INTERLEUKIN-18 RECEPTOR BINDING POLYPEPTIDES AND USES THEREOF

1 - 255 . (canceled)

256 . A polypeptide comprising an interleukin 18 (IL-18) receptor (IL-18R) binding moiety, wherein the IL-18R binding moiety comprises an IL-18R alpha binding moiety; and wherein the IL-18R alpha binding moiety comprises the amino acid sequence of X261-X262-X263-X264-X265-X266-X267-X268-X269-X270-X271-X272-X273-X274-X275-X276-X277-X278-X279-X280-X281-X282-X283-X284, wherein

X261 is G or absent;

X262 is G or absent;

X263 is any amino acid;

X264 is any amino acid;

X265 is L, M, R, S, T, Y, Q, W, I, V, F, A, G, or P;

X266 is L, M, I, T, S, V, F, Y, W, A, G, or P;

X267 is C;

X268 is F, S, or W;

X269 is R, V, L, M, H, W, F, I, Y, A, G, P, S, or T;

X270 is P;

X271 is W, or F;

X272 is E, P, Q, N, or S;

X273 is D, G, or E;

X274 is V, L, I, T, F, M, Y, W, A, G, P, or S;

X275 is E, A, D, G, F, or M;

X276 is D;

X277 is L, F, H, R, or S;

X278 is V, I, F, L, M, Y, W, A, G, P, S, or T;

X279 is C;

X280 is T, M, I, W, or S;

X281 is E, G, S, T, A, W, D, or Y;

X282 is any amino acid;

X283 is G or absent; and

X284 is G or absent (SEQ ID NO: 476).

257 . The polypeptide of claim 256 , wherein

X263 is H, E, V, N, L, R, S, T, F, or D;

X264 is D, R, Q, H, Y, S, K, or T; and

X282 is D, V, R, N, Q, T, S, L, or Y.

258 . The polypeptide of claim 256 , wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of

(SEQ ID NO: 53)

GGHDLLCFRPWEDVEDLVCTEDGG;

(SEQ ID NO: 54)

GGERLMCSVPWEDVADFICMGDGG;

(SEQ ID NO: 55)

GGVQMICWLPWPDVDDHICTEVGG;

(SEQ ID NO: 56)

GGNHRICWLPWEDVDDRICISRGG;

(SEQ ID NO: 57)

GGLYSMCFRPWEDVEDFICTTNGG;

(SEQ ID NO: 58)

GGRSTLCWVPWEGLGDRICTAQGG;

(SEQ ID NO: 59)

GGSYLTCWVPWQGLDDRFCTETGG;

(SEQ ID NO: 60)

GGTDYTCFVPWNDVFDRVCTWSGG;

(SEQ ID NO: 61)

GGSHLICWMPWPEVEDRLCTDSGG;

(SEQ ID NO: 62)

GGTKLMCWVPWQDVDDFICTSLGG;

(SEQ ID NO: 63)

GGFYQSCWHPWEDIDDHICTYSGG;

(SEQ ID NO: 64)

GGFKLSCWVPWQDTEDRICWTVGG;

(SEQ ID NO: 65)

GGSHWICWWPFSDTEDHICSEYGG;

(SEQ ID NO: 66)

GGSRLVCWVPFEDFMDSICTEYGG;

(SEQ ID NO: 67)

GGDTYTCFFPWPGLDDHFCTYSGG;

or

(ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of (i).

259 . The polypeptide of claim 256 , wherein X261, X262, X283, and X284 are absent and the IL-18R alpha binding moiety comprises (i) the amino acid sequence of

(SEQ ID NO: 68)

HDLLCFRPWEDVEDLVCTED;

(SEQ ID NO: 69)

ERLMCSVPWEDVADFICMGD;

(SEQ ID NO: 70)

VQMICWLPWPDVDDHICTEV;

(SEQ ID NO: 71)

NHRICWLPWEDVDDRICISR;

(SEQ ID NO: 72)

LYSMCFRPWEDVEDFICTTN;

(SEQ ID NO: 73)

RSTLCWVPWEGLGDRICTAQ;

(SEQ ID NO: 74)

SYLTCWVPWQGLDDRFCTET;

(SEQ ID NO: 75)

TDYTCFVPWNDVFDRVCTWS;

(SEQ ID NO: 76)

SHLICWMPWPEVEDRLCTDS;

(SEQ ID NO: 77)

TKLMCWVPWQDVDDFICTSL;

(SEQ ID NO: 78)

FYQSCWHPWEDIDDHICTYS;

(SEQ ID NO: 79)

FKLSCWVPWQDTEDRICWTV;

(SEQ ID NO: 80)

SHWICWWPFSDTEDHICSEY;

(SEQ ID NO: 81)

SRLVCWVPFEDFMDSICTEY;

or

(SEQ ID NO: 82)

DTYTCFFPWPGLDDHFCTYS;

or

(ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of (i).

