SIRP gamma antibodies for treatment of granulomatous diseases and disorders

Abstract

Provided herein are methods for treating granulomatous diseases and disorders using antibodies that bind signal regulatory protein gamma (SIRPγ).

Description

Attorney Docket No.: ELTH-009 / 01WO 336159-2073SIRP GAMMA ANTIBODIES FOR TREATMENT OF GRANULOMATOUS DISEASES AND DISORDERS CROSS REFERENCE TO RELATED APPLCATIONS

[0001] This application claims priority to U.S. provisional patent application number 63 / 765,051, filed on February 28, 2025, the contents of which are incorporated by reference herein in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (ELTH_009_01WO_SeqList_ST26.xml; Size: 346,358 bytes; and Date of Creation: February 25, 2026) are herein incorporated by reference in their entirety.BACKGROUND

[0003] Granulomatous diseases and disorders are a group of inflammatory conditions characterized by the formation of granulomas which are clusters of immune cells that form in response to persistent inflammation. One example of a granulomatous disease is giant cell arteritis (GCA), is a serious and life-threatening autoimmune disease that causes inflammation in blood vessels. GCA-associated inflammation is characterized by the presence of large, multinucleated "giant cells" made up of activated immune cells, mainly monocytes and macrophages, which infiltrate the arterial wall and contribute to vessel narrowing and potential tissue ischemia. Activated CD4+ T cells have also been described to play a central role in the inflammatory cascade by triggering the activation of macrophages and inducing inflammatory cytokine secretion. Current therapies for GCA are limited due to a high risk of serious side effects and treatment refractoriness. There is a need for agents and protocols for the treatment of granulomatous diseases and disorders such as GCA, provided herein are such agents and protocols.SUMMARY

[0004] The disclosure provides methods of treating a granulomatous disease or disorder in a subject in need thereof comprising administering to the subject an antibody that is specific for signal regulatory protein gamma (SIRPy).1331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0005] In one aspect, provided herein is a method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an antibody that is specific for SIRPy. In some embodiments, the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with polyangiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis. In exemplary embodiments, the granulomatous disease or disorder is giant cell arteritis (GCA).

[0006] In some embodiments of the methods of the disclosure, the method comprises administering an antibody comprising:the three light chain variable domain (VL) complementary determining regions (CDRs) of amino acid sequences of SEQ ID NO: 136, SEQ ID NO: 164, SEQ ID NO: 207; and comprising the three heavy chain variable domain (VH) CDRs of amino acid sequences of SEQ ID NO: 243, SEQ ID NO: 249, and SEQ ID NO: 321;the three VL CDRs of amino acid sequences of SEQ ID NO: 101, SEQ ID NO: 139, SEQ ID NO: 168, and the three VH CDRs of amino acid sequences of SEQ ID NO: 210, SEQ ID NO: 246, and SEQ ID NO: 278;the three VL CDRs of amino acid sequences of SEQ ID NO: 102, SEQ ID NO: 140, SEQ ID NO: 169, and the three VH CDRs of amino acid sequences of SEQ ID NO: 211, SEQ ID NO: 247, and SEQ ID NO: 279;the three VL CDRs of amino acid sequences of SEQ ID NO: 103, SEQ ID NO: 141, SEQ ID NO: 170, and the three VH CDRs of amino acid sequences of SEQ ID NO: 212, SEQ ID NO: 248, and SEQ ID NO: 280;the three VL CDRs of amino acid sequences of SEQ ID NO: 104, SEQ ID NO: 141, SEQ ID NO: 171, and the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 281;2331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the three VL CDRs of amino acid sequences of SEQ ID NO: 105, SEQ ID NO: 142, SEQ ID NO: 172, and the three VH CDRs of amino acid sequences of SEQ ID NO: 214, SEQ ID NO: 250, and SEQ ID NO: 282;the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 143, SEQ ID NO: 173, and the three VH CDRs of amino acid sequences of SEQ ID NO: 215, SEQ ID NO: 251, and SEQ ID NO: 283;the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 144, SEQ ID NO: 174, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 252, and SEQ ID NO: 284;the three VL CDRs of amino acid sequences of SEQ ID NO: 107, SEQ ID NO: 141, SEQ ID NO: 175, and the three VH CDRs of amino acid sequences of SEQ ID NO: 217, SEQ ID NO: 253, and SEQ ID NO: 285;the three VL CDRs of amino acid sequences of SEQ ID NO: 108, SEQ ID NO: 144, SEQ ID NO: 176, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 254, and SEQ ID NO: 286;the three VL CDRs of amino acid sequences of SEQ ID NO: 109, SEQ ID NO: 145, SEQ ID NO: 171, and the three VH CDRs of amino acid sequences of SEQ ID NO: 218, SEQ ID NO: 255, and SEQ ID NO: 287;the three VL CDRs of amino acid sequences of SEQ ID NO: 110, SEQ ID NO: 146, SEQ ID NO: 177, and the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 249, and SEQ ID NO: 288;the three VL CDRs of amino acid sequences of SEQ ID NO: 111, SEQ ID NO: 147, SEQ ID NO: 178, and the three VH CDRs of amino acid sequences of SEQ ID NO: 220, SEQ ID NO: 256, and SEQ ID NO: 289;the three VL CDRs of amino acid sequences of SEQ ID NO: 112, SEQ ID NO: 148, SEQ ID NO: 179, and the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 290;the three VL CDRs of amino acid sequences of SEQ ID NO: 113, SEQ ID NO: 143, SEQ ID NO: 180, and the three VH CDRs of amino acid sequences of SEQ ID NO: 221, SEQ ID NO: 257, and SEQ ID NO: 291;the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 149, SEQ ID NO: 181, and the three VH CDRs of amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 258, and SEQ ID NO: 292;3331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the three VL CDRs of amino acid sequences of SEQ ID NO: 114, SEQ ID NO: 150, SEQ ID NO: 182, and the three VH CDRs of amino acid sequences of SEQ ID NO: 223, SEQ ID NO: 250, and SEQ ID NO: 293;the three VL CDRs of amino acid sequences of SEQ ID NO: 115, SEQ ID NO: 151, SEQ ID NO: 183, and the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 259, and SEQ ID NO: 294;the three VL CDRs of amino acid sequences of SEQ ID NO: 116, SEQ ID NO: 152, SEQ ID NO: 184, and the three VH CDRs of amino acid sequences of SEQ ID NO: 224, SEQ ID NO: 260, and SEQ ID NO: 295;the three VL CDRs of amino acid sequences of SEQ ID NO: 117, SEQ ID NO: 153, SEQ ID NO: 185, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 261, and SEQ ID NO: 296;the three VL CDRs of amino acid sequences of SEQ ID NO: 118, SEQ ID NO: 143, SEQ ID NO: 186, and the three VH CDRs of amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 262, and SEQ ID NO: 297;the three VL CDRs of amino acid sequences of SEQ ID NO: 119, SEQ ID NO: 154, SEQ ID NO: 187, and the three VH CDRs of amino acid sequences of SEQ ID NO: 225, SEQ ID NO: 250, and SEQ ID NO: 298;the three VL CDRs of amino acid sequences of SEQ ID NO: 120, SEQ ID NO: 140, SEQ ID NO: 188, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 263, and SEQ ID NO: 299;the three VL CDRs of amino acid sequences of SEQ ID NO: 121, SEQ ID NO: 141, SEQ ID NO: 189, and the three VH CDRs of amino acid sequences of SEQ ID NO: 227, SEQ ID NO: 264, and SEQ ID NO: 300;the three VL CDRs of amino acid sequences of SEQ ID NO: 122, SEQ ID NO: 155, SEQ ID NO: 190, and the three VH CDRs of amino acid sequences of SEQ ID NO: 228, SEQ ID NO: 249, and SEQ ID NO: 301;the three VL CDRs of amino acid sequences of SEQ ID NO: 123, SEQ ID NO: 143, SEQ ID NO: 186, and the three VH CDRs of amino acid sequences of SEQ ID NO: 229, SEQ ID NO: 265, and SEQ ID NO: 302;the three VL CDRs of amino acid sequences of SEQ ID NO: 124, SEQ ID NO: 143, SEQ ID NO: 191, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 266, and SEQ ID NO: 303;4331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 156, SEQ ID NO: 192, and the three VH CDRs of amino acid sequences of SEQ ID NO: 230, SEQ ID NO: 249, and SEQ ID NO: 304;the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 145, SEQ ID NO: 193, and the three VH CDRs of amino acid sequences of SEQ ID NO: 231, SEQ ID NO: 267, and SEQ ID NO: 305;the three VL CDRs of amino acid sequences of SEQ ID NO: 125, SEQ ID NO: 143, SEQ ID NO: 194, and the three VH CDRs of amino acid sequences of SEQ ID NO: 232, SEQ ID NO: 268, and SEQ ID NO: 306;the three VL CDRs of amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 157, SEQ ID NO: 195, and the three VH CDRs of amino acid sequences of SEQ ID NO: 233, SEQ ID NO: 269, and SEQ ID NO: 307;the three VL CDRs of amino acid sequences of SEQ ID NO: 127, SEQ ID NO: 155, SEQ ID NO: 196, and the three VH CDRs of amino acid sequences of SEQ ID NO: 234, SEQ ID NO: 249, and SEQ ID NO: 308;the three VL CDRs of amino acid sequences of SEQ ID NO: 128, SEQ ID NO: 158, SEQ ID NO: 197, and the three VH CDRs of amino acid sequences of SEQ ID NO: 235, SEQ ID NO: 270, and SEQ ID NO: 309;the three VL CDRs of amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 159, SEQ ID NO: 198, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 271, and SEQ ID NO: 310;the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 143, SEQ ID NO: 199, and the three VH CDRs of amino acid sequences of SEQ ID NO: 236, SEQ ID NO: 272, and SEQ ID NO: 311;the three VL CDRs of amino acid sequences of SEQ ID NO: 130, SEQ ID NO: 155, SEQ ID NO: 200, and the three VH CDRs of amino acid sequences of SEQ ID NO: 237, SEQ ID NO: 249, and SEQ ID NO: 312;the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 141, SEQ ID NO: 201, and the three VH CDRs of amino acid sequences of SEQ ID NO: 238, SEQ ID NO: 264, and SEQ ID NO: 313;the three VL CDRs of amino acid sequences of SEQ ID NO: 132, SEQ ID NO: 140, SEQ ID NO: 202, and the three VH CDRs of amino acid sequences of SEQ ID NO: 239, SEQ ID NO: 273, and SEQ ID NO: 314;5331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the three VL CDRs of amino acid sequences of SEQ ID NO: 109, SEQ ID NO: 143, SEQ ID NO: 203, and the three VH CDRs of amino acid sequences of SEQ ID NO: 240, SEQ ID NO: 250, and SEQ ID NO: 315;the three VL CDRs of amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 160, SEQ ID NO: 191, and the three VH CDRs of amino acid sequences of SEQ ID NO: 241, SEQ ID NO: 274, and SEQ ID NO: 316;the three VL CDRs of amino acid sequences of SEQ ID NO: 134, SEQ ID NO: 161, SEQ ID NO: 204, and the three VH CDRs of amino acid sequences of SEQ ID NO: 242, SEQ ID NO: 275, and SEQ ID NO:the three VL CDRs of amino acid sequences of SEQ ID NO: 135, SEQ ID NO: 162, SEQ ID NO: 189, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 249, and SEQ ID NO: 318;the three VL CDRs of amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 155, SEQ ID NO: 205, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 276, and SEQ ID NO: 319;the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 163, SEQ ID NO: 206; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 267, and SEQ ID NO: 320;the three VL CDRs of amino acid sequences of SEQ ID NO: 100, SEQ ID NO: 138, SEQ ID NO: 167, and the three VH CDRs of amino acid sequences of SEQ ID NO: 209, SEQ ID NO: 245, and SEQ ID NO: 277;the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 165, SEQ ID NO: 208; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 269, and SEQ ID NO: 322; orthe three VL CDRs of amino acid sequences of SEQ ID NO: 137, SEQ ID NO: 166, SEQ ID NO: 169; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 244, SEQ ID NO: 256, and SEQ ID NO: 323.

