Self immolative compounds and conjugates comprising an immunomodulatory agent

Abstract

The present invention relates to self immolative compounds, and compositions comprising the self immolative compounds and uses thereof. Specifically, the invention relates to enzyme cleavable self immolative compounds and compositions comprising enzyme cleavable self immolative compounds. Also described herein are specific binding molecule – drug conjugates comprising the cleavable self immolative compounds disclosed herein.

Description

[0001] SELF IMMOLATIVE COMPOUNDS Field of Invention This invention relates to self immolative compounds, and compositions comprising the self 5 immolative compounds. This invention also relates to uses thereof. Specifically, the invention relates to enzyme cleavable self immolative compounds and compositions comprising enzyme cleavable self immolative compounds. Also described herein are specific binding molecule – drug conjugates comprising the cleavable self immolative compounds disclosed herein. 10 Background Conjugation of a drug to a binding molecule such as an antibody, are powerful tools to direct drugs (or payloads) to specific targets within the body. However, generating drug-conjugates that are both specific and efficacious is not trivial. Not only does the binding molecule need to exhibit specific target affinity, but the linker must also be stable. 15 Antibody-drug conjugates (ADCs) are complex molecules composed of an antibody linked to a biologically active payload. The payload is usually a cytotoxic payload. ADCs are often used in the treatment of cancer to target and kill tumour cells. Typically, antibody-drug conjugates (ADCs) are used to deliver a drug (or payload) to a specific site, with the antibody acting as the targeting moiety and the payload providing the biological activity. The present inventors, however, have developed a bifunctional 20 drug-conjugate, capable of providing dual-functionality with both the binding molecule and the payload able to provide independent biological activity. Only a subpopulation of patients (~ 30%) with moderate to severe autoimmune conditions such as rheumatoid arthritis or inflammatory bowel disease experience prolonged disease remission (> 1 year) with current therapies which bind to (or inhibit) one protein target and interfere with its signalling pathway. 25 These agents are typically mAbs or small molecule inhibitors. Such agents often have significant off-target effects, and are therefore of limited use. Additionally, patients often have to take a multitude of different agents to target different disease pathways. There is need to develop therapeutic agents with improved clinical efficacy (> 50% disease remission), with reduced off-target effects to treat most patients with moderate to severe autoimmune 30 conditions. Summary of Invention In one aspect the present invention provides a compound of formula (I): 35 (I) wherein: Y is a conjugating group; 40 D is a bond or a spacer; Z is an enzyme cleavable linker; 1x

[0002] M is a self-immolative linker; and X is an immunomodulatory agent; or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention provides a conjugate of formula (II): 5 or a pharmaceutically acceptable salt thereof, wherein 10 D is a bond or a spacer; Z is an enzyme cleavable linker; M is a self-immolative linker; X is an immunomodulatory agent; Y’ is a linking group; 15 A is a specific binding molecule; and N is 1 to 10. Embodiments described herein in relation to D, Z, M, and X for the compound of formula (I) also apply to the conjugates of formula (II). The inventors have developed a compound of formula (I) that can be used to prepare any suitable 20 drug-conjugate. The inventors have surprisingly found that the compound of formula (I) is able to deliver an inactive immunomodulatory agent, which is then released in an active form in a site specific manner. In a further aspect of the invention, there is provided a composition comprising the conjugate as described herein and optionally at least one pharmaceutically acceptable carrier. In a further aspect of the invention, there is provided the conjugate as described herein, or a 25 composition comprising the conjugate as described herein, for use in therapy. In a further aspect of the invention, there is provided the conjugate as described herein, or a composition comprising the conjugate as described herein, in the manufacture of a medicament for the treatment of a diseased or condition. In a further aspect of the invention, there is provided a method of treatment of a disease in a patient, comprising administering the conjugate as described herein, or a composition comprising the conjugate 30 as described herein, to said patient. In a further aspect of the invention, there is provided use of the conjugate as described herein, or a composition comprising the conjugate as described herein, for site specific delivery of an immunomodulatory agent. The inventors have developed a binding molecule drug conjugate of formula (II), which can be 35 prepared from the compound of formula (I). It is hypothesised that such a conjugate is suitable for use with any binding molecule and any immunomodulatory agent. The inventors have therefore developed a platform for multifunctional therapeutics, which bind / inhibit multiple protein targets and consequently interferes with multiple signalling pathway. This gives a high likelihood of high efficacy and prolonged remission in disease patients. It is also hypothesized that disease control could be achieved at a lower 40 dose, which may in turn limit off-target toxicities seen with monotherapy. 2x

[0003] Brief description of the figures Figure 1 and 2: Payload (Tofacitinib) release following treatment of Mal-PEG4-NPV-PABC- DMEDA-Tofacitinib with human neutrophil elastase. 5 Figure 3: Payload (Dexamethasone) release following treatment of ELN28-134-Mal-PEG4-NPV- PABC-DMEDA-Dexamethasone in the presence of human neutrophil elastase. Figure 4: Structural illustration of exemplary SDCs / A) ELN28-135-Tofacitinib, also known as ELN28-135-01. ELN28-135-01 comprises an anti-human TNF-alpha inhibiting soloMER®, ELN28-135. The suffix “01” or “Tofa” represents Tofacitinib, a drug conjugate payload which is an inhibitor of 10 intracellular cytoplasmic Janus Kinase (JAK) enzymes. B) ELN28-135v2-Tofa, structure of linker is Bromoacetamide-PEG4-NPV-PABC-DMEDA-Tofacitinib. Figure 5: Illustration of Quad-X™ ELN22-108 reformatting and mutations to enhance manufacturability and retain function in the ELN22-134 and ELN22-135. ELN22-134 and ELN22-135 are anti-human TNF-alpha bi-paratopic Quad-X™ with mutations (S239C, S442C) to allow direct conjugation 15 of linker-payload to the huIgG Fc region of the constructs. Figure 6: Binding of reformatted Quad-X™ constructs to human TNF-alpha in solution using BLI, Octet® Figure 7: Binding of reformatted Quad-X™ constructs to biosensor-immobilised biotin-human TNF-alpha using BLI, Octet® 20 Figure 8: Neutralization of human TNF-alpha induced cytotoxicity in mouse fibrosarcoma cell line, L929 cells. Figures 9 to 12: DAR 4 Conjugation demonstrated by Deconvoluted LC-MS Figure 13: Payload (Tofacitinib) release following treatment of ELN28-134-Mal-PEG4-NPV- PABC-DMEDA-Tofacitinib and ELN28-135-Mal-PEG4-NPV-PABC-DMEDA-Tofacitinib with human 25 neutrophil elastase. Figure 14: (A) ELN28-135-Tofacitinib extended stability at 37°C in human plasma. (B) Transition monitored for LC-MS / MS analysis. A calibration curve was prepared using the known concentration of analyte and the ratio of analyte to internal standard instrument response. A linear regression with 1 / X2weighing was applied and used to back calculate the sample concentration. 30 Figure 15: Inhibition of STAT3 phosphorylation by Tofacitinib in HEK-Blue Reporter cell-based assay. Figure 16: Neutralization of human TNF-alpha induced cytotoxicity in mouse fibrosarcoma cell line, L929 cells. Figure 17: Binding of soloMER™ drug conjugates to human TNF-alpha in solution using BLI, 35 Octet® Figure 18: Synergistic / Additive inhibition of PHA-induced proliferation of healthy pooled PBMCs Figure 19: Serum mouse IL6 inhibition in acute LPS induced inflammation transgenic Tg1278TNFKOhTNFR1K1 mice. Figure 20: Serum mouse CXCL1 inhibition in acute LPS induced inflammation transgenic 40 Tg1278TNFKOhTNFR1K1 mice. 3x

[0004] Figure 21: Diagrammatic representation of ELN28U-02 (Ustekinumab – Mal-PEG4-NPV-PABC- DMEDA-Upadacitinib). Ustekinumab is an anti-IL12 and IL23 specific neutralising monoclonal antibody, while Upadacitinib is an inhibitor of intracellular cytoplasmic Janus Kinase (JAK) enzymes. Figure 22: ELISA binding assay of ELN28U-02 (Ustekinumab – Mal- PEG4-NPV-PABC-DMEDA- 5 Upadacitinib) to recombinant human IL-12. Figure 23: ELISA binding assay of ELN28U-02 to recombinant human IL-23 (Ustekinumab – Mal- PEG4-NPV-PABC-DMEDA-Upadacitinib). Figure 24: Functional activity of released Upadacitinib from Mal- PEG4-NPV-PABC-DMEDA- Upadacitinib demonstrated by the inhibition of STAT3 phosphorylation in HEK-Blue Reporter cell-based 10 assay. Figure 25: Synergistic Inhibition of STAT3 phosphorylation by ELN28U-02 in HEK-Blue Reporter cell-based assay. Figure 26: Structural illustration of ELN28-134 / ELN28-135-Dexamethasone. The soloMER® drug conjugate (SDC) comprises the anti-human TNF-alpha inhibiting soloMER®, ELN28-135. The 15 immunomodulatory / anti-inflammatory payload, Dexamethasone a potent glucocorticoid. Figure 27: : Crystallisation and X-ray structures determination for VNAR-D1 and sTNF-α complex Figure 28: Surface binding to transmembrane human TNF-alpha in activated human CD4+ T cells. Fluorescence quantified surface binding of anti-TNF-α agents to tmTNF-α on PHA stimulated human CD4+ T cells at 24 h. The results are the mean ± SD (n = 2) with 2 replicates per experiment. MAB210 20 and Infliximab are commercially available anti-human TNF-alpha monoclonal antibodies. ELN22-108 is a bi-paratopic anti-human TNF-alpha VNAR D1-huFc-C4. ELN22-129 is a monoparatopic anti-human TNF- alpha D1-huFc-D1. ELN22-130 is a monoparatopic anti-human TNF-alpha C4-huFc-C4. Figure 29: Fluorescence quantified E-selection expression at 24 h timepoint. The result is the mean ± SD (n = 2) with 2 replicates. 25 Figure 30: IFN-γ secretion induced by the binding of anti-TNF-α agents to tmTNF-α on PHA stimulated CD4+ T cells were quantified using human IFN-γ DuoSet Sandwich ELISA kit. The results are the mean ± SD (n = 1) with 2 replicates per experiment, R2 = 0.97 for IFN-γ standard curve. Figure 31: A) In vivo dosing and handling of Tg197 transgenic mouse model of arthritis. B) Tg197 transgenic mouse ankle joint histopathological evaluation analysing inflammation (i), cartilage destruction 30 (ii), bone erosion (iii) and total histopathology score (iv). C) Serum inhibition of mouse CXCL1(i) and CCL2 (ii) in Tg197 transgenic mice. D) Analysis of treatment efficacy by gene expression modulation in the ankle joints of Tg197 transgenic mice. E) Restoration of the expression of genes from CXCL (i), CCL (ii) and MMP (iii) families in the ankle joints of Tg197 transgenic mice. Figure 32: Analysis of ELN28-135-Tofa concentrations in plasma (i) and ankle joint (ii) samples 35 by ELISA Figure 33: A) Analysis of test article concentration in Tg197 transgenic mouse after 7 weeks of twice weekly dosing by ELISA; comparison of TNFα targeting test articles (ELN28-135-Tofa) to non- targeting test article (ELN0-2V-135-Tofa). B) Analysis of ELN28-135-Tofa (i) and ELN0-2V-135 (ii) concentrations in Tg197 transgenic mice by LC-MS / MS. 40 Figure 34: ELN28-135v2-01 inhibition of the JAK / STAT pathway. 4x

[0005] Figure 35: Inhibition of human CXCL10 gene expression in synovial organoids. Relative quantification compared to ELN0-2V-135. Brief description of the sequences 5 In the event of any discrepancy between the sequences in the sequence listing and the sequences in the table below, the sequences in the table below should prevail. 5x

[0006] 6x

[0007] 7x

[0008] 8x

[0009] Detailed description The meanings of terms used in the specification of the present application will be explained below, and the present invention will be described in detail. 5 The term "alkyl" as used herein refers to a monovalent straight- or branched-chain hydrocarbyl moiety containing from 1 to 40 carbon atoms. Examples of alkyl groups include alkyl groups containing from 1 to 30 carbon atoms, e.g. from 1 to 20 carbon atoms, e.g. from 1 to 18 carbon atoms. Particular examples include alkyl groups containing 4, 6, 8, 10, 12 or 14 carbon atoms. Unless specifically indicated otherwise, the term “alkyl” does not include optional substituents. 10 The term "alkenyl" as used herein refers to a monovalent straight- or branched-chain alkyl group containing from 2 to 40 carbon atoms and containing, in addition, at least one carbon-carbon double bond, of either E or Z configuration unless specified. Examples of alkenyl groups include alkenyl groups containing from 2 to 28 carbon atoms, e.g. from 3 to 26 carbon atoms, e.g. from 4 to 24 carbon atoms. Examples of alkenyl groups include alkenyl groups containing from 2 to 20 carbon atoms, e.g. from 2 to 15 12 carbon atoms, e.g. from 2 to 10 carbon atoms. Particular examples include alkenyl groups containing 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl and the like. The term "alkynyl" as used herein refers to a monovalent straight- or branched-chain alkyl group containing from 2 to 40 carbon atoms and containing, in addition, at least one carbon-carbon triple bond, 20 unless specified. Examples of alkynyl groups include alkynyl groups containing from 2 to 28 carbon atoms, e.g. from 3 to 26 carbon atoms, e.g. from 4 to 24 carbon atoms. Examples of alkynyl groups include alkynyl groups containing from 2 to 20 carbon atoms, e.g. from 2 to 12 carbon atoms, e.g. from 2 to 10 carbon atoms. Particular examples include alkynyl groups containing 2, 3, 4, 5 or 6 carbon atoms. Examples of alkynyl groups include ethynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- 25 pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like. The term "cycloalkyl" as used herein refers to a monovalent saturated hydrocarbyl moiety containing from 3 to 40 carbon atoms and containing at least one ring, wherein said ring has at least 3 ring carbon atoms. The cycloalkyl groups mentioned herein may optionally have alkyl groups attached thereto. Examples of cycloalkyl groups include cycloalkyl groups containing from 3 to 16 carbon atoms, 30 e.g. from 3 to 10 carbon atoms. Particular examples include cycloalkyl groups containing 3, 4, 5 or 6 ring 9x

[0010] carbon atoms. Examples of cycloalkyl groups include groups that are monocyclic, polycyclic (e.g. bicyclic) or bridged ring system. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "heterocyclyl" as used herein refers to a cycloalkyl group having 3 to 40 carbon atoms 5 and containing at least one ring, and having, in addition to carbon atoms, from 1 to 10 heteroatoms as ring atoms, wherein said ring has at least 3 ring atoms. The heterocyclyl groups mentioned herein may optionally have alkyl groups attached thereto. Examples of heterocyclyl groups include heterocyclyl groups containing from 3 to 16 ring atoms, e.g. from 3 to 10 ring atoms. Particular examples include heterocyclyl groups containing 3, 4, 5 or 6 ring atoms. Examples of cycloalkyl groups include groups that 10 are monocyclic, polycyclic (e.g. bicyclic) or bridged ring system. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, tetrahydrothiophenyl, thianyl, imidazolidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, and morpholinyl. The term "alkylene" refers to a bivalent alkyl group. An "alkylene" is a methylene or polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer. An alkylene may be unsubstituted or 15 substituted. A substituted alkylene is an alkylene group in which one or more methylene hydrogen atoms is replaced with a substituent. Suitable substituents include those described below for a substituted alkyl group. An alkylene chain also may be substituted at one or more positions with an alkyl group or a substituted alkyl group. The term "aryl" as used herein refers to an aromatic carbocyclic ring system containing from 4 to 20 14 ring carbon atoms. Examples of aryl groups include aryl groups containing from 6 to 10 ring carbon atoms, e.g. 6 ring carbon atoms. An example of an aryl group includes a group that is a monocyclic aromatic ring system or a polycyclic ring system containing two or more rings, at least one of which is aromatic. Examples of aryl groups include aryl groups that comprise from 1 to 6 exocyclic carbon atoms in addition to ring carbon atoms. Examples of aryl groups include aryl groups that are monovalent or 25 polyvalent as appropriate. Examples of monovalent aryl groups include phenyl, benzyl naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like. An example of a divalent aryl group is 1,4-phenylene. The terms "heteroaryl" and “heteroar-” refer to an aromatic group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms and having, in addition to carbon atoms, from one to four heteroatoms as ring atoms. The term "heteroatom" refers to N, O, or S. In some embodiments, two adjacent 30 substituents on the heteroaryl, taken together with the intervening ring atoms, form an optionally substituted fused 5- to 6-membered aromatic or 4- to 8-membered non-aromatic ring having 0–3 ring heteroatoms selected from the group consisting of N, O and S. Thus, the terms "heteroaryl" and "heteroar- ", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aromatic, cycloalkyl, or heterocyclic rings, where the radical or point of attachment is on the heteroaromatic ring. 35 The term "substituted", as used herein, means that a hydrogen radical of a designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. The phrase "one or more substituents", as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites. Unless otherwise indicated, where multiple substituents are 40 present, substituents may be either the same or different. 10 x

[0011] An aryl or heteroaryl group may be optionally substituted. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include halo, -NO2, -CN, -R’, -C(R’)=C(R’)2, -C^C-R’, -OR’, -SR’, -S(O)R’, -SO2R’, -SO3R’, -SO2N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)N(R’)2, -NR’CO2R’, -NR’SO2R’, -NR’SO2N(R’)2, -O-C(O)R’, -O-CO2R’, -OC(O)N(R’), 5 -C(O)R’, -CO2R’, -C(O)N(R’)2, -P(O)(R’)2, -P(O)(OR’)2, -O-P(O)-OR’, wherein R’, independently, is hydrogen or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic or heteroaromatic moiety, or two occurrences of R’are taken together with their intervening atom(s) to form an optionally substituted 5–7-membered aromatic, heteroaromatic, cycloalkyl, or heterocyclic ring. Alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl groups may be “optionally substituted”. Unless 10 otherwise defined, suitable substituents on the saturated carbon of an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl group, are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: =O, =S, =C(R’’)2, where R’’ is hydrogen or an optionally substituted C1–6 alkyl group. In addition to the substituents defined above, optional substituents on the nitrogen of a non- 15 aromatic heterocyclic ring also include and are generally selected from R’, -N(R’)2, -C(O)R’, -C(O)OR’, -S(O)2R’, -S(O)2N(R’)2, wherein each R’is defined above. A ring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ring also may be oxidized to form the corresponding N- hydroxy or N-oxide compound. The term “disulfide bond” as used herein refers to two divalent sulfur atoms which are covalently 20 bonded to each other by a single bond (-S-S-). As used herein, “halo” refers to fluoro, chloro, bromo or iodo. As used herein, “amino” refers to –NH2, “alkylamino” refers to –NHalkyl and “dialkylamino” refers to -N(alkyl)2, wherein each alkyl may be the same or different. As used herein, the term “comprises” means “includes, but is not limited to.” As used herein, the term “amino acid residue” refers to both natural and non-natural amino acid residues. 25 ‘polyalkylene glycol’ as used herein refers to homo-polymers or co-polymers of ethylene oxide, propylene oxide, and / or butylene oxide. ‘PABC’ as used herein refers to the group p-aminobenzyl carbamate. ‘DMEDA’ as used herein refers to N,N'-dimethylethylenediamine. 30 Compounds of formula (I) Compounds of formula (I) as described herein include an immunomodulatory agent in an inactive form. Compounds of formula (I) as described herein also include an enzyme cleavable linker and a self- immolative linker. When the enzyme cleavable linker is cleaved by an enzyme, the self-immolative linker spontaneously degrades and releases the immunomodulatory agent in an active form. The active form of 35 the immunomodulatory agent therefore can be released in the presence of a suitable enzyme. Compounds of formula (I) as described herein can also be used for the preparation of conjugates of formula (II) as described herein. Enzyme cleavable linker (Z) 11 x

[0012] The enzyme cleavable linker, Z, is a linker that can be cleaved by the activity of an enzyme. Upon cleavage of the enzyme cleavable linker, the self-immolative linker spontaneously degrades, releasing the immunomodulatory agent in an active form. The expression of the enzyme may be upregulated at particular sites in the body. For example, 5 the enzyme may be an enzyme the expression of which is upregulated at sites of inflammation. The activity of the enzyme is required for release of the immunomodulatory agent in an active form. Therefore, the immunomodulatory agent in an active form is preferentially released at particular sites in the body, for example sites of inflammation. The enzyme cleavable linker may be a linker that can be cleaved by the activity of an enzyme that 10 is upregulated at sites of inflammation. For example, the enzyme cleavable linker may be a linker that can be cleaved by the activity of serine proteases (such as Elastase), MMPs (such as MMP1, 2, 3, 9 or 13), COX (such as COX1 or COX2), iNOS, Lipoxygenases (such as 5LOX, 12LOX or 15LOX), caspases (such as Caspase 1, 3 or 8), Phospholipase A2 (PLA2), Granzyme B, NADPH oxidase, Cathepsins (such as Cathepsin B, D or L), Arginase, Myeloperoxidase or any other suitable enzyme. The enzyme cleavable 15 linker may be cleaved by lysosomal protease cleaving enzymes (such as Cathepsins), a β-glucuronidase enzyme, an asparaginyl endopeptidase (such as Legumain), a phosphatase, an Esterase or a Matrix metalloproteinase (MMP). Preferably, the enzyme cleavable linker is a linker that can be cleavable by the activity of elastase. The elastase may be human neutrophil elastase. Elastase plays a key role in innate immunity and 20 physiologic inflammation and the expression of elastase is upregulated at sites of inflammation. The immunomodulatory agent is therefore selectively released in an active form at sites of inflammation. Upon cleavage of the enzyme cleavable linker, the self immolative linker undergoes spontaneous reactions to release active immunomodulatory agent. When the immunomodulatory agent is connected to the self-immolative linker, the immunomodulatory group may be inactive. Release of the 25 immunomodulatory agent from the self immolative linker may be required for activity of the immunomodulatory agent. Accordingly, the active form of the immunomodulatory agent is only released at sites where elastase is present, minimising the off-target effects of the immunomodulatory agent. This also means that the amount of the compound of formula (I) that needs to be administered to have a desired effect may be lower than that required when the same immunomodulatory agent is administered alone, 30 since the active immunomodulatory agent is selectively released at the desired site. Preferably, Z is a peptide comprising 2 to 10 amino acid residues, more preferably 2 to 4 amino acid residues. More preferably, Z is a peptide comprising 3 amino acid residues. Preferably, Z comprises an amino acid residue selected from alanine, valine, serine, glycine, leucine and / or isoleucine. Elastase has been shown to cleave peptide bonds at the C-terminus of these 35 amino-acids (this is described in: Narayananan, S. et al. (1969) Biochemistry J.114, 11–7; Gertler, A. et al. (1977) Biochemistry 16, 2709; Del Mar, E.G. (1980) Biochemistry 19, 468–72; Powers, J.C. et al. (1977) Biochimica et Biophysica Acta 485, 156–66). Accordingly, the presence of these amino-acid residues in Z allows for the cleavage of the elastase-cleavable linker in the presence of elastase. Preferably, Z comprises a small hydrophobic amino acid, for example, glycine, alanine or valine, as elastase has been 40 shown to cleave at the C-terminus of these amino acids (as described in Cotton, S.W., (2020), 12 x

