32 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0057] (c) serine at a position corresponding to amino acid 89 in the amino acid sequence set forth in SEQ ID NO: 1 and phenylalanine at a position corresponding to amino acid 104 in the amino acid sequence set forth in SEQ ID NO: 1;

[0058] (d) asparagine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0059] (e) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1;

[0060] (f) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and serine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;(g) glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 262 in the amino acid sequence set forth in SEQ ID NO: 1;

[0061] (h) aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0062] (i) glutamine at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 181 in the amino acid sequence set forth in SEQ ID NO: 1;

[0063] (j) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0064] (k) glutamic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0065] (l) aspartic acid at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1, glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and cysteine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0066] (m) leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0067] (n) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0068] (o) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0069] (p) leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and tryptophan at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0070] (q) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0071] (r) asparagine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(s) aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0072] (t) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0073] (u) aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: land glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0074] (v) serine at a position corresponding to amino acid 172 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;

[0075] (w) histidine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0076] (x) glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1; or

[0077] (y) glutamic acid at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1, arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at a position corresponding to amino acid 291 in the amino acid sequence set forth in SEQ ID NO: 1.

[0078] In one example, the receptor comprises a binding domain having at least 95% sequence identity to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1.

[0079] In each of the foregoing examples, the receptor may comprise an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. For example, the receptor may comprise an amino acid sequence having at least 92.5% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. For example, the receptor may comprise an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. For example, the receptor may comprise an amino acid sequence having at least 97.5% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1.

[0080] In some examples, the receptor described herein is capable of binding to a native C-C Chemokine Ligand 3 (CCL3), a native LD78P and / or a ligand having one or more amino acid substitutions relative to the native CCL3 or native LD78P as described herein. However, in other examples, the receptor described herein may be capable of selectively binding to a ligand having one or more amino acid substitutions relative to the native CCL3 or native LD78P as described herein. In accordance with this latter example, the receptor may bind with increasedaffinity to the ligand having one or more amino acid substitutions relative to the native CCL3 or native LD78P as described herein, relative to a native C-C Chemokine Receptor 5 (CCR5). In each of the foregoing examples describing binding of the receptor to a cognate ligand, the binding may be determined using flow cytometry.

[0081] In one example, the native CCL3 comprises the amino acid sequence set forth in SEQ ID NO: 3. Alternatively, or in addition, the native LD78P comprises the amino acid sequence set forth in SEQ ID NO: 5.

[0082] In one example, the native CCR5 comprises the amino acid sequence set forth in SEQ ID NO: 1.

[0083] In each of the foregoing examples, the receptor of the disclosure may comprise a glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1. For example, the receptor of the disclosure may comprise an amino acid sequence encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

[0084] The present disclosure also provides a ligand comprising a receptor binding domain of chemokine (C-C motif) ligand 3 (CCL3) or an isoform of CCL3, wherein the ligand comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5, and wherein the ligand comprises:

[0085] (a) alanine or arginine at a position corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5, or the amino acid corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5 is absent;

[0086] (b) serine, proline or methionine at a position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5;

[0087] (c) leucine or proline at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5;

[0088] (d) alanine, arginine, isoleucine or valine at a position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0089] (e) alanine or arginine at a position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5;

[0090] (f) aspartic acid, isoleucine or methionine at a position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0091] (g) proline or arginine at a position corresponding to amino acid 8 of the sequence set forth in SEQ ID NO: 3 or 5;

[0092] (h) threonine, leucine, proline or arginine at a position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;

[0093] (i) alanine or arginine at a position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(j) an amino acid substitution at a position corresponding to amino acid 14 of the sequence set forth in SEQ ID NO: 3 or 5, wherein the substitution is relative to the amino acid at position 14 of the sequence set forth in SEQ ID NO: 3 or 5;

[0094] (k) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine, or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;

[0095] (l) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;

[0096] (m) glutamine or arginine at a position corresponding to amino acid 22 of the sequence set forth in SEQ ID NO: 3 or 5;

[0097] (n) alanine, tyrosine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;

[0098] (o) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0099] (p) phenylalanine or arginine at a position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5;

[0100] (q) glutamic acid, arginine or tyrosine at a position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0101] (r) serine or arginine at a position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0102] (s) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0103] (t) glutamine or arginine at a position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5;

[0104] (u) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5;

[0105] (v) glycine, serine or tyrosine at a position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(w) isoleucine or arginine at a position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;

[0106] (x) lysine or arginine at a position corresponding to amino acid 45 of the sequence set forth in SEQ ID NO: 3 or 5;

[0107] (y) serine, lysine, tryptophan, or glycine at a position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0108] (z) proline or leucine at a position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5; and / or

[0109] (aa) valine or lysine at a position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

[0110] In one example, the ligand of the disclosure comprises one or more (e.g., 2 or 3 or 4 or more) of:

[0111] (a) alanine or arginine at a position corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5, or the amino acid corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5 is absent;

[0112] (b) serine, proline or methionine at a position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5;

[0113] (c) leucine or proline at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5;

[0114] (d) alanine, arginine, isoleucine or valine at a position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0115] (e) alanine or arginine at a position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5;

[0116] (f) aspartic acid, isoleucine or methionine at a position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0117] (g) proline or arginine at a position corresponding to amino acid 8 of the sequence set forth in SEQ ID NO: 3 or 5;

[0118] (h) threonine, leucine, proline or arginine at a position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;

[0119] (i) alanine or arginine at a position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0120] (j) an amino acid substitution at a position corresponding to amino acid 14 of the sequence set forth in SEQ ID NO: 3 or 5, wherein the substitution is relative to the amino acid at position 14 of the sequence set forth in SEQ ID NO: 3 or 5;

[0121] (k) isoleucine, methionine and valine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;(l) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;

[0122] (m) glutamine or arginine at a position corresponding to amino acid 22 of the sequence set forth in SEQ ID NO: 3 or 5;

[0123] (n) alanine, tyrosine, lysine or arginine at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;

[0124] (o) aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0125] (p) phenylalanine or arginine at a position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5;

[0126] (q) glutamic acid, arginine or tyrosine at a position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0127] (r) serine or arginine at a position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0128] (s) serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0129] (t) glutamine or arginine at a position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5;

[0130] (u) serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5;

[0131] (v) glycine, serine or tyrosine at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5;

[0132] (w) isoleucine or arginine at a position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;

[0133] (x) lysine or arginine at a position corresponding to amino acid 45 of the sequence set forth in SEQ ID NO: 3 or 5;

[0134] (y) serine, lysine, tryptophan, or glycine at a position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0135] (z) proline or leucine at a position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5; and / or

[0136] (aa) valine or lysine at a position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

[0137] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33,34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0138] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 91.4% identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0139] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 92.5% identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0140] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 94.2% identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0141] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 95.7% identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0142] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 97.1 % identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0143] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 98.5 % identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0144] In any of the foregoing examples describing the ligand of the disclosure, the ligand may have an increased affinity for binding to a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41, compared to binding affinity of wildtype CCL3 comprising the amino acid sequence set forth in SEQ ID NO: 3 or wildtype LD78P comprising the amino acid sequence set forth in SEQ ID NO: 5 for the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.In any of the foregoing examples, the ligand of the disclosure may comprise an amino acid substitution at residue position 26 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0145] In some examples, substitution of the amino acid at position 26 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively increases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41. In one example, the amino acid at position 26 which increases affinity of the ligand for the receptor of the disclosure is a basic amino acid having a positive charge at physiological pH. For example, the ligand may comprise a A26R or A26K substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably a A26R substitution. In another example, the amino acid substitution at position 26 which increases affinity of the ligand for the receptor of the disclosure is a A26D substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0146] In some examples, substitution of the amino acid at position 26 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively decreases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41. For example, the ligand may comprise a A26P, A26V, A26Y, or A26E substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a A26P substitution.

[0147] In any of the foregoing examples, the ligand of the disclosure may comprise an amino acid substitution at residue position 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0148] In some examples, substitution of the amino acid at position 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively increases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

[0149] In one example, the amino acid at position 36 which increases affinity of the ligand for the receptor of the disclosure is selected from the group consisting of G, F, W, Y, N, K, R, and H. For example, the amino acid at position 36 may be selected from the group consisting of F, W, Y, K, R, and H.

[0150] In one example, the amino acid at position 36 which increases affinity of the ligand for the receptor of the disclosure is a non-polar, uncharged amino acid. For example, the ligand may comprise a S36G, S36F or S36W substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36W substitution.

[0151] In one example, the amino acid at position 36 which increases affinity of the ligand for the receptor of the disclosure is a polar, uncharged amino acid. For example, the ligand may comprise a S36Y or S36N substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36Y substitution.In one example, the amino acid at position 36 which increases affinity of the ligand for the receptor of the disclosure is a positively charged amino acid having a basic side chain at neutral pH. For example, the ligand may comprise a S36K, S36R or S36H substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36R substitution.

[0152] In one example, the amino acid substitution at position 36 increases affinity of the ligand for the receptor of the disclosure and is selected some S36W, S36Y, S36K, S36R and S36H relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36W or S36R substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0153] In other examples, substitution of the amino acid at position 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively decreases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41. For example the amino acid at position 36 which decreases affinity of the ligand for the receptor of the disclosure is selected from the group consisting of C, D, E, I, M, Q and T. For example, the ligand may comprise a S36C, S36D or S36E substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36D or S36E substitution.

[0154] In any of the foregoing examples, the ligand of the disclosure may comprise an amino acid substitution at residue position 16 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0155] In some examples, substitution of the amino acid at position 16 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively increases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

[0156] In one example, the amino acid at position 16 which increases affinity of the ligand for the receptor of the disclosure is a hydrophobic amino acid, preferably an aliphatic amino acid which is hydrophobic. For example, the amino acid at position 16 may be selected from the group consisting of I, M and V. Accordingly, the ligand may comprise a T16I, T16M or T16V substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a T16I or T16V substitution.

[0157] In some examples, substitution of the amino acid at position 16 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively decreases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

[0158] In one example, the amino acid at position 16 which decreases affinity of the ligand for the receptor of the disclosure is selected from the group consisting of C, D, E, F and P. Accordingly, the ligand may comprise a T16C, T16D, T16E, T16F or T16P substitutionrelative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a T16E or T16D substitution.

[0159] According to certain examples, the ligand of the disclosure comprises an amino acid substitution at residue position 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 as described herein and an amino acid substitution at one or more further residue positions selected from 9, 22, 26, 34 and 45 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand of the disclosure may comprise an amino acid substitution at residue position 36 which increases binding affinity for the receptor of the disclosure and an amino acid substitution at one or more further residue positions selected from 9, 22, 26, 34 and 45, relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5.

[0160] In one example, the ligand of the disclosure comprises an arginine or tryptophan at residue position 36 and an arginine at one of more residue positions selected from 9, 22, 26, 34 and 45, relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand of may comprise an arginine at residue position 36 and an arginine at one of more residue positions selected from 9, 22, 26, 34 and 45, relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise a tryptophan at residue position 36 and an arginine at one of more residue positions selected from 9, 22, 26, 34 and 45, relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5.

[0161] In one example, the ligand of the disclosure comprises:

[0162] (a) an arginine at positions corresponding to amino acids 26 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36R substitutions;

[0163] (b) an arginine at positions corresponding to amino acids 9 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R and S36R substitutions;

[0164] (c) an arginine at positions corresponding to amino acids 22 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R and S36R substitutions;

[0165] (d) an arginine at the position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q34R and S36W substitutions;

[0166] (e) an arginine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises theamino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36W substitutions;

[0167] (f) an arginine at positions corresponding to amino acids 26, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, Q34R and S36R substitutions;

[0168] (g) an arginine at positions corresponding to amino acids 9, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36R substitutions;

[0169] (h) an arginine at positions corresponding to amino acids 22, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R, Q34R and S36R substitutions;

[0170] (i) an arginine at positions corresponding to amino acids 9 and 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36W substitutions; or

[0171] (j) an arginine at positions corresponding to amino acids 26, 36 and 45 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, S36R and K45R substitutions.

[0172] In one example, the ligand of the disclosure comprises:

[0173] (a) an arginine at positions corresponding to amino acids 22 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R and S36R substitutions;

[0174] (b) an arginine at the position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q34R and S36W substitutions;

[0175] (c) an arginine at positions corresponding to amino acids 26, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, Q34R and S36R substitutions;

[0176] (d) an arginine at positions corresponding to amino acids 9, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the aminoacid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36R substitutions;

[0177] (e) an arginine at positions corresponding to amino acids 22, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R, Q34R and S36R substitutions; or

[0178] (f) an arginine at positions corresponding to amino acids 26, 36 and 45 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, S36R and K45R substitutions.

[0179] As described herein, a ligand of the disclosure comprises a receptor binding domain of CCL3 or an isoform of CCL3 (e.g., LD78 ) and comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5. In certain examples, the receptor binding domain comprises an amino acid sequence which is at least 90% identical to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the receptor binding domain may comprise an amino acid sequence which is at least 95% identical to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5.

[0180] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprises:

[0181] (a) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0182] (b) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0183] (c) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0184] (d) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0185] (e) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0186] (f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0187] (g) a proline at the position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0188] (h) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0189] (i) a valine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0190] (j) an arginine at the position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0191] (k) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0192] (l) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a proline at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;

[0193] (m) a leucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0194] (n) an isoleucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0195] (o) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0196] (p) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a leucine at the position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5;

[0197] (q) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0198] (r) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;(s) a tyrosine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0199] (t) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0200] (u) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0201] (v) an arginine at the position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0202] (w) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0203] (x) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0204] (y) a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0205] (z) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;

[0206] (aa) an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5;

[0207] (bb) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0208] (cc) a glutamine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5; or

[0209] (dd) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

[0210] In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprises:(a) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0211] (b) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0212] (c) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0213] (d) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0214] (e) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0215] (f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0216] (f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0217] (g) a proline at the position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0218] (h) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0219] (i) a valine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0220] (j) an arginine at the position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0221] (k) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0222] (l) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a proline at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;(m) a leucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0223] (n) an isoleucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0224] (o) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0225] (p) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a leucine at the position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5;

[0226] (q) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0227] (r) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0228] (s) a tyrosine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0229] (t) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0230] (u) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0231] (v) an arginine at the position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0232] (w) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0233] (x) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0234] (y) a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(z) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;

[0235] (aa) an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5;

[0236] (bb) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0237] (cc) a glutamine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5; or

[0238] (dd) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

[0239] In one example, the ligand of the disclosure comprises an amino acid sequence which set forth in SEQ ID NO: 3 or 5 with the exception of amino acid substitutions resulting in one of the following:

[0240] (a) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0241] (b) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0242] (c) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0243] (d) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0244] (e) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0245] (f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0246] (f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(g) a proline at the position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0247] (h) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0248] (i) a valine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0249] (j) an arginine at the position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0250] (k) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0251] (l) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a proline at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;

[0252] (m) a leucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0253] (n) an isoleucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0254] (o) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0255] (p) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a leucine at the position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5;

[0256] (q) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0257] (r) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0258] (s) a tyrosine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(t) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0259] (u) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0260] (v) an arginine at the position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0261] (w) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0262] (x) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0263] (y) a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0264] (z) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;

[0265] (aa) an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5;

[0266] (bb) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0267] (cc) a glutamine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5; or

[0268] (dd) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

[0269] As described herein, the ligand of the disclosure is capable of binding to a native C-C Chemokine Receptor 5 (CCR5) (e.g., a native CCR5 having an amino acid sequence set forth in SEQ ID NO: 1), and / or the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41). However, in certain examples, the ligand described herein is capable of binding selectively to the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41), over thenative CCR5 e.g., a native CCR5 having an amino acid sequence set forth in SEQ ID NO: 1. For example, the ligand described herein may bind to the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41), with increased affinity compared to its affinity for binding the native CCR5 (e.g., a native CCR5 having an amino acid sequence set forth in SEQ ID NO: 1). Alternatively, or in addition, the ligand described herein may bind to the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41), with increased affinity compared to the affinity of the native CCL3 or native LD78|3 for binding the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41).

[0270] In certain examples, the ligand described herein binds to the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41), with greater affinity than that of the native CCL3 (e.g., comprising the amino acid sequence set forth in SEQ ID NO: 3) or native LD78P (e.g., comprising the amino acid sequence set forth in SEQ ID NO: 5) when binding native CCR5 (e.g., a native CCR5 having an amino acid sequence set forth in SEQ ID NO: 1).

[0271] In each of the foregoing examples described binding selectivity and / or affinity, the binding may be determined using flow cytometry and / or chemotaxis assays.

[0272] The present disclosure also provides a polynucleotide encoding a receptor disclosed herein or a ligand disclosed herein. In one example, a polynucleotide encoding a receptor disclosed herein In one example, a polynucleotide encoding a ligand disclosed herein is provided. In some examples, the polynucleotide encoding the receptor or ligand is operably-linked to one or more regulatory elements e g., a promoter. For example, the polynucleotide may comprise a promoter sequence e.g., upstream of the sequence for the receptor or ligand.

[0273] The present disclosure also provides a vector comprising a polynucleotide disclosed herein. In one example, the vector is an expression vector and / or a delivery vector. For example, the vector may be a plasmid, a minicircle or a viral vector. In accordance with an example in which the vector is a viral vector, the vector may be an adenovirus (AdV), an adeno-associated virus (AAV) or a lentivirus (LV).

[0274] The present disclosure also provides a cell comprising a receptor disclosed herein, a ligand disclosed herein, a polynucleotide disclosed herein and / or a vector disclosed herein. In some examples, the cell is a T cell, a natural killer (NK) cell, a macrophage or a dendritic cell. For example, the cell may be a cytotoxic T lymphocyte. For example, the cell may be a NK-92 cell.

[0275] The present disclosure also provides a carrier comprising a receptor disclosed herein, a ligand disclosed herein, a polynucleotide disclosed herein, a vector disclosed herein and / or a cell disclosed herein. In one example, the carrier is selected from the group consisting of: a plasmid, a virus, a lipoplex, a liposome, an exosome and a nanoparticle.The present disclosure also provides a pharmaceutical composition comprising a receptor disclosed herein, a ligand disclosed herein, a polynucleotide disclosed herein, a vector disclosed herein, a cell disclosed herein and / or a carrier disclosed herein.

[0276] The present disclosure also provides a process for producing a receptor or ligand as disclosed herein, said method comprising: culturing a cell comprising a polynucleotide encoding the receptor or ligand as described herein for a time and under conditions sufficient for the cell to express the receptor or the ligand; and optionally recovering the cell from the culture.

[0277] The present disclosure also provides a method of establishing signalling between at least two biological components in a subject, the method comprising administering to the subject a first biological component comprising and / or capable of expressing the receptor disclosed herein. The method may further comprise administering to the subject a second biological component comprising or capable of expressing the ligand of the disclosure.

[0278] The present disclosure also provides a method of establishing signalling between at least two biological components in a subject, the method comprising administering to the subject a first biological component comprising or encoding the ligand disclosed herein. The method may further comprise administering to the subject a second biological component comprising or capable of expressing the receptor of the disclosure.

[0279] The first and second biological components may be administered to the subject simultaneously or sequentially.

[0280] Exemplary receptors and ligands of the disclosure are described herein above and shall be taken to apply mutatis mutandis to each and every example describing the method of establishing signalling between at least two biological components unless stated otherwise.

[0281] In some examples, the method of establishing signalling between at least two biological components is, or forms part of, a method of treating a disease or condition requiring directional migration of one biological component to another biological component. For example, the disease or condition may be selected from the group consisting of: cancer, an autoimmune disease, a degenerative disease, a cardiovascular disease, a neurological disease, a musculoskeletal disease, a skin and soft tissue disease and an organ transplant.

[0282] In one example, the biological component comprising or capable of expressing the receptor migrates towards an abnormal cell in the subject e.g., an abnormal cell associated with a cancer, an autoimmune disease, a degenerative disease, a cardiovascular disease, a neurological disease, a musculoskeletal disease, a skin and soft tissue disease and an organ transplant.

[0283] In one example, at least one of the first and second biological components further comprises a chimeric antigen receptor (CAR). The CAR may recognise an antigen on the surface of the abnormal cell. In one example, the abnormal cell is a cancer cell from a tumour, and preferably from a solid tumour.In each of the foregoing examples describing methods of establishing signalling between at least two biological components, the first and second biological components may be T cells, Natural Killer (NK) cells or a mixture of both.

[0284] In one example, the first biological component may comprise a first T cell and / or first NK cell comprising or capable of expressing the ligand disclosed herein and the CAR, and the second biological component may comprise a second T cell and / or second NK cell comprising or capable of expressing the receptor disclosed herein.