[0007] In some embodiments of the methods of the disclosure, the method comprises administering an antibody comprising:a VH comprising the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 415, or an amino acid sequence with at least 70% sequence identity thereto;6331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073a VH comprising the amino acid sequence of SEQ ID NO: 325 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 372, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 373, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 374, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 375, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 376, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 330 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 377, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 331 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 378, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 332 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 379, or an amino acid sequence with at least 70% sequence identity thereto;7331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073a VH comprising the amino acid sequence of SEQ ID NO: 333 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 380, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 381, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 382, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 383, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 384, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 338 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 385, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 339 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 386, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 340 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 387, or an amino acid sequence with at least 70% sequence identity thereto;8331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073a VH comprising the amino acid sequence of SEQ ID NO: 341 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 388, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 389, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 390, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 391, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 392, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 346 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 393, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 347 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 394, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 348 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 395, or an amino acid sequence with at least 70% sequence identity thereto;9331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073a VH comprising the amino acid sequence of SEQ ID NO: 349 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 396, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 397, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 398, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 399, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 400, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 354 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 401, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 355 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 402, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 356 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 403, or an amino acid sequence with at least 70% sequence identity thereto;10331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073a VH comprising the amino acid sequence of SEQ ID NO: 357 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 404, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 405, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 406, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 407, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 408, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 362 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 409, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 363 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 410, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 364 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 411, or an amino acid sequence with at least 70% sequence identity thereto;11331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073a VH comprising the amino acid sequence of SEQ ID NO: 365 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 412, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 413, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 414, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 324 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 371, or an amino acid sequence with at least 70% sequence identity thereto;a VH comprising the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 416, or an amino acid sequence with at least 70% sequence identity thereto; ora VH comprising the amino acid sequence of SEQ ID NO: 370 or an amino acid sequence with at least 70% sequence identity thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 417, or an amino acid sequence with at least 70% sequence identity thereto.

[0008] In some embodiments of the methods of the disclosure for treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an antibody that is specific for SIRPy, the antibody is an antibody fragment. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a full-length antibody.

[0009] In some embodiments of the methods of the disclosure, the antibody has low or no affinity for binding SIRPa and / or SIRPpi. In some embodiments, the antibody binds to human and non-human primate SIRPy with high affinity. In some embodiments, the antibody does not bind to human and non-human primate SIRPa or SIRPP 1.12331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0010] In some embodiments of the methods of the disclosure, the antibody comprises a Fc domain. In certain embodiments, the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4 heavy chain sequence. In certain embodiments, the Fc domain is from the heavy chain IgG amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 28, optionally with one or more Fc amino acid substitutions. In certain embodiments, the Fc domain is from the heavy chain IgG amino acid sequences of any one of SEQ ID NOS: 5-36. In certain embodiments of the methods of the disclosure, the heavy chain Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 5 or SEQ ID NO: 28 at a position selected from the group consisting of: 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, and 440 wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0011] In some embodiments of the methods of the disclosure, the antibody comprises a light chain constant region comprising the amino acid sequence of any one of SEQ ID NOS: 38-42.

[0012] In some embodiments of the methods of the disclosure, the binding of the antibody does not disrupt the interaction between CD47 and SIRPy. In other embodiments, the binding of the antibody disrupts the interaction between CD47 and SIRPy.

[0013] In some embodiments of the methods of the disclosure, the binding of the antibody stabilizes or promotes the interaction between CD47 and SIRPy.

[0014] In some embodiments of the methods of the disclosure, the antibody comprises a binding affinity to SIRPy lower than about 500 nM.

[0015] In some embodiments of the methods of the disclosure, the antibody preferentially depletes of a population of SIRPy-expressing cells. In certain embodiments, the SIRPy-expressing cells are T cells, B cells and / or NK cells. In certain embodiments, the SIRPy-expressing cells are T cells. In certain embodiments, the T cells are activated (stimulated). In exemplary embodiments, the T cells are activated (stimulated), and the depletion is preferential for activated (stimulated) T cells. In certain embodiments, the T cells are exhausted. In exemplary embodiments, the T cells are exhausted, and the depletion is preferential for exhausted T cells. In certain embodiments, the T cells are naive, central memory, effector memory, exhausted, or terminal effector memory cells. In certain embodiments, the T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T 13331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073cells, natural killer T cells, mucosal associated invariant T cells, alpha beta T cells, or gamma delta T cells.

[0016] In certain embodiments, the T cells are Thl cells, Th2 cells, Thl7 cells or T follicular helper cells. In certain embodiments, the T cells are a CD3+ T cell, CD4+ T cell, CD8+ T cell, CD25+ T cell, CD69+ T cell, and / or PD1+ T cell. In certain embodiments, the T cells are CD4+ / CD8+ T cells. In certain embodiments, the T cells are CD69+ / CD8+ T cells. In certain embodiments, the T cells are CD25+ / CD8+ T cells. In certain embodiments, the T cells are PD1+ T cells. In exemplary embodiments, the depletion is preferential for stimulated T cells, as compared to unstimulated T cells. In some embodiments, the depletion is preferential for SIRPy-expressing CD8+ T cells. In some embodiments, the depletion is preferential for SIRPy-expressing CD4+ T- cells. In certain embodiments, the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T- cells. In certain embodiments, the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T- cells.

[0017] In some embodiments, the depletion is preferential for SIRPy-expressing CD8+ T cells, when compared to SIRPy-expressing CD4+ T- cells. In certain embodiments, the depletion is preferential for SIRPy-expressing CD4+ T cells, when compared to SIRPy-expressing CD8+ T- cells. In certain embodiments, the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T cells, when compared to SIRPy-expressing CD8+ / CD69- T-cells. In certain embodiments, the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T cells, when compared to SIRPy-expressing CD8+ / CD25- T- cells.

[0018] In some embodiments of the methods of the disclosure where the antibody preferentially depletes of a population of SIRPy-expressing cells, the SIRPy-expressing cells are B cells.

[0019] In some embodiments of the methods of the disclosure where the antibody preferentially depletes of a population of SIRPy-expressing cells, the SIRPy-expressing cells are NK cells.

[0020] In some embodiments of the methods of the disclosure where the antibody preferentially depletes of a population of SIRPy-expressing cells, the SIRPy-expressing cells are activated.

[0021] In some embodiments of the methods of the disclosure where the antibody preferentially depletes of a population of SIRPy-expressing cells, the population of SIRPy-14331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073expressing cells comprises tissue-resident cells. In some embodiments, the population of SIRPy-expressing cells comprises circulating cells.

[0022] In some embodiments of the methods of the disclosure where the antibody preferentially depletes of a population of SIRPy-expressing cells, the depletion involves one or more of ADCC, ADCP, and CDC.

[0023] In some embodiments of the methods of the disclosure, the antibody is administered with a pharmaceutically acceptable carrier.

[0024] In some embodiments of the methods of the disclosure, the subject is human.

[0025] In some embodiments of the methods of the disclosure, the antibody is administered subcutaneously or intravenously.

[0026] In some embodiments of the methods of the disclosure, the antibody is administered in combination with one or more of:a glucocorticoid such as dexamethasone, prednisone, prednisolone, or methylprednisolone;a cytokine inhibitor, including but not limited to anti-IL-6 receptor inhibitors (e.g., tocilizumab, sarilumab) and anti-IL-ip or IL-1 receptor inhibitors (e.g., canakinumab, anakinra); andan immune suppressant or modulator, such as methotrexate.

[0027] In another aspect, disclosed herein is a use of an antibody for the treatment of a granulomatous disease or disorder in a subject in need thereof, where the antibody is specific for SIRPy.

[0028] In another aspect, disclosed herein is a use of an antibody for the manufacture of a medicament for the treatment of granulomatous disease or disorder in a subject in need thereof, where the antibody is specific for SIRPy.

[0029] In another aspect, disclosed herein is a method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an anti-SIRPy antibody, where the antibody comprises a means for binding human SIRPy.

[0030] In some embodiments of the uses of the disclosure, the disease or disorder is a granulomatous disease or disorder. In certain embodiments, the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis,15331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073Wegener's granulomatosis (granulomatosis with polyangiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis. In exemplary embodiments, the granulomatous disease or disorder is giant cell arteritis (GCA).

[0031] In some embodiments of the uses of the disclosure, the subject is a human.

[0032] In another aspect, disclosed herein is a method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an anti-SIRPy antibody, where the antibody comprises a means for binding human SIRPy.

[0033] In some embodiments of the methods of the disclosure, the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with polyangiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis. In exemplary embodiments, the granulomatous disease or disorder is giant cell arteritis (GCA). In certain embodiments, the subject is a human. In certain embodiments, the SIRPy antibody is administered subcutaneously or intravenously.BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIGS. 1A-1C show the affinity for human SIRPy, human SIRPa, and human SIRPP for an exemplary antibody of the disclosure.

[0035] FIG. 2A-2G show the effects of an exemplary anti-SIRPy antibody in an in vivo GCA model. FIGS. 2 A and 2D provide schematics of the GCA model and the setup for the experiments. FIGS. 2B, 2C, and 2E-2G show results from an in vivo GCA study including depletion of peripheral immune cells, depletion of arterial T cells and reduction of arterial16331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073pro-inflammatory cytokines after treatment with an exemplary anti-SIRPy antibody of the disclosure.

[0036] FIG. 3 shows the expression of SIRPy on resting T cells and activated T cells.

[0037] FIG. 4 shows the results of an in vitro ADCC reporter assay using a SIRPy-expressing CHO cell line after treatment with exemplary antibodies of the disclosure.

[0038] FIGS. 5A-5B show the activity of exemplary anti-SIRPy antibodies of the disclosure with and without a modified Fc region in an in vivo GCA model. FIG. 5A shows depletion of arterial T cells in the in vivo GCA model. FIG. 5B shows levels of arterial pro-inflammatory cytokines after treatment with the exemplary anti-SIRPy antibodies with and without a modified Fc region.

[0039] FIGS. 6A-6B show the dose dependent effect of an exemplary anti-SIRPy antibody containing a canonical human IgGl Fc region in an in vivo GCA model. FIGS. 6A and 6B show results from the in vivo GCA study including depletion of peripheral immune cells, depletion of arterial T cells and reduction of arterial pro-inflammatory cytokines after treatment with an exemplary anti-SIRPy antibody containing a canonical human IgGl Fc region.DETAILED DESCRIPTION

[0040] Provided herein are antibodies that bind to signal regulatory protein gamma (SIRPy) for the treatment of granulomatous diseases and disorders. Given the restricted and unique patterns of SIRPy expression, these antibodies may be useful for targeting particular cell types, and treating diseases or conditions involving cells, or cell states expressing SIRPy, e.g. activated cells. For example, the antibodies may be used for treating granulomatous diseases and disorders.

[0041] Where elements are presented in a list format (e.g., in a Markush group), it should be understood that each possible subgroup of the elements is also disclosed, and that any one or more elements can be removed from the list or group.Definitions

[0042] It should be understood that, unless clearly indicated, in any method described or disclosed herein that includes more than one act, the order of the acts is not necessarily limited to the order in which the acts of the method are recited, but the disclosure encompasses exemplary embodiments in which the order of the acts is so limited.17331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0043] The terms used throughout the specification are defined as follows unless otherwise limited in specific instances. As used in the specification and the claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. All technical and scientific terms, acronyms, and abbreviates used in the specification and claims have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains, unless defined or stated otherwise. All numerical ranges are inclusive of the values defining the range as well as all integer values in between, unless indicated or defined otherwise.

[0044] The term “antibody” as used herein throughout is used in the broadest sense and includes a monoclonal antibody, polyclonal antibody, human antibody, humanized antibody, non-human antibody, chimeric antibody, a monovalent antibody, and an antibody fragment. The term may refer to an intact tetrameric antibody containing two light chains and two heavy chains, each with a variable region, and a constant region (“full-length”). Alternatively, it may refer to antibody fragments.

[0045] Antibody fragments of the disclosure retain SIRPy antigen binding specificity. Antibody fragments include antigen-binding fragments (Fab), variable fragments (Fv) containing VH and VL sequences, single chain variable fragments (scFv) containing VH and VL sequences linked together in one chain, single chain antibody fragments (scAb) or other antibody variable region fragments, such as Fab’, F(ab’)2, dsFv diabody, and Fd polypeptide fragments.