[0013] Contemporary Practice in Clinical Chemistry (Fourth Ed.), Ch. 33 – Evaluation of exocrine pancreatic function, pp.573-585). Preferably, Z comprises -Pro-Val-. More preferably, Z comprises -XX-Pro-Val-, wherein XX is a natural or non-natural amino acid residue. More preferably, Z comprises: -Gly-Pro-Val-, -Ala-Pro-Val-, - 5 His-Pro-Val-, -Asn-Pro-Val-, or -Nva-Pro-Val-, wherein ‘Nva’ refers to the non-natural amino acid norvaline. It has been shown that elastase selectively cleaves at the C-terminus of these amino-acid sequences (as described in WO 02 / 072151). Therefore, the presence of these residues in Z allows for the selective cleavage of Z by elastase. Thus, the incorporation of these residues in Z results in increased localisation of the active form of the immunomodulatory agent at sites of inflammation. 10 Preferably, Z is -Gly-Pro-Val-, -Ala-Pro-Val-, -His-Pro-Val-, -Asn-Pro-Val-, and / or -Nva-Pro-Val-. As noted above, elastase selectively cleaves at the C-terminus of these amino acid sequences. Therefore, when Z is one of the above sequences, Z is selectively cleaved at sites of inflammation, resulting in increased localisation of the active form of the immunomodulatory agent at sites of inflammation. More preferably, Z comprises -Asn-Pro-Val-. Most preferably, Z is -Asn-Pro-Val-. As 15 demonstrated in Example 2, compounds of formula (I) wherein Z is -Asn-Pro-Val- are cleaved in the presence of elastase under physiologically relevant conditions, resulting in the release of the immunomodulatory agent. Preferably, Z is a peptide comprising 2 to 10 amino acid residues, more preferably 2 to 4 amino acid residues, most preferably 3 amino acid residues, wherein Z is bonded to the self-immolative linker, 20 M, through the C-terminus of one of the amino acid residues, and Z is bonded to the spacer or bond, D, through the N-terminus of a different amino acid residue. More preferably, Z comprises -Pro-Val-, preferably -Gly-Pro-Val-, -Ala-Pro-Val-, -His-Pro-Val-, -Asn-Pro-Val-, or -Nva-Pro-Val-, wherein Z is bonded to M through the C-terminus of -Val- and Z is bonded to the spacer or bond, D, through the N- terminus of a different amino acid residue. Most preferably, Z comprises -Asn-Pro-Val-, wherein Z is25 bonded to M through the C-terminus of -Val- and Z is bonded to the spacer or bond, D, through the N- terminus of -Asn-. Preferably, the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof, wherein XX is Gly, Ala, His, Asn, or Nva. 30 More preferably, the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. Self-immolative linker (M) 13 x

[0014] The compound of formula (I) comprises a self-immolative linker, M, which is covalently bonded to the enzyme cleavable linker (Z) and the immunomodulatory agent (X). M may comprise one or more self- immolative groups (Mi). The self-immolative groups may be the same or different. As used herein, self- immolative groups are defined as a chemical moiety that is normally stable but spontaneously degrades 5 in response to specific stimuli. For example, in the present invention, the specific stimuli is the cleavage of the elastase cleavable linker for the self-immolative group directly bound to the enzyme cleavable linker. When M comprises more than one self-immolative group, the specific stimuli for the remaining self- immolative groups is the spontaneous degradation of a neighbouring self-immolative group. M may comprise one or more self-immolative groups. M may comprise one to five self-immolative 10 groups, preferably one to three self-immolative groups, more preferably two self-immolative groups. M may be: wherein m is 1 to 5; and 15 each Mi is a self-immolative group independently selected from: wherein J is C4-14 aryl or 5-14 membered heteroaryl, wherein the C4-14 aryl or 5-14 membered heteroaryl 20 may be optionally substituted by one or more RJ; wherein each RJis independently selected from halo, -CN, -NO2, C1-12 alkyl, C2-12 alkenyl, -OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 alkyl, -N(-C1-12 alkyl)2, -S-C1-12 alkyl, -O-C2-12 alkenyl, -NH-C2-12 alkenyl, -S-C2-12 alkenyl, -NHC(O)-C1-12 alkyl, -OC(O)-C1-12 alkyl, C4-14 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 25 W is NH, O, S, or CONH; k is 0, 1 or 2; p is 0, 1 or 2; each RBis independently selected from H or C1-12 alkyl; and q is 1 or 2, 30 or a pharmaceutically acceptable salt thereof. Preferably wherein each Mi is a self-immolative group independently selected from: 14 x

[0015] Wherein * represents the point of attachment to Z or the ** of a further Mi group; and ** represent the point of attachment to X or the * of a further Mi group. 5 M may be 1 to 3, therefore M may be -Mi-, -Mi-Mi- or -Mi-Mi-Mi-, wherein each Mi may be the same or different. Preferably, m is 2, therefore M is -Mi-Mi- wherein each Mi may be the same or different. J may be substituted by one to four RJ. Preferably, J is substituted by one RJ. More preferably, J is unsubstituted. Preferably, J is phenyl, naphthyl, biphenyl, or coumarin, more preferably phenyl, optionally 10 substituted by one or more RJ. More preferably, J is phenyl optionally substituted by one RJ. Most preferably, J is unsubstituted phenyl. Each RJmay be independently selected from C1-12 alkyl, OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 alkyl, -N(-C1-12 alkyl)2 Preferably, RJ is C1-6 alkyl.Preferably, W is N or O, more preferably N. 15 k is preferably 0 or 1, more preferably 0. P is preferably 0 or 1, more preferably 0. More preferably, k is 0 or 1 and p is 0 or 1, most preferably k and p are both 0. Preferably, W is N or O, J is phenyl, naphthyl, biphenyl, or coumarin optionally substituted by one or more RJ, each RJis independently selected from C1-12alkyl, OH, NH2, -SH, -O-C1-12alkyl, -NH-C1-12alkyl, -N(-C1-12 alkyl) are each independently 0 or 1.20 More preferably, W is N or O, J is unsubstituted phenyl, naphthyl, biphenyl, or coumarin, and k and p are each independently 0 or 1. More preferably, W is N or O, J is unsubstituted phenyl, and k and p are 0. Preferably, each RBis independently selected from H, methyl or ethyl, more preferably H and methyl. Most preferably, RBis methyl. Preferably, q is 1. Preferably, each RBis independently selected from H, methyl or ethyl and q is 1. More preferably, 25 each RBis independently selected from H and methyl, and q is 1. Most preferably, each RBis methyl and q is 1. Preferably, W is N or O, J is phenyl, naphthyl, biphenyl, or coumarin optionally substituted by one or more RJ, each RJis independently selected from C1-12 alkyl, OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 15 x

[0016] alkyl, -N(-C1-12 alkyl)2 are each independently 0 or 1, eachRBis independently selected from H, methyl or ethyl and q is 1. More preferably, W is N or O, J is unsubstituted phenyl, naphthyl, biphenyl, or coumarin, k and p are each independently 0 or 1, each RBis independently selected from H and methyl, and q is 1. More preferably, W is N or O, J is unsubstituted 5 phenyl, k and p are 0, each RBis methyl and q is 1. Each Mi may be independently selected from: 10 16 x

[0017] Preferably, m is two, wherein one Mi is and the other Mi is 5 , The self-immolative linker, M, may be bonded to Z via a covalent bond from W or -NRB- of M. 10 Preferably, Z is a peptide comprising 2 to 10 amino acid residues, more preferably 2 to 4 amino acid residues, most preferably 3 amino acid residues, and Z is bonded to the self-immolative linker, M, through a covalent bond between the C-terminus of one of the amino acid residues of Z and W or -NRB- of M. More preferably, Z comprises -Pro-Val-, preferably -Gly-Pro-Val-, -Ala-Pro-Val-, -His-Pro-Val-, -Asn-Pro- Val-, or -Nva-Pro-Val-, and Z is bonded to M through a covalent bond between the C-terminus of -Val- 15 and the W group or -NRB- of M. More preferably, Z comprises -Asn-Pro-Val-, wherein Z is bonded to M through a covalent bond between the C-terminus of -Val- and the W group or -NRB- of M. Most preferably, Z comprises -Asn-Pro-Val-, wherein Z is bonded to M through a covalent bond between the C-terminus of -Val- and the W group of M. Preferably, M is bonded to the immunomodulatory agent, X, through a covalent bond between the 20 immunomodulatory agent and the carbon atom in the group -NRBC(O)- or -C(O)O- in M. More preferably, M is bonded to the immunomodulatory agent, X, through a covalent bond between the immunomodulatory agent and the carbon atom in the group -NRBC(O)-. Preferably, the compound of formula (I) is: 18 x

[0018] wherein Y, D, Z, and X are as defined herein; W is N or O; 5 J is phenyl, naphthyl, biphenyl, or coumarin optionally substituted by one or more RJ; each RJis independently selected from C1-12 alkyl, OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 alkyl, - N(-C1-12 alkyl)2 k and p are each independently 0 or 1, each RBis independently selected from H, methyl or ethyl; and 10 q is 1; or a pharmaceutically acceptable salt thereof. More preferably, the compound of formula (I) is: wherein 15 Y, D, Z, and X are as defined herein; k and p are each independently 0 or 1, each RBis independently selected from H and methyl; or a pharmaceutically acceptable salt thereof. Most preferably, the compound of formula (I) is: 20 Wherein Y, D, Z, and X are as defined herein; or a pharmaceutically acceptable salt thereof. Preferably, the compound of formula (I) is: 25 wherein 19 x

[0019] Y, D, and X are as defined herein; XX is a natural or non-natural amino acid residue; W is N or O; J is phenyl, naphthyl, biphenyl, or coumarin optionally substituted by one or more RJ; 5 each RJis independently selected from C1-12 alkyl, OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 alkyl, - N(-C1-12 alkyl)2 k and p are each independently 0 or 1, each RBis independently selected from H, methyl or ethyl; and q is 1 10 or a pharmaceutically acceptable salt thereof. More preferably, the compound of formula (I) is: ; wherein 15 Y, D, and X are as defined herein k and p are each independently 0 or 1; each RBis independently selected from H and methyl; XX is selected from Gly, Ala, His, Asn, and Nva, preferably, XX is Asn; or a pharmaceutically acceptable salt thereof. 20 Preferably, the compound of formula (I) is of formula: Wherein Y, D, and X are as defined herein or a pharmaceutically acceptable salt thereof. 25 Immunomodulatory agent (X) As used herein, the term “immunomodulatory agent” refers to a substance that modifies or regulates one or more components or functions of the immune system. Immunomodulatory agents may enhance (stimulate) or suppress immune responses, and may act through various mechanisms including, 30 but not limited to, modulation of cytokine production, alteration of immune cell proliferation or activation, and interference with antigen presentation or receptor signalling. The immunomodulatory agent may be 20 x

[0020] naturally occurring or synthetically produced and encompasses a wide range of molecules such as small molecules, peptides, proteins, antibodies, nucleic acids, and complex biologics. The immunomodulatory agent may comprise a small molecule that modulates immune cell activity, trafficking, and / or function to attenuate immune responses. 5 Preferably, the immunomodulatory agent is bound to M through a group that is essential for the activity of the immunomodulatory agent. Thus, the immunomodulatory agent is inactive until the enzyme cleavable linker is cleaved and the self-immolative linker spontaneously degrades, resulting in the release of the immunomodulatory agent in an active form. Preferably, the immunomodulatory agent is a small molecule which modulates signalling, cell 10 trafficking, nucleic acid sensing, mitochondrial and protein degradation pathways. The immunomodulatory agent may be selected from a Janus Kinase inhibitor (JAKi), a corticosteroid, cyclosporin, an S1P receptor inhibitor, a RORγt inhibitor, an NX-13 inhibitor and a Proteolysis Targeting Chimera. Preferably, the immunomodulatory agent is a JAKi. More preferably, the immunomodulatory agent is a reversibly JAKi. The JAKi may be selected from compounds (1)-(18): 15 21 x

[0021] Compounds (1)-(18) represent the structures of the following compounds: (1) tofacitinib; (2) baricitinib; (3) upadacitinib; (4) abrocitinib; (5) ruxolitinib; (6) delgocitinib; (7) fedratinib; (8) filgotinib; (9) oclacitinib; (10) peficitinib; (11) pacritinib; (12) momelotinib; (13) brepocitinib; (14) cerdulatinib; (15) 5 decernotinib; (16) itacitinib; (17) gandotinib; and (18) gusacitinib. Compounds (1)-(12) have been approved for use in humans. Preferably, the JAKi is selected from compounds (1) to (12). More preferably, the JAKi is compound (1) or (3). The Examples demonstrate that compound (1) can be released from compounds of formula (I). Preferably, the immunomodulatory agent is a reversible JAKi that is competitive for the ATP- 10 binding site of Janus kinase, and the reversible JAKi is covalently bonded to M through a residue that is essential for the activity of the JAKi. The JAKi in the compound of formula (I) is therefore inactive in the body until the enzyme cleavable linker is cleaved, resulting in the self-immolative linker spontaneously degrading and the JAKi being released in an active form. Preferably, the immunomodulatory agent is a JAKi covalently bonded to M through a nitrogen 15 atom on the JAKi that acts as a hydrogen bond acceptor or donor at the ATP-binding site of Janus kinase. More preferably, X is a JAKi comprising a group: 22 x

[0022] wherein: R10, R11and R12together form an optionally substituted mono, bi, or tricyclic heteroaryl group; or R11and R12together form an optionally substituted mono, bi, or tricyclic heteroaryl group; and 5 R10is an optionally substituted C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group; or R10and R11together form an optionally substituted mono, bi, or tricyclic heteroaryl group; and R12is an optionally substituted C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group; wherein represents the point of attachment to M. In some embodiments, X is selected from compounds (1)-(18), wherein X is covalently bonded to 10 M through the bond specified by : 23 x

[0023] . In preferred embodiments, the immunomodulatory agent is a JAKi and the enzyme cleavable linker is an elastase cleavable linker. As elastase expression is upregulated in regions of inflammation, administration of the compound of formula (I) results in an accumulation of the Janus kinase inhibitor at the site of inflammation in a subject and avoids accumulation of the immunomodulatory agent at other 5 sites. The specific targeting of the site of inflammation in the subject allows for the compound of formula (I) to be administered at a lower concentration compared to the Janus kinase inhibitor in its active form. Signalling pathways such as TNFα and IL-17 do not use JAK. Therefore, the conjugate of the invention described herein may be able to act on multiple targets at the same time. This may allow a lower dose of the conjugate to be administered, as the drug acts only in a targeted manner. 10 The compound of formula (I) may have formula: 24 x

[0024] wherein Y, D, and Z are as defined herein; W is N or O; J is phenyl, naphthyl, biphenyl, or coumarin optionally substituted by one or more RJ; 5 each RJis independently selected from C1-12 alkyl, OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 alkyl, - N(-C1-12 alkyl)2 k and p are each independently 0 or 1, each RBis independently selected from H, methyl or ethyl; and q is 1; 10 X is a JAKi; or a pharmaceutically acceptable salt thereof. The compound of formula (I) may have formula: wherein 15 Y, D, and Z are as defined herein k and p are each independently 0 or 1, each RBis independently selected from H and methyl; wherein X is a JAKi; or a pharmaceutically acceptable salt thereof. The compound of formula (I) may have formula: 20 Wherein Y, D, and Z are as defined herein X is a JAKi; or a pharmaceutically acceptable salt thereof. 25 The compound of formula (I) may have formula: wherein Y and D are as defined herein; 25 x

[0025] XX is a natural or non-natural amino acid residue; W is N or O; J is phenyl, naphthyl, biphenyl, or coumarin optionally substituted by one or more RJ; each RJis independently selected from C1-12 alkyl, OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 alkyl, - 5N(-C1-12 alky k and p are each independently 0 or 1, each RBis independently selected from H, methyl or ethyl; and q is 1; X is a JAKi; 10 or a pharmaceutically acceptable salt thereof. The compound of formula (I) may have formula: ; wherein 15 Y and D are as defined herein; k and p are each independently 0 or 1; each RBis independently selected from H and methyl; XX is selected from Gly, Ala, His, Asn, and Nva, preferably, XX is Asn; X is a JAKi; 20 or a pharmaceutically acceptable salt thereof. The compound of formula (I) may have formula: Wherein Y and D are as defined herein; 25 X is a JAKi; or a pharmaceutically acceptable salt thereof. The compound of formula (I) may have the formula: 26 x

[0026] . or a pharmaceutically acceptable salt thereof wherein X is a JAKi. The compound of formula (I) may be of formula: 5 10 x

[0027] 5 Preferably, the compound of formula (I) is of formula: 10 30 x

[0028] 5 or a pharmaceutically acceptable salt thereof. Most preferably, the compound of formula (I) is of formula: 32 x

[0029] or a pharmaceutically acceptable salt thereof. The immunomodulatory agent of the invention is inactive when connected to the compound of 5 formula (I) and conjugate of formula (II). Cleavage of the enzyme cleavable linker is required in order to release the active immunomodulatory agent. The compound of formula (I) and conjugate of formula (II) of the invention thereby may deliver an immunomodulatory agent in an inactive form, the active form may only be generated by enzyme mediated cleavage. In preferred embodiments, the enzyme cleavable linker is an elastase cleavable linker. The immunomodulatory agent is then released in an active form 10 preferentially at sites of elastase upregulation, such as sites of inflammation. Conjugating group (Y) and spacer (D) The conjugating group, Y, and the spacer or bond, D, are relevant for the attachment of a specific binding molecule to prepare conjugates of formula (II). 15 D may be a bond. Preferably, D is a spacer. A spacer provides separation between the conjugating group and connected specific binding group, and the elastase cleavable linker. This separation ensures that elastase is able to act upon the elastase cleavable linker. The identity of D is not particularly limited. D may be a bivalent, C1-40 hydrocarbyl group, preferably a C1-30hydrocarbyl group, more preferably a C1-20hydrocarbyl group. D may comprise one or more 20 substituted or unsubstituted: alkylene, alkenylene, alkynylene, arylene, heteroarylene, heteroatoms, or combinations thereof. In some embodiments, D comprises substituted or unsubstituted: alkylene, alkenylene, alkynylene, polyalkylene glycol, polyamine, polyamide, polyester, or combinations thereof. Preferably, D comprises C1-10alkylene, C2-10alkenylene, C2-10alkynylene, polyalkylene glycol having 1-10 repeat units, polyamine having 1-10 repeat units, polyamide having 1-10 repeat units, polyester having 1- 25 10 repeat units, or combinations thereof. D may comprise polyalkylene glycol having 1-10 repeating units. Preferably, D is –(CH2-CH2-O)1- 10-RC-C(O)-, wherein RCis selected from a bond, C1-10alkylene, C2-10alkenylene, C2-10alkynylene, and combinations thereof. Preferably, RCis –(CH2)1-10-. More preferably, RCis –(CH2)2-. Most preferably, D is –(CH2-CH2-O)4-CH2-CH2-C(O)-. 30 Preferably, when D is –(CH2-CH2-O)1-10-RC-C(O)-, and Z is a peptide comprising 2 to 10 amino acid residues, more preferably 2 to 4 amino acid residues, most preferably 3 amino acid residues, the carbon atom of the -C(O)- group of D is covalently bonded to the N-terminus of an amino acid in the 33 x

[0030] elastase cleavable linker, Z. More preferably, when D is –(CH2-CH2-O)1-10-(CH2)1-10-C(O)- and the elastase cleavable linker, Z, comprises -Gly-Pro-Val-, -Ala-Pro-Val-, -His-Pro-Val-, -Asn-Pro-Val-, or -Nva-Pro-Val- , the carbon atom of the -C(O)- group of D is covalently bonded to the N-terminus of Gly, Ala, His, Asn, or Nva. Most preferably, when D is –(CH2-CH2-O)5-CH2-CH2-C(O)-, and Z comprises -Asn-Pro-Val-, and Z 5 the carbon atom of the -C(O)- group is covalently bonded to the N-terminus the carbon atom of the -C(O)- group of D is covalently bonded to the N-terminus of Asn. The compound of formula (I) may be: 10 (I) wherein: Y is a terminating group or a conjugating group; D is a bond or a spacer; Z is an enzyme cleavable linker; 15 M is a self-immolative linker; and X is an immunomodulatory agent; or a pharmaceutically acceptable salt thereof. The terminating group may be, for example, an alkyl group, a fluoroalkyl group, an alkoxy group, a silyl ether group, halo, aryl, cycloalkyl, amine, cyano, thioether, carbonyl, carboxyl, carbamoyl, sulfonyl, 20 sulfonate, hydroxy, thiol, phosphonate, phosphate, carbamate, imide, amide, nitrate, sulfoxide, thioester, and aryloxy. Further examples of terminating groups are methyl, ethyl, tert-butyl group, trifluoromethyl, methoxy,-Si(CH₃)₃,-Cl, -Br, phenyl, cyclohexyl, isopropyl, -NH₂, nitrile group, thioether, -OCH₂CH₃), - COCH₃, -COOH, -CONH₂, -SO₂H, -SO₂CH3, -SO3H, -SO3CH3, -OH, -CHO,-SH, -PO₃H₂), -PO₄H₂), - NHCO₂H, -CONHC(O)H, -ONO₂, -S(=O)H, -COSH), -CN, and -OC₆H₅. When Y is a terminating group, 25 the compound of formula (I) is an inactive form of an immunomodulatory agent, which can provide the active form of the immunomodulatory agent in the presence of a suitable enzyme by the mechanism described herein. Preferably, the conjugating group, Y, of the compound of formula (I) is a reactive group which can react with a further reactive group on another molecule to form a stable divalent moiety. Y may comprise 30 a maleimide, thiol, alkyne, azide, tetrazine, strained cycloalkene, N-hydroxysuccinimide, para-nitrophenyl ester, pentafluorophenyl ester, haloacetamide, hydroxylamine, and / or phosphinoester. Maleimides may react with thiol residues to form a thiosuccinimide group. Thiols may also react with other thiols to form di-sulphide bonds. Alkynes may react selectively with azides to provide a 1,2,3- triazole group. Tetrazine may react with strained cycloalkenes to provide a dihydropyridazine group. N- 35 hydroxysuccinimides, para-nitrophenyl esters, and pentafluorophenyl esters react with amine groups to form amide or carbamate groups. Haloacetamide groups may react with thiols to form an alpha-thio acetyl group. Phosphinoester groups may react with azides to form an amide group. Preferably, Y comprises: 34 x

[0031] , or,5 . More preferably, Y comprises maleimide. Most preferably, . More preferably, Y comprises a haloacetamide group, such as , , or . Most preferably, Y is . 10 Preferably, the compound of formula (I) is: Wherein D is as defined herein, and X is a JAKi; 35 x

[0032] or a pharmaceutically acceptable salt thereof. Preferably, the compound of formula (I) is: Wherein D is as defined herein, and X is a JAKi; 5 or a pharmaceutically acceptable salt thereof. The compound of formula (I) may be selected from the group consisting of: 10 36 x

