Single immunoglobulin domain bispecific antibodies against il-10r alpha and beta subunits and methods of use

Abstract

Provided are bispecific antibodies comprising first and second VIIII binding domains that specifically bind to the extracellular domains of interleukin- 10 receptor (IL-10R) alpha subunit (IL-10Rα) and beta subunit (IL-10Rβ), and that selectively suppress activation of myeloid cells and induce minimal or no direct activation of T cells or B cells.

Description

1569-US-NP / WO-PCTSINGLE IMMUNOGLOBULIN DOMAIN BISPECIFIC ANTIBODIES AGAINST IL-10R alpha AND beta SUBUNITS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 LJ. S. C. § 119(e) of U. S. Provisional Application No. 63 / 724,109, filed on November 22, 2024, which is hereby incorporated herein by reference in its entirety for all purposes.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in. XML format and is hereby incorporated by reference in its entirety. Said. XML copy, created on November 7, 2025, is named 1569-US-WO_SL.xml and is 1,039,098 bytes in size.BACKGROUND

[0003] Interleukin- 10 (IL- 10) is an immunoregulatory cytokine that plays a role in limiting excessive inflammation and maintaining tissue homeostasis. Despite its potent immunosuppressive effects on myeloid cells, high concentrations of IL- 10 can paradoxically activate T-cells, B-cells, and natural killer (NK) cells, counterbalancing its immunosuppressive actions in inflammatory conditions. Additionally, the activation of T-cells and B-cells by IL-10 leads to the production of IFN-y, increased levels of IgE, a rise in granulocyte-monocyte progenitor (GMP) cells, and a reduction in red blood cells and platelets. These adverse effects of recombinant IL-10 limit its therapeutic potential for treating inflammatory bowel disease (IBD) and psoriasis.SUMMARY

[0004] In one aspect, provided is a single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa). In some embodiments, the anti-IL-lORa VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively: SEQ ID NOs: 1, 2 and 3 (A01); SEQ ID NOs: 4, 5 and 6 (A06); SEQ ID NOs: 7, 8 and 9 (A09): SEQ ID NOs: 10, 11 and 12 (B07); SEQ ID NOs: 4, 13 and 14 (B08); SEQ ID NOs: 4, 15 and 16 (C09); SEQ ID NOs: 4, 17 and 18 (D08); SEQ ID NOs: 19, 20 and 21 (D14); SEQ ID NOs: 22, 23 and 24 (E07); SEQ1569-US-NP / WO-PCTID NOs: 22, 25 and 27 (huE07); SEQ ID NOs: 22, 27 and 24 (huE07); SEQ ID NOs: 4, 28 and 29 (E15); SEQ ID NOs: 4, 30 and 31 (F09); SEQ ID NOs: 22, 23 and 32 (F10); SEQ ID NOs: 33, 34 and 35 (Fl 1); SEQ ID NOs: 4, 36 and 29 (F21); SEQ ID NOs: 19, 37 and 38 (G22); SEQ ID NOs: 39, 40 and 41 (G23); SEQ ID NOs: 42, 43 and 44 (H22); SEQ ID NOs: 45, 46 and 47 (104): SEQ ID NOs: 4, 48 and 6 (J13): SEQ ID NOs: 4. 49 and 50 (J24); SEQ ID NOs: 19, 51 and 52 (E05); SEQ ID NOs: 19, 37 and 53 (El l) or SEQ ID NOs: 54, 55 and 24 (N16). In some embodiments, the anti-IL-lORa VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively: SEQ ID NOs: 56, 57 and 58 (A01): SEQ ID NOs: 59, 60 and 61 (A06); SEQ ID NOs: 62, 63 and 64 (A09); SEQ ID NOs: 65, 66 and 67 (B07); SEQ ID NOs: 59, 68 and 69 (B08); SEQ ID NOs: 59, 70 and 71 (C09); SEQ ID NOs: 59, 72 and 73 (D08) SEQ ID NOs: 74, 75 and 76 (D14); SEQ ID NOs: 77, 78 and 79 (E07) SEQ ID NOs: 77, 80 and 81 (huE07); SEQ ID NOs: 77, 82 and 79 (huE07); SEQ ID NOs: 59, 83 and 84 (El 5); SEQ ID NOs: 59, 85 and 86 (F09); SEQ ID NOs: 77, 78 and 87 (F10); SEQ ID NOs: 88, 89 and 90 (Ell); SEQ ID NOs: 59, 91 and 84 (F21); SEQ ID NOs: 92, 75 and 93 (G22); SEQ ID NOs: 94, 89 and 95 (G23); SEQ ID NOs: 96, 89 and 97 (H22); SEQ ID NOs: 98, 99 and 100 (104); SEQ ID NOs: 59, 101 and 61 (J13); SEQ ID NOs: 59, 102 and 103 (J24); SEQ ID NOs: 74, 75 and 104 (L05); SEQ ID NOs: 74, 75 and 105 (Lil) or SEQ ID NOs: 106, 107 and 79 (N16). In some embodiments, the anti-IL-lORa VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively: SEQ ID NOs: 108, 109 and 110 (A01); SEQ ID NOs: 111, 112 and 113 (A06); SEQ ID NOs: 114, 115 and 116 (A09); SEQ ID NOs: 117, 118 and 119 (B07): SEQ ID NOs: 111, 112 and 120 (B08); SEQ ID NOs: 111, 121 and 122 (C09); SEQ ID NOs: 111, 121 and 123 (D08); SEQ ID NOs: 124, 125 and 126 (D14); SEQ ID NOs: 127, 128 and 129 (E07); SEQ ID NOs: 127, 130 and 131 (huE07); SEQ ID NOs: 111, 132 and 133 (E15); SEQ ID NOs: 111, 134 and 135 (F09); SEQ ID NOs: 127, 128 and 136 (F10): SEQ ID NOs: 137, 138 and 139 (Fll); SEQ ID NOs: 111, 132 and 133 (F21); SEQ ID NOs: 140, 125 and 141 (G22); SEQ ID NOs: 142, 138 and 143 (G23); SEQ ID NOs: 124, 138 and 144 (H22); SEQ ID NOs: 145, 146 and 147 (104); SEQ ID NOs: 111, 112 and 113 (J13)); SEQ ID NOs: 111, 148 and 149 (J24); SEQ ID NOs: 124, 125 and 150; (L05); SEQ ID NOs: 124, 125 and 151: (Lil) or; SEQ ID NOs: 152, 121 and 129 (N16). In some embodiments, the anti-IL-lORa VHH comprising a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively: SEQ ID NOs: 153, 154 and 155 (A01); SEQ ID NOs: 156, 157 and 158 (A06); SEQ ID NOs: 159, 160 and 161 (A09);1569-US-NP / WO-PCTSEQ ID NOs: 162, 163 and 164 (B07); SEQ ID NOs: 156, 165 and 166 (B08); SEQ ID NOs: 156, 167 and 168 (C09); SEQ ID NOs: 156, 169 and 170 (D08); SEQ ID NOs: 171, 172 and 173 (D14); SEQ ID NOs: 174, 175 and 176 (E07); SEQ ID NOs: 174, 177 and 178 (huE07); SEQ ID NOs: 174, 179 and 176 (huE07): SEQ ID NOs: 156, 180 and 181; (E15); SEQ ID NOs: 156, 182 and 183; (F09); SEQ ID NOs: 174, 175 and 184; (F10); SEQ ID NOs: 185, 186 and 187: (Fl 1); SEQ ID NOs: 709, 186 and 187; (huFl 1); SEQ ID NOs: 156, 188 and 181; (F21); SEQ ID NOs: 189, 190 and 191; (G22); SEQ ID NOs: 192, 193 and 194; (G23); SEQ ID NOs: 195, 196 and 197; (H22); SEQ ID NOs: 198, 199 and 200; (104); SEQ ID NOs: 156, 201 and 158; (J13); SEQ ID NOs: 156, 202 and 203; (J24); SEQ ID NOs: 204, 205 and 206; (L05); SEQ ID NOs: 204, 190 and 207; (LI 1) or; SEQ ID NOs: 208, 209 and 176 (N16). In some embodiments, the anti-IL-lORa VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively: SEQ ID NOs: 22, 23 and 24; (E07; according to Kabat); SEQ ID NOs: 22, 25 and 27; (huE07; according to Kabat); SEQ ID NOs: 22, 27 and 24; (huE07; according to Kabat); SEQ ID NOs: 77, 78 and 79; (E07; according to IMGT); SEQ ID NOs: 77, 80 and 81; (huE07; according to IMGT); SEQ ID NOs: 77, 82 and 79; (huE07; according to IMGT); SEQ ID NOs: 127, 128 and 129; (E07; according to Chothia); SEQ ID NOs: 127, 130 and 131; (huE07; according to Chothia); SEQ ID NOs: 174, 175 and 176; (E07; according to Honegger); SEQ ID NOs: 174, 177 and 178; (huE07; according to Honegger) or SEQ ID NOs: 174, 179 and 176; (huE07; according to Honegger). In some embodiments, the anti-IL-lORa VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively: SEQ ID NOs: 33, 34 and 35 (Fl 1; according to Kabat); SEQ ID NOs: 88, 89 and 90 (Fl 1; according to IMGT); SEQ ID NOs: 137, 138 and 139 (Fl 1; according to Chothia); SEQ ID NOs: 185, 186 and 187 (Fl 1; according to Honegger) or SEQ ID NOs: 709, 186 and 187 (huFll; according to Honegger). In some embodiments, the anti-IL-lORa VHH comprises the amino acid sequence of any one of SEQ ID NOs: 212, 230, 233, 234, 249 and 710, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 212, 230, 233, 234, 249 and 710. In some embodiments, the anti-IL-lORa VHH comprises the amino acid sequence of any one of 210-211, 213-229, 231-232, 235-248, 250-287 and 752-755, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 210-211, 213-229, 231-232, 235-248, 250-287 and 752-755. In some embodiments, the anti-IL-lORa VHH comprises the1569-US-NP / WO-PCTamino acid sequence of any one of SEQ ID NOs: 233-240 and 724-725, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 233-240 and 724-725 (E07). In some embodiments, the anti-IL-lORa VHH comprises the amino acid sequence of any one of SEQ ID NOs: 249-252 and 752-755, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 249-252 and 752-755 (Fl 1). In some embodiments, the anti-IL-lORa VHH is humanized. In some embodiments, the anti-IL-lORa VHH binds to an epitope on IL 10Ra comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711. In some embodiments, the anti-IL-lORa VHH binds to an epitope on IL 10Ra comprising contact amino acid residues 1169, 1171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197 and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711. In some embodiments, the anti-IL-10Ra VHH binds to IL lORa with an equilibrium dissociation constant (KD) of lower than or less than 5 nM, e.g., lower than 4 nM, 3 nM or 2 nM. In some embodiments, the VHH that binds to IL 10Ra binds to both human IL-lORa and cynomolgus IL-lORa. In some embodiments, the anti-IL-lORa sdAb comprises a human fragment crystallizable (Fc) domain. In some embodiments, the Fc domain comprises a human IgGl or a human IgG4.

[0005] In another aspect, provided is a single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) beta subunit (IL 1OR ). In some embodiments, the anli-IL- lORfl VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively: SEQ ID NOs: 288, 289 and 290 (A02); SEQ ID NOs: 291, 292 and 293 (A05); SEQ ID NOs: 291, 294 and 295 (huA05); SEQ ID NOs: 296, 297 and 298 (huA05); SEQ ID NOs: 299, 300 and 301 (B10); SEQ ID NOs: 302, 303 and 304 (B12); SEQ ID NOs: 305, 306 and 307 (C01); SEQ ID NOs: 296, 308 and 309 (C04); SEQ ID NOs: 310, 311 and 312 (CIO); SEQ ID NOs: 302, 303 and 313 (D01); SEQ ID NOs: 314, 315 and 316 (E08); SEQ ID NOs: 317, 318 and 319 (E10); SEQ ID NOs: 320, 321 and 322 (G01) or; SEQ ID NOs: 323, 324 and 325 (G02). In some embodiments, the anti-IL-10R[3 VHH comprises a complementarity determining region1569-US-NP / WO-PCT(CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively: SEQ ID NOs: 326, 327 and 328 (A02); SEQ ID NOs: 329, 330 and 331 (A05); SEQ ID NOs: 329, 332 and 333 (huA05); SEQ ID NOs: 334, 335 and 336 (huA05); SEQ ID NOs: 337, 338 and 339 (BIO); SEQ ID NOs: 340, 341 and 342 (B12); SEQ ID NOs: 343, 344 and 345 (C01); SEQ ID NOs: 346, 347 and 348 (C04): SEQ ID NOs: 349, 350 and 351 (CIO); SEQ ID NOs: 352, 341 and 353 (D01); SEQ ID NOs: 354, 355 and 356 (E08); SEQ ID NOs: 357, 358 and 359 (E10); SEQ ID NOs: 360, 361 and 362 (G01) or SEQ ID NOs: 363, 364 and 365 (G02). In some embodiments, the anti-IL-10RP VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively: SEQ ID NOs: 366, 367 and 368 (A02); SEQ ID NOs: 369, 370 and 371 (A05); SEQ ID NOs: 369, 372 and 373 (huA05); SEQ ID NOs: 374, 375 and 376 (huA05); SEQ ID NOs: 377, 378 and 379 (B10); SEQ ID NOs: 380, 381 and 382 (B12); SEQ ID NOs: 383, 384 and 385 (C01); SEQ ID NOs: 386, 387 and 388 (C04); SEQ ID NOs: 389, 390 and 391 (CIO); SEQ ID NOs: 392, 381 and 393 (D01); SEQ ID NOs: 394, 395 and 396 (E08); SEQ ID NOs: 397, 398 and 399 (E10); SEQ ID NOs: 400, 401 and 402 (G01) or SEQ ID NOs: 403, 404 and 405 (G02). In some embodiments, the anti-IL-10RP VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively: SEQ ID NOs: 406, 407 and 408 (A02); SEQ ID NOs: 409, 410 and 411 (A05); SEQ ID NOs: 409, 412 and 413 (huA05); SEQ ID NOs: 414, 415 and 416 (huA05); SEQ ID NOs: 417, 418 and 419 (B10); SEQ ID NOs: 420, 421 and 422 (B12); SEQ ID NOs: 423, 424 and 425 (C01); SEQ ID NOs: 426, 427 and 428 (C04); SEQ ID NOs: 429, 430 and 431 (CIO); SEQ ID NOs: 432, 421 and 433 (D01); SEQ ID NOs: 434, 435 and 436 (E08); SEQ ID NOs: 437, 438 and 439 (E10); SEQ ID NOs: 440, 441 and 442 (G01) or; SEQ ID NOs: 443, 444 and 445 (G02). In some embodiments, the anti-IL-10RP VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively: SEQ ID NOs: 291, 292 and 293 (A05; according to Rabat); SEQ ID NOs: 291, 294 and 295 (huA05; according to Rabat); SEQ ID NOs: 296, 297 and 298 (huA05; according to Rabat); SEQ ID NOs: 329, 330 and 331 (A05; according to IMGT); SEQ ID NOs: 329, 332 and 333 (huA05; according to IMGT); SEQ ID NOs: 334, 335 and 336 (huA05; according to IMGT); SEQ ID NOs: 369. 370 and 371 (A05; according to Chothia): SEQ ID NOs: 369, 372 and 373 (huA05; according to Chothia); SEQ ID NOs: 374, 375 and 376 (huA05; according to Chothia); SEQ ID NOs: 409, 410 and 411 (A05; according to Honegger); SEQ ID NOs: 409, 412 and 413 (huA05; according to Honegger) or SEQ ID NOs: 414, 415 and 416 (huA05; according to1569-US-NP / WO-PCTHonegger). In some embodiments, the anti-IL-10RP VHH comprises the amino acid sequence of any one of SEQ ID NOs: 448, 449, 455 and 460, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 448, 449, 455 and 460. In some embodiments, the anti-IE-10RP VHH comprises the amino acid sequence of any one of SEQ ID NOs: 446-447, 450-454, 456-459 and 461-474, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 446-447, 450-454, 456-459 and 461-474. In some embodiments, the anti-IL-10RP VHH comprises the amino acid sequence of any one of SEQ ID NOs: 448-452, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 448-452 (A05). In some embodiments, the anti-IL-10RP VHH comprises the amino acid sequence of any one of SEQ ID NOs: 460-462, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 460-462 (C04). In some embodiments, the anti-IL-10RP VHH is humanized. In some embodiments, the anti-IL-10RP VHH binds to an epitope on IL-10RP comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139. Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the anti-IL-10RP VHH binds to an epitope on IL-10RP comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, DI 10, 1112, Pl 15, Q157, Q190, R192, F194, N199, A201, E203, W204 and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the anti-IL-10RP VHH binds to IL 10RP with an equilibrium dissociation constant (KD) of greater than 10 nM, e.g., greater than 20nM, 30nM, 40nM or 50nM. In some embodiments, the VHH that binds to IL 10RP binds to both human IL-10RP and cynomolgus IL-10Rp. In some embodiments, the anti-IL-10RP sdAb comprises a human fragment crystallizable (Fc) domain. In some embodiments, the Fc domain comprises a human IgGl or a human IgG4.1569-US-NP / WO-PCT

[0006] Further provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-1OR0). In some embodiments, the bispecific antibody is an IL-10R agonist that selectively suppresses activation of myeloid cells and induces minimal or no direct activation of one or both of T cells and B cells. In some embodiments, the bispecific antibody is an IL-10R agonist that predominantly suppresses activation of myeloid cells and induces minimal or no direct activation of one or both of T cells and B cells. In some embodiments, the bispecific antibody induces a maximum effective (Emax) activation of one or both of T cells and B cells that is 15% or less, e.g., 10% or less, of wild-type IL- 10. In some embodiments, the bispecific antibody is an IL-10R agonist that predominantly or selectively suppresses activation of myeloid cells and induces a maximum effect (Emax) activation of one or both of T cells and B cells that is 15% or less, e.g., 10% or less, of wild-type IL-10. In some embodiments, the bispecific antibody is an IL-10R agonist suppressing activation of myeloid cells with a half maximal effective concentration (EC50) less than 10 pM and activating one or both of T cells and B cells below a predetermined threshold level at a concentration above 1000 nM. In some embodiments, the bispecific antibody activates L cells or B cells with a maximum effect (Emax) that is 15% or less, e.g., 10% or less, of wild-type IL- 10. In some embodiments, the activation of T cells is measured by at least one of Granzyme B secretion and interferon-y (IFN-y) production. In some embodiments, the myeloid cells are selected from macrophages, monocytes and dendritic cells. In some embodiments, the bispecific antibody does not induce detectable granzyme B secretion from CD8+ T cells. In some embodiments, the bispecific antibody induces interferon-y (IFN-y) from CD8+ T cells less than 15%, e.g., less than 10%, the level of IFN-y induced by wild-type IL- 10. In some embodiments, the bispccific antibody induces minimal (e.g., less than 25%, less than 20%, less than 15%, less than 10%, in comparison to wild-type IL- 10) or no inhibition of IL 1OR0 dimerization with other IL- 10 family cytokine receptor subunits, e.g., IL-1OR0 dimerization with IL-20Ra, IL-22R, IL-28R or IL-29R. In some embodiments, the bispecific antibody agonizes the IL- 10 receptor in a tyrosine kinase 2 (TYK2; NCBI Gene ID: 7297) dependent manner. In some embodiments, the bispecific antibody induces minimal (e.g., less than 25%, less than 20%, less than 15%, less than 10%, in comparison to wild-type IL- 10) or no inhibition of intracellular signaling of other IL 1OR0-binding cytokines, e.g., minimal or no inhibition of IL-22, IL-26, IL-28 A, IL-28B, or IL-29 intracellular signaling. In some embodiments, the second VHH binds to IL 1OR0 with an1569-US-NP / WO-PCTequilibrium dissociation constant (KD) that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the KD of the first VHH binding to IL 10Ra, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first VHH binds to IL 10Ra with affinity that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the binding affinity of the second VHH binding to IL 10RP, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first variable domain binds to IL 10Ra with an equilibrium dissociation constant (KD) of lower than 2 nM and the second variable domain binds to IL 10R with a KD of greater than 10 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first variable domain binds to IL 10Ra with an equilibrium dissociation constant (KD) of lower than 2 nM and the second variable domain binds to IL 10RP with a KD of greater than 50 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first VHH binds to an epitope on IL 10Ra comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10RP comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the first VHH binds to an epitope on IL-lORa comprising contact amino acid residues 1169, 1171, K173, F178, E180, T181, H182, K183, K186, F190, L192, L193, S195, E197, and F20L wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10RP comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, DUO, 1112, Pl 15, Q157, Q190, R192, F194, N199, A201, E203, W204, and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the bispecific antibody comprises at least one polypeptide (e.g., two polypeptides) comprising the first VHH in tandem with the second VHH. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising from N-terminus toC -terminus the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-lORp. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising from N-terminus to C-terminus the second VHH that specifically binds to IL-10RP and the first VHH that specifically binds to IL-lORa. In some embodiments, the first VHH and the second VHH are connected via a linker. In some embodiments, the linker1569-US-NP / WO-PCTis selected from the group consisting of: GS (SEQ ID NO: 713), GGS (SEQ ID NO: 714), GGGS (SEQ ID NO: 715), GGSGGS (SEQ ID NO: 716), GGGSGGGS (SEQ ID NO: 717) and GGSGGSGGS (SEQ ID NO: 718). In some embodiments, the linker comprises GGGS (SEQ ID NO: 715). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1 -CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Kabat, respectively: SEQ ID NOs: 22, 23, 24, 291, 292 and 293 (877); SEQ ID NOs: 22, 25, 26, 291, 294 and 295 (647); SEQ ID NOs: 22, 27, 24, 291, 297 and 298 (195); SEQ ID NOs: 22, 23, 24, 288, 289 and 290 (048); SEQ ID NOs: 22, 25, 26, 288, 289 and 290 (049); SEQ ID NOs: 22, 27, 24, 288, 289 and 290 (050); SEQ ID NOs: 22, 23, 24, 296, 308 and 309 (274); SEQ ID NOs: 22, 25, 26, 296, 308 and 309 (771); SEQ ID NOs: 22, 27, 24, 296, 308 and 309 (772); SEQ ID NOs: 4, 28, 29, 288, 289 and 290 (054); SEQ ID NOs: 4, 28, 29, 291, 294 and 295 (883); SEQ ID NOs: 4, 28, 29, 291, 294 and 295 (784); SEQ ID NOs: 4, 28, 29, 291, 297 and 298 (785); SEQ ID NOs: 4, 5, 6, 288, 289 and 290 (046); SEQ ID NOs: 4, 5, 6, 291, 294 and 295 (875); SEQ ID NOs: 4, 5, 6, 291, 294 and 295 (776); SEQ ID NOs: 4, 5, 6, 291, 297 and 298 (777); SEQ ID NOs: 4, 5, 6, 296, 308 and 309 (272); SEQ ID NOs: 4, 15, 16, 288, 289 and 290 (052); SEQ ID NOs: 4, 15, 16, 296, 308 and 309 (278); SEQ ID NOs: 4, 17, 18, 288, 289 and 290 (047); SEQ ID NOs: 4, 17, 18, 291, 292 and 293 (876); SEQ ID NOs: 4, 17, 18, 291, 294 and 295 (778); SEQ ID NOs: 4, 17, 18, 291, 297 and 298 (779); SEQ ID NOs: 45, 46, 47, 288, 289 and 290; (062); SEQ ID NOs: 45, 46, 47, 291, 292 and 293 (891); SEQ ID NOs: 45, 46, 47, 291, 294 and 295 (780); SEQ ID NOs: 45, 46, 47, 291, 297 and 298 (781); SEQ ID NOs: 45, 46, 47, 296, 308 and 309 (290); SEQ ID NOs: 4, 48, 6, 291, 292 and 293 (892); SEQ ID NOs: 4, 48, 6, 291, 294 and 295 (793); SEQ ID NOs: 4, 48, 6, 291, 297 and 298 (794); SEQ ID NOs: 54, 55, 24, 291, 292 and 293 (894); SEQ ID NOs: 54, 55, 24, 291, 294 and 295 (795); SEQ ID NOs: 54, 55, 24, 291, 297 and 298 (796); SEQ ID NOs: 4, 30, 31, 291, 292 and 293 (884); SEQ ID NOs: 4, 30.31, 291, 294 and 295 (786); SEQ ID NOs: 4, 30, 31, 291, 297 and 298 (787); SEQ ID NOs: 4, 36, 29, 288, 289 and 290 (058); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (284); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (183); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (184); SEQ ID NOs: 19, 37, 38, 302, 303 and 304 (239); SEQ ID NOs: 19, 37. 38, 296, 308 and 309 (286) or SEQ ID NOs: 19, 51, 52, 302, 303 and 304 (247). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH1569-US-NP / WO-PCTcomprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to IMGT, respectively: SEQ ID NOs: 77, 78, 79, 329, 330 and 331 (877); SEQ ID NOs: 77, 80, 81, 329, 332 and 333 (647); SEQ ID NOs: 77, 82, 79, 334, 335 and 336 (195); SEQ ID NOs: 77, 78, 79, 326, 327 and 328 (048); SEQ ID NOs: 77, 80, 81, 326, 327 and 328 (049); SEQ ID NOs: 77, 82, 79, 326, 327 and 328 (050); SEQ ID NOs: 77, 78, 79, 346, 347 and 348 (274); SEQ ID NOs: 77, 80, 81, 346, 347 and 348 (771); SEQ ID NOs: 77, 82, 79, 346, 347 and 348 (772); SEQ ID NOs: 59, 83, 84, 326, 327 and 328 (054); SEQ ID NOs: 59, 83, 84, 329, 330 and 331 (883); SEQ ID NOs: 59, 83, 84, 329, 332 and 333 (784); SEQ ID NOs: 59, 83, 84, 334, 335 and 336 (785); SEQ ID NOs: 59, 60, 61, 326, 327 and 328 (046); SEQ ID NOs: 59, 60, 61, 329, 330 and 331 (875); SEQ ID NOs: 59, 60, 61, 329, 332 and 333 (776); SEQ ID NOs: 59, 60, 61, 334, 335 and 336 (777); SEQ ID NOs: 59, 60, 61, 346, 347 and 348 (272); SEQ ID NOs: 59, 70, 71, 326, 327 and 328 (052); SEQ ID NOs: 59, 70, 71, 346, 347 and 348 (278); SEQ ID NOs: 59, 72, 73, 326, 327 and 328 (047); SEQ ID NOs: 59, 72, 73, 329, 330 and 331 (876); SEQ ID NOs: 59, 72, 73, 329, 332 and 333 (778); SEQ ID NOs: 59, 72, 73, 334, 335 and 336 (779); SEQ ID NOs: 98, 99, 100, 326, 327 and 328 (062); SEQ ID NOs: 98, 99, 100, 329, 330 and 331 (891); SEQ ID NOs: 98, 99, 100, 329, 332 and 333 (780); SEQ ID NOs: 98, 99, 100, 334, 335 and 336 (781): SEQ ID NOs: 98, 99, 100, 326, 327 and 328 (290); SEQ ID NOs: 59, 101, 61, 329, 330 and 331 (892); SEQ ID NOs: 59, 101, 61, 329, 332 and 333 (793); SEQ ID NOs: 59, 101, 61, 334, 335 and 336 (794); SEQ ID NOs: 106, 107, 79, 329, 330 and 331 (894); SEQ ID NOs: 106, 107, 79, 329, 332 and 333 (795); SEQ ID NOs: 106, 107, 79, 334, 335 and 336 (796); SEQ ID NOs: 59, 85, 86, 329. 330 and 331 (884): SEQ ID NOs: 59, 85, 86, 329, 332 and 333 (786); SEQ ID NOs: 59, 85, 86, 334, 335 and 336 (787); SEQ ID NOs: 59, 91, 84, 326, 327 and 328 (058); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (284); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (183); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (184); SEQ ID NOs: 92, 75, 93, 340, 341 and 342 (239); SEQ ID NOs: 92, 75, 93, 326, 327 and 328 (286) or SEQ ID NOs: 74, 75, 104, 340, 341 and 342 (247). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Chothia, respectively: SEQ ID NOs: 127, 128, 129, 369, 370 and 371 (877); SEQ ID NOs: 127, 130, 131, 369, 372 and 373 (647); SEQ ID NOs: 127, 130, 131, 374, 375 and 376 (195); SEQ ID NOs: 127, 128, 129, 366, 367 and 368 (048); SEQ ID NOs: 127, 130, 131, 366,1569-US-NP / WO-PCT367 and 368 (049): SEQ ID NOs: 127, 130. 131, 366, 367 and 368 (050); SEQ ID NOs: 127, 128, 129, 386, 387 and 388 (274); SEQ ID NOs: 127, 130, 131, 386, 387 and 388 (771); SEQ ID NOs: 127, 130, 131, 386, 387 and 388 (772); SEQ ID NOs: 111, 132, 133, 366, 367 and 368 (054); SEQ ID NOs: 111, 132, 133, 369, 370 and 371 (883); SEQ ID NOs: 111, 132, 133, 369, 372 and 373 (784); SEQ ID NOs: 111, 132, 133, 374, 375 and 376 (785): SEQ ID NOs: 111, 112, 113, 366, 367 and 368 (046); SEQ ID NOs: 111, 112, 113, 369, 370 and 371 (875); SEQ ID NOs: 111, 112, 113, 369, 372 and 373 (776); SEQ ID NOs: 111, 112, 113, 374, 375 and 376 (777); SEQ ID NOs: 111, 112, 113, 386, 387 and 388 (272); SEQ ID NOs: 111, 121, 122, 366, 367 and 368 (052): SEQ ID NOs: 111, 121, 122, 386, 387 and 388 (278): SEQ ID NOs: 111, 121, 123, 366, 367 and 368 (047); SEQ ID NOs: 111, 121, 123, 369, 370 and 371 (876); SEQ ID NOs: 111, 121, 123, 369, 372 and 373 (778); SEQ ID NOs: 111, 121, 123, 374, 375 and 376 (779); SEQ ID NOs: 145, 146, 147, 366, 367 and 368 (062); SEQ ID NOs: 145, 146, 147, 369, 370 and 371 (891); SEQ ID NOs: 145, 146, 147, 369, 372 and 373 (780); SEQ ID NOs: 145, 146, 147, 374, 375 and 376 (781): SEQ ID NOs: 145, 146, 147, 386, 387 and 388 (290): SEQ ID NOs: 111, 112, 113, 369, 370 and 371 (892); SEQ ID NOs: 111, 112, 113, 369, 372 and 373 (793); SEQ ID NOs: 111, 112, 113, 374, 375 and 376 (794); SEQ ID NOs: 152, 121, 129, 369, 370 and 371 (894); SEQ ID NOs: 152, 121, 129, 369, 372 and 373 (795): SEQ ID NOs: 152, 121, 129, 374, 375 and 376 (796); SEQ ID NOs: 111. 134, 135, 369, 370 and 371 (884); SEQ ID NOs: 111, 134, 135, 369, 372 and 373 (786); SEQ ID NOs: 111, 134, 135, 374, 375 and 376 (787); SEQ ID NOs: 111, 132, 133, 366, 367 and 368 (058); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (284); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (183); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (184); SEQ ID NOs: 140, 125, 141, 380, 381 and 381 (239); SEQ ID NOs: 140, 125, 141, 386, 387 and 388 (286) or SEQ ID NOs: 124, 125, 126, 380, 381 and 381 (247). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Honegger, respectively: SEQ ID NOs: 174, 175, 176, 409, 410 and 411 (877); SEQ ID NOs: 174, 177, 178, 409, 412 and 413 (647); SEQ ID NOs: 174, 179, 176, 414, 415 and 416 (195); SEQ ID NOs: 174, 175, 176, 406, 407 and 408 (048); SEQ ID NOs: 174, 177, 178, 406, 407 and 408 (049); SEQ ID NOs: 174, 179, 176, 406, 407 and 408 (050); SEQ ID NOs: 174, 175, 176, 426, 427 and 428 (274); SEQ ID NOs: 174, 177, 178, 426, 427 and 428 (771); SEQ ID NOs: 174, 179, 176, 426, 427 and 428 (772); SEQ ID NOs: 156, 180, 181, 406, 407 and 408 (054); SEQ ID1569-US-NP / WO-PCTNOs: 156, 180, 181, 409, 410 and 411 (883); SEQ ID NOs: 156, 180, 181, 409, 412 and 413 (784); SEQ ID NOs: 156, 180, 181, 414, 415 and 416 (785); SEQ ID NOs: 156, 157, 158, 406, 407 and 408 (046); SEQ ID NOs: 156, 157, 158, 409, 410 and 411 (875); SEQ ID NOs: 156, 157, 158. 409, 412 and 413 (776); SEQ ID NOs: 156, 157, 158. 414, 415 and 416 (777); SEQ ID NOs: 156, 157, 158, 426, 427 and 428 (272); SEQ ID NOs: 156, 167, 168, 406, 407 and 408 (052); SEQ ID NOs: 156, 167, 168, 426, 427 and 428 (278); SEQ ID NOs: 156, 169, 170, 406, 407 and 408 (047); SEQ ID NOs: 156, 169, 170, 409, 410 and 411 (876); SEQ ID NOs: 156, 169, 170, 409, 412 and 413 (778); SEQ ID NOs: 156, 169, 170, 414, 415 and 416 (779); SEQ ID NOs: 198, 199, 200, 406, 407 and 408 (062); SEQ ID NOs: 198, 199, 200, 409, 410 and 411 (891); SEQ ID NOs: 198, 199, 200, 409, 412 and 413 (780); SEQ ID NOs: 198, 199, 200, 414, 415 and 416 (781); SEQ ID NOs: 198, 199, 200, 426, 427 and 428 (290); SEQ ID NOs: 156, 201, 158, 409, 410 and 411 (892); SEQ ID NOs: 156, 201, 158, 409, 412 and 413 (793); SEQ ID NOs: 156, 201, 158, 414, 415 and 416 (794); SEQ ID NOs: 208, 209, 176, 409, 410 and 411 (894); SEQ ID NOs: 208, 209, 176, 409, 412 and 413 (795); SEQ ID NOs: 208, 209, 176, 414, 415 and 416 (796); SEQ ID NOs: 156, 182, 183, 409, 410 and 411 (884); SEQ ID NOs: 156, 182, 183, 409, 412 and 413 (786); SEQ ID NOs: 156, 182, 183, 414, 415 and 416 (787); SEQ ID NOs: 156, 188, 181, 406, 407 and 408 (058); SEQ ID NOs: 185, 186, 187, 426, 427 and 428 (284); SEQ ID NOs: 709, 186, 187, 426, 427 and 428 (183); SEQ ID NOs: 709, 186, 187, 426, 427 and 428 (184); SEQ ID NOs: 189, 190, 191, 420, 421 and 422 (239); SEQ ID NOs: 189, 190, 191, 426, 427 and 428 (286) or SEQ ID NOs: 204, 205, 206, 420, 421 and 422 (247). In some embodiments, the bispecific antibody comprises a VHH1-CDR1, a VHH1-CDR2, and a VHH1-CDR3 and a VHH2-CDR1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively (E07-A05): SEQ ID NOs: 22, 23, 24, 291, 292 and 293 (877; according to Kabat); SEQ ID NOs: 22, 25, 26, 291, 294 and 295 (647; according to Kabat); SEQ ID NOs: 22, 27, 24, 291, 297 and 298 (195; according to Kabat); SEQ ID NOs: 77, 78, 79, 329, 330 and 331 (877; according to IMGT); SEQ ID NOs: 77, 80, 81, 329, 332 and 333 (647; according to IMGT); SEQ ID NOs: 77, 82, 79, 334, 335 and 336 (195; according to IMGT); SEQ ID NOs: 127, 128, 129, 369, 370 and 371 (877; according to Chothia); SEQ ID NOs: 127, 130, 131, 369, 372 and 373 (647; according to Chothia); SEQ ID NOs: 127, 130, 131, 374, 375 and 376 (195; according to Chothia): SEQ ID NOs: 174, 175, 176, 409, 410 and 411 (877; according to Honegger); SEQ ID NOs: 174, 177, 178, 409, 412 and 413 (647; according to Honegger) or SEQ ID NOs: 174, 179, 176, 414, 415 and 416 (195; according to Honegger). In some embodiments, the bispecific antibodies comprise a VHH1-CDR1, a VHH1-CDR2, and a VHH1-CDR3 and a VIIH2-CDR1, a VHH2-CDR2, and a VHII2-CDR3, comprising the1569-US-NP / WO-PCTfollowing amino acid sequences, respectively (F11-C04): SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (284; according to Kabat); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (183; according to Kabat); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (184; according to Kabat); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (284; according to IMGT); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (183; according to IMGT); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (184; according to IMGT); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (284; according to Chothia); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (183; according to Chothia); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (184; according to Chothia): SEQ ID NOs: 185, 186, 187, 426, 427 and 428 (284; according to Honegger); SEQ ID NOs: 709. 186, 187, 426, 427 and 428 (183; according to Honegger) or; SEQ ID NOs: 709, 186, 187, 426, 427 and 428 (184; according to Honegger). In some embodiments, the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 212 and 448 [A06con-A05con]; SEQ ID NOs: 212 and 449 [A06con-A05con]; SEQ ID NOs: 212 and 460 [A06con-C04con]; SEQ ID NOs: 233 and 448 [E07con-A05con]; SEQ ID NOs: 234 and 449 [E07con-A05con]; SEQ ID NOs: 233 and 460 [E07con-C04con]; SEQ ID NOs: 234 and 460 [E07con-C04con]; SEQ ID NOs: 710 and 448 [C09con-A05con]; SEQ ID NOs: 710 and 449; [C09con-A05con]; SEQ ID NOs: 710 and 460; [C09con-C04con]; SEQ ID NOs: 230 and 460 [G22con-C04con] or SEQ ID NOs: 249 and 460 [Fl lcon-C04con], In some embodiments, the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 235 and 450 (877); SEQ ID NOs: 237 and 451 (647); SEQ ID NOs: 239 and 452 (195); SEQ ID NOs: 235 and 446 (048); SEQ ID NOs: 237 and 447 (049); SEQ ID NOs: 239 and 447 (050); SEQ ID NOs: 235 and 461 (274); SEQ ID NOs: 237 and 462 (771); SEQ ID NOs: 239 and 462 (772); SEQ ID NOs: 241 and 446 (054); SEQ ID NOs: 243 and 447 (755); SEQ ID NOs: 241 and 450 (883); SEQ ID NOs: 243 and 451 (784); SEQ ID NOs: 243 and 452 (785); SEQ ID NOs: 213 and 446 (046); SEQ ID NOs: 215 and 447 (747); SEQ ID NOs: 213 and 450 (875); SEQ ID NOs: 215 and 451 (776); SEQ ID NOs: 215 and 452 (777); SEQ ID NOs: 213 and 461 (272); SEQ ID NOs: 215 and 462 (773); SEQ ID NOs: 224 and 446 (052); SEQ ID NOs: 226 and 447 (753); SEQ ID NOs: 224 and 461 (278); SEQ ID NOs: 226 and 462 (769);1569-US-NP / WO-PCTSEQ ID NOs: 227 and 446 (047); SEQ ID NOs: 229 and 447 (748); SEQ ID NOs: 227 and 450 (876); SEQ ID NOs: 229 and 451 (778); SEQ ID NOs: 229 and 452 (779); SEQ ID NOs: 267 and 446 (062); SEQ ID NOs: 269 and 447 (763); SEQ ID NOs: 267 and 450 (891); SEQ ID NOs: 269 and 451 (780); SEQ ID NOs: 269 and 452 (781); SEQ ID NOs: 267 and 461 (290); SEQ ID NOs: 269 and 462 (791); SEQ ID NOs: 270 and 450 (892); SEQ ID NOs: 272 and 451 (793); SEQ ID NOs: 272 and 452 (794); SEQ ID NOs: 285 and 450 (894); SEQ ID NOs: 287 and 451 (795); SEQ ID NOs: 287 and 452 (796); SEQ ID NOs: 244 and 450 (884); SEQ ID NOs: 246 and 451 (786); SEQ ID NOs: 247 and 452 (787); SEQ ID NOs: 253 and 446 (058); SEQ ID NOs: 255 and 447 (759); SEQ ID NOs: 250 and 461 (284); SEQ ID NOs: 251 and 462 (183); SEQ ID NOs: 252 and 462 (184); SEQ ID NOs: 256 and 456 (239); SEQ ID NOs: 258 and 457 (740); SEQ ID NOs: 256 and 461 (286); SEQ ID NOs: 258 and 462 (788); SEQ ID NOs: 278 and 456 (247) SEQ ID NOs: 280 and 457 (749); SEQ ID NOs: 752 and 461; SEQ ID NOs: 752 and 462; SEQ ID NOs: 753 and 461; SEQ ID NOs: 753 and 462; SEQ ID NOs: 754 and 461; SEQ ID NOs: 754 and 462; SEQ ID NOs: 755 and 461; or SEQ ID NOs: 755 and 462. In some embodiments, the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 236 and 450 (877); SEQ ID NOs: 238 and 451 (647); SEQ ID NOs: 240 and 452 (195); SEQ ID NOs: 236 and 446 (048); SEQ ID NOs: 238 and 447 (049); SEQ ID NOs: 240 and 447 (050); SEQ ID NOs: 236 and 461 (274); SEQ ID NOs: 238 and 462 (771); SEQ ID NOs: 240 and 462 (772); SEQ ID NOs: 242 and 446 (054); SEQ ID NOs: 243 and 447 (755); SEQ ID NOs: 242 and 450 (883); SEQ ID NOs: 243 and 451 (784); SEQ ID NOs: 243 and 452 (785); SEQ ID NOs: 214 and 446 (046); SEQ ID NOs: 215 and 447 (747); SEQ ID NOs: 214 and 450 (875); SEQ ID NOs: 215 and 451 (776); SEQ ID NOs: 215 and 452 (777); SEQ ID NOs: 214 and 461 (272); SEQ ID NOs: 215 and 462 (773); SEQ ID NOs: 225 and 446 (052); SEQ ID NOs: 226 and 447 (753); SEQ ID NOs: 225 and 461 (278); SEQ ID NOs: 226 and 462 (769); SEQ ID NOs: 228 and 446 (047); SEQ ID NOs: 229 and 447 (748); SEQ ID NOs: 228 and 450 (876); SEQ ID NOs: 229 and 451 (778); SEQ ID NOs: 229 and 452 (779); SEQ ID NOs: 268 and 446 (062); SEQ ID NOs: 269 and 447 (763); SEQ ID NOs: 268 and 450 (891); SEQ ID NOs: 269 and 451 (780); SEQ ID NOs: 269 and 452 (781); SEQ ID NOs: 268 and 461 (290); SEQ ID NOs: 269 and 462 (791); SEQ ID NOs: 271 and 450 (892); SEQ ID NOs: 273 and 451 (793); SEQ ID NOs: 274 and 452 (794); SEQ ID NOs: 286 and 450 (894); SEQ ID NOs: 287 and 451 (795); SEQ ID NOs: 2871569-US-NP / WO-PCTand 452 (796); SEQ ID NOs: 245 and 450 (884); SEQ ID NOs: 246 and 451 (786); SEQ ID NOs: 246 and 452 (787); SEQ ID NOs: 254 and 446 (058); SEQ ID NOs: 255 and 447 (759); SEQ ID NOs: 250 and 461 (284); SEQ ID NOs: 251 and 462 (183); SEQ ID NOs: 252 and 462 (184); SEQ ID NOs: 752 and 461; SEQ ID NOs: 752 and 462; SEQ ID NOs: 753 and 461; SEQ ID NOs: 753 and 462; SEQ ID NOs: 754 and 461; SEQ ID NOs: 754 and 462; SEQ ID NOs: 755 and 461; or SEQ ID NOs: 755 and 462; SEQ ID NOs: 257 and 456 (239); SEQ ID NOs: 259 and 457 (740); SEQ ID NOs: 257 and 461 (286); SEQ ID NOs: 259 and 462 (788); SEQ ID NOs: 279 and 456 (247) or SEQ ID NOs: 280 and 457 (749). In some embodiments, the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 233 and 448 [E07con-A05con]; SEQ ID NOs: 234 and 449 |E07con-A05conJ; SEQ ID NOs: 235 and 450 (877); SEQ ID NOs: 237 and 451 (647); SEQ ID NOs: 239 and 452 (195); SEQ ID NOs: 236 and 450 (877); SEQ ID NOs: 238 and 451 (647); SEQ ID NOs: 240 and 452 (195); SEQ ID NOs: 724 and 450 (E07-A05); SEQ ID NOs: 724 and 451 (E07-A05); SEQ ID NOs: 724 and 452 (E07-A05); SEQ ID NOs: 725 and 450 (E07-A05); SEQ ID NOs: 725 and 451 (E07-A05) or SEQ ID NOs: 725 and 452 (E07-A05). In some embodiments, the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 249 and 460 [Fllcon-C04con]; SEQ ID NOs: 250 and 461 (284); SEQ ID NOs: 251 and 462 (183); SEQ ID NOs: 252 and 462 (184); SEQ ID NOs: 250 and 461 (284); SEQ ID NOs: 251 and 462 (183); SEQ ID NOs: 252 and 462 (184); SEQ ID NOs: 752 and 461; SEQ ID NOs: 752 and 462; SEQ ID NOs: 753 and 461; SEQ ID NOs: 753 and 462; SEQ ID NOs: 754 and 461; SEQ ID NOs: 754 and 462; SEQ ID NOs: 755 and 461; or SEQ ID NOs: 755 and 462 (Fl 1-C04). In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-476 and 573. In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically1569-US-NP / WO-PCTbinds to IL 10Ra and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 477, 479, 481, 483, 485, 487, 489, 491, 493. 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 574, 576, 578, 580, 582, 584, 586, 588 and 590. In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 478, 480, 482, 484. 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 575, 577, 579, 581, 583, 585, 587, 589, 591, 737-751 and 757-758. In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-482 and 737-751 (E07-A05). In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 573-579 and 757-758 (Fl 1-C04). In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Ra binds to both human IL 10Ra and cynomolgus IL 10R. In some embodiments of the bispecific antibody, the second VHH that specifically binds to IL 10RP binds to both human IL 10RP and cynomolgus IL 10Rp. In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Ra binds to both human IL 10Ra and cynomolgus IL 10Ra and wherein the second VHH that specifically binds to IL 10RP binds to both human IL 10RP and cynomolgus IL 10Rp. In some embodiments, the bispecifc antibody comprises a first fragment crystallizable (Fc) domain and a1569-US-NP / WO-PCTsecond Fc domain. In some embodiments, the first Fc domain and the second Fc domain are a human IgGl or a human IgG4. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions that reduces or inhibits or eliminates antibody-dependent cell-mediated cytotoxicity (ADCC) effector function. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises effector function reducing amino acid substitutions at Fc positions (EU numbering) selected from: alanine at position 234 and alanine at position 235 (234A and 235A); glutamic acid at position 235 (235E); proline at position 228 and glutamic acid at position 235 (228P, 235E); alanine at position 237 (237A); alanine at position 234 and glutamic acid at position 235 (234A and 235E); phenylalanine at position 234, glutamic acid at position 235 and alanine at position 265 (234F, 235E and 265A); phenylalanine at position 234, glutamic acid at position 235 and alanine at position 236 (234F, 235E and 236A); phenylalanine at position 234, glutamic acid at position 235 and arginine at position 236 (234F, 235E and 236R); serine at position 234, threonine at position 235 and arginine at position 236 (234S, 235T and 236R); alanine at position 234, alanine at position 235 and glycine at position 329 (234A, 235A and 329G); alanine at position 234, alanine at position 235 and alanine at position 237 (234A, 235A and 237A); proline at position 228 and glutamic acid at position 235 (228P and 235E); proline at position 228, glutamic acid in position 235 and glycine at position 329 (228P, 235E and 329G); phenylalanine at position 234, glutamic acid at position 235 and serine at position 331 (234F, 235E and 331S); phenylalanine at position 234, glutamine at position 235 and glutamine at position 322 (234F, 235Q and 322Q); alanine at position 233, arginine at position 234 and arginine at position 235 (233A, 234R and 235R): alanine at position 233, aspartic acid at position 234 and glutamic acid at position 235 (233A, 234D and 235E); lysine at position 233, arginine at position 234 and arginine at position 235 (233K, 234R and 235R); alanine at position 234, alanine at position 235, alanine at position 237, serine at position 238, alanine at position 268, serine at position 330 and serine at position 331 (234A, 235A, 237A, 238S, 268A, 33OS and 331S); and proline at position 228, alanine at position 234, alanine at position 235, alanine at position 237 and serine at position 238 (228P, 234A, 235 A, 237A and 238S). In some embodiments, one or both of the first Fc domain and the second Fc domain comprises effector function reducing amino acid substitutions at Fc positions (EU numbering) alanine at position 234, alanine at position 235 and alanine at position 237 (234A, 235A and 237A). In some embodiments, one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions that extend serum half-life. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises serum half-life extending amino acid substitutions at Fc positions (EU1569-US-NP / WO-PCTnumbering) selected from: tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (252Y, 254T and 256E); leucine at position 428 (428L); glutamine at position 250 and leucine at position 428 (250Q and 428L); leucine at position 428 and serine at position 434 (428L and 434S); leucine at position 428 and alanine at position 434 (428L and 434A); arginine at position 311 and leucine at position 428 (311R and 428L); glycine at position 309 and leucine at position 428 (309G and 4281,); glutamine at position 307, valine at position 311 and valine at position 378 (307Q, 311V and 378V); and aspartic acid at position 256, aspartic acid at position 286, arginine at position 307, valine at position 311 and valine at position 378 (256D, 286D, 307R, 311V and 378V). In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 592-593 and 690. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622. 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 691, 693, 695, 697, 699, 701, 703, 705, and 707. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631. 633, 635, 637, 639, 641, 643, 645, 647, 649, 651, 653, 655. 657, 659, 661, 663, 665, 667, 669, 671, 673, 675. 677, 679, 681, 683, 685, 687, 689, 692, 694, 696, 698, 700. 702, 704, 706 and 708. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 592-599 (E07-A05). In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least1569-US-NP / WO-PCT93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 690-696 (Fl 1-C04). In some embodiments, the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP are both humanized. In some embodiments, the bispecific antibody has a serum half-life in a human of at least 3 days, e.g., at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, or longer.