[0046] The term “depletion” as used herein throughout refers to cell death as an Fc-mediated effector function. Without being bound to theory or mechanism, SIRPy antibodies of the disclosure which comprise a Fc domain are capable of depleting SIRPy-expressing target cells and involve effector functions for their mechanism of action. Without being bound to theory or mechanism, it is thought that SIRPy antibodies of the disclosure which comprise a Fc domain bind to SIRPy-expressing cells via their complementarity determining regions (CDR), and the Fc-regions of the antibodies interact with Fc-receptors on the surfaces of effector immune cells or circulating complement proteins, thus resulting in the depletion (cell death) of the SIRPy-expressing target cells. The depletion can be effectuated via immune cell effector processes like antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP); additionally, or alternatively, the Fc-region can bind to a complement component and cause complement-dependent cytotoxicity18331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073(CDC). The Fc-mediated cell death (depletion) described herein is independent of any CDR-mediated signal transduction that leads to cell death. However, it is acknowledged that any depletion that occurs with the use of any of the SIRPy antibodies of the disclosure may also include a CDR-mediated cell death component, but it is not required.

[0047] The terms “individual,” “subject,” and “patient” are used interchangeably herein and refer to any subject for whom treatment or therapy is desired. The subject may be a mammalian subject. Mammalian subjects including, e.g., humans, non-human primates, rodents, (e.g., rats, mice), lagomorphs (e.g., rabbits), ungulates (e.g., cows, sheep, pigs, horses, goats, and the like), etc. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate, for example a cynomolgus monkey. In some embodiments, the subject is a companion animal (e.g. cats, dogs).

[0048] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.I. SIRPy Antibodies

[0049] Without being held to any theory or mechanism, signal-regulatory protein (SIRP) gamma (SIRPy), also known as CD 172g, is a member of the SIRP family of transmembrane glycoproteins. SIRPy is primarily expressed on T cells and plays a role in cell-cell adhesion and T cell activation by interacting with CD47, a ubiquitously expressed cell surface protein. In humans, SIRPy is expressed on naive T cells at a low level and is upregulated after antigen-stimulation.

[0050] Provided herein are antibodies that bind to SIRPy. As used herein, “SIRPy” includes all isoforms, from any species. In the human, there are multiple SIRPy transcripts, including a full length, two alternatively spliced forms that lack significant portions of their extracellular domains, and one alternatively spliced form that lacks the signal peptide sequence.

[0051] As used herein, the terms “SIRPy antibody” and “anti-SIRPy antibody,” and similar expressions refer interchangeably to an antibody or antibody fragment that specifically binds to SIRPy.

[0052] The amino acid sequence of hSIRPy isoform 1 (full length) is provided as SEQ ID NO: 1 (referencing UniProtKB ID Q9P1W8 Isoform 1).1 MPVPASWPHP PGPFLLLTLL LGLTEVAGEE ELQMIQPEKL LLVTVGKTAT LHCTVTSLLP 19331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207361 VGPVLWFRGV GPGRELIYNQ KEGHFPRVTT VSDLTKRNNM DFSIRISSIT PADVGTYYCV 121 KFRKGSPENV EFKSGPGTEM ALGAKPSAPV VLGPAARTTP EHTVSFTCES HGFSPRDITL 181 KWFKNGNELS DFQTNVDPTG QSVAYSIRST ARVVLDPWDV RSQVICEVAH VTLQGDPLRG 241 TANLSEAIRV PPTLEVTQQP MRVGNQVNVT CQVRKFYPQS LQLTWSENGN VCQRETASTL 301 TENKDGTYNW TSWFLVNISD QRDDVVLTCQ VKHDGQLAVS KRLALEVTVH QKDQSSDATP 361 GPASSLTALL LIAVLLGPIY VPWKQKT (SEQ ID NO : 1)

[0053] The amino acid sequence of a splice variant hSIRPy (isoform 2) is provided as SEQ ID NO: 37. (referencing UniProtKB ID Q9P1W8 Isoform 2).MIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELI YNQKEGHFPRVTTVSDLT KRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPSAPWLGPAAR TTPEHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPTGQSVAYSIRSTARWLDPWD VRSQVICEVAHVTLQGDPLRGTANLSEAIRVPPTLEVTQQPMRVGNQVNVTCQVRKFYPQSL QLTWSENGNVCQRETASTLTENKDGTYNWTSWFLVNISDQRDDWLTCQVKHDGQLAVSKRL ALEVTVHQKDQSSDATPGPASSLTALLLIAVLLGPI YVPWKQKT ( SEQ ID NO : 37 )

[0054] The amino acid sequence of a splice variant hSIRPy (isoform 3) is provided as SEQ ID NO: 2. (referencing UniProtKB ID Q9P1W8 Isoform 3).MPVPASWPHPPGPFLLLTLLLGLTEVAGEEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVG PVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRK GSPENVEFKSGPGTEMALGGPASSLTALLLIAVLLGPI YVPWKQKT ( SEQ ID NO : 2 )

[0055] The amino acid sequence of another splice variant hSIRPy (isoform 4) is provided as SEQ ID NO: 3 (referencing UniProtKB ID Q9P1W8 Isoform 4).MPVPASWPHPPGPFLLLTLLLGLTEVAGEEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVG PVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRK GSPENVEFKSGPGTEMALGAKPSAPWLGPAARTTPEHTVSFTCESHGFSPRDITLKWFKNG NELSDFQTNVDPTGQSVAYS IRSTARWLDPWDVRSQVICEVAHVTLQGDPLRGTANLSEAI RGPASSLTALLLIAVLLGPI YVPWKQKT ( SEQ ID NO : 3 )

[0056] The amino acid sequence of cynomolgus monkey SIRPy is provided as SEQ ID NO: 4. (referencing GenBank: EHH65481.1).MPVPASWSHPPGPFLLLTLLLGFTEVAGEEELQMIQPEKLLLVAVGESATLNCTVTSLLPVG PVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADAGTYYCVKFRK GSPENVEFKSGPGTEMALRAKPSAPWSGPAARATPEHTVSFTCKSHGFSPRDITLKWFKNG NELSDFQTNVDPAGQSVSYS IRSTARWLAPWDVRSQVTCEVAHVTLQGDPLRGTANLSEAI20331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073RVPPTLEVTQQPMRAGNQVNITYQVRNFYPQNLQLTWLENGNVCRTETASTLTENKDGTYNW TSWLLVNTSDQRDDWLTCQVKHDGQLAVNKSLVLEVSAHQKDQSSDATHGPASSLTVLLLI AVLLGPIYVPWKQKS (SEQ ID NO: 4 )

[0057] Accordingly, the SIRPy antibodies of the disclosure may bind to one or more isoforms of a SIRPy of a single species. In some embodiments, the SIRPy antibodies also bind to one or more isoforms of a SIRPy of more than one species. In some embodiments, the SIRPy antibodies bind to one or more isoforms of human SIRPy. In some embodiments, the SIRPy antibodies also bind to one or more isoforms of a non-human primate SIRPy, e.g. a cynomolgus monkey SIRPy.

[0058] In some embodiments, the SIRPy antibodies bind to a plurality of SIRPy variants or isoforms found in a particular species, e.g. the SIRPy antibodies bind to more than one of SIRPy human isoforms 1-3. In some embodiments, the SIRPy antibodies bind the extracellular domain of SIRPy (e.g. amino acids 1-360 of SEQ ID NO: 1).

[0059] In some embodiments, a SIRPy antibody of the disclosure binds to a plurality of SIRPy isoforms found in a particular species, e.g. the SIRPy antibody binds to more than one SIRPy human isoform (e.g. the antibody binds to the full length and one or more splice variants). In other embodiments, the SIRPy antibody binds to some but not all SIRPy isoforms found in a particular species (e.g. the SIRPy antibody binds to one splice variant, but not all).

[0060] The skilled artisan will recognize that antibodies that exhibit little or no binding to a target antigen can be described as having a low affinity, and a high equilibrium dissociation constant (KD) for the target antigen, for example a KD of about 10 pM or greater, about 100 pM or greater, about 1 mM or greater, or about 10 mM or greater. The skilled artisan will also recognize that antibodies that exhibit little or no binding to a target antigen can be described as having a low affinity, and a high equilibrium dissociation constant (KD) for the target antigen, for example a KD of about 10 pM or greater, about 100 pM or greater, about 1 mM or greater, or about 10 mM or greater. For example, a SIRPy antibody that binds to SIRPy may bind to SIRPpi and / or SIRPa with low affinity. A SIRPy antibody of the disclosure with low affinity for SIRPpi and / or SIRPa may bind to SIRPpi and / or SIRPa with a KD of about 10 pM or greater, about 100 pM or greater, about 1 mM or greater, or about 10 mM or greater but retain higher binding affinity for SIRPy.21331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0061] In some embodiments, provided herein are SIRPy antibodies comprising a binding affinity (KD) to SIRPy of about 0.0001 nM, about 0.0005 nM, about 0.001 nM, about 0.005 nM, about O.lnM, about 0.05 nM, about 0.1 nM, about 0.5 nM, about 1 nM, about 5 nM, about 10 nM, about 50 nM, about 100 nM, about 500 nM, about 1 pM, about 2 pM or about 3 pM.

[0062] In some embodiments, provided herein are SIRPy antibodies comprising a binding affinity (KD) to SIRPy of between about 0.0001 nM and 5 pM, between about 0.0005 nM and 5 pM, between about 0.05 nM and 5 pM, between about 0.5 nM and 5 pM, between about InM and 5 pM, between about 5 nM and 5 pM, 0.0001 nM and 2 pM, between about 0.0005 nM and 2 pM, between about 0.05 nM and 2 pM, between about 0.5 nM and 2 pM, between about InM and 2 pM, between about 5 nM and 2 pM, 0.0001 nM and 1 pM, between about 0.0005 nM and 1 pM, between about 0.05 nM and IpM, between about 0.5 nM and IpM, between about InM and IpM, between about 5 nM and 1 pM, between about 0.0001 nM and 500 nM, between about 0.0005 nM and 500 nM, between about 0.05 nM and 500 nM, between about 0.5 nM and 500 nM, between about 1 nM and 500 nM, between about 5 nM and 500 nM, between about 0.0001 nM and 50 nM, between about 0.0005 nM and 50 nM, between about 0.05 nM and 50 nM, between about 0.5 nM and 50 nM, between about 1 nM and 50 nM, or between about 5 nM and 50 nM.

[0063] In some embodiments, a SIRPy antibody of the disclosure does not disrupt CD47 binding to SIRPy on a cell or other surface. Exemplary antibodies of the disclosure that do not disrupt CD47 binding to SIRPy include Antibodies 5, 6, 8, 59, 73, 80, 85, 92, and 96. The CDR and VH / VL sequences for these antibodies are provided in Tables 1 and 2. Evidence supporting such antibodies can be found in W02023 / 086906, which is hereby incorporated by reference in its entirety.

[0064] In other embodiments, a SIRPy antibody of the disclosure enhances or promotes the binding of CD47 to SIRPy on a cell or other surface. Exemplary antibodies of the disclosure that enhance or promote CD47 binding to SIRPy include Antibodies 3, 4, and 7. The CDR and VH / VL sequences for these antibodies are provided in Tables 1 and 2. Evidence supporting such antibodies can be found in W02023 / 086906, which is hereby incorporated by reference in its entirety.

[0065] In other embodiments, a SIRPy antibody of the disclosure disrupts the binding of CD47 to SIRPy on a cell or other surface. Exemplary antibodies of the disclosure that disrupt CD47 binding to SIRPy include Antibodies 54, 60, 64, 83, 84, 88, 89, 90, 94, 95, and 97. The 22331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073CDR and VH / VL sequences for these antibodies are provided in Tables 1 and 2. Evidence supporting such antibodies can be found in W02023 / 086906, which is hereby incorporated by reference in its entirety.