[0033] 5 or a pharmaceutically acceptable salt thereof. The compound of formula (I) may also be selected from the group consisting of: 39 x

[0034] Wherein D is as defined herein; or a pharmaceutically acceptable salt thereof. 5 Preferably, the compound of formula (I) is selected from the group consisting of: 10 43 x

[0035] or a pharmaceutically acceptable salt thereof. Preferably, the compound of formula (I) is selected from the group consisting of: 5 47 x

[0036] 5 or a pharmaceutically acceptable salt thereof. More preferably, the compound of formula (I) is selected from the group consisting of: 50 x

[0037] or a pharmaceutically acceptable salt thereof. More preferably, the compound of formula (I) is selected from the group consisting of: 5 53 x

[0038] 5 or a pharmaceutically acceptable salt thereof. Most preferably, the compound of formula (I) is selected from the group consisting of 55 x

[0039] or a pharmaceutically acceptable salt thereof; 5 or a pharmaceutically acceptable salt thereof. is or a pharmaceutically acceptable salt thereof. 10 Pharmaceutically acceptable salts The compounds disclosed herein may be provided as the free compound or as a suitable salt thereof. Salts should be those that are pharmaceutically acceptable, and salts can be prepared by conventional methods, such as contacting a compound of the invention with an acid or base whose counterpart ion does not interfere with the intended use of the compound. Examples of pharmaceutically 15 acceptable salts include hydrohalogenates, inorganic acid salts, organic carboxylic acid salts, organic sulphonic acid salts, amino acid salt, quaternary ammonium salts, alkaline metal salts, alkaline earth metal salts and the like. Basic moieties may form non-toxic acid addition salts with various inorganic and organic acids, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, 20 acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate and pamoate salts. Acidic moieties may form salts with various pharmacologically acceptable cations, including alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron 56 x

[0040] salts. Compounds that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. Synthesis 5 Compounds of formula (I) as defined herein may be prepared using any suitable method. For example, a compound of formula (I) may be prepared from the reaction between an immunomodulatory agent and a linker of formula (III): (III) 10 wherein RXis a leaving group. The leaving group may be para-nitrophenol. An exemplary synthetic route is described in Example 1. Mechanism 15 Without being bound by theory, it is believed that compounds of formula (I) as defined herein may release the immunomodulatory agent via the mechanism shown in Scheme 1 below. Scheme 1 20 It will be appreciated that this scheme can be applied generally to other compounds according to the definitions in the remainder of the specification by variation of the appropriate starting materials. Conjugate In an aspect of the invention there is provided a conjugate of formula (II): 25 or a pharmaceutically acceptable salt thereof, wherein D, Z, M and X are as defined herein; 57 x

[0041] Y’ is a linking group as defined herein; A is a specific binding molecule as defined herein; and n is 1 to 10. As used herein, the term “conjugate” refers to a molecule of formula (II). The term “conjugate” 5 therefore refers to a molecule of the invention. The conjugate of the invention may be prepared from the compound of formula (I) as described herein. The conjugate of the invention comprises an immunomodulatory agent as described herein. n may be 1. n may be 2. n may be 3. N may be 4. n may be 5. n may be 6. n may be 7. n may be 8. n may be 9. n may be 10. Preferably, n may be 1 or 4. 10 Linking Group (Y’) The linking group of the conjugate of the invention is defined herein as Y’. Y’ may be formed by a reaction between (i) maleimide, a thiol, alkyne, azide, tetrazine, strained cycloalkene, N- hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl ester, 15 haloacetamide, hydroxylamine, or a phosphinoester; and (ii) a thiol, amino, hydroxy, alkyne, azide, tetrazine, strained cycloalkene, or a phosphinoester. In some embodiments, Y’ may comprise succinimide, triazole, cyclooctapyridazine, ester, amide, carbamate, and / or carbonate. Preferably, Y’ comprises: 20 . 58 x

[0042] , Most preferably, . In the conjugate of the invention, the compound of formula (I) may be linked to the specific binding 5 molecule (as defined herein in formula (II) as “A”) via a reactive cysteine on A, preferably wherein the reactive cysteine reacts with a maleimide or haloacetamide (such as 2-bromoacetamide) on the compound of formula (I). In the structures of the Y’ group described herein, where the Y’ group comprises a sulphur residue, the sulphur residue may be the sulphur of the side chain of said reactive cysteine residue having reacted with a Y group. The specific binding molecule may comprise a reactive cysteine 10 for conjugation to the compound described herein. The reactive cysteine may be part of an alanine motif represented by the amino acid formula ACA or AACAA and wherein the cysteine residue is available for conjugation to a substrate. The specific binding molecule may be conjugated to the compound of formula (I) via any suitable means, including but not limited to maleimide, NHS, haloacetamide, VS, or SuFEX. 15 The specific binding molecule may further comprise a reactive cysteine to facilitate conjugation to a substrate. Optionally, reactive cysteine forms part of an the alanine motif, which may be represented by the amino acid formula ACA or AACAA, wherein the cysteine residue is available for conjugation to a substrate. However, any suitable alanine motif with a cysteine residue available for conjugation may be used. 20 Specific Binding Molecule (general) The conjugate of the invention of formula (II) comprises a specific binding molecule (defined as “A” in formula (II)). The specific binding molecule may be selected from the group comprising an immunoglobulin or antibody or functional fragment thereof, an immunoglobulin Fc region, an 25 immunoglobulin Fab region, a Fab’, a Fv, a Fv-Fc, a single chain Fv (scFv), scFv-Fc, (scFv)2, a diabody, a triabody, a tetrabody, a bispecific t-cell engager (BiTE), an intein, a VNAR domain, a VNAR-Fc fusion, a single domain antibody (sdAb), a VH domain, or a scaffold protein. The term “functional fragment thereof” as used herein with reference to the specific binding molecule refers to fragments of the specific binding molecule that retain a function of the specific binding 30 molecule as a whole. The function retained by the functional fragment may be antigen binding affinity or functionality of the specific binding molecule. The specific binding molecule may comprise an antibody or functional fragment thereof. The specific binding molecule may comprise at least one VNAR domain. The specific binding molecule may 59 x

[0043] comprise two or more VNAR domains. Each of the two or more VNAR domains may bind to the same or different epitopes of one or more specific antigens. The term “specific binding”, “specifically binds” or equivalent as used herein, generally refers to the ability of the specific binding molecule of the conjugate to preferentially bind to a particular antigen, 5 ligand, receptor or other binding partner that is present in a homogeneous mixture of different antigens, ligands, receptors or other potential binding partners. A specific binding interaction may discriminate between desirable and undesirable binding partners in a sample, in some embodiments more than about 10 to 100-fold or more (e.g., more than about 1000- or 10,000-fold). The specific antigen targeted by the specific binding molecule in the conjugate of the invention 10 may be selected from a group comprising a cytokine, a cytokine receptor, a growth factor, an enzyme, a cell surface associated molecule, a cell-surface membrane component, an intracellular molecule, an extracellular matrix component, a stromal antigen, a serum protein, a skeletal antigen, a microbial antigen or an antigen from a normally immune-privileged location (such as the eye, central nervous system or foetus). 15 The specific antigen targeted by the specific binding molecule in the conjugate of the invention may be selected from the group comprising a hormone, a growth factor (e.g. TGFbeta, epidermal growth factor (EGF), platelet derived growth factor (PDGF), nerve growth factor (NGF), colony stimulating factor (CSF), hepatocyte growth factor, insulin-like growth factor, placenta growth factor); a differentiation factor; a blood clotting factor (for example, Factor VIIa, Factor VIII, Factor IX, VonWillebrand Factor or Protein 20 C) or another protein from the blood coagulation cascade (for example, antithrombin); a cytokine e.g. an interleukin, (e.g. IL1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL- 16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32 or IL-33 or an interferon (e.g. IFN-alpha, IFN-beta and IFN-gamma), tumour necrosis factor (TNF), IFN- gamma inducing factor (IGIF), a bone morphogenetic protein (BMP, e.g. BMP-1, BMP-2, BMP-3, BMP-4, 25 BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP10, BMP-11, BMP-12, BMP-13); an interleukin receptor antagonist (e.g. IL-1ra, IL-1RII); a chemokine (e.g. MIPs (Macrophage Inflammatory Proteins) e.g. MIP1alpha and MIP1beta; MCPs (Monocyte Chemotactic Proteins) e.g. MCP1, 2 or 3; RANTES (regulated upon activation normal T-cell expressed and secreted)); a trophic factor; a cytokine inhibitor; a cytokine receptor; an enzyme, for example a free-radical scavenging enzyme e.g. superoxide dismutase 30 or catalase or a pro-drug converting enzyme (e.g. angiotensin converting enzyme, deaminases, dehydrogenases, reductases, kinases and phosphatases); a peptide mimetic; a protease inhibitor; a tissue inhibitor of metalloproteinases (TIMPs e.g. TIMP1, TIMP2, TIMP3 or TIMP4); a serpin (inhibitors of serine proteases) or an integrin (e.g. α4β7). The specific antigen targeted by the specific binding molecule in the conjugate of the invention 35 may be selected from the group comprising IL23, optionally IL23p40, TNFα, TL1A, integrin α4β7, IL6, IL17A and IL17F. In some embodiments, the specific binding molecule binds TNFa or IL23. Specific binding molecules of the conjugate of the invention may be constructed of any of the amino acid sequences for the various regions disclosed herein. The specific binding molecule may be monomers. Specific binding molecules may be linked to 40 form a multivalent binding molecule. For example, two specific binding molecules may be linked to form a dimer. Alternatively, one or more specific binding molecules may be linked to form a multimer, a fusion 60 x

[0044] protein or an immunoconjugate. The dimer may be a heterodimer. The dimer may be a homodimer. The dimer may additionally include a linker region between the specific binding molecule and the second binding molecule. Preferred linkers include but are not limited to [G4S]x , where x is 1, 2, 3, 4, 5, 5, 6, 7, 8, 9, or 10. In any of the embodiments described herein, the linker may be selected from any of the 5 following linkers. GSGGGSGGGGSG (SEQ ID NO: 54); GGGGSGGGGSGGGGSGGGGSGAHS (SEQ ID NO: 55); GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 56); GGGGSGGGGSGGGGS (SEQ ID NO: 69) Reformatting a single domain specific binding molecule of the invention in monomeric form as a multimer, fusion protein or an immunoconjugate does not significantly alter the properties of the single 10 domain specific binding molecules. For example, the affinity and / or specificity of a monomeric single domain binding molecule of the invention is not negatively impacted by the addition of a fusion partner or conjugated substrate. The single domain specific binding molecule may be formatted with an Fc region at the N- and / or C-terminus. Multiple single domain specific binding molecule may be joined together with a single Fc 15 region on the N- or C- terminus. The conjugate of the invention may comprise a specific binding molecule and an immunomodulatory agent. The specific binding molecule and immunomodulatory agent may have independent activity after the enzymatic cleavable linker in the conjugate is cleaved. The independent activity may be additive or synergistic. The conjugate of the invention may be said to be a bifunctional 20 molecule. The bifunctionality may refer to the separate and independent activities of the specific binding molecule and the immunomodulatory agent. The specific binding molecule and the immunomodulatory agent may target the same intracellular pathways. The specific binding molecule and the immunomodulatory agent may target different intracellular pathways. The specific binding molecule and the immunomodulatory agent may target the different intracellular pathways which reduce the 25 inflammatory response. In some embodiments the specific binding molecule and the immunomodulatory agent have synergistic activity. A single specific binding molecule may be conjugate to multiple compounds comprising formula (I). This is exemplified by formula (II), and can be understood to correspond to a drug-antibody ratio (DAR). As used herein, “DAR” is a quantitative measure representing the average number of drug molecules 30 conjugated to each specific binding molecule in a specific binding molecule-drug conjugate. The conjugate of the invention may have a DAR of 1. A DAR of 1 is understood to mean a single copy of the compound is attached to the specific binding molecule. In this molecule, a single copy of the immunomodulatory agent is present. The conjugate of the invention may have a DAR of 2. A DAR of 2 is understood to mean two copies of the compound are attached to the specific binding molecule. In this molecule, two copies of 35 the immunomodulatory agent are present. The conjugate of the invention may have a DAR of 3. A DAR of 3 is understood to mean three copies of the compound are attached to the specific binding molecule. In this molecule, three copies of the immunomodulatory agent are present. The conjugate of the invention may have a DAR of 4. A DAR of 4 is understood to mean four copies of the compound are attached to the specific binding molecule. In this molecule, four copies of the immunomodulatory agent are present. The 40 conjugate of the invention may have a DAR of 5. A DAR of 5 is understood to mean five copies of the compound are attached to the specific binding molecule. In this molecule, five copies of the 61 x

[0045] immunomodulatory agent are present. The conjugate of the invention may have a DAR of 6. A DAR of 6 is understood to mean six copies of the compound are attached to the specific binding molecule. In this molecule, six copies of the immunomodulatory agent are present. The conjugate of the invention may have a DAR of 7. A DAR of 7 is understood to mean seven copies of the compound are attached to the 5 specific binding molecule. In this molecule, seven copies of the immunomodulatory agent are present. The conjugate of the invention may have a DAR of 8. A DAR of 8 is understood to mean eight copies of the compound are attached to the specific binding molecule. In this molecule, eight copies of the immunomodulatory agent are present. The conjugate of the invention may have a DAR of 9. A DAR of 9 is understood to mean nine copies of the compound are attached to the specific binding molecule. In this 10 molecule, nine copies of the immunomodulatory agent are present. The conjugate of the invention may have a DAR of 10. A DAR of 10 is understood to mean ten copies of the compound are attached to the specific binding molecule. In this molecule, ten copies of the immunomodulatory agent are present. Antibodies 15 The specific binding molecule may be an antibody, or functional fragment thereof. As used herein, a “antibody” refers to a protein molecule produced by mammalian B-cells that specifically binds to a particular antigen with high affinity and specificity. An antibody typically consists of four polypeptide chains—two heavy chains and two light chains—connected by disulfide bond. Each antibody possesses at least one variable region that binds to the specific antigen and one constant region that mediates 20 interaction with other components of the immune system. This includes types of antibodies such as monoclonal antibodies, polyclonal antibodies, recombinant antibodies, and antibody fragments (e.g., Fab, F(ab’)2, single-chain variable fragments (scFv)), as well as any modifications, variants, or derivatives thereof that retain the ability to bind to the target antigen. As sued herein, the term “antibodies” may be understood be refer to so-called “conventional antibodies”. 25 The antibody may bind an antigen selected from the group comprising a hormone, a growth factor (e.g. TGFbeta, epidermal growth factor (EGF), platelet derived growth factor (PDGF), nerve growth factor (NGF), colony stimulating factor (CSF), hepatocyte growth factor, insulin-like growth factor, placenta growth factor); a differentiation factor; a blood clotting factor (for example, Factor VIIa, Factor VIII, Factor IX, VonWillebrand Factor or Protein C) or another protein from the blood coagulation cascade (for 30 example, antithrombin); a cytokine e.g. an interleukin, (e.g. IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL- 26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32 or IL-33 or an interferon (e.g. IFN-alpha, IFN-beta and IFN- gamma), tumour necrosis factor (TNF), IFN-gamma inducing factor (IGIF), a bone morphogenetic protein (BMP, e.g. BMP-1, BMP-2, BMP-3, BMP-4, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP10, 35 BMP-11, BMP-12, BMP-13); an interleukin receptor antagonist (e.g. IL-1ra, IL-1RII); a chemokine (e.g. MIPs (Macrophage Inflammatory Proteins) e.g. MIP1alpha and MIP1beta; MCPs (Monocyte Chemotactic Proteins) e.g. MCP1, 2 or 3; RANTES (regulated upon activation normal T-cell expressed and secreted)); a trophic factor; a cytokine inhibitor; a cytokine receptor; an enzyme, for example a free-radical scavenging enzyme e.g. superoxide dismutase or catalase or a pro-drug converting enzyme (e.g. angiotensin 40 converting enzyme, deaminases, dehydrogenases, reductases, kinases and phosphatases); a peptide 62 x

[0046] mimetic; a protease inhibitor; a tissue inhibitor of metalloproteinases (TIMPs e.g. TIMP1, TIMP2, TIMP3 or TIMP4) ; a serpin (inhibitors of serine proteases) or an integrin (e.g. α4β7). The antigen may be selected from the group comprising IL-23, optionally IL23p40, TNFα, TL1A, integrin α4β7, IL-6, IL-17A, IL-17F, a TNF receptor (TNFR), an IL23 receptor, DR3 and other membrane 5 bound receptors. The specific binding molecule may bind TNFa or IL-23. The specific binding molecule may be an anti-TNFa antibody or functional fragment thereof. The specific binding molecule may be an anti-IL23 antibody or functional fragment thereof. The specific binding molecule may be an anti-IL23p40 antibody or functional fragment thereof. The specific binding molecule may be an anti-TL1A antibody or functional fragment thereof. The specific binding molecule may be an anti- integrin α4β7 antibody or 10 functional fragment thereof. The specific binding molecule may be an anti- IL6 antibody or functional fragment thereof. The specific binding molecule may be an anti- IL17A antibody or functional fragment thereof. The specific binding molecule is an anti-IL17F antibody or functional fragment thereof. The specific binding molecule may be selected from any known anti-TNFa antibody. The anti- TNFa antibody may be selected from Adalimumab, Infliximab, Golimumab, Etanercept, and Certolizumab. 15 The specific binding molecule may be selected from any known anti-IL23 antibody. The specific binding molecule may be Ustekinumab. The specific binding molecule of the conjugate of the invention may comprise an antibody and the DAR is 1 or 2. When the specific binding molecule of the conjugate comprises an antibody, the molecule may be called an “Antibody-Drug conjugate”, or ADC. The ADC may be understood to be a bifunctional 20 molecule, wherein the antibody and the drug have independent activity after cleavage of the enzyme cleavable linker. The term “ADC” as used herein may, in some embodiments, encompass a VNAR-drug conjugate (VDC) or a soloMER™ drug conjugate (SDC). VNARs 25 The specific binding molecule of the conjugate may be a VNAR domain. As used herein, a “VNAR” is a Variable New Antigen Receptor. A VNAR is a type of single-domain antibody derived from the variable region of the new antigen receptor found in cartilaginous fish, such as sharks. VNARs are characterized by their small size, typically comprising approximately 11-15 kDa, and comprise a single monomeric variable domain. VNARs exhibit exceptional stability and can bind to 30 epitopes that are often inaccessible to conventional antibodies. This includes natural VNARs, as well as engineered variants and derivatives, such as those produced through recombinant DNA technology or synthetic biology methods, that retain (or have improved) the antigen-binding properties of the native VNARs. The specific binding molecule may comprise one VNAR binding domain. The specific binding 35 molecule may comprise at least one VNAR domain. The specific binding molecule may comprise two or more VNAR domains. The two or more VNAR domains may bind the same antigen on a specific antigen. The specific binding molecule may comprise two or more VNAR domains in a so-called “multi- domain specific binding molecule”. The multi-domain specific binding molecule may further comprise a spacer between the VNAR domains. As used herein, the “multi-domain specific binding molecule” may be 40 referred to as a “Quad-X™” molecule, as described in WO2019 / 063726. The Quad-X™ molecule is understood to refer to a molecule comprising the format “VNAR-Fc-VNAR”. 63 x

[0047] The specific binding molecule may comprise VNARs in a multi-domain specific binding molecule format. These VNAR domains may bind different epitopes on a specific antigen or different specific antigens. Multi-domain specific binding molecules in accordance with these embodiments may be termed bi-paratopic molecules, as further described herein. 5 Specific VNAR binding domain sequences may be combined into multivalent or multispecific entities and, within which multidomain entity each domain retains binding function, wherein the binding domains recognize distinct epitopes on a single antigen. The specific binding molecule is a bi- or multi-specific binding molecule may comprise two (or more) different VNAR domains wherein the binding specificity is for distinct epitopes on a single specific 10 antigen and in which the resultant entity shows improved properties compared to the individual VNAR binding domains. An example of an improved property includes increased agonistic or antagonistic effect compared to the monomer VNARs. The specific binding molecule may be a VNAR that may recognise an epitope not otherwise accessible to binding molecules such as antibodies, due to steric hinderance caused by the epitope’s three dimensional structure. Such epitopes may be referred to as a cryptic or 15 hidden epitope. The specific binding molecule may comprise VNAR domains in a multi-domain specific binding molecule (Quad-X ™) format. The VNAR domains in the multi domain specific binding molecule may be separated by a spacer sequence. The spacer sequence may have independent functionality which is exhibited in the binding molecule such that the linker performs a function in addition to physical spacing. 20 The spacer sequence may comprise the amino acid sequence of any one of SEQ ID Nos 74 to 76, or a functional fragment having at least 60% sequence identity thereto. The sequence may have at least 65%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 97%, at least 99% or 100% identity to the sequences of SEQ ID Nos 74 to 76. The spacer sequence may be the Fc portion of an immunoglobulin, including but not limited to a 25 human immunoglobulin Fc region. The spacer may be derived from an immunoglobulin Fc region. The spacer sequence may be derived from a human immunoglobulin Fc region. The spacer may have been modified to introduce one or more reactive cysteines for conjugation. The spacer may be derived from an Fc region, and the Fc region has been modified to introduce one of more reactive cysteines for conjugation. The spacer may be derived from a human Fc region, and the Fc region has been modified to 30 introduce one of more reactive cysteines for conjugation. The Fc region may have been modified from the wild-type sequence. The Fc region may comprise a sequence of SEQ ID NO: 39, or 62 to 65. The Fc region may be engineered to dimerise. The Fc region may have a knob in hole mutation. The Fc region may be mutated for the purpose of site specific conjugation to a payload. 35 Embodiments of the multi-domain specific binding molecule of the invention comprising two or more VNAR domains separated by a spacer sequence may be referred to herein as a Quad-X™ format. Each VNAR domain of a Quad-X™ molecule may bind the same or different antigen. The VNAR may bind an antigen selected from the group comprising a hormone, a growth factor (e.g. TGFbeta, epidermal growth factor (EGF), platelet derived growth factor (PDGF), nerve growth factor 40 (NGF), colony stimulating factor (CSF), hepatocyte growth factor, insulin-like growth factor, placenta growth factor); a differentiation factor; a blood clotting factor (for example, Factor VIIa, Factor VIII, Factor 64 x

