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WO 2019/012015 Al 17 January 2019 (17.01.2019) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2019/012015 Al 17 January 2019 (17.01.2019) W !P O PCT (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, C07K 16/28 (2006.01) A61K 39/00 (2006.01) KM, ML, MR, NE, SN, TD, TG). (21) International Application Number: Declarations under Rule 4.17: PCT/EP2018/068856 — of inventorship (Rule 4.1 7(iv)) (22) International Filing Date: Published: 11 July 2018 ( 11.07.2018) — with international search report (Art. 21(3)) (25) Filing Language: English — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (26) Publication Langi English amendments (Rule 48.2(h)) (30) Priority Data: 171 1191 .5 12 July 2017 (12.07.2017) GB 1717786.6 30 October 20 17 (30. 10.201 7) GB (71) Applicant: IONTAS LIMITED [GB/GB]; 82B High Street, Sawston Cambridgeshire CB22 3HJ (GB). (72) Inventors: KARATT VELLATT, Aneesh; 82B High Street, Sawston Cambridgeshire CB22 3HJ (GB). MC- CAFFERTY, John; 82B High Street, Sawston Cam bridgeshire CB22 3HJ (GB). SURADE, Sachin Badri- nath; 82B High Street, Sawston Cambridgeshire CB22 3HJ (GB). LUETKENS, Tim; 1163 E 200 S., Salt Lake City, Utah 84101 (US). MASTERS, Edward William; 82B High Street, Sawston Cambridgeshire CB22 3HJ (GB). DYSON, Michael Richard; 82B High Street, Sawston Cambridgeshire CB22 3HJ (GB). BELL, Damian Colin; 82B High Street, Sawston Cambridgeshire CB22 3HJ (GB). (74) Agent: SUTCLIFFE, Nicholas et al; Mewburn Ellis LLP, City Tower, 40 Basinghall Street, London Greater London EC2V 5DE (GB). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, < EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, o © (54) Title: POTASSIUM CHANNEL INHIBITORS (57) Abstract: Binding members for potassium channel Kvl .3 and their use in medicine, including for treatment of autoimmune o conditions, metabolic disorders and obesity. Binding members comprise a fusion protein containing a Kvl .3-binding peptide, e.g., HsTx, ShK or KTX ("donor diversity scaffold domain") inserted within an antibody variable domain ("recipient diversity scaffold domain"), paired with a partner domain (e.g., antibody variable domain). Potassium Channel Inhibitors Field This invention relates to binding members with altered diversity scaffold domains, the production of libraries of such binding members and the selection and screening of binding members from such libraries. The invention also relates binding members that inhibit ion channels, especially potassium channels, and their use in therapy. Background One of 80 potassium channel genes found in the human genome, Kvl .3 is a voltage-gated ion channel that opens or gates in response to cell membrane depolarisations, allowing the efflux of potassium ions (from inside to outside the cell). The Kvl.3 channel plays a key role in controlling the electrical signaling across cell membranes. In the immune system, the activity of T-effector memory (TEM) cells is modulated by activity of Kvl.3 ion channels in the cell membrane 160 . Over-activity of Kvl .3 ion channels has been shown to be a key driver of the aberrant activity in TEM cells in autoimmune diseases, including psoriasis, rheumatoid arthritis (RA), multiple sclerosis (MS) and type 1 diabetes 162 163 . Autoimmune activity has also been observed in Parkinson's disease: a-synuclein, a protein that accumulates in the brains of PD patients, activates TEM cells 163 , causing auto-reactivity to neuronal cells in PD patients. The effects of autoimmune diseases in a number of pre-clinical animal model studies have been shown to be reduced by Kvl.3 inhibiting molecules, as summarised in Table 30. (Tables are annexed to the end of the present description.) In human clinical trials, an engineered variant of ShK knottin toxin (Dalazatide, a Kvl .3 blocker derived from sea anemone venom) is currently being investigated in phase 2 clinical trials for psoriasis. Dalazatide has shown excellent safety and clinical proof of concept in a phase 1psoriasis trial. Thus, blockade of Kvl.3 represents a potential point for therapeutic intervention that could selectively ameliorate pathogenic TEM cells mediating autoimmune disorders, without impairing the function of na ve and central memory T cells involved in normal immune responses. Further areas that have been targeted by Kvl .3 channel inhibition are obesity 164 and metabolic disorders due to Kvl.3 channel activity in glucose homeostasis 165 . Increased energy