[0007] Further provided are means for agonizing an IL- 10 receptor that selectively suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells. Also provided are means for agonizing an IL- 10 receptor that predominantly suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells. In some embodiments, the means induces a maximum effective (Emax) activation of T cells or B cells that is 15% or less of wild-type IL-10. Also provided are means for agonizing an IL-10 receptor that induces a maximum effective (Emax) activation of T cells or B cells that is 15% or less of wild-type IL- 10. Also provided are means for agonizing an IL- 10 receptor that suppresses activation of myeloid cells with a half maximal effective concentration (EC50) less than 10 pM and activating T cells and B cells below a predetermined threshold level at a concentration above 1000 nM. In some embodiments, the means agonizes the IL- 10 receptor in a tyrosine kinase 2 (TYK2; NCBI Gene ID: 7297) dependent manner. In some embodiments, the activation of T cells is measured by at least one of Granzyme B secretion and interferon-y (IFN-y) production. In some embodiments, the means does not induce detectable granzyme B the secretion from CD8+ T cells. In some embodiments, the means induces interferon-y (IFN-y) from CD8+ T cells less than 15% the level of IFN-y induced by wild-type IL-10. In some embodiments, the myeloid cells are selected from macrophages, monocytes and dendritic cells. In some embodiments, the means induces minimal (e.g., less than 25% in comparison to wildtype IL-10) or no inhibition of IL-10RP dimerization with other IL-10 family cytokine receptor subunits, e.g., IL-1OR dimerization with IL-20Ra, IL-22R, IL-28R or IL-29R. In some embodiments, the means induces minimal e.g., less than 25% in comparison to wild-type IL- 10) or no inhibition of intracellular signaling of other IL-10R|3-binding cytokines, e.g., minimal or no inhibition of IL-22, IL-26, IL-28A, IL-28B, or IL-29 intracellular signaling. In some embodiments, the means binds to IL-10RP with an equilibrium dissociation constant (KD) that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the KD of binding to IL-lORa, e.g., wherein the binding affinity is1569-US-NP / WO-PCTdetermined by surface plasmon resonance (SPR). In some embodiments, the means binds to IL-lORa with an equilibrium dissociation constant (KD) of lower than 2 nM and binds to IL-10RP with a KD of greater than 10 nM, e.g., greater than 50 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the means binds to IL-lORa contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, Fl 80, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and binds to IL-1OR0 contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, VI 48 and N 150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the means binds to IL-lORa contact amino acid residues 1169, 1171, K173, F178, F180, T181, H182, K183, K186, Fl 90, L192, L193, S195, E197, and F201, wherein the amino acid residue positions arc with respect to SEQ ID NO: 711 and binds to IL-1OR contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, DUO, 1112, Pl 15, QI 57, QI 90, R192, Fl 94, N 199, A201, E203, W204, and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712.

[0008] Further provided is a polynucleotide that encode the sdAb that binds to IL-lORa; the sdAb that binds to IL-1OR0 or the bispecific antibody, as described above and herein. In some embodiments, the polynucleotide is DNA or RNA, e.g., cDNA or mRNA. Further provided is an expression cassette comprising one or more regulatory sequences operably linked to the polynucleotide, as described above and herein. In some embodiments, the one or more regulatory sequences comprise a constitutive promoter. Further provided in an expression vector comprising one or more regulatory sequences operably linked to the polynucleotide or polynucleotides or the expression cassette or expression cassettes as described above and herein. In some embodiments, the expression vector comprises a plasmid vector or a viral vector.

[0009] Further provided is a method of producing an IL-10R binding molecule, as described herein. In some embodiments, the method comprises: (a) culturing a cell or population of cells as described herein transformed with the polynucleotide as described herein, or the expression cassette as described herein in a cell culture under conditions sufficient to express the IL-10R binding molecule; and (b) isolating or purifying the antigen binding molecules from the cell culture. Further provided is cell or population of cells, comprising the polynucleotide or polynucleotides, the expression cassette, or the expression vector as described above and herein. In some embodiments, the cell or population of cells comprises a eukaryotic cell. In some embodiments, the cell or population of cells comprises a mammalian cell, an1569-US-NP / WO-PCTinsect cell, a plant cell or a yeast cell. In some embodiments, the mammalian cell is a Chinese Hamster Ovary (CHO) cell.

[0010] Further provided is a method of preventing or treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a bispecific antibody as described above and herein. Also provided is a method of reducing the severity of or mitigating on or more symptoms of an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a bispecific antibody as described above and herein. In some embodiments, the inflammatory disease is mediated by an IL- 10 deficiency or deficient signaling through the IL-10R. In some embodiments, the inflammatory disease is an autoimmune disease. In some embodiments, the inflammatory disease is an inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is selected from ulcerative colitis, Crohn’s disease, mucosal proctocolitis and celiac disease. In some embodiments, the inflammatory disease is an inflammatory dermatitis disease. In some embodiments, the inflammatory dermatitis disease is selected from atopic dermatitis (AD), hidradenitis suppurativa (HS), and psoriasis. In some embodiments, the inflammatory disease is selected from ulcerative colitis, Crohn’s disease, mucosal proctocolitis and celiac disease, rheumatoid arthritis (RA), juvenile idiopathic arthritis, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis, systemic lupus erythematosus (SLE), Behget’s disease, type 1 diabetes, primary sclerosing cholangitis, ankylosing spondylitis, and multiple sclerosis. In some embodiments, the inflammatory disease is acute or chronic. In some embodiments, the bispecific antibody is administered subcutaneously, intravenously or orally. In some embodiments, the bispecific antibody is administered via a device. In some embodiments, the device is configured for sustained delivery. In some embodiments, the device is configured for self-administration. In some embodiments, the device is a prefilled syringe. In some embodiments, the device is an ingestible device configured for local delivery to the intestine. In some embodiments, the bispecific antibody is combined or co-administered with one or more additional agents. In some embodiments, the one or more additional agents are selected from infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, ustekinumab, natalizumab, mesalamine, diazo-bonded 5-ASA, sulfasalazine, balsalazide, olsalazine, a corticosteroid (e.g., budesonide, hydrocortisone, methylprednisolone, prednisone); an immunosuppressant (e.g., azathioprine, 6-mercaptopurine, cyclosporine, methotrexate), and combinations thereof. In some embodiments, the one or more additional agents are selected from a PPAR6 inhibitor, an IRAK4 inhibitor, a TPL2 inhibitor, an (14 7 inhibitor, a BTLA agonist, a PD-1 agonist, a CD200R1569-US-NP / WO-PCTagonist, or a FXR agonist. In some embodiments, the one or more additional agents are selected from seladelpar, edecesertib, tilpisertib fosmecarbil, GS-1427, GS 0272, GS-0151, GS-6791 and cilofexor.

[0011] Further provided is a kit comprising one or more unitary doses of a bispecific antibody as described above and herein. In some embodimens, the one or more unitary doses are the same or different. In some embodiments, the one or more unitary doses are in one or more ampoules, vials, pre-loaded syringes or delivery devices. In some embodiments, the bispecific antibody is combined or co-administered with one or more additional agents. In some embodiments, the one or more additional agents are selected from infliximab, adalimumab, golimumab, vedolizumab, tofacirinib, ustekinumab, natalizumab, mesalamine, diazo-bonded 5-ASA, sulfasalazine, balsalazide, olsalazine, a corticosteroid (e.g., budesonide, hydrocortisone, methylprednisolone, prednisone); an immunosuppressant (e.g., azathioprine, 6-mercaptopurine, cyclosporine, methotrexate), and combinations thereof. In some embodiments, the one or more additional agents are selected from a PPAR6 inhibitor, an IRAK4 inhibitor, a TPL2 inhibitor, an (1407 inhibitor, a BTLA agonist, a PD-1 agonist, a CD200R agonist, or a FXR agonist. In some embodiments, the one or more additional agents are selected from seladelpar, edecesertib, tilpisertib fosmecarbil, GS-1427, GS 0272, GS-0151, GS-6791 and cilofexor.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 illustrates potency of IL-10R agonistic potency, as determined by Emax, of aIL-10Ra-IL-10RP tandem VHH1-VHH2 bispecific molecules in a HEK293T IL-10R-pSTAT3 luciferase reporter assay. Percentage of Emax was nomralized by recombinant IL- 10.

[0013] Figures 2A-2D illustrate cryo-EM structure of IL-lORa + IL- 1OR0 + E07-A05 tandem VHH1-VHH2. Figure 2A depicts the overall structure of IL-lORa + IL-1OR0 + E07-A05 tandem VHH1-VHH2 complex. Figures 2B and 2C depict the E07 epitope contact residues. Figure 2D depicts the A05 epitope contact residues. Underlined amino acid positions are residues on the VHH, while amino acid positions without an underline are residues on IL-lORa or IL-1OR0.

[0014] Figures 3 A-3D illustrate cryo-EM structure of IL-lORa + IL- 1OR0 + Fl 1 -C04 tandem VHH1-VHH2. Figure 3A depicts the overall structure of IL-lORa + IL-1OR0 + Fl 1-C04 tandem VHH1-VHH2 complex. Figure 3B depicts the Fll epitope contact residues.Figures 3C and 3D depicts the C04 epitope contact residues. Underlined amino acid positions1569-US-NP / WO-PCTare residues on the VHH, while amino acid positions without an underline are residues on IL-10Ra or IL-10Rp.

[0015] Figure 4 illustrates cryo-EM structure of IL-10RP + VHH A05 + VHH C04.

[0016] Figure 5 illustrates tandem VHH1-VHH2 bispecific molecules profiled in a Colo 205 IL-22R-pSTAT3 luciferase reporter assay.

[0017] Figure 6 illustrates tandem VHH1-VHH2 bispecific molecules profiled in a HEK293T IL-29 reporter assay.

[0018] Figure 7 illustrates data from the dose-response curves for phospho-STAT3 in human whole blood stimulated with IL-10-Fc or our VHH1-VHH2 bispecific molecules 195 and 184, analyzed by flow cytometry. Data are shown as phospho-STAT3 MFI (N = 2).

[0019] Figures 8A-8B illustrate that VHH1-VHH2 bispecific molecules 195 and 184 inhibit lipopolysaccharide (LPS) induced IL-6 secretion from peripheral blood mononuclear cells (PBMC).

[0020] Figure 9 illustrates that VHH1-VHH2 bispecific molecules 195 and 184 do not significantly induce IFN-y secretion from primary CD8+ T cells.

[0021] Figure 10 illustrates that comparator anti-lL-l()RaP VHH1-VHH2-Fc bispecific molecule (Cl) inhibits TNFa release by LPS.

[0022] Figure 11 illustrates that comparator anli-IL- l()Raf> VHH1-VHH2-Fc bispecific molecule (Cl) induces STAT3 phosphorylation in monocytes, CD4+ T cells, CD8+ T cells, and B cells.

[0023] Figure 12 illustrates that comparator anti-IL-10RaP VHH1-VHH2-Fc bispecific molecule (Cl) promotes T cell production of IFN-y and granzyme B.

[0024] Figures 13A-13E illustrate dose-response curves for phospho-STAT3 in monocytes (Fig. 13 A), CD8+ T cells (Fig. 13B), CD4+ T cells (Fig. 13C), NK cells (Fig. 13D) and B cells (Fig. 13E) from human whole blood stimulated with IL-10-Fc, VHH1-VHH2 bispecific molecules 195 and 184, and comparator VHH1-VHH2 bispecific molecules, analyzed by flow cytometry. Data are expressed as phospho-STAT3 MFI (N = 3).

[0025] Figure 14 illustrates the VHH1-VHH2-His monovalent version of 302 (monovalent 195) and 196 (monovalent 184) induces less IFN-y secretion from primary CD8+ T cells in comparison to VHH1-VHH2-His monovalent versions of comparator molecules.1569-US-NP / WO-PCT

[0026] Figure 15 illustrates VHH1-VHH2-Fc version of 195 and 184 induce less IFN-y secretion from primary CD8+ T cells in comparison to VHH1-VHH2-Fc versions of comparator molecules.

[0027] Figure 16 illustrates that VHH1-VHH2 bispecific molecules 195 and 184 inhibit monocyte differentiation into dendritic cells (defined as CDla+CD14- cells). IL-10-Fc was included as a positive control for comparison. Each dot represents an individual human donor.

[0028] Figure 17 illustrates that VHH1-VHH2 bispecific molecules 195 and 184 inhibit lipopolysaccharide (LPS)-induced dendritic cell maturation, measured by the expression of DC activation marker CD83 and co-stimulatory marker CD86. Activated DCs were quantified as CD83+CD86+ cells. IL-10-Fc was included as a positive control for comparison. Each dot represents an individual human donor.

[0029] Figure 18 illustrates that VHH1-VHH2 bispecific molecules 195 and 184 inhibit zymosan induced dendritic cell secretion of TNFa and IL-23. IL-10-Fc was included as a positive control for comparison. Each dot represents an individual human donor.

[0030] Figure 19 illustrates that VHH1-VHH2 bispecific molecules 195 and 184 inhibit dendritic cell (DC) antigen presentation and tetramer-positive T-cell expansion. IL-10-Fc was included for comparison. Each dot represents an individual human donor.

[0031] Figures 20A-20D illustrate that both IL-10-Fc and VHH1-VHH2 bispecific molecules 195 and 184 demonstrate potent inhibition of proinflammatory cytokines IL- 17 (20A), IL-6 (20B), IL-12p70 (20C) and TNFa (20D) during dose titration.

[0032] Figures 21 A-21C illustrate data from an efficacy test of VHH1-VHH2 bispecific molecule 877 in a dextran sulfate sodium (DSS)-induced colitis model. Figure 21A shows the ratio of colon length and colon weight in different treatment groups. Figure 21 B shows inflammatory cytokine gene expression level in colon tissue using quantitative PCR. Figure 21 C shows neutrophil frequency change in spleen using flow cytometry and Csf3r (neutrophil marker) gene expression change in colon tissue using quantitative PCR.

[0033] Figure 22 illustrates results of an assay measuring pre-existing anti-drug antibodies (ADA) against VHH1-VHH2 bispecific molecules 184, 183, 647 and 195 and positive control caplacizumab-Fc. RLU = relative light units.

[0034] Figure 23 illustrates the results of an assay measuring the T-cell immunogenicity elicited by VHH1-VHH2 bispecific molecules 195, 647, 183 and 184 in human PBMCs.1569-US-NP / WO-PCTAvastin (bevacizumab) was used as negative control and both bococizumab and keyhole limpet hemocyanin (KLH) protein were used as positive controls in this assay.

[0035] Figure 24 illustrates pharmacokinetic profiles for anti-IL-10RaP agonist VHH1-VHH2-Fc molecules 195 (circle) and 184 (square) after 100 mg / kg IV bolus infusion in naive cynomolgus macaques. Each symbol is the measured mean ± standard deviation (SD) plasma concentration.

[0036] Figure 25 illustrates STAT3 phosphorylation (pSTAT3) of human macrophages (white I no fill); TYK2 CRISPR knock-out (KO) human macrophages (dark gray); and control (non-targeted RNA) CRISPR KO human macrophages (light gray). Wild-type IL- 10 or VHH1-VHH2 bispecific molecule 184 were added to indicated human macrophages. pSTAT3 was quantified by flow cytometry analysis.

[0037] Figure 26 illustrates Western blotting of phosphorylated TYK2 (pTYK2), total TYK2, phosphorylated JAK1 (pIAKl), total JAK1, phosphorylated STAT3 (pSTAT3), and GADPH at different time points after addition of wild-type IL- 10 or VHH1-VHH2 bispecific molecule 877 at indicated time points.

[0038] Figures 27 A- 27 C. PBMCs from two donors were stimulated with LPS in the presence of the indicated molecules and a TYK2 small-molecule inhibitor. Cell culture supernatants were analyzed for levels of cytokines, including TNF (Fig. 27 A), IL-6 (Fig. 27B), and IL- Ip (Fig. 27 C).

[0039] Figure 28 illustrates comparative potency analysis of anti-IL-10RaP agonist VHH1-VHH2-Fc molecules and comparator molecules in HEK293 IL-10R pSTAT3 luciferase reporter cells.

[0040] Figure 29 illustrates confirmation of TYK2 knockout in HEK293 TYK2 KO IL-10R pSTAT3 luciferase reporter cells.

[0041] Figure 30 illustrates comparative potency analysis of anti-IL-10RaP agonist VHH1-VHH2-Fc molecules and comparator molecules in HEK293 TYK2 KO IL-10R pSTAT3 luciferase reporter cells.

[0042] Figure 31 illustrates the effect of IL-10-Fc in the collagen induced arthritis (CIA) mouse model. Clinical arthritis scores from indicated group treated with isotype control. IL- 10-Fc, or anti-IL-17A antibody.1569-US-NP / WO-PCT

[0043] Figure 32 illustrates the effect of IL-10-Fc in the mannan induced inflammatory dermatitis mouse model. Clinical dermatitis scores from indicated group treated with isotype control, IL-10-Fc, or anti-IL-17A antibody.DETAILED DESCRIPTION1. Introduction

[0044] In this study, we employed extensive protein engineering on single-domain antibodies to generate potent anti-IL-10 receptor alpha subunit and anti-IL-10 beta subunit (IL-10RaP) agonists that selectively target myeloid cells. These IL-10RaP agonists exhibit strong myeloid cell specific immunosuppressive functions without activating T-cells, B-cells, or NK cells.2. IL-lORa Single Immunoglobulin Variable Domain (VHH) Binders

[0045] Provided are single immunoglobulin variable domain (VHH) binders that specifically bind to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa). Illustrative IL-lORa single immunoglobulin variable domain (VHH) binders are provided in Tables A1-A4 and B, below. The IL-lORa single immunoglobulin variable domain (VHH) binders can be humanized and incorporated into antibodies, including multispecific antibodies, e.g., bispecific antibodies, e.g., comprising a human Fc domain, e.g., a human IgGl or a human IgG4. The IL-lORa single immunoglobulin variable domain (VHH) binders described herein are suitable to use with an antigen binding domain that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) beta subunit (IL 10RP), including the IL-10RP single immunoglobulin variable domain (VHH) binders described herein.

[0046] With regard to the binding of an antibody or antigen-binding fragment thereof to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a nontarget molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule. An antibody or antigen-binding fragment thereof that “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular1569-US-NP / WO-PCTpolypeptide is one that binds to that particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. Affinities of antibodies can be readily determined using conventional techniques, for example, those described by Scatchard et al. (Ann. N. Y. Acad. Sci. USA 51: 660 (1949), ELISA assays, biolayer interferometry (BLI) assays, and surface plasmon resonance (SPR) assays). Binding properties of an antibody to antigens, cells or tissues thereof may generally be determined and assessed using immunodetection methods including, for example, immunofluorescence-based assays, such as immuno-histochemistry (IHC) and / or fluorescence- activated cell sorting (FACS).

[0047] In some embodiments, the VHH binds to IL 10Ra with an equilibrium dissociation constant (KD) of lower than about 5 nM, e.g., lower than about 4 nM, lower than about 3 nM or lower than about 2 nM.

[0048] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively:1) SEQ ID NOs 1, 2 and 3; (A01)2) SEQ ID NOs 4, 5 and 6; (A06)3) SEQ ID NOs 7, 8 and 9: (A09)4) SEQ ID NOs 10, 11 and 12; (B07)5) SEQ ID NOs 4, 13 and 14; (B08)6) SEQ ID NOs 4, 15 and 16; (C09)7) SEQ ID NOs 4, 17 and 18; (D08)8) SEQ ID NOs 19, 20 and 21; (D14)9) SEQ ID NOs 22, 23 and 24; (E07)10) SEQ ID NOs 22, 25 and 27; (huE07)11) SEQ ID NOs 22, 27 and 24; (huE07)12) SEQ ID NOs 4, 28 and 29; (El 5)13) SEQ ID NOs 4, 30 and 31; (F09)14) SEQ ID NOs 22, 23 and 32; (F10)15) SEQ ID NOs 33, 34 and 35; (Fl 1)16) SEQ ID NOs 4, 36 and 29; (F21)17) SEQ ID NOs 19, 37 and 38; (G22)18) SEQ ID NOs 39, 40 and 41; (G23)1569-US-NP / WO-PCT19) SEQ ID NOs: 42, 43 and 44; (H22)20) SEQ ID NOs: 45, 46 and 47; (104)21) SEQ ID NOs: 4, 48 and 6; (J 13)22) SEQ ID NOs: 4, 49 and 50; (J24)23) SEQ ID NOs: 19, 51 and 52; (L05)24) SEQ ID NOs: 19, 37 and 53; (El l) or25) SEQ ID NOs: 54, 55 and 24 (N16).

[0049] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively:1) SEQ ID NOs 56, 57 and 58; (AOI)2) SEQ ID NOs 59, 60 and 61; (A06)3) SEQ ID NOs 62, 63 and 64; (A09)4) SEQ ID NOs 65, 66 and 67; (B07)5) SEQ ID NOs 59, 68 and 69; (B08)6) SEQ ID NOs 59, 70 and 71; (C09)7) SEQ ID NOs 59, 72 and 73; (D08)8) SEQ ID NOs 74, 75 and 76; (D14)9) SEQ ID NOs 77, 78 and 79; (E07)10) SEQ ID NOs 77, 80 and 81; (huE07)11) SEQ ID NOs 77, 82 and 79; (huE07)12) SEQ ID NOs 59, 83 and 84; (E15)13) SEQ ID NOs 59. 85 and 86; (F09)14) SEQ ID NOs 77, 78 and 87; (F10)15) SEQ ID NOs 88, 89 and 90; (Fl 1)16) SEQ ID NOs 59, 91 and 84; (F21)17) SEQ ID NOs 92, 75 and 93; (G22)18) SEQ ID NOs 94, 89 and 95; (G23)19) SEQ ID NOs 96, 89 and 97; (H22)20) SEQ ID NOs 98, 99 and 100; (104)21) SEQ ID NOs 59, 101 and 61; (J13)22) SEQ ID NOs 59, 102 and 103: (J24)23) SEQ ID NOs 74, 75 and 104; (E05)1569-US-NP / WO-PCT24) SEQ ID NOs: 74, 75 and 105; (LI 1) or25) SEQ ID NOs: 106, 107 and 79 (N16).

[0050] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively:1) SEQ ID NOs 108, 109 and 110; (A01)2) SEQ ID NOs 111, 112 and 113; (A06)3) SEQ ID NOs 114, 115 and 116; (A09)4) SEQ ID NOs 117, 118 and 119; (B07)5) SEQ ID NOs 111, 112 and 120; (B08)6) SEQ ID NOs 111, 121 and 122; (C09)7) SEQ ID NOs 111, 121 and 123; (D08)8) SEQ ID NOs 124, 125 and 126; (D14)9) SEQ ID NOs 127, 128 and 129; (E07)10) SEQ ID NOs 127, 130 and 131; (huE07)11) SEQ ID NOs 111, 132 and 133; (E15)12) SEQ ID NOs 111, 134 and 135; (F09)13) SEQ ID NOs 127, 128 and 136; (F10)14) SEQ ID NOs 137, 138 and 139; (Fll)15) SEQ ID NOs 111, 132 and 133; (F21)16) SEQ ID NOs 140, 125 and 141; (G22)17) SEQ ID NOs 142, 138 and 143; (G23)18) SEQ ID NOs 124, 138 and 144; (H22)19) SEQ ID NOs 145, 146 and 147; (104)20) SEQ ID NOs 111, 112 and 113; (JI 3))21) SEQ ID NOs 111, 148 and 149; (J24)22) SEQ ID NOs 124, 125 and 150; (L05)23) SEQ ID NOs 124, 125 and 151; (Lil) or24) SEQ ID NOs 152, 121 and 129 (N16).

[0051] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively:1) SEQ ID NOs: 153, 154 and 155; (A01)1569-US-NP / WO-PCT2) SEQ ID NOs 156, 157 and 158; (A06)3) SEQ ID NOs: 159, 160 and 161; (A09)4) SEQ ID NOs 162, 163 and 164; (B07)5) SEQ ID NOs 156, 165 and 166; (B08)6) SEQ ID NOs 156, 167 and 168; (C09)7) SEQ ID NOs 156, 169 and 170; (D08)8) SEQ ID NOs 171, 172 and 173; (D14)9) SEQ ID NOs 174, 175 and 176; (E07)10) SEQ ID NOs 174, 177 and 178; (huE07)11) SEQ ID NOs 174, 179 and 176; (huE07)12) SEQ ID NOs 156, 180 and 181; (E15)13) SEQ ID NOs 156, 182 and 183; (F09)14) SEQ ID NOs 174, 175 and 184; (F10)15) SEQ ID NOs 185, 186 and 187; (Fl 1)16) SEQ ID NOs 709, 186 and 187; (huFll)17) SEQ ID NOs 156, 188 and 181; (F21)18) SEQ ID NOs 189, 190 and 191; (G22)19) SEQ ID NOs 192, 193 and 194; (G23)20) SEQ ID NOs 195, 196 and 197; (H22)21) SEQ ID NOs 198, 199 and 200; (104)22) SEQ ID NOs 156, 201 and 158; (J13)23) SEQ ID NOs 156, 202 and 203; (J24)24) SEQ ID NOs 204, 205 and 206; (L05)25) SEQ ID NOs 204, 190 and 207; (Lil) or26) SEQ ID NOs 208, 209 and 176 (N16).