[0048] IX, VonWillebrand Factor or Protein C) or another protein from the blood coagulation cascade (for example, antithrombin); a cytokine e.g. an interleukin, (e.g. IL1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL- 26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32 or IL-33 or an interferon (e.g. IFN-alpha, IFN-beta and IFN- 5 gamma), tumour necrosis factor (TNF), IFN-gamma inducing factor (IGIF), a bone morphogenetic protein (BMP, e.g. BMP-1, BMP-2, BMP-3, BMP-4, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP10, BMP-11, BMP-12, BMP-13); an Interleukin receptor antagonist (e.g. IL-1ra, IL-1RII); a chemokine (e.g. MIPs (Macrophage Inflammatory Proteins) e.g. MIP1alpha and MIP1beta; MCPs (Monocyte Chemotactic Proteins) e.g. MCP1, 2 or 3; RANTES (regulated upon activation normal T-cell expressed and secreted)); 10 a trophic factor; a cytokine inhibitor; a cytokine receptor; an enzyme, for example a free-radical scavenging enzyme e.g. superoxide dismutase or catalase or a pro-drug converting enzyme (e.g. angiotensin converting enzyme, deaminases, dehydrogenases, reductases, kinases and phosphatases); a peptide mimetic; a protease inhibitor; a tissue inhibitor of metalloproteinases (TIMPs e.g. TIMP1, TIMP2, TIMP3 or TIMP4) ; a serpin (inhibitors of serine proteases) or an integrin (e.g. α4β7). 15 The antigen may be selected from the group comprising IL23, optionally IL23p40, TNFα, TL1A, integrin α4β7, IL6, IL17A and IL17F. The specific binding molecule may binds TNFa or IL23. The specific binding molecule may be an anti-TNF VNAR. The specific binding molecule may be an anti-IL23 VNAR. The specific binding molecule may be an anti-IL23p40 VNAR. The specific binding molecule may be an anti-TL1A VNAR. The specific binding molecule may be an anti- integrin α4β7 VNAR. The specific binding 20 molecule may be an anti- IL6 VNAR. The specific binding molecule may be an anti- IL17A VNAR. The specific binding molecule may be an anti-IL17F VNAR. The specific binding molecule of the conjugate of the invention may recognize human TNF and bind to an epitope that is different from all other well characterized anti-TNF antibody and VHH binders that are currently used to treat disease. 25 The specific binding molecule of the conjugate may comprise at least one VNAR domain and each VNAR domain may comprise an amino acid sequence represented by the formula: FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4. The specific binding molecule may comprise at least one, or two or more TNF-alpha specific VNAR binding domain comprising the following CDRs and hyper-variable regions (HV): 30 CDR1: HCATSS (SEQ ID NO:3) or NCGLSS (SEQ ID NO:22) HV2: TNEESISKG(SEQ ID NO:5 or 24) HV4: SGSKS (SEQ ID NO:7) or EGSKS (SEQ ID NO:26) CDR3: ECQYGLAEYDV (SEQ ID NO:9) or SWWTQNWRCSNSDV (SEQ ID NO:28) or a functional variant thereof with a sequence identity of at least 60%. The sequence variation may be 35 outside the CDR and HV regions. The specific binding molecule may comprise the CDR. HV and / or framework regions from the domains termed “D1” and “C4”, herein. The wild-type sequences of D1 and C4 are as follows. The CDR and HV regions of the below sequences may be introduced to any of the framework regions disclosed herein. FW1 CDR1 FW2 HV2 40 D1 ARVDQTPQTITKETGESLTINCVLRDS HCATSS TYWYRKKSGS TNEESISKG C4 ARVDQTPQTITKETGESLTINCVLRDS NCGLSS TYWYRKKSGS TNEESISKG FW3a HV4 FW3b 65 x

[0049] D1 GRYVETVN SGSKS FSLRINDLTVEDSGTYRCAS C4 GRYVETIN EGSKS FSLRINDLTVEDSGTYRCKL CDR3 FW4 5 D1 ECQYGLAEYDV YGGGTVVTVN SEQ ID NO: 1 C4 SWWTQNWRCSNSDV YGGGTVVTVN SEQ ID NO: 20 The specific binding molecule may comprise at least one TNF-alpha specific VNAR binding domain comprising the amino acid sequence of SEQ ID NO: 1, or 20, or a functional variant thereof with 10 a sequence identity of at least 60, at least 65%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 97%, at least 99% or 100%. The sequence variation may be outside the CDR and HV regions. The specific binding molecule may comprise two or more TNF-alpha specific VNAR binding domains, wherein at least one of the VNAR binding domains comprises the amino acid sequence of SEQ 15 ID NO: 1 or 20, or a functional variant thereof with a sequence identity of at least 60% at least 65%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 97%, at least 99% or 100%. The sequence variation may be outside the CDR and HV regions. Two of the two or more TNF-alpha specific VNAR binding domain may comprise the amino acid sequence of SEQ IS NO: 1 or 20, or a functional variant thereof with a sequence identity of at least 60% at least 65%, at least 70%, at least 80%, 20 at least 90%, at least 95%, at least 97%, at least 97%, at least 99% or 100%. The sequence variation may be outside the CDR and HV regions. The specific binding molecule may comprise two or more VNAR domains in a Quad-X™ format. Each VNAR domain may independently comprise the following CDRs and hyper-variable regions (HV): CDR1: HCATSS or NCGLSS 25 HV2: TNEESISKG HV4: SGSKS or EGSKS CDR3: ECQYGLAEYDV or SWWTQNWRCSNSDV or a functional variant thereof with a sequence identity of at least 60%. The sequence variation may be outside the CDR and HV regions. Each VNAR domain may independently comprise the following CDRs 30 and hyper-variable regions (HV): CDR1: HCATSS HV2: TNEESISKG HV4: SGSKS CDR3: ECQYGLAEYDV 35 or a functional variant thereof with a sequence identity of at least 60%, or the following CDRs and hyper- variable regions (HV): CDR1: NCGLSS HV2: TNEESISKG HV4: EGSKS 40 CDR3: SWWTQNWRCSNSDV or a functional variant thereof with a sequence identity of at least 60%. The sequence variation imay be outside the CDR and HV regions. When the specific binding molecule comprises a Quad-X molecule, the first VNAR domain may comprise the following CDRs and hyper-variable regions (HV): 66 x

[0050] CDR1: HCATSS HV2: TNEESISKG HV4: SGSKS CDR3: ECQYGLAEYDV 5 or a functional variant thereof with a sequence identity of at least 60%, and the second VNAR domain may comprise following CDRs and hyper-variable regions (HV): CDR1: NCGLSS HV2: TNEESISKG HV4: EGSKS 10 CDR3: SWWTQNWRCSNSDV or a functional variant thereof with a sequence identity of at least 60%. The specific binding molecule comprises two or more VNAR domains in a Quad-X™ format. Each VNAR domain may independently comprise any of the following SEQ ID NOs:1 or 20 or a functional variant thereof with a sequence identity of at least 60%. Each VNAR domain may independently comprise 15 any of the following SEQ ID NO: 1 or a functional variant thereof with a sequence identity of at least 60%, or any of the following SEQ ID NO: 20 or a functional variant thereof with a sequence identity of at least 60%. When the specific binding molecule comprises a Quad-X™ molecule, the first VNAR domain may comprise any of the following SEQ ID NOs: 1 or a functional variant thereof with a sequence identity of at least 60%, and the second VNAR domain may any of the following SEQ ID NOs: 20 or a functional variant 20 thereof with a sequence identity of at least 60%. The sequence variation may be outside the CDR and HV regions. When the specific binding molecule comprises a Quad-X™ molecule, the first VNAR may comprises a sequence according to SEQ ID NO: 1 and the second VNAR may comprise the sequence according to SEQ ID NO: 20. 25 The specific binding molecule may comprise a Quad-X™ molecule, wherein each VNAR domain is separated by a spacer. The spacer may derived from an immunoglobulin Fc region. The immunoglobulin Fc region may be a human immunoglobulin Fc region. The spacer may further comprises a linker. The linker may be any known linker. Preferably the linker is a (G4S)x linker, wherein X is 1 or 2, or 3, or 4, or 5. The VNAR domains in a Quad-X molecule may be separated by a sequence selected from SEQ ID 30 Nos:54, 55, 56 and 69. The specific binding molecule of the conjugate of the invention may comprise at least one VNAR domain and the DAR is 1 or 2 or 3 or 4. Tthe specific binding molecule of the conjugate of the invention may comprise a multi-domain specific binding molecule in the Quad-X™ format and the DAR is 4. When the specific binding molecule of the conjugate comprises a VNAR, the molecule may be called an “VNAR- 35 Drug conjugate”, or VDC. The VDC may be understood to be a bifunctional molecule, wherein the VNAR and the drug have independent activity after cleavage of the enzyme cleavable linker. VNAR Humanisation The specific binding molecule may comprise a VNAR domain which is modified at one or more 40 amino acid sequence position to reduce the potential for immunogenicity in vivo, by for example humanization, deimmunization or similar technologies, while retaining functional binding activity for the 67 x

[0051] specific epitopes on the specific antigen. The term “modified” is understood to be compared to the wild- type, or native sequence. The specific binding molecule may be humanised. The specific binding molecule may comprise a humanised VNAR domain. The specific binding molecule may comprise two or more humanised VNAR domains. The specific binding molecule may comprise two or more VNAR domains, 5 one of which is humanised. Accordingly, the specific binding molecule may comprise at least one, or two or more TNF-alpha specific VNAR binding domain that are humanised or de-immunised. The specific binding molecule may comprise at least one humanized VNAR domain. The degree of humanisation may be designed according to the properties required, including affinity. A suitable degree of humanisation may be 50%, or 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% homology to the 10 corresponding human germline sequence for a Framework Region or a CDR Region specific to the antigen epitope of interest. Suitable methods for humanisation are provided in e.g. WO 2014 / 173959, WO2019063726 and WO 2022 / 129524. Humanisation of antibody variable domains is a technique well-known in the art, which involves modifying an antibody which has been raised, in a species other than humans, against a therapeutically 15 useful target, to reduce the risk of an unwanted immunological reaction when administered to a human subject. Typically, humanisation involves modifying the variable domains, and in particular, the framework regions of the variable domains, to increase their similarity to antibody variants produced naturally in humans without negatively impacting their specificity or potency. Suitable methods involved in humanisation are known in the art. 20 Although IgNARs have distinct origins compared to immunoglobulins and have very little sequence homology compared to immunoglobulin variable domains there are some structural similarities between immunoglobulin and IgNAR variable domains, so that similar processes can be applied to the VNAR domain. For example, WO2013 / 167883, and WO 2022 / 129524 provide a description of the humanization of VNARs, see also Kovalenko et al. J Biol Chem.2013.288(24): p.17408-19. 25 For example, a humanised specific binding molecule according to the invention may differ from a wild-type specific binding molecule by substituting one or more framework amino acid residues with a corresponding framework amino acid residue of DPK-9. DPK-9 is a human germline VL scaffold, a member of the variable kappa subgroup 1 (VK1). DPK-9 has a sequence of: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNVVYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGT 30 DFTLTISSLQPEDFATYYCQQSYSTPNTFGQGTKVEIK. The specific binding molecule may comprise a multi-domain molecule, known as Quad-X ™. One or both VNAR domains in the multi-domain specific binding molecule may have an amino acid sequence selected from the group comprising SEQ ID Nos: 12 to 19 and 31 to 38 , or a functional variant thereof with a sequence identity of at least 60%. 35 The at least one TNF-alpha specific VNAR binding domain may comprise the amino acid sequence of SEQ ID NOs: 12 to 19 and 31 to 38, or a functional variant thereof with a sequence identity of at least 60%. The two or more TNF-alpha specific VNAR binding domain may comprises the amino acid sequence of SEQ ID NO: 12 to 19 and 31 to 38, or a functional variant thereof with a sequence identity of at least 60%. At least one of the two or more TNF-alpha specific VNAR binding domain may 40 comprise the amino acid sequence of SEQ IS NO: 12 to 19 and 31 to 38, or a functional variant thereof with a sequence identity of at least 60%. The sequence variation may be outside the CDR and HV regions. 68 x

[0052] The specific binding molecule may comprise two or more VNAR domains in a Quad-X™ format. Each VNAR domain may independently comprise any of the following SEQ ID NOs: 12 to 19 and 31 to 38 or a functional variant thereof with a sequence identity of at least 60%. Each VNAR domain may independently comprise any of the following SEQ ID NOs:12 to 19 or a functional variant thereof with a 5 sequence identity of at least 60%, or any of the following SEQ ID NOs: 31 to 38 or a functional variant thereof with a sequence identity of at least 60%. When the specific binding molecule comprises a Quad- X™ molecule, the first VNAR domain may comprise any of the following SEQ ID NOs: 12 to 19 or a functional variant thereof with a sequence identity of at least 60%, and the second VNAR domain may any of the following SEQ ID NOs:31 to 38 or a functional variant thereof with a sequence identity of at least 10 60%. The sequence variation may be is outside the CDR and HV regions. When the specific binding molecule comprises a Quad-X™ molecule, the first VNAR may comprise a sequence according to SEQ ID NO: 18 and the second VNAR may comprise the sequence according to SEQ ID NO: 37. The specific binding molecule may comprise at least one VNAR domain. The at least one VNAR 15 domain may comprise a VNAR-VNAR dimer. The VNAR-VNAR dimer may be selected from: D1 WT and D1 WT, D1 WT and D1-V7, D1 WT and C4 WT, D1 WT and C4-V7, D1-V7 and D1 WT, D1-V7 and D1- V7, D1-V7 and C4 WT, D1-V7 and C4-V7, C4 WT and D1 WT, C4 WT and D1-V7, C4 WT and C4 WT, C4 WT and C4-V7, C4-V7 and D1 WT, C4-V7 and D1-V7, C4-V7 and C4 WT, C4-V7 and C4-V7. The at least one VNAR domain may comprise a VNAR-Fc-VNAR multimer. The VNAR-Fc-VNAR 20 multimer may be selected from: D1 WT -Fc- D1 WT, D1 WT -Fc- D1-V7, D1 WT -Fc- C4 WT, D1 WT -Fc- C4-V7, D1-V7 -Fc- D1 WT, D1-V7 -Fc- D1-V7, D1-V7 -Fc- C4 WT, D1-V7 -Fc- C4-V7, C4 WT -Fc- D1 WT, C4 WT -Fc- D1-V7, C4 WT -Fc- C4 WT, C4 WT -Fc- C4-V7, C4-V7 -Fc- D1 WT, C4-V7 -Fc- D1-V7, C4-V7 -Fc- C4 WT, C4-V7 -Fc- C4-V7. The linker may be selected from any of the following linkers: GSGGGSGGGGSG (SEQ ID NO: 25 54); GGGGSGGGGSGGGGSGGGGSGAHS (SEQ ID NO: 55); GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 56); GGGGSGGGGSGGGGS (SEQ ID NO: 69) The specific binding molecule may comprises at least one VNAR binding domain comprising the CDR and HV regions from the D1 and C4 domains disclosed herein. The CDR and HV regions of the D1 and C4 VNAR domains may be included in any framework regions disclosed herein. The CDR and HV 30 regions of the D1 and C4 may be included in wild-type (shark) framework sequences. The CDRs and HV regions of the D1 and C4 may be included in humanised or deimmunised framework sequences. The CDR and HV regions disclosed herein may be included in framework regions that are linked to a spacer. The spacer may be derived from an immunoglobulin Fc region. The spacer may be derived from a human immunoglobulin Fc region. 35 The CDR and HV regions disclosed herein may be included in framework regions that are linked to at least one other VNAR domain. The CDR and HV regions may be included in a framework that is directly or indirectly linked to at least one other VNAR domain. As used in this context, the term “directly linked” means that a first VNAR domain is linked via a linker to a second VNAR domain. As used in this context, the term “indirectly linked” means that a first VNAR domain is linked via a third domain to a second 40 VNAR domain. The third domain may be derived from an immunoglobulin Fc region. The third domain may be derived from a human immunoglobulin Fc region. 69 x

[0053] The specific binding molecule may comprise the CDR and HV regions of D1. The specific binding molecule may comprise the CDR and HV regions of C4. The specific binding molecule may comprise a sequence with at least 60% identity to at least one of D1, D1-v1, D1-v2, D1-v3, D1-v4, D1-v5, D1-v6, D1- v7, D1-v8, C4, C4-v1, C4-v2, C4-v3, C4-v4, C4-v5, C4-v6, C4-v7, or C4-v8. The specific binding molecule 5 may comprise a sequence with at least 60% identity to at least one of D1, D1-v7, C4 and C4-v7. specific binding molecule comprises a sequence with at least 60% identity to at least one of D1-v7 and C4-v7. The specific binding molecule may comprise a sequence with at least 60% identity to at least one of D1, D1-v1, D1-v2, D1-v3, D1-v4, D1-v5, D1-v6, D1-v7, D1-v8, C4, C4-v1, C4-v2, C4-v3, C4-v4, C4-v5, C4-v6, C4-v7, or C4-v8, linked to an immunoglobulin Fc region or fragment or derivative thereof. The10 specific binding molecule may comprises a sequence with at least 60% identity to at least one of D1, D1- v1, D1-v2, D1-v3, D1-v4, D1-v5, D1-v6, D1-v7, D1-v8, C4, C4-v1, C4-v2, C4-v3, C4-v4, C4-v5, C4-v6, C4-v7, or C4-v8, linked to a human immunoglobulin Fc region or fragment or derivative thereof. The specific binding molecule may comprise a sequence selected from the following table, where 1 refers to a linker with sequence GGGGSGGGGSGGGGSGGGGGSGAHS (SEQ ID NO: 73), and 2 15 refers to a linker with sequence GGGGSGGGGSGGGGSGGGGSGGGGS GGGGSGGGGSGGGGSGGGGGSGAHS (SEQ ID NO:74), or a sequence with at least 60% identity thereto Table 1: Combinations of VNAR-VNAR dimers with exemplary linkers 70 x

[0054] The specific binding molecule may be selected from the following, where 3 refers to a linker-Fc- linker region with sequence GSGGGSGGGGSGEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP 5 EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGAHS GGGGSGGGGSGGGGSGGGGGSGAHS (SEQ ID NO:75), and 4 refers to a linker-Fc-linker region with sequence 10 GSGGGSGGGGSGEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO:76) 15 Table 2: Combinations of VNAR-Fc-VNAR multimers with exemplary linkers The linker- Fc–- linker region may comprise a sequence of EPKSCDKTHTCPPCPAPELLGGPCVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE 71 x

[0055] VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLCLSPGKGGGGS (SEQ ID NO: 78), or a sequence with at least 60% identity thereto. 5 In a preferred embodiment, the specific binding molecule is selected from: ARVDQSPSSLSASVGDRVTITCVLRDSHCATSSTYWYRKKSGSTNEESISKGGRYVETVNSGSKSFTLT ISSLQPEDFATYYCASECQYGLAEYDVYGGGTVVTVNGSGGGSGGGGSGEPKSSDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK 10 GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSARVDQSPSSLSASVGDRVTITCVLRDSNCG LSSTYWYRKKSGSTNEESISKGGRYVETINEGSKSFSLRINDLTVEDSGTYRCKLSWWTQNWRCSNSD VYGGGTVVTVN (SEQ ID NO:51); 15 ARVDQTPQTITKETGESLTINCVLRDSHCATSSTYWYRKKSGSTNEESISKGGRYVETVNSGSKSFSLRI NDLTVEDSGTYRCASECQYGLAEYDVYGGGTVVTVNGGGGSGGGGSGGGGSEPKSSDKTHTCPPCP APELLGGPCVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN 20 HYTQKSLCLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSARVDQTPQTITKETGESLTINCVLRDSN CGLSSTYWYRKKSGSTNEESISKGGRYVETINEGSKSFSLRINDLTVEDSGTYRCKLSWWTQNWRCSN SDVYGGGTVVTVN(SEQ ID NO:66); ARVDQTPQTITKETGESLTINCVLRDSHCATSSTYWYRKKSGSTNEESISKGGRYVETVNSGSKSFSLRI 25 NDLTVEDSGTYRCASECQYGLAEYDVYGGGTVVTVNEPKSCDKTHTCPPCPAPELLGGPCVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLCLSPGKGGGG SARVDQTPQTITKETGESLTINCVLRDSNCGLSSTYWYRKKSGSTNEESISKGGRYVETINEGSKSFSLR 30 INDLTVEDSGTYRCKLSWWTQNWRCSNSDVYGGGTVVTVN(SEQ ID NO:67); and ARVDQSPSSLSASVGDRVTITCVLRDSHCATSSTYWYRKKSGSTNEESISKGGRYVETVNSGSKSFTLT ISSLQPEDFATYYCASECQYGLAEYDVYGGGTVVTVNEPKSCDKTHTCPPCPAPELLGGPCVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN 35 GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLCLSPGKGGGG SARVDQSPSSLSASVGDRVTITCVLRDSNCGLSSTYWYRKKSGSTNEESISKGGRYVETINEGSKSFSL RINDLTVEDSGTYRCKLSWWTQNWRCSNSDVYGGGTVVTVN(SSEQ ID NO:68). Any of the combinations of linkers, Fc regions and VNAR domains disclosed herein are envisaged. The VNAR domain or domains of the specific binding molecule may be modified at one or more 40 amino acid sequence position to reduce the potential for immunogenicity in vivo, by for example 72 x

[0056] humanization, deimmunization or similar technologies, while retaining functional binding activity for the specific epitopes on the specific antigen. Specific binding molecules of the conjugate of the invention may therefore be constructed of any of the amino acid sequences for the various regions disclosed herein according to the basic structure: 5 FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4. The specific binding molecule of the conjugate of the invention may comprise at least one humanised VNAR domain and the DAR is 1 or 2 or 3 or 4. The specific binding molecule of the conjugate of the invention may comprise a multi-domain specific binding molecule in the Quad-X™ format and the DAR is 4. When the specific binding molecule of the conjugate comprises a humanised VNAR domain, 10 the molecule may be called an “SoloMER™-Drug conjugate”, or SDC. The SDC may be understood to be a bifunctional molecule, wherein the VNAR and the drug have independent activity after cleavage of the enzyme cleavable linker. The activity may be synergistic or additive. The term SoloMER™ refers to a humanised VNAR sequence as described herein. 15 Specific combinations of features The conjugate of formula (II) may comprises a specific binding molecule as described herein, a linking group as described herein, a spacer or bond as described herein, an enzyme cleavable linker as described herein, a self-immolative linker as described herein and a immunomodulatory agent as described herein. 20 When the specific binding molecule comprises a VNAR domain, the VNAR domain may have a sequence of SEQ ID Nos: 1, 12 to 20, 31 to 38, 40 to 68. When the specific binding molecule comprises a VNAR, the VNAR may have a sequence of SEQ ID Nos: 1, 12 to 20, 31 to 38, 40 to 68 and the immunomodulatory agent may be a JAKi. When the specific binding molecule comprises a VNAR domain, the VNAR domain may comprise a sequence of SEQ ID NO: 51 or a sequence with at least 60% identity 25 thereto. When the specific binding molecule comprises a VNAR domain, the VNAR domain may comprise a sequence of SEQ ID NO: 51 or a sequence with at least 60% identity thereto, and the immunomodulatory agent may be a JAKi as described herein. The conjugate of the invention may be cleaved by elastase. The conjugate of the invention may be cleaved by human neutrophil elastase. After said enzymatic cleavage, the specific binding molecule 30 and immunomodulatory agent are released. The specific binding molecule and immunomodulatory agent may have independent functionality after cleavage of the elastase cleavable linker. Compositions According to a further aspect of the invention, there is provided a composition comprising the 35 compound of formula (I) or a pharmaceutically accepted salt thereof, or the conjugate of formula (II), or a pharmaceutically accepted salt thereof. The composition may be a pharmaceutical composition. The pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier. Such compositions may comprise any suitable and pharmaceutically acceptable carrier, diluent, adjuvant or buffer solution. The composition may comprise a further pharmaceutically active agent. Such 40 carriers may include, but are not limited to, saline, buffered saline, dextrose, liposomes, water, glycerol, ethanol and combinations thereof. 73 x