[0285] In another example, the first biological component may comprise a first T cell and / or first NK cell comprising or encoding the receptor disclosed herein and the CAR, and the second biological component may comprise a second T cell and / or second NK cell comprising or capable of expressing the ligand disclosed herein. The present disclosure also provides a method of treating a tumour in a subject, the method comprising:

[0286] i) administering to the subject a first T cell and / or first NK cell comprising or capable of expressing the ligand disclosed herein, and a second T cell and / or second NK cell comprising or capable of expressing the receptor disclosed herein and a CAR e.g., that recognises a cellsurface antigen in the tumour; or

[0287] ii) administering to the subject a first T cell and / or first NK cell comprising or capable of expressing the ligand disclosed herein and a CAR e g., that recognises a cell-surface antigen in the tumour, and a second T cell and / or second NK cell comprising or capable of expressing the receptor disclosed herein

[0288] In some examples, the tumour is a solid tumour.

[0289] The first T cell and / or first NK cell and the second T cell and / or second NK cell may be administered to the subject simultaneously or sequentially.

[0290] The present disclosure also provides the use of a T cell and / or NK cell comprising or capable of expressing a receptor disclosed herein and a chimeric antigen receptor (CAR) that recognises an antigen expressed by a tumour, in the manufacture of a medicament for treating the tumour in a subject, wherein treating the tumour comprises:

[0291] i) administering the medicament with a T cell and / or NK cell comprising or capable of expressing a ligand disclosed herein, or

[0292] ii) administering the medicament to a subject who has already been administered, or who will be administered, a T cell and / or NK cell comprising or capable of expressing a ligand disclosed herein.

[0293] Accordingly, the medicament and the T cell and / or NK cell comprising or capable of expressing the ligand disclosed herein may be provided for administration to a subject simultaneously or sequentially. In one example, the medicament further comprises the T cell and / or NK cell comprising or capable of expressing the ligand disclosed herein such that administration is simultaneous.The present disclosure also provides the use of a T cell and / or NK cell comprising or capable of expressing a ligand disclosed herein, in the manufacture of a medicament for treating a tumour in a subject, wherein treating the tumour comprises:

[0294] i) administering the medicament with a T cell and / or NK cell comprising or capable of expressing a receptor disclosed herein and a chimeric antigen receptor (CAR) that recognises an antigen expressed by the tumour; or

[0295] ii) administering the medicament to a subject who has already been administered, or who will be administered, a T cell and / or NK cell comprising or capable of expressing a receptor disclosed herein and a CAR that recognises an antigen expressed by the tumour.

[0296] Accordingly, the medicament and the T cell and / or NK cell comprising or capable of expressing the receptor and the CAR may be provided for administration to a subject simultaneously or sequentially. In one example, the medicament further comprises the T cell and / or NK cell comprising or capable of expressing the ligand disclosed herein and the CAR such that administration is simultaneous.

[0297] In accordance with the foregoing examples described uses, the T cell comprising the receptor disclosed herein and CAR may be provided for administration with the T cell comprising the ligand disclosed herein. Similarly, the NK cell comprising the receptor disclosed herein and CAR may be provided for administration with a NK cell comprising the ligand disclosed herein.

[0298] The present disclosure also provides a kit comprising:

[0299] (a) the receptor disclosed herein and the ligand disclosed herein;

[0300] (b) a polynucleotide encoding the receptor disclosed herein and a polynucleotide encoding the ligand disclosed herein;

[0301] (c) a vector comprising a polynucleotide encoding the receptor disclosed herein and a vector comprising a polynucleotide encoding the ligand disclosed herein; or

[0302] (d) a cell comprising or capable of expressing the receptor disclosed herein and a cell comprising or capable of expressing the ligand disclosed herein.

[0303] The present disclosure also provides a method of screening for a receptor capable of being used to establish signalling between at least two biological components, the method comprising:

[0304] (a) substituting one or more amino acids in a binding domain of a receptor of native C-C Chemokine Ligand 3 (CCL3) or an isoform thereof,;

[0305] (b) identifying one or more amino acid substitutions in the binding domain of the receptor of CCL3 or the isoform thereof that results in increased or decreased affinity and / or chemotaxis of the receptor to native CCL3 and / or a native isoform of CCL3 (e.g., LD78P), relative to affinity and / or chemotaxis of a corresponding native receptor e.g., C-C Chemokine Receptor 5 (CCR5), to CCL3 or the isoform thereof; and

[0306] (c) selecting the receptor with the one or more amino acid substitutions that result in increased or decreased affinity and / or chemotaxis to a native CCL3 and / or a native LD78Prelative to the affinity of the corresponding native receptor e.g., native CCR5, to CCL3 or the isoform thereof. In one example, the binding domain of the receptor of native CCL3 or the isoform thereof corresponds to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1.

[0307] The present disclosure also provides a method of screening for a ligand capable of being used to establish signalling between at least two biological components, the method comprising:

[0308] (a) substituting one or more amino acids in a binding domain of a receptor of native C-C Chemokine Ligand 3 (CCL3) or an isoform thereof,;

[0309] (b) identifying one or more amino acid substitutions in the binding domain of the receptor of CCL3 or the isoform thereof that results in increased or decreased affinity and / or chemotaxis of the receptor to native CCL3 and / or a native isoform of CCL3 (e.g., LD78 ), relative to affinity and / or chemotaxis of a corresponding native receptor e.g., C-C Chemokine Receptor 5 (CCR5), to CCL3 or the isoform thereof; and

[0310] (c) selecting the receptor with the one or more amino acid substitutions that result in increased or decreased affinity and / or chemotaxis to a native CCL3 and / or a native LD78P relative to the affinity of the corresponding native receptor e.g., native CCR5, to CCL3 or the isoform thereof. In one example, the binding domain of the receptor of native CCL3 or the isoform thereof corresponds to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO : 1.

[0311] Particularly preferred embodiments are described herein, including in the independent claims.

[0312] Brief description of the drawings

[0313] The following figures form part of the present specification and are included to further demonstrate certain embodiments of the present disclosure. The disclosure may be better understood by reference to one or more of these figures in combination with the detailed description of specific embodiments presented herein. It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0314] Figure l is a pictorial representation of the structural similarities of CCL3 (yellow) and CCL5 (red).

[0315] Figure 2 is a pictorial representation of different stimulation software showing the predicted docking interaction between the crystal structures of CCL3 (red, blue and yellow) and the crystal structure of CCR5 (green). Schrodinger (red), Haddock (blue), and ClusPro (yellow).Figure 3 is a pictorial representation comparing the crystal structure of CCL5 (red) bound to the crystal structure of CCR5 (green) and the docked model (i.e., predicted conformation) of CCL3 (yellow) from Schrodinger.

[0316] Figure 4 is a pictorial representation of the CCR5 residues (red) predicted to interact with CCL3 (blue) at docking.

[0317] Figure 5 is a pictorial representation of the retroviral vector used for expression of (A) the synthetic ligands and (B) the synthetic receptors.

[0318] Figure 6 is a flow cytometry scatter plot following FACS analysis of Human Jurkat T cells stained with 3A9 antibody. Red: cells transduced with synthetic receptor S12, grey: untransduced control cells.

[0319] Figure 7 is a confocal micrograph through the mid-plane of an EL4 cell surface expressing synthetic receptor S12.

[0320] Figure 8 is a graphical representation of synthetic ligands binding to EL4 cells expressing synthetic receptor S12 (red) compared to untransduced control EL4 cells (grey).

[0321] Figure 9 is a graphical representation of synthetic ligands (Cl 8 and C21) binding to cells expressing synthetic receptor S12. EL4 T cell lymphoma cells (A), primary mouse CD8+ OT-I T cells (B), and human Jurkat T cells (C).

[0322] Figure 10 is a schematic representation of a chemotaxis assay setup.

[0323] Figure 11 is a graphical representation of results of transwell migration of EL4 T cells expressing the synthetic receptor S12 towards synthetic ligands (A) C18 and (B) C21.

[0324] Figure 12 is a graphical representation of results of transwell migration of primary mouse CD8+ OT-I T cells expressing synthetic receptor S12 towards synthetic ligand C21.

[0325] Figure 13 is a pictorial representation of the extracellular, transmembrane and intracellular domains of CCR5.

[0326] Figure 14 is a graphical representation of synthetic ligand C21 binding to NK-92 human Natural Killer cells expressing synthetic receptor A08 (red) compared to untransduced control NK-92 cells (grey).

[0327] Figure 15 is a graphical representation of pooled mutant LD78P ligands binding to synthetic S05 receptor compared to wild-type LD780 ligand. Binding was assessed by fluorescence-activated cell sorting (FACS) and Overton binding scores are plotted on the y-axis. The red-dotted line indicates the wild-type LD78P ligand condition.

[0328] Figure 16 is a graphical representation of point mutant variants of LD78P ligand at amino acid position 16, 26 and 36 corresponding to the sequence set forth in SEQ ID NO: 5 binding to wild-type CCR5 and synthetic receptor S05. Binding was assessed by FACS and Overton binding scores are plotted on the y-axis. The red-dotted line indicates the wild-type LD78P ligand condition.

[0329] Figure 17 is a graphical representation of machine learning (ML)-designed LD78P ligand mutant variants binding to wild-type CCR5 and synthetic receptor S05. Binding wasassessed by FACS and Overton binding scores are plotted on the y-axis. The red-dotted line indicates the wild-type LD78P ligand condition.

[0330] Figure 18 is a graphical representation of results of FACS binding assay of (A) ML-designed mutant LD78 ligand variants and (B) amino acid position 36 mutant LD78 ligand variants binding to synthetic receptor S05. Fold-changes mean fluorescence intensity (MFI) were calculated relative to wild-type LD78 binding and are plotted on the y-axis Figure 19 is a graphical representation of the change in binding of (A) ML-designed mutant LD78 ligand variants and (B) amino acid position 36 mutant LD78 ligand variants to synthetic receptor S05 relative to wild-type CCR5 receptor. Binding was assessed by FACS and the fold changes in MFI were calculated as a ratio of S05:CCR5 relative to wild-type LD78 ligand.

[0331] Key to Sequence Listing

[0332] SEQ ID NO: 1 Amino acid sequence of CCR5

[0333] SEQ ID NO: 2 Nucleotide sequence of CCR5

[0334] SEQ ID NO: 3 Amino acid sequence of CCL3

[0335] SEQ ID NO: 4 Nucleotide sequence of CCL3

[0336] SEQ ID NO: 5 Amino acid sequence of LD780

[0337] SEQ ID NO: 6 Nucleotide sequence of LD78P

[0338] SEQ ID NO: 7 Nucleotide sequence of A01 (E18R L32D K171M)

[0339] SEQ ID NO: 8 Nucleotide sequence of A02 (KI 7 IE)

[0340] SEQ ID NO: 9 Nucleotide sequence of A03 (KI 7 ID)

[0341] SEQ ID NO: 10 Nucleotide sequence of A04 (KI 7 IS)

[0342] SEQ ID NO: 11 Nucleotide sequence of A05 (KI 71 E K 19 IL)

[0343] SEQ ID NO: 12 Nucleotide sequence of A06 (K171E Y187S)

[0344] SEQ ID NO: 13 Nucleotide sequence of A07 (S179E)

[0345] SEQ ID NO: 14 Nucleotide sequence of A08 (S180E)

[0346] SEQ ID NO: 15 Nucleotide sequence of A09 (S180Q H181E)

[0347] SEQ ID NO: 16 Nucleotide sequence of A 10 (Y184D)

[0348] SEQ ID NO: 17 Nucleotide sequence of All (Y184G)

[0349] SEQ ID NO: 18 Nucleotide sequence of A12 (Y184D K191H)

[0350] SEQ ID NO: 19 Nucleotide sequence of B01 (Y184E Y187E)

[0351] SEQ ID NO: 20 Nucleotide sequence of B02 (Y 187R)

[0352] SEQ ID NO: 21 Nucleotide sequence of B03 (Y187H K191M)

[0353] SEQ ID NO: 22 Nucleotide sequence of B04 (K191E)

[0354] SEQ ID NO: 23 Nucleotide sequence of B05 (K191M)

[0355] SEQ ID NO: 24 Nucleotide sequence of B06 (N258H)

[0356] SEQ ID NO: 25 Nucleotide sequence of B07 (E172S N258E)

[0357] SEQ ID NO: 26 Nucleotide sequence of B08 (E18D K171E K191C)SEQ ID NO 27 Nucleotide sequence of B09 (Q280T)

[0358] SEQ ID NO 28 Nucleotide sequence of BIO (Q280E E283R T291R) SEQ ID NO 29 Nucleotide sequence of L01 (N258E E283R) SEQ ID NO 30 Nucleotide sequence of L02 (K191E E262D) SEQ ID NO 31 Nucleotide sequence of L03 (K171Q E283R) SEQ ID NO 32 Nucleotide sequence of PO 1 (El 8R)

[0359] SEQ ID NO 33 Nucleotide sequence of P02 (E 18L)

[0360] SEQ ID NO 34 Nucleotide sequence of P03 (Q170L)

[0361] SEQ ID NO 35 Nucleotide sequence of P04 (Q170N_K171M) SEQ ID NO 36 Nucleotide sequence of P05 (E18K Y184D) SEQ ID NO 37 Nucleotide sequence of SOI (K171E K191E) SEQ ID NO 38 Nucleotide sequence of S02 (K171D K191E) SEQ ID NO 39 Nucleotide sequence of S03 (K171N K191E) SEQ ID NO 40 Nucleotide sequence of S04 (K171Q KI 9 IE) SEQ ID NO 41 Nucleotide sequence of S05 (K171Q K191D) SEQ ID NO 42 Nucleotide sequence of S06 (K171D K191L) SEQ ID NO 43 Nucleotide sequence of S07 (K171E K191H) SEQ ID NO 44 Nucleotide sequence of S10 (K171L K191W) SEQ ID NO 45 Nucleotide sequence of S12 (K171L K191H) SEQ ID NO 46 Nucleotide sequence of C01 (D6I E30Y)

[0362] SEQ ID NO 47 Nucleotide sequence of C02 (T9L S32R)

[0363] SEQ ID NO 48 Nucleotide sequence of C03 (E30R G39Y) SEQ ID NO 49 Nucleotide sequence of C04 (F29R G39Y) SEQ ID NO 50 Nucleotide sequence of C05 (A10R P54L) SEQ ID NO 51 Nucleotide sequence of C06 (A4I S47W)

[0364] SEQ ID NO 52 Nucleotide sequence of C07 (A26Y S33R) SEQ ID NO 53 Nucleotide sequence of C08 (S2M A4I)

[0365] SEQ ID NO 54 Nucleotide sequence of C09 (S33R V63K) SEQ ID NO 55 Nucleotide sequence of CIO (E30R I41R)

[0366] SEQ ID NO 56 Nucleotide sequence of Cl 1 (A10R E30Q) SEQ ID NO 57 Nucleotide sequence of C12 (D27R G39Y) SEQ ID NO 58 Nucleotide sequence of C13 (S2P D6M)

[0367] SEQ ID NO 59 Nucleotide sequence of C14 (S2M A4R)

[0368] SEQ ID NO 60 Nucleotide sequence of C15 (S2P A10R)

[0369] SEQ ID NO 61 Nucleotide sequence of C16 (S2P S33R)

[0370] SEQ ID NO 62 Nucleotide sequence of C17 (S2P S47K)

[0371] SEQ ID NO 63 Nucleotide sequence of Cl 8 (L3P D6M)

[0372] SEQ ID NO 64 Nucleotide sequence of C19 (A4I D6M)

[0373] SEQ ID NO 65 Nucleotide sequence of C20 (A4V D6M)SEQ ID NO 66 Nucleotide sequence of C21 (A5R D6M)

[0374] SEQ ID NO 67 Nucleotide sequence of C22 (D6M T9P)

[0375] SEQ ID NO 68 Nucleotide sequence of C23 (D6M E30Q)

[0376] SEQ ID NO 69 Nucleotide sequence of C24 (D6I S32R)

[0377] SEQ ID NO 70 Nucleotide sequence of C25 (D6M A10R)

[0378] SEQ ID NO 71 Nucleotide sequence of C26 (D6I D27R)

[0379] SEQ ID NO 72 Nucleotide sequence of C27 (A10R S33R)

[0380] SEQ ID NO 73 Nucleotide sequence of C28 (D27Q E30Y)

[0381] SEQ ID NO 74 Nucleotide sequence of C29 (D27R S33R)

[0382] SEQ ID NO 75 Nucleotide sequence of C30 (E30R S32R)

[0383] SEQ ID NO 76 Nucleotide sequence of C31 (E30Y S33R)

[0384] SEQ ID NO 77 Nucleotide sequence of C32 (AIR)

[0385] SEQ ID NO 78 Nucleotide sequence of C33 (S2P)

[0386] SEQ ID NO 79 Nucleotide sequence of C34 (A4R)

[0387] SEQ ID NO 80 Nucleotide sequence of C35 (D6M)

[0388] SEQ ID NO 81 Nucleotide sequence of C36 (P8R)