[0052] In some embodiments, the VHH comprises the amino acid sequence, or an amino acid sequence of any one of SEQ ID NOs: 212, 230, 233, 234, 249, 710 and 724-725, or that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of any one of SEQ ID NOs: 212, 230, 233, 234, 249, 710 and 724-725. In some embodiments, the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 210-211, 213-229, 231-232, 235-248, 250-287, 710 and 724-725, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at1569-US-NP / WO-PCTleast 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of any one of SEQ ID NOs: 210-211, 213-229, 231-232, 235-248, 250-287, 710 and 724-725.

[0053] “Homology” or “identity” or “similarity” as used herein in the context of nucleic acids and polypeptides refers to the relationship between two polypeptides or two nucleic acid molecules based on an alignment of the amino acid sequences or nucleic acid sequences, respectively. Homology and identity can each be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When an equivalent position in the compared sequences is occupied by the same base or amino acid, then the molecules are identical at that position; when the equivalent site occupied by the same or a similar amino acid residue (e.g., similar in steric and / or electronic nature), then the molecules can be referred to as homologous (similar) at that position. Expression as a percentage of homology / similarity or identity refers to a function of the number of identical or similar amino acids at positions shared by the compared sequences. In comparing two sequences, the absence of residues (amino acids or nucleic acids) or presence of extra residues also decreases the identity and homology / similarity.

[0054] As used herein, “identity” means the percentage of identical nucleotide or amino acid residues at corresponding positions in two or more sequences when the sequences are aligned to maximize sequence matching, i.e., taking into account gaps and insertions. Sequences are generally aligned for maximum correspondence over a designated region, e.g., a region at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 or more amino acids or nucleotides in length, and can be up to the full length of the reference polypeptide or polynucleotide sequence. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer program, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Otherwise, standard parameters can be used. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0055] When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used1569-US-NP / WO-PCTherein, refers to a segment of at least 20 contiguous positions, usually 30 to 75, 40 to 50, or the full length of a sequence, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0056] Optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (e.g., GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by inspection.

[0057] One example of algorithms that are suitable for determining percent sequence identity are the Basic Local Alignment Search Tool (BLAST), BLAST 2.0 and PSLBLAST algorithms, which are described in Altschul, et al., J. Mol. Biol. (1990) 215: 403-410, Altschul, et al., Nucleic Acids Res. (1977) 25: 3389-3402, and Altschul, et al., Nucleic Acids Res. (1997) 25(17):3389-402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (blast.ncbi.nlm.nih.gov / Blast.cgi).

[0058] In one illustrative example, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <()). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTP program (for polypeptide sequences) or the BLASTN program (for polynucleotide sequences) uses as defaults a word length (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915) alignments, (B) of 50, expectation (E) of 10, M=5, N=-4 and a comparison of both strands.

[0059] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue1569-US-NP / WO-PCTalignments; or the end of either sequence is reached. The BLASTP algorithm parameters W, T and X determine the sensitivity and speed of the alignment.

[0060] In one approach, the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0061] Residue positions which are not identical can differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine (Gly, G), alanine (Ala, A), valine (Vai, V), leucine (Leu, L), and isoleucine (He, I); a group of amino acids having aliphatic-hydroxyl side chains is serine (Ser, S) and threonine (Thr, T); a group of amino acids having amide-containing side chains is asparagine (Asn, N) and glutamine (Gin, Q); a group of amino acids having aromatic side chains is phenylalanine (Phe, F), tyrosine (Tyr, Y), and tryptophan (Trp, W); a group of amino acids having basic side chains is lysine (Lys, K), arginine (Arg, R), and histidine (His, H); and a group of amino acids having sulfur-containing side chains is cysteine (Cys, C) and methionine (Met, M). Further, glutamic acid (Glu, E) and aspartic acid (Asp, D) are conservative amino acid substitutions.

[0062] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 2 and 3 (according to Kabat);2) SEQ ID NOs: 56, 57 and 58 (according to IMGT);3) SEQ ID NOs: 108, 109 and 110 (according to Chothia); or4) SEQ ID NOs: 153, 154 and 155 (according to Honegger).1569-US-NP / WO-PCTIn some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 210-211, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 210-211 (VHH A01).

[0063] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 4, 5 and 6 (according to Kabat);2) SEQ ID NOs: 59, 60 and 61 (according to IMGT);3) SEQ ID NOs: 111, 112 and 113 (according to Chothia); or4) SEQ ID NOs: 156, 157 and 158 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 212-215, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 212-215 (VHH A06).

[0064] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VILCDR2, a VILCDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 7, 8 and 9 (according to Kabat);2) SEQ ID NOs: 62, 63 and 64 (according to IMGT);3) SEQ ID NOs: 114, 115 and 116 (according to Chothia); or4) SEQ ID NOs: 159, 160 and 161 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 216-217, or an1569-US-NP / WO-PCTamino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 216-217 (VHH A09).

[0065] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 10, 11 and 12 (according to Kabat);2) SEQ ID NOs: 65, 66 and 67 (according to IMGT);3) SEQ ID NOs: 117, 118 and 119 (according to Chothia): or4) SEQ ID NOs: 162, 163 and 164 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 218-219, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 218-219 (VHH B07).

[0066] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 4, 13 and 14 (according to Kabat);2) SEQ ID NOs: 59, 68 and 69 (according to IMGT);3) SEQ ID NOs: 111, 112 and 120 (according to Chothia); or4) SEQ ID NOs: 156, 165 and 166 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 220-223, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 220-223 (VHH B08).1569-US-NP / WO-PCT

[0067] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1 ) SEQ ID NOs: 4, 15 and 16 (according to Kabat);2) SEQ ID NOs: 59, 70 and 71 (according to IMGT);3) SEQ ID NOs: 111, 121 and 122 (according to Chothia); or4) SEQ ID NOs: 156, 167 and 168 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 224-226 and 710, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 224-226 and 710 (VHH C09).

[0068] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 4, 17 and 18 (according to Kabat);2) SEQ ID NOs: 59, 72 and 73 (according to IMGT);3) SEQ ID NOs: 111, 121 and 123 (according to Chothia); or4) SEQ ID NOs: 156, 169 and 170 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 227-229 and 710, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 227-229 and 710 (VHH D08).

[0069] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3,1569-US-NP / WO-PCTa light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 19, 20 and 21 (according to Kabat);2) SEQ ID NOs: 74, 75 and 76 (according to IMGT);3) SEQ ID NOs: 124, 125 and 126 (according to Chothia): or4) SEQ ID NOs: 171, 172 and 173 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 230-232, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 230-232 (VHH D14).

[0070] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 22, 23 and 24; or 22, 25 and 26; or 22, 27 and 24 (according to Kabat); 2) SEQ ID NOs: 77, 78 and 79; or 77, 80 and 81; or 77, 82 and 79 (according to IMGT); 3) SEQ ID NOs: 127, 128 and 129; or 127, 130 and 131 (according to Chothia); or 4) SEQ ID NOs: 174, 175 and 176; or 174, 177 and 178; or 174, 179 and 176 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 233-240 and 724-725, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 233-240 and 724-725. In some embodiments, the VHH binds to an epitope on IL 10Ra comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711. (VHH E07).

[0071] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain1569-US-NP / WO-PCTvariable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 4, 28 and 29 (according to Kabat);2) SEQ ID NOs: 59, 83 and 84 (according to IMGT);3) SEQ ID NOs: 111, 132 and 133 (according to Chothia); or4) SEQ ID NOs: 156, 180 and 181 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 241-243 and 710, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 241-243 and 710 (VHH E15).

[0072] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 4, 30 and 31 (according to Kabat);2) SEQ ID NOs: 59, 85 and 86 (according to IMGT);3) SEQ ID NOs: 111, 134 and 135 (according to Chothia); or4) SEQ ID NOs: 156, 182 and 183 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 244-246, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 244-246 (VHH F09).

[0073] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1569-US-NP / WO-PCT1) SEQ ID NOs: 22, 23 and 32 (according to Kabat);2) SEQ ID NOs: 77, 78 and 87 (according to IMGT);3) SEQ ID NOs: 127, 128 and 136 (according to Chothia); or4) SEQ ID NOs: 174, 175 and 184 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 247-248, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 247-248 (VHH F10).

[0074] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 33, 34 and 35 (according to Kabat);2) SEQ ID NOs: 88, 89 and 90 (according to IMGT);3) SEQ ID NOs: 137, 138 and 139 (according to Chothia); or4) SEQ ID NOs: 185, 186 and 187 or 709, 186 and 187 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 249-252 and 752-755, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 249-252 and 752-755. In some embodiments, the VHH binds to an epitope on IL 10Ra comprising contact amino acid residues 1169, 1171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197 and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711. (VHH Fl 1 ).

[0075] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1569-US-NP / WO-PCT1) SEQ ID NOs: 4, 36 and 29 (according to Kabat);2) SEQ ID NOs: 59, 91 and 84 (according to IMGT);3) SEQ ID NOs: 111, 132 and 133 (according to Chothia); or4) SEQ ID NOs: 156, 188 and 181 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 253-255 and 710, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 253-255 and 710 (VHH F21).

[0076] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 19, 37 and 38 (according to Kabat);2) SEQ ID NOs: 92, 75 and 93 (according to IMGT);3) SEQ ID NOs: 140, 125 and 141 (according to Chothia); or4) SEQ ID NOs: 189, 190 and 191 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 256-259, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 256-259 (VHH G22).

[0077] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 19, 37 and 38 (according to Kabat);2) SEQ ID NOs: 92, 75 and 93 (according to IMGT);3) SEQ ID NOs: 140, 125 and 141 (according to Chothia); or1569-US-NP / WO-PCT4) SEQ ID NOs: 189, 190 and 191 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 260-263, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 260-263 (VHH G23).

[0078] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 42, 43 and 44 (according to Kabat);2) SEQ ID NOs: 96, 89 and 97 (according to IMGT);3) SEQ ID NOs: 124, 138 and 144 (according to Chothia); or4) SEQ ID NOs: 195, 196 and 197 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 264-266, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 264-266 (VHH H22).

[0079] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 45, 46 and 47 (according to Kabat);2) SEQ ID NOs: 98, 99 and 100 (according to IMGT);3) SEQ ID NOs: 145, 146 and 147 (according to Chothia); or4) SEQ ID NOs: 198, 199 and 200 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise,1569-US-NP / WO-PCTrespectively, the amino acid sequences set forth in any of SEQ ID NOs: 267-269, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any of SEQ ID NOs: 267-269 (VHH 104).

[0080] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 4, 48 and 6 (according to Kabat);2) SEQ ID NOs: 59, 101 and 61 (according to IMGT);3) SEQ ID NOs: 111, 112 and 113 (according to Chothia); or4) SEQ ID NOs: 156, 201 and 158 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 270-273, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 270-273 (VHH J13).

[0081] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 4, 49 and 50 (according to Kabat);2) SEQ ID NOs: 59, 102 and 103 (according to IMGT);3) SEQ ID NOs: 111, 148 and 149 (according to Chothia); or4) SEQ ID NOs: 156, 202 and 203 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 274-277, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical1569-US-NP / WO-PCTto, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 274-277 (VHH J24).

[0082] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 19, 51 and 52 (according to Kabat);2) SEQ ID NOs: 74, 75 and 104 (according to IMGT);3) SEQ ID NOs: 124, 125 and 150 (according to Chothia); or4) SEQ ID NOs: 204. 205 and 206 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 278-280, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 278-280 (VHH L05).

[0083] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 19, 37 and 53 (according to Kabat);2) SEQ ID NOs: 74, 75 and 105 (according to IMGT);3) SEQ ID NOs: 124, 125 and 151 (according to Chothia); or4) SEQ ID NOs: 204, 190 and 207 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 281-284, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 281-284 (VHH LI 1).1569-US-NP / WO-PCT

[0084] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-lORa comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1 ) SEQ ID NOs: 54, 55 and 24 (according to Kabat);2) SEQ ID NOs: 106, 107 and 79 (according to IMGT);3) SEQ ID NOs: 152, 121 and 129 (according to Chothia); or4) SEQ ID NOs: 208, 209 and 176 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORa, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 285-287, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 285-287 (VHH N16).

[0085] Generally, the herein described VHH that bind to IL-lORa bind to both human IL-lORa and cynomolgus IL-lORa, within a 10-fold affinity difference, e.g., within a 5 -fold or within a 3-fold affinity difference e.g., as determined by SPR and expressed as an equilibrium dissociation constant (KD)). Amino acid sequences of complementarity determining regions (CDRs) of illustrative VHH that bind to IL-lORa are provided in Tables A1-A4. Amino acid sequences of variable regions of illustrative VHH that bind to IL-lORa are provided in Table B.Table Al - Illustrative IL-lORa Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences(according to Rabat)VHH name VHH - CDR1 VHH - CDR2 VHH - CDR3A01 NYWVD AINKDGGSAYYADSVKG DYGSGMHDSEQ ID NO: 1 SEQ ID NO: 2 SEQ ID NO: 3A06 SYGMG AINWIPGTTYYADSVKG RRRIDNYYRASEYDY SEQ ID NO: 4 SEQ ID NO: 5 SEQ ID NO: 6A09 SYAID CISSSGISTTYADSVKG AALCMSGTYYAGPGY SEQ ID NO: 7 SEQ ID NO: 8 SEQ ID NO: 9B07 YYAIG CISSSGGSTYYADSVKG DAACMWAGTLILPDDY SEQ ID NO: 10 SEQ ID NO: 11 SEQ ID NO: 12B08 SYGMG TINWIPGSTYYADSVKG RRRIESYYRASEYDY SEQ ID NO: 4 SEQ ID NO: 13 SEQ ID NO: 141569-US-NP / WO-PCTTable Al - Illustrative IL-lORa Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences(according to Rabat)VHH name VHH - CDR1 VHH - CDR2 VHH - CDR3C09 SYGMG AISWIGGGTYYADSVKG KYYPDSYFAAASYAY SEQ ID NO: 4 SEQ ID NO: 15 SEQ ID NO: 16D 08 SYGMG AISWIGGSTYYADSVKG KYYTDSYFAATSYAY SEQ ID NO: 4 SEQ ID NO: 17 SEQ ID NO: 18D 14 GYGMG SINWIYGATYYTDSVKG KINGGSYFNTGSFGF SEQ ID NO: 19 SEQ ID NO: 20 SEQ ID NO: 21E 07 AYGMG AIRWIGDSTYYADSVKG KTSVTSYLSEKSYNY SEQ ID NO: 22 SEQ ID NO: 23 SEQ ID NO: 24 huE07 AYGMG AIRWYGEGTYYAESVKG KTRPDSYLSEKSYGY SEQ ID NO: 22 SEQ ID NO: 25 SEQ ID NO: 26 huE07 AYGMG AIRWIGDATYYAESVKG KTSVTSYLSEKSYNY SEQ ID NO: 22 SEQ ID NO: 27 SEQ ID NO: 24E 15 SYGMG Al S W I GNS AYYAD S VKG KYYTDSYYAAASYAY SEQ ID NO: 4 SEQ ID NO: 28 SEQ ID NO: 29F 09 SYGMG AISWIGSATDYADSVRG RRSPMSRTSVLQYDY SEQ ID NO: 4 SEQ ID NO: 30 SEQ ID NO: 31F 10 AYGMG AIRWIGDSTYYADSVKG KTSVTSYLSEKAYNY SEQ ID NO: 22 SEQ ID NO: 23 SEQ ID NO: 32F l l SHTVG AITWNGDTTYFGDFVEG ATGQVWSLQYLRESSYAY SEQ ID NO: 33 SEQ ID NO: 34 SEQ ID NO: 35F21 SYGMG Al S W I GNS T YYAD S VKG KYYTDSYYAAASYAY SEQ ID NO: 4 SEQ ID NO: 36 SEQ ID NO: 29G22 GYGMG AINWIYGATYYADSVKG KINAGSYFNIGSFGS SEQ ID NO: 19 SEQ ID NO: 37 SEQ ID NO: 38G23 DDTVG AITWNGDTTYYGDSVKG AAGQDWSLGYLRESSYAY SEQ ID NO: 39 SEQ ID NO: 40 SEQ ID NO: 41H22 GYTVG AITWNGDTTYFGDSVKG ATGQEWSLQYLRESSYAY SEQ ID NO: 42 SEQ ID NO: 43 SEQ ID NO: 44104 NYAMA AINWFGRATEYADSVKD RTKVTTGRRNQAEYDY SEQ ID NO: 45 SEQ ID NO: 46 SEQ ID NO: 47J13 SYGMG T INW I P GNT YYAD S VKG RRRIDNYYRASEYDY SEQ ID NO: 4 SEQ ID NO: 48 SEQ ID NO: 6J24 SYGMG TI IGWIPGNTYYADSVKG RRRIDSYYRASEYDY SEQ ID NO: 4 SEQ ID NO: 49 SEQ ID NO: 50L05 GYGMG SINWIYGATYYSDSVKG KINGESYFNTGSFGS SEQ ID NO: 19 SEQ ID NO: 51 SEQ ID NO: 52Li l GYGMG AINWIYGATYYADSVKG KINGGSYFNIGSFGS SEQ ID NO: 19 SEQ ID NO: 37 SEQ ID NO: 53N16 YYGMG AIRWIGGDTYYADSVKG KTSVTSYLSEKSYNY SEQ ID NO: 54 SEQ ID NO: 55 SEQ ID NO: 241569-US-NP / WO-PCTTable A2 - Illustrative IL-lORa Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to IMGT)VHH name VHH - CDR1 VHH - CDR2 VHH - CDR3A01 GFTFSNYW INKDGGSA AKDYGSGMHDSEQ ID NO: 56 SEQ ID NO: 57 SEQ ID NO: 58 AO 6 GRTFSSYG INWIPGTT AARRRIDNYYRASEYDY SEQ ID NO: 59 SEQ ID NO: 60 SEQ ID NO: 61 AO 9 GFTLDSYA ISSSGIST AAAALCMSGTYYAGPGY SEQ ID NO: 62 SEQ ID NO: 63 SEQ ID NO: 64 BO V DFTLDYYA ISSSGGST AADAACMWAGTLILPDDY SEQ ID NO: 65 SEQ ID NO: 66 SEQ ID NO: 67 B08 GRTFSSYG INWIPGST AARRRIESYYRASEYDY SEQ ID NO: 59 SEQ ID NO: 68 SEQ ID NO: 69 C09 GRTFSSYG ISWIGGGT AAKYYPDSYFAAASYAY SEQ ID NO: 59 SEQ ID NO: 70 SEQ ID NO: 71 D08 GRTFSSYG ISWIGGST AAKYYTDSYFAATSYAY SEQ ID NO: 59 SEQ ID NO: 72 SEQ ID NO: 73 D14 GRTFSGYG INWIYGAT AAKINGGSYFNTGSFGF SEQ ID NO: 74 SEQ ID NO: 75 SEQ ID NO: 76 E07 GRTFSAYG IRWIGDST AAKTSVTSYLSEKSYNY SEQ ID NO: 77 SEQ ID NO: 78 SEQ ID NO: 79 huEO V GRTFSAYG IRWYGEGT AAKTRPDSYLSEKSYGY SEQ ID NO: 77 SEQ ID NO: 80 SEQ ID NO: 81 huEO V GRTFSAYG IRWIGDAT AAKTSVTSYLSEKSYNY SEQ ID NO: 77 SEQ ID NO: 82 SEQ ID NO: 79 E15 GRTFSSYG ISWIGNSA AAKYYTDSYYAAASYAY SEQ ID NO: 59 SEQ ID NO: 83 SEQ ID NO: 84 F09 GRTFSSYG ISWIGSAT AARRSPMSRTSVLQYDY SEQ ID NO: 59 SEQ ID NO: 85 SEQ ID NO: 86 F10 GRTFSAYG IRWIGDST AAKTSVTSYLSEKAYNY SEQ ID NO: 77 SEQ ID NO: 78 SEQ ID NO: 87 Fl l GRTFSSHT ITWNGDTT AAATGQVWS LQYLRE S S YAY SEQ ID NO: 88 SEQ ID NO: 89 SEQ ID NO: 90 F21 GRTFSSYG ISWIGNST AAKYYTDSYYAAASYAY SEQ ID NO: 59 SEQ ID NO: 91 SEQ ID NO: 84 G22 GRTFDGYG INWIYGAT AAKINAGSYFNIGSFGS SEQ ID NO: 92 SEQ ID NO: 75 SEQ ID NO: 93 G23 GRTFSDDT ITWNGDTT AAAAGQD WS LGYLRE S S YAY SEQ ID NO: 94 SEQ ID NO: 89 SEQ ID NO: 95 H22 GRTFSGYT ITWNGDTT AAATGQEWSLQYLRESSYAY SEQ ID NO: 96 SEQ ID NO: 89 SEQ ID NO: 971569-US-NP / WO-PCTTable A2 - Illustrative IL-lORa Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to IMGT)VHH name VHH - CDR1 VHH - CDR2 VHH - CDR3104 GRTFSNYA INWFGRAT AARTKVT T GRRNQAE YD Y SEQ ID NO: 98 SEQ ID NO: 99 SEQ ID NO: 100 J13 GRTFSSYG INWIPGNT AARRRIDNYYRASEYDY SEQ ID NO: 59 SEQ ID NO: 101 SEQ ID NO: 61 J24 GRTFSSYG IIGWIPGNT AARRRIDSYYRASEYDY SEQ ID NO: 59 SEQ ID NO: 102 SEQ ID NO: 103 L05 GRTFSGYG INWIYGAT AAKINGESYFNTGSFGS SEQ ID NO: 74 SEQ ID NO: 75 SEQ ID NO: 104 Li l GRTFSGYG INWIYGAT AAKINGGSYFNIGSFGS SEQ ID NO: 74 SEQ ID NO: 75 SEQ ID NO: 105 N16 GGTFSYYG IRWIGGDT AAKTSVTSYLSEKSYNY SEQ ID NO: 106 SEQ ID NO: 107 SEQ ID NO: 79Table A3 - Illustrative IL-lORct Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to Chothia)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameA01 GFTFSNY KDGG YGSGMHSEQ ID NO: 108 SEQ ID NO: 109 SEQ ID NO: 110AO 6 GRTFSSY WIPG RRIDNYYRASEYDSEQ ID NO: 111 SEQ ID NO: 112 SEQ ID NO: 113 A09 GFTLDSY SSGI ALCMSGTYYAGPGSEQ ID NO: 114 SEQ ID NO: 115 SEQ ID NO: 116 B07 DFTLDYY SSGG AACMWAGTLILPDD SEQ ID NO: 117 SEQ ID NO: 118 SEQ ID NO: 119 B08 GRTFSSY WIPG RRIESYYRASEYDSEQ ID NO: 111 SEQ ID NO: 112 SEQ ID NO: 120 C09 GRTFSSY WIGG YYPDSYFAAASYASEQ ID NO: 111 SEQ ID NO: 121 SEQ ID NO: 122 D 08 GRTFSSY WIGG YYTDSYFAATSYASEQ ID NO: 111 SEQ ID NO: 121 SEQ ID NO: 123 D 14 GRTFSGY WIYG INGGSYFNTGSFGSEQ ID NO: 124 SEQ ID NO: 125 SEQ ID NO: 126 E 07 GRTFSAY WIGD TSVTSYLSEKSYNSEQ ID NO: 127 SEQ ID NO: 128 SEQ ID NO: 129 huE07 GRTFSAY WYGE TRPDSYLSEKSYGSEQ ID NO: 127 SEQ ID NO: 130 SEQ ID NO: 131 E 15 GRTFSSY WIGN YYTDSYYAAASYA1569-US-NP / WO-PCTTable A3 - Illustrative IL-lORa Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to Chothia)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameSEQ ID NO: 111 SEQ ID NO: 132 SEQ ID NO: 133 F 09 GRTFSSY WIGS RSPMSRTSVLQYDSEQ ID NO: 111 SEQ ID NO: 134 SEQ ID NO: 135 F 10 GRTFSAY WIGD TSVTSYLSEKAYNSEQ ID NO: 127 SEQ ID NO: 128 SEQ ID NO: 136 F ll GRTFSSH WNGD TGQVWSLQYLRESSYA SEQ ID NO: 137 SEQ ID NO: 138 SEQ ID NO: 139 F21 GRTFSSY WIGN YYTDSYYAAASYASEQ ID NO: 111 SEQ ID NO: 132 SEQ ID NO: 133 G22 GRTFDGY WIYG INAGSYFNIGSFGSEQ ID NO: 140 SEQ ID NO: 125 SEQ ID NO: 141 G23 GRTFSDD WNGD AGQDWSLGYLRESSYA SEQ ID NO: 142 SEQ ID NO: 138 SEQ ID NO: 143 H22 GRTFSGY WNGD TGQEWSLQYLRESSYA SEQ ID NO: 124 SEQ ID NO: 138 SEQ ID NO: 144104 GRTFSNY WFGR TKVTTGRRNQAEYD SEQ ID NO: 145 SEQ ID NO: 146 SEQ ID NO: 147 J13 GRTFSSY WIPG RRIDNYYRASEYDSEQ ID NO: 111 SEQ ID NO: 112 SEQ ID NO: 113 J24 GRTFSSY GWIPG RRIDSYYRASEYDSEQ ID NO: 111 SEQ ID NO: 148 SEQ ID NO: 149 L05 GRTFSGY WIYG INGESYFNTGSFGSEQ ID NO: 124 SEQ ID NO: 125 SEQ ID NO: 150 Lil GRTFSGY WIYG INGGSYFNIGSFGSEQ ID NO: 124 SEQ ID NO: 125 SEQ ID NO: 151 N16 GGTFSYY WIGG TSVTSYLSEKSYNSEQ ID NO: 152 SEQ ID NO: 121 SEQ ID NO: 129Table A4 - Illustrative IL-10Ra Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to Honegger)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameA01 ASGFTFSNYW INKDGGSAYYADSVKGR DYGSGMHSEQ ID NO: 153 SEQ ID NO: 154 SEQ ID NO: 155 AO 6 ASGRTFSSYG INWIPGTTYYADSVKGR RRRIDNYYRASEYD SEQ ID NO: 156 SEQ ID NO: 157 SEQ ID NO: 158 A09 ASGFTLDSYA ISSSGISTTYADSVKGR AALCMSGTYYAGPG1569-US-NP / WO-PCTTable A4 - Illustrative IL-lORa Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to Honegger)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameSEQ ID NO: 159 SEQ ID NO: 160 SEQ ID NO: 161 B07 ASDFTLDYYA ISSSGGSTYYADSVKGR DAACMVVAGTLILPDD SEQ ID NO: 162 SEQ ID NO: 163 SEQ ID NO: 164 B08 ASGRTFSSYG INWIPGSTYYADSVKGR RRRIESYYRASEYD SEQ ID NO: 156 SEQ ID NO: 165 SEQ ID NO: 166 C09 ASGRTFSSYG I S W I GGGT Y YAD S VKGR KYYPDSYFAAASYA SEQ ID NO: 156 SEQ ID NO: 167 SEQ ID NO: 168 D 08 ASGRTFSSYG ISWIGGSTYYADSVKGR KYYTDSYFAATSYA SEQ ID NO: 156 SEQ ID NO: 169 SEQ ID NO: 170 D 14 ASGRTFSGYG INWIYGATYYTDSVKGR KINGGSYFNTGSFG SEQ ID NO: 171 SEQ ID NO: 172 SEQ ID NO: 173 E 07 ASGRTFSAYG IRWIGDSTYYADSVKGR KTSVTSYLSEKSYN SEQ ID NO: 174 SEQ ID NO: 175 SEQ ID NO: 176 huE07 ASGRTFSAYG IRWYGEGTYYAESVKGR KTRPDSYLSEKSYG SEQ ID NO: 174 SEQ ID NO: 177 SEQ ID NO: 178 huE07 ASGRTFSAYG TRW I GD AT Y YAE S VKGR KTSVTSYLSEKSYN SEQ ID NO: 174 SEQ ID NO: 179 SEQ ID NO: 176 E 15 ASGRTFSSYG I S W I GNS AY YAD S VKGR KYYTDSYYAAASYA SEQ ID NO: 156 SEQ ID NO: 180 SEQ ID NO: 181 F 09 ASGRTFSSYG ISWIGSATDYADSVRGR RRSPMSRTSVLQYD SEQ ID NO: 156 SEQ ID NO: 182 SEQ ID NO: 183 F 10 ASGRTFSAYG IRWIGDSTYYADSVKGR KTSVTSYLSEKAYN SEQ ID NO: 174 SEQ ID NO: 175 SEQ ID NO: 184 F l l NSGRTFSSHT ITWNGDTTYFGDFVEGR ATGQVWSLQYLRESSYA SEQ ID NO: 185 SEQ ID NO: 186 SEQ ID NO: 187 huFll ASGRTFSSHT ITWNGDTTYFGDFVEGR ATGQVWSLQYLRESSYA SEQ ID NO: 709 SEQ ID NO: 186 SEQ ID NO: 187 F21 ASGRTFSSYG ISWIGNSTYYADSVKGR KYYTDSYYAAASYA SEQ ID NO: 156 SEQ ID NO: 188 SEQ ID NO: 181 G22 ASGRTFDGYG INWIYGATYYADSVKGR KINAGSYFNIGSFG SEQ ID NO: 189 SEQ ID NO: 190 SEQ ID NO: 191 G23 ASGRTFSDDT ITWNGDTTYYGDSVKGR AAGQDWSLGYLRESSYA SEQ ID NO: 192 SEQ ID NO: 193 SEQ ID NO: 194 H22 ASGRTFSGYT ITWNGDTTYFGDSVKGR ATGQEWSLQYLRESSYA SEQ ID NO: 195 SEQ ID NO: 196 SEQ ID NO: 197 104 ASGRTFSNYA I NWF G RAT E Y AD S VKD R RTKVTTGRRNQAEYD SEQ ID NO: 198 SEQ ID NO: 199 SEQ ID NO: 200 J13 ASGRTFSSYG INWIPGNTYYADSVKGR RRRIDNYYRASEYD SEQ ID NO: 156 SEQ ID NO: 201 SEQ ID NO: 1581569-US-NP / WO-PCTTable A4 - Illustrative IL-lORa Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to Honegger)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameJ2 4 ASGRTFSSYG IIGWIPGNTYYADSVKGR RRRIDSYYRASEYD SEQ ID NO: 156 SEQ ID NO: 202 SEQ ID NO: 203 L05 NSGRTFSGYG INWIYGATYYSDSVKGR KINGESYFNTGSFG SEQ ID NO: 204 SEQ ID NO: 205 SEQ ID NO: 206 Lil NSGRTFSGYG I NW I Y G AT Y Y AD S VKGR KINGGSYFNIGSFG SEQ ID NO: 204 SEQ ID NO: 190 SEQ ID NO: 207 N16 ASGGTFSYYG IRWIGGDTYYADSVKGR KTSVTSYLSEKSYN SEQ ID NO: 208 SEQ ID NO: 209 SEQ ID NO: 176Table B - Illustrative IL-10Ra Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameA01 SEQ ID NO: 210 DVQLVESGGGWQPGGSLRLSCAASGFTFSNYWVDWLRQAPGKGLEWVSAINKDG GSAYYADSVKGRFTISRDNAKNTLYLQMTSLKPEDTAVYYCAKDYGSGMHDWGKG TQVTVSShuAOl SEQ ID NO: 211EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWVDWLRQAPGKGLEWVSAINKDG GSAYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDYGSGMHDWGQG TMVTVSS AO 6 SEQ ID NO: 212con X1X2LQLVESGGGX3VQX4GGSLRLSCAASGRTFSSYGMGWFRQAPGKERX5X6VA X7lXsNWIPGX9TYYADSVKGRFTIXioGDKX:iKNTLYLQMDXi2LXi3Xi4EDTAVYY CAARRRIX15X16YYRASEYDYWGQGTX17VTVSSXi is S, GG, AS, ASS or absent (i. e., no amino acid residues )X2 is E or QX3is L, S or VX4is A or PX5 is E or GXs is F or LX? is A or TXg is I or absentX9is N, S or TX10 is S or TXu is D or SX12 is N or SX13 is K or RX14 is A or PX15 is D or E1569-US-NP / WO-PCT Table B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameXie is N or SXi? is L or QAO 6 SEQ ID NO: 213Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 214Xi is AS XiQLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINWI PGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYRAS EYDYWGQGTQVTVSShuAO 6 SEQ ID NO: 215ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWIP GTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRASE YDYWGQGTLVTVSSA09 SEQ ID NO: 216 DLQLVESGGGLVQPGGSLRLSCAASGFTLDSYAIDWFRQAPGKEREGVSCISSSG ISTTYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAAALCMSGTYYAG PGYWGQGTQVTVSShuAO 9 SEQ ID NO: 217ELQLVESGGGLVQPGGSLRLSCAASGFTLDSYAIDWFRQAPGKEREGVSCISSSG ISTTYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAAAALCMSGTYYAG PGYWGQGTTVTVSSB07 SEQ ID NO: 218 DVQLVESGGGLVQPGGSLRLSCAASDFTLDYYAIGWFRQAPGKEREGVSCISSSG GSTYYADSVKGRFTISRDNAKNTVSLQMNSLKPEDTAVYYCAADAACMWAGTLI LPDDYWGQGTQVTVSShuB07 SEQ ID NO: 219EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREGVSCISSSG GSTYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADAACMWAGTLI LPDDYWGQGTLVTVSSB08 SEQ ID NO: 220Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 221Xi is AS XiQVQLVESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGFVATINWI PGSTYYADSVKGRFTISGDKDNNTVYLQMDNLKPEDTAVYYCAARRRIESYYRAS EYDYWGQGTQVTVSS1569-US-NP / WO-PCTTable B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenamehuB08 SEQ ID NO: 222Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 223Xi is AS XiQVQLVESGGGVVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINWI PGSTYYADSVKGRFTISGDKSKNTVYLQMNSLRAEDTAVYYCAARRRIESYYRAS EYDYWGQGTLVTVSSC09 SEQ ID NO: 710Con X1X2VQLX3ESGGGLVQX4GGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAIS w / WIGX5X6X7YYADSVKGRFTLSX8DNX9KNX10X11X12LQMNSLX13X14EDTAVYYCA D08, AKYYXi5DSYX16AAXi7SYAYWGQGTXlsVTVSSE15, Xi is S, GG, AS, ASS or absent (i. e., no amino acid F21 residues )X2 is E or QX3 is L or QX4 is A or PX5 is G or NXe is G or SX? is A or TX8is G, R or SXg is A or SX10 is M, R or TXu is I, L or VX12 is A or YXi 3 is K or RX14 is A or PX15 is P or TXie is F or YX17 is A or TXis is L or QC09 SEQ ID NO: 224Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 225Xi is AS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNAKNMVYLQMNSLKPEDTAVYYCAAKYYPDSYFAAA SYAYWGQGTQVTVSShuC09 SEQ ID NO: 226EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG GGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAAAS YAYWGQGTLVTVSS1569-US-NP / WO-PCTTable B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameD08 SEQ ID NO: 227Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 228Xi is AS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGSTYYADSVKGRFTLSSDNAKNRIALQMNSLKPEDTAVYYCAAKYYTDSYFAAT SYAYWGQGTQVTVSShuD08 SEQ ID NO: 229EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG GGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAAAS YAYWGQGTLVTVSSG22 SEQ ID NO: 230con X1X2LQLX3ESGGGLVQX4GGSLX5LSCX6X7SGRTFSGYGMGWFRQX8PGKEREFVS w / X9INWIYGATYYXioDSVKGRFXiiXi2SXi3DKXi4KXi5TXi6YLQMXi7SLXisXi9ED D14, TAVYYCAAKINGX20SYFNX21GSFGFWGQGTX22VTVSSL05, Xi is S, GG, AS, ASS or absent (i. e., no amino acid Lil residues )X2 is E or QX3 is L, Q or VX4is A or PX5 is K or RX6is A, S or TX7 is A or NX9is A or PX9is A or SX10 is A, S or TXu is A or TX12 is L or VX13 is G or RX14 is A, D or SX15 is G or NXis is L, M or VX17 is D, N or SXis is K or RXi9is A or PX20 is E or GX21 is I or TX22 is L or QD14 SEQ ID NO: 231 ELQLVESGGGLVQAGGSLKLSCTASGRTFSGYGMGWFRQAPGKEREFVSSINWIY GATYYTDSVKGRFAVSRDKDKNTMYLQMSSLKPEDTAVYYCAAKINGGSYFNTGS FGFWGQGTQVTVSS1569-US-NP / WO-PCTTable B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenamehuD14 SEQ ID NO: 232ELQLVESGGGLVQPGGSLRLSCAASGRTFSGYGMGWFRQAPGKEREFVSSINWIY GATYYTDSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINGGSYFNTGS FGFWGQGTLVTVSSE07 SEQ ID NO: 233coni XIX2LQLVESGGGLVX3X4GX5SLRLSCAASGRTFSAYGMGWFRQAPGKX6X7EFVXSAIRWX9GX10X11TYYAX12SVKGRFTISKDX13X14KNTLYLQMX15SLX16X17EDTAV YYCAAKTXi3Xi9X2oSYLSEKSYX2iYWGQGTX22VTVSSXI is S, GG, AS, ASS or absent (i. e., no amino acid residues )X2 is E or QX3 is Q or RX4 is A or PX5 is D or GXs is E or GX7 is L or RXg is A or SX9 is I or YX10 is D or EXn is A, G or SX12 is D or EX13 is N or SX14 is A or SXis is N or SXis is K or RX17 is A or PXis is R or SX19 is P or VX20 is D or TX21 is G or NX22is M or QE07 SEQ ID NO: 234con2 X1QLQLVESGGGLVX3X4GGSLRLSCAASGRTFSAYGMGWFRQAPGKX6REFVX7AI RWXgGXoXioTYYAXiiSVKGRFTISKDNXisKNTLYLQMX^SLXisXisEDTAVYYCA AKTXi7Xi8Xi9SYLSEKSYX2oYWGQGTX2iVTVSSXI is S, GG, AS, ASS or absent (i. e., no amino acid residues )X2is Q or RX4 is A or PXs is E or G1569-US-NP / WO-PCT Table B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameX? is A or SXs is I or YXs is D or EX10 is A, G or SXu is D or EXis is A or SX14 is N or SX15 is K or RXis is A or PX17 is R or SXis is P or VX19 is D or TX20 is G or NX21 is M or QE07 SEQ ID NO: 235Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 236Xi is AS XiQLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRWI GDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLSEK SYNYWGQGTQVTVSShuE07 SEQ ID NO: 724ELQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRWIG DSTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEKS YNYWGQGTMVTVSShuE07 SEQ ID NO: 725ELQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRWIG DSTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEKS YNYWGQGTMVTVSShuE07 SEQ ID NO: 237Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 238Xi is AS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRWY GEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLSEK SYGYWGQGTMVTVSS1569-US-NP / WO-PCTTable B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenamehuE07 SEQ ID NO: 239Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 240Xi is AS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRWI GDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEK SYNYWGQGTMVTVSSE15 SEQ ID NO: 241Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 242Xi is AS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSAYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYAAA SYAYWGQGTQVTVSShuE15 SEQ ID NO: 243EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG NSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAAAS YAYWGQGTLVTVSSF09 SEQ ID NO: 244Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 245Xi is AS XiQVQLQESGGGLVQAGGSLSLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GSATDYADSVRGRFTISGDNAKNTVYLLMNNLKPEDTAVYYCAARRSPMSRTSVL QYDYWGQGTQVTVSShuF09 SEQ ID NO: 246EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG SATDYADSVRGRFTISGDNSKNTVYLQMNSLRAEDTAVYYCAARRSPMSRTSVLQ YDYWGQGTLVTVSSF10 SEQ ID NO: 247 EVQLVESGGGLVQAGDSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRWIG DSTYYADSVKGRFTISKDSAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLSEKA YNYWGQGTQVTVSShuFlO SEQ ID NO: 248EVQLVESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRWIG DSTYYADSVKGRFTISKDSSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEKA YNYWGQGTMVTVSS1569-US-NP / WO-PCT Table B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameFll SEQ ID NO: 249con EX1QLX2ESGGGLVQX3GGSLRLSCAX4SGRTFSSHTVGWFRQAPGKX5REFVX6AI TWNGDTTYFGDFVEGRFX7lSRDXsX9KNTLYLXioMNXiiLX:2Xi3EDTAVYYCAAA TGQVWSLQYLRESSYAYWGQGTX14VTVSSXi is L or VX2 is L or VX3is A or PX4 is A or NX5 is E or GXs is A or EX7is S or TX3is N or SX9 is A or SX10 is E or QXn is K or SX12 is K or RX13 is A or PX14 is L or QFll SEQ ID NO: 250 ELQLVESGGGLVQAGGSLRLSCANSGRTFSSHTVGWFRQAPGKEREFVAAITWNG DTTYFGDFVEGRFSISRDSAKNTLYLEMNKLKPEDTAVYYCAAATGQVWSLQYLR E S S Y AYWGQGTQVTVS ShuFll SEQ ID NO: 251EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVAAITWNG DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR ESSYAYWGQGTLVTVSShuFll SEQ ID NO: 252ELQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWNG DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR ESSYAYWGQGTLVTVSShuFll SEQ ID NO: 752EVQLLESGGGLVQPGGSLRLSCANSGRTFSSHTVGWFRQAPGKGREFVSAITWNG DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR ESSYAYWGQGTLVTVSShuFll SEQ ID NO: 753EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWNG DTTYFGDFVEGRFTISRDSSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR ESSYAYWGQGTLVTVSS1569-US-NP / WO-PCTTable B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenamehuFll SEQ ID NO: 754EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVAAITWNG DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR ESSYAYWGQGTLVTVSShuFll SEQ ID NO: 755ELQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWNG DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR ESSYAYWGQGTLVTVSSF21 SEQ ID NO: 253Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 254Xi is AS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSTYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYAAA SYAYWGQGTQVTVSShuF21 SEQ ID NO: 255EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG NSTYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAAAS YAYWGQGTLVTVSSG22 SEQ ID NO: 256Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 257Xi is AS XiQLQLVESGGGLVQAGGSLKLSCTASGRTFDGYGMGWFRQAPGKEREFVSAINWI YGATYYADSVKGRFAVSRDKAKGTMYLQMNSLKPEDTAVYYCAAKINAGSYFNIG SFGSWGQGTQVTVSShuG22 SEQ ID NO: 258Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 259Xi is AS XiQLQLVESGGGLVQPGGSLRLSCSASGRTFDGYGMGWFRQAPGKEREFVSAINWI YGATYYADSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINAGSYFNIG SFGSWGQGTLVTVSSG23 SEQ ID NO: 260Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )1569-US-NP / WO-PCTTable B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameSEQ ID NO: 261Xi is AS XiQLQLVESGGGLVQAGGSLRLSCAASGRTFSDDTVGWFRQAPGKEREFVAAITWN GDTTYYGDSVKGRFTISRDSAKNTLYLDMNKLEPEDTAVYYCAAAAGQDWSLGYL RE S S YAYWGQGTQVTVS ShuG23 SEQ ID NO: 262Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 263Xi is AS XiQLQLVESGGGLVQPGGSLRLSCSASGRTFSDDTVGWFRQAPGKEREFVAAITWN GDTTYYGDSVKGRFTISRDSSKNTLYLQMNSLRAEDTAVYYCAAAAGQDWSLGYL RESSYAYWGQGTLVTVSSH22 SEQ ID NO: 264Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 265Xi is AS XiQVQLQESGGGLVQAGDSLRLSCAASGRTFSGYTVGWFRQAPGKEREFVAAITWN GDTTYFGDSVKGRFTISRDSAKNTLYLEMNKLKPEDTAVYYCAAATGQEWSLQYL RE S S YAYWGQGTQVTVS ShuH22 SEQ ID NO: 266EVQLLESGGGLVQPGGSLRLSCAASGRTFSGYTVGWFRQAPGKEREFVAAITWNG DTTYFGDSVKGRETISRDSSKNTLYLQMNSLRAEDTAVYYCAAATGQEWSLQYLR ESSYAYWGQGTLVTVSS104 SEQ ID NO: 267Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 268Xi is AS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRRNQ AEYDYWGQGTQVTVSShuI04 SEQ ID NO: 269EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWFG RATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRNQA EYDYWGQGTLVTVSSJ13 SEQ ID NO: 270Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )1569-US-NP / WO-PCT Table B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameSEQ ID NO: 271Xi is AS XiQVQLVESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGFVATINWI PGNTYYADSVKGRFTISGEEDKNTVYLQMDNLKPEDTAVYYCAARRRIDNYYRAS EYDYWGQGTQVTVSShuJ13 SEQ ID NO: 272Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 273Xi is AS XiQVQLVESGGGVVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINWI PGNTYYADSVKGRFTISGDESKNTVYLQMNSLRAEDTAVYYCAARRRIDNYYRAS EYDYWGQGTLVTVSSJ24 SEQ ID NO: 274Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 275Xi is AS XiQVQLQESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGFVATIIGW IPGNTYYADSVKGRFTITGDKDKNTVYLQMDNLKPEDTAVYYCAARRRIDSYYRA SEYDYWGQGTQVTVSShuJ24 SEQ ID NO: 276Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 277Xi is AS XiQVQLVESGGGVVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATIIGW IPGNTYYADSVKGRFTISGDKSKNTVYLQMNSLRAEDTAVYYCAARRRIDSYYRA SEYDYWGQGTLVTVSS LOS SEQ ID NO: 278Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 279Xi is AS XiQVQLLESGGGLVQAGGSLKLSCTNSGRTFSGYGMGWFRQPPGKEREFVSSINWI YGATYYSDSVKGRFALSRDKAKNTVYLQMDSLKPEDTAVYYCAAKINGESYFNTG SFGSWGQGTQVTVSS1569-US-NP / WO-PCTTable B - Illustrative IL-lORa Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenamehuL05 SEQ ID NO: 280EVQLLESGGGLVQPGGSLRLSCAASGRTFSGYGMGWFRQAPGKEREFVSSINWIY GATYYSDSVKGRFTLSRDKSKNTVYLQMNSLRAEDTAVYYCAAKINGESYFNTGS FGSWGQGTLVTVSSLil SEQ ID NO: 281Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 282Xi is AS XiQLQLQESGGGLVQAGGSLKLSCTNSGRTFSGYGMGWFRQAPGKEREFVSAINWI YGATYYADSVKGRFAVSGDKAKNTLYLQMNSLKPEDTAVYYCAAKINGGSYFNIG SFGSWGQGTQVTVSShuLll SEQ ID NO: 283Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 284Xi is AS XiQLQLVESGGGLVQPGGSLRLSCSASGRTFSGYGMGWFRQAPGKEREFVSAINWI YGATYYADSVKGRFTVSGDKSKNTLYLQMNSLRAEDTAVYYCAAKINGGSYFNIG SFGSWGQGTLVTVSSN16 SEQ ID NO: 285Xi is S, GG, AS, ASS or absent (i. e., no amino acid residues )SEQ ID NO: 286Xi is AS XiQVQLVESGGGLVQAGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWI GGDTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLSEK SYNYWGQGTQVTVSShuNl 6 SEQ ID NO: 287EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWIG GDTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEKS YNYWGQGTLVTVSS