[0057] Such compositions may comprise a further pharmaceutically active agent as indicated. The additional agents may be therapeutic compounds, e.g. anti-inflammatory drugs, cytotoxic agents, cytostatic agents or antibiotics. Such additional agents may be present in a form suitable for administration to patient in need thereof and such administration may be simultaneous, separate or sequential. The 5 components may be prepared in the form of a kit which may comprise instructions as appropriate. The pharmaceutical compositions may be administered in any effective, convenient manner effective for treating a patient’s disease including, for instance, administration by oral, topical, intravenous, intramuscular, intranasal, subcutaneous or intradermal routes among others. In therapy or as a prophylactic, the active agent may be administered to an individual as an injectable composition, for 10 example as a sterile aqueous dispersion, preferably isotonic. Alternatively, the active agent may be administered as a capsule or tablet. The active agent may be administered via any suitable systemic administration route. For administration to mammals, and particularly humans, it is expected that the daily dosage of the active agent will be from 0.01 mg / kg body weight, typically around 1 mg / kg, 2 mg / kg or up to 4 mg / kg. 15 The physician in any event will determine the actual dosage which will be most suitable for an individual which will be dependent on factors including the age, weight, sex and response of the individual. The above dosages are exemplary of the average case. There can, of course, be instances where higher or lower dosages are merited, and such are within the scope of this invention. The compositions described herein may be administered at any frequency. The frequency of 20 administration may be determined as needed by a qualified practitioner. The frequency of administration may be daily, weekly, monthly, or yearly. The administration may be multiple times per day, twice a week, twice a monthly, twice a year. Any suitable frequency of administration is envisaged. It will be understood that the sequence of any VNAR disclosed herein may, or may not include any tags disclosed herein or known to the skilled person. Any sequence of any VNAR of the invention also 25 includes the sequences including and excluding a tag. In should be understood that tags may exist for extraction or purification purposes only. The skilled person would be aware of how to remove or add a tag to a given sequence of the invention. Medical use / Method of treatment of conjugate 30 According to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically accepted salt thereof, a conjugate of formula (II), or a pharmaceutically accepted salt thereof or a composition comprising the compound of formula (I) or a pharmaceutically accepted salt thereof, or the conjugate of formula (II), or a pharmaceutically accepted salt thereof for use in medicine. This aspect of the invention therefore extends to the use of a compound or conjugate of the invention in 35 the manufacture of a medicament. The medicament may be for the treatment of a disease or condition. This aspect of the invention also extends to compositions comprising the compound or conjugate of the invention. Such uses also encompass methods of treating diseases in patients in need of such treatment, the methods comprising administering to the patient a therapeutically effective dosage of a compound of 40 formula (I) or a pharmaceutically accepted salt thereof, a conjugate of formula (II), or a pharmaceutically accepted salt thereof or a composition comprising the compound of formula (I) or a pharmaceutically 74 x

[0058] accepted salt thereof, or the conjugate of formula (II), or a pharmaceutically accepted salt thereof, or a pharmaceutical composition as defined herein, comprising a compound or conjugate of the invention. The compound, conjugate or (pharmaceutical) composition comprising the conjugate may be administered before, during, or after another therapy. The compound, conjugate or (pharmaceutical) 5 composition comprising the conjugate may be co-administered with another therapy. The conjugate or composition comprising the conjugate may be administered as part of a plethora of other treatments. The compound, conjugate or (pharmaceutical) composition comprising the conjugate may be administered only once, or on multiple occasions separated by a period of time. The period of time may be minutes, hours, day, weeks or months. 10 In addition, there are provided herein compounds, conjugates and compositions as described above for use in therapy. Furthermore, there are provided herein compounds, conjugates and compositions for use in the treatment of inflammation and / or auto-immune diseases or conditions. The uses described herein extend to uses of a (pharmaceutical) composition comprising the conjugate of the invention. 15 The disease or condition may be an autoimmune disease or condition. The disease or condition may be an inflammatory disease or condition. In some embodiments, the autoimmune disease or condition is selected from inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, rheumatoid arthritis, Psoriatic arthritis, Enteropathic Arthritis, Spondyloarthritis, Sjogren’s syndrome, Psoriasis, Giant cell arteritis, Behçet’s disease, ANCA-associated vasculitis, including granulomatosis with polyangiitis 20 (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), Hidradenitis Suppurativa, Psoriatic Arthritis, Axial Spondyloarthritis, Non-infectious uveitis, Juvenile idiopathic arthritis, Pyoderma gangrenosum and Takayasu’s arteritis. As used herein, the term “treatment” includes any regime that can benefit a human or a non- human animal. The treatment of “non-human animals” in veterinary medicine extends to the treatment of 25 domestic animals, including horses and companion animals (e.g. cats and dogs) and farm / agricultural animals including members of the ovine, caprine, porcine, bovine and equine families. The treatment may be a therapeutic treatment in respect of any existing condition or disorder, or may be prophylactic (preventive treatment). The treatment may be of an inherited or an acquired disease. The treatment may be of an acute or chronic condition. The treatment may be of a condition / disorder associated with 30 inflammation and / or auto-immunity. The compounds, conjugates and compositions of the invention may be used in the treatment of a disorder, including, but not limited to inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, rheumatoid arthritis, Psoriatic arthritis, Enteropathic Arthritis, Spondyloarthritis, Sjogren’s syndrome, Psoriasis, Giant cell arteritis, Behçet’s disease, ANCA-associated vasculitis, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic 35 granulomatosis with polyangiitis (EGPA), Hidradenitis Suppurativa, Psoriatic Arthritis, Axial Spondyloarthritis, Non-infectious uveitis, Juvenile idiopathic arthritis, Pyoderma gangrenosum and Takayasu’s arteritis Also provided herein is the use of compounds, conjugates and composition, according to the above aspects in the manufacture of a medicament for the treatment of a disease in a patient in need 40 thereof. Also provided herein is a method of treatment of a disease in a patient in need of treatment comprising administration to said patient of a therapeutically effective dosage of compounds, conjugates 75 x

[0059] and compositions according to the above aspects. The disease may be an inflammatory disease or condition. The disease may be an autoimmune disease or condition. Bifunctional, Site specific 5 As will be appreciated, the specific binding molecule-drug conjugates described herein may be considered as a first in class, bifunctional molecule, with each of the specific binding molecule and the immunomodulatory agent having independent functionality after cleavable of the enzyme cleavable linker. Molecules of the invention can therefore be used to target to separate and independent disease pathways at the same time. In this invention by targeting at the same time two independent signalling pathways 10 known to be involved in the pathology of a disease, rather than just one, the conjugate of the invention is expected to have better clinical efficacy in individual patients and broader efficacy across the entire patient population. In a further aspect of the invention there is provide the use of the compounds, conjugates and compositions of the invention, for site specific delivery of an immunomodulatory agent. The 15 immunomodulatory agent may be any immunomodulatory agent described herein. Preferably, the immunomodulatory agent is a JAKi. The site specific delivery of the immunomodulatory agent may be mediated by the specific binding molecule as defined herein. The site to which the agent is delivered may be an inflammatory microenvironment. As used herein “inflammatory microenvironment” refers to a localized tissue environment characterized by the 20 presence of inflammation, typically due to a response to infection, injury, or chronic disease. This environment is marked by the accumulation of immune cells, signalling molecules such as cytokines and chemokines, and other bioactive substances that collectively contribute to inflammation. Also upregulated in an inflammatory microenvironment are enzymes, such as, proteases (such as serine proteases such as Elastase), MMPs (such as MMP1, 2, 3, 9 or 13), COX (such as COX1 or COX2), iNOS, Lipoxygenases 25 (such as 5LOX, 12LOX or 15LOX), caspases (such as Caspase 1, 3 or 8), Phospholipase A2 (PLA2), Granzyme B, NADPH oxidase, Cathepsins (such as Cathepsin B, D or L), Arginase, Myeloperoxidase or any other suitable enzyme. The enzyme cleavable linker may be cleaved by lysosomal protease cleaving enzymes (such as Cathepsins), a β-glucuronidase enzyme, an asparaginyl endopeptidase (such as Legumain), a phosphatase, an Esterase or a Matrix metalloproteinase (MMP). 30 The enzyme cleavable linker may be a linker that can be cleaved by the activity enzymes present in the inflammatory microenvironment. The enzyme may not be present in healthy environments, or may not be at a concentration high enough to cause cleavage of the cleavable linker. The cleavable linker described herein may be cleaved in an inflammatory microenvironment. As a result, the specific binding molecule may be released. The specific binding molecule may then be free 35 to independently act on the target. Cleavage of the enzyme cleavable linker described herein may also release the immunomodulatory agent. As described herein, the immunomodulatory agent may be inactive when bound to the conjugate. However, cleavage of the linker in the inflammatory microenvironment may result in spontaneous activation of the immunomodulatory agent. The released immunomodulatory agent may then be free to independently act on the target. 40 VNAR Epitopes 76 x

[0060] The anti-TNF VNAR domains described herein as “D1” and “C4”, and any variant of the sequences described herein may preferentially bind to soluble TNFa (sTNFa), over membrane bound, or transmembrane TNFa (tmTNF). Soluble TNFa (sTNFa) is generated through the proteolytic cleavage of its precursor form, 5 transmembrane TNFa (tmTNFa), by the enzyme TNFa converting enzyme (TACE or ADAM-17). Soluble fragment of human TNFa may be understood to be residues 77-233 of the membrane bound form of TNFa 77ubercut ID PO1375). It is known that both tmTNFa and sTNFa exert their biological activities through type 1 and type 2 TNF receptors in TNF receptor expressing cells. tmTNFa can act as either a ligand by activating TNF receptors, or a receptor that transmits outside-to-inside signals (reverse 10 signalling) after binding to native receptors. Anti-TNFa agents that bind tmTNFa can induce reverse signalling to various degrees. This can result in several side-effects most notably infections. Anti-TNFa biologics have been successfully implemented in the clinic for the treatment of chronic inflammatory diseases such as Rheumatoid Arthritis, Ulcerative Colitis, Crohn’s Disease, psoriatic arthritis (PsA), psoriasis (PsO), and ankylosing spondylitis (AS). However, there is a two-to-four-fold increased 15 risk of granulomatous infectious diseases, including active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial and viral infections by a range of opportunistic pathogens. There also appears to be differences in the clinical efficacy of the anti-TNF-α drug class for certain inflammatory disease indications. Some of these adverse events may be explained by the binding of anti-TNFa biologics to tmTNFa, and the triggering of “reverse signalling” that induces cell-cycle arrest, suppression of T-cell 20 proliferation and apoptosis of tmTNFa bearing cells. All five anti-TNF-α biologics (Adalimumab, Infliximab, Golimumab, Etanercept, and Certolizumab) currently in clinical use can neutralise TNF-α, however increasing evidence shows that all five drugs have differences in their therapeutic efficacy and utility and the occurrence of unwanted side-effects. Patients that are receiving anti-TNF-α therapies suffering severe and life-threatening opportunistic infections and 25 malignancies. For other patients their clinical history, combined with the risk of these side-effects, excludes them from ever receiving systemic anti-TNF therapies. The inventors have surprisingly found that the domains D1 and C4 represent a novel mechanism of TNF-α neutralisation, delivering predicted improvements in clinical safety, especially for high-risk autoimmune / inflammatory patients or patients currently contra-indicated for anti-TNF therapies. The 30 inventors have shown that D1 and C4 preferentially bind sTNF (Examples 14 and 15). Binding to sTNF is thought to reduce overall side-effects from TNF therapies and may also provide, for the first time, access to anti-TNF drugs for patient groups that are currently unable to benefit from this drug class (e.g., patients with latent bacterial or viral infections, patients at risk of malignancies). The invention also provides an anti-TNFa VNAR that preferentially binds sTNF or a fragment 35 thereof. The anti-TNFa VNAR may be used in methods of treating patients that are currently unable to received anti-TNF therapies. The patients may be patients with latent bacterial or viral infections (for example, tuberculosis), and / or patients at risk of malignancies, including tumour formation. The invention also provides compositions comprising an anti-TNFa VNAR that preferentially binds sTNF or a fragment thereof, and uses thereof in medicine. 40 The conjugate described herein may comprise an anti-TNFa VNAR that preferentially binds sTNF. The conjugate of the invention may be used in methods of treating patients unable to receive current anti- 77 x

[0061] TNF therapies. The patients may be patients with latent bacterial or viral infections, patients at risk of malignancies. Definitions 5 The term “protein” in this text means, in general terms, a plurality of amino acid residues joined together by peptide bonds. It is used interchangeably and means the same as peptide, oligopeptide, oligomer or polypeptide, and includes glycoproteins and derivatives thereof. The term “protein” is also intended to include fragments, analogues, variants and derivatives of a protein wherein the fragment, analogue, variant or derivative retains essentially the same biological activity or function as a reference 10 protein. Examples of protein analogues and derivatives include peptide nucleic acids, and DARPins (Designed Ankyrin Repeat Proteins). VNAR domains comprise four regions which are necessary for antigen binding. Each VNAR typically has two “complementarity determining regions” (CDRs) identified as CDR1 and CDR3, and two “hypervariable loop” (HV) regions identified as HV2 and HV4. Each antigen binding region may comprise 15 amino acid residues from a “complementarity determining region” and / or those residues from a “hypervariable loop” (HV). In some instances, an antigen binding region can include amino acids from both a CDR region and a hypervariable loop. According to the generally accepted nomenclature for VNAR molecules, a CDR2 region is not present. As used herein, whenever a CDR or HV is said to “comprise” a sequence, this term also includes a CDR or HV “consisting of” the same sequence. 20 “Framework regions” (FW) are those VNAR residues other than the CDR residues. Each VNAR typically has five framework regions identified as FW1, FW2, FW3a, FW3b and FW4. As used herein, whenever a FW is said to “comprise” a sequence, this term also includes a FW “consisting of” the same sequence. “Identity” as known in the art is the relationship between two or more polypeptide sequences or 25 two or more polynucleotide sequences, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness (homology) between polypeptide or polynucleotide sequences, as the case may be, as determined by the match between strings of such sequences. While there exist a number of methods to measure identity between two polypeptide or two polynucleotide sequences, methods commonly employed to determine identity are codified in computer programs. 30 Preferred computer programs to determine identity between two sequences include, but are not limited to, GCG program package (Devereux, et al., Nucleic acids Research, 12, 387 (1984), BLASTP, BLASTN, and FASTA (Atschul et al., J. Molec. Biol.215, 403 (1990). Preferably, the amino acid sequence of the protein has at least 50% identity, using the default parameters of the BLAST computer program (Atschul et al., J. Mol. Biol.215, 403-410 (1990) provided by 35 HGMP (Human Genome Mapping Project), at the amino acid level, to the amino acid sequences disclosed herein. More preferably, the protein sequence may have at least 55%, 60%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, 90% and still more preferably 95% (still more preferably at least 96%, 97%, 98% or 99%) identity, at the nucleic acid or amino acid level, to the amino acid sequences as shown herein. The protein may also comprise a sequence which has at least 50%, 55%, 60%, 65%, 66%, 67%, 40 68%, 69%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with a sequence disclosed 78 x

[0062] herein, using the default parameters of the BLAST computer program provided by HGMP, thereto. %. The sequence variation may be outside the CDR and HV regions. As used herein, when referring to the Quad-X™ molecule, “monoparatopic” refers to a format where both VNAR domains are the same. The term “bi-paratopic” refers to a format where each of the 5 VNAR domains binds a different epitope of the same antigen. All possible combinations and permutations of the framework regions, complementarity determining regions and hypervariable regions listed above are explicitly contemplated herein. Any references are incorporated in their entirety to the fullest extent permitted by the law. The present invention will be further understood by reference to the following non-limiting 10 examples. Examples The following examples of the invention are provided to aid understanding of the invention but should not be taken to limit the scope of the invention. Unless otherwise described, reagents may be 15 commercially available or prepared according to procedures in the literature. The molecules used herein are as follows: ELN28-135 is an anti-TNF-alpha, GlySer Linker reformatted and Fc mutated (S239C, S442C) Quad-X part of the soloMER drug conjugate to any JAKi. 20 ELN28-135-01 is an anti-TNF-alpha, GlySer Linker reformatted and Fc mutated (S239C, S442C) Quad-X conjugated to Tofacitinib (DAR 4). ELN22-135 is an anti-TNF-alpha, GlySer Linker reformatted and Fc mutated (S239C, S442C) Quad-X. “V2” as used herein refers to a molecule wherein Y comprises a bromoacetamide group. 25 Example 1 – Synthesis of Compounds of Formula (I) Compounds of formula (I) according to the present invention were prepared using the following methods. Part A – Synthesis of Mal-PEG4-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine 79 x

[0063] Mal-PEG4-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine was synthesised according to the following methods. It will be appreciated that this scheme can be applied generally to the synthesis of other compounds according to the definitions in the remainder of the specification by variation of the appropriate starting materials. 5 Fmoc-Asn(Trt)-Pro-Val-PABC-N-(Boc)-N,N′-dimethylethylenediamine 10 Fmoc-Asn(Trt)-Pro-Val-PABC-N-(Boc)-N,N′-dimethylethylenediamine was synthesised following procedures from Chemistry–- A European Journal, 2019, vol. 25, # 7, p. 1696 – 1700. (Scheme S5, compounds 39-43) using commercial Fmoc-L-Valine-OH, Fmoc-L-Proline-OH and Fmoc-L-Asn(Trt)-OH. h-Asn(Trt)-Pro-Val-PABC-N-(Boc)-N,N′-dimethylethylenediamine 80 x

[0064] To a solution of Fmoc-Asn(Trt)-Pro-Val-PABC-N-(Boc)-N,N′-dimethylethylenediamine (0.8 g, 0.719 mmol) in DMF (15 mL) was added piperidine (853 µL, 8.63 mmol). The reaction mixture was stirred for 1 h at room temperature (r.t.). DMF was concentrated in vacuo. The solid residue was extracted with 5 hexane (2 x 30 mL) and combined hexane extract was discarded. The residue was purified by reverse phase C-18 column chromatography using buffer A (water: 0.05% trifluoroacetic acid (TFA) (v / v)) and buffer B (acetonitrile: 0.05% trifluoroacetic acid (v / v)) with a gradient elution from 100:0 (v / v) to 0:80 (v / v). Fractions were combined and lyophilised to give the desired product (0.45 g, 62.3%) as a TFA salt. MS (ESI+), m / z: [M+2H]2+(395.90, 100%), [M+H]+(890.60, 90%). 10 To a solution of h-Asn(Trt)-Pro-Val-PABC-N-(Boc)-N,N′-dimethylethylenediamine TFA salt (0.45 g, 0.448 mmol) in DMF (10mL) was added Mal-PEG4-NHS (0.198 g, 0.448 mmol) and N-methylmorpholine (147 15 µL, 1.34 mmol). The reaction mixture was stirred for 4 h at r.t. DMF was partially concentrated in vacuo. The residue was purified by reverse phase C-18 column chromatography, using buffer A (water: 0.05% trifluoroacetic acid (TFA) (v / v)) and buffer B (acetonitrile: 0.05% trifluoroacetic acid (v / v)) with a gradient elution from 95:5 (v / v) to 0:90 (v / v). Combined fractions were concentrated in vacuo then lyophilised to give the desired product (0.45 g, 82.5%). MS (ESI+), m / z: [M-Boc+2H]2+(559.56, 100%), [M-Boc+H]+20 (1117.61, 20%). 81 x

[0065] To a solution of Mal-PEG4-Asn(Trt)-Pro-Val-PABC-N-(Boc)-N,N′-dimethylethylenediamine (0.45 g, 0.369 mmol) in DCM (5 mL) was added TIPS (1 mL). The flask was placed in an ice-bath and TFA (4 mL) was added slowly. The reaction mixture was stirred for 1 h at r.t. then concentrated in vacuo. The residue was 5 purified by reverse phase C-18 column chromatography using buffer A (water: 0.05% trifluoroacetic acid (TFA) (v / v)) and buffer B (acetonitrile: 0.05% trifluoroacetic acid (v / v)) with a gradient elution from 100:0 (v / v) to 0:80 (v / v). Combined fractions were concentrated in vacuo then lyophilised to give the desired product (0.336 g, 91.8%) as a TFA salt. MS (ESI+), m / z: [M+2H]2+(438.58, 100%), [M+H]+(875.52, 22%). 10 Part B – Synthesis of a compound of Formula (I) Mal-PEG4-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine-Tofacitinib was synthesised as follows. Tofacitinib-PNP carbonate 15 Tofacitinib-PNP carbonate was synthesized following a modified procedure from Journal of Medicinal Chemistry, 2022, vol.65, # 6, p.4926 – 4948. Briefly, Tofacitinib (312 mg, 1 mmol) was dissolved in MeCN (15 mL). Bis(4-nitrophenyl) carbonate (425 mg, 1.4 mmol) was added in one portion followed by N-ethyl- N,N-diisopropylamine (350 µL, 2 mmol). The resulting reaction mixture was stirred for 5 h at r.t. and 20 concentrated in vacuo. The residue was triturated with diethyl ether (30 mL). Yellow solids were collected by filtration and subsequently used without further purification. MS (ESI+), m / z: [M+H]+(478.28, 100%), [M+Na]+(500.25, 5%). Mal-PEG4-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine-Tofacitinib 82 x

[0066] To a solution of Mal-PEG4-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine TFA salt (0.336 mg, 0.339 mmol) in DMF (5 mL) was added Tofacitinib-PNP carbonate (152 mg, 0.339 mmol) and N- methylmorpholine (150 µL, 1.36 mmol). The reaction mixture was stirred for 2 h at r.t. then concentrated 5 in vacuo. The residue was purified by reverse phase C-18 column chromatography, using buffer A (water: 0.05% trifluoroacetic acid (TFA) (v / v)) and buffer B (acetonitrile: 0.05% trifluoroacetic acid (v / v)) with a gradient elution from 95:5 (v / v) to 0:90 (v / v). Combined fractions were concentrated in vacuo then lyophilised to give the desired product (0.169 mg, 41.1%) as a white solid. Material purity was determined to be > 99% by HPLC at 214 nm and 254 nm. MS (ESI+), m / z: [M+2H]2+(607.68, 100%), [M+H]+(1213.58,10 33%). Part C – Synthesis of a further compound of formula (I) Bromoacetamide-PEG4-NPV-PABC-DMEDA-Tofacitinib was synthesised as follows. 15 Fmoc-Asn(NH2)-Pro-Val-PABC-N,N′-dim amine To a solution of Fmoc-Asn(Trt)-Pro-Val-PABC-N-(Boc)-N,N′-dimethylethylenediamine (653 mg, 0.588 mmol) in DCM (10 mL) was added TIPS (1.5 mL). The flask was placed in an ice-bath and TFA (5 mL) was added dropwise. The reaction mixture was stirred for 20 min at 0 °C and then for 40 min at room 20 temperature. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase C-18 column chromatography using buffer A (water: 0.05% trifluoroacetic acid (TFA) (v / v)) and buffer B (acetonitrile: 0.05% trifluoroacetic acid (v / v)) with a gradient elution from 100:0 (v / v) to 30:70 (v / v). Combined fractions were concentrated in vacuo then lyophilised to give the desired product as a TFA salt (411 mg, 79.0%) as off-white solid. MS (ESI+), m / z: [M+2H]2+ (385.30, 100%), [M+H]+ (790.8, 65%). 25 83 x