[0389] SEQ ID NO 82 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16C SEQ ID NO 83 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16D SEQ ID NO 84 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16E SEQ ID NO 85 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16F SEQ ID NO 86 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16H SEQ ID NO 87 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16I SEQ ID NO 88 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16M SEQ ID NO 89 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16N SEQ ID NO 90 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16P SEQ ID NO 91 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16Q SEQ ID NO 92 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16R SEQ ID NO 93 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16V SEQ ID NO 94 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16Y SEQ ID NO 95 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16A SEQ ID NO 96 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16G SEQ ID NO 97 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16K SEQ ID NO 98 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16L SEQ ID NO 99 Nucleotide sequence of Aldel_S2P_G39S_S47G_T16S SEQ ID NO 100 Nucleotide sequence of Aldel S2P G39S S47G T16W SEQ ID NO 101 Amino acid sequence of Aldel_S2P_G39S_S47G_T16C SEQ ID NO 102 Amino acid sequence of Aldel_S2P_G39S_S47G_T16D SEQ ID NO 103 Amino acid sequence of Aldel_S2P_G39S_S47G_T16E SEQ ID NO 104 Amino acid sequence of Aldel S2P G39S S47G T16FSEQ ID NO 105 Amino acid sequence of Aldel_S2P_G39S_S47G_T16H SEQ ID NO 106 Amino acid sequence of Aldel_S2P_G39S_S47G_T16I SEQ ID NO 107 Amino acid sequence of Aldel_S2P_G39S_S47G_T16M SEQ ID NO 108 Amino acid sequence of Aldel_S2P_G39S_S47G_T16N SEQ ID NO 109 Amino acid sequence of Aldel_S2P_G39S_S47G_T16P SEQ ID NO 110 Amino acid sequence of Aldel_S2P_G39S_S47G_T16Q SEQ ID NO 111 Amino acid sequence of Aldel_S2P_G39S_S47G_T16R SEQ ID NO 112 Amino acid sequence of Aldel_S2P_G39S_S47G_T16V SEQ ID NO 113 Amino acid sequence of Aldel_S2P_G39S_S47G_T16Y SEQ ID NO 114 Amino acid sequence of Aldel_S2P_G39S_S47G_T16A SEQ ID NO 115 Amino acid sequence of Aldel_S2P_G39S_S47G_T16G SEQ ID NO 116 Amino acid sequence of Aldel_S2P_G39S_S47G_T16K SEQ ID NO 117 Amino acid sequence of Aldel_S2P_G39S_S47G_T16L SEQ ID NO 118 Amino acid sequence of Aldel S2P G39S S47G T16S SEQ ID NO 119 Amino acid sequence of Aldel_S2P_G39S_S47G_T16W SEQ ID NO 120 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17A SEQ ID NO 121 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17C SEQ ID NO 122 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17D SEQ ID NO 123 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17E SEQ ID NO 124 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17F SEQ ID NO 125 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17G SEQ ID NO 126 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17H SEQ ID NO 127 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17I SEQ ID NO 128 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17K SEQ ID NO 129 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17L SEQ ID NO 130 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17M SEQ ID NO 131 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17N SEQ ID NO 132 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17P SEQ ID NO 133 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17Q SEQ ID NO 134 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17R SEQ ID NO 135 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17T SEQ ID NO 136 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17V SEQ ID NO 137 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17W SEQ ID NO 138 Nucleotide sequence of Aldel_S2P_G39S_S47G_S17Y SEQ ID NO 139 Amino acid sequence of Aldel S2P G39S S47G S 17A SEQ ID NO 140 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17C SEQ ID NO 141 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17D SEQ ID NO 142 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17E SEQ ID NO 143 Amino acid sequence of Aldel S2P G39S S47G S 17FSEQ ID NO 144 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17G SEQ ID NO 145 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17H SEQ ID NO 146 Amino acid sequence of Aldel_S2P_G39S_S47G_S 171 SEQ ID NO 147 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17K SEQ ID NO 148 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17L SEQ ID NO 149 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17M SEQ ID NO 150 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17N SEQ ID NO 151 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17P SEQ ID NO 152 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17Q SEQ ID NO 153 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17R SEQ ID NO 154 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17T SEQ ID NO 155 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17V SEQ ID NO 156 Amino acid sequence of Aldel_S2P_G39S_S47G_S 17W SEQ ID NO 157 Amino acid sequence of Aldel S2P G39S S47G S 17Y SEQ ID NO 158 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26D SEQ ID NO 159 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26E SEQ ID NO 160 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26F SEQ ID NO 161 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26H SEQ ID NO 162 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26K SEQ ID NO 163 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26L SEQ ID NO 164 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26P SEQ ID NO 165 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26R SEQ ID NO 166 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26S SEQ ID NO 167 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26V SEQ ID NO 168 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26Y SEQ ID NO 169 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26C SEQ ID NO 170 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26G SEQ ID NO 171 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26I SEQ ID NO 172 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26M SEQ ID NO 173 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26N SEQ ID NO 174 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26Q SEQ ID NO 175 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26T SEQ ID NO 176 Nucleotide sequence of Aldel_S2P_G39S_S47G_A26W SEQ ID NO 177 Amino acid sequence of Aldel_S2P_G39S_S47G_A26D SEQ ID NO 178 Amino acid sequence of Aldel S2P G39S S47G A26E SEQ ID NO 179 Amino acid sequence of Aldel_S2P_G39S_S47G_A26F SEQ ID NO 180 Amino acid sequence of Aldel_S2P_G39S_S47G_A26H SEQ ID NO 181 Amino acid sequence of Aldel_S2P_G39S_S47G_A26K SEQ ID NO 182 Amino acid sequence of Aldel S2P G39S S47G A26LSEQ ID NO 183 Amino acid sequence of Aldel_S2P_G39S_S47G_A26P SEQ ID NO 184 Amino acid sequence of Aldel_S2P_G39S_S47G_A26R SEQ ID NO 185 Amino acid sequence of Aldel_S2P_G39S_S47G_A26S SEQ ID NO 186 Amino acid sequence of Aldel_S2P_G39S_S47G_A26V SEQ ID NO 187 Amino acid sequence of Aldel_S2P_G39S_S47G_A26Y SEQ ID NO 188 Amino acid sequence of Aldel_S2P_G39S_S47G_A26C SEQ ID NO 189 Amino acid sequence of Aldel_S2P_G39S_S47G_A26G SEQ ID NO 190 Amino acid sequence of Aldel_S2P_G39S_S47G_A26I SEQ ID NO 191 Amino acid sequence of Aldel_S2P_G39S_S47G_A26M SEQ ID NO 192 Amino acid sequence of Aldel_S2P_G39S_S47G_A26N SEQ ID NO 193 Amino acid sequence of Aldel_S2P_G39S_S47G_A26Q SEQ ID NO 194 Amino acid sequence of Aldel_S2P_G39S_S47G_A26T SEQ ID NO 195 Amino acid sequence of Aldel_S2P_G39S_S47G_A26W SEQ ID NO 196 Nucleotide sequence of Aldel S2P G39S S47G D27A SEQ ID NO 197 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27C SEQ ID NO 198 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27E SEQ ID NO 199 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27F SEQ ID NO 200 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27G SEQ ID NO 201 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27H SEQ ID NO 202 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27I SEQ ID NO 203 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27K SEQ ID NO 204 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27L SEQ ID NO 205 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27M SEQ ID NO 206 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27N SEQ ID NO 207 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27P SEQ ID NO 208 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27Q SEQ ID NO 209 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27R SEQ ID NO 210 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27S SEQ ID NO 211 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27T SEQ ID NO 212 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27V SEQ ID NO 213 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27W SEQ ID NO 214 Nucleotide sequence of Aldel_S2P_G39S_S47G_D27Y SEQ ID NO 215 Amino acid sequence of Aldel_S2P_G39S_S47G_D27A SEQ ID NO 216 Amino acid sequence of Aldel_S2P_G39S_S47G_D27C SEQ ID NO 217 Amino acid sequence of Aldel S2P G39S S47G D27E SEQ ID NO 218 Amino acid sequence of Aldel_S2P_G39S_S47G_D27F SEQ ID NO 219 Amino acid sequence of Aldel_S2P_G39S_S47G_D27G SEQ ID NO 220 Amino acid sequence of Aldel_S2P_G39S_S47G_D27H SEQ ID NO 221 Amino acid sequence of Aldel S2P G39S S47G D27ISEQ ID NO Ill Amino acid sequence of Aldel_S2P_G39S_S47G_D27K SEQ ID NO 223 Amino acid sequence of Aldel_S2P_G39S_S47G_D27L SEQ ID NO 224 Amino acid sequence of Aldel_S2P_G39S_S47G_D27M SEQ ID NO 225 Amino acid sequence of Aldel_S2P_G39S_S47G_D27N SEQ ID NO 226 Amino acid sequence of Aldel_S2P_G39S_S47G_D27P SEQ ID NO 227 Amino acid sequence of Aldel_S2P_G39S_S47G_D27Q SEQ ID NO 228 Amino acid sequence of Aldel_S2P_G39S_S47G_D27R SEQ ID NO 229 Amino acid sequence of Aldel_S2P_G39S_S47G_D27S SEQ ID NO 230 Amino acid sequence of Aldel_S2P_G39S_S47G_D27T SEQ ID NO 231 Amino acid sequence of Aldel_S2P_G39S_S47G_D27V SEQ ID NO 232 Amino acid sequence of Aldel_S2P_G39S_S47G_D27W SEQ ID NO 233 Amino acid sequence of Aldel_S2P_G39S_S47G_D27Y SEQ ID NO 234 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33A SEQ ID NO 235 Nucleotide sequence of Aldel S2P G39S S47G S33C SEQ ID NO 236 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33D SEQ ID NO 237 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33E SEQ ID NO 238 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33F SEQ ID NO 239 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33G SEQ ID NO 240 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33H SEQ ID NO 241 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33I SEQ ID NO 242 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33K SEQ ID NO 243 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33L SEQ ID NO 244 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33M SEQ ID NO 245 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33N SEQ ID NO 246 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33P SEQ ID NO 247 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33Q SEQ ID NO 248 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33R SEQ ID NO 249 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33T SEQ ID NO 250 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33V SEQ ID NO 251 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33W SEQ ID NO 252 Nucleotide sequence of Aldel_S2P_G39S_S47G_S33Y SEQ ID NO 253 Amino acid sequence of Aldel_S2P_G39S_S47G_S33A SEQ ID NO 254 Amino acid sequence of Aldel_S2P_G39S_S47G_S33C SEQ ID NO 255 Amino acid sequence of Aldel_S2P_G39S_S47G_S33D SEQ ID NO 256 Amino acid sequence of Aldel S2P G39S S47G S33E SEQ ID NO 257 Amino acid sequence of Aldel_S2P_G39S_S47G_S33F SEQ ID NO 258 Amino acid sequence of Aldel_S2P_G39S_S47G_S33G SEQ ID NO 259 Amino acid sequence of Aldel_S2P_G39S_S47G_S33H SEQ ID NO 260 Amino acid sequence of Aldel S2P G39S S47G S33ISEQ ID NO 261 Amino acid sequence of Aldel_S2P_G39S_S47G_S33K SEQ ID NO 262 Amino acid sequence of Aldel_S2P_G39S_S47G_S33L SEQ ID NO 263 Amino acid sequence of Aldel_S2P_G39S_S47G_S33M SEQ ID NO 264 Amino acid sequence of Aldel_S2P_G39S_S47G_S33N SEQ ID NO 265 Amino acid sequence of Aldel_S2P_G39S_S47G_S33P SEQ ID NO 266 Amino acid sequence of Aldel_S2P_G39S_S47G_S33Q SEQ ID NO 267 Amino acid sequence of Aldel_S2P_G39S_S47G_S33R SEQ ID NO 268 Amino acid sequence of Aldel_S2P_G39S_S47G_S33T SEQ ID NO 269 Amino acid sequence of Aldel_S2P_G39S_S47G_S33V SEQ ID NO 270 Amino acid sequence of Aldel_S2P_G39S_S47G_S33W SEQ ID NO 271 Amino acid sequence of Aldel_S2P_G39S_S47G_S33Y SEQ ID NO 272 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36C SEQ ID NO 273 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36D SEQ ID NO 274 Nucleotide sequence of Aldel S2P G39S S47G S36E SEQ ID NO 275 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36F SEQ ID NO 276 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36G SEQ ID NO 277 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36H SEQ ID NO 278 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36I SEQ ID NO 279 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36K SEQ ID NO 280 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36M SEQ ID NO 281 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36N SEQ ID NO 282 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36Q SEQ ID NO 283 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36R SEQ ID NO 284 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36T SEQ ID NO 285 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36W SEQ ID NO 286 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36Y SEQ ID NO 287 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36A SEQ ID NO 288 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36L SEQ ID NO 289 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36P SEQ ID NO 290 Nucleotide sequence of Aldel_S2P_G39S_S47G_S36V SEQ ID NO 291 Amino acid sequence of Aldel_S2P_G39S_S47G_S36C SEQ ID NO 292 Amino acid sequence of Aldel_S2P_G39S_S47G_S36D SEQ ID NO 293 Amino acid sequence of Aldel_S2P_G39S_S47G_S36E SEQ ID NO 294 Amino acid sequence of Aldel_S2P_G39S_S47G_S36F SEQ ID NO 295 Amino acid sequence of Aldel S2P G39S S47G S36G SEQ ID NO 296 Amino acid sequence of Aldel_S2P_G39S_S47G_S36H SEQ ID NO 297 Amino acid sequence of Aldel_S2P_G39S_S47G_S36I SEQ ID NO 298 Amino acid sequence of Aldel_S2P_G39S_S47G_S36K SEQ ID NO 299 Amino acid sequence of Aldel S2P G39S S47G S36MSEQ ID NO: 300 Amino acid sequence of Aldel_S2P_G39S_S47G_S36N

[0390] SEQ ID NO: 301 Amino acid sequence of Aldel_S2P_G39S_S47G_S36Q

[0391] SEQ ID NO: 302 Amino acid sequence of Aldel_S2P_G39S_S47G_S36R

[0392] SEQ ID NO: 303 Amino acid sequence of Aldel_S2P_G39S_S47G_S36T

[0393] SEQ ID NO: 304 Amino acid sequence of Aldel_S2P_G39S_S47G_S36W

[0394] SEQ ID NO: 305 Amino acid sequence of Aldel_S2P_G39S_S47G_S36Y

[0395] SEQ ID NO: 306 Amino acid sequence of Aldel_S2P_G39S_S47G_S36A

[0396] SEQ ID NO: 307 Amino acid sequence of Aldel_S2P_G39S_S47G_S36L

[0397] SEQ ID NO: 308 Amino acid sequence of Aldel_S2P_G39S_S47G_S36P

[0398] SEQ ID NO: 309 Amino acid sequence of Aldel_S2P_G39S_S47G_S36V

[0399] SEQ ID NO: 310 Nucleotide sequence of B2_ML (Aldel_S2P_A26R_S36R_G39S_S47G) SEQ ID NO: 311 Nucleotide sequence of B3_ML (Aldel_S2P_T9R_S36R_G39S_S47G) SEQ ID NO: 312 Nucleotide sequence of B4_ML_(Aldel_S2P_Q22R_S36R_G39S_S47G) SEQ ID NO: 313 Nucleotide sequence of B5 ML (Aldel S2P Q34R S36W G39S S47G) SEQ ID NO: 314 Nucleotide sequence of B6 ML (Aldel_S2P_A26R_S36W_G39S_S47G) SEQ ID NO: 315 Nucleotide sequence of B7 ML (Aldel_S2P_A26R_Q34R_S36R_G39S_S47G) SEQ ID NO: 316 Nucleotide sequence of B8 ML (Aldel_S2P_T9R_Q34R_S36R_G39S_S47G) SEQ ID NO: 317 Nucleotide sequence of B9 ML (Aldel_S2P_Q22R_Q34R_S36R_G39S_S47G) SEQ ID NO: 318 Nucleotide sequence of B10 ML (Aldel_S2P_T9R_Q34R_S36W_G39S_S47G) SEQ ID NO: 319 Nucleotide sequence of B11 ML

[0400] (A 1 del_S2P_A26R_S36R G39S_K45R_S47G)

[0401] SEQ ID NO: 320 Amino acid sequence of B2_ML (Aldel_S2P_A26R_S36R_G39S_S47G) SEQ ID NO: 321 Amino acid sequence of B3_ML (Aldel_S2P_T9R_S36R_G39S_S47G) SEQ ID NO: 322 Amino acid sequence of B4_ML_(Aldel_S2P_Q22R_S36R_G39S_S47G) SEQ ID NO: 323 Amino acid sequence of B5_ML (Aldel_S2P_Q34R_S36W_G39S_S47G) SEQ ID NO: 324 Amino acid sequence of B6_ML (Aldel_S2P_A26R_S36W_G39S_S47G) SEQ ID NO: 325 Amino acid sequence of B7_ML (Aldel_S2P_A26R_Q34R_S36R_G39S_S47G)

[0402] SEQ ID NO: 326 Amino acid sequence of B8_ML (Aldel_S2P_T9R_Q34R_S36R_G39S_S47G) SEQ ID NO: 327 Amino acid sequence of B9_ML (Aldel_S2P_Q22R_Q34R_S36R_G39S_S47G)

[0403] SEQ ID NO: 328 Amino acid sequence of B10 ML

[0404] (A 1 del_S2P_T9R_Q34R_S36W G39S S47G)

[0405] SEQ ID NO: 329 Amino acid sequence of B 11_ML

[0406] (A 1 del S2P A26R S36R G39S K45R S47G)

[0407] Detailed description

[0408] General Techniques and DefinitionsUnless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in genomics, immunology, molecular biology, immunohistochemistry, biochemistry, oncology, and pharmacology).

[0409] The present disclosure is performed using, unless otherwise indicated, conventional techniques of molecular biology, microbiology, recombinant DNA technology and immunology. Such procedures are described, for example in Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, New York, Fourth Edition (2012), whole of Vols I, II, and III; DNA Cloning: A Practical Approach, Vols. I and II (D. N. Glover, Second Edition., 1995), IRL Press, Oxford, whole of text; Oligonucleotide Synthesis: A Practical Approach (M. J. Gait, ed, 1984) IRL Press, Oxford, whole of text, and particularly the papers therein by Gait, ppi -22; Atkinson et al, pp35-81; Sproat etal, pp 83-115; and Wu etal, pp 135-151; 4. Nucleic Acid Hybridization: A Practical Approach (B. D. Hames & S. J. Higgins, eds., 1985) IRL Press, Oxford, whole of text; Immobilized Cells and Enzymes: A Practical Approach (1986) IRL Press, Oxford, whole of text; Perbal, B., A Practical Guide to Molecular Cloning (1984) and Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.), whole of series.

[0410] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features. Thus, each feature of any particular example or embodiment of the present disclosure may be applied mutatis mutandis to any other example or embodiment of the present disclosure.

[0411] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and methods are clearly within the scope of the disclosure, as described herein.

[0412] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0413] As used herein, the singular forms of “a”, “and” and “the” include plural forms of these words, unless the context clearly dictates otherwise.

[0414] The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.

[0415] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated element, integer or step,or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0416] The term “about” in relation to a numerical value x is optional and means, for example, any number within 1, 5 or 10% of the referenced number. The term “about” also encompasses the exact number recited.

[0417] Modified Receptors

[0418] As described herein, the inventors have identified and produced modified receptors having reduced binding properties for the cognate native ligands and / or which have improved binding properties for the ligands of the present disclosure. In particular, the inventors have identified and produced variants of C-C Chemokine Receptor 5 (CCR5) comprising amino acid substitutions relative to the native CCR5 which confer improved binding properties to the variant CCR5 relative to the native CCR5. CCR5 is a protein on the surface of white blood cells that acts as a receptor for chemokines (e.g., CCL3 and LD78P). The amino acid sequence of CCR5 is publicly-available and an exemplary amino acid sequence of native CCR5 is set forth in SEQ ID NO: 1. An exemplary nucleotide sequence of native CCR5 is set forth in SEQ ID NO: 2. In some examples, the CCR5 variants of the disclosure have increased affinity for binding to the ligand disclosed herein relative the affinity of the native CCR5 to bind the ligand disclosed herein. Alternatively, or in addition, the CCR5 variants of the disclosure have decreased affinity for binding to the native CCL3 ligand (or native isoforms thereof) relative the affinity of the native CCR5 to bind the native CCL3 ligand (or native isoforms thereof).

[0419] Accordingly, the present disclosure provides a receptor comprising a binding domain corresponding to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1. That is, a binding domain corresponding to CCR5.

[0420] As used herein, the term “receptor” will be understood to refer generally to a polypeptide or protein molecule which is capable of binding to one or more cognate molecules or substances (e.g., a ligand), and thereby cause some effect in a cell or biological system, including, but not limited to, chemical signalling between and within cells.

[0421] As used herein, the terms “binds” or “binding” in reference to the interaction of a receptor and a ligand will be understood to mean that an interaction occurs between particular structure(s) on the receptor and particular structure(s) on the ligand which leads to an association between the receptor and the ligand. Such terminology is commonly used and understood in the art, and such understanding is suitable in the context of the present disclosure.

[0422] As described, the receptor of the disclosure comprises a binding domain. As used herein, the term “binding domain” refers to a region or regions of a peptide, polypeptide or protein which is capable of binding to a particular structure(s) on another molecule (e.g., on a ligand). The receptor of the disclosure comprises a “binding domain” corresponding to the binding domain of native CCR5. For example, the receptor of the disclosure may comprise abinding domain corresponding to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1. Preferably the binding domain of the receptor will have a high level of sequence identity relative to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1. For example, the binding domain may have at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1.

[0423] Terms of the art used to describe sequence relationships between respective proteins and nucleic acids, including “comparison window”, “sequence identity”, “percentage of sequence identity” and “substantial identity” may be used herein. Because respective nucleic acids / proteins may each comprise (1) only one or more portions of a complete nucleic acid / protein sequence that are shared by the nucleic acids / proteins, and (2) one or more portions which are divergent between the nucleic acids / proteins, sequence comparisons are typically performed by comparing sequences over a “comparison window” to identify and compare local regions of sequence similarity. A “comparison window” refers to a conceptual segment of contiguous residues that is compared to a reference sequence. The comparison window may comprise additions or deletions (i.e., gaps) of about 20% or less as compared to the reference sequence for optimal alignment of the respective sequences. Optimal alignment of sequences for aligning a comparison window may be conducted by computerised implementations of algorithms (Geneworks program by Intelligenetics; GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Drive Madison, WI, USA, incorporated herein by reference) or by inspection and the best alignment (i.e., resulting in the highest percentage homology over the comparison window) generated by any of the various methods selected. Reference also may be made to the BLAST family of programs as for example disclosed by Altschul et al., 1991, Nucl. Acids Res. 253389, which is incorporated herein by reference. A detailed discussion of sequence analysis can be found in Unit 19.3 of Current Protocols In Molecular Biology Eds. Ausubel et al. (John Wiley & Sons Inc NY, 1995-1999). Thus, for example, the identification of a “binding domain” as disclosed herein may be performed using a comparison window constructed by reference to any one or more exemplary sequences herein.

[0424] Specifically, the term “sequence identity” is used herein in its broadest sense to include the number of exact nucleotide or amino acid matches having regard to an appropriate alignment using a standard algorithm, having regard to the extent that sequences are identical over a window of comparison. Thus, a “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U) or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., thewindow size; e.g., the size of the binding domain as described herein), and multiplying the result by 100 to yield the percentage of sequence identity.

[0425] In addition to having a high level of sequence identity relative to the binding domain of CCR5 as described herein, the receptor of the disclosure may have a high level of sequence identity to the full-length amino acid sequence of CCR5. For examples, the receptor disclosed herein may comprise an amino acid sequence having at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1.

[0426] In accordance with certain examples, the receptor disclosed herein may comprise an extracellular domain, such as an extracellular domain corresponding to the extracellular domain of CCR5. As used herein, the term “extracellular domain” shall be understood to mean a region or regions of a peptide or polypeptide or protein of the receptor which occurs, or is situated, outside of a cell. In some examples, the extracellular domain of the receptor disclosed herein may correspond to amino acids 1 to 27, 93 to 95, 168 to 178 and 265 to 274 in the amino acid sequence set forth in SEQ ID NO: 1. For example, the receptor disclosed herein may comprise an extracellular domain comprising or consisting of an amino acid sequence having at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to amino acids 1 to 27, 93 to 95, 168 to 178 and 265 to 274 in the amino acid sequence set forth in SEQ ID NO: 1.