[0086] In some embodiments, the VHH binds to an epitope on IL 10Ra comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 (e.g., VHH E07). In some embodiments, the VHH binds to an epitope on IL 10Ra comprising contact amino acid residues 1169, 1171, K173,1569-US-NP / WO-PCTF178, F180, T18L H182, K183, K186, F190, L192, L193, S195. E197 and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 (e.g., VHH Fl 1).Human IL-10RA amino add sequence - NP_001549.2 / Uniprot Q136511 MLPCLWLLA ALLSLRLGSD AHGTELPSPP SVWFEAEFFH HILHWTPIPN QSESTCYEVA 61 LLRYGIESWN SISNCSQTLS YDLTAVTLDL YHSNGYRARV RAVDGSRHSN WTVTNTRFSV 121 DEVTLTVGSV NLEIHNGFIL GKIQLPRPKM APANDTYESI FSHFREYEIA IRKVPGNFTF 181 THKKVKHENF SLLTSGEVGE FCVQVKPSVA SRSNKGMWSK EECISLTRQY FTVTNVIIFF 241 AFVLLLSGAL AYCLALQLYV RRRKKLPSVL LFKKPSPFIF ISQRPSPETQ DTIHPLDEEA 301 FLKVSPELKN LDLHGSTDSG FGSTKPSLQT EEPQFLLPDP HPQADRTLGN REPPVLGDSC 361 SSGSSNSTDS GICLQEPSLS PSTGPTWEQQ VGSNSRGQDD SGIDLVQNSE GRAGDTQGGS 421 ALGHHSPPEP EVPGEEDPAA VAFQGYLRQT RCAEEKATKT GCLEEESPLT DGLGPKFGRC 481 LVDEAGLHPP ALAKGYLKQD PLEMTLASSG APTGQWNQPT EEWSLLALSS CSDLGISDWS 541 FAHDLAPLGC VAAPGGLLGS FNSDLVTLPL ISSLQSSE (SEQ ID NO: 711 )3. IL-lORp Single Immunoglobulin Variable domain (VHH) Binders

[0087] Provided are single immunoglobulin variable domain (VHH) binders that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) beta subunit (IL-1OR0). Illustrative IL-10RP single immunoglobulin variable domain (VHH) binders are provided in Tables C1-C4 and D, below. The IL-10RP single immunoglobulin variable domain (VHH) binders can be humanized and incorporated into antibodies, including multispecific antibodies, e.g., bispecific antibodies, e.g., comprising a human Fc domain, e.g., a human IgGl or a human IgG4. The IL-10RP single immunoglobulin variable domain (VHH) binders described herein are suitable to use with an antigen binding domain that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra), including the IL-lORa single immunoglobulin variable domain (VHH) binders described herein.

[0088] In some embodiments, the VHH binds to IL 10RP with an equilibrium dissociation constant (KD) of greater than of greater than about 10 nM, e.g., greater than about 20nM, greater than about 30nM, greater than about 40nM or greater than about 50nM.

[0089] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively:1) SEQ ID NOs: 288, 289 and 290; (A02)2) SEQ ID NOs: 291, 292 and 293; (A05)3) SEQ ID NOs: 291, 294 and 295; (huA05)4) SEQ ID NOs: 296, 297 and 298; (huA05)5) SEQ ID NOs: 299, 300 and 301; (B10)6) SEQ ID NOs: 302, 303 and 304; (B12)1569-US-NP / WO-PCT7) SEQ ID NOs: 305, 306 and 307: (CO 1)8) SEQ ID NOs: 296, 308 and 309; (C04)9) SEQ ID NOs: 310, 311 and 312; (CIO)10) SEQ ID NOs: 302, 303 and 313; (D01)11) SEQ ID NOs: 314, 315 and 316; (E08)12) SEQ ID NOs: 317, 318 and 319; (E10)13) SEQ ID NOs: 320, 321 and 322; (G01) or14) SEQ ID NOs: 323, 324 and 325 (G02).

[0090] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively:1) SEQ ID NOs 326, 327 and 328; (A02)2) SEQ ID NOs 329, 330 and 331; (A05)3) SEQ ID NOs 329, 332 and 333; (huA05)4) SEQ ID NOs 334, 335 and 336; (huA05)5) SEQ ID NOs 337, 338 and 339; (B10)6) SEQ ID NOs 340, 341 and 342; (Bl 2)7) SEQ ID NOs 343, 344 and 345; (C01)8) SEQ ID NOs 346, 347 and 348; (C04)9) SEQ ID NOs 349, 350 and 351; (CIO)10) SEQ ID NOs 352, 341 and 353; (D01)11) SEQ ID NOs 354, 355 and 356; (E08)12) SEQ ID NOs 357, 358 and 359; (E10)13) SEQ ID NOs 360, 361 and 362; (GOI) or14) SEQ ID NOs 363, 364 and 365 (G02).

[0091] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively:1) SEQ ID NOs: 366, 367 and 368; (A02)2) SEQ ID NOs: 369, 370 and 371; (A05)3) SEQ ID NOs: 369, 372 and 373; (huA05)4) SEQ ID NOs: 374, 375 and 376; (huA05)5) SEQ ID NOs: 377, 378 and 379; (B10)1569-US-NP / WO-PCT6) SEQ ID NOs: 380, 381 and 382; (B12)7) SEQ ID NOs: 383, 384 and 385; (C01)8) SEQ ID NOs: 386, 387 and 388; (C04)9) SEQ ID NOs: 389, 390 and 391; (CIO)10) SEQ ID NOs: 392, 381 and 393; (DOI)11 ) SEQ ID NOs: 394, 395 and 396; (E08)12) SEQ ID NOs: 397, 398 and 399; (E10)13) SEQ ID NOs: 400, 40 l and 402; (GO 1) or14) SEQ ID NOs: 403, 404 and 405 (G02).

[0092] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively:1) SEQ ID NOs: 406, 407 and 408; (A02)2) SEQ ID NOs: 409, 410 and 41 l; (A05)3) SEQ ID NOs: 409, 412 and 413; (huA05)4) SEQ ID NOs: 414, 415 and 416; (huA05)5) SEQ ID NOs: 417, 418 and 419; (B10)6) SEQ ID NOs: 420, 421 and 422; (B12)7) SEQ ID NOs: 423, 424 and 425; (C01)8) SEQ ID NOs: 426, 427 and 428; (C04)9) SEQ ID NOs: 429, 430 and 431; (CIO)10) SEQ ID NOs: 432, 421 and 433; (D01)11) SEQ ID NOs: 434, 435 and 436; (E08)12) SEQ ID NOs: 437, 438 and 439; (E10)13) SEQ ID NOs: 440, 441 and 442; (GO 1) or14) SEQ ID NOs: 443, 444 and 445 (G02).

[0093] In some embodiments, the VHH comprises the amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 448, 449, 455 and 460. In some embodiments, the VHH comprises the amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%1569-US-NP / WO-PCTidentical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 446-447, 450-454, 456-459 and 461-474.

[0094] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 288, 289 and 290 (according to Kabat);2) SEQ ID NOs: 326, 327 and 328 (according to IMGT);3) SEQ ID NOs: 366, 367 and 368 (according to Chothia); or4) SEQ ID NOs: 406, 407 and 408 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10RP, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 446-447 (VHH A02).

[0095] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 291, 292 and 293; or 291, 294 and 295; or 296, 297 and 298 (according to Kabat);2) SEQ ID NOs: 329, 330 and 331; or 329, 332 and 333; or 334, 335 and 336 (according to IMGT);3) SEQ ID NOs: 369, 370 and 371; or 369, 372 and 373; or 374, 375 and 376 (according to Chothia); or4) SEQ ID NOs: 409, 410 and 411; 409, 412 and 413; or 414, 415 and 416 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IE-10RP, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or an amino acid sequence at least 90%,1569-US-NP / WO-PCT91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 448-452 (VHH A05).

[0096] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 299, 300 and 301 (according to Kabat);2) SEQ ID NOs: 337, 338 and 339 (according to IMGT);3) SEQ ID NOs: 377, 378 and 379 (according to Chothia); or4) SEQ ID NOs: 417, 418 and 419 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10RP, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 453-454, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 453.454 (VHH B10).

[0097] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 302, 303 and 304 (according to Kabat);2) SEQ ID NOs: 340, 341 and 342 (according to IMGT);3) SEQ ID NOs: 380, 381 and 382 (according to Chothia); or4) SEQ ID NOs: 420, 421 and 422 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10RP, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 455-457, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 455-457 (VHH B 12).1569-US-NP / WO-PCT

[0098] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1 ) SEQ ID NOs: 305, 306 and 307 (according to Rabat);2) SEQ ID NOs: 343, 344 and 345 (according to IMGT);3) SEQ ID NOs: 383, 384 and 385 (according to Chothia); or4) SEQ ID NOs: 423, 424 and 425 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10RP, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 458-459, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 458-459 (VHH C01).

[0099] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 296, 308 and 309 (according to Rabat);2) SEQ ID NOs: 346, 347 and 348 (according to IMGT);3) SEQ ID NOs: 386, 387 and 388 (according to Chothia); or4) SEQ ID NOs: 426, 427 and 428 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10RP, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 460-462, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 460-462 (VHH C04).

[0100] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3,1569-US-NP / WO-PCTa light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 310, 311 and 312 (according to Kabat);2) SEQ ID NOs: 349, 350 and 351 (according to IMGT);3) SEQ ID NOs: 389. 390 and 391 (according to Chothia): or4) SEQ ID NOs: 429, 430 and 431 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-1OR, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 463-464, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 463-464 (VHH CIO).

[0101] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-1OR comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 302, 303 and 313 (according to Kabat);2) SEQ ID NOs: 352, 341 and 353 (according to IMGT):3) SEQ ID NOs: 392, 381 and 393 (according to Chothia); or4) SEQ ID NOs: 432, 421 and 433 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-1OR, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 455 and 465-466, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 455 and 465-466 (VHH D01).

[0102] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 314, 315 and 316 (according to Kabat);1569-US-NP / WO-PCT2) SEQ ID NOs: 354, 355 and 356 (according to IMGT);3) SEQ ID NOs: 394, 395 and 396 (according to Chothia); or4) SEQ ID NOs: 434, 435 and 436 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-lORp, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 467-468, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 467-468 (VHH E08).

[0103] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-I0RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 317, 318 and 319 (according to Kabat);2) SEQ ID NOs: 357, 358 and 359 (according to IMGT);3) SEQ ID NOs: 397, 398 and 399 (according to Chothia); or4) SEQ ID NOs: 437, 438 and 439 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10RP, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 469-470, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 469-470 (VHH EI0).

[0104] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 320, 321 and 322 (according to Kabat);2) SEQ ID NOs: 360, 361 and 362 (according to IMGT);3) SEQ ID NOs: 400, 401 and 402 (according to Chothia); or4) SEQ ID NOs: 440, 441 and 442 (according to Honegger).1569-US-NP / WO-PCTIn some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-1OR, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 471-472, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 471-472 (VHH GO 1).

[0105] In some embodiments, provided is a single domain antibody (sdAb) or antigenbinding fragment thereof (VHH) that specifically binds to IL-10RP comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 323, 324 and 325 (according to Kabat);2) SEQ ID NOs: 363, 364 and 365 (according to IMGT);3) SEQ ID NOs: 403, 404 and 405 (according to Chothia); or4) SEQ ID NOs: 443, 444 and 445 (according to Honegger).In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10RP, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 473-474, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 473.474 (VHH G02).

[0106] Generally, the herein described VHH that bind to IL-10RP bind to both human IL-10RP and cynomolgus IL-10RP, within a 10-fold affinity difference, e.g., within a 5-fold or within a 3-fold affinity difference e.g., as determined by SPR and expressed as an equilibrium dissociation constant (KD)). Amino acid sequences of complementarity determining regions (CDRs) of illustrative VHH that bind to IL-10RP are provided in Tables C1-C4. Amino acid sequences of variable regions of illustrative VHH that bind to IL-10RP are provided in Table D.1569-US-NP / WO-PCTTable Cl - Illustrative IL-10RP Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences(according to Rabat)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameA02 EGVIG CISARDGST H Y AN AVKG SLWGLGCKREEDYDY SEQ ID NO: 288 SEQ ID NO: 289 SEQ ID NO: 290 A05 YPTIG CISASDGSTHYADSVKG SLWGLGCKSEADYDY SEQ ID NO: 291 SEQ ID NO: 292 SEQ ID NO: 293 huA05 YPTIG AISASDASTHYADAVKG SLHGLGAKSEADYDY SEQ ID NO: 291 SEQ ID NO: 294 SEQ ID NO: 295 huA05 YSTIG CISASEGSTHYADAVKG SLHGLGCKSEADYDY SEQ ID NO: 296 SEQ ID NO: 297 SEQ ID NO: 298 BI O LDHMG YMFTDGRTQYGEPVKG QGI SEQ ID NO: 299 SEQ ID NO: 300 SEQ ID NO: 301 B12 ISTMA RIIWSSGATNYADSVKG AISQTRGTFWTYSEQ ID NO: 302 SEQ ID NO: 303 SEQ ID NO: 304 C01 SYGMS QINTGGGSTSYADSVKG SSRLYSSSWYGSREYDY SEQ ID NO: 305 SEQ ID NO: 306 SEQ ID NO: 307 C04 YSTIG C I S S S GRGVNANY I D S VRG NCWRLTSPAADNSEQ ID NO: 296 SEQ ID NO: 308 SEQ ID NO: 309 CI O YYSIS CISRSGGRINYADSVKG TRLPLSGLCVIGSSDNAL SEQ ID NO: 310 SEQ ID NO: 311 SEQ ID NO: 312 D O I ISTMA RI I WS S GATNYAD S VKG AISQRSGTFWTY SEQ ID NO: 302 SEQ ID NO: 303 SEQ ID NO: 313 E 08 GYAVA S I S S S G I RTNYKD S VKG KRGP ILFGTYTHSEQ ID NO: 314 SEQ ID NO: 315 SEQ ID NO: 316 E 10 IFAMG AVTLRSGITSYLDSVKG RDYRSRDYSEQ ID NO: 317 SEQ ID NO: 318 SEQ ID NO: 319 G01 RYAIG CITTSGGGSNYADSVKG TPLNYYCGIDFNPDKYDY SEQ ID NO: 320 SEQ ID NO: 321 SEQ ID NO: 322 G02 FAPMG AINRDFSTYYANSVKG SPGRIWSGTILPPAPDRWS SEQ ID NO: 323 SEQ ID NO: 324 SEQ ID NO: 325Table C2 - Illustrative IL-10RP Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to IMGT)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameA02 GISLDEGV ISARDGST AASLWGLGCKREEDYDY SEQ ID NO: 326 SEQ ID NO: 327 SEQ ID NO: 328 A05 GNSLDYPT ISASDGST AASLWGLGCKSEADYDY SEQ ID NO: 329 SEQ ID NO: 330 SEQ ID NO: 3311569-US-NP / WO-PCTTable C2 - Illustrative IL-lORp Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to IMGT)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3namehuAO 5 GNSLDYPT ISASDAST AASLHGLGAKSEADYDY SEQ ID NO: 329 SEQ ID NO: 332 SEQ ID NO: 333 huAO 5 GNSLDYST ISASEGST AASLHGLGCKSEADYDY SEQ ID NO: 334 SEQ ID NO: 335 SEQ ID NO: 336 BI O GSTSTLDH MFTDGRT GAQGI SEQ ID NO: 337 SEQ ID NO: 338 SEQ ID NO: 339 B12 GSFSSIST I IWSSGAT SGAISQTRGTFWTYSEQ ID NO: 340 SEQ ID NO: 341 SEQ ID NO: 342 C01 GFAFSSYG INTGGGST AASSRLYSSSWYGSREYDY SEQ ID NO: 343 SEQ ID NO: 344 SEQ ID NO: 345 C04 GFTSPYST ISSSGRGVNA ATNCWRLTSPAADNSEQ ID NO: 346 SEQ ID NO: 347 SEQ ID NO: 348 CI O GLTLDYYS ISRSGGRI AATRLPLSGLCVIGSSDNAL SEQ ID NO: 349 SEQ ID NO: 350 SEQ ID NO: 351 D O I GNFSSIST I IWSSGAT AGAISQRSGTFWTY SEQ ID NO: 352 SEQ ID NO: 341 SEQ ID NO: 353 E 08 ISTLNGYA ISSSGIRT AAKRGP ILFGTYTHSEQ ID NO: 354 SEQ ID NO: 355 SEQ ID NO: 356 E 10 GSALSIFA VTLRSGIT NVRDYRSRDYSEQ ID NO: 357 SEQ ID NO: 358 SEQ ID NO: 359 G01 GFTVDRYA ITTSGGGS AATPLNYYCGIDFNPDKYDY SEQ ID NO: 360 SEQ ID NO: 361 SEQ ID NO: 362 G02 ETI INFAP INRDFST AASPGRIWSGTILPPAPDRWS SEQ ID NO: 363 SEQ ID NO: 364 SEQ ID NO: 365Table C3 - Illustrative IL-lORp Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to Chothia)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameA02 GISLDEG ARDG LWGLGCKREEDYDSEQ ID NO: 366 SEQ ID NO: 367 SEQ ID NO: 368A05 GNSLDYP ASDG LWGLGCKSEADYDSEQ ID NO: 369 SEQ ID NO: 370 SEQ ID NO: 371huAO 5 GNSLDYP ASDA LHGLGAKSEADYDSEQ ID NO: 369 SEQ ID NO: 372 SEQ ID NO: 373huAO 5 GNSLDYS ASEG LHGLGCKSEADYDSEQ ID NO: 374 SEQ ID NO: 375 SEQ ID NO: 3761569-US-NP / WO-PCTTable C3 - Illustrative IL-lORp Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences (according to Chothia)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameBIO GSTSTLD TDG G SEQ ID NO: 377 SEQ ID NO: 378 SEQ ID NO: 379B12 GSFSSIS WSSG ISQTRGTFWTSEQ ID NO: 380 SEQ ID NO: 381 SEQ ID NO: 382C01 GFAFSSY TGGG SRLYSSSWYGSREYDSEQ ID NO: 383 SEQ ID NO: 384 SEQ ID NO: 385C04 GFTSPYS SSGRGV CWRLTSPAADSEQ ID NO: 386 SEQ ID NO: 387 SEQ ID NO: 388CIO GLTLDYY RSGG RLPLSGLCVIGSSDNA SEQ ID NO: 389 SEQ ID NO: 390 SEQ ID NO: 391D OI GNFSSIS WSSG ISQRSGTFWT SEQ ID NO: 392 SEQ ID NO: 381 SEQ ID NO: 393E 08 ISTLNGY SSGI RGP ILFGTYTSEQ ID NO: 394 SEQ ID NO: 395 SEQ ID NO: 396E 10 GSALSIF LRSG DYRSRDSEQ ID NO: 397 SEQ ID NO: 398 SEQ ID NO: 399G01 GFTVDRY TSGG PLNYYCGIDFNPDKYD SEQ ID NO: 400 SEQ ID NO: 401 SEQ ID NO: 402G02 ETIINFA RDF PGRIWSGTILPPAPDRW SEQ ID NO: 403 SEQ ID NO: 404 SEQ ID NO: 405Table C4 - Illustrative IL-lORp Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences(according to Honegger)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameAO 2 ASGISLDEGV ISARDGSTHYANAVKGR SLWGLGCKREEDYD SEQ ID NO: 406 SEQ ID NO: 407 SEQ ID NO: 408 AO 5 ASGNSLDYPT ISASDGSTHYADSVKGR SLWGLGCKSEADYD SEQ ID NO: 409 SEQ ID NO: 410 SEQ ID NO: 411 huA05 ASGNSLDYPT ISASDASTHYADAVKGR SLHGLGAKSEADYD SEQ ID NO: 409 SEQ ID NO: 412 SEQ ID NO: 413 huA05 ASGNSLDYST ISASEGSTHYADAVKGR SLHGLGCKSEADYD SEQ ID NO: 414 SEQ ID NO: 415 SEQ ID NO: 416 BI O ASGSTSTLDH MFTDGRTQYGEP VKGR QG SEQ ID NO: 417 SEQ ID NO: 418 SEQ ID NO: 419 B12 ASGSFSS IST 11 WS SGATNYAD SVKGR AISQTRGTFWTSEQ ID NO: 420 SEQ ID NO: 421 SEQ ID NO: 4221569-US-NP / WO-PCTTable C4 - Illustrative IL-lORp Single Immunoglobulin Variable domain (VHH) Binder CDR amino acid sequences(according to Honegger)VHH VHH - CDR1 VHH - CDR2 VHH - CDR3nameC01 ASGFAFSSYG INTGGGSTSYAD SVKGR SSRLYSSSWYGSREYD SEQ ID NO: 423 SEQ ID NO: 424 SEQ ID NO: 425 C04 ASGFTSPYST I S S S GRGVNANY ID S VRGR NCWRLTSPAADSEQ ID NO: 426 SEQ ID NO: 427 SEQ ID NO: 428 CI O ASGLTLDYYS I SRS GGRINYAD SVKGR TRLPLSGLCVIGSSDNA SEQ ID NO: 429 SEQ ID NO: 430 SEQ ID NO: 431 DO I ASGNFSS IST 11 WS SGATNYAD SVKGR AISQRSGTFWTSEQ ID NO: 432 SEQ ID NO: 421 SEQ ID NO: 433 E08 SSI STLNGYA I S S S GI RTNYKD SVKGR KRGP ILFGTYTSEQ ID NO: 434 SEQ ID NO: 435 SEQ ID NO: 436 E10 ASGSALS IFA VTLRSGITSYLD SVKGR RDYRSRDSEQ ID NO: 437 SEQ ID NO: 438 SEQ ID NO: 439 G01 ASGFTVDRYA ITTSGGGSNYADSVKGR TPLNYYCGIDFNPDKYD SEQ ID NO: 440 SEQ ID NO: 441 SEQ ID NO: 442 G02 ASET I INFAP INRDFSTYYANSVKGR SPGRIWSGTILPPAPDRW SEQ ID NO: 443 SEQ ID NO: 444 SEQ ID NO: 445Table D - Illustrative IL-lORp Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameA02 SEQ ID NO: 446 QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGWFRRAPGKEREGVSCISARDG STHYANAVKGRFTISRDNTKNTVDLQMNNLEPEDAGRYYCAASLWGLGCKREEDYD YWGQGTQVTVSShuA02 SEQ ID NO: 447EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWFRQAPGKEREGVSCISARDG STHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAASLWGLGCKREEDYD YWGQGTLVTVSSA05 SEQ ID NO: 448coni X1VQLX2ESGGGLVQPGGSLX3LSCAASGX4SLDX5X6X7IGWFRX8APGKX9X10EGVS X:iI SAX12DXi3STHYAXi4XibVKGRFTISRDNXibKNTVXi / LQMNXi8LXiyX2oED X21X22X23YYCAASLX24GLGX25KX26EX27DYDYWGQGTX28VTVSSX3is E or QX2 is L or QX3 is K or RX4 is I or NX5 is E or YX6is G, P or S1569-US-NP / WO-PCT Table D - Illustrative IL-10RP Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameX- is V or TXg is Q or RXg is E or GXgg is L or RXgg is A or CXgg is R or SXgg is A or GXg4 is D or NXgg is A or SXgg is S or TXgg is D or YXgg is N or SXgg is K or RX20 is A or PXgg is A or TX22 is A or GX23is H or VX24 is H or WX25 is A or CX26 is R or SX27 is A or EX28 is L, M or QA05 SEQ ID NO: 449con2 X2VQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWFRQAPGKX2X3EGVSX4ISA SDX5STHYADX6VKGRFTI SRDNX7KNTVXgLQMNXoLX1oXiiEDTX12Xi3YYCAASL XggGLGXisKSEADYDYWGQGTXieVTVSSXg is E or QX2 is E or GX3 is L or RX4 is A or CXs is A or GXg is A or SX / is S or TX° is D or YXg is N or SXgo is K or RXgg is A or PXgg is A or GXg3is H or VXgg is H or WXgg is A or CXgg is M or Q1569-US-NP / WO-PCTTable D - Illustrative IL-10RP Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameA05 SEQ ID NO: 450 QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWFRQAPGKEREGVSCISASDG STHYADSVKGRFTISRDNTKNTVDLQMNNLKPEDTGHYYCAASLWGLGCKSEADYD YWGQGTQVTVSShuA05 SEQ ID NO: 451EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWFRQAPGKGLEGVSAISASDA STHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAASLHGLGAKSEADYD YWGQGTMVTVSShuA05 SEQ ID NO: 452EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWFRQAPGKGLEGVSCISASEG STHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAASLHGLGCKSEADYD YWGQGTMVTVSS BIO SEQ ID NO: 453QVQL VE S GGGWQAGG S LRL S CAAS GS T S TLD HMGWYRQAP GKSRE L VGYMF TD GR TQYGEPVKGRFTVSRDNGRNTIFLQMNNLKLEDTAVYYCGAQGIWGQGTQVTVSShuBlO SEQ ID NO: 454QVQL VE S GGGWQP GG S LRL S C AAS GS T S TLD HMGWYRQAP GKSRE LVGYMF TD GR TQYGEPVKGRFTVSRDNSKNTIYLQMNSLRAEDTAVYYCGAQGIWGQGTMVTVSSB12 SEQ ID NO: 455Con X1VQLX2ESGGGLVX3X4GGSLRLSCAASGX5FSSISTMAWYRQX6PGKQREWX7ARI w / IWSSGATNYADSVKGRFTX8SRDNX9KNTMYLQMX1OX11LX12X13EDTAAYX14CSGA DOI ISQXisRGTFWTYXisSQGTXnVTVSSX: is E or QX2 is L, Q or VX3 is K or QX4is A or PX5 is N or SXs is A or VX? is L or VX8is A or IX9is A, S or TX20 is D or NXu is R or SX22 is R or TX23 is A or PX24 is L or YX25 is R or TXss is K or WX27 is L or QB12 SEQ ID NO: 456 EVQLVESGGGLVQAGGSLRLSCAASGSFSSISTMAWYRQVPGKQREWLARIIWSSG ATNYADSVKGRFTISRDNTKNTMYLQMDRLTPEDTAAYLCSGAISQTRGTFWTYKS QGTQVTVSS1569-US-NP / WO-PCTTable D - Illustrative IL-10RP Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenamehuB12 SEQ ID NO: 457EVQLVESGGGLVQPGGSLRLSCAASGSFSSISTMAWYRQAPGKQREWLARIIWSSG ATNYADSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCSGAISQTRGTFWTYKG QGTLVTVSSC01 SEQ ID NO: 458 QVQLQESGGGLVQPGGSLRLSCAASGFAFSSYGMSWVRQAPGKGLEWVSQINTGGG STSYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAASSRLYSSSWYGSRE YDYWGQGTQVTVSShuCOl SEQ ID NO: 459EVQLLESGGGLVQPGGSLRLSCAASGFAFSSYGMSWVRQAPGKGLEWVSQINTGGG STSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAASSRLYSSSWYGSRE YDYWGQGTLVTVSSC04 SEQ ID NO: 460con X1VQLVESGGGLVQX2GGSLRLSCX3ASGFTSPYSTIGWFRQAPGKX4REGVACISS SGRGVNANYIDSVRGRFTISRDNX£KNTVYLQMNXSLKX7X3DTAX9YYCATNCWRLT SPAADNWGQGTX10VTVSSX: is E or QX2 is P or SX?, is S or VX4 is E or GXs is A or SXg is K or SX? is A or PX3 is D or EX9 is I or VX20 is M or QC04 SEQ ID NO: 461 QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGWFRQAPGKEREGVACISSSGR GVNANYIDSVRGRFTISRDNAKNTVYLQMNKLKPDDTAIYYCATNCWRLTSPAADN WGQGTQVTVSShuC04 SEQ ID NO: 462EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGWFRQAPGKGREGVACISSSGR GVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCATNCWRLTSPAADN WGQGTMVTVSS CIO SEQ ID NO: 463 DLQLVESGGGLVQPGGSLRLSCAASGLTLDYYSISWFRQGPGNEREAVSCISRSGG RINYADSVKGRFTISRDSAKNTVYLQMNSLKPEDTAVYYCAATRLPLSGLCVIGSS DNALWGQGTQVTVSShuClO SEQ ID NO: 464ELQLVESGGGLVQPGGSLRLSCAASGLTLDYYSISWFRQAPGKEREAVSCISRSGG RINYADSVKGRFTISRDSSKNTVYLQMNSLRAEDTAVYYCAATRLPLSGLCVIGSS DNALWGQGTLVTVSS1569-US-NP / WO-PCTTable D - Illustrative IL-10RP Single Immunoglobulin Variable Domain (VHH) amino acid sequencesVHH VHH amino acid sequencenameDOI SEQ ID NO: 465 QVQLQESGGGLVQAGGSLRLSCAASGNFSSISTMAWYRQVPGKQREWVARIIWSSG ATNYADSVKGRFTASRDNTKNTMYLQMDRLTPEDTAVYLCAGAISQRSGTFWTYWG QGTQVTVSShuDOl SEQ ID NO: 466QVQLLESGGGLVKPGGSLRLSCAASGNFSSISTMAWYRQAPGKQREWVARIIWSSG ATNYADSVKGRFTASRDNAKNSMYLQMNSLRAEDTAVYYCAGAISQRSGTFWTYWG QGTLVTVSSE08 SEQ ID NO: 467 QLQLVESGGGLVQPGGSLTLSCASSISTLNGYAVAWFRQAPGKERSAVSSISSSGI RTNYKDSVKGRFTIWRDNAKAAVYLQLNNLEPEDTAMYYCAAKRGP ILFGTYTHWG QGTQVTVSShuE08 SEQ ID NO: 468QLQLVESGGGLVKPGGSLRLSCAASGSTLNGYAVAWFRQAPGKEREAVSSISSSGI RTNYKDSVKGRFTISRDNAKNSVYLQMNSLRAEDTAVYYCAAKRGP ILFGTYTHWG QGTLVTVSSE10 SEQ ID NO: 469 EVQLVESGGGLVQAGGSLRLSCAASGSALSIFAMGWYRQTPGKQSVSVAAVTLRSG ITSYLDSVKGRFIISIDRAKNTMYLEMNDLKPEDTAIYYCNVRDYRSRDYWGQGTQ VTVSShuElO SEQ ID NO: 470EVQLVESGGGLVQPGGSLRLSCAASGSALSIFAMGWYRQAPGKQSESVAAVTLRSG ITSYLDSVKGRFTISIDRSKNTMYLQMNSLRAEDTAVYYCNVRDYRSRDYWGQGTL VTVSSG01 SEQ ID NO: 471 QVQLQESGGGLVQPGGSLRLSCAASGFTVDRYAIGWFRQAPGKEREGVQCITTSGG GSNYADSVKGRFTIARDNAKNTVYLQMDSLKPEDTAIYYCAATPLNYYCGIDFNPD KYDYWGQGTQVTVSShuGOl SEQ ID NO: 472EVQLLESGGGLVQPGGSLRLSCAASGFTVDRYAIGWFRQAPGKEREGVQCITTSGG GSNYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAATPLNYYCGIDFNPD KYDYWGQGTMVTVSSG02 SEQ ID NO: 473QVQLVESGGGLVQPGGSLRLSCVASETI INFAPMGWYRQAPGTERELVAAINRDFS TYYANSVKGRFTISRDNAKKMLSLQMNSLNPEDTAMYYCAASPGRIWSGTILPPAP DRWSWGQGTQVTVSShuG02 SEQ ID NO: 474QVQLVESGGGLVQPGGSLRLSCSASGTI INFAPMGWYRQAPGKERELVAAINRDFS TYYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAASPGRIWSGTILPPAP DRWSWGQGTMVTVSS1569-US-NP / WO-PCT