[0066] In some embodiments, a SIRPy antibody of the disclosure comprises a means for binding human SIRPy. In some embodiments, a SIRPy antibody of the disclosure comprises a means for not binding human SIRPa. In some embodiments, a SIRPy antibody of the disclosure comprises a means for not binding human SIRPp. In certain embodiments, a SIRPy antibody of the disclosure comprises (i) a means for not binding human SIRPa and (ii) a means for not binding human SIRPp. In certain embodiments, a SIRPy antibody of the disclosure comprises (i) a means for binding human SIRPy and (ii) a means for not binding human SIRPa. In certain embodiments, a SIRPy antibody of the disclosure comprises (i) a means for binding human SIRPy and (ii) a means for not binding human SIRPp. In certain embodiments, a SIRPy antibody of the disclosure comprises (i) a means for binding human SIRPy, (ii) a means for not binding human SIRPa, and (iii) a means for not binding human SIRPp.

[0067] In some embodiments, a SIRPy antibody of the disclosure comprises a means for disrupting the binding of CD47 to SIRPy on a cell or other surface. In some embodiments, a SIRPy antibody of the disclosure comprises a means for enhancing or promoting the binding of CD47 to SIRPy on a cell or other surface.

[0068] In other embodiments, a SIRPy antibody of the disclosure comprises a means for not disrupting the binding of CD47 to SIRPy on a cell or other surface.

[0069] Also provided herein are SIRPy antibodies comprising a Fc domain. In some embodiments, the Fc domain (interchangeably referred to as a Fc sequence, Fc region, or simply Fc) of the SIRPy antibody is a human Fc domain. In some embodiments, the Fc domain of a SIRPy antibody is human IgGl, human IgG2, human IgG3, or human IgG4. In some embodiments, the Fc domain of a SIRPy antibody is that of a mouse. In some embodiments, the Fc domain of a SIRPy antibody is mouse IgGl or mouse IgG2a. In some embodiments, the Fc domain of a SIRPy antibody is that of a rat. In some embodiments, the Fc domain of a SIRPy antibody is rat IgGl or rat IgG2b. In embodiments, the Fc domain of a SIRPy antibody is that of a non-human primate, e.g. it is a cynomolgus monkey Fc domain.

[0070] In some embodiments, the SIRPy antibodies provided herein are full-length antibodies (comprising an intact tetrameric antibody containing two light chains and two heavy chains, each with a variable region, and a constant region). In some embodiments, the 23331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073constant region of the full-length SIRPy antibodies comprises a human Fc domain. In some embodiments, the Fc domain of a full-length SIRPy antibody is from a human IgGl, human IgG2, human IgG3, or human IgG4. In some embodiments, the Fc domain of a full-length SIRPy antibody is that of a mouse immunoglobulin. In some embodiments, the Fc domain of a full-length SIRPy antibody is that of a mouse IgGl or mouse IgG2a. In some embodiments, the Fc domain of a full-length SIRPy antibody is that of a rat. In some embodiments, the Fc domain of a full-length SIRPy antibody is from a rat IgGl or rat IgG2b. In embodiments, the Fc domain of a full-length SIRPy antibody is that of a non-human primate, e.g. it is a cynomolgus monkey Fc domain.

[0071] In some embodiments, the SIRPy antibodies provided herein comprise a Fc domain (referred to as an “Fc-containing antibody”), wherein binding of the Fc-containing antibody to a SIRPy-expressing cell can mediate effector cell-mediated depletion of the SIRPy-expressing cell. In some embodiments, the Fc domain of a SIRPy antibody is a human IgGl Fc. Exemplary, but non-limiting, sequences of heavy chain constant regions (CH) of human IgGl encompassing Fc domains of interest are provided as SEQ ID NO: 5-27, and SEQ ID NO: 36. SEQ ID NO: 5 provides the canonical human IgGl heavy chain constant region (CH) sequence. In some embodiments, the Fc domains disclosed herein comprises a terminal lysine. In some embodiments, the terminal lysine is absent or cleaved, which may occur due to post-translational modifications.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 5 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 6)331845966Attorney Docket No.: ELTH-009 / 01WO 336159-20731 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO 7)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO 8)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO 9)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO 10)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 11)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 12 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV LHEALHNHYT QKSLSLSPGK (SEQ ID NO : 13 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHSHYT QKSLSLSPGK (SEQ ID NO : 14 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV LHEALHNHYT QKSLSLSPGK (SEQ ID NO : 15 )331845966Attorney Docket No.: ELTH-009 / 01WO 336159-20731 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHSHYT QKSLSLSPGK (SEQ ID NO 16)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO 17)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO 18)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO 19)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073241 MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 20 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 21)1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 22 )

[0072] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 23, wherein XI is V or A.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKXiEP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 23 )

[0073] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 24, wherein XI is V or A; X2 is G or A; X3 is S or D; and X4 is I or E.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKXiEP KSCDKTHTCP PCPAPELLX2G 121 PX3VFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPX4EKTIS KAKGQPREPQ VYTLPPSRDE28331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 24)

[0074] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 25, wherein XI is V or A.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKXiEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCWVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV LHEALHSHYT QKSLSLSPGK (SEQ ID NO : 25)

[0075] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 26, wherein XI is V or A; X2 is M or L; and X3 is N or S.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKXiEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCWVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV X2HEALHX3HYT QKSLSLSPGK (SEQ ID NO : 26)

[0076] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 27, wherein XI is K or R; X2 is D or E; and X3 is L or M.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKXiVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMISRTP EVTCWVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRX2E 241 X3TKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO : 27 )

[0077] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 36, and comprises L234A, L235A, P329G substitutions (referred to as LALA-PG substitutions).29331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 36)

[0078] In some embodiments, the Fc domain of a Fc-containing SIRPy antibody is a human IgG4 Fc. Exemplary, but non-limiting, sequences of heavy chain constant regions (CH) of human IgG4 encompassing Fc domains of interest are provided as SEQ ID NO: 28-35. SEQ ID NO: 28 provides the canonical human IgG4 heavy chain constant region (CH) sequence. ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK (SEQ ID NO: 28 ) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK (SEQ ID NO: 29) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFEGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK (SEQ ID NO: 30) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL30331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK (SEQ ID NO: 31 ) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEALGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK (SEQ ID NO: 32 ) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEAAGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK (SEQID NO: 33) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFAGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK (SEQ ID NO: 34 )

[0079] In some embodiments, the constant region of human IgG4 heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 35, wherein XI is S or P; AND X2 is L or E.ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPX1CPAPEFX2GGPSVFL FPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLGK (SEQ ID NO: 35)

[0080] In some embodiments, the SIRPy antibodies provided herein comprise a human variable region and a human constant region. In exemplary embodiments, the human constant region comprises sequences from human IgGl, human IgG2, human IgG3, or human IgG4.31331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0081] The EU numbering scheme is one of many available antibody numbering schemes based on the residue numbers assigned to a canonical antibody sequence. Accordingly, a skilled artisan would understand that reference to a particular residue using the EU numbering scheme may or may not be exactly the residue in one of the SIRPy antibodies of the disclosure. For example, if a SIRPy antibody of the disclosure comprises a V215A substitution in the Fc region of the heavy chain, wherein the position number of the amino acid residue is of the EU numbering scheme, the residue may not be the actual residue 215 in that particular SIRPy antibody. It may be actual residue number 213, or 214, or 215, or 216 or others. Accordingly, a skilled artisan will understand how to correspond the recited residue using the EU numbering scheme, to the actual residue in a SIRPy antibody of the disclosure. The EU numbering system for antibodies is known in the art and is described, for example, at imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html.

[0082] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 5), and heavy chain Fc substitutions are introduced to increase effector function (e.g. those that exhibit increased affinity to FcyR or promote complement protein binding).

[0083] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 5), and heavy chain Fc substitutions are introduced to decrease effector function (e.g. silence).

[0084] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 5), and heavy chain Fc substitutions are introduced to increase antibody half-life.

[0085] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 28), and heavy chain Fc substitutions are introduced to increase effector function (e.g. those that exhibit increased affinity to FcyR or promote complement protein binding).

[0086] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 28), and heavy chain Fc substitutions are introduced to decrease effector function (e.g. silence).

[0087] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 28), and heavy chain Fc substitutions are introduced to increase antibody half-life.32331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0088] In some embodiments, the Fc domain of a SIRPy antibody is an IgGl Fc domain (e.g. the Fc domain from any one of the IgGl constant heavy chain sequences of SEQ ID NOS: 5-27, 36) or is an IgG4 human Fc domain (e.g. the Fc domain from any one of the IgG4 constant heavy chain sequences of SEQ ID NOS: 28-35).

[0089] In some embodiments, the Fc domain of a SIRPy antibody is an IgGl Fc domain (e.g. the Fc domain from any one of the IgGl constant heavy chain sequences of SEQ ID NOS: 5-27, or 36) or is an IgG4 human Fc domain (e.g. the Fc domain from any one of the IgG4 constant heavy chain sequences of SEQ ID NOS: 28, 29 or 35), and comprises at least one amino acid substitution in the heavy chain at a position selected from the group consisting of: 214, 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 356, 358, 396, 428, 430, 433, 434, and 440 wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0090] In some embodiments, the Fc domain of a SIRPy antibody is from heavy chain SEQ ID NOS: 5-27, or 36, optionally with one or more heavy chain Fc amino acid substitutions, for example at least one amino acid substitution at a position selected from the group consisting of: 214, 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 356, 358, 396, 428, 430, 433, 434, and 440 wherein the position numbers of the amino acid residues are of the EU numbering scheme. Exemplary substitutions include one or more of K214R, V215A, G236A, S239D, I332E, D356E, L358M, M428L, N434S, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0091] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 5-27, or 36), and heavy chain Fc substitutions are introduced to, among other effects, increase effector function (e.g. one or more of FcR binding on an immune effector cell, and binding to complement Clq), selected from the group consisting of V215A, G236A, S239D, I332E, G236A / S239D, G236A / I332E, S239D / I332E, V215A / G236A / S239D / I332E, G236A / S239D / I332E, V215A / G236A / S239D / I332E, K326W / E333S, S267E / H268F / S324T, E345R, E430G, E345K, S440Y, K326W, E333S, S267E, H268F, S324T, and E345R / E430G / S440Y, F243L / R292P / Y300L / V305I / P396L, S239D / I332E, S298A / E333A / K334A,33331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073L234Y / L235Q / G236W / S239M / H268D / D270E / S298A, and D270E / K326D / A330M / K334E wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0092] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 5-27, or 36), and heavy chain Fc substitutions are introduced to reduce (e.g. silence) effector function, including one or more of N297A, N297Q, N297G, L235E, L234A, L235A, K214R, P329G, D356E, and L358M, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0093] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 36), and heavy chain Fc substitutions are introduced to reduce effector function (e.g. silence), including L234A, L235A, and P329G, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0094] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NOS: 28, 29 or 35), and heavy chain Fc substitutions are introduced to reduce effector function, including one or more of L235E, and F234A / L235A, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0095] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgG2 constant heavy chain, and heavy chain Fc substitutions are introduced to reduce effector function, including H268Q / V309L / A330S / P331S and V234A / G237A / P238S / H268A / V309L / A330S / P331S, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0096] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 28), and the antibody is prone to the dynamic process of Fab-arm exchange. Accordingly, in some embodiments the IgG4 heavy chain Fc domain comprises a S228P substitution, resulting in the reduction of Fab-arm exchange, wherein the position number of the amino acid residues are of the EU numbering scheme.

[0097] In some embodiments, the Fc domain of a SIRPy antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 28, 29 or 35), and one or more of the following heavy chain Fc substitution are introduced to reduce effector function: L235A, L235E, S228P, L235E / S228P, S228P / F234A, S228P / F234A / L235A, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0098] In other embodiments, the Fc domain of a SIRPy antibody is altered to increase its serum half-life. Such alterations include heavy chain Fc substitutions of a human IgGl, IgG2,34331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073IgG3 or IgG4 such as M428L, N343S, T250Q / M428L, M252Y / S254T / T256E, M428L / N434S, S267E / L328F, N325S / L328F, and H433K / N434F, wherein the position number of the amino acid residues are of the EU numbering scheme.