[0427] The receptor disclosed herein may also comprise a transmembrane domain, such as a transmembrane domain corresponding to the transmembrane domain of CCR5. By “transmembrane domain” it is meant a region(s) of a peptide or polypeptide or protein which spans the membrane of a cell (e.g., spans a phospholipid bilayer). The transmembrane domain of the receptor disclosed herein may correspond to amino acids 28 to 57, 61 to 92, 96 to 120, 141 to 167, 179 to 215, 236 to 264 and 275 to 300 in the amino acid sequence set forth in SEQ ID NO: 1. The receptor disclosed herein may comprise a transmembrane domain comprising or consisting of an amino acid sequence having at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to amino acids 28 to 57, 61 to 92, 96 to 120, 141 to 167, 179 to 215, 236 to 264 and 275 to 300 in the amino acid sequence set forth in SEQ ID NO: 1.

[0428] The receptor disclosed herein may comprise an extracellular domain and transmembrane domain as disclosed herein. Accordingly, the receptor disclosed herein may comprise an extracellular domain comprising or consisting of an amino acid sequence having at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to amino acids 1 to 27, 93 to 95, 168 to 178 and 265 to 274 in the amino acid sequence set forth in SEQ ID NO: 1, and may comprise a transmembrane domain comprising or consisting of an aminoacid sequence having at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to amino acids 28 to 57, 61 to 92, 96 to 120, 141 to 167, 179 to 215, 236 to 264 and 275 to 300 in the amino acid sequence set forth in SEQ ID NO: 1.

[0429] The receptor disclosed herein may comprise an intracellular domain, such as an intracellular domain corresponding to the intracellular domain of CCR5. By “intracellular domain” it is meant a region or regions of a peptide or polypeptide or protein which occurs, or is situated within, a cell. The intracellular domain of the receptor disclosed herein may correspond to amino acids 58 to 60, 121 to 140, 216 to 235 and 301 to 352 in the amino acid sequence set forth in SEQ ID NO: 1. Thus, the receptor disclosed herein may comprise an intracellular domain comprising or consisting of an amino acid sequence having at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to amino acids 58 to 60, 121 to 140, 216 to 235 and 301 to 352 in the amino acid sequence set forth in SEQ ID NO: 1.

[0430] As described herein, the receptors of the disclosure are variants of CCR5 comprising amino acid substitutions relative to the native CCR5. Exemplary amino acid substitutions are described below. However, it will be appreciated that the receptor, and / or the binding domain therein, may further comprise one or more conservative amino acid substitution(s) in addition to those amino acid substitutions set out below. As used herein, a “conservative substitution” shall be understood to mean the replacement of an amino acid in a polypeptide by another amino acid with similar characteristics; such substitutions are not likely to change the shape of the polypeptide chain (e.g., substituting one hydrophobic amino acid for another). Methods for determining conservative substitutions are known in the art and any such method can be employed herein. Conservative substitutions are known in the art and any such conservative substitutions can be employed herein.

[0431] In one example, the receptor of the disclosure comprises a binding domain corresponding to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1 (e.g., a binding domain having at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1) wherein the receptor comprises one or more (e.g., two, or three, or four, or five, or six, or seven, or eight, or nine, or ten or more) of the following amino acids:

[0432] (a) aspartic acid at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;

[0433] (b) leucine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;(c) arginine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;

[0434] (d) lysine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;

[0435] (e) aspartic acid at a position corresponding to amino acid 32 in the amino acid sequence set forth in SEQ ID NO: 1;

[0436] (f) serine at a position corresponding to amino acid 89 in the amino acid sequence set forth in SEQ ID NO: 1;

[0437] (g) alanine at a position corresponding to amino acid 94 in the amino acid sequence set forth in SEQ ID NO: 1;

[0438] (h) phenylalanine at a position corresponding to amino acid 104 in the amino acid sequence set forth in SEQ ID NO: 1;

[0439] (i) asparagine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1;

[0440] (j) leucine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1;

[0441] (k) aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0442] (l) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0443] (m) leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0444] (n) asparagine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0445] (o) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0446] (p) serine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0447] (q) methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;

[0448] (r) serine at a position corresponding to amino acid 172 in the amino acid sequence set forth in SEQ ID NO: 1;

[0449] (s) glutamic acid at a position corresponding to amino acid 179 in the amino acid sequence set forth in SEQ ID NO: 1;

[0450] (t) glutamic acid at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1;

[0451] (u) glutamine at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1;(v) glutamic acid at a position corresponding to amino acid 181 in the amino acid sequence set forth in SEQ ID NO: 1;

[0452] (w) aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;

[0453] (x) glutamic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;

[0454] (y) glycine at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;

[0455] (z) serine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0456] (aa) glutamic acid at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0457] (bb) arginine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0458] (cc) histidine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;

[0459] (dd) glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0460] (ee) leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0461] (ff) histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0462] (gg) aspartic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0463] (hh) tryptophan at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0464] (ii) serine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0465] (jj) cysteine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0466] (kk) methionine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;

[0467] (11) histidine at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;

[0468] (mm) glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;

[0469] (nn) arginine at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;(oo) aspartic acid at a position corresponding to amino acid 262 in the amino acid sequence set forth in SEQ ID NO: 1;

[0470] (pp) threonine at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1;

[0471] (qq) glutamic acid at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1;

[0472] (rr) arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1;

[0473] (ss) arginine at a position corresponding to amino acid 291 in the amino acid sequence set forth in SEQ ID NO: 1; or

[0474] (tt) any combination thereof with the exception of combinations of different amino acids at the same position relative to the sequence set forth in SEQ ID NO: 1.

[0475] The receptor disclosed herein may comprise aspartic acid at position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1.

[0476] The receptor disclosed herein may comprise leucine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1.

[0477] The receptor disclosed herein may comprise arginine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1.

[0478] The receptor disclosed herein may comprise lysine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1.

[0479] The receptor disclosed herein may comprise aspartic acid at a position corresponding to amino acid 32 in the amino acid sequence set forth in SEQ ID NO: 1.

[0480] The receptor disclosed herein may comprise serine at a position corresponding to amino acid 89 in the amino acid sequence set forth in SEQ ID NO: 1.

[0481] The receptor disclosed herein may comprise alanine at a position corresponding to amino acid 94 in the amino acid sequence set forth in SEQ ID NO: 1.

[0482] The receptor disclosed herein may comprise phenylalanine at a position corresponding to amino acid 104 in the amino acid sequence set forth in SEQ ID NO: 1.

[0483] The receptor disclosed herein may comprise asparagine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1.

[0484] The receptor disclosed herein may comprise leucine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1.

[0485] The receptor disclosed herein may comprise methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1.

[0486] The receptor disclosed herein may comprise serine at a position corresponding to amino acid 172 in the amino acid sequence set forth in SEQ ID NO: 1.

[0487] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 179 in the amino acid sequence set forth in SEQ ID NO: 1.The receptor disclosed herein may comprise glutamine at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1.

[0488] The receptor disclosed herein may comprise glycine at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1.

[0489] The receptor disclosed herein may comprise arginine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1.

[0490] The receptor disclosed herein may comprise histidine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1.

[0491] The receptor disclosed herein may comprise methionine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0492] The receptor disclosed herein may comprise histidine at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1.

[0493] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1.

[0494] The receptor disclosed herein may comprise arginine at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1.

[0495] The receptor disclosed herein may comprise aspartic acid at position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1.

[0496] The receptor disclosed herein may comprise glutamic acid at position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1.

[0497] The receptor disclosed herein may comprise leucine at position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1.

[0498] The receptor disclosed herein may comprise asparagine at position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1.

[0499] The receptor disclosed herein may comprise glutamine at position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1.

[0500] The receptor disclosed herein may comprise serine at position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1.

[0501] The receptor disclosed herein may comprise glutamic acid at position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1.

[0502] The receptor disclosed herein may comprise glutamic acid at position corresponding to amino acid 181 in the amino acid sequence set forth in SEQ ID NO: 1.

[0503] The receptor disclosed herein may comprise aspartic acid at position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1.

[0504] The receptor disclosed herein may comprise glutamic acid at position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1.

[0505] The receptor disclosed herein may comprise serine at position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1.The receptor disclosed herein may comprise glutamic acid at position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1.

[0506] The receptor disclosed herein may comprise glutamic acid at position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0507] The receptor disclosed herein may comprise leucine at position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0508] The receptor disclosed herein may comprise histidine at position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0509] The receptor disclosed herein may comprise aspartic acid at position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0510] The receptor disclosed herein may comprise tryptophan at position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0511] The receptor disclosed herein may comprise serine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0512] The receptor disclosed herein may comprise cysteine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0513] The receptor disclosed herein may comprise aspartic acid at a position corresponding to amino acid 262 in the amino acid sequence set forth in SEQ ID NO: 1.

[0514] The receptor disclosed herein may comprise threonine at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1.

[0515] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1.

[0516] The receptor disclosed herein may comprise arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1.

[0517] The receptor disclosed herein may comprise arginine at a position corresponding to amino acid 291 in the amino acid sequence set forth in SEQ ID NO: 1.

[0518] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and serine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1.

[0519] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 262 in the amino acid sequence set forth in SEQ ID NO: 1.

[0520] The receptor disclosed herein may comprise aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0521] The receptor disclosed herein may comprise glutamine at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at aposition corresponding to amino acid 181 in the amino acid sequence set forth in SEQ ID NO: 1.

[0522] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0523] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1.

[0524] The receptor disclosed herein may comprise aspartic acid at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1, glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and cysteine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0525] The receptor disclosed herein may comprise leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0526] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0527] The receptor disclosed herein may comprise glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0528] The receptor disclosed herein may comprise leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and tryptophan at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0529] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0530] The receptor disclosed herein may comprise asparagine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.The receptor disclosed herein may comprise aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0531] The receptor disclosed herein may comprise glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0532] The receptor disclosed herein may comprise aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0533] The receptor disclosed herein may comprise lysine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1.

[0534] The receptor disclosed herein may comprise arginine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1, aspartic acid at a position corresponding to amino acid 32 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1

[0535] The receptor disclosed herein may comprise serine at a position corresponding to amino acid 89 in the amino acid sequence set forth in SEQ ID NO: 1 and phenylalanine at a position corresponding to amino acid 104 in the amino acid sequence set forth in SEQ ID NO: 1.

[0536] The receptor disclosed herein may comprise asparagine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1.

[0537] The receptor disclosed herein may comprise glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1.

[0538] The receptor disclosed herein may comprise serine at a position corresponding to amino acid 172 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1.

[0539] The receptor disclosed herein may comprise histidine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1.

[0540] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at aposition corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1.

[0541] The receptor disclosed herein may comprise glutamic acid at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1, arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at a position corresponding to amino acid 291 in the amino acid sequence set forth in SEQ ID NO: 1.

[0542] In addition, the receptor disclosed herein may be encoded by any of the polynucleotide sequences disclosed herein, such as those set forth in SEQ ID NOs: 7 to 45. For example, the receptor of the disclosure may comprise an amino acid sequence encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

[0543] As used herein the phrase “corresponding to” in reference to the position of an amino acid in a SEQ ID NO should be understood as reference to an amino acid residue or position within a given polypeptide or protein (e.g., a receptor or a ligand), without necessarily requiring that given polypeptide or protein to have the entire or exact sequence set out in the recited SEQ ID NO

[0544] As used herein, an “amino acid substitution” refers to the replacement of an amino acid at a particular position in a polypeptide sequence with another amino acid. Exemplary methods for introducing amino acid substitutions to a polypeptide sequence are described herein or known in the art, and include:

[0545] • mutagenesis of DNA (Thie et al., Methods Mol. Biol. 525: 309-322, 2009) or RNA (Kopsidas et al., Immunol. Lett. 707: 163-168, 2006; Kopsidas etal. BMC Biotechnology, 7: 18, 2007; and WO1999 / 058661);

[0546] • introducing a nucleic acid encoding the polypeptide into a mutator cell, e.g., XL-lRed, XL-mutS and XL-mutS-Kanr bacterial cells (Stratagene);

[0547] • DNA shuffling, e.g., as disclosed in Stemmer, Nature 370: 389-91, 1994; and • site directed mutagenesis, e.g., as described in Dieffenbach (ed) and Dveksler (ed) (In: PCR Primer: A Laboratory Manual, Cold Spring Harbor Laboratories, NY, 1995).

[0548] The receptor disclosed herein may be capable of binding to a native (or ‘wild-type’, or ‘unmodified’, or ‘naturally occurring’) C-C Chemokine Ligand 3 (CCL3). CCL3 is a cytokine belonging to the CC chemokine family that is involved in the acute inflammatory state in the recruitment and activation of leukocytes through binding to the receptors CCR1, CCR4 and / or CCR5. The amino acid sequence of CCL3 is publicly available and an exemplary amino acid sequence of native CCL3 is set forth in SEQ ID NO: 3. An exemplary nucleotide sequence of native CCL3 is set forth in SEQ ID NO: 4.

[0549] Alternatively, or in addition, the receptor disclosed herein may be capable of binding to a native (or ‘wild-type’, or ‘unmodified’, or ‘naturally occurring’) LD78 . LD78P (also known as CCL3L1) is an isoform of CCL3 and is a cytokine belonging to the CC chemokine family that is involved in the acute inflammatory state in the recruitment and activation ofleukocytes through binding to the receptor CCR5 and P-chemokine receptor. The amino acid sequence of LD78 is publicly available and an exemplary amino acid sequence of native LD78 is set forth in SEQ ID NO: 5. An exemplary nucleotide sequence of native LD78 is set forth in SEQ ID NO: 6.

[0550] Alternatively, or in addition, the receptor disclosed herein may be capable of binding to any one or more of the ligands disclosed herein. Alternatively, or in addition, the receptor disclosed herein may be capable of selectively binding to any one or more of the ligands disclosed herein.

[0551] As used herein, the term “selectively binding” or “binding selectively” shall be taken to mean that a receptor or a ligand of the disclosure reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a cognate ligand or cognate receptor or cell expressing or secreting same than it does with alternative ligands, receptors or cells. The term “selectively binding” or “binding selectively” can also be taken to mean that a receptor or a ligand of the disclosure reacts or associates with a specific cognate ligand and does not show any significant level of binding to an alternative ligand. Generally, but not necessarily, reference to binding means specific binding, and each term shall be understood to provide explicit support for the other term.

[0552] The receptor disclosed herein may bind with increased affinity to the ligand disclosed herein relative to the affinity of the native CCR5 to bind the ligand disclosed herein. As described herein, the amino acid sequence of CCR5 is publicly available and an exemplary amino acid sequence of native CCR5 is set forth in SEQ ID NO: 1. An exemplary nucleotide sequence of native CCR5 is set forth in SEQ ID NO: 2.

[0553] The terms “increased binding” and “increased affinity” are used herein to refer to an elevated or more frequent level of binding or affinity of a receptor and ligand pair bind. Any suitable relative threshold value may be applied to indicate such an increased binding or affinity. For example, a 10%, 20%, 30%, 40%, 50% or greater level of binding between a test receptor or ligand and a cognate partner compared to a control receptor or ligand binding to the same cognate partner may be a suitable indicator of an “increased” binding or affinity.

[0554] Conversely, the terms “reduced binding” and “reduced affinity” as used herein refer to a decreased or less frequent level of binding or affinity of a receptor and ligand pair to bind. Any suitable relative threshold value may be applied to indicate such a decreased binding or affinity. For example, a 10%, 20%, 30%, 40%, 50% or lesser level of binding between a test receptor or ligand and a cognate partner compared to a control receptor or ligand binding to the same cognate partner may be a suitable indicator of a “decreased” binding or affinity.

[0555] For the purposes of clarification, and as will be apparent to the skilled person based on the exemplified subject matter herein, reference to “affinity” in this specification is a reference to the interaction, binding or association of a receptor with a ligand.

[0556] The receptor disclosed herein may bind to a native CCL3. Alternatively, or in addition, the receptor disclosed herein may bind to a native LD78p. Alternatively, or in addition, thereceptor disclosed herein may bind to a ligand disclosed herein. However, in certain examples, the receptor described herein may be capable of selectively binding to a ligand having one or more amino acid substitutions relative to the native CCL3 or native LD78P as described herein, over the native CCL3 counterpart or isoforms there (e.g., LD780).

[0557] Methods for determining the binding affinity of a receptor to a ligand (or vice versa) will be apparent to the skilled person and / or are described herein. For example, binding affinity may be determined using one or more of flow cytometry, competitive binding assays, radioligand binding assays, surface plasmon resonance (SPR), NMR spectroscopy, biolayer interferometry (BLI), or isothermal titration calorimetry (ITC), as well as other assays known in the art for measuring binding kinetics.

[0558] For example, binding may be determined by comparing the fluorescence of a control population (e.g., cells expressing no test receptor) to a sample population (e.g., transduced cells expressing a test receptor), wherein the fluorescence results from a fluorescent moiety tagged to a test ligand and / or the test receptor. For example, the control population may not bind to a test ligand and as a result may not exhibit any fluorescence (i.e., no detectable fluorescence emanating from a fluorescent moiety tagged to the test ligand) and the sample population may bind to a test ligand and therefore exhibit fluorescence emanating from a fluorescent moiety tagged to the test ligand (for example, but without limitation, mScarlet-I fluorescence). The binding of a test receptor to a test ligand may be determined using any suitable means, (for example, but without limitation, by flow cytometry), and calculated as a proportional difference between the control population and sample population. Any suitable threshold may be set according to the specific assay method used, to demarcate significant or detectable binding from non-significant or undetectable binding.

[0559] Alternatively, the binding or affinity may be determined by immunoassays, surface plasmon resonance (SPR; e.g., using BIAcore surface plasmon resonance), isothermal titration calorimetry (ITC) or other kinetic interaction assays known in the art.

[0560] The affinity constant (KD), dissociation constant (Kd) and association constant (Ka) may be determined. For example, the affinity constant (KD) is the ratio of the dissociation constant (Kd) and association constant (Ka) (i.e., KD = Kd / Ka).

[0561] Modi fied Ligands

[0562] The inventors have also identified and produced modified ligands having reduced binding properties for the cognate native receptors and / or which have improved binding properties for the receptors of the present disclosure. In particular, the inventors have identified and produced variants of C-C Chemokine Ligand 3 (CCL3) or native isoforms thereof, said variant ligands comprising amino acid substitutions relative to the native CCL3 or its isoform LD78P which improve the binding properties to the variant ligand relative to the native CCL3 or its isoform LD78 . As described herein, CCL3 is a proinflammatory cytokine belonging to the CC chemokine family, and plays a key role in the immune system by regulating thetrafficking of immune cells and the formation of the immune landscape through its binding with CCR1, CCR4 and / or CCR5. The amino acid sequence of CCL3 is publicly-available and an exemplary amino acid sequence of native CCL3 is set forth in SEQ ID NO: 3. An exemplary nucleotide sequence of native CCL3 is set forth in SEQ ID NO: 4. LD780 (also known as CCL3L1) is an isoform of CCL3 and is a cytokine belonging to the CC chemokine family that is involved in the acute inflammatory state in the recruitment and activation of leukocytes through binding to the receptor CCR5 and P-chemokine receptor. The amino acid sequence of LD78P is publicly available and an exemplary amino acid sequence of native LD78P is set forth in SEQ ID NO: 5. An exemplary nucleotide sequence of native LD78 is set forth in SEQ ID NO: 6. In some examples, the modified ligands of the disclosure may have increased affinity for binding to the receptor disclosed herein relative the affinity of the native CCL3 or LD78P to bind the receptor disclosed herein. Alternatively, or in addition, the modified ligands of the disclosure have decreased affinity for binding to the native CCR5 receptor relative the affinity of the native CCL3 or LD78P to bind the native CCR5 receptor.