[0067] Fmoc-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine-Tofacitinib To a stirred mixture of Tofacitinib (187 mg, 0.6 mmol) and bis-(4-nitrophenyl) carbonate (219 mg, 0.72 mmol) in DCM (6 mL) was added triethylamine (168 µL, 1.2 mmol). The reaction mixture was heated to 5 45 °C and stirred at this temperature for 5 h. The reaction mixture was then cooled to room temperature. HPLC analysis confirmed formation of Tofacitinib PNP carbonate and full consumption of bis-(4- nitrophenyl) carbonate. To the above solution, Fmoc-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine TFA salt (411 mg, 10 0.465 mmol) in DMF (5 mL) was added, followed by additional triethylamine (335 µL, 2.4 mmol). The resulting reaction mixture was stirred for 4 h at room temperature, then concentrated in vacuo. The residue was purified by reverse phase C-18 column chromatography using buffer A (water: 0.05% trifluoroacetic acid (TFA) (v / v)) and buffer B (acetonitrile: 0.05% trifluoroacetic acid (v / v)) with a gradient elution from 90:10 (v / v) to 20:80 (v / v). Combined fractions were concentrated in vacuo then lyophilised to give the 15 desired product (324 mg, 62.9%) as off-white solid. MS (ESI+), m / z: [M+2H]2+ (554.78, 100%), [M+H]+ (1108.79, 33%). h-Asn(NH2)-Pro-Val-PABC-N,N′-dim diamine-Tofacitinib 20 To a solution of Fmoc-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine-Tofacitinib (308 mg, 0.278 mmol) in DMF (3 mL) was added piperidine (138 µL, 1.39 mmol). The reaction mixture was stirred for 1 h at room temperature. DMF was concentrated in vacuo. The solid residue was extracted with hexane (2 x 15 mL) and combined hexane extract was discarded. The residue was purified by reverse phase C-18 column chromatography using buffer A (water: 0.05% trifluoroacetic acid (TFA) (v / v)) and buffer B 25 (acetonitrile: 0.05% trifluoroacetic acid (v / v)) with a gradient elution from 100:0 (v / v) to 20:80 (v / v). Fractions were combined and lyophilised to give the desired product TFA salt (115 mg, 41.3%) as white solid. MS (ESI+), m / z: [M+H]+ (886.13, 100%) 84 x

[0068] Bromoacetamide-PEG4-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine-Tofacitinib To a solution of h-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine-Tofacitinib TFA salt (115 mg, 0.115 mmol) in DMF (2 mL) was added bromoacetamide-PEG4-NHS ester (67 mg, 0.138 mmol) and 5 DIPEA (40 µL, 0.23 mmol). The reaction mixture was stirred for 2 h at room temperature, and then directly purified by reverse phase C-18 column chromatography, using buffer A (water: 0.05% trifluoroacetic acid (TFA) (v / v)) and buffer B (acetonitrile: 0.05% trifluoroacetic acid (v / v)) with a gradient elution from 100:0 (v / v) to 30:70 (v / v). Combined fractions were concentrated in vacuo then lyophilised to give the desired product (63 mg, 42.8%) as white solid. Material purity was determined to be > 98% by HPLC at 214 nm 10 and 254 nm. MS (ESI+), m / z: [M+2H]2+ (627.8, 100%), [M+H]+ (1253.2, 33% and 1255.0, 55%). Example 2 – Payload release studies Payload release studies were undertaken to validate the ability of a compound of formula (I) to release the immunomodulatory agent, tofacitinib, in an active form. The study investigated the cleavage of the 15 compound of formula (I) by human Neutrophil Elastases under physiologically relevant conditions or enzymatic assay conditions with tofacitinib release monitored by LC-MS / MS. Part A – Physiological conditions Method 20 Mal-PEG4-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine-Tofacitinib was prepared at 4 µg / mL in the relevant reaction buffer for each Neutrophil Elastase enzyme: Human–- 100 mM Tris-HCl, 500 mM NaCl, pH 7.5; Mouse–- 50 mM Tris-HCl, 1 M NaCl, pH 7.5) Activated Human Neutrophil Elastase (324681) or Mouse Neutrophil Elastase activated prior to use with associated protocol (4517-SE) was spiked into the aliquots to a final concentration of 0.1 µg / mL and incubated at 37^C for the specified time 25 (10 min, 30 min, 1 h, 4 h, 24 h and 72 h). Due to the mouse elastase requiring activation by Cathepsin C (2336-CY), a control sample was prepared with cathepsin spiked at 0.1 µg / mL (equivalent concentration of cathepsin in elastase spiked samples) and incubated at 37^C for 24 h. The enzymatic release was terminated by spiking with 1.5 µL of formic acid (pH ≈ 3) after incubation, the 0 h time point was spiked with formic acid prior to elastase addition. Samples were frozen at -80 ^C after incubation; prior to 30 analysis by LC-MS. Concentration of released payload calculated based on calibration standards and reported as percentage of administer payload. LC-MS analysis 85 x

[0069] Calibration standards and QC samples were prepared by spiking blank buffer with Tofacitinib. Calibration line consisting of 8 standards between 15–- 1500 ng / mL. QC samples at 15, 45, 750 and 1125 ng / mL. 50 μL sample volume required. Dilution prior to analysis by LC-MS. Internal standard Fluticasone Propionate was spiked at 750 ng / mL final concentration. Analysis conducted on Waters Acquity UPLC 5 online with Xevo TQS-micro mass spectrometer. Transitions monitored: Tofacitinib 313.211 > 107.024, Fluticasone Propionate 501.155 > 313.196. Reverse Phase LC Chromatography: Waters Acquity Premier BEH C181.7 um 2.1 x 50 mm (186009452), Mobile Phase A – H2O:Formic Acid 100:0.1 (v:v), Mobile Phase B – Acetonitrile:Formic Acid 100:0.1 (v:v), Column Temperature 40°C, Gradient elution 5- 80% MPB over 4.75 minutes 10 Results Mouse elastase Human elastase 15 Part B–- Enzymatic Assay Conditions Method Mal-PEG4-Asn(NH2)-Pro-Val-PABC-N,N′-dimethylethylenediamine-Tofacitinib was prepared at 50 µg / mL in 100 mM Tris-HCl, 500 mM NaCl, pH 7.5). Activated Human Neutrophil Elastase (324681) was spiked 20 into the aliquots to a final concentration of 1.7 µg / mL and incubated at 37^C for the specified time (10 min, 30 min, 1 h, 4 h and 24 h). The enzymatic release was terminated by spiking with 1.5 µL of formic acid (pH ≈ 3) after incubation, the 0 h time point was spiked with formic acid prior to elastase addition. Samples were frozen at -80 ^C after incubation; prior to analysis by LC-MS. Concentration of released payload calculated based on calibration standards and reported as percentage of administer payload. 25 LC-MS analysis 86 x

[0070] Calibration standards and QC samples were prepared by spiking blank buffer with Tofacitinib. Calibration line consisting of 8 standards between 15–- 1500 ng / mL. QC samples at 15, 45, 750 and 1125 ng / mL. 50 μL sample volume required. Dilution prior to analysis by LC-MS. Internal standard Fluticasone Propionate was spiked at 750 ng / mL final concentration. Analysis conducted on Waters Acquity UPLC 5 online with Xevo TQS-micro mass spectrometer. Transitions monitored: Tofacitinib 313.211 > 107.024, Fluticasone Propionate 501.155 > 313.196. Reverse Phase LC Chromatography: Waters Acquity Premier BEH C181.7 um 2.1 x 50 mm (186009452), Mobile Phase A – H2O: Formic Acid 100:0.1 (v:v), Mobile Phase B – Acetonitrile: Formic Acid 100:0.1 (v:v), Column Temperature 40°C, Gradient elution 5- 80% MPB over 4.75 minutes 10 Results Mouse elastase Human elastase 15 Part C – Dexamethasone Enzymatic Assay Conditions Method The release of dexamethasone from Mal-PEG4-NPV-PABC-DMEDA-Dexamethasone was studied according to the same method used in Example 2 Part B. 20 Results 87 x

[0071] Example 3 Production of a specific-binding molecule drug conjugate Starting material Quad-X (D1-Fc-C4) containing additional engineered cysteines were expressed in TurboCHO-Express 2.0 system and purified using protein A affinity chromatography. These then 5 underwent full reduction, 15 mM DTT, 22°C for 1 hour, PBS, pH 7.2, 2 mM EDTA, followed by buffer exchange into DPBS, 5 mM EDTA, pH 7.5 using CentriPure column / Vivaspin concentrator (PES, 30 kDa MXCO). Re-oxidation was then carried out using 30 equivalents of Dehydroascorbic acid (DHAA), PBS pH 7.2, 2 mM EDTA, 22°C, 1 hour, followed by conjugation using 10-12 equivalents of maleimide linker payload, PBS, pH 7.5, 5 mM EDTA, 10% DMSO, 22°C, 1 hour. ADC Quad-X-conjugates were then 10 purified by preparative SEC using HiLoad Superdex 200 pg column with isocratic elution in DPBS, pH 7.1 followed by concentration using Vivaspin 20, 30 kDa MWCO. To determine binding kinetics of the above molecule, Octet® R8 biolayer interferometry (BLI) was used (Figure 6). Anti-TNF-α VNAR Quad-X® prepared in 1% BSA in PBS + 0.01% Tween 20, pH 7.4 (assay buffer) at a different concentration starting 20nM and 2-fold dilution for 7 points were loaded on 15 assay buffer-equilibrated anti-human IgG Fc Capture (AHC2) biosensors for 10 min, followed by 30 min association step fixed concentration of 10nM TNF-α prepared in assay buffer and a 30 min dissociation step. Data were analysed using the Octet® BLI Analysis Studio 143 software 12.2., and global 1:1 fit model. Alternatively, Octet® R8 biolayer interferometry (BLI) was used to determine binding kinetics of 20 Anti-TNF-α VNAR Quad-X® prepared in 1% BSA in PBS + 0.01% Tween 20, pH 7.4 (assay buffer) (Figure 7). 10nM of Biotin-huTNF alpha were loaded on assay buffer-equilibrated SAX biosensors for 10 min, followed by 30 min association step with Anti-TNF-α prepared in assay buffer with different concentration starting with 20nM and followed by 2-fold dilution for 7 points and a 30 min dissociation step. Data were analysed using the Octet® BLI Analysis Studio 143 software 12.2., and global 1:1 fit model. 25 Example 4 Neutralisation of human TNF-alpha L929 cells were seeded at 5000cells / well in 150µL of complete DMEM media. Incubated for 48hrs at 37 degree 5% CO2. Discarded the spent media. Treated the cells with differential concentration of the drug in the volume of 100µL / well. Following treatment, added a volume of 5µl / well of Actinomycin D 30 (Tocris, A7592 ) to final concentration of 1µg / mL and 3µL / well of human TNF alpha (Acro #TNA-H4211) to a final concentration of 0.3ng / mL. Incubated for 24hrs at 37 degree 5% CO2. Added 50µL of WST -1 reagent (Merck, 11644807001) diluted to 1:15 RPMI media to all wells. Read absorbance at 450nm at 24hrs (Figure 8). 35 Example 5 Drug – antibody ration (DAR) Figures 9 and 10 show DAR4 conjugation of the Quad-X molecule. RP-LC-MS analysis 88 x

[0072] Liquid chromatography mass spectrometry (LC-MS) analysis was carried out using a Waters XEVO G2S TOF mass spectrometer and a Waters BioResolve mAb RP Polyphenyl 450Å (2.1 x 30 mm, 2.7 µm) connected to a Waters Acquity H Class Ultrahigh-performance liquid chromatography (UPLC) system. The mobile phase was buffer A (0.1 % formic acid in water). A gradient (2.5 min 10% B, 10-80% B gradient 5 in 3.5 min) was applied using Buffer B (acetonitrile, 0.1 % formic acid) at a flow rate of 0.4 mL / min. The column was maintained at 55 °C throughout the analysis. The SDCs were analysed after dilution to 0.05 mg / mL in LC-MS grade water.10 µL of SDC solution (1 µg) were injected for analysis. ^ DAR calculation Average DAR was calculated as the weighted average of the observed DAR species signal intensity (SI) 10 for each DAR species (i, from DAR 0 to DAR 5) on the deconvoluted m / z spectra, as follows: Figures 11 and 12 show an alternative method RP-LC-MS analysis Liquid chromatography mass spectrometry (LC-MS) analysis was carried out using a Waters XEVO 15 G2S TOF mass spectrometer and a Waters BioResolve mAb RP Polyphenyl 450Å (2.1 x 30 mm, 2.7 µm) connected to a Waters Acquity H Class Ultrahigh-performance liquid chromatography (UPLC) system. The mobile phase was buffer A (0.1 % formic acid in water). A gradient (2.5 min 10% B, 10-80% B gradient in 3.5 min) was applied using Buffer B (acetonitrile, 0.1 % formic acid) at a flow rate of 0.4 mL / min. The column was maintained at 55 °C throughout the analysis. The SDCs were analysed after dilution to 0.05 20 mg / mL in LC-MS grade water.10 µL of SDC solution (1 µg) were injected for analysis. ^ DAR calculation Average DAR was calculated as the weighted average of the observed DAR species signal intensity (SI) for each DAR species (i, from DAR 0 to DAR 5) on the deconvoluted m / z spectra, as follows: 25 Example 6 Payload Release using conjugates For human elastase 100 mM Tris-HCl, 500 mM NaCl, pH 7.5, For mouse elastase 50 mM Tris- HCl, 1 M NaCl, pH 7.5. ADC was spiked at 6 µM. Activated human or mouse Elastase (324681, 4517- SE) was spiked into the aliquots to a final concentration of 4.425 µg / mL and incubated at 37°C for the 30 specified time (0, 2 or 24 h). Due to the mouse elastase requiring activation by Cathepsin C (2336-CY), a control sample was prepared with cathepsin spiked at 4.425 µg / mL (equivalent concentration of cathepsin in elastase spiked samples) and incubated at 37°C for 24 h. The enzymatic release was terminated by spiking with 1.1 µL of formic acid (pH ≈ 3) after incubation, the 0 h time point was spiked with formic acid prior to elastase addition. (figures 13 and 14) 35 Samples were frozen at -80 °C after incubation; prior to analysis by LC-MS. Concentration of released payload calculated based on calibration standards and reported as percentage of administer payload. LC-MS analysis Calibration standards and QC samples were prepared by spiking blank buffer with Tofacitinib. 40 Calibration line consisting of 8 standards between 15–- 1500 ng / mL. QC samples at 15, 45, 750 and 1125 89 x

[0073] ng / mL. 50 μL sample volume required. Dilution prior to analysis by LC-MS. Internal standard Fluticasone Propionate was spiked at 750 ng / mL final concentration. Analysis conducted on Waters Acquity UPLC online with Xevo TQS-micro mass spectrometer. Transitions monitored: Tofacitinib 313.211 > 107.024, Fluticasone Propionate 501.155 > 313.196. Reverse Phase LC Chromatography: Waters Acquity 5 Premier BEH C181.7 um 2.1 x 50 mm (186009452), Mobile Phase A – H2O: Formic Acid 100:0.1 (v:v), Mobile Phase B – Acetonitrile:Formic Acid 100:0.1 (v:v), Column Temperature 40°C, Gradient elution 5- 80% MPB over 4.75 minutes. Example 7 ELN28-135-Tofacitinib extended stability at 37°C in human plasma. 10 SDCs were spiked into plasma at 1 mg / mL and incubated at 37°C for up to 168 h. Samples were collected at 0, 24, 48, 96, 144 and 168 h and stored at –80°C pending analysis. Stability timepoints in human and mouse plasma (LiHep) were analysed in a single analytical run along with calibration standards and quality control (QC) samples. A calibration line was prepared by spiking Tofacitinib in human plasma at concentrations between 15.0 ng / ml to 15000 ng / ml with independent QC 15 samples at (15.0, 45.0, 750 and 1125 ng / ml). Incubated plasma stability timepoints, calibration standards and QC samples were extracted prior to LC-MS analysis: 50 µL of sample were spiked with 150 µL of Fluticasone Propionate (internal standard–- IS) at 1000 ng / mL in acetonitrile:formic acid (100:0.1 v:v). Samples were mixed for 5 mins at 900 rpm before centrifugation at 2250 x g, 4°C for 10 minutes in a Fresco 21 refrigerated Microcentrifuge (Thermo Scientific). After centrifugation, 100 µL of the supernatant 20 were transferred to a clean plate well and diluted with 275 µL 0.1% formic acid in water. LC-MS Analysis The extracted samples were analysed by LC-MS / MS using an Acquity UPLC in line with a Xevo TQ-S Premier mass spectrometer (Waters). Separation was performed using an Acquity Premier C18 (1.7 µm, 25 1.0 x 50 mm) column. The chromatographic method consists of a gradient starting at 95% mobile phase A (0.1% formic acid in LC-MS grade water) to 80% mobile phase B (0.1% formic acid in LC-MS grade acetonitrile) over 4.75 min. Mass spectrometric analysis was performed in positive ion mode, with targeted MS / MS set-up as reported in Table 1. 30 Example 8 Payload activity in vitro IL23 HEK Blue reporter cells (Invivogen, Cat#hkb-il23) were seeded at the density of 50K cells / well in volume of 50ul in 96-well flat bottom cell culture plate. Test samples were pre incubated with or without HNE (Sigma, Cat # 324681) @50nM final concentration for 24 h at 37 °C and added to the cells. Stimulated the cells with 25 uL / well of human IL 23 (biotechne, Cat# 1290-IL-500 / CF) at final 35 concentration of 1ng / ml, Incubated all at 37 °C for 24 hours. Transferred 10µl of supernatant to a 384 well transparent plate and added 30 µL of the Quanti blue detection reagent Invivogen, Cat #rep-qbs). Incubated for 15 minutes in the dark at room temperature and measured the colour at 620-655 nm. (Figure 15) 40 Neutralisation in vitro 90 x

[0074] The L929 cells were seeded at 5000cells / well in 150µL of complete DMEM media. Incubated for 48hrs at 37 degree 5% CO2. Discarded the spent media. Treated the cells with differential concentration of the drug in the volume of 100µL / well. Following treatment, added a volume of 5µl / well of Actinomycin D (Tocris, A7592 ) to final concentration of 1µg / mL and 3µL / well of human TNF alpha (Acro #TNA-H4211) 5 to a final concentration of 0.3ng / mL. Incubated for 24hrs at 37 degree 5% CO2. Added 50µL of WST -1 reagent (Merck, 11644807001) diluted to 1:15 RPMI media to all wells. Read absorbance at 450nm at 24hrs.(figure 16) Example 9 Binding of soloMER drug conjugates to human TNF-alpha in solution 10 Octet® R8 biolayer interferometry (BLI) was used to determine binding kinetics of Anti-TNF-α VNAR Quad-X® SDC prepared in 1% BSA in PBS + 0.01% Tween 20, pH 7.4 (assay buffer) at a different concentration starting 20nM and 2-fold dilution for 7 points were loaded on assay buffer-equilibrated anti- human IgG Fc Capture (AHC2) biosensors for 10 min, followed by 30 min association step fixed concentration of 10nM TNF-α prepared in assay buffer and a 30 min dissociation step. Data were analysed 15 using the Octet® BLI Analysis Studio 143 software 12.2., and global 1:1 fit model. (figure 17) Example 10 In vitro effect of SDC Keynote: HNE, human neutrophil elastase; PBMC, Peripheral blood mononuclear cells; SDC, soloMER® drug conjugates. 20 Healthy Human PBMC were seeded at the density of 100K cells / well in 100µL of complete RPMI media. Added 25µL volume of Tofacitinib and SDC’s at the desired test concentration. Added 10µL / well of HNE (Sigma, Cat # 324681) @50nM final concentration to all wells. Added PHA (Sigma, Cat# 11249738001) at final concentration of 2ug / mL to make up the volume to 150µL / well and incubated at 37 degree 5% CO2 for 72 h. Added 15µL of WST -1 reagent (Merck, 11644807001) diluted to 1:10 and 25 dispensed to each well. Read absorbance at 450nm at 4-5hrs.(figure 18) IL6 and mCXCL1 inhibition Transgenic mice were administered with intraperitoneal injections of test articles and 2 hours later were treated with LPS. Following euthanasia, 5 hours post LPS challenge, blood was collected by cardiac puncture, allowed to clot at room temperature for 20 mins before serum was collected by centrifugation. 30 For measurement of IL6, one 50 μl serum aliquot collected at 5 hours post LPS challenge from each experimental animal was used for the detection of mIL-6 (R&D SYSTEMS, Quantikine ELISA, mIL-6, #M6000B-01, Lot: P392211, Exp: 03 July 2024) and MCP-1 (R&D SYSTEMS, Quantikine ELISA, CCL2 / JE / MCP-1, #MJE00B, Lot: P399041, Exp: 14 Aug 2024) by ELISA and were performed according to manufacturer’s protocol. (figure 19).mCXCL1 levels present in the serum were measured using the 35 DuoSet ELISA kit (biotechne, R&D systems, DY453-05. Briefly: capture antibodies is coated in wells of a MaxiSorp 96 well ELISA plate overnight at 4°C, wells are washed with PBST (PBS 0.05 % Tween 20) and blocked with reagent diluent (1% BSA in PBS), serum samples were diluted 1:200 in reagent diluent and incubated for 2 hours at RT, wells washed PBST, binding detected using kit biotinylated-detection antibody followed by kit streptavidin-HRP, then TMB and stopped 2N H2SO4. On the same plate a dilution series 40 of the kit standard is used to generate a standard curve. Plate read at 450 nM and concentrations calculated based on standard curve. (figure 20) 91 x