[0099] In some embodiments the SIRPy antibody comprises a light chain constant region, in addition to the SIRPy antigen-binding light chain variable region, for example the exemplary CDR-containing light chain variable regions provided in Table 2. Exemplary light chain constant region amino acid sequences are provided in SEQ ID NOS: 38-42.

[0100] In some embodiments, the SIRPy antibody contains a kappa light chain constant region. An exemplary kappa light chain constant region is provided as SEQ ID NO: 38. RTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 38 )

[0101] In some embodiments, the SIRPy antibody contains a lambda light chain constant region. Exemplary lambda light chain constant regions are provided as SEQ ID NO: 39-41. GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQS NNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 39) GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQS NNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 40) GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQS NNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 41 ) GQPKAAPSVTLFPPSSEELQANKATLVCLVSDFNPGAVTVAWKADGSPVKVGVETTKPSKQS NNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPAECS (SEQ ID NO: 42 )

[0102] In some embodiments the SIRPy antibody comprises a light chain constant region and heavy chain constant region, in addition to the SIRPy antigen-binding light and heavy chain variable regions, for example the exemplary CDR-containing light chain and heavy chain variable regions provided in Table 2. Exemplary light chain constant region amino acid sequences of the disclosure are provided in SEQ ID NOS: 38-42; and exemplary heavy chain constant region amino acid sequences of the disclosure are provided in SEQ ID NOS: 5-36.

[0103] In exemplary embodiments, the SIRPy antibodies provided herein are monoclonal antibodies (mAbs). In exemplary embodiments, the SIRPy antibodies provided herein are human antibodies. In exemplary embodiments, the SIRPy antibodies provided herein are 35331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073humanized antibodies. In exemplary embodiments, the SIRPy antibodies provided herein are monoclonal human antibodies, or monoclonal humanized antibodies. In some embodiments, the SIRPy antibody is provided as an antibody fragment.

[0104] Also provided herein are SIRPy antibody-drug conjugates, bispecific antibodies comprising at least one arm specific for SIRPy, and multispecific antibodies that exhibit binding for SIRPy.

[0105] In some embodiments, the SIRPy antibody-drug conjugates of the disclosure comprise a SIRPy antibody described herein and a therapeutic agent.

[0106] In some embodiments, the bispecific antibodies of the disclosure comprise a SIRPy antibody described herein. In some embodiments, the multispecific antibodies of the disclosure comprise a SIRPy antibody described herein.i. Exemplary SIRPY Antibodies - CDR Sequences

[0107] Provided herein are sequences for exemplary SIRPy antibodies of the disclosure. Included are complementarity determining region (CDR) sequences and the variable heavy chain domain (VH) and variable light chain domain (VL) sequences that constitute the SIRPy antigen binding domains of the disclosure.

[0108] As referred below, a light chain variable domain (VL) CDR1 region is referred to as CDR-L1; a VL CDR2 region is referred to as CDR-L2; a VL CDR3 region is referred to as CDR-L3; a heavy chain variable domain (VH) CDR1 region is referred to as CDR-H1; a VH CDR2 region is referred to as CDR-H2; and a VH CDR3 region is referred to as CDR-H3. Table 1 provides 47 exemplary CDR combinations of SIRPy antibodies of the disclosure. Table 1: Exemplary SIRPy Antibody CDR Combinations331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207337331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0109] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 100, SEQ ID NO: 138, SEQ ID NO: 167; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 209, SEQ ID NO: 245, and SEQ ID NO: 277.

[0110] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 101, SEQ ID NO: 139, SEQ ID NO: 168; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 210, SEQ ID NO: 246, and SEQ ID NO: 278.[OHl] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 102, SEQ ID NO: 140, SEQ ID NO: 169; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 211, SEQ ID NO: 247, and SEQ ID NO: 279.44331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0112] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 103, SEQ ID NO: 141, SEQ ID NO: 170; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 212, SEQ ID NO: 248, and SEQ ID NO: 280.

[0113] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 104, SEQ ID NO: 141, SEQ ID NO: 171; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 281.

[0114] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 105, SEQ ID NO: 142, SEQ ID NO: 172; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 214, SEQ ID NO: 250, and SEQ ID NO: 282.

[0115] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 106, SEQ ID NO: 143, SEQ ID NO: 173; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 215, SEQ ID NO: 251, and SEQ ID NO: 283.

[0116] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 106, SEQ ID NO: 144, SEQ ID NO: 174; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 216, SEQ ID NO: 252, and SEQ ID NO: 284.

[0117] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 107, SEQ ID NO: 141, SEQ ID NO: 175; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 217, SEQ ID NO: 253, and SEQ ID NO: 285.

[0118] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-45331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073terminus): SEQ ID NO: 108, SEQ ID NO: 144, SEQ ID NO: 176; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 216, SEQ ID NO: 254, and SEQ ID NO: 286.

[0119] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 109, SEQ ID NO: 145, SEQ ID NO: 171; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 218, SEQ ID NO: 255, and SEQ ID NO: 287.

[0120] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 110, SEQ ID NO: 146, SEQ ID NO: 177; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 219, SEQ ID NO: 249, and SEQ ID NO: 288.

[0121] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 111, SEQ ID NO: 147, SEQ ID NO: 178; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 220, SEQ ID NO: 256, and SEQ ID NO: 289.

[0122] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 112, SEQ ID NO: 148, SEQ ID NO: 179; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 290.

[0123] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 113, SEQ ID NO: 143, SEQ ID NO: 180; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 221, SEQ ID NO: 257, and SEQ ID NO: 291.

[0124] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 106, SEQ ID NO: 149, SEQ ID NO: 181; and / or comprises the331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 222, SEQ ID NO: 258, and SEQ ID NO: 292.

[0125] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 114, SEQ ID NO: 150, SEQ ID NO: 182; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 223, SEQ ID NO: 250, and SEQ ID NO: 293.

[0126] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 115, SEQ ID NO: 151, SEQ ID NO: 183; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 219, SEQ ID NO: 259, and SEQ ID NO: 294.

[0127] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 116, SEQ ID NO: 152, SEQ ID NO: 184; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 224, SEQ ID NO: 260, and SEQ ID NO: 295.

[0128] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 117, SEQ ID NO: 153, SEQ ID NO: 185; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 216, SEQ ID NO: 261, and SEQ ID NO: 296.

[0129] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 118, SEQ ID NO: 143, SEQ ID NO: 186; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 222, SEQ ID NO: 262, and SEQ ID NO: 297.

[0130] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 119, SEQ ID NO: 154, SEQ ID NO: 187; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 225, SEQ ID NO: 250, and SEQ ID NO: 298.47331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0131] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 120, SEQ ID NO: 140, SEQ ID NO: 188; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 226, SEQ ID NO: 263, and SEQ ID NO: 299.

[0132] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 121, SEQ ID NO: 141, SEQ ID NO: 189; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 227, SEQ ID NO: 264, and SEQ ID NO: 300.

[0133] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 122, SEQ ID NO: 155, SEQ ID NO: 190; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 228, SEQ ID NO: 249, and SEQ ID NO: 301.

[0134] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 123, SEQ ID NO: 143, SEQ ID NO: 186; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 229, SEQ ID NO: 265, and SEQ ID NO: 302.

[0135] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 124, SEQ ID NO: 143, SEQ ID NO: 191; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 216, SEQ ID NO: 266, and SEQ ID NO: 303.

[0136] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 106, SEQ ID NO: 156, SEQ ID NO: 192; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 230, SEQ ID NO: 249, and SEQ ID NO: 304.

[0137] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-48331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073terminus): SEQ ID NO: 106, SEQ ID NO: 145, SEQ ID NO: 193; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 231, SEQ ID NO: 267, and SEQ ID NO: 305.

[0138] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 125, SEQ ID NO: 143, SEQ ID NO: 194; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 232, SEQ ID NO: 268, and SEQ ID NO: 306.

[0139] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 126, SEQ ID NO: 157, SEQ ID NO: 195; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 233, SEQ ID NO: 269, and SEQ ID NO: 307.

[0140] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 127, SEQ ID NO: 155, SEQ ID NO: 196; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 234, SEQ ID NO: 249, and SEQ ID NO: 308.

[0141] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 128, SEQ ID NO: 158, SEQ ID NO: 197; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 235, SEQ ID NO: 270, and SEQ ID NO: 309.

[0142] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 129, SEQ ID NO: 159, SEQ ID NO: 198; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 226, SEQ ID NO: 271, and SEQ ID NO: 310.

[0143] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 106, SEQ ID NO: 143, SEQ ID NO: 199; and / or comprises the331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 236, SEQ ID NO: 272, and SEQ ID NO: 311.

[0144] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 130, SEQ ID NO: 155, SEQ ID NO: 200; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 237, SEQ ID NO: 249, and SEQ ID NO: 312.

[0145] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 131, SEQ ID NO: 141, SEQ ID NO: 201; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 238, SEQ ID NO: 264, and SEQ ID NO: 313.

[0146] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 132, SEQ ID NO: 140, SEQ ID NO: 202; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 239, SEQ ID NO: 273, and SEQ ID NO: 314.

[0147] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 109, SEQ ID NO: 143, SEQ ID NO: 203; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 240, SEQ ID NO: 250, and SEQ ID NO: 315.

[0148] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 133, SEQ ID NO: 160, SEQ ID NO: 191; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 241, SEQ ID NO: 274, and SEQ ID NO: 316.

[0149] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 134, SEQ ID NO: 161, SEQ ID NO: 204; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 242, SEQ ID NO: 275, and SEQ ID NO: 317.50331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0150] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 135, SEQ ID NO: 162, SEQ ID NO: 189; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 216, SEQ ID NO: 249, and SEQ ID NO: 318.

[0151] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 129, SEQ ID NO: 155, SEQ ID NO: 205; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 226, SEQ ID NO: 276, and SEQ ID NO: 319.

[0152] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 131, SEQ ID NO: 163, SEQ ID NO: 206; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 219, SEQ ID NO: 267, and SEQ ID NO: 320.

[0153] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 136, SEQ ID NO: 164, SEQ ID NO: 207; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 243, SEQ ID NO: 249, and SEQ ID NO: 321.

[0154] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 131, SEQ ID NO: 165, SEQ ID NO: 208; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 213, SEQ ID NO: 269, and SEQ ID NO: 322.

[0155] In some embodiments, provided herein is a SIRPy antibody, wherein the antibody comprises the amino acid sequences of the following three VL CDRs (from N-terminus to C-terminus): SEQ ID NO: 137, SEQ ID NO: 166, SEQ ID NO: 169; and / or comprises the amino acid sequences of the following three VH CDRs (from N-terminus to C-terminus): SEQ ID NO: 244, SEQ ID NO: 256, and SEQ ID NO: 323.

[0156] Also included are variants of the foregoing CDRs that do no alter binding to SIRPy. In some embodiments, variants have 1, 2, 3, 4, or 5 modifications (e.g. substitutions,51331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073additions, and / or deletions) in any one or more of the individual CDRs, for example, any one or more the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or CDR-L3 provided in the foregoing.ii. Exemplary SIRPy Antibodies - Variable Region Sequences

[0157] The term variable domain and variable region are used interchangeably and refer to the portions of the light and heavy chains of an antibody that include the complementarity determining regions and framework regions (FRs).

[0158] Table 2 provides amino acid sequences for the variable domains of exemplary SIRPy antibodies of the disclosure. Accordingly, in some embodiments a SIRPy antibody of the disclosure comprises a heavy chain variable domain (VH) comprising an amino acid sequence selected from SEQ ID NOS: 324-370, or at least 80% sequence identity thereto; and / or in some embodiments a SIRPy antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence selected from SEQ ID NOS: 371- 417, or at least 80% sequence identity thereto.