[0563] Accordingly, the present disclosure provides a ligand comprising a receptor binding domain of CCL3 or an isoform of CCL3 (e.g., LD78P), wherein the ligand comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5, wherein the ligand comprises:

[0564] (a) alanine or arginine at a position corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5, or the amino acid corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5 is absent;

[0565] (b) serine, proline or methionine at a position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5;

[0566] (c) leucine or proline at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5;

[0567] (d) alanine, arginine, isoleucine or valine at a position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0568] (e) alanine or arginine at a position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5;

[0569] (f) aspartic acid, isoleucine or methionine at a position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0570] (g) proline or arginine at a position corresponding to amino acid 8 of the sequence set forth in SEQ ID NO: 3 or 5;

[0571] (h) threonine, leucine, proline or arginine at a position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;

[0572] (i) alanine or arginine at a position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(j) an amino acid substitution at a position corresponding to amino acid 14 of the sequence set forth in SEQ ID NO: 3 or 5, wherein the substitution is relative to the amino acid at position 14 of the sequence set forth in SEQ ID NO: 3 or 5;

[0573] (k) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine or tyrosine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;

[0574] (l) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;

[0575] (m) glutamine or arginine at a position corresponding to amino acid 22 of the sequence set forth in SEQ ID NO: 3 or 5;

[0576] (n) alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;

[0577] (o) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0578] (p) phenylalanine or arginine at a position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5;

[0579] (q) glutamic acid, arginine or tyrosine at a position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0580] (r) serine or arginine at a position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0581] (s) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0582] (t) glutamine or arginine at a position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5;

[0583] (u) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5;

[0584] (v) glycine, serine or tyrosine at a position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(w) isoleucine or arginine at a position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;

[0585] (x) lysine or arginine at a position corresponding to amino acid 45 of the sequence set forth in SEQ ID NO: 3 or 5;

[0586] (y) serine, lysine, tryptophan, or glycine at a position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0587] (z) proline or leucine at a position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5; and / or

[0588] (aa) valine or lysine at a position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

[0589] In one example, the ligand comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 and comprises one or more of the amino acid substitutions described herein.

[0590] In one example, the ligand comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 5 and comprises one or more of the amino acid substitutions described herein.

[0591] As used herein, the term “ligand” will be understood to refer to a molecule that binds to another molecule or structure (e.g., a receptor). The ligand may be a peptide or polypeptide or protein.

[0592] As described herein, the ligand comprises a receptor binding domain corresponding to CCL3 or an isoform thereof (e.g., LD780). The term “receptor binding domain” as used herein shall be understood to mean a region or regions of a peptide or polypeptide which binds to a region or regions on or from a cognate receptor (e.g., a binding domain of a receptor, as described herein). In accordance with examples in which the ligand comprises a receptor binding domain corresponding to CCL3 or LD780, the receptor binding domain has at least 90% (e.g., at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%) sequence identity to amino acids 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 in the amino acid sequence set forth in SEQ ID NO: 3 or 5. For example, the receptor binding domain may have at least 90% (e.g., at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%) sequence identity to amino acids 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 in the amino acid sequence set forth in SEQ ID NO: 3. For example, the receptor binding domain may have at least 90% (e.g., at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%) sequence identity to amino acids 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 in the amino acid sequence set forth in SEQ ID NO: 5.

[0593] In some examples, the ligand disclosed herein comprises an amino acid sequence having at least 90%, or at least 91.4%, or at least 92.5%, or at least 94.2%, or at least 95.7%, or at least 97.1%, or at least 98.5% sequence identity to the amino acid sequence set forth inSEQ ID NO: 3. For example, the ligand may comprise 1, or 2, or 3, or 4, or 5 or 6 or 7 amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO: 3.

[0594] In some examples, the ligand disclosed herein comprises an amino acid sequence having at least 90%, or at least 91.4%, or at least 92.5%, or at least 94.2%, or at least 95.7%, or at least 97.1%, or at least 98.5% sequence identity to the amino acid sequence set forth in SEQ ID NO: 5. For example, the ligand may comprise 1, or 2, or 3, or 4, or 5 or 6 or 7 amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO: 5.

[0595] Exemplary amino acid substitutions are described above and below relative to native CCL3 and LD78p. However, it will be appreciated that the ligand may further comprise one or more conservative amino acid substitution(s) in addition to those amino acid substitutions set out below. As used herein, a “conservative substitution” shall be understood to mean the replacement of an amino acid in a polypeptide by another amino acid with similar characteristics; such substitutions are not likely to change the shape of the polypeptide chain (e.g., substituting one hydrophobic amino acid for another). Methods for determining conservative substitutions are known in the art and any such method can be employed herein. Conservative substitutions are known in the art and any such conservative substitutions can be employed herein.

[0596] In one example, the ligand disclosed herein comprises an alanine or arginine at a position corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5, or the amino acid corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5 is absent. Alternatively, or in addition, the ligand disclosed herein comprises a serine, proline or methionine at a position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a leucine or proline at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine, arginine, isoleucine or valine at a position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine or arginine at a position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an aspartic acid, isoleucine or methionine at a position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a proline or arginine at a position corresponding to amino acid 8 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a threonine, leucine, proline or arginine at a position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine or arginine at a position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an amino acid substitution at a position corresponding to amino acid 14 of the sequence set forth in SEQ ID NO: 3 or 5, wherein the substitution is relative to the aminoacid at position 14 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a glutamine or arginine at a position corresponding to amino acid 22 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a phenylalanine or arginine at a position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a glutamic acid, arginine or tyrosine at a position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a serine or arginine at a position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a glutamine or arginine at a position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a glycine, serine or tyrosine at a position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an isoleucine or arginine at a position corresponding to amino acid 41 of the sequence set forthin SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a lysine or arginine at a position corresponding to amino acid 45 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a serine, lysine, tryptophan, or glycine at a position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a proline or leucine at a position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a valine or lysine at a position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

[0597] In one example, the ligand of the disclosure comprises one or more (e.g., 2 or 3 or 4 or more) amino acid substitutions at residue positions 16, 17, 26, 27, 33 and 33 relative to the sequence set forth in SEQ ID NO: 3 or 5.

[0598] In one example, the ligand of the disclosure may comprise one or more (e.g., 2 or 3 or 4 or more) of:

[0599] (a) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;

[0600] (b) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;

[0601] (c) alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;

[0602] (d) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0603] (e) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5; and / or

[0604] (f) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.In one example, the ligand disclosed herein comprises alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

[0605] In one example, the ligand of the disclosure comprises one or more (e.g., 2 or 3 or 4 or more) of:

[0606] (a) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;

[0607] (b) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;

[0608] (c) alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;(d) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0609] (e) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5; and / or

[0610] (f) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

[0611] In one example, the ligand of the disclosure comprises alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

[0612] In one example, the ligand of the disclosure comprises one or more (e.g., 2 or 3 or 4 or more) of:(a) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;

[0613] (b) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;

[0614] (c) alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;

[0615] (d) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0616] (e) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5; and / or

[0617] (f) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

[0618] In one example, the ligand of the disclosure comprises alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a positioncorresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

[0619] In one example, the ligand of the disclosure comprises one or more (e.g., 2 or 3 or 4 or more) of:

[0620] (a) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;

[0621] (b) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;

[0622] (c) alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;

[0623] (d) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0624] (e) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5; and / or

[0625] (f) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

[0626] In one example, the ligand of the disclosure comprises alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively,or in addition, the ligand disclosed herein comprises alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

[0627] In another example, the ligand of the disclosure comprises one or more (e.g., 2 or 3 or 4 or more) of:

[0628] (a) alanine or arginine at a position corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5, or the amino acid corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5 is absent;

[0629] (b) serine, proline or methionine at a position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5;

[0630] (c) leucine or proline at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5;

[0631] (d) alanine, arginine, isoleucine or valine at a position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0632] (e) alanine or arginine at a position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5;

[0633] (f) aspartic acid, isoleucine or methionine at a position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0634] (g) proline or arginine at a position corresponding to amino acid 8 of the sequence set forth in SEQ ID NO: 3 or 5;

[0635] (h) threonine, leucine, proline or arginine at a position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;(i) alanine or arginine at a position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0636] (j) an amino acid substitution at a position corresponding to amino acid 14 of the sequence set forth in SEQ ID NO: 3 or 5, wherein the substitution is relative to the amino acid at position 14 of the sequence set forth in SEQ ID NO: 3 or 5;

[0637] (k) isoleucine, methionine and valine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;

[0638] (l) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;

[0639] (m) glutamine or arginine at a position corresponding to amino acid 22 of the sequence set forth in SEQ ID NO: 3 or 5;

[0640] (n) alanine, tyrosine, lysine or arginine at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;

[0641] (o) aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0642] (p) phenylalanine or arginine at a position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5;

[0643] (q) glutamic acid, arginine or tyrosine at a position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0644] (r) serine or arginine at a position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0645] (s) serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0646] (t) glutamine or arginine at a position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5;

[0647] (u) serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5;

[0648] (v) glycine, serine or tyrosine at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5;

[0649] (w) isoleucine or arginine at a position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;

[0650] (x) lysine or arginine at a position corresponding to amino acid 45 of the sequence set forth in SEQ ID NO: 3 or 5;

[0651] (y) serine, lysine, tryptophan, or glycine at a position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;(z) proline or leucine at a position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5; and / or

[0652] (aa) valine or lysine at a position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

[0653] In one example, the ligand disclosed herein comprises an alanine or arginine at a position corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5, or the amino acid corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5 is absent. Alternatively, or in addition, the ligand disclosed herein comprises a serine, proline or methionine at a position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises a leucine or proline at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine, arginine, isoleucine or valine at a position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an alanine or arginine at a position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an aspartic acid, isoleucine or methionine at a position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein comprises an proline or arginine at a position corresponding to amino acid 8 of the sequence set forth in SEQ ID NO: 3 or 5 Alternatively, or in addition, the ligand disclosed herein comprises a threonine, leucine, proline or arginine at a position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise an alanine or arginine at a position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise an amino acid substitution at a position corresponding to amino acid 14 of the sequence set forth in SEQ ID NO: 3 or 5, wherein the substitution is relative to the amino acid at position 14 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise an isoleucine, methionine and valine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise an alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a glutamine or arginine at a position corresponding to amino acid 22 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise an alanine, tyrosine, lysine or arginine at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise an aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of thesequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a phenylalanine or arginine at a position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a glutamic acid, arginine or tyrosine at a position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a serine or arginine at a position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a glutamine or arginine at a position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a glycine, serine or tyrosine at a position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise an isoleucine or arginine at a position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a lysine or arginine at a position corresponding to amino acid 45 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a serine, lysine, tryptophan, or glycine at a position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a proline or leucine at a position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5. Alternatively, or in addition, the ligand disclosed herein may comprise a valine or lysine at a position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

[0654] According to some examples, the ligand of the disclosure comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5 (e.g., at least 91.4%, or at least 92.5%, or at least 94.2%, or at least 95.7%, or at least 97.1%, or at least 98.5% identical to the sequence set forth in SEQ ID NO: 3 or 5) and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5 (e.g., at least 91.4%, or at least 92.5%, or at least 94.2%, or at least 95.7%, or at least 97.1%, or at least 98.5% identical to the sequence set forth in SEQ ID NO: 3 or 5) and comprising one or more amino acid substitutions at residue positions selected from 16, 17, 26, 27, 33 and 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.The ligand disclosed herein may have an increased affinity for binding to a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41 compared to binding affinity of wildtype CCL3 comprising the amino acid sequence set forth in SEQ ID NO: 3, or wildtype LD78P comprising the amino acid sequence set forth in SEQ ID NO: 5, to the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

[0655] In certain examples, the ligand of the disclosure may comprise an amino acid substitution at residue position 26 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0656] In some examples, substitution of the amino acid at position 26 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively increases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41. In one example, the amino acid at position 26 which increases affinity of the ligand for the receptor of the disclosure is a basic amino acid having a positive charge at physiological pH. For example, the ligand may comprise a A26R or A26K substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably a A26R substitution. In another example, the amino acid substitution at position 26 which increases affinity of the ligand for the receptor of the disclosure is a A26D substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0657] In some examples, substitution of the amino acid at position 26 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively decreases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41. For example, the ligand may comprise a A26P, A26V, A26Y, or A26E substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a A26P substitution.

[0658] In certain examples, the ligand of the disclosure may comprise an amino acid substitution at residue position 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0659] In some examples, substitution of the amino acid at position 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively increases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

[0660] In one example, the amino acid at position 36 which increases affinity of the ligand for the receptor of the disclosure is selected from the group consisting of G, F, W, Y, N, K, R, and H. For example, the amino acid at position 36 may be selected from the group consisting of F, W, Y, K, R, and H.

[0661] In one example, the amino acid at position 36 which increases affinity of the ligand for the receptor of the disclosure is a non-polar, uncharged amino acid. For example, the ligand may comprise a S36G, S36F or S36W substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36W substitution.In one example, the amino acid at position 36 which increases affinity of the ligand for the receptor of the disclosure is a polar, uncharged amino acid. For example, the ligand may comprise a S36Y or S36N substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36Y substitution.

[0662] In one example, the amino acid at position 36 which increases affinity of the ligand for the receptor of the disclosure is a positively charged amino acid having a basic side chain at neutral pH. For example, the ligand may comprise a S36K, S36R or S36H substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36R substitution.

[0663] In one example, the amino acid substitution at position 36 increases affinity of the ligand for the receptor of the disclosure and is selected some S36W, S36Y, S36K, S36R and S36H relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36W or S36R substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0664] In other examples, substitution of the amino acid at position 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively decreases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41. For example the amino acid at position 36 which decreases affinity of the ligand for the receptor of the disclosure is selected from the group consisting of C, D, E, I, M, Q and T. For example, the ligand may comprise a S36C, S36D or S36E substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a S36D or S36E substitution.

[0665] In certain examples, the ligand of the disclosure may comprise an amino acid substitution at residue position 16 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

[0666] In some examples, substitution of the amino acid at position 16 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively increases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41. The amino acid at position 16 which increases affinity of the ligand for the receptor of the disclosure may be a hydrophobic amino acid, preferably an aliphatic amino acid which is hydrophobic. For example, the amino acid at position 16 may be selected from the group consisting of I, M and V. Accordingly, the ligand may comprise a T16I, T16M or T16V substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a T16I or T16V substitution.

[0667] In some examples, substitution of the amino acid at position 16 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively decreases affinity of the ligand for the receptor of the disclosure e.g., a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41. The amino acid at position 16 which decreases affinity of the ligand for the receptor of the disclosure may be selected from the group consisting of C, D, E, F and P.Accordingly, the ligand may comprise a T16C, T16D, T16E, T16F or T16P substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively. For example, the ligand may comprise a T16E or T16D substitution.

[0668] In one example, the ligand disclosed herein may comprise an amino acid substitution at residue position 36 and one or more further amino acid substitutions at positions selected from 9, 22, 26, 34 and 45, relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5, preferably comprising an arginine or tryptophan at residue position 36 and an arginine at one or more residue positions selected from 9, 22, 26, 34 and 45, relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand of the disclosure may comprise:

[0669] (a) an arginine at positions corresponding to amino acids 26 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36R substitutions;

[0670] (b) an arginine at positions corresponding to amino acids 9 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R and S36R substitutions;

[0671] (c) an arginine at positions corresponding to amino acids 22 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R and S36R substitutions;

[0672] (d) an arginine at the position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q34R and S36W substitutions;

[0673] (e) an arginine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36W substitutions;

[0674] (f) an arginine at positions corresponding to amino acids 26, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, Q34R and S36R substitutions;

[0675] (g) an arginine at positions corresponding to amino acids 9, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36R substitutions;(h) an arginine at positions corresponding to amino acids 22, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R, Q34R and S36R substitutions;

[0676] (i) an arginine at positions corresponding to amino acids 9 and 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36W substitutions; or

[0677] (j) an arginine at positions corresponding to amino acids 26, 36 and 45 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, S36R and K45R substitutions.

[0678] In one example, the ligand of the disclosure comprises:

[0679] (a) an arginine at positions corresponding to amino acids 22 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R and S36R substitutions;

[0680] (b) an arginine at the position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q34R and S36W substitutions;

[0681] (c) an arginine at positions corresponding to amino acids 26, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, Q34R and S36R substitutions;

[0682] (d) an arginine at positions corresponding to amino acids 9, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36R substitutions;

[0683] (e) an arginine at positions corresponding to amino acids 22, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R, Q34R and S36R substitutions; or

[0684] (f) an arginine at positions corresponding to amino acids 26, 36 and 45 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, S36R and K45R substitutions.In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 26 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 9 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 22 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at the position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q34R and S36W substitutions. In one example, the ligand disclosed herein may comprise an arginine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36W substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 26, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, Q34R and S36R substitutions. For example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 9, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 22, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R, Q34R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 9 and 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36W substitutions. For example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 26, 36 and 45 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, S36R and K45R substitutions. Inone example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 22 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at the position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q34R and S36W substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 26, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, Q34R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 9, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 22, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R, Q34R and S36R substitutions. In one example, the ligand disclosed herein may comprise an arginine at positions corresponding to amino acids 26, 36 and 45 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, S36R and K45R substitutions.

[0685] In certain examples, a ligand of the disclosure which is at least 90% (e.g., at least 91.4%, or at least 92.5%, or at least 94.2%, or at least 95.7%, or at least 97.1%, or at least 98.5% identical to the sequence set forth in SEQ ID NO: 3 or 5) identical to the amino acid sequence set forth in SEQ ID NO: 3 or 5, may comprise a receptor binding domain comprising an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical or at least 97% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5. In one example, the ligand of the disclosure comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5 and comprises:

[0686] (a) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0687] (b) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;(c) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0688] (d) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;

[0689] (e) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;

[0690] (f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0691] (f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0692] (g) a proline at the position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0693] (h) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0694] (i) a valine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0695] (j) an arginine at the position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;

[0696] (k) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0697] (l) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a proline at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;

[0698] (m) a leucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0699] (n) an isoleucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(o) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;

[0700] (p) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a leucine at the position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5;

[0701] (q) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0702] (r) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;

[0703] (s) a tyrosine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0704] (t) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0705] (u) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0706] (v) an arginine at the position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0707] (w) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;

[0708] (x) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;

[0709] (y) a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;

[0710] (z) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;

[0711] (aa) an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5;(bb) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;

[0712] (cc) a glutamine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5; or

[0713] (dd) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

[0714] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5 and comprises an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5.

[0715] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5.

[0716] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5.In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5.

[0717] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5

[0718] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5.

[0719] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO:3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5.

[0720] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a proline at the position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a proline at the position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5.

[0721] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5.

[0722] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a valine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a valine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5.

[0723] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with theexception of an arginine at the position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5.

[0724] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

[0725] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a proline at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a proline at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5.

[0726] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a leucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a leucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5.

[0727] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an isoleucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may compriseor consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an isoleucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5.

[0728] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5.

[0729] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a leucine at the position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a leucine at the position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5.

[0730] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5.

[0731] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to aminoacid 30 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

[0732] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a tyrosine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a tyrosine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5.

[0733] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5.

[0734] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5.

[0735] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 29 of thesequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5.

[0736] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5.

[0737] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5.

[0738] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5.

[0739] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ IDNO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5.

[0740] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

[0741] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5.

[0742] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth in positions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises a glutamine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of a glutamine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

[0743] In one example, the ligand disclosed herein comprises an amino acid sequence which is at least 90% identical (e.g., at least 94.5% identical) to the amino acid sequence set forth inpositions 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 of the sequence set forth in SEQ ID NO: 3 or 5, and comprises an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5. For example, the ligand may comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

[0744] In other examples, the ligand disclosed herein may be any ligand having an amino acid sequence encoded by a polynucleotide sequence disclosed herein, such as those set forth in SEQ ID NOs: 46 to 81, 82 to 100, 120 to 138, 158 to 176, 196 to 214, 234 to 252, 272 to 290, or 310 to 319. For example, the ligand disclosed herein may have an amino acid sequence encoded by a polynucleotide sequence set forth in any one of SEQ ID NOs: 46 to 81. For example, the ligand disclosed herein may have an amino acid sequence encoded by a polynucleotide sequence set forth in any one of SEQ ID NOs: 82 to 100 (e.g., such as a ligand having an amino acid sequence set forth in any one of SEQ ID NOs: 101 to 119 respectively). For example, the ligand disclosed herein may have an amino acid sequence encoded by a polynucleotide sequence set forth in any one of SEQ ID NOs: 120 to 138 (e g., such as a ligand having an amino acid sequence set forth in any one of SEQ ID NOs: 139 to 157 respectively). For example, the ligand disclosed herein may have an amino acid sequence encoded by a polynucleotide sequence set forth in any one of SEQ ID NOs: 158 to 176 (e g., such as a ligand having an amino acid sequence set forth in any one of SEQ ID NOs: 177 to 195 respectively). For example, the ligand disclosed herein may have an amino acid sequence encoded by a polynucleotide sequence set forth in any one of SEQ ID NOs: 196 to 214 (e g., such as a ligand having an amino acid sequence set forth in any one of SEQ ID NOs: 215 to 233 respectively). For example, the ligand disclosed herein may have an amino acid sequence encoded by a polynucleotide sequence set forth in any one of SEQ ID NOs: 234 to 252 (e g., such as a ligand having an amino acid sequence set forth in any one of SEQ ID NOs: 253 to 271 respectively). For example, the ligand disclosed herein may have an amino acid sequence encoded by a polynucleotide sequence set forth in any one of SEQ ID NOs: 272 to 290 (e g., such as a ligand having an amino acid sequence set forth in any one of SEQ ID NOs: 291 to 309 respectively). For example, the ligand disclosed herein may have an amino acid sequence encoded by a polynucleotide sequence set forth in any one of SEQ ID NOs: 310 to 319 (e g., such as a ligand having an amino acid sequence set forth in any one of SEQ ID NOs: 320 to 329 respectively).