[0075] Example 11 ELN28U-02 (Ustekinumab – Mal-PEG4-NPV-PABC-DMEDA-Upadacitinib IL12 (Figure 22) and IL23 (Figure 23) MaxiSorp 96 well plates were coated with streptavidin (5 µg / ml) overnight followed by washing 5 with PBST (PBS 0.05 % Tween 20) and blocked with 4 % milk (Marvel powdered milk) in PBS. Biotinylated target proteins were added at 1 µg / ml: hIL12 (biotechne, R& D systems, 10018-IL-050 / CF), biotinylated using EZ-link NHS-PEG4-Biotin (Thermo Fisher, 21362), or : hIL23 (biotechne, R& D systems, 1290-IL- 500 / CF), biotinylated using EZ-link NHS-PEG4-Biotin (Thermo Fisher, 21362). . Plates were washed PBST and antibodies or ADC were added: Ustekinumab (purchased Evidentic), Risankizumab (purchased 10 Evidentic), Ustekinumab (S293C_S442C) (custom synthesised) and ELN28U-02 were diluted in PBS to a starting concentration of 100 nM in PBS and then a 12 point 1:2 dilution series prepared in PBS. Plates were washed and binding was detected through the human IgG using the Fc specific antibody A0170 (Sigma Aldrich), followed by TMB and stopped 2N H2SO4. Plate read at 450 nM and EC50 calculated using Graph Pad Prism software. (figure 22) 15 Binding IL23 HEK Blue reporter cells (Invivogen, Cat#hkb-il23) were seeded at the density of 50K cells / well in volume of 50ul in 96-well flat bottom cell culture plate. Test samples were pre incubated with or without HNE (Sigma, Cat # 324681) @50nM final concentration for 24 h at 37 °C and added to the cells. 20 Stimulated the cells with 25 uL / well of human IL 23 (biotechne, Cat# 1290-IL-500 / CF) at final concentration of 1ng / ml, Incubated all at 37 °C for 24 hours. Transferred 10µl of supernatant to a 384 well transparent plate and added 30 µL of the Quanti blue detection reagent Invivogen, Cat #rep-qbs). Incubated for 15 minutes in the dark at room temperature and measured the colour at 620-655 nm. (figures 24 and 25) 25 Example 12 Dexamethasone payload Starting material Quad-X containing additional engineered cysteines were expressed in TurboCHO-Express 2.0 system and purified using protein A affinity chromatography. These then underwent full reduction, 15 mM DTT, 22°C for 1 hour, PBS, pH 7.2, 2 mM EDTA, followed by buffer 30 exchange into DPBS, 5 mM EDTA, pH 7.5 using CentriPure column / Vivaspin concentrator (PES, 30 kDa MXCO). Re-oxidation was then carried out using 30 equivalents of Dehydroascorbic acid (DHAA), PBS pH 7.2, 2 mM EDTA, 22°C, 1 hour, followed by conjugation using 10-12 equivalents of maleimide linker payload, PBS, pH 7.5, 5 mM EDTA, 10% DMSO, 22°C, 1 hour. ADC Quad-X-conjugates were then purified by preparative SEC using HiLoad Superdex 200 pg column with isocratic elution in DPBS, pH 7.1 35 followed by concentration using Vivaspin 20, 30 kDa MWCO. Dexamethasone payload release is described above Example 13: Crystallisation and X-ray structures determination for VNAR-D1 and sTNF-α complex Crystallisation conditions for sTNF-α-VNAR-D1 were screened following the sitting drop vapour 40 diffusion protocol (Stevens 2000). Drops were monitored regularly using an optical microscope. Initial hits were refined in 48-well plates using hanging drop setups with 500 µL reservoir solution and 1 – 6 µL drops 92 x

[0076] with streak seeding. The best crystals grew after several rounds of seeding in a condition containing 19 % PEG 8000, 0.2 M ammonium sulphate and 0.1 M MES pH 6.0 at 18 °C. Crystals were harvested with nylon loops, transferred to a cryoprotectant (reservoir solution supplemented with 10 – 20 % glycerol, ethylene glycol, propylene glycol or PEG 400) and flash-frozen in liquid nitrogen. X-ray diffraction data 5 was collected at beamline P14, German Electron Synchrotron DESY, Hamburg, and a complete dataset was collected at 3.31 Å resolution (Table S1). Diffraction images were processed using XDS (Kabsch 2010). Phases were obtained by molecular replacement with PHASER (Read, McCoy et al.2007) using the TNF trimer from Protein Data Bank (PDB) entry 1TNF. The model was completed with COOT (Emsley, Cowtan 2004) and refined using REFMAC5 (Murshudov, Skubák et al.2011). Protein-protein interfaces 10 were analysed using PISA (Krissinel, Henrick 2007). PyMOL and COOT were used for refinement of the crystal structure and comparison of the sTNF-α-VNAR-D1 structure to other known soluble huTNF-α / anti- TNF-α complexes. The VNAR-D1: sTNF-α crystallisation and X-ray structural determination was carried out at moloX GmbH, Berlin Germany. Crystallisation and X-ray structures determination for VNAR-C4 and sTNF-α complex 15 Purified sTNF-α and VNAR-C4 were mixed at ~1:1 molar ratio and the complex formed was isolated using a Superdex200 size-exclusion chromatography (SEC) column operating with 10 mM Tris-HCl (pH 7.4) and 150 mM NaCl. The isolated complex was concentrated by ultrafiltration to ~10 mg / ml and subjected to crystallization. The sTNF-α-VNAR-C4 complex was crystallized by the sitting drop vapor diffusion method, using a reservoir solution containing 0.1 M MES, pH 6, 0.1M magnesium chloride, 8% w / v polyethylene 20 glycol 6000. The crystals grew to full size in three days. The crystals were cryo-protected by briefly soaking in the reservoir solution supplemented with 25% ethylene glycol and flash-cooled by plunging into liquid nitrogen. X-ray diffraction data were collected at the Advanced Photon Source NE-CAT beamline 24-ID- C. All X-ray diffraction data were processed using XDS version 20210205 (Kabsch 2010). Molecular replacement calculations were performed using PHASER version 2.8 (McCoy, Grosse-Kunstleve et al. 25 2007). Iterative manual model building and refinement were done using COOT version 7766 and PHENIX version v.1.19.2-4158, respectively (Emsley, Lohkamp et al.2010, Adams 2009). The summary of data collection and model refinement statistics is shown in Table S2. The VNAR-C4:sol huTNF-α crystallisation and X-ray structural determination was carried out at the Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis. 30 Example 14 Binding of VNAR domains to TNF Healthy human CD4+ T cells (BioIVT, lot no. HumanCD4-0111394) were cultured in supplemented RPMI at density of 0.2 x 106cells / mL in 96-well flat bottom cell culture plates, 37 °C, 5 % CO2. CD4+ T cells were stimulated with 0.1 μg / mL PHA (Sigma, Cat# 11249738001) for 12 h. PHA 35 activated cells were washed with acidified buffer (50 mM glycine-HCl containing 150 mM NaCl, pH 207 3.0) for 3 min at 4 °C to remove traces of sTNF-α. Acidified buffer was removed by washing the cells three times with PBS containing 1 % BSA. PHA activated cell were treated with anti- TNF-α VNARs at different concentrations. (I) For tmTNF-alpha binding, cells were stained with PE conjugated Goat anti-Human IgG Fc 40 Antibody (Thermofisher , Catalog # 12-4998-82) 1 µg / test and incubated for 1 hr at 4 °C in the dark 93 x

[0077] followed by fixing the cell with 0.5 % paraformaldehyde (PFA) for 15 min, 4 °C, and fluorescence intensity measured using 212 CLARIOstar® plus microplate reader and Attune™ NxT flow cytometer. (II) Cells were stained for E-selectin using anti-human CD62E-FITC conjugated antibody (R&D systems, Cat# BBA21) 1 µg / test and incubated for 1 hr at 4 °C in the dark followed by fixing the cell with 5 0.5 % paraformaldehyde (PFA) for 15 min, 4 °C, and fluorescence intensity measured using 212 CLARIOstar® plus microplate reader and Attune™ NxT flow cytometer. (iii) The IFN-γ levels was measured in anti-TNF-α treated activated CD4+ T cells supernatant using the human IFN-γ DuoSet Sandwich ELISA kit (R&D systems, Cat no. DY285B-05). 10 Example 15 – Production of a further specific-binding molecule drug conjugate ELN22-135 (399 mg; 5.0 mg / mL) in buffer (Dulbecco’s PBS, pH 7.2, 5 mM EDTA) was reduced with 15 mM DTT. After 2h incubation at 22 °C, the reduced Quad-X SoloMER™ was buffer exchanged by Tangential Flow Filtration using Sartocon® Slice 200 (30 kDa MWCO).10 mM sodium acetate buffer, pH 5.2 was initially used to remove excess DTT (7 diafiltration volumes), followed Dulbecco’s PBS, pH 7.3, 5 15 mM EDTA (7 diafiltration volumes). The buffer-exchanged Quad-X SoloMER™ at 5 mg / mL in Dulbecco’s PBS, pH 7.3, 5 mM EDTA was re-oxidised with 30 eq. DHAA per antibody for 1 h at 22 °C. The reduced and re-oxidised Quad-X SoloMER™ was buffer exchanged by gel filtration into 50 mM sodium phosphate, pH 8 buffer. Conjugation with 16 eq. of Bromoacetamide-PEG4-NPV-PABC-DMEDA-Tofacitinib linker- payload per antibody was then performed. This was achieved by concentrating the Quad-X SoloMER™20 solution to 13.6 mg / mL followed by the addition of Bromoacetamide-PEG4-NPV-PABC-DMEDA- Tofacitinib linker-payload in DMSO (10 % v / v DMSO) with final concentration of SoloMER™ solution adjusted to 10 mg / mL. The solution was then mixed gently and incubated at 22 ˚C for 1h. After 1h, the reaction mixture was purified by preparative SEC on a HiLoad 26 / 600 Superdex 200 pg column equilibrated with Dulbecco’s PBS, pH 7.1. The flow rate was kept constant at 2.3 mL / min. Fractions were 25 collected and analysed by analytical SEC. Fractions containing monomeric SDC were pooled and concentrated using Vivaspin 20 centrifugal concentrators (PES membrane, 50 kDa MWCO). The concentrated SDC sample was then purified by preparative hydrophobic interaction chromatographic. The SDC sample was diluted with an equal volume of 6 M sodium chloride, 50 mM sodium phosphate, pH 7.0 and loaded onto a 20 mL column packed with ToyoPearl® Butyl-650S HIC resin and equilibrated with 30 buffer A: 3.0 M sodium chloride, 50 mM sodium phosphate, pH 7.0. Elution was carried out with a constant flow of 3.0 mL / min and a 0-100% gradient in buffer B: 50 mM sodium phosphate, 20% isopropanol, pH 7.0. Fractions were analysed by LC-MS, analytical HIC and SEC and pooled based on average DAR 4 ± 0.2 (LC-MS). Pooled fractions were buffer exchanged and concentrated to >10 mg / mL using a CentriPure P100 gel filtration column to buffer exchange into Dulbecco’s PBS, pH 7.1 and Vivaspin 20 centrifugal 35 concentrator (PES membrane, 50 kDa MWCO) to concentrate the SDC. The concentrated SDC sample (98.8 mg; 6.75 mL) was then sterile filtered through a 0.22 µm pore size, PVDF membrane filter and quantified by UV-A280 and characterised by SEC, LC-MS, HIC and LAL endotoxin assay. 94 x

[0078] Example 16: ELN28-135-Tofa is superior to non-conjugated anti-TNFs ELN22-108 and Humira in controlling Tg197 chronic severe inflammation at the molecular and gene expression level The efficacy of ELN28-135-01 was compared against the non-conjugated anti-TNF ELN22-108 and Humira. A non-targeting isotype control conjugated to Tofacitinib, ELN0-2V-135-01 was also included. 5 Tg197 is a transgenic mouse model of polyarthritis, with inflammation primarily localized to the ankle joints. The disease is mainly driven by soluble TNF; therefore, any effect of JAK inhibition is likely to be minimal on macroscopic observation. The Tg197 transgenic mouse model for arthritis (Keffer et al., 1991) was used to demonstrate the superiority of ELN28-135-Tofa to Humira. In this model mice develop chronic polyarthritis with 100% 10 incidence at 4-7 weeks of age driven by the overexpression of human TNFα. For this study, mice were assigned to groups consisting of 8 gender and age matched mice. Groups were as follows: PBS only vehicle control, ELN28-135-Tofa anti-TNFα Quad-X-Tofacitinib SDC, ELN0-2V-135-Tofa non-binding Quad-X-Tofacitinib isotype control, Humira anti-TNFα monoclonal antibody and ELN22-108 anti-TNFα Quad-X™. At 3 weeks of age, prior to the establishment of arthritis pathology mice were treated with test 15 articles subcutaneously at 10 µl / g of body weight. For administration test articles were diluted in PBS to 0.3 mg / ml concentrations to allow dosing at 3 mg / kg. Animals were weighed using an electronic scale on the day of dosing to determine necessary volume to achieve correct dose. Animals were dosed twice a week for 7 weeks to give a total duration of the study of 10 weeks. During the course of the study in vivo arthritic score was recorded once a week for each ankle joint using a set of characteristics and a scale of 20 0-3 (0 = no disease, 0.5 = mild disease, 1 = mild to moderate disease, 1.5 = moderate disease, 2 = moderate to severe disease, 2.5 severe disease, 3 = very severe disease). An additional group of 4 mice were left untreated and sacrificed at 3 weeks of age to serve as a control group. See figure 31A. At the end of the 10-week study animals were sacrificed, their right ankle joint was collected, the skin was removed and fixed in 4% aqueous formaldehyde solution at room temperature overnight. 25 Demineralisation was then performed by incubating in 13% EDTA in 0.1 M sodium phosphate at room temperature for 30 days. Samples were embedded in paraffin in the sagittal plane, were sectioned using a microtome and slides generated. Separately, slides were stained with H&E (haematoxylin and eosin stain), safranin O or TRAP (Tartrate resistant acid phosphatase) to evaluate inflammation, cartilage destruction and bone erosion respectively using a light microscope. In each case histopathology severity 30 was scored using a scale of 0-3, was carried out in a blinded fashion with a score assigned to each individual ankle joint. Individual values were plotted with group mean and SD, Y-axis were broken to highlight differences between ELN28-135-Tofa and ELN22-108 treated mice. See Figure 31B At the end of the 10-week study animals were sacrificed, blood was drawn via cardiac puncture, allowed to clot for 20 mins at room temperature and supernatant collected by centrifugation. The 35 concentration of two disease associated cytokines, mCXCL1 and mMCP-1, were then assessed in all serum samples. Commercially available ELISA kits, R&D Systems DuoSet DY453 for mCXCL1 and DuoSet DY479 for mMCP-1 were used as per manufacturer’s instructions. In both cases serum samples were diluted 1:25 in reagent buffer and compared to a standard curve of kit supplied standard to calculate concentration. Individual values were plotted with group mean and SD, Y-axis were broken to highlight 40 differences between ELN28-135-Tofa, ELN22-108 and Humira treated mice. See figure 31C. 95 x

[0079] The left ankle joint from 4 mice from each of the following groups: PBS vehicle (Tg), ELN22-108 3 mg / kg (G3), ELN28-135-Tofa 3 mg / kg (G5) and ELN0-2V-135-Tofa 3 mg / kg (G8) treated mice, and 10- week old wild type littermate animals (Wt) were used for differential gene expression analysis. Total RNA was extracted using Trizol reagent from each sample and RNASeq carried out. Raw FASTQ files were 5 generated using standard pipelines and subjected to quality controls. Reads were mapped to the mm10 reference genome and gene counts were quantified. The quantification of 14432 differentially expressed genes was possible. By comparing the 10-week vehicle treated mice to the 10-week wild type control mice 2736 disease associated genes were identified (Tg / Wt). The differential gene expression of these 2736 genes was compared for ELN22-1083 mg / kg (G3) / Wt, ELN28-135-Tofa 3 mg / kg (G5) / Wt and ELN0- 10 2V-135-Tofa 3 mg / kg (G8) / Wt. Darker shading indicates greater difference from Wt with lighter shading indicating less difference from Wt. RNASeq scatter plot of differentially expressed genes (DEGs). Log fold change of Disease (Tg) vs control (Wt) (x-axis) was plotted against the log2 fold change of treatment group vs Wt (y-axis). A high positive slope shows correlation with the disease and therefore a lack of response to treatment. A small 15 slope with horizontal regression indicates effective treatment with a restoration of Wt profile. Restored, Not-restored and altered genes definitions used: Restored genes are DEGs in Tg197 / Wt (e.g. having logFC>=1, p-adjusted <=0.05) and which do not fulfil these criteria in the treated samples; Not-restored genes are DEGs in Tg197 / Wt and remain so in the treated samples; Altered genes are genes which are not DEGs in Tg197 but which fulfil the differential expression criteria in the treated samples. See figure 20 31D. ELN28-135-01 demonstrated a two-fold superiority over ELN22-108 in restoring the ankle joints of treated mice to a healthy, non-diseased state. In contrast, mice treated with ELN0-2V-135-Tofa showed no signs of Tofacitinib activity. RNA sequencing data of the ankle joint tissue indirectly confirmed that ELN28-135-01 was present as an intact molecule in the ankle joint and that Tofacitinib was released in the joint tissue. 25 Examples of differential gene modulation in genes associated with inflammation and the JAK / STAT pathway. The Fold change in expression compared to Wild type was plotted for Tg197 untreated diseased mice, ELN22-108 treated Tg197 mice and ELN28-135-Tofa treated mice. Genes associated with the chemokine (C-X-C motif) ligand CXCL family, chemokine (C-C motif) ligand CCL family and the matrix metalloproteinase MMP family were plotted. See figure 31E. 30 This demonstrates the in vivo release of the Tofacitinib payload in a site-specific manner by targeting TNF-alpha accumulated at the site of inflammation. The additive efficacy for ELN28-135-01 compared to ELN22-108 and superiority to Humira in ankle joint tissue histopathology, RNA sequencing, and serum cytokine expression levels is demonstrates. The non-targeted isotype molecule did not elicit any pharmacological activity. 35 Example 17: Single dose Biodistribution of ELN28-135-Tofa in Active Disease Tg197 Biodistribution of ELN28-135-Tofa to inflamed ankle joints after single dose in active disease Tg197. Fifteen female mice at 7 weeks of age were assigned to 5 groups of 3 so that there was equal distribution of body weight and arthritic score among groups. ELN28-135-Tofa was diluted to 0.3 mg / ml 40 in PBS, 12 mice were administered the test article at 10 ml / kg to give a dose of 3 mg / kg; 3 mice received no treatment. Groups of 3 mice were sacrificed at times, 1, 8, 48 and 72 hours; the no treatment group 96 x

[0080] were sacrificed at 0 hours. Following euthanasia blood was collected via cardiac puncture into K2EDTA coated tubes, centrifuged at 1,500 g for 15 minutes at RT and plasma transferred to fresh tubes. Ankle joints were collected from all mice, skin was removed and immediately snap frozen in N2(l). See Figure 32. 5 Plasma samples were diluted in PBS for analysis. Ankle joints of known weight were homogenised into PBS using a Bead Mill Homogeniser. ELN28-135-Tofa levels were measured by sandwich ELISA, where the human-Fc containing SDC was captured using an anti-human IgG polyclonal antibody raised in goat and detecting using an anti-human IgG polyclonal antibody raised in goat conjugated to HRP. Concentrations were calculated by comparison to a standard curve of ELN28-135-Tofa SDC. 10 Concentrations are reported as % injected dose (ID) per ml of plasma and as % injected dose (ID) per g of ankle joint. This confirms the presence of at least 1% of the injected dose per gram (ID / g) in the inflamed ankle joints of Tg197 mice. Over 4% of the injected dose (ID) per gram of ankle joint tissue at the 48-hour time point after drug administration was seen. 15 Example 18: hTNFα targeting SDC biodistribution in Tg197 mice after 7 weeks of dosing At the end of the 10-week study animals were sacrificed, their left ankle joints were collected, the skin was removed, weighed, and immediately snap frozen in N2(l). Ankle joints of known weight from mice dosed at 3 mg / kg were homogenised into PBS using a Bead Mill Homogeniser. Test article levels were 20 measured by sandwich ELISA, where the human-Fc containing drugs were captured using an anti-human IgG polyclonal antibody raised in goat and detecting using an anti-human IgG polyclonal antibody raised in goat conjugated to HRP. Concentrations were calculated by comparison to a standard curve of ELN28- 135-Tofa SDC. Concentrations are reported as % Final Dose (FD) per g. See figure 33A 3 mice from the 3 mg / kg ELN28-135-Tofa and 3 mice from 3 mg / kg ELN0-2V-135-Tofa groups 25 were analysed. Ankle joints of known weight were homogenised into PBS, 5% Triton X-100 using a bead mill homogeniser. Total antibody measurement: Prior to LC-MS / MS analysis total antibody was immunoprecipitated from ankle joint homogenates. In parallel immunoprecipitation of known concentrations of ELN28-135-Tofa or ELN02V-135-Tofa were carried out. Study samples and controls (10 µl) were diluted in 50 mM Tris-HCl with 1 mg / ml BSA pH 7.5 and added to pre-washed protein A / G 30 magnetic beads and incubated at room temperature for 2 hours. After this time the beads were pelleted using a magnetic stand and then supernatant discarded. The beads were washed 3 times with 50 mM Tris-HCl pH 7.5 with 1 mg / ml BSA and subsequently captured antibody was eluted by incubating for 10 min with 60 µl of 0.5% formic acid (FA) at 95°C. The eluate was neutralised with 15 µl of 1 M Tris-HCl pH 8.8 and 20 µl internal standard (IS) P14R 100 nM, 10 µl 10% N-octyl-glucoside, and 5 µl of 100 mM DTT 35 were added successively and incubated for 1 hour at 60°C. The mixture was then incubated with 5 µl of 300 mM iodoacetamide (IAM) for 30 min at room temperature in the dark. The sample was diluted with 50 µl 50 mM NH4HCO3 and 20 µl of trypsin solution for 3.5 hours at 37°C. The digestion reaction was quenched with 5 µl FA, the magnetic beads were pelleted by a magnetic stand, the supernatant collected, filter and centrifuged ready for LC-MS / MS analysis. Analysis of 20 µl of digest reaction was carried out 40 using LC30AD (Shimadzu, Japan) HPLC system with Phenomenex Synergi 2.5µ Polar-RP 100 A (50*3.0 mm) column using a gradient of solution A (5% acetonitrile in water, 0.1% FA) and solution B (95% 97 x