[0159] In some embodiments, a SIRPy antibody of the disclosure comprises the combination of VH / VL amino acid sequences of any one of the 47 combinations presented in Table 2.Table 2: Exemplary Heavy Chain Variable Domain and Light Chain Variable Domain Amino Acid Sequence Combinations of SIRPy Antibodies52331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207353331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207354331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207355331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207356331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207357331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207358331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207359331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0100]

[0160] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 324 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 371, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0161] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 325 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID 60331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073NO: 372, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0162] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 373, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0163] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 374, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0164] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 375, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0165] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%,61331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207378%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 376, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0166] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 330 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 377, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0167] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 331 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 378, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0168] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 332 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 379, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.62331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0169] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 333 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 380, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0170] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 381, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0171] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 382, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0172] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID 63331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073NO: 383, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0173] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 384, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0174] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 338 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 385, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0175] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 339 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 386, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0176] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 340 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%,64331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207378%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 387, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0177] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 341 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 388, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0178] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 389, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0179] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 390, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.65331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0180] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 391, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0181] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 392, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0182] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 346 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 393, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0183] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 347 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID 66331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073NO: 394, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0184] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 348 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 395, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0185] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 349 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 396, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0186] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 397, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0187] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%,67331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207378%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 398, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0188] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 399, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0189] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 400, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0190] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 354 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 401, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.68331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0191] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 355 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 402, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0192] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 356 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 403, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0193] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 357 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 404, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0194] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID 69331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073NO: 405, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0195] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 406, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0196] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 407, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0197] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 408, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0198] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 362 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%,70331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207378%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 409, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0199] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 363 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 410, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0200] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 364 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 411, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0201] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 365 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 412, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.71331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0202] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 413, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0203] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 414, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0204] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 415, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0205] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID 72331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073NO: 416, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0206] In some embodiments, provided herein is a SIRPy antibody, wherein the heavy chain variable domain (VH) of the antibody comprises the amino acid sequence of SEQ ID NO: 370 or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable domain (VL) of the antibody comprises the amino acid sequence of SEQ ID NO: 417, or an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0207] Also included are variants thereof, for example, variants having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 modifications (e.g. substitutions, additions, and / or deletions) in one or more framework regions of any one or more of the foregoing VH and / or VL sequences.

[0208] By way of explanation, making reference to Tables 1 and 2, forty-seven (47) combinations of unique antibody sequences are provided (CDR sequences in Table 1; VH / VL sequences in Table 2). By way of example, and guidance to read the tables: Antibodies 1, 3, 4, 7, and 110 share the same combination of CDR sequences and also share the same combination of VH / VL sequences, but differ in some other aspect, e.g. may have different Fc regions. Likewise, it is noted that Antibodies 2, 5, 6, 8, and 111 share the same combination of CDR sequences and also share the same combination of VH / VL sequences but differ in some other aspect, e.g. may have different Fc regions.

[0209] Antibodies 1 and 2 comprise a rat IgG2b Fc.

[0210] Antibodies 3, 5, and 83-97 comprise a human IgGl Fc of the disclosure.

[0211] Antibodies 4, 6, and 54-82 comprise a human IgGl Fc of the disclosure comprising certain substitutions that lead to increased effector function, exhibiting increased affinity to FcyR.

[0212] Antibodies 7 and 8 comprise a human IgG4 Fc of the disclosure comprising certain substitutions that lead to a decrease in the dynamic process of Fab-arm exchange, and further reduced effector function.73331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0213] Antibodies 98-111 comprise a human IgGl Fc of the disclosure comprising certain substitutions that lead to reduced effector function, leading to the silencing of the Fc (e.g. can comprise the LALA-PG substitutions).II. Therapeutic SIRPy Antibodies

[0214] As discussed in the preceding section, provided herein are antibodies that recognize and bind to SIRPy. In some embodiments the antibody does not disrupt the binding of CD47 to SIRPy. In some embodiments, the antibody shows increased binding to activated SIRPy-expressing cells. The antibodies disclosed herein may be used as therapeutics in a subject suffering from one or more granulomatous diseases and disorders.

[0215] Accordingly, provided herein are methods of treating one or more granulomatous diseases or disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a SIRPy antibody of the disclosure, or a pharmaceutical composition thereof. In some embodiments, the subject is a mammalian subject. In some embodiments, the mammalian subject is a human subject. In some embodiments, the mammalian subject is a non-human primate, e.g. a cynomolgus monkey. In some embodiments, the mammalian subject is a model organism, e.g. a mouse, whereas treatment effects are modeled. An exemplary model includes a mouse GCA model.

[0216] In some embodiments of the methods of treating one or more granulomatous diseases or disorders in a subject in need thereof, the SIRPy antibody comprises a means for binding human SIRPy. In some embodiments, the SIRPy antibody comprises a means for not binding human SIRPa. In some embodiments, the SIRPy antibody comprises a means for not binding human SIRPp. In certain embodiments, the SIRPy antibody comprises (i) a means for not binding human SIRPa and (ii) a means for not binding human SIRPp. In certain embodiments, the SIRPy antibody comprises (i) a means for binding human SIRPy and (ii) a means for not binding human SIRPa. In certain embodiments, the SIRPy antibody comprises (i) a means for binding human SIRPy and (ii) a means for not binding human SIRPp. In certain embodiments, the SIRPy antibody comprises (i) a means for binding human SIRPy, (ii) a means for not binding human SIRPa, and (iii) a means for not binding human SIRPp.

[0217] In some embodiments, the SIRPy antibody comprises a means for disrupting the binding of CD47 to SIRPy on a cell or other surface. In some embodiments, the SIRPy antibody comprises a means for enhancing or promoting the binding of CD47 to SIRPy on a cell or other surface.74331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0218] In some embodiments, the SIRPy antibodies provided herein are useful for depleting a population of SIRPy-expressing cells in the subject, for the treatment of a granulomatous disease or disorder. In some embodiments, the population of SIRPy-expressing cells comprises tissue-resident cells. In some embodiments, the population of SIRPy-expressing cells comprises circulating cells. In some embodiments, the SIRPy-expressing cell is a T cell, a B cell, or aNK cell.

[0219] In some embodiments, the SIRPy-expressing cell is in an activated state. Without being held to any theory or mechanism, the SIRPy antibodies of the disclosure may be used to preferentially deplete pathogenic, activated T cells (or other cells) sparing naive T cell (or other cells), allowing for the maintenance of immune surveillance.

[0220] In some embodiments, the SIRPy-expressing cell is a T cell.

[0221] In certain embodiments, the T cell is activated (stimulated). In exemplary embodiments, the T cell is activated (stimulated), and the depletion is preferential for activated (stimulated) T cells.

[0222] In certain embodiments, the T cell is exhausted. In exemplary embodiments, the T cell is exhausted, and the depletion is preferential for exhausted T cells.

[0223] In some embodiments, the T cell is a naive, central memory, effector memory, exhausted, or terminal effector memory cell. In some embodiments, the T cell is a cytotoxic T cell, helper T cell, memory T cell, regulatory T cell, natural killer T cell, mucosal associated invariant T cell, alpha beta T cell, or gamma delta T cell. In certain embodiments, the T cell is a Thl cell, Th2 cell, Thl7 cell or T follicular helper cell.

[0224] In some embodiments, the T cell is a CD3+ T cell, CD4+ T cell, CD8+ T cell, CD25+ T cell, CD69+ T cell, and / or PD1+ T cell. In certain embodiments, the T cell is CD4+ / CD8+ T cells. In certain embodiments, the T cell is CD69+ / CD8+ T cells. In certain embodiments, the T cell is CD25+ / CD8+ T cells. In certain embodiments, the T cell is PD1+ T cells.

[0225] In some embodiments, the depletion is preferential for stimulated T cells, as compared to unstimulated T cells. In some embodiments, the depletion is preferential for SIRPy-expressing CD8+ T cells. In some embodiments, the depletion is preferential for SIRPy-expressing CD4+ T- cells. In some embodiments, the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T- cells. In some embodiments, the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T- cells.75331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0226] In some embodiments, the depletion is preferential for SIRPy-expressing CD8+ T cells, when compared to SIRPy-expressing CD4+ T- cells. In other embodiments, the depletion is preferential for SIRPy-expressing CD4+ T cells, when compared to SIRPy-expressing CD8+ T- cells.

[0227] In some embodiments, the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T cells, when compared to SIRPy-expressing CD8+ / CD69- T- cells.

[0228] In some embodiments, the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T cells, when compared to SIRPy-expressing CD8+ / CD25- T- cells.

[0229] In some embodiments, the SIRPy-expressing cells are B cells.

[0230] In some embodiments, the SIRPy-expressing cells are NK cells.

[0231] In some embodiments, the SIRPy-expressing cells are activated.

[0232] In some embodiments the SIRPy-expressing cell expresses one or more isoforms of SIRPy. In some embodiments, a therapeutically effective amount of the antibody or the pharmaceutical composition is sufficient to deplete a population of SIRPy-expressing cells in the subject, e.g. by ADCC, ADCP, and / or CDC. In some embodiments, the SIRPy-expressing cells are tissue resident cells. In other embodiments, the SIRPy-expressing cells are circulating. In some embodiments, the cell depletion is antibody dose-dependent.

[0233] Also disclosed herein is a use of an antibody for the treatment of a granulomatous disease or disorder in a subject in need thereof, where the antibody is specific for SIRPy.

[0234] Also disclosed herein is a use of an antibody for the manufacture of a medicament for the treatment of granulomatous disease or disorder in a subject in need thereof, where the antibody is specific for SIRPy.

[0235] In some embodiments of the uses of the disclosure, the disease or disorder is a granulomatous disease or disorder. In certain embodiments, the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with polyangiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded 76331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073Neutrophilic Granulomatous Dermatitis. In exemplary embodiments, the granulomatous disease or disorder is giant cell arteritis (GCA). In some embodiments of the uses of the disclosure, the subject is a human.III. Granulomatous diseases and disorders

[0236] The SIRPy antibodies provided herein are useful for the treatment of a granulomatous disease or disorder. Provided herein are methods of treating one or more granulomatous diseases or disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a SIRPy antibody of the disclosure, or a pharmaceutical composition thereof. In some embodiments, the granulomatous disease or disorder is selected from the group consisting of: giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with poly angiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease) and Palisaded Neutrophilic Granulomatous Dermatitis. In exemplary embodiments, the granulomatous disease or disorder is giant cell arteritis (GCA).IV. Combination therapies

[0237] Any of the anti-SIRPy antibodies provided herein may be administered alone or in combination with one or more additional therapeutic agents or treatment modalities. In some embodiments, an anti-SIRPy antibody of the disclosure is co-administered with an antiinflammatory agent, an immunosuppressant, a cytokine inhibitor, a chemotherapeutic agent, or any other drug that modulates immune responses or disease pathology. The agents may be administered simultaneously, sequentially, or in a time-staggered manner, either as part of a fixed-dose regimen or as separate formulations.

[0238] In some embodiments, an anti-SIRPy antibody of the disclosure is administered in combination with a glucocorticoid such as dexamethasone, prednisone, prednisolone, or methylprednisolone. In some embodiments, an anti-SIRPy antibody of the disclosure is administered in combination with a cytokine inhibitor, including but not limited to anti-IL-6 receptor inhibitors (e.g., tocilizumab, sarilumab) and / or anti-IL-ip or IL-1 receptor inhibitors 77331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073(e.g., canakinumab, anakinra). In some embodiments, an anti-SIRPy antibody of the disclosure is administered in combination with immune suppressants or modulators, such as methotrexate.V. Administration

[0239] The administration of the therapeutic SIRPy antibodies described herein may be carried out intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, intrathecally, intraventricularly, intranasally, transmucosally, through implantation, or through inhalation. Intravenous administration may be carried out via injection or infusion. In some embodiments, the SIRPy antibodies of the disclosure are administered intravenously. In some embodiments, the SIRPy antibodies of the disclosure are administered intraperitoneally. In some embodiments, the SIRPy antibodies of the disclosure are administered subcutaneously. Administration of the therapeutic SIRPy antibodies may be performed with any suitable excipients, carriers, or other agents to provide suitable or improved tolerance, transfer, delivery, and the like.

[0240] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0241] All documents, or portions of documents, cited herein, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. In the event that one or more of the incorporated documents or portions of documents define a term that contradicts that term’s definition in the application, the definition that appears in this application controls. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment, or any form of suggestion, that they constitute valid prior art or form part of the common general knowledge in any country in the world.

[0242] Any of the aspects and embodiments described herein can be combined with any other aspect or embodiment as disclosed here in the Summary, in the Drawings, and / or in the Detailed Description, including the below specific, non-limiting, examples / embodiments of the present disclosure.