[0745] In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 310 (e g., a ligand having an amino acid sequence set forth in SEQ ID NO: 320). In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 311 (e.g., a ligand having an amino acid sequence set forth in SEQ ID NO: 321).In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 312 (e g., a ligand having an amino acid sequence set forth in SEQ ID NO: 322).

[0746] In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 313 (e g., a ligand having an amino acid sequence set forth in SEQ ID NO: 323).

[0747] In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 314 (e g., a ligand having an amino acid sequence set forth in SEQ ID NO: 324).

[0748] In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 315 (e.g., a ligand having an amino acid sequence set forth in SEQ ID NO: 325).

[0749] In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 316 (e g., a ligand having an amino acid sequence set forth in SEQ ID NO: 326).

[0750] In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 317 (e g., a ligand having an amino acid sequence set forth in SEQ ID NO: 327).

[0751] In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 318 (e g , a ligand having an amino acid sequence set forth in SEQ ID NO: 328).

[0752] In one example, the ligand disclosed herein has an amino acid sequence encoded by a polynucleotide sequence set forth in SEQ ID NO: 319 (e g., a ligand having an amino acid sequence set forth in SEQ ID NO: 329).

[0753] In one example, the ligand disclosed herein may comprise methionine at any one or more positions in the amino acid sequence set forth in SEQ ID NO: 3 or 5.

[0754] The ligand of the disclosure is capable of binding to a native C-C Chemokine Receptor 5 (CCR5) (e.g., a native CCR5 having an amino acid sequence set forth in SEQ ID NO: 1), and / or the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41). However, in certain examples, the ligand described herein is capable of binding selectively to the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41), over the native CCR5 e.g., a native CCR5 having an amino acid sequence set forth in SEQ ID NO: 1. For example, the ligand described herein may bind to the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41), with increased affinity compared to its affinity for binding the native CCR5 (e.g., a native CCR5 having an amino acid sequence set forth in SEQ ID NO: 1). Alternatively, or in addition, the ligand described herein may bind to the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41), with increased affinity compared to the affinity of the native CCL3or native LD78P for binding the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41).

[0755] In certain examples, the ligand described herein binds to the receptor of the disclosure (e.g., the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41), with greater affinity than that of the native CCL3 (e.g., comprising the amino acid sequence set forth in SEQ ID NO: 3) or native LD78P (e.g., comprising the amino acid sequence set forth in SEQ ID NO: 5) when binding native CCR5 (e.g., a native CCR5 having an amino acid sequence set forth in SEQ ID NO: 1).

[0756] In each of the foregoing examples described binding selectivity and / or affinity, the binding may be determined using flow cytometry and / or chemotaxis assays. However, other methods known in the art for measuring binding affinity and / or selectivity of molecules are contemplated and may be used to determine binding selectivity and / or affinity of the ligand of the disclosure for a cognate receptor. Methods for determining the binding affinity include flow cytometry, competitive binding assays, radioligand binding assays, surface plasmon resonance (SPR), NMR spectroscopy, biolayer interferometry (BLI), or isothermal titration calorimetry (ITC), as well as other assays known in the art for measuring binding kinetics.

[0757] Polynucleotides and vectors

[0758] The present disclosure also provides polynucleotides, vectors and cells encoding the receptor and / or ligand as disclosed herein.

[0759] Accordingly, in one example, the present disclosure provides a polynucleotide encoding the receptor disclosed herein. The present disclosure also provides a polynucleotide encoding the ligand disclosed herein.

[0760] The polynucleotide encoding a receptor disclosed herein may comprise a polynucleotide sequence selected from the group consisting of SEQ ID NOs: 7-45, or a polynucleotide having at least 90%, at least 95%, at least 98%, at least 99% identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 7-45.

[0761] The polynucleotide encoding a ligand disclosed herein may comprise a nucleotide sequence selected from the group consisting of SEQ ID NOs: 46-81, or a polynucleotide having at least 90%, at least 95%, at least 98%, at least 99% identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 46-81.

[0762] As used herein, the term “polynucleotide” refers a molecular chain of nucleotides chemically bonded by a series of ester linkages between the phosphoryl group of one nucleotide and the hydroxyl group of the sugar in an adjacent nucleotide.

[0763] The terms “encode”, “encodes”, “encoding” or “codes for”, as used in the context of a polynucleotide of the disclosure, shall be understood to mean that the polynucleotide described herein, or part thereof, is capable of undergoing transcription and / or translation into a polypeptide or protein. In the case of a polynucleotide of the disclosure comprising a DNA sequence, the polynucleotide may be capable of undergoing transcription and / or translationinto a polypeptide or protein. However, in the case of a polynucleotide of the disclosure comprising an RNA sequence, the polynucleotide may be capable of undergoing translation into a polypeptide or protein. It therefore follows that the polynucleotide of the present disclosure may be DNA or RNA (e.g., mRNA). For example, the polynucleotide may be DNA (e.g., DNA). Alternatively, the polynucleotide may be RNA (e.g., RNA or mRNA).

[0764] A polynucleotide encoding the receptor of the disclosure and / or the ligand of the disclosure may comprise, or be operably-linked to, one or more regulatory elements. As used herein, the term “operably-linked” or “operable linkage” (or similar) means that a coding sequence within the polynucleotide (e.g., a sequence encoding the receptor and / or the ligand of the disclosure) is linked to, or in association with, a regulatory element, e.g., a promoter, in a manner which facilitates expression of the coding sequence. Regulatory elements (or regulatory sequences) include promoters, enhancers, and other expression control elements that are art-recognized and are selected to direct expression of the coding sequence. In one example, the polynucleotide comprises, and / or is in operable linkage with, a promoter. In some examples, the promoter may be positioned upstream of the sequence encoding the ligand and / or receptor. Suitable promoters for use in conjunction with the polynucleotide of the disclosure may be selected or determined according to the particular cell type in which expression and / or secretion of the receptor or ligand disclosed herein is intended to be expressed in, as will be known to a person skilled in the art.

[0765] The polynucleotide may further comprise at least one marker. The marker may be a fluorescent marker, such as (but without limitation to) green fluorescent protein (GFP). Alternatively, the marker may be a red fluorescent protein (mScarlet-I). For example, the polynucleotide encoding the receptor may comprise a polynucleotide sequence encoding GFP. The polynucleotide encoding the ligand may comprise a polynucleotide sequence encoding mScarlet-I.

[0766] The polynucleotide disclosed herein may further comprise a polynucleotide sequence encoding a linker. The linker may be located between a receptor or ligand disclosed herein and a marker, such as a fluorescent marker. For example, the polynucleotide may encode a DPPVAT linker.

[0767] The polynucleotide disclosed herein may further comprise a polynucleotide sequence encoding a signal sequence allowing effective trafficking of the translated protein to a cell surface and / or effective secretion of the translated protein. Suitable signalling sequences may be selected or determined according to the particular cell type in which expression and / or secretion of the receptor or ligand disclosed herein is intended to be expressed in, as will be understood by a person skilled in the art.

[0768] The polynucleotide disclosed herein may further comprise a polynucleotide sequence encoding a chimeric antigen receptor (CAR). For example, the polynucleotide may encode the receptor disclosed herein and a CAR. Alternatively, or in addition, the polynucleotide may encode the ligand disclosed herein and a CAR. The term “chimeric antigen receptor” or “CAR”shall be understood to mean an engineered receptor that includes an extracellular antigenbinding domain, a transmembrane domain, a hinge domain and an intracellular signalling domain (also referred to as a cytoplasmic signalling domain). The intracellular signalling domain may comprise a functional signalling domain derived from a stimulatory molecule and / or costimulatory molecule. For example, the CAR may comprise a single-chain variable fragment (scFv) derived from a monoclonal antibody fused to a transmembrane and intracellular domain of a T cell co-receptor, such as the CD3s chain. Alternatively, the CAR. may comprise any receptor engineered to express an extracellular antigen-binding domain fused or linked to any intracellular signalling molecule. Many CARs are known in the art and any such CAR can be suitably used in combination with the receptor and / or ligand disclosed herein.

[0769] .As used herein, the term "antigen-binding domain" shall be understood to mean a protein or region thereof that recognizes and binds to an antigen. An exemplary antigen binding domain is one which binds to a tumour antigen or a viral antigen expressed on a cell surface.

[0770] The terms "tumour antigen" or “cancer-associated antigen” refer to a molecule (typically protein, carbohydrate or lipid) that is preferentially expressed on the surface of a cancer cell, either entirely or as a fragment (e.g., MHC / peptide), in comparison to a normal cell, and which is useful for the preferential targeting of a pharmacological agent to the cancer cell. In some examples, the tumour antigen is an antigen that is common to a specific proliferative disorder. In some examples, a cancer-associated antigen is a cell surface molecule that is overexpressed in a cancer cell in comparison to a normal cell, for instance, 1-35 fold over expression, 2-fold overexpression, 3-fold overexpression or more in comparison to a normal cell. In some examples, a cancer-associated antigen is a cell surface molecule that is inappropriately synthesized in the cancer cell, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell. In some examples, a cancer-associated antigen will be expressed exclusively on the cell surface of a cancer cell, entirely or as a fragment (e.g., MHC / peptide), and not synthesized or expressed on the surface of a normal cell. Exemplary tumour antigens will be known to the skilled person.

[0771] As used herein, the term "transmembrane domain" refers to a polypeptide that spans the plasma membrane. In one example, it links an extracellular sequence, e.g., a switch domain, an extracellular recognition element, e.g., an antigen binding domain, an inhibitory counter ligand binding domain or costimulatory ECD domain, to an intracellular sequence, e.g., a switch domain or an intracellular signalling domain. Exemplary transmembrane domains are described herein.

[0772] As used herein, the term "intracellular signalling domain" refers to an intracellular portion of a molecule. In some examples, the intracellular signal domain transduces the effector function signal and directs the cell to perform a specialized function. The term "effector function" refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. While the entireintracellular signalling domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signalling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal. The term intracellular signalling domain is thus meant to include any truncated portion of the intracellular signalling domain sufficient to transduce the effector function signal. In one example, the intracellular signalling domain may comprise a primary intracellular signalling domain. Exemplary primary intracellular signalling domains include those derived from the molecules responsible for primary stimulation, or antigen dependent simulation. In one example, the intracellular signalling domain comprises a costimulatory intracellular domain. Exemplary costimulatory intracellular signalling domains include those derived from molecules responsible for costimulatory signals, or antigen independent stimulation. For example, in the case of a CAR-T cell, a primary intracellular signalling domain can comprise cytoplasmic sequences of the T cell receptor, and a costimulatory intracellular signalling domain can comprise cytoplasmic sequence from co-receptor or costimulatory molecule.

[0773] As used herein, the term "costimulatory signalling domain" refers to an intracellular signalling domain of a molecule e.g., an endogenous molecule, of the CAR-T cell that, upon binding to its cognate counter ligand on a target cell, enhance e.g., increases, an immune effector response. A costimulatory intracellular signalling domain can be the intracellular portion of a costimulatory molecule. A "costimulatory molecule" refers to a molecule comprising a "costimulatory signalling domain." A costimulatory intracellular signalling domain can be derived from the intracellular portion of a costimulatory molecule. The intracellular signalling domain can comprise the entire intracellular portion, or the entire native intracellular signalling domain, of the molecule from which it is derived, or a functional fragment thereof. Exemplary costimulatory molecules are described in the art and will be known to the skilled person.

[0774] Polynucleotides of the disclosure can be isolated or produced using any method known in the art, for example, amplification (e.g., using PCR or splice overlap extension), or by any other method described herein.

[0775] Polynucleotides (e.g., genomic DNA or RNA that is then reverse transcribed to form cDNA) may be used as a template in a polymerase chain reaction (PCR) to amplify a polynucleotide of the disclosure. Methods of PCR are known in the art and described, for example, in Dieffenbach (ed) and D’Veksler (ed), 1995. Generally, for PCR two non-complementary nucleic acid primer molecules comprising at least about 20 nucleotides in length, and more preferably at least 25 nucleotides in length are hybridized to different strands of a nucleic acid template, and specific nucleic acid copies of the template are amplified enzymatically. The primers may hybridise to nucleic acid adjacent to a polynucleotide of the disclosure, thereby facilitating amplification of the entire nucleic acid. Other methods for theproduction of a polynucleotide of the disclosure will be apparent to the skilled artisan, for example, in Ausubel et al 1987, Sambrook et al, 2001.

[0776] Polynucleotides of the disclosure may be introduced into a vector using a standard method in the art (such as those described in Sambrook et al., 2001). Methods for cloning a polynucleotide into a vector of the disclosure will be apparent to the skilled artisan.

[0777] Accordingly, the present disclosure also provides a vector comprising a polynucleotide disclosed herein.

[0778] As used herein, the term “vector” shall be understood to mean vectors used in accordance with the present disclosure as a vehicle for introducing into and expressing a desired receptor in a cell or secreting a desired ligand from the cell. As known to those skilled in the art, such vectors may easily be selected from the group consisting of plasmids, phages, viruses, retroviruses and other naturally occurring or artificially synthesised vectors. For example, the vector may be a retrovirus. The vector disclosed herein may therefore comprise a suitable promoter sequence.

[0779] Numerous different types of vectors may be employed for the purposes of the present disclosure. For example, vectors utilising DNA elements which are derived from human viruses such as human immunodeficiency virus (HIV) or animal viruses such as bovine papilloma virus, polyoma virus, adenovirus, adeno-associated virus (AAV), lentivirus (LV), vaccinia virus, baculovirus, retroviruses (e.g., MSCV, RSV, MMTV or MOMLV) or SV40 virus may be used. Suitably, the vector may be a murine stem cell virus (MSCV) retrovirus.

[0780] Some vectors may involve the use of polycistronic polynucleotides. Vectors may also comprise one or more markers that allow selected of transfected cells. The marker may be a fluorescent protein. The marker may provide for prototrophy to an auxotrophic host. The marker may provide for biocide resistance (e.g., antibiotics) or resistance to heavy metals such as copper. The marker can either be directly linked to the polynucleotide sequences to be expressed or introduced into the same cell by co-transformation. Additional elements may also be needed for optimal synthesis of mRNA. These elements may include signal sequences, splice signals, as well as transcriptional promoters, enhancers, and termination signals.

[0781] Compositions and carriers

[0782] In some examples, the vector comprising the polynucleotide encoding the receptor and / or ligand as described herein, is / are provided in one or more compositions. For example, the one or more compositions may be formulated such that they are suitable for introduction to a cell or population of cells, such as immune cells e.g., T-cells, NK cells, macrophage and / or dendritic cells.

[0783] For example, a composition of the disclosure may comprise the vector of the disclosure and one or more carriers or diluents e.g., suitable for use with cells e.g., T-cells, NK cells, macrophages and / or dendritic cells. In one example, the carrier(s) or diluent(s) may bepharmaceutically acceptable. In one example, the carrier may be formulated to assist with introduction of the vector of the disclosure to a cell e.g., in cell culture.

[0784] In some examples, the carrier is a lipid-based carrier, cationic lipid, or liposome nucleic acid complex, a liposome, a micelle, a virosome, a lipid nanoparticle or a mixture thereof.

[0785] In some examples, the carrier is a biodegradable polymer-based carrier, such that a cationic polymer-nucleic acid complex is formed. Use of cationic polymers for delivery compositions to cells is known in the art, such as described in Judge etal. Nature 25: 457-462 (2005), the contents of which is incorporated herein by reference.

[0786] In a further example, the carrier is a cyclodextrin-based carrier such as a cyclodextrin polymer-nucleic acid complex.

[0787] In a further example, the carrier is a protein-based carrier such as a cationic peptidenucleic acid complex.

[0788] In another example, the carrier is a lipid nanoparticle. Exemplary nanoparticles are described, for example, in US7514099.

[0789] In some examples, the vector comprising the polynucleotide encoding the receptor and / or ligand of the disclosure may be formulated with a lipid nanoparticle composition comprising a cationic lipid / Cholesterol / PEG-C-DMA / DSPC e.g., in a 40 / 48 / 2 / 10 ratio), a cationic lipid / Cholesterol / PEG-DMG / DSPC (e.g., in a 40 / 48 / 2 / 10 ratio), or a cationic lipid / Cholesterol / PEG-DMG (e.g., in a 60 / 38 / 2 ratio). In some examples, the cationic lipid is Octyl CL in DMA, DL in DMA, L-278, DLinKC2DMA, or MC3.

[0790] In another example, the vector comprising the polynucleotide encoding the receptor and / or ligand of the disclosure may be formulated with any of the cationic lipid formulations described in WO 2010 / 021865; WO 2010 / 080724; WO 2010 / 042877; WO 2010 / 105209 or WO 2011 / 022460.

[0791] In another example, the vector comprising the polynucleotide encoding the receptor and / or ligand of the disclosure may be conjugated to or complexed with another compound, e.g., to facilitate delivery. Non-limiting, examples of such conjugates are described in US 2008 / 0152661 and US 2004 / 0162260 (e.g., CDM-LBA, CDM-Pip-LBA, CDM-PEG, CDM-NAG, etc.).

[0792] In another example, polyethylene glycol (PEG) is covalently attached to the vector of the disclosure. The attached PEG can be any molecular weight, e.g.,. from about 100 to about 50,000 daltons (Da).

[0793] In yet other example, the vector comprising the polynucleotide encoding the receptor and / or ligand of the disclosure may be formulated with a carrier comprising surface-modified liposomes containing polyethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes), such as is disclosed in for example, WO 96 / 10391; WO 96 / 10390; or WO 96 / 10392.Other carriers include cyclodextrins (see for example, Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; or WO 03 / 46185), poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (see for example US 2002130430).

[0794] Compositions will desirably include materials that increase the biological stability of the vector of the disclosure and / or materials that increase the ability of the compositions to localise to target cells e.g., T cells, NK cells, macrophages or dendritic cells.

[0795] Cells and methods of producin same

[0796] The present disclosure also provides a cell comprising the receptor disclosed herein, the ligand disclosed herein, the polynucleotide disclosed herein and / or the vector disclosed herein.

[0797] The cell of the disclosure may be an immune cell, such as a T cell, a dendritic cell, macrophages or a Natural Killer cell.

[0798] As used herein, the term “T cell” shall be understood to refer to a T lymphocyte and encompasses all classes and subclasses of T lymphocytes including CD4+, CD8+ T cells as well as effector T cells, memory T cells, regulatory T cells, and the like.

[0799] As used herein, the term “NK cell” or “Natural Killer cell” shall be understood to refer to a natural killer cell, also known as large granular lymphocyte, and encompasses all classes and subclasses of natural killer cells, including cells expressing both high and low levels of CD56.

[0800] As used herein, the term “dendritic cell” or “DC” shall be understood to refer to a type of phagocyte and antigen-presenting cell (APC) that captures, processes, and presents antigens to lymphocytes to initiate and regulate the adaptive immune response.

[0801] In one particular example, the cell of the disclosure is a T cell. Exemplary T cell populations include naive T cells, T helper cells (TH cells), terminally differentiated effector T cells (Terr cells), effector memory T cells (Temcells), central memory T cells (Tcmcells), cytotoxic T cells (CTLs) and regulatory T cells (Treg cells). Suitably, the T cell of the disclosure may be a cytotoxic T lymphocyte (CTL).

[0802] T cells may be obtained from the blood of a subject by venous puncture, aspiration of bone marrow, steady state leukapheresis or cytokine primed leukapheresis and subsequent isolation of peripheral blood mononuclear cells including T cells using density gradient separation. T cells may be sorted by flow cytometry or purified using antibodies to antigens expressed on T cells and magnetic beads to obtain a population of pure T cells. Specific subpopulations of T cells, such as CD3+, CD28+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells, can be isolated by positive or negative selection techniques. For example, the T cells may may be sorted based on their expression of CD3 to obtain a whole T cell fraction. Alternatively, T cells of the disclosure may be sorted based on their expression of CD4 or CD8 to obtain a population of either CD4+ T cells or CD8+ T cells. T cells of the disclosure may be obtained from the subject in need of CAR T-cell therapy. Alternatively, T cells may be obtained from adonor subject who is not the intended recipient of CAR T-cell therapy. In this regard, T-cells can be obtained from a subject or a cell bank.