260 . The polypeptide of claim 256 , wherein X261 and X262 are absent and the IL-18R alpha binding moiety comprises (i) the amino acid sequence of GGICWVPFHYLDELMCTGG (SEQ ID NO: 2) or an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of SEQ ID NO: 2.

261 . A polypeptide comprising an interleukin 18 (IL-18) receptor (IL-18R) binding moiety, wherein the IL-18R binding moiety comprises an IL-18R alpha binding moiety; and wherein the IL-18R alpha binding moiety comprises the amino acid sequence of X61-X62-X63-X64-X65-X66-X67-X68-X69-X70-X71-X72-X73-X74-X75-X76-X77-X78-X79-X80-X81-X82-X83-X84, wherein:

(i) one or more of X61, X62, X63, X64, X65, X80, X81, X82, X83, and X84 are optional,

X61 is G or absent;

X62 is G or absent;

X63 is absent or any amino acid;

X64 is G, N, S, V, D, Y, E, A or absent;

X65 is M, A, P, T, W, F, G, Y, F, S, V, H, D, K, L, I, or absent;

X66 is I, V, Y, A, G, P, T, S, F, M, L, or W;

X67 is Q, E, or D;

X68 is C;

X69 is L, F, W, A, or Y;

X70 is W or Y;

X71 is E or S;

X72 is P;

X73 is L, G, H, T, S, or Y;

X74 is W, H, E, Q, or A;

X75 is E, V, Y, H, or L;

X76 is C or W;

X77 is W or C;

X78 is T, I, S, M, or W;

X79 is D, P, or T;

X80 is G, S, H, I, T, A, or absent;

X81 is M, W, A, P, S, T, G, L, V, F, Y, Q, I, or absent;

X82 is V, F, Y, A, S, G, M, I, T, N, F, D, L, Q, W, P, or absent;

X83 is G or absent; and

X84 is G or absent (SEQ ID NO: 485).

262 . The polypeptide of claim 261 , wherein

X63 is any amino acid;

X64 is N, D, or E;

X65 is D, I, L, M, V, F, Y, W, A, G, P, S, T, H, or Y;

X66 is I, L, M, V, F, Y, W, A, G, P, S, or T;

X67 is E, or D;

X68 is C;

X69 is F;

X70 is W or Y;

X71 is S;

X72 is P,

X73 is G or S;

X74 is Q;

X75 is E, V, or Y;

X76 is W;

X77 is C;

X78 is I;

X79 is P;

X80 is S;

X81 is I, L, M, V, F, Y, W, A, G, P, S, or T; and

X82 is I, L, M, V, F, Y, W, A, G, P, S, or T (SEQ ID NO: 460).

263 . The polypeptide of claim 261 , wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of

(SEQ ID NO: 97)

GGANYLECFYSPTQEWCIPHLMGG;

(SEQ ID NO: 98)

GGESFLECFYSPAEWCIPSVIGG;

(SEQ ID NO: 99)

GGFVFMECFWSPSQEWCIPSFTGG;

(SEQ ID NO: 100)

GGGVSFDCFWSPGQYWCIPDYNGG;

(SEQ ID NO: 101)

GGLDVMECFWSPSQVWCMPSVFGG;

(SEQ ID NO: 102)

GGLYHFECAWSPYQHWCWPSQDGG;

(SEQ ID NO: 103)

GGREDMECFWSPGQVWCIPSYLGG;

(SEQ ID NO: 104)

GGREKLECFWSPGQEWCIPILQGG;

(SEQ ID NO: 105)

GGRGFLECFYSPGQEWCIPSIWGG;

(SEQ ID NO: 106)

GGSALLECFYSPTQEWCIPTLWGG;

(SEQ ID NO: 107)

GGSSYSECFWSPGQLWCIPSFPGG;

(SEQ ID NO: 108)

GGVSIFECFYSPTQEWCIPSFIGG;

(SEQ ID NO: 109)

GGWDILECFYSPGQEWCIPSFLGG;

or

(SEQ ID NO: 110)

GGYGSWECYWSPSEEWCIPAQLGG;

or

(ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to any one of (i).