[0107] In some embodiments, the VHH binds to an epitope on IL-10RP comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712 (e.g., VHH A05). In some embodiments, the VHH binds to an epitope on IL-10RP comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, DI 10, Il 12, Pl 15, Q157, Q190, R192, Fl 94, N199, A201, E203, W204 and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712 (e.g., VHH C04).Human IL-10RB amino acid sequence - NP_000619.3 / Uniprot Q083341 MAWSLGSWLG GCLLVSALGM VPPPENVRMN SVNFKNILQW ESPAFAKGNL TFTAQYLSYR 61 IFQDKCMNTT LTECDFSSLS KYGDHTLRVR AEFADEHSDW VNITFCPVDD TIIGPPGMQV 121 EVLADSLHMR FLAPKIENEY ETWTMKNVYN SWTYNVQYWK NGTDEKFQIT PQYDFEVLRN 181 LEPWTTYCVQ VRGFLPDRNK AGEWSEPVCE QTTHDETVPS WMVAVILMAS VFMVCLALLG 241 CFALLWCVYK KTKYAFSPRN SLPQHLKEFL GHPHHNTLLF FSFPLSDEND VFDKLSVIAE 301 DSESGKQNPG DSCSLGTPPG QGPQS (SEQ ID NO: 712 )4. IL-lORa / IL-lORp Bispecific Binders

[0108] Provided are bispecific antibodies comprising a first immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-R) alpha subunit (IL-lORa) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP). With respect to function, in some embodiments, the bispecific antibody is an IL-10R agonist that selectively suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells. In some embodiments, the bispecific antibody is an IL-10R agonist that predominantly suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells. In some embodiments, the bispecific antibody is an IL-10R agonist suppressing activation of myeloid cells (e.g., macrophages, monocytes and dendritic cells) with a half maximal effective concentration (EC50) less than about 10 pM and activating T cells and B cells below a predetermined threshold level at a concentration above about 1000 nM, e.g., above about 1500 nM, e.g., above about 2000 nM, e.g., above about 2500 nM, e.g., above about 3000 nM, e.g., above about 3500 nM, e.g., above about 4000 nM, e.g., above about 4500 nM, e.g., above about 5000 nM. In some embodiments, the bispecific antibody activates T cells or B cells with a maximum effect (Emax) that is 15% or less, e.g., 10% or less, e.g., 5% or less, in comparison to wild-type IL 10. In some embodiments, the activation of T cells is measured by at least one of Granzyme B secretion and interferon-y (IFN-y) production. In some embodiments, the bispecific antibody does not induce detectable granzyme B secretion from1569-US-NP / WO-PCTCD8+ T cells. In some embodiments, the bispecific antibody induces interferon-y (IFN-y) from CD8+ T cells less than 15%, e.g., less than 10%, e.g., less than 5%, the level of IFN-y induced by wild-type IL- 10. In some embodiments, the bispecific antibody agonizes the IL- 10 receptor in a tyrosine kinase 2 (TYK2; NCBI Gene ID: 7297) dependent manner (i.e., requiring a functional TYK2, e.g., requiring the phosphorylation activity of TYK2). In some embodiments, the bispecific antibody induces minimal (e.g., less than 25% in comparison to wild-type IL-10) or no inhibition of IL 10R|3 dimerization with other IL- 10 family cytokine receptor subunits, e.g., IL-1OR0 dimerization with IL-20Ra, IL-22R, IL-28R or IL-29R. In some embodiments, the bispecific antibody induces minimal (e.g., less than 25% in comparison to wild-type IL- 10) or no inhibition of intracellular signaling of other IL-10R|3-binding cytokines, e.g., minimal or no inhibition of IL-22, IL-26, IL-28A, IL-28B, or IL-29 intracellular signaling. In some embodiments, the second VHH binds to IL 10RP with an equilibrium dissociation constant (KD) that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold greater, 15-fold greater, 20-fold greater, 25-fold greater, or more, than the KD of the first VHH binding to IL 10Ra, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first VHH binds to IL 10Ra with affinity that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the binding affinity of the second VHH binding to IL 10Rp, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first variable domain binds to IL 10Ra with an equilibrium dissociation constant (KD) of lower than 2 nM and the second variable domain binds to IL 10RP with a KD of greater than 10 nM, e.g., greater than 20 nM, e.g., greater than 30 nM, e.g., greater than 40 nM, e.g., greater than 50 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR).

[0109] In some embodiments, the first VHH binds to an epitope on IL 10Ra comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10RP comprising contact amino acid residues S78, S80, K81. Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712 (e.g., E07-A05). In some embodiments, the first VHH binds to an epitope on IL 10Ra comprising contact amino acid residues 1169, 1171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197, and F20L wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope1569-US-NP / WO-PCTon IL-10RP comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, DUO, 1112, Pl 15, Q157, Q190, R192, F194, N199, A201, E203, W204, and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712 (e.g., Fl 1-C04).

[0110] With respect to structure, in some embodiments, the bispecific antibody comprises at least one polypeptide comprising the first VHH in tandem with the second VHH (e.g., in a single fusion protein). In some embodiments, the polypeptide comprises from N-terminus to C-terminus the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL 10Rp. In some embodiments, the polypeptide comprises from N-terminus to C-terminus the second VHH that specifically binds to IL 10RP and the first VHH that specifically binds to IL 10Ra. In some embodiments, the first VHH and the second VHH are connected or fused via a linker. In some embodiments, the linker is selected from the group consisting of: GS (SEQ ID NO: 713), GGS (SEQ ID NO: 714), GGGS (SEQ ID NO: 715), GGSGGS (SEQ ID NO: 716), GGGSGGGS (SEQ ID NO: 717) and GGSGGSGGS (SEQ ID NO: 718). In some embodiments, the linker comprises GGGS (SEQ ID NO: 715). The amino acid sequences of illustrative bispecific antibodies described herein are provided in Tables E and F, below.First and Second VHH

[0111] In some embodiments of the bispecific antibody, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Kabat, respectively:1) SEQ ID NOs: 22, 23, 24, 291, 292 and 293; (877)2) SEQ ID NOs: 22, 25, 26, 291, 294 and 295; (647)3) SEQ ID NOs: 22, 27, 24, 291, 297 and 298; (195)4) SEQ ID NOs: 22, 23, 24, 288, 289 and 290; (048)5) SEQ ID NOs: 22, 25, 26, 288, 289 and 290; (049)6) SEQ ID NOs: 22, 27, 24, 288, 289 and 290; (050)7) SEQ ID NOs: 22, 23, 24, 296, 308 and 309; (274)8) SEQ ID NOs: 22, 25, 26, 296, 308 and 309; (771)9) SEQ ID NOs: 22, 27, 24, 296, 308 and 309; (772)10) SEQ ID NOs: 4, 28, 29, 288, 289 and 290; (054)1569-US-NP / WO-PCT11) SEQ ID NOs: 4, 28, 29, 291, 294 and 295; (883)12) SEQ ID NOs: 4, 28, 29, 291, 294 and 295; (784)13) SEQ ID NOs: 4, 28, 29, 291, 297 and 298; (785)14) SEQ ID NOs: 4, 5, 6, 288, 289 and 290; (046)15) SEQ ID NOs: 4, 5, 6, 291, 294 and 295; (875)16) SEQ ID NOs: 4, 5, 6, 291, 294 and 295; (776)17) SEQ ID NOs: 4, 5, 6, 291, 297 and 298; (777)18) SEQ ID NOs: 4, 5, 6, 296, 308 and 309; (272)19) SEQ ID NOs: 4, 15, 16, 288, 289 and 290; (052)20) SEQ ID NOs: 4, 15, 16, 296, 308 and 309; (278)21) SEQ ID NOs: 4, 17, 18, 288, 289 and 290; (047)22) SEQ ID NOs: 4, 17, 18, 291, 292 and 293; (876)23) SEQ ID NOs: 4, 17, 18, 291, 294 and 295; (778)24) SEQ ID NOs: 4, 17, 18, 291, 297 and 298; (779)25) SEQ ID NOs: 45, 46, 47, 288, 289 and 290; (062)26) SEQ ID NOs: 45, 46, 47, 291, 292 and 293; (891)27) SEQ ID NOs: 45, 46, 47, 291, 294 and 295; (780)28) SEQ ID NOs: 45, 46, 47, 291, 297 and 298; (781)29) SEQ ID NOs: 45, 46, 47, 296, 308 and 309; (290)30) SEQ ID NOs: 4, 48, 6, 291, 292 and 293; (892)31) SEQ ID NOs: 4, 48, 6, 291, 294 and 295; (793)32) SEQ ID NOs: 4, 48, 6, 291, 297 and 298; (794)33) SEQ ID NOs: 54, 55, 24, 291, 292 and 293; (894)34) SEQ ID NOs: 54, 55, 24, 291, 294 and 295; (795)35) SEQ ID NOs: 54, 55, 24, 291, 297 and 298; (796)36) SEQ ID NOs: 4, 30, 31, 291, 292 and 293; (884)37) SEQ ID NOs: 4, 30, 31, 291, 294 and 295; (786)38) SEQ ID NOs: 4, 30, 31, 291, 297 and 298; (787)39) SEQ ID NOs: 4, 36, 29, 288, 289 and 290; (058)40) SEQ ID NOs: 33, 34, 35, 296, 308 and 309; (284)41) SEQ ID NOs: 33, 34, 35. 296, 308 and 309; (183)42) SEQ ID NOs: 33, 34, 35, 296, 308 and 309; (184)43) SEQ ID NOs: 19, 37, 38, 302, 303 and 304; (239)44) SEQ ID NOs: 19, 37, 38, 296, 308 and 309; (286) or1569-US-NP / WO-PCT45) SEQ ID NOs: 19, 51, 52, 302, 303 and 304; (247)

[0112] In some embodiments of the bispecific antibody, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to IMGT, respectively:1) SEQ ID NOs: 77, 78, 79, 329, 330 and 331; (877)2) SEQ ID NOs: 77, 80, 81, 329, 332 and 333; (647)3) SEQ ID NOs: 77. 82, 79, 334, 335 and 336; (195)4) SEQ ID NOs: 77, 78, 79, 326, 327 and 328; (048)5) SEQ ID NOs: 77, 80, 81, 326, 327 and 328; (049)6) SEQ ID NOs: 77, 82, 79, 326, 327 and 328; (050)7) SEQ ID NOs: 77, 78, 79, 346, 347 and 348; (274)8) SEQ ID NOs: 77, 80, 81. 346, 347 and 348; (771)9) SEQ ID NOs: 77, 82, 79, 346, 347 and 348; (772)10) SEQ ID NOs: 59, 83, 84, 326, 327 and 328; (054)11) SEQ ID NOs: 59, 83, 84, 329, 330 and 331; (883)12) SEQ ID NOs: 59, 83. 84, 329, 332 and 333; (784)13) SEQ ID NOs: 59, 83, 84, 334, 335 and 336; (785)14) SEQ ID NOs: 59, 60, 61, 326, 327 and 328; (046)15) SEQ ID NOs: 59, 60, 61, 329, 330 and 331; (875)16) SEQ ID NOs: 59. 60, 61, 329, 332 and 333; (776)17) SEQ ID NOs: 59, 60, 61, 334, 335 and 336; (777)18) SEQ ID NOs: 59, 60, 61, 346, 347 and 348; (272)19) SEQ ID NOs: 59, 70, 71, 326, 327 and 328; (052)20) SEQ ID NOs: 59, 70, 71, 346, 347 and 348; (278)21) SEQ ID NOs: 59, 72, 73. 326, 327 and 328; (047)22) SEQ ID NOs: 59, 72, 73, 329, 330 and 331; (876)23) SEQ ID NOs: 59, 72, 73, 329, 332 and 333; (778)24) SEQ ID NOs: 59, 72, 73, 334, 335 and 336; (779)25) SEQ ID NOs: 98, 99. 100, 326, 327 and 328; (062)26) SEQ ID NOs: 98, 99, 100, 329, 330 and 331; (891)1569-US-NP / WO-PCT27) SEQ ID NOs: 98, 99, 100, 329, 332 and 333; (780)28) SEQ ID NOs: 98, 99, 100, 334, 335 and 336; (781)29) SEQ ID NOs: 98, 99, 100, 326, 327 and 328; (290)30) SEQ ID NOs: 59. 101, 61, 329, 330 and 331; (892)31) SEQ ID NOs: 59, 101, 61, 329, 332 and 333; (793)32) SEQ ID NOs: 59, 101, 61, 334, 335 and 336; (794)33) SEQ ID NOs: 106, 107, 79, 329, 330 and 331; (894)34) SEQ ID NOs: 106, 107, 79, 329, 332 and 333; (795)35) SEQ ID NOs: 106, 107, 79, 334, 335 and 336; (796)36) SEQ ID NOs: 59, 85, 86, 329, 330 and 331; (884)37) SEQ ID NOs: 59, 85, 86, 329, 332 and 333; (786)38) SEQ ID NOs: 59, 85, 86, 334, 335 and 336; (787)39) SEQ ID NOs: 59, 91. 84, 326, 327 and 328; (058)40) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (284)41) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (183)42) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (184)43) SEQ ID NOs: 92, 75, 93, 340, 341 and 342; (239)44) SEQ ID NOs: 92, 75, 93, 326, 327 and 328; (286) or45) SEQ ID NOs: 74, 75, 104, 340, 341 and 342; (247).

[0113] In some embodiments of the bispecific antibody, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Chothia, respectively:1) SEQ ID NOs: 127, 128, 129, 369, 370 and 371; (877)2) SEQ ID NOs: 127, 130, 131, 369, 372 and 373; (647)3) SEQ ID NOs: 127, 130, 131, 374, 375 and 376; (195)4) SEQ ID NOs: 127, 128, 129, 366, 367 and 368; (048)5) SEQ ID NOs: 127, 130, 131, 366, 367 and 368; (049)6) SEQ ID NOs: 127, 130, 131, 366, 367 and 368; (050)7) SEQ ID NOs: 127, 128, 129, 386, 387 and 388; (274)8) SEQ ID NOs: 127, 130, 131, 386, 387 and 388; (771)1569-US-NP / WO-PCT9) SEQ ID NOs: 127, 130, 131, 386, 387 and 388; (772)10) SEQ ID NOs: 111, 132, 133, 366, 367 and 368; (054)11) SEQ ID NOs: 111, 132, 133, 369, 370 and 371; (883)12) SEQ ID NOs: 111, 132, 133, 369, 372 and 373; (784)13) SEQ ID NOs: 111, 132, 133. 374, 375 and 376; (785)14) SEQ ID NOs: 111, 112, 113, 366, 367 and 368; (046)15) SEQ ID NOs: 111, 112, 113, 369, 370 and 371; (875)16) SEQ ID NOs: 111, 112, 113, 369, 372 and 373; (776)17) SEQ ID NOs: 111, 112, 113, 374, 375 and 376; (777)18) SEQ ID NOs: 111, 112, 113, 386, 387 and 388; (272)19) SEQ ID NOs: 111, 121, 122, 366, 367 and 368; (052)20) SEQ ID NOs: 111, 121, 122, 386, 387 and 388; (278)21) SEQ ID NOs: 111, 121, 123, 366, 367 and 368; (047)22) SEQ ID NOs: 111, 121, 123, 369, 370 and 371; (876)23) SEQ ID NOs: 111, 121, 123, 369, 372 and 373; (778)24) SEQ ID NOs: 111, 121, 123, 374, 375 and 376; (779)25) SEQ ID NOs: 145, 146, 147, 366, 367 and 368; (062)26) SEQ ID NOs: 145, 146, 147. 369, 370 and 371; (891)27) SEQ ID NOs: 145, 146, 147, 369, 372 and 373; (780)28) SEQ ID NOs: 145, 146, 147, 374, 375 and 376; (781)29) SEQ ID NOs: 145, 146, 147, 386, 387 and 388; (290)30) SEQ ID NOs: 111, 112, 113, 369, 370 and 371; (892)31) SEQ ID NOs: 111, 112, 113, 369, 372 and 373; (793)32) SEQ ID NOs: 111, 112, 113, 374, 375 and 376; (794)33) SEQ ID NOs: 152, 121, 129, 369, 370 and 371; (894)34) SEQ ID NOs: 152, 121, 129, 369, 372 and 373; (795)35) SEQ ID NOs: 152, 121, 129, 374, 375 and 376; (796)36) SEQ ID NOs: 111, 134, 135, 369, 370 and 371; (884)37) SEQ ID NOs: 111, 134, 135, 369, 372 and 373; (786)38) SEQ ID NOs: 111, 134, 135, 374, 375 and 376; (787)39) SEQ ID NOs: 111, 132, 133. 366, 367 and 368; (058)40) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (284)41) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (183)42) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (184)1569-US-NP / WO-PCT43) SEQ ID NOs: 140, 125, 141, 380, 381 and 381; (239)44) SEQ ID NOs: 140, 125, 141, 386, 387 and 388; (286) or45) SEQ ID NOs: 124, 125, 126, 380, 381 and 381 (247).

[0114] In some embodiments of the bispecific antibody, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Honegger, respectively:1) SEQ ID NOs: 174, 175, 176, 409, 410 and 411; (877)2) SEQ ID NOs: 174, 177, 178. 409, 412 and 413; (647)3) SEQ ID NOs: 174, 179, 176, 414, 415 and 416; (195)4) SEQ ID NOs: 174, 175, 176, 406, 407 and 408; (048)5) SEQ ID NOs: 174, 177, 178, 406, 407 and 408; (049)6) SEQ ID NOs: 174, 179, 176, 406, 407 and 408; (050)7) SEQ ID NOs: 174, 175, 176, 426, 427 and 428; (274)8) SEQ ID NOs: 174, 177, 178, 426, 427 and 428; (771)9) SEQ ID NOs: 174, 179, 176, 426, 427 and 428; (772)10) SEQ ID NOs: 156, 180, 181, 406, 407 and 408; (054)11) SEQ ID NOs: 156, 180, 181, 409, 410 and 411; (883)12) SEQ ID NOs: 156, 180, 181, 409, 412 and 413; (784)13) SEQ ID NOs: 156, 180, 181, 414, 415 and 416; (785)14) SEQ ID NOs: 156, 157, 158, 406, 407 and 408; (046)15) SEQ ID NOs: 156, 157, 158. 409, 410 and 411; (875)16) SEQ ID NOs: 156, 157, 158, 409, 412 and 413; (776)17) SEQ ID NOs: 156, 157, 158, 414, 415 and 416; (777)18) SEQ ID NOs: 156, 157, 158, 426, 427 and 428; (272)19) SEQ ID NOs: 156, 167, 168, 406, 407 and 408; (052)20) SEQ ID NOs: 156, 167, 168, 426, 427 and 428; (278)21) SEQ ID NOs: 156, 169, 170, 406, 407 and 408; (047)22) SEQ ID NOs: 156, 169, 170, 409, 410 and 411; (876)23) SEQ ID NOs: 156, 169, 170, 409, 412 and 413; (778)24) SEQ ID NOs: 156, 169, 170, 414, 415 and 416; (779)1569-US-NP / WO-PCT25) SEQ ID NOs: 198, 199, 200, 406, 407 and 408; (062)26) SEQ ID NOs: 198, 199, 200, 409, 410 and 411; (891)27) SEQ ID NOs: 198, 199, 200, 409, 412 and 413; (780)28) SEQ ID NOs: 198, 199, 200, 414, 415 and 416; (781)29) SEQ ID NOs: 198, 199, 200. 426, 427 and 428; (290)30) SEQ ID NOs: 156, 201, 158, 409, 410 and 411; (892)31) SEQ ID NOs: 156, 201, 158, 409, 412 and 413; (793)32) SEQ ID NOs: 156, 201, 158, 414, 415 and 416; (794)33) SEQ ID NOs: 208, 209, 176, 409, 410 and 411; (894)34) SEQ ID NOs: 208, 209, 176, 409, 412 and 413; (795)35) SEQ ID NOs: 208, 209, 176, 414, 415 and 416; (796)36) SEQ ID NOs: 156, 182, 183, 409, 410 and 411; (884)37) SEQ ID NOs: 156, 182, 183, 409, 412 and 413; (786)38) SEQ ID NOs: 156, 182, 183, 414, 415 and 416; (787)39) SEQ ID NOs: 156, 188, 181, 406, 407 and 408; (058)40) SEQ ID NOs: 185, 186, 187, 426, 427 and 428; (284)41) SEQ ID NOs: 709, 186, 187.426, 427 and 428; (183)42) SEQ ID NOs: 709, 186, 187.426, 427 and 428; (184)43) SEQ ID NOs: 189, 190, 191, 420, 421 and 422; (239)44) SEQ ID NOs: 189, 190, 191, 426, 427 and 428; (286) or45) SEQ ID NOs: 204, 205, 206, 420, 421 and 422; (247).

[0115] In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 212 and 448; [A06con-A05con]2) SEQ ID NOs: 212 and 449; [A06con-A05con]3) SEQ ID NOs: 212 and 460; [A06con-C04con]4) SEQ ID NOs: 233 and 448; [E07con-A05con]5) SEQ ID NOs: 234 and 449; [E07con-A05con]6) SEQ ID NOs: 233 and 460; [E07con-C04con]7) SEQ ID NOs: 234 and 460; [E07con-C04conJ1569-US-NP / WO-PCT8) SEQ ID NOs: 710 and 448; [C09con-A05con]9) SEQ ID NOs: 710 and 449; [C09con-A05con]10) SEQ ID NOs: 710 and 460; [C09con-C04con]11) SEQ ID NOs: 230 and 460 [G22con-C04con] or12) SEQ ID NOs: 249 and 460 [Fl lcon-C04con],

[0116] In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL lORa and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs 235 and 450; (877)2) SEQ ID NOs 237 and 451; (647)3) SEQ ID NOs 239 and 452; (195)4) SEQ ID NOs 235 and 446; (048)5) SEQ ID NOs 237 and 447; (049)6) SEQ ID NOs 239 and 447; (050)7) SEQ ID NOs 235 and 461; (274)8) SEQ ID NOs 237 and 462; (771)9) SEQ ID NOs 239 and 462; (772)10) SEQ ID NOs 241 and 446; (054)11) SEQ ID NOs 243 and 447; (755)12) SEQ ID NOs 241 and 450; (883)13) SEQ ID NOs 243 and 451; (784)14) SEQ ID NOs 243 and 452; (785)15) SEQ ID NOs 213 and 446; (046)16) SEQ ID NOs 215 and 447; (747)17) SEQ ID NOs 213 and 450; (875)18) SEQ ID NOs 215 and 451; (776)19) SEQ ID NOs 215 and 452; (777)20) SEQ ID NOs 213 and 461; (272)21) SEQ ID NOs 215 and 462; (773)22) SEQ ID NOs 224 and 446; (052)23) SEQ ID NOs 226 and 447; (753)1569-US-NP / WO-PCT24) SEQ ID NOs 224 and 461; (278)25) SEQ ID NOs 226 and 462; (769)26) SEQ ID NOs 227 and 446; (047)27) SEQ ID NOs 229 and 447; (748)28) SEQ ID NOs 227 and 450; (876)29) SEQ ID NOs 229 and 451; (778)30) SEQ ID NOs 229 and 452; (779)31) SEQ ID NOs 267 and 446; (062)32) SEQ ID NOs 269 and 447; (763)33) SEQ ID NOs 267 and 450; (891)34) SEQ ID NOs 269 and 451; (780)35) SEQ ID NOs 269 and 452; (781)36) SEQ ID NOs 267 and 461; (290)37) SEQ ID NOs 269 and 462; (791)38) SEQ ID NOs 270 and 450; (892)39) SEQ ID NOs 272 and 451; (793)40) SEQ ID NOs 272 and 452; (794)41) SEQ ID NOs 285 and 450; (894)42) SEQ ID NOs 287 and 451; (795)43) SEQ ID NOs 287 and 452; (796)44) SEQ ID NOs 244 and 450; (884)45) SEQ ID NOs 246 and 451; (786)46) SEQ ID NOs 247 and 452; (787)47) SEQ ID NOs 253 and 446; (058)48) SEQ ID NOs 255 and 447; (759)49) SEQ ID NOs 250 and 461; (284)50) SEQ ID NOs 251 and 462; (183)51) SEQ ID NOs 252 and 462; (184)52) SEQ ID NOs 256 and 456; (239)53) SEQ ID NOs 258 and 457; (740)54) SEQ ID NOs 256 and 461; (286)55) SEQ ID NOs 258 and 462; (788)56) SEQ ID NOs 278 and 456; (247) or57) SEQ ID NOs 280 and 457; (749).1569-US-NP / WO-PCT

[0117] In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs 236 and 450; (877)2) SEQ ID NOs 238 and 451; (647)3) SEQ ID NOs 240 and 452; (195)4) SEQ ID NOs 236 and 446; (048)5) SEQ ID NOs 238 and 447; (049)6) SEQ ID NOs 240 and 447; (050)7) SEQ ID NOs 236 and 461; (274)8) SEQ ID NOs 238 and 462; (771)9) SEQ ID NOs 240 and 462; (772)10) SEQ ID NOs 242 and 446; (054)11) SEQ ID NOs 243 and 447; (755)12) SEQ ID NOs 242 and 450; (883)13) SEQ ID NOs 243 and 451; (784)14) SEQ ID NOs 243 and 452; (785)15) SEQ ID NOs 214 and 446; (046)16) SEQ ID NOs 215 and 447; (747)17) SEQ ID NOs 214 and 450; (875)18) SEQ ID NOs 215 and 451; (776)19) SEQ ID NOs 215 and 452; (777)20) SEQ ID NOs 214 and 461; (272)21) SEQ ID NOs 215 and 462; (773)22) SEQ ID NOs 225 and 446; (052)23) SEQ ID NOs 226 and 447; (753)24) SEQ ID NOs 225 and 461; (278)25) SEQ ID NOs 226 and 462; (769)26) SEQ ID NOs 228 and 446; (047)27) SEQ ID NOs 229 and 447; (748)28) SEQ ID NOs 228 and 450; (876)29) SEQ ID NOs 229 and 451; (778)1569-US-NP / WO-PCT30) SEQ ID NOs 229 and 452; (779)31) SEQ ID NOs 268 and 446; (062)32) SEQ ID NOs 269 and 447; (763)33) SEQ ID NOs 268 and 450; (891)34) SEQ ID NOs 269 and 451; (780)35) SEQ ID NOs 269 and 452; (781)36) SEQ ID NOs 268 and 461; (290)37) SEQ ID NOs 269 and 462; (791)38) SEQ ID NOs 271 and 450; (892)39) SEQ ID NOs 273 and 451; (793)40) SEQ ID NOs 274 and 452; (794)41) SEQ ID NOs 286 and 450; (894)42) SEQ ID NOs 287 and 451; (795)43) SEQ ID NOs 287 and 452; (796)44) SEQ ID NOs 245 and 450; (884)45) SEQ ID NOs 246 and 451; (786)46) SEQ ID NOs 246 and 452; (787)47) SEQ ID NOs 254 and 446; (058)48) SEQ ID NOs 255 and 447; (759)49) SEQ ID NOs 250 and 461; (284)50) SEQ ID NOs 251 and 462; (183)51) SEQ ID NOs 252 and 462; (184)52) SEQ ID NOs 257 and 456; (239)53) SEQ ID NOs 259 and 457; (740)54) SEQ ID NOs 257 and 461; (286)55) SEQ ID NOs 259 and 462; (788)56) SEQ ID NOs 279 and 456; (247) or57) SEQ ID NOs 280 and 457; (749).

[0118] In some embodiments, the bispecific antibody comprises a polypeptide comprising in tandem the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-1OR0, comprising the following amino acid sequence, or an amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least1569-US-NP / WO-PCT93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-476 and 573.

[0119] In some embodiments, the bispecific antibody comprises a polypeptide comprising in tandem the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-1OR0, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533. 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557. 559, 561, 563, 565, 567, 569, 571, 574, 576, 578, 580, 582, 584, 586, 588 and 590.

[0120] In some embodiments, the bispecific antibody comprises a polypeptide comprising in tandem the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-1OR0, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 575, 577, 579, 581, 583, 585, 587, 589, 591, 737-751 and 757-758.

[0121] In some embodiments, the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-10RP are humanized. Illustrative humanized VHH sequences provided herein are designated with an “hu” prefix.