[0803] For example, the cell may be an EL4 mouse T cell lymphoma cell. Alternatively, the cell may be a human Jurkat T cell leukemia cell. The cell may also be a mouse primary CD8+ OT-I T cell. The cell may be a human NK-92 natural killer cell. The cell may be a human PBMC cell. The cell may be a THP-1 monocytes. The cell may be a RAW cell. The cell may be a JAWS-II dendritic cell.

[0804] The present disclosure also provides methods of producing cells of the disclosure, such as those described herein above. In order to produce a cell of the disclosure, a polynucleotide encoding a receptor and / or ligand of the disclosure, or a vector comprising said polynucleotide, may be introduced into an appropriate cell (e.g., an immune cell, such as a T cell, NK cell or DC) using any means known in the art. That is, cells may be transformed or transduced (as appropriate) with a vector of the disclosure. The introduction of a vectors into a cell may be accomplished by various techniques well-known to those of skill in the art.

[0805] In some examples, a polynucleotide encoding a receptor or a ligand as disclosed herein, or a vector comprising same, is introduced into a suitable cell using recombinant infectious virus particles, such as e.g., vectors derived from simian virus 40 (SV40), adenoviruses or adeno-associated virus (AAV).

[0806] In some examples, a polynucleotide encoding a receptor or a ligand as disclosed herein, or a vector comprising same, is introduced into a suitable cell using recombinant lentiviral vectors or retroviral vectors, such as gamma-retroviral vectors e g., as described herein. Methods of lentiviral transduction are known in the art and contemplated herein. Exemplary methods are described in e.g., Wang et al. (2012) J. Immunother. 35(9): 689-701; Cooper et al. (2003) Blood. 101: 1637-1644; Verhoeyen et al. (2009) Methods Mol Biol. 506: 97-114; and Cavalieri et al. (2003) Blood. 102(2): 497-505.

[0807] In some examples, a polynucleotide encoding a receptor or a ligand as disclosed herein, or a vector comprising same, is introduced into a suitable cell via electroporation {see, e.g., Chicaybam et al, (2013) PLoS ONE 8(3): e60298 and Van Tedeloo et al. (2000) Gene Therapy 7(16): 1431-1437). In other examples, a polynucleotide encoding a receptor or a ligand as disclosed herein, or a vector comprising same, is introduced into a cell via transposition (see, e.g., Manuri et al. (2010) Hum Gene Ther 21(4): 427-437; Sharma et al. (2013) Molec Ther Nucl Acids 2, e74; and Huang et al. (2009) Methods Mol Biol 506: 115-126). Other methods of introducing and expressing genetic material in cells e.g., immune cells, include calcium phosphate transfection (e.g., as described in Current Protocols in Molecular Biology, John Wiley & Sons, New York. N.Y.), cationic liposome-mediated transfection; tungsten particle-facilitated microparticle bombardment (Johnston, Nature, 346: 776-777 (1990)); and strontium phosphate DNA co- precipitation (Brash et al., Mol. Cell Biol., 7: 2031-2034 (1987)).

[0808] The transformed cells may be grown under conditions appropriate for expression of the receptor or secretion of the ligand and assayed for expression and / or secretion. Exemplaryassay techniques include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or fluorescence-activated cell sorter analysis (FACS), immunohistochemistry and the like.

[0809] In some examples, prior to introducing the polynucleotide encoding the ligand or receptor of the disclosure, or a vector comprising same, to a cell (such as a T cell, NK cell, a macrophage or dendritic cell), the cell can be obtained e.g., from a subject or a cell bank. In this regard, immune cells (such as T cells, NK cells, macrophages and / or dendritic cells) can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. Alternatively, cell lines commercially available in the art, may be used.

[0810] In some examples, immune cells (e.g., such as T cells, NK cells, macrophages and / or dendritic cells) can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as Ficoll™ separation. In another example, cells from the circulating blood of an individual are obtained by apheresis. Immune cells collected by apheresis may be washed to remove the plasma fraction and optionally placed in an appropriate buffer or media for subsequent processing steps. A washing step may be accomplished by methods known to those in the art, such as by using a semi -automated "flowthrough" centrifuge (for example, the Cobe 2991 cell processor, the Baxter CytoMate, or the Haemonetics Cell Saver 5) according to the manufacturer's instructions.

[0811] In some examples, immune cells (e.g., such as T cells, NK cells, macrophages and / or dendritic cells) may be isolated from peripheral blood lymphocytes by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLL ™ gradient or by counterflow centrifugal elutriation.

[0812] In one example, T cells are obtained and produced. Exemplary T cell populations include naive T cells, T helper cells (TH cells), terminally differentiated effector T cells (Terr cells), effector memory T cells (Temcells), central memory T cells (Tcmcells), cytotoxic T cells (CTLs) and regulatory T cells (Tregcells). In some examples, a specific subpopulation of T cells, such as CD3+, CD28+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells, can be further isolated by positive or negative selection techniques. In some examples, the T cell subpopulations are isolated by positive selection e.g., before or after introduction of the the polynucleotide encoding the ligand or receptor of the disclosure, or a vector comprising same. For example, the T cells isolated from the blood of a subject can be incubated with an antibody that specifically recognizes a particular cell-surface protein under condition suitable for antibody binding. In some examples, the antibody may be conjugated to a fluorescent molecule, e.g., FITC, and the T cells are sorted using flow cytometry.

[0813] In one example, a subpopulation of T-cells which are resistant to an immunosuppressant may be isolated by culturing the T-cell in the presence of an immunosuppressant and selecting those T-cells which survive.Methods of preparing T-cells as described herein can include more than one selection step. For example, in addition to positive selection described above, further enrichment of a T cell population by negative selection can be accomplished, e.g., with a combination of antibodies directed to surface markers unique to the negatively selected cells, for example regulatory T cells or tumour cells. One such method is cell sorting and / or selection via flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected. Such antibodies include anti-GITR, anti-CD25, or anti-tumor antigen antibodies.

[0814] In some examples, the collection of blood samples or apheresis product from a subject is made at a time period prior to when the expanded cells might be needed. As such, the source of the cells to be expanded can be collected at any time point necessary, and desired T cells may be isolated and frozen for later use in, e.g., T cell therapy for any number of diseases or conditions that would benefit from such T cell therapy.

[0815] A T cell produced in accordance with the methods described herein can be allogeneic e.g., an allogeneic T cell lacking expression of a functional TCR and / or expressing a CAR.

[0816] The methods of the disclosure may further comprise HLA typing the T-cell(s).

[0817] The present disclosure also provides a process for producing a cell which expresses a receptor as described herein and / or which secretes a ligand as described herein, comprising culturing a cell disclosed herein for a time and under conditions sufficient for the cell to express the receptor and / or secrete the ligand of the disclosure. In some examples, in vitro production can be “scaled-up” to give large amounts of cells expressing the receptor or the ligand disclosed herein. Techniques for mammalian cell cultivation under tissue culture conditions are known in the art and include homogeneous suspension culture (e.g., in an airlift reactor or in a continuous stirrer reactor), or immobilized or entrapped cell culture (e.g., in hollow fibers, microcapsules, on agarose microbeads or ceramic cartridges). If necessary and / or desired, the solutions of polypeptides can be purified by the customary chromatography methods, for example gel filtration, ion-exchange chromatography, chromatography over DEAE-cellulose and / or (immuno-) affinity chromatography.

[0818] Expression of the receptor on the surface of the cell may be confirmed using any suitable method known in the art, such as (without limitation) by using antibody staining and flow cytometry. Alternatively, or in addition, expression of the receptor on the surface of the cell may be confirmed using microscopy.

[0819] In some examples, the method of the disclosure includes first stimulating cell growth, e.g., T cell growth, proliferation, and / or activation, followed by transduction of the activated cells, and expansion in culture to numbers sufficient for clinical applications.

[0820] It is also contemplated that the polynucleotides encoding the receptor or ligand of the disclosure can be expressed in non-mammalian cells, such as bacteria or yeast or plant cells. In this regard it will be appreciated that various unicellular non-mammalian microorganisms such as bacteria can also be transformed (i.e., those capable of being grown in cultures orfermentation). Bacteria susceptible to transformation, include members of the Enterobacteriaceae, such as strains of Escherichia coli or Salmonella. In addition to prokaryotes, eukaryotic microbes may also be used. For example, Saccharomyces cerevisiae or common baker's yeast may be used.

[0821] Phenotyping of cells for use in therapy or banking

[0822] In accordance with examples in which T cells of the disclosure are to be used for allogeneic cell therapy, it may be desirable to HLA-allele phenotype the cells. The knowledge of a HLA phenotype can facilitate subsequent selection of cells for the preparation of the composition of the present disclosure, and for selection of cells for use in clinical applications. Accordingly, in one example, T cells which comprise or express a receptor or ligand of the disclosure may be HLA-allele phenotyped. For example, the cells of the disclosure may be partially HLA-allele phenotyped.

[0823] In one example, the cells have alleles selected from major HLA, such as any Class I, II or III HLA, minor HLA, and non-polymorphic alleles, such as any member of the CD1 family members.

[0824] Major HLA alleles may more specifically be selected from any class I HLA such as HLA-A1, HLA-A2, HLA-A3, HLA-A24, HLA-A11 , HLA-A28, HLA-A29, HLA-A32, HLA-B15, HLA-B5, HLA-B7, HLA-B8, HLA-B12, HLA-B14, HLA-B18, HLA-B35, HLA-B40, HLA-C group 1, HLA-C group 2 for example, any class II HLA-DPB9, HLA-DPB11, HLA-DPB35, HLA-DPB55, HLA-DPB56, HLA-DPB69 HLA-DPB84 HLA-DPB 87, HLA-DRB1, HLA-DQA1 , HLA-DQB1 , or any class III HLA

[0825] In one example, at least one class II HLA is phenotyped. For example, at least one of HLA-DR, HLA-DP or HLA-DQ is phenotyped.

[0826] In one example, at least one HLA-allele in the T cells of the present disclosure is matched to at least one HLA-allele in a subject to which a composition comprising the T cells of the present disclosure is to be administered. For example, at least one class II HLA is matched. For example, at least one of HLA-DR, HLA-DP and HLA-DQ is matched.

[0827] In one example, the HLA allele is HLA-DR. For example, the phenotype of HLA-DR in the cells of the present disclosure is matched to an HLA-DR allele in the subject to which the composition comprising the T cells of the present disclosure is to be administered. In one example, the method of treating a subject comprises determining an HLA allele in the subject, matching the HLA allele to an HLA allele in T cells within a T cell bank, selecting T cells which possess a HLA allele match and administering to the subject a composition comprising T cells having the same HLA allele as that in the subject.

[0828] Cell formulations

[0829] Cells of the disclosure (e.g., T cells, NK cells, macrophages and / or dendritic cells as described herein) may be formulated for administration to a subject. That is, cells of thedisclosure (e.g., T cells, NEC cells, macrophages and / or dendritic cells as described herein) may be formulated into a pharmaceutical composition.

[0830] Formulation of the composition to be administered will vary according to the route of administration and formulation (e.g., solution, emulsion) selected. An appropriate pharmaceutical composition comprising the composition of the present disclosure to be administered can be prepared in a physiologically acceptable carrier. A mixture of compositions can also be used. For solutions or emulsions, suitable carriers include, for example, aqueous or alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. A variety of appropriate aqueous carriers are known to the skilled artisan, including water, buffered water, buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), dextrose solution and glycine. Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally, Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. 1980). The compositions can optionally contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents and toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate.

[0831] The optimum concentration of cell populations in the chosen medium can be determined empirically, according to procedures well known to the skilled artisan, and will depend on the ultimate pharmaceutical formulation desired, as well as the subject to be treated taking into consideration the age, sex, weight and general health condition thereof, factors that will depend on the judgement of the practitioner.

[0832] A pharmaceutical composition comprising cells of the disclosure may be packaged within a container.

[0833] Methods of establishing signalling between biological components

[0834] The receptor and / or the ligand of the present disclosure may be suitable for establishing signalling between at least two biological components. Accordingly, the present disclosure provides a method of establishing signalling between at least two biological components in a subject, the method comprising administering to the subject a first biological component comprising and / or capable of expressing a receptor of the disclosure. The method may further comprise administering to the subject a second biological component comprising or capable of expressing the ligand of the disclosure.

[0835] The present disclosure also provides a method of establishing signalling between at least two biological components in a subject, the method comprising administering to the subject a first biological component comprising or encoding the ligand disclosed herein. The method may further comprise administering to the subject a second biological component comprising or capable of expressing the receptor of the disclosure.The first and second biological components may be administered to the subject simultaneously or sequentially.

[0836] In accordance with examples in which the method of establishing signalling between at least two biological components occurs in vitro or ex vivo, the method may comprise providing to an in vitro or ex vivo biological system a first biological component comprising and / or capable of expressing a receptor of the disclosure. The method may further comprise providing to the in vitro or ex vivo biological system a second biological component comprising or capable of expressing the ligand of the disclosure.

[0837] In accordance with examples in which the method of establishing signalling between at least two biological components occurs in vitro or ex vivo, the method may comprise providing to an in vitro or ex vivo biological system a first biological component comprising or encoding the ligand disclosed herein. The method may further comprise providing to the in vitro or ex vivo biological system a second biological component comprising or capable of expressing the receptor of the disclosure.

[0838] The first and second biological components may be provided to the biological system simultaneously or sequentially.

[0839] As used herein, the term or phrase “zzz vitro or in vivo biological system” shall be understood to refer to living cells, living tissue or a living organ that has been removed from an organism. In accordance with examples in which the method of establishing signalling between at least two biological components is performed in vitro or ex vivo, the method may comprise isolating cells or tissue from a subject prior to introducing the first biological component and / or second biological component thereto.

[0840] As used herein the phrase “establishing signalling” shall be understood to refer to initiating the communication between at least two biological components. For example, the signalling may be chemotactic signalling.

[0841] As used herein the term a “biological component” shall be understood to refer to cells (e.g., T cells, NK cells, allogeneic cytokine-induced killer (CIK) cells, multipotent mesenchymal stromal cells), carriers (e.g., liposomes, lipid nanoparticles, polymeric nanoparticles, hydrogels), viruses, polynucleotides (e.g., DNA or RNA), polypeptides (e.g., recombinant protein), antibodies, and combinations thereof. However, in particular examples, the biological component is a cell as described herein or a population of cells as described herein.

[0842] Exemplary receptors and ligands of the disclosure are described hereinabove and shall be taken to apply mutatis mutandis to each and every example describing the method of establishing signalling between at least two biological components unless stated otherwise.

[0843] Suitably, the method may comprise providing a first biological component with a receptor comprising glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartate at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1. The method may further compriseproviding a second biological component with a ligand comprising proline at a position corresponding to amino acid 3 in the amino acid sequence set forth in SEQ ID NO: 3 and methionine at a position corresponding to amino acid 6 in the amino acid sequence set forth in SEQ ID NO: 3.

[0844] In another example, the method may comprise providing a first biological component with a receptor comprising glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartate at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1. The method may further comprise providing a second biological component with a ligand comprising arginine at a position corresponding to amino acid 5 in the amino acid sequence set forth in SEQ ID NO: 3 and methionine at a position corresponding to amino acid 6 in the amino acid sequence set forth in SEQ ID NO: 3.

[0845] In another example, the method may comprise providing a first biological component with a receptor comprising glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartate at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1. The method may further comprise providing a second biological component with a second biological component with a ligand comprising an arginine at positions corresponding to amino acids 26 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36R substitutions.

[0846] In another example, the method may comprise providing a first biological component with a receptor comprising glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartate at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1. The method may further comprise providing a second biological component with a second biological component with a ligand comprising an arginine at positions corresponding to amino acids 9 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the a...

Claims

Claims:

1. A receptor comprising a binding domain corresponding to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1, wherein the receptor comprises:(a) aspartic acid at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO : 1 ;(b) leucine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;(c) arginine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;(d) lysine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1;(e) aspartic acid at a position corresponding to amino acid 32 in the amino acid sequence set forth in SEQ ID NO : 1 ;(f) serine at a position corresponding to amino acid 89 in the amino acid sequence set forth in SEQ ID NO: 1;(g) alanine at a position corresponding to amino acid 94 in the amino acid sequence set forth in SEQ ID NO: 1;(h) phenylalanine at a position corresponding to amino acid 104 in the amino acid sequence set forth in SEQ ID NO : 1 ;(i) asparagine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO : 1 ;(j) leucine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1;(k) aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO : 1 ;(l) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO : 1 ;(m) leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;(n) asparagine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO : 1 ;(o) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;(p) serine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;(q) methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;(r) serine at a position corresponding to amino acid 172 in the amino acid sequence set forth in SEQ ID NO: 1;(s) glutamic acid at a position corresponding to amino acid 179 in the amino acid sequence set forth in SEQ ID NO: 1;(t) glutamic acid at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO : 1 ;(u) glutamine at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1;(v) glutamic acid at a position corresponding to amino acid 181 in the amino acid sequence set forth in SEQ ID NO : 1 ;(w) aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO : 1 ;(x) glutamic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO : 1 ;(y) glycine at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;(z) serine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;(aa) glutamic acid at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO : 1 ;(bb) arginine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;(cc) histidine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;(dd) glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO : 1 ;(ee) leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(ff) histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(gg) aspartic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO : 1 ;(hh) tryptophan at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO : 1 ;(ii) serine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(jj) cysteine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(kk) methionine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO : 1 ;(11) histidine at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;(mm) glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO : 1 ;(nn) arginine at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;(oo) aspartic acid at a position corresponding to amino acid 262 in the amino acid sequence set forth in SEQ ID NO : 1 ;(pp) threonine at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1;(qq) glutamic acid at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO : 1 ;(rr) arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1;(ss) arginine at a position corresponding to amino acid 291 in the amino acid sequence set forth in SEQ ID NO: 1; or(tt) any combination thereof with the exception of combinations of different amino acids at the same position relative to the sequence set forth in SEQ ID NO: 1.

2. The receptor of claim 1, wherein the receptor comprises:(a) lysine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1;(b) arginine at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1, aspartic acid at a position corresponding to amino acid 32 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;(c) serine at a position corresponding to amino acid 89 in the amino acid sequence set forth in SEQ ID NO: 1 and phenylalanine at a position corresponding to amino acid 104 in the amino acid sequence set forth in SEQ ID NO: 1;(d) asparagine at a position corresponding to amino acid 170 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1;(e) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1;(f) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and serine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;(g) glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 262 in the amino acid sequence set forth in SEQ ID NO: 1;(h) aspartic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(i) glutamine at a position corresponding to amino acid 180 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 181 in the amino acid sequence set forth in SEQ ID NO: 1;(j) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(k) glutamic acid at a position corresponding to amino acid 184 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1;(l) aspartic acid at a position corresponding to amino acid 18 in the amino acid sequence set forth in SEQ ID NO: 1, glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and cysteine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(m) leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(n) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and histidine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(o) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(p) leucine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and tryptophan at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(q) glutamic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(r) asparagine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(s) aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and leucine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(t) glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(u) aspartic acid at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1and glutamic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(v) serine at a position corresponding to amino acid 172 in the amino acid sequence set forth in SEQ ID NO: 1 and glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1;(w) histidine at a position corresponding to amino acid 187 in the amino acid sequence set forth in SEQ ID NO: 1 and methionine at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1;(x) glutamic acid at a position corresponding to amino acid 258 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1; or(y) glutamic acid at a position corresponding to amino acid 280 in the amino acid sequence set forth in SEQ ID NO: 1, arginine at a position corresponding to amino acid 283 in the amino acid sequence set forth in SEQ ID NO: 1 and arginine at a position corresponding to amino acid 291 in the amino acid sequence set forth in SEQ ID NO: 1.

3. The receptor of claim 1 or 2, wherein the binding domain has at least 95% sequence identity to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1.

4. The receptor of any one of claims 1 to 3, wherein:the receptor comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; and / orthe receptor is capable of binding to a native C-C Chemokine Ligand 3 (CCL3), a native LD78P and / or the ligand of any one of claims 6 to 31;the receptor is capable of selectively binding to the ligand of any one of claims 6 to 31; the receptor binds with increased affinity to the ligand of any one of claims 6 to 31 relative to a native C-C Chemokine Receptor 5 (CCR5), optionally wherein binding is determined using flow cytometry.

5. The receptor of claim 4, wherein:the native CCL3 comprises the amino acid sequence set forth in SEQ ID NO: 3 and / or the native LD78P comprises the amino acid sequence set forth in SEQ ID NO: 5;the native CCR5 comprises the amino acid sequence set forth in SEQ ID NO: 1.