[0081] acetonitrile in water, 0.1% FA), 3-90-3% solution B over 4 min at a flow rate of 0.6 ml / min; and API 6500+ QTRAP (AB Sciex, USA) mass spectrophotometer. Standard calibration curves based on analyte peak area were generated using 10 known concentrations of ELN28-135-Tofa or ELN0-2V-135-Tofa. Total antibody concentration in study samples was determined by comparing their analyte peak area (counts) 5 to the standard calibration curve. For ELN28-135-Tofa the peptide ETGESLTINC[CAM]VLR (Q1746.38, Q3774.43) was used for quantification, and for ELN0-2V-135-Tofa the peptide AQSLAISTR (Q1473.77, Q3747.44); the internal standard P14R (Q1512.11, Q3292.20) was included with all samples. ADC equivalent measurement: Prior to LC-MS / MS analysis total antibody was immunoprecipitated from ankle joint homogenates. In parallel immunoprecipitation of known concentrations of standards was carried out. 10 Study samples and controls were diluted in 50 mM Tris-HCl with 1 mg / ml BSA pH 7.5 and added to pre- washed protein A / G magnetic beads and incubated at room temperature for 2 hours. After this time the beads were pelleted using a magnetic stand and then supernatant discarded. The beads were washed 3 times with 50 mM Tris-HCl pH 7.5 with 1 mg / ml BSA before 100 µl of 0.5 mg / ml elastase (from pig pancreas, MCE, HY-P2974) in 100 mM Tris-HCl, 500 mM NaCl pH 7.5 was added and incubated at 37°C 15 for 2 hours to release tofacitinib payload. The reaction was quenched with 5 µl FA. 200 µl of acetonitrile precipitant (acetonitrile) containing IS mixture (Carbamazepine / Dexamethasone / Verapamil) was added to all samples, except the double blank sample, solutions were filtered using a protein precipitation plate, and diluted 1:3 with water prior to LC-MS / MS analysis. Analysis of 20 µl of digest reactions were carried out using LC30AD (Shimadzu, Japan) HPLC system with Phenomenex Synergi 2.5µ Polar-RP 100 A 20 (50*3.0 mm) column using a gradient of solution A (5% acetonitrile in water, 0.1% FA) and solution B (95% acetonitrile in water, 0.1% FA), 10-90-10% solution B over 2.5 min at a flow rate of 0.6 ml / min; and API 6500+ QTRAP (AB Sciex, USA) mass spectrophotometer. A standard calibration curves based on analyte peak area were generated using 10 known concentrations of ELN28-135-Tofa or ELN0-2V-135-Tofa. Tofacitinib concentration in study samples was determined by comparing their analyte peak area (counts) 25 to the standard calibration curve, Q1313.07, Q3149.10 for tofacitinib with Q1455.30, Q3165.20 for internal standard verapamil. The measured tofacitinib concentration was recorded and used to calculate ADC equivalent in µg / g based on the molecular weight of ELN28-135-Tofa and considering DAR 3.9; or on the molecular weight of ELN0-2V-135-Tofa taking into account DAR 4.0. Data are presented as % Final Dose (FD) / g. See Figure 33B). 30 This demonstrates the presence of ELN28-135-01 to be more than 4% FD / g of ankle joint tissue, which is two-fold higher than Humira, while the isotype control was not detected in the ankle joint following twice-weekly dosing for a total of 14 doses. The ELN28-135-01 level was greater than 6% FD / g in individual mice M39 and M40. Finally, the direct products of neutrophil elastase cleaving of ELN28-135- 01 were abundantly detected in the ankle joints of Tg197 mice. 35 Example 19: Functional characterisation of ELN28-135v2-Tofa IL23 HEK Blue reporter cells (Invivogen, Cat#hkb-il23) were seeded at the density of 50K cells / well in volume of 50 ul in 96-well flat bottom cell culture plate. Test samples were pre incubated with or without HNE (Sigma, Cat # 324681) at 50 nM final concentration for 24 h at 37 °C and added to the cells. 40 Stimulated the cells with 25 uL / well of human IL 23 (biotechne, Cat# 1290-IL-500 / CF) at final concentration of 1ng / ml, Incubated all at 37 °C for 24 hours. Transferred 10µl of supernatant to a 384 well 98 x

[0082] transparent plate and added 30 µL of the Quanti blue detection reagent Invivogen, Cat #rep-qbs). Incubated for 15 minutes in the dark at room temperature and measured the colour at 620-655 nm. % inhibition calculated based on 100% inhibition by 8 µM tofacitinib. IC50 calculated using GraphPad Prism 10.2.0. Figure 34 5 This demonstrates comparable functional inhibition of the JAK / STAT pathway by both SDC versions, confirming the efficient and identical cleaving of the linker payload by human neutrophil elastase (HNE). This assay is independent of TNF-alpha inhibition Example 20: Synovial organoid generation 10 Synovial organoids were established by co-culturing monocytes derived from healthy peripheral blood mononuclear cells healthy donor (PBMC) with Human Umbilical Vein Endothelial Cells (HUVECs) and Rheumatoid Arthritis-derived Fibroblast-Like Synoviocytes (RAFLS). Cells were obtained from commercial sources: RAFLS (female, 35 years old; Accegen, Cat# ABC-TC3621), HUVECs (male, neonatal; Lonza, Cat# C2517A, Batch# 20TL134214), and healthy PBMCs (Precision for Medicine). 15 Cell culture: RAFLS were cultured in DMEM (Thermo Fisher Scientific, Cat# 11995-065), supplemented with 10% Fetal Bovine Serum (FBS), qualified, heat inactivated, United States (Thermo Fisher Scientific; Cat# 16140071), 100 μg / mL penicillin–streptomycin (Thermo Fisher Scientific, Cat# 15140-122), 2 mM L-glutamine (Thermo Fisher Scientific, Cat# 25030-081), 10 mM HEPES (Thermo Fisher Scientific, Cat# 15630-080) and 250 μg / mL gentamicin (Thermo Fisher Scientific, Cat# 15710- 20 064), Essential Amino Acids (Thermo Fisher Scientific, Cat# 11130-051), Non-Essential Amino Acids (Thermo Fisher Scientific, Cat# 11140-050), 2-mercaptoethanol (Thermo Fisher Scientific, Cat# 21985-023), up to passage 9. HUVECs were cultured in EGM-2 Endothelial Cell Growth Medium-2 (Lonza, Cat# 900001, Lot# 0001300073), supplemented with the accompanying EGM-2 BulletKit growth supplements (Lonza, Cat# 900002, Lot# 0001298489), according to the manufacturer’s instructions. 25 Cells were seeded at a density of 2500-5000 cells / cm² in tissue culture-treated flasks and maintained at 37 °C in a humidified incubator with 5% CO₂ up to passage 9. Monocytes were isolated from frozen PBMCs using a brief adherence-based method. Cryopreserved PBMC vials were rapidly thawed in a 37 °C incubator and immediately transferred into pre-warmed RPMI 1640 medium (Gibco, Cat# 12004997), supplemented with 10% heat-inactivated FBS and 100 μg / mL penicillin–streptomycin to get rid of the 30 freezing media, cell suspension was centrifuged at 1200 rpm for 5 min and the supernatant was discarded. Cell pellet was resuspended in 15 mL of pre warmed RPMI media and plated in a petri dish. Cells were incubated at 37 °C in a humidified 5% CO₂ incubator for 30–40 minutes to allow monocytes to loosely adhere to the plastic surface, while non-adherent peripheral blood lymphocytes (PBLs) remained in suspension. After incubation, floating PBLs were gently removed by aspirating the 35 supernatant without disturbing the attached cells. The loosely adherent monocytes were carefully detached by gentle pipetting with warm RPMI and collected and counted with a hemocytometer. Poly-HEMA coating was prepared by dissolving 410 mg of Poly(2-hydroxyethyl methacrylate) (Poly- HEMA; Sigma-Aldrich, Cat# 192066-10G) in 41 mL of pre-heated 200-proof ethanol (Deacon Labs, Inc, Cat# 2716) in a 50 mL tube. The mixture was incubated in a water-bath set at 60 °C for 1–2 h with 40 vortexing every 5–10 minutes, followed by continuous incubation for 16–24 hours until the crystals dissolved completely. A total of 1 mL of the Poly-HEMA solution was dispensed into each well of a 12- 99 x

[0083] well plate pre-warmed to 50 °C for 30 minutes. Plates were then dried in a 50 °C incubator with lids on for 16–24 hours and stored at RT until use. Organoid generation: Cells were harvested, pooled together with the density of 0.2 × 106RAFLS, 0.2 × 106HUVEC and 0.1 × 106monocytes per organoid and pelleted down in a pre-chilled 15 5 mL falcon tube. The pooled cell pellet was resuspended with Matrigel (Matrigel® Growth Factor Reduced (GFR) Basement Membrane Matrix, Phenol Red-Free; Corning; Cat# 356231) in a volume of 35 µL per organoid. Using a chilled 200 µL-micropipette tip, 35 µL of the Matrigel-cell suspension was slowly dispensed into the centre of each well of a pre-warmed, Poly-HEMA–coated 12-well tissue culture plate. The plate was carefully transferred to a 37 °C humidified incubator with 5% CO₂ for 1-2 hours to 10 allow Matrigel polymerization. A volume of 2 mL of pre-warmed EGM2 medium (without hydrocortisone) was added dropwise to each well. The organoids were maintained in culture for 15 days at 37 °C, 5% CO₂, changing the media twice per week to support organoid formation. Organoid treatment: on day 14, culture supernatants were collected and stored at –20 °C for further analysis. Organoids were then washed twice with 2 mL of sterile PBS and replenished with 2 mL 15 of fresh pre-warmed EGM2 medium (without hydrocortisone), either alone or supplemented with test compounds. Treatments included 400 nM Tofacitinib, 100 nM ELN0-2V-135 (isotype control), and 100 nM ELN28-135v2-Tofa. The organoids were incubated with the test samples for 24 h at 37 °C in a humidified 5% CO₂ incubator. Following treatment, supernatants were collected and stored at –20 °C and organoids were subsequently washed and processed for analysis.20 RNA isolation: RNA was isolated using RNeasy Plus (Qiagen, Cat# 74134), according to manufacturer’sinstructions. Briefly, four organoids per condition were pooled and homogenised in 600 µL of Buffer RLT Plus using FisherbrandTMBead Mill 24 Homogeniser (4.85 m / s, 1 cycle of 20 seconds). Lysate was loaded into a QIAshredder homogenizer column (Qiagen, Cat# 79654) and centrifuged for 2 minutes at maximum speed. Homogenised lysate was transferred to a gDNA eliminator spin column and 25 centrifuged for 30 s at 8000 g. Flow-through was collected, mixed with 600 µL of 70% ethanol, transferred to a RNeasy spin column and centrifuged for 15 s at 8000 g. Flow-through was discarded and RNeasy Mini spin column was loaded with 700 µL of Buffer RW1 and centrifuged for 15 s at 8000 g. Flow-through was discarded and RNeasy column was washed with 500 µL of Buffer RPE and centrifuged for 15 s at 8000 g. Flow-through was discarded and RNeasy column was washed again with30 500 µL of Buffer RPE and centrifuged for 2 min at 8000 g. RNA was eluted by adding 30 µL of RNase- free water into the spin column and centrifuging for 1 min at 8000 g. Real-time quantitative PCR (qRT- PCR): First strand cDNA was synthesised using SuperScript® III First-Strand Synthesis System (Thermo Fisher Scientific) following manufacturer’s recommendations. Briefly, 0.6 μg of total RNA were incubated with 5 µM of oligo (dT)20 and 1 mM of dNTP mix at 65 °C for 5 min. RT Buffer, 5 mM MgCl2, 35 10 mM DTT, 2 U / µL of RNase OUT and 10 U / µL of SuperScript III RT were added to the mix and incubated at 50 °C for 50 min, followed by 5 min at 85 °C. Quantitative PCR was performed using TaqMan® gene expression assay (Thermo Fisher Scientific).4.5 µL of cDNA were combined with 5.5 µL of TaqMan™ Fast Advanced Master Mix containing the TaqMan probe (Thermo Fisher Scientific, Hs00171042_m1) and analysed in a LightCycler® 480 Real-time PCR System (Roche). As an internal 40 control, gene expression was normalised to GAPDH (Thermo Fisher Scientific, Hs02786624_g1) and relative expression was calculated as relative quantification (RQ = 2−ΔΔCt).See figure 35. 100 x

[0084] This demonstrated the superior potency of ELN28-135v2-01 in blocking the production of CXCL10, as measured by qPCR. 101 x

Claims

Claims 1. A compound of formula (I): 5 (I) wherein: Y is a conjugating group; 10 D is a bond or a spacer; Z is an enzyme cleavable linker; M is a self-immolative linker; and X is an immunomodulatory agent; 15 or a pharmaceutically acceptable salt thereof.

2. The compound of claim 2, wherein Z is an elastase cleavable linker 3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, 20 wherein Z is a peptide comprising 2 to 10 amino acid residues, preferably 2 to 4 amino acid residues.

4. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Z is a peptide comprising 3 amino acid residues, optionally wherein Z comprises alanine, valine, serine, glycine, leucine and / or isoleucine. 25 5. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Z comprises: -Gly-Pro-Val-, -Ala-Pro-Val-, -His-Pro-Val-, -Asn-Pro-Val-, and / or -Nva-Pro-Val-, preferably wherein Z is: -Gly-Pro-Val-, -Ala-Pro-Val-, -His-Pro-Val-, -Asn-Pro-Val-, or -Nva-Pro-Val-. 30 6. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Z comprises -Asn-Pro-Val-, preferably wherein Z is -Asn-Pro-Val- 7. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein M is: 35wherein m is 1 to 5; and each Mi is a self-immolative group independently selected from: 102 xwherein J is C4-14 aryl or 5-14 membered heteroaryl, wherein the aryl and heteroaryl may be optionally substituted 5 by one or more RJ; wherein each RJis independently selected from halo, -CN, -NO2, C1-12 alkyl, C2-12 alkenyl, -OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 alkyl, -N(-C1-12 alkyl)2, -S-C1-12 alkyl, -O-C2-12 alkenyl, -NH-C2-12 alkenyl, -S-C2-12 alkenyl, -NHC(O)-C1-12 alkyl, -OC(O)-C1-12 alkyl, C4-14 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, 3- 14 membered heterocyclyl,10 W is NH, O, S, or CONH; k is 0, 1 or 2; p is 0, 1 or 2; each RBis independently selected from H or C1-12 alkyl; and q is 1 or 2, 15 or a pharmaceutically acceptable salt thereof.

8. The compound of according to claim 7, or a pharmaceutically acceptable salt thereof, wherein J is phenyl, naphthyl, biphenyl, or coumarin, optionally substituted by one or more RJ. 20 9. The compound of according to claim 7 or claim 8, or a pharmaceutically acceptable salt thereof, wherein each RJis independently selected from C1-12 alkyl, OH, NH2, -SH, -O-C1-12 alkyl, -NH-C1-12 alkyl, - N(-C1-12 alkyl)210. The compound of according to any one of claims 7 to 9, or a pharmaceutically acceptable salt 25 thereof, wherein each RBis independently selected from H, methyl or ethyl.

11. The compound of according to any one of claims 7 to 10, or a pharmaceutically acceptable salt thereof, wherein m is 1 to 3. 30 12. The compound of according to any one of claims 7 to 11, or a pharmaceutically acceptable salt thereof, wherein k is 0 or 1 and p is 0 or 1. 103 x13. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein M comprises:

5. 10 14. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:or a pharmaceutically acceptable salt thereof. 15 15. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Y comprises a maleimide, thiol, alkyne, azide, tetrazine, strained cycloalkene, N- hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl ester, haloacetamide, hydroxylamine, and / or phosphinoester. 20 16. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Y comprises maleimide, optionally wherein Y is:. 25 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable saltthereof, wherein Y comprises 2-bromoacetamide, optionally wherein Y is: . 104 x18. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein D comprises one or more substituted or unsubstituted: alkylene, alkenylene, alkynylene, arylene, heteroarylene, heteroatoms, or combinations thereof, optionally 5 wherein D comprises substituted or unsubstituted: alkylene, alkenylene, alkynylene, polyalkylene glycol, polyamine, polyamide, polyester, or combinations thereof.

19. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein D comprises: C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, polyalkylene glycol having 1-1010 repeat units, polyamine having 1-10 repeat units, polyamide having 1-10 repeat units, polyester having 1- 10 repeat units, or combinations thereof.

20. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein D comprises polyalkylene glycol having 1-10 repeating units, optionally 15 wherein D comprises polyethylene glycol having 1-10 repeating units.

21. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein D is –(CH2-CH2-O)1-10-RC-C(O)-, wherein RCis selected from a bond, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, and combinations thereof, preferably wherein RCis–-(CH2)1-10. 20 22. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein X is an immunomodulatory agent, optionally a signalling modulator, a cell trafficking modulator, a nucleic acid sensing modulator, a mitochondrial modulator, or protein degradation pathway modulator. 25 23. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein X is a Janus kinase inhibitor, preferably a reversible Janus kinase inhibitor.

24. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein X is selected from compounds (1) to (18): 30105 xand pharmaceutically acceptable salts thereof.

25. The compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein X is 5 selected from compounds (1) to (12), or a pharmaceutically acceptable salt thereof, optionally wherein X is compound (1) or (3), or a pharmaceutically acceptable salt thereof.

26. The compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula: 10 15107 x5or a pharmaceutically acceptable salt thereof.

27. A composition comprising the compound according to any preceding claim, or a pharmaceutically acceptable salt thereof. 10 28. The composition according to claim 27, for use in therapy. 110 x29. The composition comprising the compound according to any one of claims 27 or 28, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease or condition. 5 30. A method of treatment of a disease in a patient comprising administrating to said patient the composition comprising the compound of claim 27, or a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 1 to 26, or composition of claim 27, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition. 10 32. The compound or composition for use of claim 31, wherein the disease or condition is selected from the group comprising an inflammatory disease or condition, an auto-immune disease or condition and cancer. 15 33. A conjugate of formula (II):or a pharmaceutically acceptable salt thereof, wherein 20 D, Z, M and X are as defined in any one of the preceding claims; Y’ is a linking group; A is a specific binding molecule; and n is 1 to 10. 25 34. The conjugate of claim 33, or a pharmaceutically acceptable salt thereof, wherein Y’ is formed by a reaction between (i) maleimide, a thiol, alkyne, azide, tetrazine, strained cycloalkene, N- hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl ester, haloacetamide, hydroxylamine, or a phosphinoester; and (ii) a thiol, amino, hydroxy, alkyne, azide, tetrazine, strained cycloalkene, or a phosphinoester. 30 35. The conjugate of claim 33 or claim 34, or a pharmaceutically acceptable salt thereof, wherein Y’ comprises succinimide, triazole, cyclooctapyridazine, ester, amide, carbamate, and / or carbonate.

36. The conjugate of any one of claims 33 to 35, or a pharmaceutically acceptable salt thereof, 35 wherein Y’ is:. 111 xor wherein Y’ is:. 5 37. The conjugate of any one of claims 33 to 36, wherein the specific binding molecule comprises a reactive cysteine for conjugation.

38. The conjugate of claim 37, wherein the reactive cysteine is part of an alanine motif represented by the amino acid formula ACA or AACAA and wherein the cysteine residue is available for conjugation 10 to a substrate.

39. The conjugate of any of claims 33 to 38, wherein the specific binding molecule is selected from the group comprising a VNAR domain, a VNAR-Fc fusion, an immunoglobulin or antibody, an immunoglobulin Fc region, an immunoglobulin Fab region, a Fab’, a Fv, a Fv-Fc, a single chain Fv (scFv), 15 scFv-Fc, (scFv)2, a diabody, a triabody, a tetrabody, a bispecific t-cell engager (BiTE), an intein, a single domain antibody (sdAb), a VH domain, or a scaffold protein.

40. The conjugate of any one of claims 33 to 39, wherein the specific binding molecule comprises at least one VNAR domain, optionally , wherein the specific binding molecule comprises two or more VNAR 20 domains.

41. The conjugate of claim 40, wherein each of the two or more VNAR domains bind to the same or different epitopes of one or more specific antigens 25 42. The conjugate of any one of claims 39 to 41, wherein the VNAR domain(s) comprises an amino acid sequence represented by the formula: FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4.

43. The conjugate of any one of claims 40 to 42, further comprising a spacer sequence between the 30 VNAR domains, optionally, wherein the spacer sequence is derived from an immunoglobulin Fc region.

44. The conjugate of claim 43, wherein the spacer sequence is derived from a human immunoglobulin Fc region. 35 45. The conjugate of claim 43 or claim 44, wherein the Fc region has been modified to introduce one of more reactive cysteines for conjugation.

46. The conjugate of any one of claims 33 to 46, wherein the specific binding molecule binds an antigen selected from the group comprising of a cytokine, a growth factor, an enzyme, a hormone, a cell 112 xsurface associated molecule, a cell-surface membrane component, an intracellular molecule, an extracellular matrix component, a stromal antigen, a serum protein, a skeletal antigen, a microbial antigen, or an antigen from a normally immune-privileged location. 5 47. The conjugate of claim 46, wherein the antigen is selected from the group comprising IL23, TNFα, TL1A, integrin α4β7, IL17A and IL17F.

48. The conjugate of any one of claims 33 to 47, wherein the specific binding molecule binds TNFa or IL23, optionally IL23p40, optionally wherein the specific binding molecule is an anti-TNF VNAR or 10 antibody.

49. The conjugate of any one of claims 33 to 49, wherein the specific binding molecule comprises at least one VNAR domain, and wherein the at least one VNAR domain comprising the following CDRs and hyper-variable regions (HV): 15 CDR1: HCATSS or NCGLSS HV2: TNEESISKG HV4: SGSKS or EGSKS CDR3: ECQYGLAEYDV or SWWTQNWRCSNSDV or a functional variant thereof with a sequence identity of at least 60%. 20 50. The conjugate of claim 49, wherein the at least one VNAR domain comprises the amino acid sequence of SEQ ID NOs: 1, 12 to 20, 31 to 38, 40 to 53, 58 to 61, 66 to 68, or a functional variant thereof with a sequence identity of at least 60%, or wherein the conjugate comprises two or more VNAR domains, and wherein the two or more VNAR 25 domains comprises the amino acid sequence of SEQ ID NOs: 1, 12 to 20, 31 to 38, 40 to 53, 58 to 61, 66 to 68, or a functional variant thereof with a sequence identity of at least 60%.

51. The conjugate of any one of claims 33 to 50, wherein the specific binding molecule comprises at least one VNAR domain and wherein the VNAR domain is humanized or de-immunized. 30 52. The conjugate of any one of claims 49 to 51, wherein the VNAR domain comprises the amino acid sequence of SEQ ID NO: 1, 12 to 20, or 31 to 38 or a sequence with at least 60% identity thereto, optionally, wherein two or more of the VNAR domains have an amino acid sequence selected from the group comprising SEQ ID NOs: 1, 12 to 20, 31 to 38, 40 to 53, 58 to 61, 66 to 68 or a functional variant 35 thereof with a sequence identity of at least 60%.

53. The conjugate according to any one of claims 33 to 52, wherein: a. A comprises a VNAR or antibody or function fragment thereof, b. Y’ comprise a linking group according to claim 35, 40 c. D comprises a spacer or bond according to claim 20, d. Z comprises an enzyme cleavable linker according to any of claims 5 or 6, 113 xe. M comprises a self-immolative linker according to any of claims 7 to 11, f. X comprises an immunomodulatory agent according to claim 24, and g. n is 1 to 10. 5 54. The conjugate of any of claims 33 to 53, wherein each of A and X have independent activity after Z is cleaved.

55. A composition comprising the conjugate of any one of claims 33 to 54 and optionally at least onepharmaceutically acceptable carrier or diluent. 10 56. The conjugate of any one of claims 33 to 54 or the composition of claim 55, for use in therapy.

57. The conjugate of any one of claims 33 to 54, or the composition of claim 55, in the manufacture of a medicament for the treatment of a disease or condition. 15 58. A method of treatment of a disease in a patient comprising administrating to said patient a therapeutically effective dosage of a pharmaceutical composition of claim 55.

59. The conjugate of any one of claims 33 to 54, or the composition of claim 55, for use in a method 20 of treating a disease.

60. The method of claim 58 or the use of claim 59 wherein the disease is an autoimmune disease or condition, or an inflammatory disease or condition, optionally wherein the autoimmune or inflammatory disease is selected frominflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, 25 rheumatoid arthritis, Psoriatic arthritis, Enteropathic Arthritis, Spondyloarthritis, Sjogren’s syndrome, Psoriasis, Giant cell arteritis, Behçet’s disease, ANCA-associated vasculitis, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), Hidradenitis Suppurativa, Psoriatic Arthritis, Axial Spondyloarthritis, Non-infectious uveitis, Juvenile idiopathic arthritis, Pyoderma gangrenosum and Takayasu’s arteritis. 30 61. Use of the conjugate of any one of claims 33 to 54, for site specific delivery of an active agent.

62. The use of claim 61, wherein the site is an inflammatory microenvironment. 35 114 x

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