[0122] Amino acid sequence of illustrative aIL-10Ra / odL-lORp Tandem Single Immunoglobulin Domain (VHH- VHH) are provided in Table E, below.Table E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH- VHH) amino acid sequencesVHH— VHH VHH-VHH amino acid sequencenameaIL-10Rcc-aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) 774 SEQ ID NO: 475X1X2LQLVESGGGLVX3X4GX5SLRLSCAASGRTFSAYGMGWFRQAPGKX6REFVX7 E07-A05 AIRWX8GX9X1OTYYAX11SVKGRFTISKDX12X13KNTLYLQMX14SLX15X16EDTAV coni YYCAAKTX1 / X18X19SYLSEKSYX20YWGQGTX21VTVSSX22X23VQLX24ESGGGLV1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencenameQPGGSLX25LSCAASGX26SLDX27X28X29IGWFRX30APGKX31X32EGVSX33ISA X34DX35STHYAX36X37VKGRFTISRDNX38KNTVX39LQMNX40LX41X42EDX43X44 X45YYCAASLX46GLGX47KX48EX49DYDYWGQGTX50VTVSSXI is S, GG, AS, ASS or absent (i. e., no amino acid residues )X2 is E or QX3 is Q or RX4 is A or PX5 is D or GXs is E or GX7 is A or SX8is I or YX9 is D or EX10 is A, G or SXu is D or EX12 is N or SX13 is A or SX14 is N or SXis is K or RXis is A or PX17 is R or SXis is P or VX19 is D or TX20 is G or NX21 is M or QX22 is GGGS, GGGGS, or GGGSGGGSX23 is E or QX24 is L or QX25 is K or RX26 is I or NX27 is E or YX28 is G, P or SX29 is V or TX30 is Q or RX31 is E or GX32 is L or RX33 is A or CX34 is R or SX35 is A or GXss is D or NX37 is A or SX33 is S or TX39 is D or Y1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencenameX40 is N or SX41 is K or RX42 is A or PX43 is A or TX44 is A or GX45 is H or VX40 is H or WX47 is A or CX4S is R or SX49 is A or EX50 is L, M or Q775 SEQ ID NO: 476X1QLQLVESGGGLVX3X4GGSLRLSCAASGRTFSAYGMGWFRQAPGKX6REFVX7A E07-A05 IRWXgGXgXioTYYAXuSVKGRFTI SKDNX13KNTLYLQMX14SLX15X16EDTAVYY con2 CAAKTX17XlsXi9SYLSEKSYX2oYWGQGTX2iVTVSSX22X23VQLVESGGGLVQPG GSLRLSCAASGNSLDYPTIGWFRQAPGKX24X25EGVSX26ISASDX27STHYADX28 VKGRFTISRDNX29KNTVX30LQMNX31LX32X33EDTX34X35YYCAASLX36GLGX37 KSEADYDYWGQGTXsaVTVSSXi is S, GG, AS, ASS or absent (i. e., no amino acid residues )X3 is Q or RX4 is A or PXe is E or GX7 is A or SXg is I or YX9 is D or EX10 is A, G or SXu is D or EX13 is A or SX14 is N or SXis is K or RXis is A or PX17 is R or SXig is P or VX19 is D or TX20 is G or NX21 is M or QX22 is GGGS, GGGGS, or GGGSGGGSX23 is E or QX24 is E or GX25is L or RX26 is A or C1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencenameX27 is A or GX28 is A or SX29 is S or TX30 is D or YX31 is N or SX32 is K or RX33 is A or PX34 is A or GX35 is H or VXss is H or WX37 is A or CX33 is M or Q877 SEQ ID NO: 477Xi is S, GG, AS, ASS or absent (i. e., no amino acid E07-A05 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 478Xi is AS; X2is GGGS XiQLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS647 SEQ ID NO: 479Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huA05 X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 480Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS EKSYGYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS195 SEQ ID NO: 481Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huA05 X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 482Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencenameEKSYNYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS048 SEQ ID NO: 483Xi is S, GG, AS, ASS or absent (i. e., no amino acid E07-A02 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 484Xx is AS; X2is GGGS XiQLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS049 SEQ ID NO: 485Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huA02 X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 486Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS EKSYGYWGQGTMVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS050 SEQ ID NO: 487Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huA02 X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 488Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTMVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS274 SEQ ID NO: 489Xi is S, GG, AS, ASS or absent (i. e., no amino acid E07-C04 residues )X2is GGGS, GGGGS, or GGGSGGGS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencenameSEQ ID NO: 490Xi is AS; X2is GGGS XiQLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW FRQAP GKE RE GVAC I S S S GRGVNANY I D S VRGRFT I SRDNAKNT VYLQMNKLKP DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS771 SEQ ID NO: 491Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huC04 X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 492Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS EKSYGYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS772 SEQ ID NO: 493Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huC04 X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 494Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS054 SEQ ID NO: 495Xi is S, GG, AS, ASS or absent (i. e., no amino acid E15-A02 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 496Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGNSAYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS1569-US-NP / WO-PCT Table E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename755 SEQ ID NO: 497X is GGGSrGGGGS, or GGGSGGGShuE15- SEQ ID NO: 498huA02 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS883 SEQ ID NO: 499Xi is S, GG, AS, ASS or absent (i. e., no amino acid E15-A05 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 500Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGNSAYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA AASYAYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS784 SEQ ID NO: 501X2is GGGS, GGGGS, or GGGSGGGShuE15- SEQ ID NO: 502huA05 X i s GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS785 SEQ ID NO: 503X2is GGGS, GGGGS, or GGGSGGGShuE15- SEQ ID NO: 504huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename046 SEQ ID NO: 505Xi is S, GG, AS, ASS or absent (i. e., no amino acid A06-A02 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 506Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR ASEYDYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS747 SEQ ID NO: 507X2 is GGGS, GGGGS, or GGGSGGGShuA06- SEQ ID NO: 508huA02 X2is GGGS ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA SEYDYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS875 SEQ ID NO: 509Xi is S, GG, AS, ASS or absent (i. e., no amino acid A06-A05 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 510Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS776 SEQ ID NO: 511X2 is GGGS, GGGGS, or GGGSGGGShuA06- SEQ ID NO: 512huA05 X2is GGGS ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename777 SEQ ID NO: 513X is GGGS, GGGGS, or GGGSGGGShuA06- SEQ ID NO: 514huA05 X2is GGGS ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS272 SEQ ID NO: 515Xi is S, GG, AS, ASS or absent (i. e., no amino acid A06-C04 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 516Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW FRQAP GKE RE GVAC I S S S GRGVNANY I D S VRGRFT I SRDNAKNT VYLQMNKLKP DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS773 SEQ ID NO: 517X2is GGGS, GGGGS, or GGGSGGGShuA06- SEQ ID NO: 518huC04 X i s GGGS ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGWF RQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRAE DTAVYYCATNCWRLTSPAADNWGQGTMVTVSS052 SEQ ID NO: 519Xi is S, GG, AS, ASS or absent (i. e., no amino acid C09-A02 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 520Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGGGTYYADSVKGRFTLSRDNAKNMVYLQMNSLKPEDTAVYYCAAKYYPDSYFA AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename753 SEQ ID NO: 521X is GGGSrGGGGS, or GGGSGGGShuC09- SEQ ID NO: 522huA02 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS278 SEQ ID NO: 523Xi is S, GG, AS, ASS or absent (i. e., no amino acid C09-C04 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 524Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGGGTYYADSVKGRFTLSRDNAKNMVYLQMNSLKPEDTAVYYCAAKYYPDSYFA AASYAYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW FRQAP GKE RE GVAC I S S S GRGVNANY I D S VRGRFT I SRDNAKNT VYLQMNKLKP DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS769 SEQ ID NO: 525X2is GGGS, GGGGS, or GGGSGGGShuC09- SEQ ID NO: 526huC04 X i s GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGWF RQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRAE DTAVYYCATNCWRLTSPAADNWGQGTMVTVSS047 SEQ ID NO: 527Xi is S, GG, AS, ASS or absent (i. e., no amino acid D08-A02 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 528Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGGSTYYADSVKGRFTLSSDNAKNRIALQMNSLKPEDTAVYYCAAKYYTDSYFA ATSYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS1569-US-NP / WO-PCT Table E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename748 SEQ ID NO: 529X is GGGSrGGGGS, or GGGSGGGShuD08- SEQ ID NO: 530huA02 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS876 SEQ ID NO: 531Xi is S, GG, AS, ASS or absent (i. e., no amino acid D08-A05 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 532Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGGSTYYADSVKGRFTLSSDNAKNRIALQMNSLKPEDTAVYYCAAKYYTDSYFA ATSYAYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS778 SEQ ID NO: 533X2is GGGS, GGGGS, or GGGSGGGShuD08- SEQ ID NO: 534huA05 X i s GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS779 SEQ ID NO: 535X2is GGGS, GGGGS, or GGGSGGGShuD08- SEQ ID NO: 536huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename062 SEQ ID NO: 537Xi is S, GG, AS, ASS or absent (i. e., no amino acid I04-A02 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 538Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW FGRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRR NQAEYDYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIG WFRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPE DAGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS763 SEQ ID NO: 539X2 is GGGS, GGGGS, or GGGSGGGShuI04- SEQ ID NO: 540huA02 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN QAEYDYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS891 SEQ ID NO: 541Xi is S, GG, AS, ASS or absent (i. e., no amino acid I04-A05 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 542Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW FGRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRR NQAEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIG WFRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPE DTGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS780 SEQ ID NO: 543X2 is GGGS, GGGGS, or GGGSGGGShuI04- SEQ ID NO: 544huA05 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename781 SEQ ID NO: 545X is GGGSrGGGGS, or GGGSGGGShuI04- SEQ ID NO: 546huA05 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS290 SEQ ID NO: 547Xi is S, GG, AS, ASS or absent (i. e., no amino acid I04-C04 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 548Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW FGRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRR NQAEYDYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIG WFRQAPGKEREGVACISSSGRGVNANYIDSVRGRFTISRDNAKNTVYLQMNKLK PDDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS791 SEQ ID NO: 549X2is GGGS, GGGGS, or GGGSGGGShuI04- SEQ ID NO: 550huC04 X i s GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS892 SEQ ID NO: 551Xi is S, GG, AS, ASS or absent (i. e., no amino acid J13-A05 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 552Xi is AS; X2is GGGS XiQVQLVESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGFVATINW IPGNTYYADSVKGRFTISGEEDKNTVYLQMDNLKPEDTAVYYCAARRRIDNYYR ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename793 SEQ ID NO: 553Xi is S, GG, AS, ASS or absent (i. e., no amino acid hu J13- residues )huA05 X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 554Xi is AS; X2is GGGS XiQVQLVESGGGWQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINW IPGNTYYADSVKGRFTISGDESKNTVYLQMNSLRAEDTAVYYCAARRRIDNYYR ASEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS794 SEQ ID NO: 555hu J13- Xi is S, GG, AS, ASS or absent (i. e., no amino acid huA05 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 556Xi is AS; X2is GGGS XiQVQLVESGGGWQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINW IPGNTYYADSVKGRFTISGDESKNTVYLQMNSLRAEDTAVYYCAARRRIDNYYR ASEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS894 SEQ ID NO: 557Xi is S, GG, AS, ASS or absent (i. e., no amino acid N16-A05 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 558Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRW IGGDTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS795 SEQ ID NO: 559X2is GGGS, GGGGS, or GGGSGGGShuN16- SEQ ID NO: 560huA05 X2 i s GGGS EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWI GGDTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSE KSYNYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencenameRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS796 SEQ ID NO: 561X2 is GGGS, GGGGS, or GGGSGGGShuN16- SEQ ID NO: 562huA05 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWI GGDTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSE KSYNYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS884 SEQ ID NO: 563Xi is S, GG, AS, ASS or absent (i. e., no amino acid F09-A05 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 564Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLSLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGSATDYADSVRGRFTISGDNAKNTVYLLMNNLKPEDTAVYYCAARRSPMSRTS VLQYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS786 SEQ ID NO: 565X2 is GGGS, GGGGS, or GGGSGGGShuF09- SEQ ID NO: 566huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GSATDYADSVRGRFTISGDNSKNTVYLQMNSLRAEDTAVYYCAARRSPMSRTSV LQYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS787 SEQ ID NO: 567X2 is GGGS, GGGGS, or GGGSGGGShuF09- SEQ ID NO: 568huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GSATDYADSVRGRFTISGDNSKNTVYLQMNSLRAEDTAVYYCAARRSPMSRTSV LQYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename058 SEQ ID NO: 569Xi is S, GG, AS, ASS or absent (i. e., no amino acid F21-A02 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 570Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGNSTYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS759 SEQ ID NO: 571X2 is GGGS, GGGGS, or GGGSGGGShuF21- SEQ ID NO: 572huA02 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSTYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS767 SEQ ID NO: 573EX1QLX2ESGGGLVQX3GGSLRLSCAX4SGRTFSSHTVGWFRQAPGKX5REFVX6A F11-C04 ITWNGDTTYFGDFVEGRFX7ISRDX8X9KNTLYLXioMNXiiLXi2Xi3EDTAVYYCA con AATGQVWSLQYLRESSYAYWGQGTX14VTVSSX15X16VQLVESGGGLVQX17GGSL RLSCXlsASGFTSPYSTIGWFRQAPGKX29REGVACISSSGRGVNANYIDSVRGRF TISRDNX20KNTVYLQMNX21LKX22X23DTAX24YYCATNCWRLTSPAADNWGQGT X25VTVSSXI is L or VX2is L or VX3 is A or PX4is A or NX5 is E or GXg is A or EX7is S or TXg is N or SXy is A or SX10 is E or QXu is K or SX12 is K or RX13 is A or PX14 is L or QX15 is GGGS, GGGGS, or GGGSGGGSXis is E or Q1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencenameXi? is P or SXis is S or VXia is E or GX20 is A or SX21 is K or SX22 is A or PX23 is D or EX24 is I or VX25 is M or Q284 SEQ ID NO: 574X2 is GGGS, GGGGS, or GGGSGGGSF11-C04 SEQ ID NO: 575X2 is GGGS ELQLVESGGGLVQAGGSLRLSCANSGRTFSSHTVGWFRQAPGKEREFVAAITWN GDTTYFGDFVEGRFSISRDSAKNTLYLEMNKLKPEDTAVYYCAAATGQVWSLQY LRESSYAYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTI GWF RQAP GKE RE GVAC I S S S GRGVNANY I D S VRGRF T I S RDNAKNT VY LQMNKL KPDDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS183 SEQ ID NO: 576X2is GGGS, GGGGS, or GGGSGGGShuFll- SEQ ID NO: 577huC04 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVAAITWN GDTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQY LRESSYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTI GWFRQAP GKGRE GVAC I S S S GRGVNANY ID S VRGRF T I SRDNSKNT VY LQMNS L RAEDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS184 SEQ ID NO: 578X2 is GGGS, GGGGS, or GGGSGGGShuFll- SEQ ID NO: 579huC04 X2is GGGS ELQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWN GDTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQY LRESSYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTI GWFRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSL RAEDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS239 SEQ ID NO: 580Xi is S, GG, AS, ASS or absent (i. e., no amino acid G22-B12 residues )X2 is GGGS, GGGGS, or GGGSGGGS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencenameSEQ ID NO: 581Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLKLSCTASGRTFDGYGMGWFRQAPGKEREFVSAINW IYGATYYADSVKGRFAVSRDKAKGTMYLQMNSLKPEDTAVYYCAAKINAGSYFN IGSFGSWGQGTQVTVSSX2EVQLVESGGGLVQAGGSLRLSCAASGSFSSISTMAW YRQVP GKQREWLARI I WS SGATNYAD SVKGRF T I SRDNTKNTMYLQMDRLTPED TAAYLCSGAISQTRGTFWTYKSQGTQVTVSS740 SEQ ID NO: 582Xi is S, GG, AS, ASS or absent (i. e., no amino acid huG22- residues )huB12 X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 583Xi is AS; X2is GGGS XiQLQLVESGGGLVQPGGSLRLSCSASGRTFDGYGMGWFRQAPGKEREFVSAINW IYGATYYADSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINAGSYFN IGSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGSFSSISTMAW YRQAP GKQREWLARI IWSSGATNYADSVKGRFTISRDNSKNTMYLQMNSLRAED TAVYYCSGAISQTRGTFWTYKGQGTLVTVSS286 SEQ ID NO: 584Xi is S, GG, AS, ASS or absent (i. e., no amino acid G22-C04 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 585Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLKLSCTASGRTFDGYGMGWFRQAPGKEREFVSAINW IYGATYYADSVKGRFAVSRDKAKGTMYLQMNSLKPEDTAVYYCAAKINAGSYFN IGSFGSWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW FRQAP GKE RE GVAC I S S S GRGVNANY I D SVRGRFT I SRDNAKNT VYLQMNKLKP DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS788 SEQ ID NO: 586Xi is S, GG, AS, ASS or absent (i. e., no amino acid huG22- residues )huC04 X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 587Xi is AS; X2is GGGS XiQLQLVESGGGLVQPGGSLRLSCSASGRTFDGYGMGWFRQAPGKEREFVSAINW IYGATYYADSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINAGSYFN IGSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS1569-US-NP / WO-PCTTable E - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) amino acid sequencesVHH-VHH VHH-VHH amino acid sequencename247 SEQ ID NO: 588Xi is S, GG, AS, ASS or absent (i. e., no amino acid L05-B12 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 589Xi is AS; X2is GGGS XiQVQLLESGGGLVQAGGSLKLSCTNSGRTFSGYGMGWFRQPPGKEREFVSSINW IYGATYYSDSVKGRFALSRDKAKNTVYLQMDSLKPEDTAVYYCAAKINGESYFN TGSFGSWGQGTQVTVSSX2EVQLVESGGGLVQAGGSLRLSCAASGSFSSISTMAW YRQVP GKQREWLARI I WS SGATNYAD SVKGRF T I SRDNTKNTMYLQMDRLTPED TAAYLCSGAISQTRGTFWTYKSQGTQVTVSS749 SEQ ID NO: 590X2 is GGGS, GGGGS, or GGGSGGGShuL05- SEQ ID NO: 591huB12 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSGYGMGWFRQAPGKEREFVSSINWI YGATYYSDSVKGRFTLSRDKSKNTVYLQMNSLRAEDTAVYYCAAKINGESYFNT GSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGSFSSISTMAWY RQAPGKQREWLARIIWSSGATNYADSVKGRFTISRDNSKNTMYLQMNSLRAEDT AVYYCSGAISQTRGTFWTYKGQGTLVTVSSFc Domains

[0123] In some embodiments, the bispecific antibodies described herein are symmetrical, comprising two identical polypeptide chains. In some embodiments, the bispecific antibodies described herein comprise a first fragment crystallizable (Fc) domain and a second Fc domain that have the same amino acid sequences. Fusion of the tandem VHH1-VHH2 domains with an Fc can increase both serum half-life and potency. In some embodiments, the first Fc domain and the second Fc domain are a human IgGl or a human IgG4.

[0124] In some embodiments, one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions that reduces or inhibits or eliminates antibody-dependent cell-mediated cytotoxicity (ADCC) effector function. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises effector function reducing amino acid substitutions at Fc positions (EU numbering) selected from:a) alanine at position 234 and alanine at position 235 (234A and 235A);b) glutamic acid at position 235 (235E);1569-US-NP / WO-PCTc) proline at position 228 and glutamic acid at position 235 (228P, 235E);d) alanine at position 237 (237A);e) alanine at position 234 and glutamic acid at position 235 (234A and 235E); f) phenylalanine at position 234, glutamic acid at position 235 and alanine at position 265 (234F, 235E and 265A);g) phenylalanine at position 234, glutamic acid at position 235 and alanine at position 236 (234F, 235E and 236A);h) phenylalanine at position 234, glutamic acid at position 235 and arginine at position 236 (234F, 235E and 236R);i) serine at position 234, threonine at position 235 and arginine at position 236 (234S, 235T and 236R);j) alanine at position 234, alanine at position 235 and glycine at position 329 (234A, 235A and 329G);k) alanine at position 234, alanine at position 235 and alanine at position 237 (234A, 235A and 237A);l) proline at position 228 and glutamic acid at position 235 (228P and 235E); m) proline at position 228, glutamic acid in position 235 and glycine at position 329 (228P, 235E and 329G);n) phenylalanine at position 234, glutamic acid at position 235 and serine at position 331 (234F, 235E and 331S);o) phenylalanine at position 234, glutamine at position 235 and glutamine at position 322 (234F, 235Q and 322Q);p) alanine at position 233, arginine at position 234 and arginine at position 235 (233A, 234R and 235R);q) alanine at position 233, aspartic acid at position 234 and glutamic acid at position 235 (233A, 234D and 235E);r) lysine at position 233, arginine at position 234 and arginine at position 235 (233K, 234R and 235R);s) alanine at position 234, alanine at position 235, alanine at position 237, serine at position 238, alanine at position 268, serine at position 330 and serine at position 331 (234A, 235 A, 237A, 238S, 268A, 33OS and 33 IS); andt) proline at position 228, alanine at position 234, alanine at position 235, alanine at position 237 and serine at position 238 (228P, 234A, 235A, 237A and 238S).1569-US-NP / WO-PCT

[0125] In some embodiments, one or both of the first Fc domain and the second Fc domain comprises effector function reducing amino acid substitutions at Fc positions (EU numbering) alanine at position 234, alanine at position 235 and alanine at position 237 (234A, 235A and 237A).

[0126] In some embodiments, one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions that extend serum half-life. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises serum half-life extending amino acid substitutions at Fc positions (EU numbering) selected from: a) tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (252Y, 254T and 256E);b) leucine at position 428 (428L);c) glutamine at position 250 and leucine at position 428 (250Q and 428L);d) leucine at position 428 and serine at position 434 (428L and 434S);e) leucine at position 428 and alanine at position 434 (428L and 434A);f) arginine at position 311 and leucine at position 428 (311R and 428L);g) glycine at position 309 and leucine at position 428 (309G and 428L);h) glutamine at position 307, valine at position 311 and valine at position 378 (307Q, 31 IV and 378V): andi) aspartic acid at position 256, aspartic acid at position 286, arginine at position 307, valine at position 311 and valine at position 378 (256D, 286D, 307R, 311V and 378V).Full-length VHH-VHH-Fc polypeptides

[0127] In some embodiments the bispecific antibody comprises at least one polypeptide (e.g., first and second polypeptides) comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 592-593 and 690. In some embodiments the bispecific antibody comprises at least one polypeptide (e.g., first and second polypeptides) comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652,1569-US-NP / WO-PCT654, 656, 658, 660, 662. 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 691, 693, 695, 697, 699, 701, 703, 705, and 707. In some embodiments the bispecific antibody comprises at least one polypeptide (e.g., first and second polypeptides) comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 635, 637, 639, 641, 643, 645, 647, 649, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683. 685, 687, 689, 692, 694, 696, 698, 700, 702, 704, 706 and 708.

[0128] Generally, the herein described tandem single immunoglobulin domain bispecific (VHH-VHH-Fc) bind to human IL-lORa I IL-10RP complex and cynomolgus IL-lORa I IL-10RP complex, within a 10-fold affinity difference, e.g., within a 5-fold or within a 3-fold affinity difference e.g., as determined by SPR and expressed as an equilibrium dissociation constant (KD)). Amino acid sequences of illustrative aIL-10Ra / aIL-10Rp tandem single immunoglobulin domain bispecific (VHH-VHH-Fc) are provided in Table F, below.

[0129] The aIL-10Ra-aIL-10RP tandem single immunoglobulin domain heavy chains (VHH-VHH-Fc) described herein have a C-terminal lysine. It is possible that the C-terminal lysine might be clipped. Accordingly, in the aIL-10Ra-aIL-10RP tandem single immunoglobulin domain heavy chains (VHH-VHH-Fc) described herein, in some embodiments, the C-terminal lysine is present or absent.Table F - Illustrative ctIL-10Ra / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameaIL-10Rot-otIL-10Rp Tandem Single Immunoglobulin Domain (VHH-VHH) 774 SEQ ID NO: 592X1X2LQLVESGGGLVX3X4GX5SLRLSCAASGRTFSAYGMGWFRQAPGKX6REFVX7 E07-A05 AIRWXeGXgXioTYYAXuSVKGRFTISKDX^XisKNTLYLQMX^SLXxsXicEDTAV coni YYCAAKTXi7Xi8Xi9SYLSEKSYX2oYWGQGTX2iVTVSSX22X23VQLX24ESGGGLV QPGGSLX25LSCAASGX26SLDX27X28X29IGWFRX30APGKX31X32EGVSX33ISA X34DX35STHYAX36X37VKGRFTISRDNX38KNTVX39LQMNX40LX41X42EDX43X44 X45YYCAASLX46GLGX47KX48EX49DYDYWGQGTX50VTVSSGSDKTHTCPPCPAP EAAGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKXi is S, GG, AS, ASS or absent (i. e., no amino acid residues )X2 is E or QX3 is Q or RX4 is A or PX5 is D or GXs is E or GX? is A or SX8is I or YX9 is D or EX10 is A, G or SXu is D or EX12 is N or SX13 is A or SX14 is N or SXis is K or RXis is A or PXi? is R or SXi8 is P or VX19 is D or TX20 is G or NX21 is M or QX22 is GGGS, GGGGS, or GGGSGGGSX23 is E or QX24 is L or QX25 is K or RX26 is I or NX27 is E or YX23 is G, P or SX29 is V or TX30 is Q or RX31 is E or GX32 is L or RX33 is A or CX34 is R or SX35 is A or GX36 is D or NX37 is A or SXss is S or TX39 is D or Y1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameX40 is N or SX41 is K or RX42 is A or PX43 is A or TX44 is A or GX45 is H or VX46 is H or WX47 is A or CX48 is R or SX49 is A or EX50 is L, M or Q775 SEQ ID NO: 593X1QLQLVESGGGLVX3X4GGSLRLSCAASGRTFSAYGMGWFRQAPGKX6REFVX7A E07-A05 IRWXsGXoXioTYYAXuSVKGRFTI SKDNXisKNTLYLQMXi iSLXisXibEDTAVYY con2 CAAKTX17X18X19SYLSEKSYX20YWGQGTX21VTVSSX22X23VQLVESGGGLVQPG GSLRLSCAASGNSLDYPTIGWFRQAPGKX24X25EGVSX26ISASDX27STHYADX28 VKGRFTISRDNX29KNTVX30LQMNX31LX32X33EDTX34X35YYCAASLX36GLGX37 KSEADYDYWGQGTXssVTVSSGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVL TVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKXi is S, GG, AS, ASS or absent (i. e., no amino acid residues )X3 is Q or RX4 is A or PXe is E or GX7 is A or SXs is I or YX9 is D or EX10 is A, G or SXu is D or EXis is A or SX14 is N or SXia is K or RXie is A or PX17 is R or SXis is P or VX19 is D or TX20 is G or NX21 is M or Q1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameX22 is GGGS, GGGGS, 01? GGGSGGGSX23 is E or QX24 is E or GX25 is L or RX26 is A or CX27 is A or GX28 is A or SX29 is S or TX30 is D or YX31 is N or SX32 is K or RX33 is A or PX34 is A or GX35 is H or VX36 is H or WX37 is A or CX38 is M or Q877 SEQ ID NO: 594Xi is S, GG, AS, ASS or absent (i. e., no amino acid E07-A05 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 595Xi is AS; X2is GGGS XiQLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK647 SEQ ID NO: 596Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huA05 X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 597Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS EKSYGYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW1569-US-NP / WO-PCT Table F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameFRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGAP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTI SKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK195 SEQ ID NO: 598Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huA05 X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 599Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGAP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTI SKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK048 SEQ ID NO: 600Xi is S, GG, AS, ASS or absent (i. e., no amino acid E07-A02 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 601Xi is AS; X2is GGGS XiQLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTI SKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencename049 SEQ ID NO: 602Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huA02 X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 603Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS EKSYGYWGQGTMVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK050 SEQ ID NO: 604Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huA02 X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 605Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTMVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK274 SEQ ID NO: 606Xi is S, GG, AS, ASS or absent (i. e., no amino acid E07-C04 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 607Xi is AS; X2is GGGS XiQLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW1569-US-NP / WO-PCT Table F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameFRQAP GKE RE GVAC I S S S GRGVNANY I D SVRGRFT I SRDNAKNT VYLQMNKLKP DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK771 SEQ ID NO: 608Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huC04 X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 609Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS EKSYGYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK772 SEQ ID NO: 610Xi is S, GG, AS, ASS or absent (i. e., no amino acid huE07- residues )huC04 X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 611Xi is AS; X2is GGGS XiQLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencename054 SEQ ID NO: 612Xi is S, GG, AS, ASS or absent (i. e., no amino acid E15-A02 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 613Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGNSAYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK755 SEQ ID NO: 614X2 is GGGS, GGGGS, or GGGSGGGShuE15- SEQ ID NO: 615huA02 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK883 SEQ ID NO: 616Xi is S, GG, AS, ASS or absent (i. e., no amino acid E15-A05 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 617Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGNSAYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA AASYAYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK784 SEQ ID NO: 618X2is GGGS, GGGGS, or GGGSGGGShuE15- SEQ ID NO: 619huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK785 SEQ ID NO: 620X2is GGGS, GGGGS, or GGGSGGGSE15- SEQ ID NO: 621huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK046 SEQ ID NO: 622Xi is S, GG, AS, ASS or absent (i. e., no amino acid A06-A02 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 623Xi is AS; X2is GGGS XxQLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR ASEYDYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW1569-US-NP / WO-PCT Table F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameFRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK747 SEQ ID NO: 624X2is GGGS, GGGGS, or GGGSGGGShuA06- SEQ ID NO: 625huA02 X2is GGGS ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA SEYDYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK875 SEQ ID NO: 626Xi is S, GG, AS, ASS or absent (i. e., no amino acid A06-A05 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 627Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencename776 SEQ ID NO: 628X2is GGGS, GGGGS, or GGGSGGGShuA06- SEQ ID NO: 629huA05 X2i s GGGS ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK777 SEQ ID NO: 630X2is GGGS, GGGGS, or GGGSGGGShuA06- SEQ ID NO: 631huA05 X2is GGGS ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK272 SEQ ID NO: 632Xi is S, GG, AS, ASS or absent (i. e., no amino acid A06-C04 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 633Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW FRQAP GKE RE GVAC I S S S GRGVNANY I D S VRGRFT I SRDNAKNT VYLQMNKLKP DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK773 SEQ ID NO: 634X is GGGS, GGGGS, or GGGSGGGShuA06- SEQ ID NO: 635huC04 X2is GGGS ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGWF RQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRAE DTAVYYCATNCWRLTSPAADNWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPSV FLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK052 SEQ ID NO: 636Xi is S, GG, AS, ASS or absent (i. e., no amino acid C09-A02 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 637Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGGGTYYADSVKGRFTLSRDNAKNMVYLQMNSLKPEDTAVYYCAAKYYPDSYFA AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK753 SEQ ID NO: 638X2is GGGS, GGGGS, or GGGSGGGShuC09- SEQ ID NO: 639huA02 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSXoEVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSSGSDKTHTCPPCPAPEAAGGPS1569-US-NP / WO-PCT Table F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK278 SEQ ID NO: 640Xi is S, GG, AS, ASS or absent (i. e., no amino acid C09-C04 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 641Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGGGTYYADSVKGRFTLSRDNAKNMVYLQMNSLKPEDTAVYYCAAKYYPDSYFA AASYAYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW FRQAP GKE RE GVAC I S S S GRGVNANY I D SVRGRFT I SRDNAKNT VYLQMNKLKP DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK769 SEQ ID NO: 642X2is GGGS, GGGGS, or GGGSGGGShuC09- SEQ ID NO: 643huC04 X2i s GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGWF RQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRAE DTAVYYCATNCWRLTSPAADNWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPSV FLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencename047 SEQ ID NO: 644Xi is S, GG, AS, ASS or absent (i. e., no amino acid D08-A02 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 645Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGGSTYYADSVKGRFTLSSDNAKNRIALQMNSLKPEDTAVYYCAAKYYTDSYFA ATSYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK748 SEQ ID NO: 646X2 is GGGS, GGGGS, or GGGSGGGShuD08- SEQ ID NO: 647huA02 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK876 SEQ ID NO: 648Xi is S, GG, AS, ASS or absent (i. e., no amino acid D08-A05 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 649Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGGSTYYADSVKGRFTLSSDNAKNRIALQMNSLKPEDTAVYYCAAKYYTDSYFA ATSYAYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK778 SEQ ID NO: 650X2is GGGS, GGGGS, or GGGSGGGShuD08- SEQ ID NO: 651huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK779 SEQ ID NO: 652X2is GGGS, GGGGS, or GGGSGGGShuD08- SEQ ID NO: 653huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK062 SEQ ID NO: 654Xi is S, GG, AS, ASS or absent (i. e., no amino acid I04-A02 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 655Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW FGRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRR NQAEYDYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIG1569-US-NP / WO-PCT Table F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameWFRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPE DAGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGG PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK763 SEQ ID NO: 656X2is GGGS, GGGGS, or GGGSGGGShuI04- SEQ ID NO: 657huA02 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN QAEYDYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK891 SEQ ID NO: 658Xi is S, GG, AS, ASS or absent (i. e., no amino acid I04-A05 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 659Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW FGRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRR NQAEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIG WFRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPE DTGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGG PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencename780 SEQ ID NO: 660X2is GGGS, GGGGS, or GGGSGGGShuI04- SEQ ID NO: 661huA05 X2i s GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK781 SEQ ID NO: 662X2is GGGS, GGGGS, or GGGSGGGShuI04- SEQ ID NO: 663huA05 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK290 SEQ ID NO: 664Xi is S, GG, AS, ASS or absent (i. e., no amino acid I04-C04 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 665Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW FGRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRR NQAEYDYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIG WFRQAPGKEREGVACISSSGRGVNANYIDSVRGRFTISRDNAKNTVYLQMNKLK PDDTAIYYCATNCWRLTSPAADNWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK791 SEQ ID NO: 666X is GGGS, GGGGS, or GGGSGGGShuI04- SEQ ID NO: 667huC04 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK892 SEQ ID NO: 668Xi is S, GG, AS, ASS or absent (i. e., no amino acid J13-A05 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 669Xi is AS; X2is GGGS XiQVQLVESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGFVATINW IPGNTYYADSVKGRFTISGEEDKNTVYLQMDNLKPEDTAVYYCAARRRIDNYYR ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK793 SEQ ID NO: 670Xi is S, GG, AS, ASS or absent (i. e., no amino acid hu J13- residues )huA05 X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 671Xi is AS; X2is GGGS XiQVQLVESGGGWQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINW IPGNTYYADSVKGRFTISGDESKNTVYLQMNSLRAEDTAVYYCAARRRIDNYYR ASEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW1569-US-NP / WO-PCT Table F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameFRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK794 SEQ ID NO: 672Xi is S, GG, AS, ASS or absent (i. e., no amino acid hu J13- residues )huA05 X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 673Xi is AS; X2is GGGS XiQVQLVESGGGWQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINW IPGNTYYADSVKGRFTISGDESKNTVYLQMNSLRAEDTAVYYCAARRRIDNYYR ASEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK894 SEQ ID NO: 674Xi is S, GG, AS, ASS or absent (i. e., no amino acid N16-A05 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 675Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRW IGGDTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencename795 SEQ ID NO: 676X2is GGGS, GGGGS, or GGGSGGGShuN16- SEQ ID NO: 677huA05 X2i s GGGS EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWI GGDTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSE KSYNYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK796 SEQ ID NO: 678X2is GGGS, GGGGS, or GGGSGGGShuN16- SEQ ID NO: 679huA05 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWI GGDTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSE KSYNYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK884 SEQ ID NO: 680Xi is S, GG, AS, ASS or absent (i. e., no amino acid F09-A05 residues )X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 681Xi is AS; X2is GGGS XiQVQLQESGGGLVQAGGSLSLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGSATDYADSVRGRFTISGDNAKNTVYLLMNNLKPEDTAVYYCAARRSPMSRTS VLQYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK786 SEQ ID NO: 682X is GGGS, GGGGS, or GGGSGGGShuF09- SEQ ID NO: 683huA05 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GSATDYADSVRGRFTISGDNSKNTVYLQMNSLRAEDTAVYYCAARRSPMSRTSV LQYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK787 SEQ ID NO: 684X is GGGS, GGGGS, or GGGSGGGShuF09- SEQ ID NO: 685huA05 X is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GSATDYADSVRGRFTISGDNSKNTVYLQMNSLRAEDTAVYYCAARRSPMSRTSV LQYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK058 SEQ ID NO: 686Xi is S, GG, AS, ASS or absent (i. e., no amino acid F21-A02 residues )X is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 687Xi is AS; X2is GGGS XiQVQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW IGNSTYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGP1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK759 SEQ ID NO: 688X2is GGGS, GGGGS, or GGGSGGGShuF21- SEQ ID NO: 689huA02 X2is GGGS EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI GNSTYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK767 SEQ ID NO: 690EX1QLX2ESGGGLVQX3GGSLRLSCAX4SGRTFSSHTVGWFRQAPGKX5REFVX6A F11-C04 ITWNGDTTYFGDFVEGRFXvISRDXgXgKNTLYLXioMNXuLX^XiaEDTAVYYCA con AATGQVWSLQYLRESSYAYWGQGTX14VTVSSX15X16VQLVESGGGLVQX17GGSL RLSCX13ASGFTSPYSTIGWFRQAPGKX29REGVACISSSGRGVNANYIDSVRGRF TISRDNX2OKNTVYLQMNX2ILKX22X23DTAX24YYCATNCWRLTSPAADNWGQGT X23VTVSSGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEY KCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGKXi is L or VX2is L or VX3is A or PX4is A or NX5is E or GX3is A or EX7is S or TX3is N or SX9is A or SX10 is E or QXu is K or SX22is K or RXi3is A or PX14 is L or QX15 is GGGS, GGGGS, or GGGSGGGS1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameXis is E or QX17 is P or SXis is S or VX19 is E or GX20 is A or SX21 is K or SX22 is A or PX23 is D or EX24 is I or VX25 is M or Q284 SEQ ID NO: 691X2 is GGGS, GGGGS, or GGGSGGGSF11-C04 SEQ ID NO: 692X2is GGGS ELQLVESGGGLVQAGGSLRLSCANSGRTFSSHTVGWFRQAPGKEREFVAAITWN GDTTYFGDFVEGRFSISRDSAKNTLYLEMNKLKPEDTAVYYCAAATGQVWSLQY LRESSYAYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTI GWF RQAP GKE RE GVAC I S S S GRGVNANY I D S VRGRF T I S RDNAKNT VY LQMNKL KPDDTAIYYCATNCWRLTSPAADNWGQGTQVTVSSGSDKTHTCPPCPAPEAAGG PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK183 SEQ ID NO: 693X2is GGGS, GGGGS, or GGGSGGGShuFll- SEQ ID NO: 694huC04 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVAAITWN GDTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQY LRESSYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTI GWFRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSL RAEDTAVYYCATNCWRLTSPAADNWGQGTMVTVSSGSDKTHTCPPCPAPEAAGA PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK184 SEQ ID NO: 695X2is GGGS, GGGGS, or GGGSGGGShuFll- SEQ ID NO: 696huC04 X2is GGGS1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameELQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWN GDTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQY LRESSYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTI GWFRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSL RAEDTAVYYCATNCWRLTSPAADNWGQGTMVTVSSGSDKTHTCPPCPAPEAAGA PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK239 SEQ ID NO: 697Xi is S, GG, AS, ASS or absent (i. e., no amino acid G22-B12 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 698Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLKLSCTASGRTFDGYGMGWFRQAPGKEREFVSAINW IYGATYYADSVKGRFAVSRDKAKGTMYLQMNSLKPEDTAVYYCAAKINAGSYFN IGSFGSWGQGTQVTVSSX2EVQLVESGGGLVQAGGSLRLSCAASGSFSSISTMAW YRQVP GKQREWLARI I WS SGATNYAD SVKGRF T I SRDNTKNTMYLQMDRLTPED TAAYLCSGAISQTRGTFWTYKSQGTQVTVSSGSDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK740 SEQ ID NO: 699Xi is S, GG, AS, ASS or absent (i. e., no amino acid huG22- residues )huB12 X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 700Xi is AS; X2is GGGS XiQLQLVESGGGLVQPGGSLRLSCSASGRTFDGYGMGWFRQAPGKEREFVSAINW IYGATYYADSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINAGSYFN IGSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGSFSSISTMAW YRQAPGKQREWLARIIWSSGATNYADSVKGRFTISRDNSKNTMYLQMNSLRAED TAVYYCSGAISQTRGTFWTYKGQGTLVTVSSGSDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQ YNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencename247 SEQ ID NO: 701Xi is S, GG, AS, ASS or absent (i. e., no amino acid L05-B12 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 702Xi is AS; X2is GGGS XiQVQLLESGGGLVQAGGSLKLSCTNSGRTFSGYGMGWFRQPPGKEREFVSSINW IYGATYYSDSVKGRFALSRDKAKNTVYLQMDSLKPEDTAVYYCAAKINGESYFN TGSFGSWGQGTQVTVSSX2EVQLVESGGGLVQAGGSLRLSCAASGSFSSISTMAW YRQVPGKQREWLARI IWSSGATNYADSVKGRFTISRDNTKNTMYLQMDRLTPED TAAYLCSGAISQTRGTFWTYKSQGTQVTVSSGSDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK748 SEQ ID NO: 703X2 is GGGS, GGGGS, or GGGSGGGShuL05- SEQ ID NO: 704huB12 X2is GGGS EVQLLESGGGLVQPGGSLRLSCAASGRTFSGYGMGWFRQAPGKEREFVSSINWI YGATYYSDSVKGRFTLSRDKSKNTVYLQMNSLRAEDTAVYYCAAKINGESYFNT GSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGSFSSISTMAWY RQAPGKQREWLARIIWSSGATNYADSVKGRFTISRDNSKNTMYLQMNSLRAEDT AVYYCSGAISQTRGTFWTYKGQGTLVTVSSGSDKTHTCPPCPAPEAAGGPSVFL FPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK286 SEQ ID NO: 705Xi is S, GG, AS, ASS or absent (i. e., no amino acid G22-C04 residues )X2 is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 706Xi is AS; X2is GGGS XiQLQLVESGGGLVQAGGSLKLSCTASGRTFDGYGMGWFRQAPGKEREFVSAINW IYGATYYADSVKGRFAVSRDKAKGTMYLQMNSLKPEDTAVYYCAAKINAGSYFN IGSFGSWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW FRQAP GKE RE GVAC I S S S GRGVNANY I D S VRGRFT I SRDNAKNT VYLQMNKLKP DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSSGSDKTHTCPPCPAPEAAGGPS1569-US-NP / WO-PCTTable F - Illustrative aIL-10Roc / aIL-10Rp Tandem Single Immunoglobulin Domain Bispecific (VHH-VHH-Fc) amino acid sequencesVHH-VHH VHH-VHH-Fc amino acid sequencenameVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK788 SEQ ID NO: 707Xi is S, GG, AS, ASS or absent (i. e., no amino acid huG22- residues )huC04 X2is GGGS, GGGGS, or GGGSGGGSSEQ ID NO: 708Xi is AS; X2is GGGS XiQLQLVESGGGLVQPGGSLRLSCSASGRTFDGYGMGWFRQAPGKEREFVSAINW IYGATYYADSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINAGSYFN IGSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSSGSDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKBispecific E07-A05

[0130] In some embodiments, provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 22, 23, 24, 291, 292 and 293; (877; according to Kabat)2) SEQ ID NOs: 22, 25, 26, 291, 294 and 295; (647; according to Kabat)3) SEQ ID NOs: 22, 27, 24, 291, 297 and 298; (195; according to Kabat)4) SEQ ID NOs: 77, 78, 79, 329, 330 and 331; (877; according to IMGT)1569-US-NP / WO-PCT5) SEQ ID NOs: 77, 80, 81, 329, 332 and 333; (647; according to IMGT)6) SEQ ID NOs: 77, 82, 79, 334, 335 and 336; (195; according to IMGT)7) SEQ ID NOs: 127, 128, 129, 369, 370 and 371; (877; according to Chothia) 8) SEQ ID NOs: 127, 130, 131, 369, 372 and 373; (647; according to Chothia) 9) SEQ ID NOs: 127, 130, 131. 374, 375 and 376; (195; according to Chothia) 10) SEQ ID NOs: 174, 175, 176, 409, 410 and 411; (877; according to Honegger) 11) SEQ ID NOs: 174, 177, 178, 409, 412 and 413; (647; according to Honegger) or 12) SEQ ID NOs: 174, 179, 176, 414, 415 and 416; (195; according to Honegger).