[0243] The disclosure is further illustrated by the following examples that should not be construed as limiting. The contents of all references, patents and published patent78331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073applications cited throughout this application, as well as the Figures, are incorporated herein by reference for all purposes.EXEMPLARY EMBODIMENTS

[0244] Embodiment 1-1. A method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an antibody that is specific for SIRPy.

[0245] Embodiment 1-2. The method of embodiment 1-1, wherein the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with poly angiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis. In exemplary embodiments, the granulomatous disease or disorder is giant cell arteritis (GCA).

[0246] Embodiment 1-3. The method of embodiment 1-1 or 1-2, wherein the granulomatous disease or disorder is giant cell arteritis (GCA).

[0247] Embodiment 1-4. The method of any one of embodiments 1-1 to 1-3, wherein the antibody comprises:a) the three VL CDRs of amino acid sequences of SEQ ID NO: 100, SEQ ID NO: 138, SEQ ID NO: 167, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 209, SEQ ID NO: 245, and SEQ ID NO: 277; b) the three VL CDRs of amino acid sequences of SEQ ID NO: 101, SEQ ID NO: 139, SEQ ID NO: 168, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 210, SEQ ID NO: 246, and SEQ ID NO: 278; c) the three VL CDRs of amino acid sequences of SEQ ID NO: 102, SEQ ID NO: 140, SEQ ID NO: 169, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 211, SEQ ID NO: 247, and SEQ ID NO: 279;79331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073d) the three VL CDRs of amino acid sequences of SEQ ID NO: 103, SEQ ID NO: 141, SEQ ID NO: 170, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 212, SEQ ID NO: 248, and SEQ ID NO: 280; e) the three VL CDRs of amino acid sequences of SEQ ID NO: 104, SEQ ID NO: 141, SEQ ID NO: 171, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 281; f) the three VL CDRs of amino acid sequences of SEQ ID NO: 105, SEQ ID NO: 142, SEQ ID NO: 172, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 214, SEQ ID NO: 250, and SEQ ID NO: 282; g) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 143, SEQ ID NO: 173, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 215, SEQ ID NO: 251, and SEQ ID NO: 283; h) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 144, SEQ ID NO: 174, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 252, and SEQ ID NO: 284; i) the three VL CDRs of amino acid sequences of SEQ ID NO: 107, SEQ ID NO: 141, SEQ ID NO: 175, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 217, SEQ ID NO: 253, and SEQ ID NO: 285; j) the three VL CDRs of amino acid sequences of SEQ ID NO: 108, SEQ ID NO: 144, SEQ ID NO: 176, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 254, and SEQ ID NO: 286; k) the three VL CDRs of amino acid sequences of SEQ ID NO: 109, SEQ ID NO: 145, SEQ ID NO: 171, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 218, SEQ ID NO: 255, and SEQ ID NO: 287; l) the three VL CDRs of amino acid sequences of SEQ ID NO: 110, SEQ ID NO: 146, SEQ ID NO: 177, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 249, and SEQ ID NO: 288; m) the three VL CDRs of amino acid sequences of SEQ ID NO: 111, SEQ ID NO: 147, SEQ ID NO: 178, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 220, SEQ ID NO: 256, and SEQ ID NO: 289; n) the three VL CDRs of amino acid sequences of SEQ ID NO: 112, SEQ ID NO: 148, SEQ ID NO: 179, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 290;80331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073o) the three VL CDRs of amino acid sequences of SEQ ID NO: 113, SEQ ID NO: 143, SEQ ID NO: 180, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 221, SEQ ID NO: 257, and SEQ ID NO: 291; p) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 149, SEQ ID NO: 181, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 258, and SEQ ID NO: 292; q) the three VL CDRs of amino acid sequences of SEQ ID NO: 114, SEQ ID NO: 150, SEQ ID NO: 182, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 223, SEQ ID NO: 250, and SEQ ID NO: 293; r) the three VL CDRs of amino acid sequences of SEQ ID NO: 115, SEQ ID NO: 151, SEQ ID NO: 183, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 259, and SEQ ID NO: 294; s) the three VL CDRs of amino acid sequences of SEQ ID NO: 116, SEQ ID NO: 152, SEQ ID NO: 184, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 224, SEQ ID NO: 260, and SEQ ID NO: 295; t) the three VL CDRs of amino acid sequences of SEQ ID NO: 117, SEQ ID NO: 153, SEQ ID NO: 185, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 261, and SEQ ID NO: 296; u) the three VL CDRs of amino acid sequences of SEQ ID NO: 118, SEQ ID NO: 143, SEQ ID NO: 186, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 262, and SEQ ID NO: 297; v) the three VL CDRs of amino acid sequences of SEQ ID NO: 119, SEQ ID NO: 154, SEQ ID NO: 187, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 225, SEQ ID NO: 250, and SEQ ID NO: 298; w) the three VL CDRs of amino acid sequences of SEQ ID NO: 120, SEQ ID NO: 140, SEQ ID NO: 188, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 263, and SEQ ID NO: 299; x) the three VL CDRs of amino acid sequences of SEQ ID NO: 121, SEQ ID NO: 141, SEQ ID NO: 189, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 227, SEQ ID NO: 264, and SEQ ID NO: 300; y) the three VL CDRs of amino acid sequences of SEQ ID NO: 122, SEQ ID NO: 155, SEQ ID NO: 190, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 228, SEQ ID NO: 249, and SEQ ID NO: 301;81331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073z) the three VL CDRs of amino acid sequences of SEQ ID NO: 123, SEQ ID NO: 143, SEQ ID NO: 186, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 229, SEQ ID NO: 265, and SEQ ID NO: 302; aa) the three VL CDRs of amino acid sequences of SEQ ID NO: 124, SEQ ID NO: 143, SEQ ID NO: 191, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 266, and SEQ ID NO: 303; bb)the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 156, SEQ ID NO: 192, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 230, SEQ ID NO: 249, and SEQ ID NO: 304; cc) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 145, SEQ ID NO: 193, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 231, SEQ ID NO: 267, and SEQ ID NO: 305; dd)the three VL CDRs of amino acid sequences of SEQ ID NO: 125, SEQ ID NO: 143, SEQ ID NO: 194, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 232, SEQ ID NO: 268, and SEQ ID NO: 306; ee) the three VL CDRs of amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 157, SEQ ID NO: 195, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 233, SEQ ID NO: 269, and SEQ ID NO: 307; ff) the three VL CDRs of amino acid sequences of SEQ ID NO: 127, SEQ ID NO: 155, SEQ ID NO: 196, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 234, SEQ ID NO: 249, and SEQ ID NO: 308; gg)the three VL CDRs of amino acid sequences of SEQ ID NO: 128, SEQ ID NO: 158, SEQ ID NO: 197, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 235, SEQ ID NO: 270, and SEQ ID NO: 309; hh)the three VL CDRs of amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 159, SEQ ID NO: 198, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 271, and SEQ ID NO: 310; ii) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO: 143, SEQ ID NO: 199, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 236, SEQ ID NO: 272, and SEQ ID NO: 311; jj) the three VL CDRs of amino acid sequences of SEQ ID NO: 130, SEQ ID NO: 155, SEQ ID NO: 200, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 237, SEQ ID NO: 249, and SEQ ID NO: 312;82331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073kk) the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 141, SEQ ID NO: 201, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 238, SEQ ID NO: 264, and SEQ ID NO: 313; 11) the three VL CDRs of amino acid sequences of SEQ ID NO: 132, SEQ ID NO: 140, SEQ ID NO: 202, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 239, SEQ ID NO: 273, and SEQ ID NO: 314; mm) the three VL CDRs of amino acid sequences of SEQ ID NO: 109, SEQ ID NO: 143, SEQ ID NO: 203, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 240, SEQ ID NO: 250, and SEQ ID NO: 315; nn)the three VL CDRs of amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 160, SEQ ID NO: 191, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 241, SEQ ID NO: 274, and SEQ ID NO: 316; oo)the three VL CDRs of amino acid sequences of SEQ ID NO: 134, SEQ ID NO: 161, SEQ ID NO: 204, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 242, SEQ ID NO: 275, and SEQ ID NO: pp)the three VL CDRs of amino acid sequences of SEQ ID NO: 135, SEQ ID NO: 162, SEQ ID NO: 189, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 249, and SEQ ID NO: 318; qq)the three VL CDRs of amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 155, SEQ ID NO: 205, and / or the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 276, and SEQ ID NO: 319; rr) comprising the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 163, SEQ ID NO: 206; and / or comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 267, and SEQ ID NO: 320;ss) comprising the three VL CDRs of amino acid sequences of SEQ ID NO: 136, SEQ ID NO: 164, SEQ ID NO: 207; and / or comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 243, SEQ ID NO: 249, and SEQ ID NO: 321;tt) comprising the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 165, SEQ ID NO: 208; and / or comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 269, and SEQ ID NO: 322; or83331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073uu) comprising the three VL CDRs of amino acid sequences of SEQ ID NO: 137, SEQ ID NO: 166, SEQ ID NO: 169; and / or comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 244, SEQ ID NO: 256, and SEQ ID NO: 323.

[0248] Embodiment 1-5. The method of embodiments 1-1 to 1-4, wherein:a) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 324 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 371, or an amino acid sequence with at least 70% sequence identity thereto;b) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 325 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 372, or an amino acid sequence with at least 70% sequence identity thereto;c) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 373, or an amino acid sequence with at least 70% sequence identity thereto;d) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 374, or an amino acid sequence with at least 70% sequence identity thereto;e) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 375, or an amino acid sequence with at least 70% sequence identity thereto;f) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of 84331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073SEQ ID NO: 376, or an amino acid sequence with at least 70% sequence identity thereto;g) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 330 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 377, or an amino acid sequence with at least 70% sequence identity thereto;h) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 331 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 378, or an amino acid sequence with at least 70% sequence identity thereto;i) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 332 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 379, or an amino acid sequence with at least 70% sequence identity thereto;j) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 333 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 380, or an amino acid sequence with at least 70% sequence identity thereto;k) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 381, or an amino acid sequence with at least 70% sequence identity thereto;l) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 382, or an amino acid sequence with at least 70% sequence identity thereto;85331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073m) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 383, or an amino acid sequence with at least 70% sequence identity thereto;n) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 384, or an amino acid sequence with at least 70% sequence identity thereto;o) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 338 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 385, or an amino acid sequence with at least 70% sequence identity thereto;p) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 339 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 386, or an amino acid sequence with at least 70% sequence identity thereto;q) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 340 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 387, or an amino acid sequence with at least 70% sequence identity thereto;r) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 341 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 388, or an amino acid sequence with at least 70% sequence identity thereto;s) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of 86331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073SEQ ID NO: 389, or an amino acid sequence with at least 70% sequence identity thereto;t) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 390, or an amino acid sequence with at least 70% sequence identity thereto;u) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 391, or an amino acid sequence with at least 70% sequence identity thereto;v) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 392, or an amino acid sequence with at least 70% sequence identity thereto;w) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 346 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 393, or an amino acid sequence with at least 70% sequence identity thereto;x) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 347 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 394, or an amino acid sequence with at least 70% sequence identity thereto;y) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 348 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 395, or an amino acid sequence with at least 70% sequence identity thereto;87331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073z) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 349 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 396, or an amino acid sequence with at least 70% sequence identity thereto;aa) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 397, or an amino acid sequence with at least 70% sequence identity thereto;bb)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 398, or an amino acid sequence with at least 70% sequence identity thereto;cc) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 399, or an amino acid sequence with at least 70% sequence identity thereto;dd)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 400, or an amino acid sequence with at least 70% sequence identity thereto;ee) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 354 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 401, or an amino acid sequence with at least 70% sequence identity thereto;ff) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 355 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of 88331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073SEQ ID NO: 402, or an amino acid sequence with at least 70% sequence identity thereto;gg)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 356 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 403, or an amino acid sequence with at least 70% sequence identity thereto;hh)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 357 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 404, or an amino acid sequence with at least 70% sequence identity thereto;ii) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 405, or an amino acid sequence with at least 70% sequence identity thereto;jj) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 406, or an amino acid sequence with at least 70% sequence identity thereto;kk)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 407, or an amino acid sequence with at least 70% sequence identity thereto;11) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 408, or an amino acid sequence with at least 70% sequence identity thereto;89331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073mm) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 362 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 409, or an amino acid sequence with at least 70% sequence identity thereto;nn)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 363 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 410, or an amino acid sequence with at least 70% sequence identity thereto;oo)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 364 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 411, or an amino acid sequence with at least 70% sequence identity thereto;pp)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 365 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 412, or an amino acid sequence with at least 70% sequence identity thereto;qq)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 413, or an amino acid sequence with at least 70% sequence identity thereto;rr) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 414, or an amino acid sequence with at least 70% sequence identity thereto;ss) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of 90331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073SEQ ID NO: 415, or an amino acid sequence with at least 70% sequence identity thereto;tt) the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 416, or an amino acid sequence with at least 70% sequence identity thereto; oruu)the VH domain of the antibody comprises the amino acid sequence of SEQ ID NO: 370 or an amino acid sequence with at least 70% sequence identity thereto, and / or the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 417, or an amino acid sequence with at least 70% sequence identity thereto.