6. The receptor of any one of claims 1 to 5, wherein:the receptor is a modified CCR5; and / orthe receptor comprises a glutamine at a position corresponding to amino acid 171 in the amino acid sequence set forth in SEQ ID NO: 1 and aspartic acid at a position corresponding to amino acid 191 in the amino acid sequence set forth in SEQ ID NO: 1, optionally wherein the receptor comprises an amino acid sequence encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

7. A ligand comprising a receptor binding domain of chemokine (C-C motif) ligand 3 (CCL3) or an isoform CCL3, wherein the ligand comprises an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5, and wherein the ligand comprises:(a) alanine or arginine at a position corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5, or the amino acid corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5 is absent;(b) serine, proline or methionine at a position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5;(c) leucine or proline at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5;(d) alanine, arginine, isoleucine or valine at a position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;(e) alanine or arginine at a position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5;(f) aspartic acid, isoleucine or methionine at a position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(g) proline or arginine at a position corresponding to amino acid 8 of the sequence set forth in SEQ ID NO: 3 or 5;(h) threonine, leucine, proline or arginine at a position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;(i) alanine or arginine at a position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(j) an amino acid substitution at a position corresponding to amino acid 14 of the sequence set forth in SEQ ID NO: 3 or 5, wherein the substitution is relative to the amino acid at position 14 of the sequence set forth in SEQ ID NO: 3 or 5;(k) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine, or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;(l) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;(m) glutamine or arginine at a position corresponding to amino acid 22 of the sequence set forth in SEQ ID NO: 3 or 5;(n) alanine, tyrosine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;(o) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;(p) phenylalanine or arginine at a position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5;(q) glutamic acid, arginine, or tyrosine at a position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;(r) serine or arginine at a position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(s) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(t) glutamine or arginine at a position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5;(u) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5;(v) glycine, serine or tyrosine at a position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(w) isoleucine or arginine at a position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;(x) lysine or arginine at a position corresponding to amino acid 45 of the sequence set forth in SEQ ID NO: 3 or 5;(y) serine, lysine, tryptophan, or glycine at a position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;(z) proline or leucine at a position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5; and / or(aa) valine or lysine at a position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

8. The ligand of claim 7, comprising one or more of:(a) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine, or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;(b) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;(c) alanine, tyrosine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;(d) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;(e) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine,valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5; and / or(f) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

9. The ligand of claim 7, comprising one or more of:(a) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;(b) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;(c) alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;(d) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;(e) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5; and / or(f) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

10. The ligand of claim 7, comprising one or more of:(a) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;(b) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;(c) alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;(d) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;(e) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5; and / or(f) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

11. The ligand of claim 7, comprising one or more of:(a) alanine, glycine, lysine, leucine, serine, tryptophan, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, proline, glutamine, arginine, valine, tyrosine or threonine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;(b) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;(c) alanine, lysine, arginine, aspartic acid, glutamic acid, phenylalanine, histidine, leucine, proline, serine, valine, tyrosine, cysteine, glycine, isoleucine, methionine, asparagine, glutamine, threonine, or tryptophan at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;(d) alanine, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, serine, threonine, valine, tryptophan, tyrosine, aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;(e) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, threonine, valine, tryptophan, tyrosine, serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5; and / or(f) alanine, leucine, proline, valine, cysteine, aspartic acid, glutamic acid, isoleucine, methionine, asparagine, glutamine, threonine, serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5.

12. The ligand of claim 7, comprising:(a) alanine or arginine at a position corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5, or the amino acid corresponding to amino acid 1 in the sequence set forth in SEQ ID NO: 3 or 5 is absent;(b) serine, proline or methionine at a position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5;(c) leucine or proline at a position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5;(d) alanine, arginine, isoleucine or valine at a position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;(e) alanine or arginine at a position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5;(f) aspartic acid, isoleucine or methionine at a position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(g) proline or arginine at a position corresponding to amino acid 8 of the sequence set forth in SEQ ID NO: 3 or 5;(h) threonine, leucine, proline or arginine at a position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;(i) alanine or arginine at a position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(j) an amino acid substitution at a position corresponding to amino acid 14 of the sequence set forth in SEQ ID NO: 3 or 5, wherein the substitution is relative to the amino acid at position 14 of the sequence set forth in SEQ ID NO: 3 or 5;(k) isoleucine, methionine and valine at a position corresponding to amino acid 16 of the sequence set forth in SEQ ID NO: 3 or 5;(l) alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, threonine, valine, tryptophan, tyrosine, or serine at a position corresponding to amino acid 17 of the sequence set forth in SEQ ID NO: 3 or 5;(m) glutamine or arginine at a position corresponding to amino acid 22 of the sequence set forth in SEQ ID NO: 3 or 5;(n) alanine, tyrosine, lysine or arginine at a position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5;(o) aspartic acid, glutamine or arginine at a position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;(p) phenylalanine or arginine at a position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5;(q) glutamic acid, arginine, or tyrosine at a position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;(r) serine or arginine at a position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(s) serine or arginine at a position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(t) glutamine or arginine at a position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5;(u) serine, glycine, phenylalanine, tryptophan, tyrosine, lysine, arginine or histidine at a position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5;(v) glycine, serine or tyrosine at a position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(w) isoleucine or arginine at a position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;(x) lysine or arginine at a position corresponding to amino acid 45 of the sequence set forth in SEQ ID NO: 3 or 5;(y) serine, lysine, tryptophan, or glycine at a position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;(z) proline or leucine at a position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5; and / or(aa) valine or lysine at a position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5.

13. The ligand of claim 7, comprising an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

14. The ligand of claim 7, comprising an amino acid sequence which is at least 91.4% identical (optionally at least 92.5% identical or at least 94.2% identical or at least 95.7% identical or at least 97.1% identical or at least 98.5% identical) to the sequence set forth in SEQ ID NO: 3 or 5 and comprising one or more amino acid substitutions at residue positions selected from 9, 14, 16, 17, 22, 26, 27, 33, 34, 36, 45, 47, 54, 60 and 63 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

15. The ligand of any one of claims 7 to 14, said ligand having an increased affinity for binding to a receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41 compared to binding affinity of wildtype CCL3 comprising the amino acid sequence set forth in SEQ ID NO: 3, or wildtype LD78 comprising the amino acid sequence set forth in SEQ ID NO: 5, to the receptor encoded by the polynucleotide sequence set forth in SEQ ID NO: 41.

16. The ligand of any one of claims 7 to 15, comprising an amino acid substitution at residue position 26 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, optionally wherein the amino acid at position 26 is substituted with a basic amino acid having a positive charge at physiological pH.

17. The ligand of claim 16, comprising:a A26R or A26K substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising the A26R substitution;a A26D substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively; ora A26P, A26V, A26Y, or A26E substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising a A26P substitution.

18. The ligand of any one of claims 7 to 17, comprising an amino acid substitution at residue position 36 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, optionally wherein the amino acid at position 36 is selected from the group consisting of G, F, W, Y, N, K, R, and H, preferably selected from the group consisting of F, W, Y, K, R, and H.

19. The ligand of claim 18, wherein:the amino acid at position 36 is a non-polar, uncharged amino acid, optionally wherein the ligand comprises a S36G, S36F or S36W substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising the S36W substitution;the amino acid at position 36 is a polar, uncharged amino acid, optionally wherein the ligand comprises a S36Y or S36N substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising the S36Y substitution;the amino acid at position 36 is a positively charged amino acid having a basic side chain at neutral pH, optionally wherein the ligand comprises a S36K, S36R or S36H substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising the S36R substitution;the ligand comprises a S36W, S36Y, S36K, S36R or S36H substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, optionally wherein the ligand comprises a S36W or S36R substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising the S36R substitution; orthe amino acid at position 36 is selected from the group consisting of C, D, E, I, M, Q and T, optionally wherein the ligand comprises a S36C, S36D or S36E substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising the S36D or S36E substitution.

20. The ligand of any one of claims 7 to 19, comprising an amino acid substitution at residue position 16 relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

21. The ligand of claim 20, wherein:the amino acid at position 16 is a hydrophobic amino acid, preferably an aliphatic amino acid which is hydrophobic;the amino acid at position 16 is selected from the group consisting of I, M and V; and / or the ligand comprises a T16I, T16M or T16V substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising the T16I or T16V substitution.

22. The ligand of claim 20, wherein:the amino acid at position 16 is selected from the group consisting of C, D, E, F and P; and / orthe ligand comprises a T16C, T16D, T16E, T16F or T16P substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively, preferably comprising a T16E or T16D substitution.

23. The ligand of claim 20, comprising a T16D or T16E substitution relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5 respectively.

24. The ligand of any one of claims 7 to 14, comprising an amino acid substitution at residue position 36 and one or more further residue positions selected from 9, 22, 26, 34 and 45, relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5, optionally comprising an arginine or tryptophan at residue position 36 and an arginine at one of more residue positions selected from 9, 22, 26, 34 and 45, relative to the amino acid sequence set forth in SEQ ID NO: 3 or 5.

25. The ligand of claim 24, wherein the ligand comprises:(a) an arginine at positions corresponding to amino acids 26 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36R substitutions;(b) an arginine at positions corresponding to amino acids 9 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R and S36R substitutions;(c) an arginine at positions corresponding to amino acids 22 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R and S36R substitutions;(d) an arginine at the position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q34R and S36W substitutions;(e) an arginine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R and S36W substitutions;(f) an arginine at positions corresponding to amino acids 26, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, Q34R and S36R substitutions;(g) an arginine at positions corresponding to amino acids 9, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acidsequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36R substitutions;(h) an arginine at positions corresponding to amino acids 22, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R, Q34R and S36R substitutions;(i) an arginine at positions corresponding to amino acids 9 and 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36W substitutions; or(j) an arginine at positions corresponding to amino acids 26, 36 and 45 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, S36R and K45R substitutions,optionally wherein the ligand comprises:(i) an arginine at positions corresponding to amino acids 22 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R and S36R substitutions;(ii) an arginine at the position corresponding to amino acid 34 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q34R and S36W substitutions;(iii) an arginine at positions corresponding to amino acids 26, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, Q34R and S36R substitutions;(iv) an arginine at positions corresponding to amino acids 9, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the T9R, Q34R and S36R substitutions;(v) an arginine at positions corresponding to amino acids 22, 34 and 36 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the Q22R, Q34R and S36R substitutions; or(vi) an arginine at positions corresponding to amino acids 26, 36 and 45 of the sequence set forth in SEQ ID NO: 3 or 5, preferably wherein the ligand comprises the amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of the A26R, S36R and K45R substitutions.

26. The ligand of claim 7, wherein the receptor binding domain of CCL3 corresponds to amino acids 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 in the amino acid sequence set forth in SEQ ID NO: 3 or 5.

27. The ligand of claim 7 or 26, comprising an amino acid sequence which is at least 90% identical, optionally at least 95% identical, to the sequence set forth in SEQ ID NO: 3 or 5 and comprising:(a) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;(b) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;(c) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(d) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;(e) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;(f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(g) a proline at the position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(h) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(i) a valine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(j) an arginine at the position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(k) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;(l) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a proline at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;(m) a leucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(n) an isoleucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(o) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(p) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a leucine at the position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5;(q) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(r) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;(s) a tyrosine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(t) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(u) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(v) an arginine at the position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(w) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(x) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(y) a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(z) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;(aa) an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5;(bb) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;(cc) a glutamine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5; or(dd) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

28. The ligand of claim 7, comprising an amino acid sequence set forth in SEQ ID NO: 3 or 5 with the exception of amino acid substitutions resulting in one of the following:(a) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a tryptophan at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;(b) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;(c) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(d) a methionine at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5;(e) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 47 of the sequence set forth in SEQ ID NO: 3 or 5;(f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(f) a proline at the position corresponding to amino acid 2 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(g) a proline at the position corresponding to amino acid 3 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(h) an isoleucine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(i) a valine at the position corresponding to amino acid 4 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(j) an arginine at the position corresponding to amino acid 5 of the sequence set forth in SEQ ID NO: 3 or 5 and a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5;(k) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;(l) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and a proline at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5;(m) a leucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(n) an isoleucine at the position corresponding to amino acid 9 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(o) a methionine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5;(p) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a leucine at the position corresponding to amino acid 54 of the sequence set forth in SEQ ID NO: 3 or 5;(q) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(r) an arginine at the position corresponding to amino acid 10 of the sequence set forth in SEQ ID NO: 3 or 5 and a glutamine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5;(s) a tyrosine at the position corresponding to amino acid 26 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(t) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(u) an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(v) an arginine at the position corresponding to amino acid 29 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(w) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an a tyrosine at the position corresponding to amino acid 39 of the sequence set forth in SEQ ID NO: 3 or 5;(x) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 32 of the sequence set forth in SEQ ID NO: 3 or 5;(y) a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5;(z) an arginine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 41 of the sequence set forth in SEQ ID NO: 3 or 5;(aa) an arginine at the position corresponding to amino acid 33 of the sequence set forth in SEQ ID NO: 3 or 5 and a lysine at the position corresponding to amino acid 63 of the sequence set forth in SEQ ID NO: 3 or 5;(bb) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an arginine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5;(cc) a glutamine at the position corresponding to amino acid 27 of the sequence set forth in SEQ ID NO: 3 or 5 and a tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5; or(dd) an isoleucine at the position corresponding to amino acid 6 of the sequence set forth in SEQ ID NO: 3 or 5 and an tyrosine at the position corresponding to amino acid 30 of the sequence set forth in SEQ ID NO: 3 or 5.

29. The ligand of any one of claims 7 to 28, wherein said ligand is capable of binding to a native C-C Chemokine Receptor 5 (CCR5) and / or the receptor of any one of claims 1 to 6, optionally wherein binding is determined using flow cytometry and / or chemotaxis assays.

30. The ligand of any one of claims 7 to 28, wherein said ligand is capable of selectively binding to the receptor of any one of claims 1 to 6 over the native CCR5, optionally wherein the native CCR5 comprises the amino acid sequence set forth in SEQ ID NO: 1, optionally wherein binding is determined using flow cytometry and / or chemotaxis assays.

31. The ligand of any one of claims 7 to 28, wherein said ligand binds with increased affinity to the receptor of any one of claims 1 to 6 compared to binding of wildtype CCL3 or wildtype LD78P to the receptor of any one of claims 1 to 13, optionally wherein the wildtype CCL3 comprises the amino acid sequence set forth in SEQ ID NO: 3 and / or the wildtype LD78P comprises the amino acid sequence set forth in SEQ ID NO: 5, optionally wherein binding is determined using flow cytometry and / or chemotaxis assays.

32. A polynucleotide encoding the receptor of any one of claims 1 to 6 or the ligand of any one of claims 7 to 31.

33. A vector comprising the polynucleotide of claim 32, optionally wherein the vector is a plasmid or a virus.

34. A cell comprising the receptor of any one of claims 1 to 6, the ligand of any one of claims 7 to 31, the polynucleotide of claim 32 and / or the vector of claim 33, optionally wherein the cell is a T cell or NK cell, for example, a cytotoxic T lymphocyte or an NK-92 cell.

35. A carrier comprising the receptor of any one of claims 1 to 6, the ligand of any one of claims 7 to 31, the polynucleotide of claim 32 and / or the vector of claim 33 and / or the cell of claim 34, optionally wherein the carrier is selected from the group consisting of: a plasmid, a virus, a lipoplex, a liposome, an exosome and a nanoparticle.

36. A pharmaceutical composition comprising the receptor of any one of claims 1 to 6, the ligand of any one of claims 7 to 31, the polynucleotide of claim 32 and / or the vector of claim 33 and / or the cell of claim 34 and / or the carrier of claim 35.

37. A process for producing a receptor and / or a ligand comprising culturing a cell of claim 34 so that the polynucleotide is expressed and the receptor and / or the ligand produced.

38. A method of establishing signalling between at least two biological components, the method comprising providing a first biological component with the receptor of any one of claims 1 to 6, optionally further comprising providing a second biological component with the ligand of any one of claims 7 to 31.

39. A method of establishing signalling between at least two biological components, the method comprising providing a first biological component with the ligand of any one of claims 7 to 31, optionally further comprising providing a second biological component with the receptor of any one of claims 1 to 6.

40. The method of claim 38 or 39, wherein the method is a method of treating a disease or condition requiring directional migration of one biological component to another biological component, optionally wherein the disease or condition is selected from the group consisting of: cancer, an autoimmune disease, a degenerative disease, a cardiovascular disease, a neurological disease, a musculoskeletal disease, a skin and soft tissue disease and an organ transplant..

41. The method of any one of claims 38 to 40, wherein the biological component with the receptor migrates towards an abnormal cell.

42. The method of any one of claims 38 to 41, wherein at least one biological component further comprises a chimeric antigen receptor (CAR), optionally wherein the CAR recognises an antigen on the surface of the abnormal cell, and optionally wherein the abnormal cell is a cancer cell from a tumour, preferably from a solid tumour.

43. A method of treating a tumour in a subject, the method comprising:i) administering to the subject a first T cell and / or first NK cell comprising the receptor of any one of claims 1 to 6 and a chimeric antigen receptor (CAR), and a second T cell and / or second NK cell comprising the ligand of any one of claims 7 to 31; orii) administering to the subject a first T cell and / or first NK cell comprising the ligand of any one of claims 7 to 31 and a chimeric antigen receptor (CAR), and a second T cell and / or second NK cell comprising the receptor of any one of claims 1 to 6,optionally wherein the first T cell and / or first NK cell and the second T cell and / or second NK cell are administered to the subject simultaneously or sequentially.

44. Use of a T cell and / or NK cell comprising the receptor of any one of claims 1 to 6 and a chimeric antigen receptor (CAR) in the manufacture of a medicament for treating a tumour in a subject, wherein the medicament is provided for administration with a T cell and / or NK cell comprising the ligand of any one of claims 7 to 31.

45. Use of a T cell and / or NK cell comprising the ligand of any one of claims 7 to 31 in the manufacture of a medicament for treating a tumour in a subject, wherein the medicament is provided for administration with a T cell and / or NK cell comprising the receptor of any one of claims 1 to 6 and a chimeric antigen receptor (CAR).

46. The method of claim 43 or the use of claim 44 or 45, wherein the tumour is a solid tumour.

47. The use of any one of claims 44 to 46, wherein the medicament and the T cell and / or NK cell are provided for administration to a subject simultaneously or sequentially.

48. A kit comprising:(a) the receptor of any one of claims 1 to 6 and the ligand of any one of claims 7 to 31;(b) a polynucleotide encoding the receptor of any one of claims 1 to 6 and a polynucleotide encoding the ligand of any one of claims 7 to 31 ;(c) a vector comprising the receptor of any one of claims 1 to 6 or a polynucleotide encoding the receptor of any one of claims 1 to 6 and a vector comprising the ligand of any one of claims 7 to 3 lor a polynucleotide encoding the ligand of any one of claims 7 to 31; or(d) a cell comprising the receptor of any one of claims 1 to 6 and a cell comprising the ligand of any one of claims 7 to 31.

49. A method of screening for a receptor capable of being used to establish signalling between at least two biological components, the method comprising:(a) substituting one or more amino acids in a binding domain of the receptor, wherein the binding domain corresponds to amino acids 16 to 33, 86 to 95, 103 to 109, 169 to 192 and 257 to 298 in the amino acid sequence set forth in SEQ ID NO: 1;(b) identifying one or more amino acid substitutions in the binding domain of the receptor that result in increased or decreased affinity to a native C-C Chemokine Ligand 3 (CCL3) and / or a native LD78P relative to a native C-C Chemokine Receptor 5 (CCR5); and (c) selecting a receptor with the one or more amino acid substitutions that result in increased or decreased affinity to a native CCL3 and / or a native LD78P relative to a native CCR5.

50. A method of screening for a ligand capable of being used to establish signalling between at least two biological components, the method comprising:(a) substituting one or more amino acids in a receptor binding domain of the ligand, wherein the receptor binding domain corresponds to amino acids 1 to 11, 25 to 42, 46 to 49, 53 to 55 and 62 to 64 in the amino acid sequence set forth in SEQ ID NO: 3 or 5;(b) identifying one or more amino acid substitutions in the receptor binding domain of the ligand that result in increased or decreased affinity to a native C-C Chemokine Receptor 5 (CCR5) relative to a native C-C Chemokine Ligand 3 (CCL3) and / or a native LD78P; and (c) selecting a ligand with the one or more amino acid substitutions that result in increased or decreased affinity to a native CCR5 relative to a native CCL3 and / or a native LD78P..

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