[0131] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 233 and 448; [E07con-A05con] or2) SEQ ID NOs: 234 and 449; [E07con-A05con],

[0132] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 235 and 450; (877)2) SEQ ID NOs: 237 and 451; (647)3) SEQ ID NOs: 239 and 452; (195)4) SEQ ID NOs: 236 and 450; (877)5) SEQ ID NOs: 238 and 451; (647) or6) SEQ ID NOs: 240 and 452; (195).

[0133] In some embodiments, the bispecific antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-482 and 737-751. In some embodiments, the bispecific antibody comprises at least one polypeptide (e.g., a first polypeptide and a second polypeptide)1569-US-NP / WO-PCTcomprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 592-599 (bispecific antibodies 195, 647 and 877; E07-A05 and humanized and consensus versions thereof).Bispecific E07-A02

[0134] In some embodiments, provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 22, 23, 24, 288, 289 and 290; (048; according to Kabat)2) SEQ ID NOs: 22, 25, 26, 288, 289 and 290; (049; according to Kabat)3) SEQ ID NOs: 22, 27, 24, 288, 289 and 290; (050; according to Kabat)4) SEQ ID NOs: 77, 78, 79, 326, 327 and 328; (048; according to IMGT)5) SEQ ID NOs: 77, 80, 81. 326, 327 and 328; (049; according to IMGT)6) SEQ ID NOs: 77, 82, 79, 326, 327 and 328; (050; according to IMGT)7) SEQ ID NOs: 127, 128, 129, 366, 367 and 368; (048; according to Chothia) 8) SEQ ID NOs: 127, 130, 131, 366, 367 and 368; (049; according to Chothia) 9) SEQ ID NOs: 127, 130, 131, 366, 367 and 368; (050; according to Chothia) 10) SEQ ID NOs: 174, 175, 176, 406, 407 and 408; (048; according to Honegger) 11) SEQ ID NOs: 174, 177, 178, 406, 407 and 408; (049; according to Honegger) or 12) SEQ ID NOs: 174, 179, 176, 406, 407 and 408; (050; according to Honegger).

[0135] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1569-US-NP / WO-PCT1) SEQ ID NOs: 235 and 446; (048)2) SEQ ID NOs: 237 and 447; (049)3) SEQ ID NOs: 239 and 447; (050)4) SEQ ID NOs: 236 and 446; (048)5) SEQ ID NOs: 238 and 447; (049) or6) SEQ ID NOs: 240 and 447; (050).

[0136] In some embodiments, the bispecific antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 483-488. In some embodiments, the bispccific antibody comprises at least one polypeptide (e.g., a first polypeptide and a second polypeptide) comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 600-605 (bispecific antibodies 048, 049 and 050; E07-A02 and humanized and consensus versions thereof).Bispecific E07-C04

[0137] In some embodiments, provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 22, 23, 24, 296, 308 and 309; (274; according to Kabat)2) SEQ ID NOs: 22, 25, 26, 296, 308 and 309; (771; according to Kabat)3) SEQ ID NOs: 22, 27, 24, 296, 308 and 309; (772; according to Kabat)4) SEQ ID NOs: 77, 78, 79, 346, 347 and 348; (274; according to IMGT)1569-US-NP / WO-PCT5) SEQ ID NOs: 77, 80, 81, 346, 347 and 348; (771; according to IMGT)6) SEQ ID NOs: 77, 82, 79, 346, 347 and 348; (772; according to IMGT)7) SEQ ID NOs: 127, 128, 129, 386, 387 and 388; (274; according to Chothia) 8) SEQ ID NOs: 127, 130, 131, 386, 387 and 388; (771; according to Chothia) 9) SEQ ID NOs: 127, 130, 131, 386, 387 and 388; (772; according to Chothia) 10) SEQ ID NOs: 174, 175, 176, 426, 427 and 428; (274; according to Honegger) 11) SEQ ID NOs: 174, 177, 178, 426, 427 and 428; (771; according to Honegger) or 12) SEQ ID NOs: 174, 179, 176, 426, 427 and 428; (772; according to Honegger).

[0138] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 233 and 460; [E07con-C04con] or2) SEQ ID NOs: 234 and 460; [E07con-C04con],

[0139] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 235 and 461; (274)2) SEQ ID NOs: 237 and 462; (771)3) SEQ ID NOs: 239 and 462; (772)4) SEQ ID NOs: 236 and 461; (274)5) SEQ ID NOs: 238 and 462; (771) or6) SEQ ID NOs: 240 and 462; (772).

[0140] In some embodiments, the bispecific antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 489-494. In some embodiments, the bispecific antibody comprises at least one polypeptide (e.g., a first polypeptide and a second polypeptide) comprising the1569-US-NP / WO-PCTfollowing amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 606-611 (bispecific antibodies 274, 771 and 772; E07-C04 and humanized and consensus versions thereof).Bispecific E15-A02

[0141] In some embodiments, provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-1OR0). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 4, 28, 29, 288, 289 and 290; (054; according to Rabat)2) SEQ ID NOs: 59, 83, 84, 326, 327 and 328; (054; according to IMGT)3) SEQ ID NOs: 111, 132, 133, 366, 367 and 368; (054; according to Chothia) or 4) SEQ ID NOs: 156, 180, 181, 406, 407 and 408; (054; according to Honegger).

[0142] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-IOR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 241 and 446; (054)2) SEQ ID NOs: 243 and 447: (755)3) SEQ ID NOs: 242 and 446; (054) or4) SEQ ID NOs: 243 and 447; (755).

[0143] In some embodiments, the bispecific antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at1569-US-NP / WO-PCTleast 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 495-498. In some embodiments, the bispecific antibody comprises at least one polypeptide (e.g., a first polypeptide and a second polypeptide) comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 612-615 (bispecific antibodies 054 and 755; E15-A02 and humanized and consensus versions thereof).Bispecific E15-A05

[0144] In some embodiments, provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain ( VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 4, 28, 29, 291, 294 and 295; (883; according to Kabat)2) SEQ ID NOs: 4, 28, 29, 291. 294 and 295: (784; according to Kabat)3) SEQ ID NOs: 4, 28, 29, 291, 297 and 298; (785; according to Kabat)4) SEQ ID NOs: 59, 83, 84, 329, 330 and 331; (883; according to IMGT)5) SEQ ID NOs: 59, 83, 84, 329, 332 and 333; (784; according to IMGT)6) SEQ ID NOs: 59, 83. 84, 334, 335 and 336; (785; according to IMGT)7) SEQ ID NOs: 111, 132, 133, 369, 370 and 371; (883; according to Chothia) 8) SEQ ID NOs: 111, 132, 133, 369, 372 and 373; (784; according to Chothia) 9) SEQ ID NOs: 111, 132, 133, 374, 375 and 376; (785; according to Chothia) 10) SEQ ID NOs: 156, 180, 181, 409, 410 and 411; (883; according to Honegger) 11) SEQ ID NOs: 156, 180, 181, 409, 412 and 413; (784; according to Honegger) or 12) SEQ ID NOs: 156, 180, 181, 414, 415 and 416; (785; according to Honegger).

[0145] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP comprise1569-US-NP / WO-PCTthe following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 241 and 450; (883)2) SEQ ID NOs: 243 and 451; (784)3) SEQ ID NOs: 243 and 452; (785)4) SEQ ID NOs: 242 and 450; (883)5) SEQ ID NOs: 243 and 451; (784) or6) SEQ ID NOs: 243 and 452; (785).

[0146] In some embodiments, the bispecific antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL- 1OR0, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 499-504. In some embodiments, the bispecific antibody comprises at least one polypeptide (e.g., a first polypeptide and a second polypeptide) comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 616-621 (bispecific antibodies 784-785 and 883; E15-A05 and humanized and consensus versions thereof).Bispecific A06-A02

[0147] In some embodiments, provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-1OR0). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 4, 5, 6, 288, 289 and 290; (046; according to Kabat)1569-US-NP / WO-PCT2) SEQ ID NOs: 59, 60, 61, 326, 327 and 328; (046; according to IMGT)3) SEQ ID NOs: 111, 112, 113, 366, 367 and 368; (046; according to Chothia) or 4) SEQ ID NOs: 156, 157, 158, 406, 407 and 408; (046; according to Honegger).

[0148] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 213 and 446; (046)2) SEQ ID NOs: 215 and 447; (747)3) SEQ ID NOs: 214 and 446; (046) or4) SEQ ID NOs: 215 and 447; (747).

[0149] In some embodiments, the bispecific antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 505-508. In some embodiments, the bispecific antibody comprises at least one polypeptide (e.g., a first polypeptide and a second polypeptide) comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 622-625 (bispecific antibodies 046 and 747; A06-A02 and humanized and consensus versions thereof).Bispecific A06-A05

[0150] In some embodiments, provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL 10Ra) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH 1 -complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a1569-US-NP / WO-PCTVHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 4, 5, 6, 291, 294 and 295; (875; according to Kabat)2) SEQ ID NOs: 4, 5, 6, 291, 294 and 295; (776; according to Kabat)3) SEQ ID NOs: 4, 5, 6, 291, 297 and 298; (777; according to Kabat)4) SEQ ID NOs: 59, 60, 61, 329, 330 and 331; (875; according to IMGT)5) SEQ ID NOs: 59, 60, 61, 329, 332 and 333; (776; according to IMGT)6) SEQ ID NOs: 59, 60, 61, 334, 335 and 336; (777; according to IMGT)7) SEQ ID NOs: 111, 112, 113, 369, 370 and 371; (875; according to Chothia) 8) SEQ ID NOs: 111, 112, 113, 369, 372 and 373; (776; according to Chothia) 9) SEQ ID NOs: 111, 112, 113, 374, 375 and 376; (777; according to Chothia) 10) SEQ ID NOs: 156, 157, 158, 409, 410 and 411; (875; according to Honegger) 11) SEQ ID NOs: 156, 157, 158, 409, 412 and 413; (776; according to Honegger) or 12) SEQ ID NOs: 156, 157, 158, 414, 415 and 416; (777; according to Honegger).

[0151] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0 comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 212 and 448; [A06con-A05con] or2) SEQ ID NOs: 212 and 449; [A06con-A05con],

[0152] In some embodiments, the bispecific antibody comprises a first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-lORf) comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 213 and 450; (875)2) SEQ ID NOs: 215 and 451; (776)3) SEQ ID NOs: 215 and 452; (777)4) SEQ ID NOs: 214 and 450; (875)5) SEQ ID NOs: 215 and 451; (776) or6) SEQ ID NOs: 215 and 452; (777).1569-US-NP / WO-PCT

[0153] In some embodiments, the bispecific antibody comprises in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%,...

Claims

1569-US-NP / WO-PCTCLAIMSWhat is claimed is:

1. A single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa), the VHH comprising a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively:1) SEQ ID NOs 1, 2 and 3; (A01)2) SEQ ID NOs 4, 5 and 6; (A06)3) SEQ ID NOs 7, 8 and 9: (A09)4) SEQ ID NOs 10. 11 and 12; (B07)5) SEQ ID NOs 4, 13 and 14; (B08)6) SEQ ID NOs 4, 15 and 16; (C09)7) SEQ ID NOs 4, 17 and 18; (D08)8) SEQ ID NOs 19, 20 and 21; (D14)9) SEQ ID NOs 22, 23 and 24; (E07)10) SEQ ID NOs 22, 25 and 27; (huE07)11) SEQ ID NOs 22, 27 and 24; (huE07)12) SEQ ID NOs 4, 28 and 29; (El 5)13) SEQ ID NOs 4, 30 and 31; (F09)14) SEQ ID NOs 22, 23 and 32; (F10)15) SEQ ID NOs 33, 34 and 35; (Fl 1)16) SEQ ID NOs 4, 36 and 29; (F21)17) SEQ ID NOs 19. 37 and 38; (G22)18) SEQ ID NOs 39, 40 and 41; (G23)19) SEQ ID NOs 42, 43 and 44; (H22)20) SEQ ID NOs 45, 46 and 47; (104)21) SEQ ID NOs 4, 48 and 6; (J 13)22) SEQ ID NOs 4, 49 and 50; (J24)23) SEQ ID NOs 19, 51 and 52; (L05)24) SEQ ID NOs 19, 37 and 53; (LI 1) or25) SEQ ID NOs 54, 55 and 24 (N16).1569-US-NP / WO-PCT2. A single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa), the VHH comprising a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively:1) SEQ ID NOs 56, 57 and 58; (A01)2) SEQ ID NOs 59, 60 and 61; (A06)3) SEQ ID NOs 62, 63 and 64; (A09)4) SEQ ID NOs 65, 66 and 67; (B07)5) SEQ ID NOs 59, 68 and 69; (B08)6) SEQ ID NOs 59, 70 and 71; (C09)7) SEQ ID NOs 59, 72 and 73; (D08)8) SEQ ID NOs 74, 75 and 76; (D14)9) SEQ ID NOs 77, 78 and 79; (E07)10) SEQ ID NOs 77, 80 and 81; (huE07)11) SEQ ID NOs 77, 82 and 79; (huE07)12) SEQ ID NOs 59, 83 and 84; (El 5)13) SEQ ID NOs 59, 85 and 86; (F09)14) SEQ ID NOs 77, 78 and 87; (F10)15) SEQ ID NOs 88, 89 and 90; (Fl 1)16) SEQ ID NOs 59, 91 and 84; (F21)17) SEQ ID NOs 92. 75 and 93; (G22)18) SEQ ID NOs 94, 89 and 95; (G23)19) SEQ ID NOs 96, 89 and 97; (H22)20) SEQ ID NOs 98, 99 and 100; (104)21) SEQ ID NOs 59, 101 and 61; (J13)22) SEQ ID NOs 59, 102 and 103; (.124)23) SEQ ID NOs 74, 75 and 104; (L05)24) SEQ ID NOs 74, 75 and 105; (Lil) or25) SEQ ID NOs 106, 107 and 79 (N16).

3. A single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa), the VHH comprising a complementarity determining region (CDR) 1, a1569-US-NP / WO-PCTVHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively:1) SEQ ID NOs 108, 109 and 110; (A01)2) SEQ ID NOs 111, 112 and 113; (A06)3) SEQ ID NOs 114, 115 and 116; (A09)4) SEQ ID NOs 117, 118 and 119; (B07)5) SEQ ID NOs 111, 112 and 120; (B08)6) SEQ ID NOs 111, 121 and 122; (C09)7) SEQ ID NOs 111, 121 and 123; (D08)8) SEQ ID NOs 124, 125 and 126; (DI 4)9) SEQ ID NOs 127, 128 and 129; (E07)10) SEQ ID NOs 127, 130 and 131; (huE07)11) SEQ ID NOs 111, 132 and 133; (E15)12) SEQ ID NOs 111, 134 and 135; (E09)13) SEQ ID NOs 127, 128 and 136; (F10)14) SEQ ID NOs 137, 138 and 139; (Fll)15) SEQ ID NOs 111, 132 and 133; (F21)16) SEQ ID NOs 140, 125 and 141; (G22)17) SEQ ID NOs 142, 138 and 143; (G23)18) SEQ ID NOs 124, 138 and 144; (H22)19) SEQ ID NOs 145, 146 and 147; (104)20) SEQ ID NOs 111, 112 and 113; (J13))21) SEQ ID NOs 111, 148 and 149; (J24)22) SEQ ID NOs 124, 125 and 150; (L05)23) SEQ ID NOs 124, 125 and 151; (Lil) or24) SEQ ID NOs 152, 121 and 129 (N16).

4. A single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa), the VHH comprising a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively:1) SEQ ID NOs: 153, 154 and 155; (A01)2) SEQ ID NOs: 156, 157 and 158; (A06)1569-US-NP / WO-PCT3) SEQ ID NOs 159, 160 and 161; (A09)4) SEQ ID NOs 162, 163 and 164; (B07)5) SEQ ID NOs 156, 165 and 166; (B08)6) SEQ ID NOs 156, 167 and 168; (C09)7) SEQ ID NOs 156, 169 and 170; (D08)8) SEQ ID NOs 171, 172 and 173; (D14)9) SEQ ID NOs 174, 175 and 176; (E07)10) SEQ ID NOs 174, 177 and 178; (huE07)11) SEQ ID NOs 174, 179 and 176; (huE07)12) SEQ ID NOs 156, 180 and 181; (E15)13) SEQ ID NOs 156, 182 and 183; (F09)14) SEQ ID NOs 174, 175 and 184; (F10)15) SEQ ID NOs 185, 186 and 187; (Fl 1)16) SEQ ID NOs 709, 186 and 187; (huFl 1)17) SEQ ID NOs 156, 188 and l81; (F21)18) SEQ ID NOs 189, 190 and 191; (G22)19) SEQ ID NOs 192, 193 and 194; (G23)20) SEQ ID NOs 195, 196 and 197; (H22)21) SEQ ID NOs 198, 199 and 200; (104)22) SEQ ID NOs 156, 201 and 158; (J13)23) SEQ ID NOs 156, 202 and 203; (J24)24) SEQ ID NOs 204, 205 and 206; (L05)25) SEQ ID NOs 204, 190 and 207; (Li l) or26) SEQ ID NOs 208, 209 and 176 (N16).

5. The sdAb of any one of claims 1 to 4, wherein the VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 22, 23 and 24; (E07; according to Kabat)2) SEQ ID NOs: 22, 25 and 27; (huE07; according to Kabat) 3) SEQ ID NOs: 22, 27 and 24; (huE07; according to Kabat) 4) SEQ ID NOs: 77, 78 and 79; (E07; according to IMGT)5) SEQ ID NOs: 77, 80 and 81; (huE07; according to IMGT) 6) SEQ ID NOs: 77, 82 and 79; (huE07; according to IMGT)1569-US-NP / WO-PCT7) SEQ ID NOs: 127, 128 and 129; (E07; according to Chothia) 8) SEQ ID NOs: 127, 130 and 131; (huE07; according to Chothia)9) SEQ ID NOs: 174, 175 and 176; (E07; according to Honegger)10) SEQ ID NOs: 174, 177 and 178; (huE07: according to Honegger) or 11) SEQ ID NOs: 174, 179 and 176; (huE07: according to Honegger).

6. The sdAb of any one of claims 1 to 4, wherein the VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 33, 34 and 35; (Fl 1; according to Kahat) 2) SEQ ID NOs: 88, 89 and 90; (Fl 1; according to IMGT) 3) SEQ ID NOs: 137, 138 and 139; (Ell; according to Chothia)4) SEQ ID NOs: 185, 186 and 187; (Fl 1; according to Honegger) or 5) SEQ ID NOs: 709, 186 and 187; (huFl 1; according to Honegger).

7. The sdAb of any one of claims 1 to 6, wherein the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 212, 230, 233, 234, 249 and 710, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 212, 230, 233, 234, 249 and 710.

8. The sdAb of any one of claims 1 to 7, wherein the VHH comprises the amino acid sequence of any one of 210-211, 213-229, 231-232, 235-248, 250-287 and 752-755, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 210-211, 213-229, 231-232, 235-248, 250-287 and 753-755.

9. The sdAb of any one of claims 1 to 8, wherein the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 233-240 and 724-725, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 233-240 and 724-725 (E07).

10. The sdAb of any one of claims 1 to 8, wherein the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 249-252 and 752-755, or an amino acid1569-US-NP / WO-PCTsequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 249-252 and 752-755 (Fl 1).

11. The sdAb of any one of claims 1 to 10, wherein the VHH is humanized.

12. The sdAb of any one of claims 1 to 11, wherein the VHH binds to an epitope on IL-lORa comprising contact amino acid residues W33, E35, E37, H40, 142, H44, 1’46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711.

13. The sdAb of any one of claims 1 to 11, wherein the VHH binds to an epitope on IL-lORa comprising contact amino acid residues 1169, 1171, K173, F178, F180, T181, Hl 82, KI 83, KI 86, Fl 90, El 92, El 93, SI 95, El 97 and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711.

14. The sdAb of any one of claims 1 to 13, wherein the VHH that binds to IL-lORa with an equilibrium dissociation constant (KD) of lower than 5 nM, e.g., lower than 4 nM, 3 nM or 2 nM.

15. The sdAb of any one of claims 1 to 14, wherein the VHH that binds to IL-lORa binds to both human IL-lORa and cynomolgus IL-lORa.

16. The sdAb of any one of claims 1 to 15, comprising a human fragment crystallizable (Fc) domain.

17. The sdAb of claim 16, wherein the Fc domain comprises a human IgGl or a human IgG4.

18. A single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) beta subunit (IL-1OR0), the VHH comprising a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively:1) SEQ ID NOs: 288, 289 and 290; (A02)2) SEQ ID NOs: 291, 292 and 293; (A05)3) SEQ ID NOs: 291, 294 and 295; (huA05)1569-US-NP / WO-PCT4) SEQ ID NOs: 296, 297 and 298; (huA05)5) SEQ ID NOs: 299, 300 and 301; (BIO)6) SEQ ID NOs: 302, 303 and 304; (B 12)7) SEQ ID NOs: 305, 306 and 307; (C01)8) SEQ ID NOs: 296, 308 and 309; (C04)9) SEQ ID NOs: 310, 311 and 312; (CIO)10) SEQ ID NOs: 302, 303 and 313; (DO 1 )11) SEQ ID NOs: 314, 315 and 316; (E08)12) SEQ ID NOs: 317, 318 and 319; (E10)13) SEQ ID NOs: 320, 321 and 322; (G01) or14) SEQ ID NOs: 323, 324 and 325 (G02).

19. A single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) beta subunit (IL-1OR0), the VHH comprising a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively:1) SEQ ID NOs: 326, 327 and 328; (A02)2) SEQ ID NOs: 329, 330 and 331; (A05)3) SEQ ID NOs: 329, 332 and 333; (huA05)4) SEQ ID NOs: 334, 335 and 336; (huA05)5) SEQ ID NOs: 337, 338 and 339; (B 10)6) SEQ ID NOs: 340, 341 and 342; (B12)7) SEQ ID NOs: 343, 344 and 345; (C01)8) SEQ ID NOs: 346, 347 and 348; (C04)9) SEQ ID NOs: 349, 350 and 351; (CIO)10) SEQ ID NOs: 352, 341 and 353; (D01)11) SEQ ID NOs: 354, 355 and 356; (E08)12) SEQ ID NOs: 357, 358 and 359; (E10)13) SEQ ID NOs: 360, 361 and 362; (G01) or14) SEQ ID NOs: 363, 364 and 365 (G02).

20. A single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) beta subunit (IL-10RP), the VHH comprising a complementarity determining region (CDR) 1, a1569-US-NP / WO-PCTVHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively:1) SEQ ID NOs: 366, 367 and 368; (A02)2) SEQ ID NOs: 369, 370 and 371; (A05)3) SEQ ID NOs: 369, 372 and 373; (huA05)4) SEQ ID NOs: 374, 375 and 376; (huA05)5) SEQ ID NOs: 377, 378 and 379; (BIO)6) SEQ ID NOs: 380, 381 and 382; (Bl 2)7) SEQ ID NOs: 383, 384 and 385; (C01)8) SEQ ID NOs: 386, 387 and 388; (C04)9) SEQ ID NOs: 389, 390 and 391; (CIO)10) SEQ ID NOs: 392, 381 and 393; (D01)11) SEQ ID NOs: 394, 395 and 396; (E08)12) SEQ ID NOs: 397, 398 and 399; (E10)13) SEQ ID NOs: 400, 401 and 402; (G01) or14) SEQ ID NOs: 403, 404 and 405 (G02).

21. A single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) beta subunit (IL-10RP), the VHH comprising a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively:1) SEQ ID NOs: 406, 407 and 408; (A02)2) SEQ ID NOs: 409, 410 and 411; (A05)3) SEQ ID NOs: 409, 412 and 413; (huA05)4) SEQ ID NOs: 414, 415 and 416; (huA05)5) SEQ ID NOs: 417, 418 and 419; (B10)6) SEQ ID NOs: 420, 421 and 422; (Bl 2)7) SEQ ID NOs: 423, 424 and 425; (C01)8) SEQ ID NOs: 426, 427 and 428; (C04)9) SEQ ID NOs: 429, 430 and 431; (C 10)10) SEQ ID NOs: 432, 421 and 433; (D01)11) SEQ ID NOs: 434, 435 and 436; (E08)12) SEQ ID NOs: 437, 438 and 439; (E10)1569-US-NP / WO-PCT13) SEQ ID NOs: 440, 441 and 442; (G01) or14) SEQ ID NOs: 443, 444 and 445 (G02).

22. The sdAb of any one of claims 18 to 21, wherein the VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively:1) SEQ ID NOs: 291, 292 and 293; (A05; according to Kabat) 2) SEQ ID NOs: 291, 294 and 295; (huA05; according to Kabat) 3) SEQ ID NOs: 296, 297 and 298; (huA05; according to Kabat) 4) SEQ ID NOs: 329, 330 and 331; (A05; according to IMGT) 5) SEQ ID NOs: 329, 332 and 333; (huA05; according to IMGT)6) SEQ ID NOs: 334, 335 and 336; (huA05; according to IMGT)7) SEQ ID NOs: 369, 370 and 371; (A05; according to Chothia) 8) SEQ ID NOs: 369, 372 and 373; (huA05; according to Chothia)9) SEQ ID NOs: 374, 375 and 376; (huA05; according to Chothia)10) SEQ ID NOs: 409, 410 and 411; (A05; according to Honegger)11) SEQ ID NOs: 409, 412 and 413; (huA05; according to Honegger) or 12) SEQ ID NOs: 414, 415 and 416; (huA05; according to Honegger).

23. The sdAb of any one of claims 18 to 22, wherein the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 448, 449, 455 and 460, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 448, 449, 455 and 460.

24. The sdAb of any one of claims 18 to 23, wherein the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 446-447, 450-454, 456-459 and 461-474, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 446-447, 450-454, 456-459 and 461-474.

25. The sdAb of any one of claims 18 to 24, wherein the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 448-452, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at1569-US-NP / WO-PCTleast 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 448-452 (A05).

26. The sdAb of any one of claims 18 to 24, wherein the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 460-462, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96', at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 460-462 (C04).

27. The sdAb of any one of claims 18 to 26, wherein the VHH is humanized.

28. The sdAb of any one of claims 18 to 27, wherein the VHH binds to an epitope on IL-1OR comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712.

29. The sdAb of any one of claims 18 to 27, wherein the VHH binds to an epitope on IE-10RP comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, DUO, 1112, Pl 15, Q157, Q190, R192, F194, N199, A201, E203, W204 and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712.

30. The sdAb of any one of claims 18 to 29, wherein the VHH binds to IL-10RP with an equilibrium dissociation constant (KD) of greater than 10 nM, e.g., greater than 20nM, 30nM, 40nM or 50nM.

31. The sdAb of any one of claims 18 to 30, wherein the VHH that binds to IL-10RP binds to both human IL-10RP and cynomolgus IL-lORp.

32. The sdAb of any one of claims 18 to 31, comprising a human fragment crystallizable (Fc) domain.

33. The sdAb of claim 32, wherein the Fc domain comprises a human IgGl or a human IgG4.

34. A bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP),1569-US-NP / WO-PCTwherein the bispecific antibody is an IL-10R agonist that selectively suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells.

35. A bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP), wherein the bispecific antibody is an IL-10R agonist that predominantly suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells.

36. The bispecific antibody of claim 35, wherein the bispecific antibody induces a maximum effective (Emax) activation of T cells or B cells that is 15% or less of wildtype IL- 10.

37. A bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-10R) alpha subunit (IL-lORa) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-1OR ), wherein the bispecific antibody is an IL-10R agonist that predominantly or selectively suppresses activation of myeloid cells and induces a maximum effect (Emax) activation of T cells or B cells that is 15% or less of wild-type IL-10.

38. A bispecific antibody comprising a first immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin- 10 receptor (IL-R) alpha subunit (IL-lORa) and the second VHH specifically binds to the extracellular domain of interleukin- 10 receptor beta subunit (IL-10RP), wherein the bispecific antibody is an IL-10R agonist suppressing activation of myeloid cells with a half maximal effective concentration (EC50) less than 10 pM and activating T cells and B cells below a predetermined threshold level at a concentration above 1000 nM.

39. The bispecific antibody of claim 38, wherein the bispecific antibody activates T cells or B cells with a maximum effect (Emax) that is 15% or less of wild-type IL- 10.1569-US-NP / WO-PCT40. The bispecific antibody of any one of claims 34 to 39, wherein activation of T cells is measured by at least one of Granzyme B secretion and interferon-y (IFN-y) production.

41. The bispecific antibody of any one of claims 34 to 40, wherein the myeloid cells are selected from macrophages, monocytes and dendritic cells.

42. The bispecific antibody of any one of claims 34 to 41, wherein the bispecific antibody does not induce detectable granzyme B secretion from CD8+ T cells.

43. The bispecific antibody of any one of claims 34 to 42, wherein the bispecific antibody induces interferon-y (IFN-y) from CD8+ T cells less than 15% the level of IFN-y induced by wild-type IL- 10.

44. The bispecific antibody of any one of claims 34 to 43, wherein the bispecific antibody induces minimal (e.g., less than 25% in comparison to wild-type IL- 10) or no inhibition of IL-IORP dimerization with other IL-10 family cytokine receptor subunits, e.g., IL-10RP dimerization with IL-20Ra, IL-22R, IL-28R or IL-29R.

45. The bispecific antibody of any one of claims 34 to 44, wherein the bispecific antibody induces minimal e.g., less than 25% in comparison to wild-type IL- 10) or no inhibition of intracellular signaling of other IL-10RP-binding cytokines, e.g., minimal or no inhibition of IL-22, IL-26, IL-28A, IL-28B, or IL-29 intracellular signaling.

46. The bispecific antibody of any one of claims 34 to 45, wherein the bispecific antibody agonizes the IL-10 receptor in a tyrosine kinase 2 (TYK2; NCBI Gene ID: 7297) dependent manner.

47. The bispecific antibody of any one of claims 34 to 45, wherein the second VHH binds to IL-10RP with an equilibrium dissociation constant (KD) that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the KD of the first VI II I binding to IL-lORa, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR).

48. The bispecific antibody of any one of claims 34 to 47, wherein the first variable domain binds to IL-lORa with an equilibrium dissociation constant (KD) of lower than1569-US-NP / WO-PCT2 nM and the second variable domain binds to IL-1OR with a KD of greater than 10 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR).

49. The bispecific antibody of any one of claims 34 to 47, wherein the first variable domain binds to IL- 1 OR a with an equilibrium dissociation constant (KD) of lower than 2 nM and the second variable domain binds to IL-10RP with a KD of greater than 50 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR).

50. The bispecific antibody of any one of claims 34 to 48, wherein the first VHH binds to an epitope on IT-lORa comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, E79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10RP comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712.

51. The bispecific antibody of any one of claims 34 to 47 and 49, wherein the first VHH binds to an epitope on IL-lORa comprising contact amino acid residues 1169, 1171, K173, F178, F180, T181, H182, K183, K186, Fl 90, E192, L193, S195, E197, and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10RP comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, DUO, 1112, Pl 15, Q157, Q190, R192, F194, N199, A201, E203, W204, and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712.

52. The bispecific antibody of any one of claims 34 to 51, comprising at least one polypeptide comprising the first VHH in tandem with the second VHH.

53. The bispecific antibody of any one of claims 34 to 52, comprising at least one polypeptide comprising from N-terminus to C-terminus the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-lORp.

54. The bispecific antibody of any one of claims 34 to 52, comprising at least one polypeptide comprising from N-terminus to C-terminus the second VHH that specifically binds to IL-10RP and the first VHH that specifically binds to IL-lORa.1569-US-NP / WO-PCT55. The bispecific antibody of any one of claims 52 to 54, wherein the first VHH and the second VHH are connected via a linker.

56. The bispecific antibody of claim 55, wherein the linker is selected from the group consisting of: GS (SEQ ID NO: 713), GGS (SEQ ID NO: 714), GGGS (SEQ ID NO: 715), GGSGGS (SEQ ID NO: 716), GGGSGGGS (SEQ ID NO: 717) and GGSGGSGGS (SEQ ID NO: 718).

57. The bispecific antibody of any one of claims 34 to 56, wherein the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Kabat, respectively:1) SEQ ID NOs 22, 23, 24, 291, 292 and 293; (877)2) SEQ ID NOs 22, 25, 26, 291, 294 and 295; (647)SEQ ID NOs 22, 27, 24, 291, 297 and 298; (195)4) SEQ ID NOs 22, 23, 24, 288, 289 and 290; (048)SEQ ID NOs 22, 25, 26, 288, 289 and 290; (049)6) SEQ ID NOs 22, 27, 24, 288, 289 and 290; (050)SEQ ID NOs 22, 23, 24, 296, 308 and 309; (274)8) SEQ ID NOs 22, 25, 26, 296, 308 and 309; (771)9) SEQ ID NOs 22, 27, 24, 296, 308 and 309; (772)10) SEQ ID NOs 4, 28, 29, 288, 289 and 290; (054)H) SEQ ID NOs 4, 28, 29, 291, 294 and 295; (883)12) SEQ ID NOs 4, 28, 29, 291, 294 and 295; (784)13) SEQ ID NOs 4, 28, 29, 291, 297 and 298; (785)14) SEQ ID NOs 4, 5, 6, 288, 289 and 290; (046)SEQ ID NOs 4, 5, 6, 291, 294 and 295; (875)16) SEQ ID NOs 4, 5, 6, 291, 294 and 295; (776)17) SEQ ID NOs 4, 5, 6, 291, 297 and 298; (777)18) SEQ ID NOs 4, 5, 6, 296, 308 and 309; (272)19) SEQ ID NOs 4, 15, 16, 288, 289 and 290; (052)20) SEQ ID NOs 4, 15, 16, 296, 308 and 309; (278)21) SEQ ID NOs 4, 17, 18, 288, 289 and 290; (047)1569-US-NP / WO-PCT22) SEQ ID NOs 4, 17, 18, 291. 292 and 293; (876)23) SEQ ID NOs 4, 17, 18, 291, 294 and 295; (778)24) SEQ ID NOs 4, 17, 18, 291, 297 and 298; (779)25) SEQ ID NOs 45, 46, 47, 288, 289 and 290; (062)26) SEQ ID NOs 45, 46. 47, 291, 292 and 293; (891)27) SEQ ID NOs 45, 46, 47, 291, 294 and 295; (780)28) SEQ ID NOs 45, 46, 47, 291, 297 and 298; (781)29) SEQ ID NOs 45, 46, 47, 296, 308 and 309; (290)30) SEQ ID NOs 4, 48, 6, 291, 292 and 293; (892)31) SEQ ID NOs 4, 48, 6, 291, 294 and 295; (793)32) SEQ ID NOs 4, 48, 6, 291, 297 and 298; (794)33) SEQ ID NOs 54, 55, 24, 291, 292 and 293; (894)34) SEQ ID NOs 54, 55, 24, 291, 294 and 295; (795)35) SEQ ID NOs 54, 55, 24, 291, 297 and 298; (796)36) SEQ ID NOs 4, 30, 31, 291, 292 and 293; (884)37) SEQ ID NOs 4, 30, 31, 291, 294 and 295; (786)38) SEQ ID NOs 4, 30, 31, 291, 297 and 298; (787)39) SEQ ID NOs 4, 36, 29, 288, 289 and 290; (058)40) SEQ ID NOs 33, 34, 35, 296, 308 and 309; (284)41) SEQ ID NOs 33, 34, 35, 296, 308 and 309; (183)42) SEQ ID NOs 33, 34, 35, 296, 308 and 309; (184)43) SEQ ID NOs 19. 37, 38, 302, 303 and 304; (239)44) SEQ ID NOs 19, 37, 38, 296, 308 and 309; (286) or45) SEQ ID NOs 19, 51, 52, 302, 303 and 304; (247).The bispecific antibody of any one of claims 34 to 56, wherein the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to IMGT, respectively:1) SEQ ID NOs: 77, 78, 79, 329, 330 and 331; (877)SEQ ID NOs: 77, 80, 81, 329, 332 and 333; (647)SEQ ID NOs: 77, 82, 79, 334, 335 and 336; (195)1569-US-NP / WO-PCT4) SEQ ID NOs: 77, 78, 79, 326, 327 and 328; (048)5) SEQ ID NOs: 77, 80, 81, 326, 327 and 328; (049)6) SEQ ID NOs: 77, 82, 79, 326, 327 and 328; (050)7) SEQ ID NOs: 77, 78, 79, 346, 347 and 348; (274)8) SEQ ID NOs: 77, 80. 81, 346, 347 and 348; (771)9) SEQ ID NOs: 77, 82, 79, 346, 347 and 348; (772)10) SEQ ID NOs: 59, 83, 84, 326, 327 and 328; (054)11) SEQ ID NOs: 59, 83, 84, 329, 330 and 331; (883)12) SEQ ID NOs: 59, 83, 84, 329, 332 and 333; (784)13) SEQ ID NOs: 59, 83, 84, 334, 335 and 336; (785)14) SEQ ID NOs: 59, 60, 61, 326, 327 and 328; (046)15) SEQ ID NOs: 59, 60, 61, 329, 330 and 331; (875)16) SEQ ID NOs: 59, 60, 61, 329, 332 and 333; (776)17) SEQ ID NOs: 59, 60. 61, 334, 335 and 336; (777)18) SEQ ID NOs: 59, 60, 61, 346, 347 and 348; (272)19) SEQ ID NOs: 59, 70, 71, 326, 327 and 328; (052)20) SEQ ID NOs: 59, 70, 71, 346, 347 and 348; (278)21) SEQ ID NOs: 59, 72. 73, 326, 327 and 328; (047)22) SEQ ID NOs: 59, 72, 73, 329, 330 and 331; (876)23) SEQ ID NOs: 59, 72, 73, 329, 332 and 333; (778)24) SEQ ID NOs: 59, 72, 73, 334, 335 and 336; (779)25) SEQ ID NOs:

98. 99, 100, 326, 327 and 328: (062)26) SEQ ID NOs: 98, 99, 100, 329, 330 and 331; (891)27) SEQ ID NOs: 98, 99, 100, 329, 332 and 333; (780)28) SEQ ID NOs: 98, 99, 100, 334, 335 and 336; (781)29) SEQ ID NOs: 98, 99, 100, 326, 327 and 328: (290)30) SEQ ID NOs: 59, 101, 61, 329, 330 and 331; (892)31) SEQ ID NOs: 59, 101, 61, 329, 332 and 333; (793)32) SEQ ID NOs: 59, 101, 61, 334, 335 and 336; (794)33) SEQ ID NOs: 106, 107, 79. 329, 330 and 331; (894)34) SEQ ID NOs: 106, 107, 79, 329, 332 and 333; (795)35) SEQ ID NOs: 106, 107, 79, 334, 335 and 336; (796)36) SEQ ID NOs: 59, 85, 86, 329, 330 and 331; (884)37) SEQ ID NOs: 59, 85, 86, 329, 332 and 333; (786)1569-US-NP / WO-PCT38) SEQ ID NOs: 59, 85, 86, 334, 335 and 336; (787)39) SEQ ID NOs: 59, 91, 84, 326, 327 and 328; (058)40) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (284)41) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (183)42) SEQ ID NOs: 88, 89. 90, 326, 327 and 328; (184)43) SEQ ID NOs: 92, 75, 93, 340, 341 and 342; (239)44) SEQ ID NOs: 92, 75, 93, 326, 327 and 328; (286) or45) SEQ ID NOs: 74, 75, 104, 340, 341 and 342; (247).