264 . The polypeptide of claim 261 , wherein X61, X62, X83, and X84 are absent; and

wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of

(SEQ ID NO: 111)

ANYLECFYSPTQEWCIPHLM;

(SEQ ID NO: 112)

ESFLECFYSPSAEWCIPSVI;

(SEQ ID NO: 113)

FVFMECFWSPSQEWCIPSFT;

(SEQ ID NO: 114)

GVSFDCFWSPGQYWCIPDYN;

(SEQ ID NO: 115)

LDVMECFWSPSQVWCMPSVF;

(SEQ ID NO: 116)

LYHFECAWSPYQHWCWPSQD;

(SEQ ID NO: 117)

REDMECFWSPGQVWCIPSYL;

(SEQ ID NO: 118)

REKLECFWSPGQEWCIPILQ;

(SEQ ID NO: 119)

RGFLECFYSPGQEWCIPSIW;

(SEQ ID NO: 120)

SALLECFYSPTQEWCIPTLW;

(SEQ ID NO: 121)

SSYSECFWSPGQLWCIPSFP;

(SEQ ID NO: 122)

VSIFECFYSPTQEWCIPSFI;

(SEQ ID NO: 123)

WDILECFYSPGQEWCIPSFL;

or

(SEQ ID NO: 124)

YGSWECYWSPSEEWCIPAQL;

or

(ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to any one of (i).

265 . The polypeptide of claim 261 , wherein X61, X62, X83, and X84 are absent; and wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of GGFFECFYSPGHEWCIPSGG (SEQ ID NO: 126)

or (ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of (i).

266 . The polypeptide of claim 261 , wherein X61, X62, X63, X64, X81, X82, X83, and X84 are absent; and wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of FFECFYSPGHEWCIPS (SEQ ID NO: 127) or (ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of (i).

267 . The polypeptide of claim 261 , wherein X61, X62, X63, X82, X83, and X84 are absent; and wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of GGMECWYSPHEVWCSTGG (SEQ ID NO: 128) or (ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of (i).

268 . The polypeptide of claim 261 , wherein X61, X62, X63, X64, X65, X80, X81, X82, X83, and X84 are absent; and wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of MECWYSPHEVWCST (SEQ ID NO: 129) or (ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of (i).

269 . A polypeptide comprising an interleukin 18 (IL-18) receptor (IL-18R) binding moiety, wherein the IL-18R binding moiety comprises an IL-18R alpha binding moiety; and wherein the IL-18R alpha binding moiety comprises the amino acid sequence of X105-X106-X107-X108-X109-X110-X111-X112-X113-X114-X115-X116-X117-X118-X119-X120-X121-X122-X123-X124-X125-X126-X127-X128, wherein:

X105 is G or absent;

X106 is G or absent;

X107 is G or Q or absent;

X108 is any amino acid or absent;

X109 is any amino acid;

X110 is L or C;

X111 is H, F, or W;

X112 is C, W, Q, or I;

X113 is F, V, D, or S;

X114 is E, N, Y, D, or L;

X115 is S, D, or P;

X116 is R, M, or G;

X117 is any amino acid;

X118 is any amino acid;

X119 is M, F, Y, W, A, G, P, S, T, D, V, L, or I;

X120 is I, L, M, F, Y, A, G, P, S, T, F, H, W, V, or Y;

X121 is C;

X122 is any amino acid;

X123 is any amino acid or absent;

X124 is any amino acid or absent;

X125 is any amino acid or absent;

X126 is S or absent;

X127 is G or absent; and

X128 is G or absent (SEQ ID NO: 486).

270 . The polypeptide of claim 269 , wherein

X108 is any amino acid;

X109 is any amino acid;

X110 is L or C;

X111 is H or W;

X112 is C or Q;

X113 is F or D;

X114 is E, N, or D;

X115 is S or P;

X116 is R or G;

X117 is any amino acid;

X118 is any amino acid;

X119 is D, I, L, M, V, F, Y, W, A, G, P, S, or T;

X120 is I, L, M, V, F, Y, W, A, G, P, S, T, or H;

X121 is C;

X122 is any amino acid;

X123 is any amino acid;

X124 is any amino acid; and

X125 is any amino acid (SEQ ID NO: 463).

271 . The polypeptide of claim 269 , wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of GGQTFLHCFESRGIDWCIPWKSGG (SEQ ID NO:

176 . or (ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of (i).

272 . The polypeptide of claim 269 , wherein X105, X106, X127, and X128 are absent; and wherein the IL-18R alpha binding moiety comprises (i) the amino acid sequence of QTFLHCFESRGIDWCIPWKS (SEQ ID NO: 177) or (ii) an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to the amino acid sequence of (i).

273 . The polypeptide of any one of claims 261 , wherein the IL-18R binding moiety comprises a first IL-18R alpha binding moiety and a second IL-18R alpha binding moiety.

274 . The polypeptide of claim 273 , wherein the first IL-18R alpha binding moiety comprises the amino acid sequence of

GGREDMECFWSPGQVWCIPSYLGG-CONH2 (SEQ ID NO: 403);

REDMECFWSPGQVWCIPSYL-CONH2 (SEQ ID NO: 405); or an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to SEQ ID NO: 403 or 405; and wherein the second IL-18R alpha binding moiety comprises the amino acid sequence of

YLDTCWVPFHYVNYLMCNVE (SEQ ID NO: 44);

REDMECFWSPGQVWCIPSYL (SEQ ID NO: 117);

REDMECFWSPGQVWCIPSYLGG (SEQ ID NO: 162);

YLDTCWVPFHYVNYLMCNVEGG (SEQ ID NO: 480); or an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to any one of SEQ ID NOs: 44, 117, 162, and 480.