expenditure and concomitant weight loss is proposed by blocking Kvl.3 ion channels on brown adipose tissue cells and skeletal muscle, stimulating insulin sensitivity, increasing glucose uptake and thermogenesis 166 . Obesity-related and other metabolic disorders are numerous including, among others: Type 2 diabetes, coronary heart disease, hypertension, hypercholesterolaemia (including familial variant), hyperlipidaemia, hypertriglyceridaemia, lipidodystrophy, insulin resistance, glucose intolerance and metabolic syndrome. With these key roles in autoimmune disease, obesity and metabolic disorders, much effort and expenditure has been spent by pharmaceutical and biotechnology companies in a quest to generate selective molecules that inhibit Kvl.3 ion channels. However, there has been little success. Small molecules are limited in their selectivity by the chemical space available: PAP-1 is one of the few small molecules that has shown activity in animal models (see Table 30). Larger biological molecules such as antibodies would in principle offer greater potential for deriving selectivity, but generation of antibodies against voltage-gated ion channels like Kvl.3 is particularly challenging due to the limited extracellular peptide sequences available for binding. The structure of the Kv channel is as follows: four subunits, with each subunit having six a - helical transmembrane spanning segments (S1-S6), form a homotetrameric structure, circling and forming a central ion channel or pore, allowing flux of potassium ions across the lipid cell membrane. The first four transmembrane segments in each domain (S1-S4) form the voltage-sensing domain (VSD). The S4 transmembrane segment contains several positively charged amino acids which sense changes in membrane voltage. The S5 and S6 transmembrane segments are linked by peptide loops that form the pore and ion selectivity filter. The N- and C-termini are intracellular. From this molecular structure, based on numerous structural studies, including several atomic-scale voltage-gated potassium channel crystal structures158 159, it is clear that much of the Kvl .3 protein is buried in lipid membrane or found intracellularly; or, the externally facing peptide regions of the channel are limited to unstructured peptide sequences linking transmembrane segments (e.g., externally facing peptide loops link transmembrane segments: SI to S2, S3 to S4 and the re-entrant pore forming loop between S5 and S6). Consequently, these limited sequences of external peptide loops make it very challenging to generate antibodies to Kvl.3 channels. In addition, structural conservation of the external peptide loops across different ion channels also means that antibodies or other molecules binding to these loops may lack specificity or selectivity for Kvl.3, potentially resulting in off-target effects of the binding molecules, which is undesirable in a candidate therapeutic drug. For example, other voltage gated potassium channels (Kvl.x) such as Kvl.l are structurally related to Kvl.3, and selective inhibition of Kvl.3 over Kvl.l is desirable in a therapeutic molecule. In nature, small cysteine rich ion channel blocking peptide knottins are found in a multitude of venomous species across the animal kingdom (e.g., spiders) 145 148. However, despite a vast collection of naturally occurring knottin blockers of ion channels only a few molecules possess sufficient specificity and potency for therapeutic development. Ziconitide (Prialt), a synthetic version of the knottin toxin CmMVIIa that inhibits Cav2.2 ion channels, has been approved by the FDA and EMA to treat chronic neuropathic, post-operative and cancer pain. Several drug discovery programmes have used knottin toxins in native, modified or derived forms to target ion channels aimed to treat disease states, e.g., Kvl.3 knottin-based molecules as potential treatments for autoimmunity 169 and Navl.7 knottin-based molecules have been developed to potentially treat pain 149 151. However, efforts to improve the specificity and potency of naturally occurring knottins are often hampered by their limited compatibility to robust directed evolution technologies such as phage display (i.e. they are technically challenging to engineer). Moreover, even the knottins that have been engineered to enhance specificity, such as Dalazatide/ShK-186 (see above) suffer from a short in vivo half-life due to rapid renal clearance 152 .
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