59. The bispecific antibody of any one of claims 34 to 56, wherein the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Chothia, respectively:1) SEQ ID NOs 127, 128, 129, 369, 370 and 371; (877)2) SEQ ID NOs 127, 130, 131, 369, 372 and 373; (647)3) SEQ ID NOs 127, 130, 131, 374, 375 and 376; (195)4) SEQ ID NOs 127, 128, 129, 366, 367 and 368; (048)5) SEQ ID NOs 127, 130, 131, 366, 367 and 368; (049)6) SEQ ID NOs 127, 130, 131, 366, 367 and 368; (050)7) SEQ ID NOs 127, 128, 129, 386, 387 and 388; (274)8) SEQ ID NOs 127, 130, 131, 386, 387 and 388; (771)9) SEQ ID NOs 127, 130, 131, 386, 387 and 388; (772)10) SEQ ID NOs 111, 132, 133, 366, 367 and 368; (054)11) SEQ ID NOs 111, 132, 133, 369, 370 and 371; (883)12) SEQ ID NOs 111, 132, 133, 369, 372 and 373; (784)13) SEQ ID NOs 111, 132, 133, 374, 375 and 376; (785)14) SEQ ID NOs 111, 112, 113, 366, 367 and 368; (046)15) SEQ ID NOs 111, 112, 113, 369, 370 and 371; (875)16) SEQ ID NOs 111, 112, 113, 369, 372 and 373; (776)17) SEQ ID NOs 111, 112, 113, 374, 375 and 376; (777)18) SEQ ID NOs 111, 112, 113, 386, 387 and 388; (272)19) SEQ ID NOs 111, 121, 122, 366, 367 and 368; (052)1569-US-NP / WO-PCT20) SEQ ID NOs 111, 121, 122. 386, 387 and 388; (278)21) SEQ ID NOs 111, 121, 123, 366, 367 and 368; (047)22) SEQ ID NOs 111, 121, 123, 369, 370 and 371; (876)23) SEQ ID NOs 111, 121, 123, 369, 372 and 373; (778)24) SEQ ID NOs 111, 121, 123, 374, 375 and 376; (779)25) SEQ ID NOs 145, 146, 147, 366, 367 and 368; (062)26) SEQ ID NOs 145, 146, 147, 369, 370 and 371; (891)27) SEQ ID NOs 145, 146, 147, 369, 372 and 373; (780)28) SEQ ID NOs 145, 146, 147, 374, 375 and 376; (781)29) SEQ ID NOs 145, 146, 147, 386, 387 and 388; (290)30) SEQ ID NOs 111, 112, 113, 369, 370 and 371; (892)31) SEQ ID NOs 111, 112, 113, 369, 372 and 373; (793)32) SEQ ID NOs 111, 112, 113, 374, 375 and 376; (794)33) SEQ ID NOs 152, 121, 129. 369, 370 and 371; (894)34) SEQ ID NOs 152, 121, 129, 369, 372 and 373; (795)35) SEQ ID NOs 152, 121, 129, 374, 375 and 376; (796)36) SEQ ID NOs 111, 134, 135, 369, 370 and 371; (884)37) SEQ ID NOs 111, 134, 135, 369, 372 and 373; (786)38) SEQ ID NOs 111, 134, 135, 374, 375 and 376; (787)39) SEQ ID NOs 111, 132, 133, 366, 367 and 368; (058)40) SEQ ID NOs 137, 138, 139, 386, 387 and 388; (284)41) SEQ ID NOs 137, 138, 139, 386, 387 and 388; (183)42) SEQ ID NOs 137, 138, 139, 386, 387 and 388; (184)43) SEQ ID NOs 140, 125, 141, 380, 381 and 381; (239)44) SEQ ID NOs 140, 125, 141, 386, 387 and 388; (286) or 45) SEQ ID NOs 124, 125, 126, 380, 381 and 381 (247).

60. The bispecific antibody of any one of claims 34 to 56, wherein the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Honegger, respectively:1) SEQ ID NOs: 174, 175, 176, 409, 410 and 411; (877)1569-US-NP / WO-PCT2) SEQ ID NOs: 174, 177, 178.409, 412 and 413; (647)3) SEQ ID NOs: 174, 179, 176.414, 415 and 416; (195)4) SEQ ID NOs: 174, 175, 176, 406, 407 and 408; (048)5) SEQ ID NOs: 174, 177, 178.406, 407 and 408; (049)6) SEQ ID NOs: 174, 179, 176. 406, 407 and 408; (050)7) SEQ ID NOs: 174, 175, 176, 426, 427 and 428; (274)8) SEQ ID NOs: 174, 177, 178.426, 427 and 428; (771)9) SEQ ID NOs: 174, 179, 176, 426, 427 and 428; (772)10) SEQ ID NOs: 156, 180, 181.406, 407 and 408; (054)11) SEQ ID NOs: 156, 180, 181.409, 410 and 411; (883)12) SEQ ID NOs: 156, 180, 181.409, 412 and 413; (784)13) SEQ ID NOs: 156, 180, 181, 414, 415 and 416; (785)14) SEQ ID NOs: 156, 157, 158.406, 407 and 408; (046)15) SEQ ID NOs: 156, 157, 158.409, 410 and 411; (875)16) SEQ ID NOs: 156, 157, 158, 409, 412 and 413; (776)17) SEQ ID NOs: 156, 157, 158, 414, 415 and 416; (777)18) SEQ ID NOs: 156, 157, 158.426, 427 and 428; (272)19) SEQ ID NOs: 156, 167, 168.406, 407 and 408; (052)20) SEQ ID NOs: 156, 167, 168.426, 427 and 428; (278)21) SEQ ID NOs: 156, 169, 170, 406, 407 and 408; (047)22) SEQ ID NOs: 156, 169, 170, 409, 410 and 411; (876)23) SEQ ID NOs: 156, 169, 170, 409, 412 and 413; (778)24) SEQ ID NOs: 156, 169, 170.414, 415 and 416; (779)25) SEQ ID NOs: 198, 199, 200, 406, 407 and 408; (062)26) SEQ ID NOs: 198, 199, 200, 409, 410 and 411; (891)27) SEQ ID NOs: 198, 199, 200, 409, 412 and 413; (780)28) SEQ ID NOs: 198, 199, 200. 414, 415 and 416; (781)29) SEQ ID NOs: 198, 199, 200, 426, 427 and 428; (290)30) SEQ ID NOs: 156, 201, 158, 409, 410 and 411; (892)31) SEQ ID NOs: 156, 201, 158, 409, 412 and 413; (793)32) SEQ ID NOs: 156, 201, 158.414, 415 and 416; (794)33) SEQ ID NOs: 208, 209, 176, 409, 410 and 411; (894)34) SEQ ID NOs: 208, 209, 176, 409, 412 and 413; (795)35) SEQ ID NOs: 208, 209, 176, 414, 415 and 416; (796)1569-US-NP / WO-PCT36) SEQ ID NOs: 156, 182, 183, 409, 410 and 411; (884)37) SEQ ID NOs: 156, 182, 183, 409, 412 and 413; (786)38) SEQ ID NOs: 156, 182, 183, 414, 415 and 416; (787)39) SEQ ID NOs: 156, 188, 181, 406, 407 and 408; (058)40) SEQ ID NOs: 185, 186, 187. 426, 427 and 428; (284)41) SEQ ID NOs: 709, 186, 187, 426, 427 and 428; (183)42) SEQ ID NOs: 709, 186, 187, 426, 427 and 428; (184)43) SEQ ID NOs: 189, 190, 191, 420, 421 and 422; (239)44) SEQ ID NOs: 189, 190, 191, 426, 427 and 428; (286) or45) SEQ ID NOs: 204, 205, 206, 420, 421 and 422; (247).

61. The bispecific antibody of any one of claims 34 to 60, comprising a VHH1-CDR1, a VHH1-CDR2, and a VHH1-CDR3 and a VHH2-CDR1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively (E07-A05):1) SEQ ID NOs: 22, 23, 24, 291, 292 and 293; (877; according to Kabat)2) SEQ ID NOs: 22, 25, 26, 291, 294 and 295; (647; according to Kabat)3) SEQ ID NOs:

22. 27, 24, 291, 297 and 298; (195; according to Kabat)4) SEQ ID NOs: 77, 78, 79, 329, 330 and 331; (877; according to IMGT)5) SEQ ID NOs: 77, 80, 81, 329, 332 and 333; (647; according to IMGT)6) SEQ ID NOs: 77, 82, 79, 334, 335 and 336; (195; according to IMGT)7) SEQ ID NOs: 127, 128, 129, 369, 370 and 371; (877; according to Chothia) 8) SEQ ID NOs: 127, 130, 131, 369, 372 and 373; (647; according to Chothia) 9) SEQ ID NOs: 127, 130, 131, 374, 375 and 376; (195; according to Chothia) 10) SEQ ID NOs: 174, 175, 176, 409, 410 and 411; (877; according to Honegger) 11) SEQ ID NOs: 174, 177, 178, 409, 412 and 413; (647; according to Honegger) or 12) SEQ ID NOs: 174, 179, 176, 414, 415 and 416; (195; according to Honegger).

62. The bispecific antibody of any one of claims 34 to 60, comprising a VHH1-CDR1, a VIIII1-CDR2, and a VIIH1-CDR3 and a VIIII2-CDR1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively (F11-C04):1) SEQ ID NOs: 33, 34, 35, 296, 308 and 309; (284; according to Kabat)2) SEQ ID NOs: 33, 34, 35, 296, 308 and 309; (183; according to Kabat)3) SEQ ID NOs: 33, 34, 35, 296, 308 and 309; (184; according to Kabat)4) SEQ ID NOs:

88. 89, 90, 326, 327 and 328; (284; according to IMGT)5) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (183; according to IMGT)1569-US-NP / WO-PCT6) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (184; according to IMGT)7) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (284; according to Chothia) 8) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (183; according to Chothia) 9) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (184; according to Chothia) 10) SEQ ID NOs: 185, 186, 187. 426, 427 and 428; (284; according to Honegger) 11) SEQ ID NOs: 709, 186, 187, 426, 427 and 428; (183; according to Honegger) or 12) SEQ ID NOs: 709, 186, 187, 426, 427 and 428; (184; according to Honegger).

63. The bispecific antibody of any one of claims 34 to 61, wherein the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 212 and 448; [A06con-A05con]2) SEQ ID NOs: 212 and 449; [A06con-A05con]3) SEQ ID NOs: 212 and 460; [A06con-C04con]4) SEQ ID NOs: 233 and 448; [E07con-A05con]5) SEQ ID NOs: 234 and 449; [E07con-A05con]6) SEQ ID NOs: 233 and 460; [E07con-C04con]7) SEQ ID NOs: 234 and 460; [E07con-C04con]8) SEQ ID NOs: 710 and 448; [C09con-A05con]9) SEQ ID NOs: 710 and 449; [C09con-A05con]10) SEQ ID NOs: 710 and 460; [C09con-C04con]11) SEQ ID NOs: 230 and 460 [G22con-C04con] or12) SEQ ID NOs: 249 and 460 [Fl lcon-C04con],64. The bispecific antibody of any one of claims 34 to 63, wherein the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 235 and 450; (877)2) SEQ ID NOs: 237 and 451; (647)1569-US-NP / WO-PCT3) SEQ ID NOs 239 and 452; (195)4) SEQ ID NOs 235 and 446; (048)5) SEQ ID NOs 237 and 447; (049)6) SEQ ID NOs 239 and 447; (050)7) SEQ ID NOs 235 and 461; (274)8) SEQ ID NOs 237 and 462; (771)9) SEQ ID NOs 239 and 462; (772)10) SEQ ID NOs 241 and 446; (054)11) SEQ ID NOs 243 and 447; (755)12) SEQ ID NOs 241 and 450; (883)13) SEQ ID NOs 243 and 451; (784)14) SEQ ID NOs 243 and 452; (785)15) SEQ ID NOs 213 and 446; (046)16) SEQ ID NOs 215 and 447; (747)17) SEQ ID NOs 213 and 450; (875)18) SEQ ID NOs 215 and 451; (776)19) SEQ ID NOs 215 and 452; (777)20) SEQ ID NOs 213 and 461; (272)21) SEQ ID NOs 215 and 462; (773)22) SEQ ID NOs 224 and 446; (052)23) SEQ ID NOs 226 and 447; (753)24) SEQ ID NOs 224 and 461; (278)25) SEQ ID NOs 226 and 462; (769)26) SEQ ID NOs 227 and 446; (047)27) SEQ ID NOs 229 and 447; (748)28) SEQ ID NOs 227 and 450; (876)29) SEQ ID NOs 229 and 451; (778)30) SEQ ID NOs 229 and 452; (779)31) SEQ ID NOs 267 and 446; (062)32) SEQ ID NOs 269 and 447; (763)33) SEQ ID NOs 267 and 450; (891)34) SEQ ID NOs 269 and 451; (780)35) SEQ ID NOs 269 and 452; (781)36) SEQ ID NOs 267 and 461; (290)1569-US-NP / WO-PCT37) SEQ ID NOs 269 and 462; (791)38) SEQ ID NOs 270 and 450; (892)39) SEQ ID NOs 272 and 451; (793)40) SEQ ID NOs 272 and 452; (794)41) SEQ ID NOs 285 and 450; (894)42) SEQ ID NOs 287 and 451; (795)43) SEQ ID NOs 287 and 452; (796)44) SEQ ID NOs 244 and 450; (884)45) SEQ ID NOs 246 and 451; (786)46) SEQ ID NOs 247 and 452; (787)47) SEQ ID NOs 253 and 446; (058)48) SEQ ID NOs 255 and 447; (759)49) SEQ ID NOs 250 and 461; (284)50) SEQ ID NOs 251 and 462; (183)51) SEQ ID NOs 252 and 462; (184)52) SEQ ID NOs 256 and 456; (239)53) SEQ ID NOs 258 and 457; (740)54) SEQ ID NOs 256 and 461; (286)55) SEQ ID NOs 258 and 462; (788)56) SEQ ID NOs 278 and 456; (247) or57) SEQ ID NOs 280 and 457; (749).

65. The bispecific antibody of any one of claims 34 to 64, wherein the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 236 and 450; (877)2) SEQ ID NOs: 238 and 451; (647)3) SEQ ID NOs: 240 and 452; (195)4) SEQ ID NOs: 236 and 446; (048)5) SEQ ID NOs: 238 and 447; (049)6) SEQ ID NOs: 240 and 447; (050)1569-US-NP / WO-PCT7) SEQ ID NOs 236 and 461; (274)8) SEQ ID NOs 238 and 462; (771)9) SEQ ID NOs 240 and 462; (772)10) SEQ ID NOs 242 and 446; (054)11) SEQ ID NOs 243 and 447; (755)12) SEQ ID NOs 242 and 450; (883)13) SEQ ID NOs 243 and 451; (784)14) SEQ ID NOs 243 and 452; (785)15) SEQ ID NOs 214 and 446; (046)16) SEQ ID NOs 215 and 447; (747)17) SEQ ID NOs 214 and 450; (875)18) SEQ ID NOs 215 and 451; (776)19) SEQ ID NOs 215 and 452; (777)20) SEQ ID NOs 214 and 461; (272)21) SEQ ID NOs 215 and 462; (773)22) SEQ ID NOs 225 and 446; (052)23) SEQ ID NOs 226 and 447; (753)24) SEQ ID NOs 225 and 461; (278)25) SEQ ID NOs 226 and 462; (769)26) SEQ ID NOs 228 and 446; (047)27) SEQ ID NOs 229 and 447; (748)28) SEQ ID NOs 228 and 450; (876)29) SEQ ID NOs 229 and 451; (778)30) SEQ ID NOs 229 and 452; (779)31) SEQ ID NOs 268 and 446; (062)32) SEQ ID NOs 269 and 447; (763)33) SEQ ID NOs 268 and 450; (891)34) SEQ ID NOs 269 and 451; (780)35) SEQ ID NOs 269 and 452; (781)36) SEQ ID NOs 268 and 461; (290)37) SEQ ID NOs 269 and 462; (791)38) SEQ ID NOs 271 and 450; (892)39) SEQ ID NOs 273 and 451; (793)40) SEQ ID NOs 274 and 452; (794)1569-US-NP / WO-PCT41) SEQ ID NOs 286 and 450; (894)42) SEQ ID NOs 287 and 451; (795)43) SEQ ID NOs 287 and 452; (796)44) SEQ ID NOs 245 and 450; (884)45) SEQ ID NOs 246 and 451; (786)46) SEQ ID NOs 246 and 452; (787)47) SEQ ID NOs 254 and 446; (058)48) SEQ ID NOs 255 and 447; (759)49) SEQ ID NOs 250 and 461; (284)50) SEQ ID NOs 251 and 462; (183)51) SEQ ID NOs 252 and 462; (184)52) SEQ ID NOs 257 and 456; (239)53) SEQ ID NOs 259 and 457; (740)54) SEQ ID NOs 257 and 461; (286)55) SEQ ID NOs 259 and 462; (788)56) SEQ ID NOs 279 and 456; (247) or57) SEQ ID NOs 280 and 457; (749).

66. The bispecific antibody of any one of claims 34 to 65, wherein the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 233 and 448; [E07con-A05con]2) SEQ ID NOs: 234 and 449; [E07con-A05con]3) SEQ ID NOs: 235 and 450; (877)4) SEQ ID NOs: 237 and 451; (647)5) SEQ ID NOs: 239 and 452; (195)6) SEQ ID NOs: 236 and 450; (877)7) SEQ ID NOs: 238 and 451; (647)8) SEQ ID NOs: 240 and 452; ( 195)9) SEQ ID NOs: 724 and 450;10) SEQ ID NOs: 724 and 451;1569-US-NP / WO-PCT11) SEQ ID NOs: 724 and 452;12) SEQ ID NOs: 725 and 450;13) SEQ ID NOs: 725 and 451; or14) SEQ ID NOs; 725 and 452; (E07-A05).

67. The bispecific antibody of any one of claims 34 to 65, wherein the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-10RP comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:1) SEQ ID NOs: 249 and 460; [Fl lcon-C04con]2) SEQ ID NOs: 250 and 461; (284)3) SEQ ID NOs: 251 and 462; (183)4) SEQ ID NOs: 252 and 462; (184)5) SEQ ID NOs: 250 and 461; (284)6) SEQ ID NOs: 251 and 462; (183)7) SEQ ID NOs: 252 and 462; (184)8) SEQ ID NOs: 752 and 461;9) SEQ ID NOs: 752 and 462;10) SEQ ID NOs: 753 and 461;11) SEQ ID NOs: 753 and 462;12) SEQ ID NOs: 754 and 461;13) SEQ ID NOs: 754 and 462;14) SEQ ID NOs: 755 and 461; or15) SEQ ID NOs: 755 and 462 (Fl 1-C04).

68. The bispecific antibody of any one of claims 34 to 67, comprising in tandem the first VIIII that specifically binds to IL-lORa and the second VIIII that specifically binds to IL-1OR, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-476 and 573.1569-US-NP / WO-PCT69. The bispecific antibody of any one of claims 34 to 68, comprising in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 574, 576, 578, 580, 582, 584. 586, 588 and 590.

70. The bispecific antibody of any one of claims 34 to 69, comprising in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498. 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522. 524, 526, 528, 530, 532, 534, 536, 538, 540, 542. 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566. 568, 570, 572, 575, 577, 579, 581, 583, 585, 587, 589, 591, 737-751 and 757-758.

71. The bispecific antibody of any one of claims 34 to 70, comprising in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-482 and 737-751 (E07-A05).

72. The bispecific antibody of any one of claims 34 to 70, comprising in tandem the first VHH that specifically binds to IL-lORa and the second VHH that specifically binds to IL-1OR0, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 573-579 and 757-758 (F11-C04).1569-US-NP / WO-PCT73. The bispecific antibody of any one of claims 34 to 72, wherein the first VHH that specifically binds to IL-lORa binds to both human IL-lORa and cynomolgus IL-lORa.

74. The bispecific antibody of any one of claims 34 to 73, wherein the second VHH that specifically binds to IL-10RP binds to both human IL-1OR0 and cynomolgus IL-1OR.

75. 1'he bispecific antibody of any one of claims 34 to 74, wherein the first VHH that specifically binds to IL-lORa binds to both human IL-lORa and cynomolgus IL-lORa and wherein the second VHH that specifically binds to IL-10RP binds to both human IL-10RP and cynomolgus IL-10Rp.

76. The bispecific antibody of any one of claims 34 to 75, comprising a first fragment crystallizable (Fc) domain and a second Fc domain.

77. The bispecific antibody of claim 76, wherein the first Fc domain and the second Fc domain are a human IgGl or a human IgG4.

78. The bispecific antibody of any one of claims 76 to 77, wherein one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions that reduces or inhibits or eliminates antibody-dependent cell-mediated cytotoxicity (ADCC) effector function.

79. The bispecific antibody of any one of claims 76 to 78, wherein one or both of the first Fc domain and the second Fc domain comprises effector function reducing amino acid substitutions at Fc positions (EU numbering) selected from:a) alanine at position 234 and alanine at position 235 (234A and 235A); b) glutamic acid at position 235 (235E);c) proline at position 228 and glutamic acid at position 235 (228P, 235E); d) alanine at position 237 (237 A);e) alanine at position 234 and glutamic acid at position 235 (234A and 235E);f) phenylalanine at position 234, glutamic acid at position 235 and alanine at position 265 (234F, 235E and 265A);1569-US-NP / WO-PCTg) phenylalanine at position 234, glutamic acid at position 235 and alanine at position 236 (234F, 235E and 236A);h) phenylalanine at position 234, glutamic acid at position 235 and arginine at position 236 (234F, 235E and 236R);i) serine at position 234, threonine at position 235 and arginine at position 236 (234S, 235T and 236R);j) alanine at position 234, alanine at position 235 and glycine at position 329 (234A, 235A and 329G);k) alanine at position 234, alanine at position 235 and alanine at position 237 (234A, 235A and 237A);l) proline at position 228 and glutamic acid at position 235 (228P and 235E);m) proline at position 228, glutamic acid in position 235 and glycine at position 329 (228P, 235E and 329G);n) phenylalanine at position 234, glutamic acid at position 235 and serine at position 331 (234F, 235E and 33 IS);o) phenylalanine at position 234, glutamine at position 235 and glutamine at position 322 (234F, 235Q and 322Q);p) alanine at position 233, arginine at position 234 and arginine at position 235 (233A, 234R and 235R);q) alanine at position 233, aspartic acid at position 234 and glutamic acid at position 235 (233A, 234D and 235E);r) lysine at position 233, arginine at position 234 and arginine at position 235 (233K, 234R and 235R);s) alanine at position 234, alanine at position 235, alanine at position 237, serine at position 238, alanine at position 268, serine at position 330 and serine at position 331 (234A, 235 A, 237A, 238S, 268A, 330S and 33 IS); andt) proline at position 228, alanine at position 234, alanine at position 235, alanine at position 237 and serine at position 238 (228P, 234A, 235A, 237A and 238S).1569-US-NP / WO-PCT80. The bispecific antibody of any one of claims 76 to 79, wherein one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions that extend serum half-life.

81. The bispecific antibody of any one of claims 76 to 80, wherein one or both of the first Fc domain and the second Fc domain comprises serum half-life extending amino acid substitutions at Fc positions (EU numbering) selected from:a) tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (252Y, 254T and 256E);b) leucine at position 428 (428L);c) glutamine at position 250 and leucine at position 428 (250Q and 428L); d) leucine at position 428 and serine at position 434 (428L and 434S); e) leucine at position 428 and alanine at position 434 (428L and 434A); f) arginine at position 311 and leucine at position 428 (311 R and 428L); g) glycine at position 309 and leucine at position 428 (309G and 428L); h) glutamine at position 307, valine at position 311 and valine at position 378 (307Q, 311V and 378V); andi) aspartic acid at position 256, aspartic acid at position 286, arginine at position 307, valine at position 311 and valine at position 378 (256D, 286D, 307R, 311V and 378V).

82. The bispecific antibody of any one of claims 34 to 81, comprising at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 592-593 and 690.

83. The bispecific antibody of any one of claims 34 to 82, comprising at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 691, 693, 695, 697, 699, 701, 703, 705, and 707.1569-US-NP / WO-PCT84. The bispecific antibody of any one of claims 34 to 83, comprising at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 635, 637, 639, 641, 643, 645, 647, 649, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 685, 687, 689, 692, 694, 696, 698, 700, 702, 704, 706 and 708.

85. The bispecific antibody of any one of claims 34 to 84, comprising at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 592-599 (E07-A05).

86. The bispecific antibody of any one of claims 34 to 84, comprising at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 690-696 (Fl 1-C04).

87. The bispecific antibody of any one of claims 34 to 86, wherein the first VHH that specifically binds to IL 10Ra and the second VHH that specifically binds to IL-10RP are both humanized.

88. The bispecific antibody of any one of claims 34 to 87, wherein the bispecific antibody has a serum half-life in a human of at least 3 days, e.g., at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, or longer.

89. Means for agonizing an IL- 10 receptor that selectively suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells.

90. Means for agonizing an IL- 10 receptor that predominantly suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells.1569-US-NP / WO-PCT91. The means of any one of claims 89 to 90, wherein the means induces a maximum effective (Emax) activation of T cells or B cells that is 15% or less of wild-type IL- 10.

92. Means for agonizing an IL- 10 receptor that induces a maximum effective (Emax) activation of T cells or B cells that is 15% or less of wild-type IL-10.

93. Means for agonizing an IL- 10 receptor that suppresses activation of myeloid cells with a half maximal effective concentration (ECso) less than 10 pM and activating T cells and B cells below a predetermined threshold level at a concentration above 1000 nM.

94. The means of any one of claims 89 to 93, wherein the means agonizes the IL- 10 receptor in a tyrosine kinase 2 (TYK2; NCBI Gene ID: 7297) dependent manner.

95. The means of any one of claims 89 to 94, wherein activation of T cells is measured by at least one of Granzyme B secretion and interferon-y (IFN-y) production.

96. The means of claim 95, wherein the means does not induce detectable granzyme B secretion from CD8+ T cells.

97. The means of claim 95, wherein the means induces interferon-y (IFN-y) from CD8+ T cells less than 15% the level of IFN-y induced by wild-type IL- 10.

98. The means of any one of claims 89 to 97, wherein the myeloid cells are selected from macrophages, monocytes and dendritic cells.

99. The means of any one of claims 89 to 98, wherein the means induces minimal (e.g., less than 25% in comparison to wild-type IL-10) or no inhibition of IL- 10R 3 dimerization with other IL- 10 family cytokine receptor subunits, e.g., IL-10RP dimerization with IL-20Ra, TL-22R, IL-28R orTL-29R.

100. The means of any one of claims 89 to 99, wherein the means induces minimal {e.g., less than 25% in comparison to wild-type IL- 10) or no inhibition of intracellular signaling of other IL-1 ORP-binding cytokines, e.g., minimal or no inhibition of TL-22, IL-26, IL-28A, IL-28B, or IL-29 intracellular signaling.

101. The means of any one of claims 89 to 100, wherein the means binds to IL-10RP with an equilibrium dissociation constant (KD) that is at least 5-fold greater, e.g., at1569-US-NP / WO-PCTleast 7-fold greater, e.g.. at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the KD of binding to IL-lORa, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR).

102. The means of any one of claims 89 to 101, wherein the means binds to IL-lORa with an equilibrium dissociation constant (KD) of lower than 2 nM and binds to IL-10RP with a KD of greater than 10 nM, e.g., greater than 50 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR).

103. The means of any one of claims 89 to 102, wherein the means binds to IL-lORa contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and binds to IL-10RP contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712.

104. The means of any one of claims 89 to 102, wherein the means binds to IL-lORa contact amino acid residues 1169, 1171, K173, F178, F180, T181, H182, K183, K186, Fl 90, L192, L193, S195, E197, and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and binds to IL-10RP contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, DI 10, 1112, Pl 15, Q157, Q190, R192, F194, N199, A201, E203, W204, and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712.

105. A polynucleotide that encodes the sdAb that binds to IL-lORa of any one of claims 1 to 17; the sdAb that binds to IL-10RP of any one of claims 18 to 33 or the bispecific antibody of any one of claims 34 to 88.

106. The polynucleotide of claim 105, wherein:a) the polynucleotide encoding the sdAb that binds to IL-lORa comprises a polynucleotide of any one of SEQ ID NOs: 764-769, or a polynucleotide that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a polynucleotide of any one of SEQ ID NOs: 764-769;1569-US-NP / WO-PCTb) the polynucleotide encoding the sdAb that binds to IL-10RP comprises a polynucleotide of any one of SEQ ID NOs: 770-775, or a polynucleotide that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a polynucleotide of any one of SEQ ID NOs: 770-775; orc) the polynucleotide encoding the bispecific antibody comprises a polynucleotide of any one of SEQ ID NOs: 776-787, or a polynucleotide that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a polynucleotide of any one of SEQ ID NOs: 776-787.

107. The polynucleotide of any one of claims 105 to 106, wherein the polynucleotide is DNA or RNA, e.g., cDNA or mRNA.

108. An expression cassette comprising one or more regulatory sequences operably linked to the polynucleotide of any one of claims 105 to 107.

109. The expression cassette of claim 108, wherein the one or more regulatory sequences comprise a constitutive promoter.

110. An expression vector comprising one or more regulatory sequences operably linked to the polynucleotide or polynucleotides of any one of claims 105 to 107, or the expression cassette or expression cassettes any one of claims 108 to 109.

111. The expression vector of claim 110, wherein the expression vector comprises a plasmid vector or a viral vector.

112. A cell or population of cells, comprising the polynucleotide or polynucleotides of any one of claims 105 to 107, the expression cassette of any one of claims 108 to 109, or the expression vector or expression vectors of any one of claims 110 to 111.

113. The cell or population of cells of claim 112, wherein the cell or population of cells comprises a eukaryotic cell.1569-US-NP / WO-PCT114. The cell or population of cells of any one of claims 112 to 113, wherein the cell or population of cells comprises a mammalian cell, an insect cell, a plant cell or a yeast cell.

115. The cell or population of cells of any one of claims 112 to 114, wherein the mammalian cell is a Chinese Hamster Ovary (CHO) cell.

116. A method of producing an IL-10R binding molecule, the method comprising:a) culturing a cell or population of cells of any one of claims 112 to 115 transformed with the polynucleotide of any one of claims 105 to 107, or the expression cassette of any one of claims 108 to 109 in a cell culture under conditions sufficient to express the IL-10R binding molecule: andb) isolating or purifying the antigen binding molecules from the cell culture.

117. A method of preventing or treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a bispecific antibody of any one of claims 34 to 88.

118. A method of reducing the severity of or mitigating on or more symptoms of an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a bispecific antibody of any one of claims 34 to 88.

119. The method of any one of claims 117 to 118, wherein the inflammatory disease is mediated by an IL- 10 deficiency or deficient signaling through the IL-10R.

120. The method of any one of claims 117 to 119, wherein the inflammatory disease is an autoimmune disease.

121. The method of any one of claims 117 to 120, wherein the inflammatory disease is an inflammatory bowel disease.

122. The method of claim 121, wherein the inflammatory bowel disease is selected from ulcerative colitis, Crohn’s disease, mucosal proctocolitis and celiac disease.

123. The method of any one of claims 117 to 120, wherein the inflammatory disease is an inflammatory dermatitis disease.1569-US-NP / WO-PCT124. The method of claim 123, wherein the inflammatory dermatitis disease is selected from atopic dermatitis (AD), hidradenitis suppurativa (HS), and psoriasis.

125. The method of any one of claims 117 to 124, wherein the inflammatory disease is selected from ulcerative colitis, Crohn’s disease, mucosal proctocolitis and celiac disease, rheumatoid arthritis (RA), juvenile idiopathic arthritis, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis, systemic lupus erythematosus (SLE), Behget’s disease, type 1 diabetes, primary sclerosing cholangitis, ankylosing spondylitis, and multiple sclerosis.

126. The method of any one of claims 117 to 125, wherein the inflammatory disease is acute.

127. The method of any one of claims 117 to 125, wherein the inflammatory disease is chronic.

128. The method of any one of claims 117 to 127, wherein the bispecific antibody is administered subcutaneously, intravenously or orally.

129. The method of any one of claims 117 to 128, wherein the bispecific antibody is administered via a device.

130. The method of claim 129, wherein the device is configured for sustained delivery.

131. The method of any one of claims 129 to 130, wherein the device is configured for self-administration.

132. The method of claim 131, wherein the device is a prefilled syringe.

133. The method of any one of claims 129 to 130, wherein the device is an ingestible device configured for local delivery to the intestine.

134. The method of any one of claims 117 to 133, wherein the bispecific antibody is combined or co-administered with one or more additional agents.

135. The method of claim 134, wherein the one or more additional agents are selected from infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, ustekinumab, natalizumab, mesalamine, diazo-bonded 5-ASA, sulfasalazine, balsalazide, olsalazine, a1569-US-NP / WO-PCTcorticosteroid (e.g., budesonide, hydrocortisone, methylprednisolone, prednisone); an immunosuppressant (e.g., azathioprine, 6-mercaptopurine, cyclosporine, methotrexate), and combinations thereof.

136. The method of any one of claims 134 to 135, wherein the one or more additional agents are selected from a PPAR8 inhibitor, an IRAK4 inhibitor, a TPL2 inhibitor, an a407 inhibitor, a BTLA agonist, a PD- 1 agonist, a CD200R agonist, or a FXR agonist.

137. The method of any one of claims 134 to 135, wherein the one or more additional agents are selected from seladelpar, edecesertib, tilpisertib fosmecarbil, GS-1427, GS-0272, GS-0151, GS-6791 and cilofexor.

138. A kit comprising one or more unitary doses of a bispecific antibody of any one of claims 34 to 88.

139. The kit of claim 138, wherein the one or more unitary doses are the same.

140. The kit of claim 138, wherein the one or more unitary doses are different.

141. The kit of any one of claims 138 to 140, wherein the one or more unitary doses are in one or more ampoules, vials, pre-loaded syringes or delivery devices.

142. The kit of any one of claims 138 to 141, wherein the bispecific antibody is combined or co-administered with one or more additional agents.

143. The kit of claim 142, wherein the one or more additional agents are selected from infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, ustekinumab, natalizumab, mesalamine, diazo-bonded 5-ASA, sulfasalazine, balsalazide, olsalazine, a corticosteroid (e.g., budesonide, hydrocortisone, methylprednisolone, prednisone); an immunosuppressant (e.g., azathioprine, 6-mercaptopurine, cyclosporine, methotrexate), and combinations thereof.

144. The kit of any one of claims 142 to 143, wherein the one or more additional agents are selected from a PPAR8 inhibitor, an IRAK4 inhibitor, a TPL2 inhibitor, an a4f)7 inhibitor, a BTLA agonist, a PD- 1 agonist, a CD200R agonist, or a FXR agonist.1569-US-NP / WO-PCT145. The kit of any one of claims 142 to 144, wherein the one or more additional agents are selected from seladelpar, edecesertib, tilpisertib fosmecarbil, GS-1427, GS-0272, GS-0151, GS-6791 and cilofexor.

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