275 . The polypeptide of claim 273 , wherein the polypeptide is in a N-N orientation, a N-C orientation, a C-N orientation, or a C-C orientation.

276 . The polypeptide of claim 273 , further comprising a linker between the first IL-18R alpha binding moiety and the second IL-18R alpha binding moiety, wherein the linker comprises SEQ ID NO: 401, SEQ ID NO: 401, formula I, formula II, formula III, formula IV, formula IV, or formula VI.

277 . The polypeptide of claim 261 , wherein the IL-18R binding moiety comprises a IL-18R alpha binding moiety and a IL-18R beta binding moiety.

278 . The polypeptide of claim 277 , wherein the IL-18R alpha binding moiety comprises the amino acid sequence of

GGREDMECFWSPGQVWCIPSYLGG-CONH2 (SEQ ID NO: 403);

REDMECFWSPGQVWCIPSYL-CONH2 (SEQ ID NO: 405);

GGREDMECFWSPGQVWCIPSYLGGSG-CONH2 (SEQ ID NO: 410);

GGREDMECFWSPGQVWCIPSYLGGSG (SEQ ID NO: 412);

REDMECFWSPGQVWCIPSYLGGS-CONH2 (SEQ ID NO: 419);

REDMECFWSPGQVWCIPSYLGGS (SEQ ID NO: 420); or an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to any one of SEQ ID NOs: 403, 405, 410, 412, 419, and 420; and wherein the IL-18R beta binding moiety comprises the amino acid sequence of

GGTSRLCWYFAGTVPGPCLEAIGG (SEQ ID NO: 224);

TSRLCWYFAGTVPGPCLEAI (SEQ ID NO: 253);

GGLCWYFGGTVRGPCLGG-CONH2 (SEQ ID NO: 404);

GGTSRLCWYFAGTVPGPCLEAIGG-CONH2 (SEQ ID NO: 407);

TSRLCWYFAGTVPGPCLEAI-CONH2 (SEQ ID NO: 408);

GGTSRLCWYFAGTVPGPCLEAI (SEQ ID NO: 409); or an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to any one of SEQ ID NOs: 224, 253, 404, 407, 408 and 409.

279 . The polypeptide of claim 277 , wherein the polypeptide is in a N-N orientation, a N-C orientation, a C-N orientation, or a C-C orientation.

280 . The polypeptide of claim 277 , further comprising a linker between the IL-18R alpha binding moiety and the IL-18R beta binding moiety, wherein the linker comprises SEQ ID NO: 401, SEQ ID NO: 401, formula I, formula II, formula III, formula IV, formula IV, or formula VI.

281 . The polypeptide of claim 261 , wherein the IL-18R binding moiety comprises an IL-18R alpha binding moiety and a peptide, wherein the IL-18R alpha binding moiety comprises the amino acid sequence of GGREDMECFWSPGQVWCIPSYLGG-CONH2 (SEQ ID NO: 403), REDMECFWSPGQVWCIPSYL-CONH2 (SEQ ID NO: 405), or an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to SEQ ID NO: 403 or 405; and wherein the peptide comprises the amino acid sequence of FEWTPGYWQPYALPLL (SEQ ID NO: 483) or an amino acid sequence having 1, 2, 3, or 4 substitution(s), addition(s), and/or deletion(s) relative to SEQ ID NO: 483.

282 . The polypeptide of claim 261 , wherein the IL-18R binding moiety is an IL-18R antagonist.

283 . The polypeptide of claim 261 , wherein the IL-18R binding moiety (a) binds to IL-18R alpha with a K D of less than 10 μM, (b) has an IC50 of less than 10 μM, or a combination of (a) and (b).

284 . The polypeptide of claim 261 , wherein the IL-18R alpha binding moiety (a) does not bind to an IL-18BP or (b) binds to an IL-18BP with a KD that is at least 1,000-fold higher than the KD of the interaction between the IL-18R alpha binding moiety and IL-18R alpha.

285 . A pharmaceutical composition comprising the polypeptide of claim 261 and a pharmaceutically acceptable excipient.

286 . A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 285 , wherein the disease or disorder comprises a cancer, an autoimmune disease, an inflammatory disease or disorder, an infectious disease or disorder, a metabolic disease or disorder, a neurodegenerative disease or disorder, a myocardial infarction, emphysema, psoriasis, a hemophagocytic syndrome, a macrophage activation syndrome, sepsis, acute kidney injury, or a combination thereof.