[0249] Embodiment 1-6. The method of any one of embodiments 1-1 to 1-5, wherein the antibody is an antibody fragment.

[0250] Embodiment 1-7. The method of any one of embodiments 1-1 to 1-5, wherein the antibody is a human antibody.

[0251] Embodiment 1-8. The method of any one of embodiments 1-1 to 1-5, wherein the antibody is a humanized antibody.

[0252] Embodiment 1-9. The method of any one of embodiments 1-1 to 1-5, wherein the antibody is a full-length antibody.

[0253] Embodiment I- 10. The method of any one of embodiments 1-1 to 1-9, wherein the antibody wherein the antibody has low or no affinity for binding SIRPa and / or SIRPpi .

[0254] Embodiment 1-11. The method of any one of embodiments 1-1 to 1-10, wherein the antibody binds to human and non-human primate SIRPy with high affinity.

[0255] Embodiment 1-12. The method of any one of embodiments 1-1 to 1-10, wherein the antibody does not bind to human and non-human primate SIRPa or SIRPpi .

[0256] Embodiment 1-13. The method of any one of embodiments 1-1 to 1-12, wherein the antibody comprises a Fc domain.

[0257] Embodiment 1-14. The method of embodiment 1-13, wherein the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4 heavy chain sequence.91331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0258] Embodiment 1-15. The method of embodiment 1-14, wherein the Fc domain is from the heavy chain IgG amino acid sequences of SEQ ID NO: 5 or SEQ ID NO: 28, optionally with one or more Fc amino acid substitutions.

[0259] Embodiment 1-16. The method of embodiment 1-15, wherein the Fc domain is from the heavy chain IgG amino acid sequences of any one of SEQ ID NOS: 5-36.

[0260] Embodiment 1-17. The method embodiment 1-15, wherein the heavy chain Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 5 or SEQ ID NO: 28 at a position selected from the group consisting of: 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, and 440 wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0261] Embodiment 1-18. The method of any one of embodiments 1-1 to 1-17, wherein the antibody comprises a light chain constant region that is from the amino acid sequences of any one of SEQ ID NOS: 38-42.

[0262] Embodiment 1-19. The method of any one of embodiments 1-1 to 1-18, wherein the binding of the antibody does not disrupt the interaction between CD47 and SIRPy.

[0263] Embodiment 1-20. The method of any one of embodiments 1-1 to 1-18, wherein the binding of the antibody disrupts the interaction between CD47 and SIRPy.

[0264] Embodiment 1-21. The method of any one of embodiments 1-1 to 1-18, wherein the binding of the antibody stabilizes or promotes the interaction between CD47 and SIRPy.

[0265] Embodiment 1-22. The method comprising of anyone of embodiments 1-1 to 1-21, wherein the antibody comprises a binding affinity to SIRPy lower than about 500 nM.

[0266] Embodiment 1-23. The method of any one of embodiments 1-1 to 1-22, wherein the antibody preferentially depletes of a population of SIRPy-expressing cells.

[0267] Embodiment 1-24. The method of embodiment 1-23, wherein the SIRPy-expressing cells are T cells, B cells and / or NK cells.

[0268] Embodiment 1-25. The method of embodiment 1-23, wherein the SIRPy-expressing cells are T cells.

[0269] Embodiment 1-26. The method of embodiment 1-25, wherein the T cells are activated (stimulated).92331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0270] Embodiment 1-27. The method of embodiment 1-25, wherein the T cells are activated (stimulated), and the depletion is preferential for activated (stimulated) T cells.

[0271] Embodiment 1-28. The method of embodiment 1-25, wherein the T cells are exhausted.

[0272] Embodiment 1-29. The method of embodiment 1-25, wherein the T cells are exhausted, and the depletion is preferential for exhausted T cells.

[0273] Embodiment 1-30. The method of embodiment 1-25, wherein the T cells are naive, central memory, effector memory, exhausted, or terminal effector memory cells.

[0274] Embodiment 1-31. The method of embodiment 1-25, wherein the T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosal associated invariant T cells, alpha beta T cells, or gamma delta T cells.

[0275] Embodiment 1-32. The method of embodiment 1-25, wherein the T cells are Thl cells, Th2 cells, Thl7 cells or T follicular helper cells

[0276] Embodiment 1-33. The method of embodiment 1-25, wherein the T cells are a CD3+ T cell, CD4+ T cell, CD8+ T cell, CD25+ T cell, CD69+ T cell, and / or PD1+ T cell.

[0277] Embodiment 1-34. The method of embodiment 1-33, wherein the T cells are CD4+ / CD8+ T cells.

[0278] Embodiment 1-35. The method of embodiment 1-33, wherein the T cells are CD69+ / CD8+ T cells.

[0279] Embodiment 1-36. The method of embodiment 1-33, wherein the T cells are CD25+ / CD8+ T cells.

[0280] Embodiment 1-37. The method of embodiment 1-33, wherein the T cells are PD1+ T cells.

[0281] Embodiment 1-38. The method of embodiment 1-33, wherein the depletion is preferential for stimulated T cells, as compared to unstimulated T cells.

[0282] Embodiment 1-39. The method of embodiment 1-33, wherein the depletion is preferential for SIRPy-expressing CD8+ T cells.

[0283] Embodiment 1-40. The method of embodiment 1-33, wherein the depletion is preferential for SIRPy-expressing CD4+ T- cells.

[0284] Embodiment 1-41. The method of embodiment 1-33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T- cells.

[0285] Embodiment 1-42. The method of embodiment 1-33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T- cells.93331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0286] Embodiment 1-43. The method of embodiment 1-33, wherein the depletion is preferential for SIRPy-expressing CD8+ T cells, when compared to SIRPy-expressing CD4+ T- cells.

[0287] Embodiment 1-44. The method of embodiment 1-33, wherein the depletion is preferential for SIRPy-expressing CD4+ T cells, when compared to SIRPy-expressing CD8+ T- cells.

[0288] Embodiment 1-45. The method of embodiment 1-33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T cells, when compared to SIRPy-expressing CD8+ / CD69- T- cells.

[0289] Embodiment 1-46. The method of embodiment 1-33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T cells, when compared to SIRPy-expressing CD8+ / CD25- T- cells.

[0290] Embodiment 1-47. The method of embodiment 1-23, wherein the SIRPy-expressing cells are B cells.

[0291] Embodiment 1-48. The method of embodiment 1-23, wherein the SIRPy-expressing cells are NK cells.

[0292] Embodiment 1-49. The method of any one of embodiments 1-23 to 1-48, wherein, the SIRPy-expressing cells are activated.

[0293] Embodiment 1-50. The method any one of embodiments 1-23 to 1-49, wherein the population of SIRPy-expressing cells comprises tissue-resident cells.

[0294] Embodiment 1-51. The method any one of embodiments 1-23 to 1-50, wherein the population of SIRPy-expressing cells comprises circulating cells.

[0295] Embodiment 1-52. The method of any one of embodiments 1-23 to 1-51, wherein the depletion involves one or more of ADCC, ADCP, and CDC.

[0296] Embodiment 1-53. The method of any one of embodiments 1-1 to 1-52, wherein the antibody is administered with a pharmaceutically acceptable carrier.

[0297] Embodiment 1-54. The method of any one of embodiments 1-1 to 1-53, wherein the subject is human.

[0298] Embodiment 1-55. The method of any one of embodiments 1-1 to 1-54, wherein the antibody is administered in combination with one or more ofa) a glucocorticoid such as dexamethasone, prednisone, prednisolone, or methylprednisolone;94331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073b) a cytokine inhibitor, including but not limited to anti-IL-6 receptor inhibitors (e.g., tocilizumab, sarilumab) and anti-IL-ip or IL-1 receptor inhibitors (e.g., canakinumab, anakinra); andc) an immune suppressant or modulator, such as methotrexate.

[0299] Embodiment 1-56. Use of an antibody for the treatment of a granulomatous disease or disorder in a subject in need thereof, wherein the antibody is specific for SIRPy.

[0300] Embodiment 1-57. Use of an antibody for the manufacture of a medicament for the treatment of granulomatous disease or disorder in a subject in need thereof, wherein the antibody is specific for SIRPy.

[0301] Embodiment 1-58. A method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an anti-SIRPy antibody, wherein the antibody comprises a means for binding human SIRPy.

[0302] Embodiment 11-1. A method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an antibody that is specific for signal regulatory protein gamma (SIRPy).

[0303] Embodiment II-2. The method of embodiment 11-1, wherein the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with poly angiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis.

[0304] Embodiment 11-3. The method of embodiment 11-1 or 11-2, wherein the granulomatous disease or disorder is giant cell arteritis (GCA).

[0305] Embodiment II-4. The method of any one of embodiments 11-1 to 11-3, wherein the antibody comprises:a) the three light chain variable domain (VL) complementary determining regions (CDRs) of amino acid sequences of SEQ ID NO: 136, SEQ ID NO: 164, SEQ ID 95331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073NO: 207; and comprising the three heavy chain variable domain (VH) CDRs of amino acid sequences of SEQ ID NO: 243, SEQ ID NO: 249, and SEQ ID NO: 321;b) the three VL CDRs of amino acid sequences of SEQ ID NO: 112, SEQ ID NO:148, SEQ ID NO: 179, and the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 290;c) the three VL CDRs of amino acid sequences of SEQ ID NO: 102, SEQ ID NO:140, SEQ ID NO: 169, and the three VH CDRs of amino acid sequences of SEQ ID NO: 211, SEQ ID NO: 247, and SEQ ID NO: 279;d) the three VL CDRs of amino acid sequences of SEQ ID NO: 103, SEQ ID NO:141, SEQ ID NO: 170, and the three VH CDRs of amino acid sequences of SEQ ID NO: 212, SEQ ID NO: 248, and SEQ ID NO: 280;e) the three VL CDRs of amino acid sequences of SEQ ID NO: 104, SEQ ID NO:141, SEQ ID NO: 171, and the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 281;f) the three VL CDRs of amino acid sequences of SEQ ID NO: 105, SEQ ID NO:142, SEQ ID NO: 172, and the three VH CDRs of amino acid sequences of SEQ ID NO: 214, SEQ ID NO: 250, and SEQ ID NO: 282;g) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:143, SEQ ID NO: 173, and the three VH CDRs of amino acid sequences of SEQ ID NO: 215, SEQ ID NO: 251, and SEQ ID NO: 283;h) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:144, SEQ ID NO: 174, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 252, and SEQ ID NO: 284;i) the three VL CDRs of amino acid sequences of SEQ ID NO: 107, SEQ ID NO:141, SEQ ID NO: 175, and the three VH CDRs of amino acid sequences of SEQ ID NO: 217, SEQ ID NO: 253, and SEQ ID NO: 285;j) the three VL CDRs of amino acid sequences of SEQ ID NO: 108, SEQ ID NO:144, SEQ ID NO: 176, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 254, and SEQ ID NO: 286;k) the three VL CDRs of amino acid sequences of SEQ ID NO: 109, SEQ ID NO:145, SEQ ID NO: 171, and the three VH CDRs of amino acid sequences of SEQ ID NO: 218, SEQ ID NO: 255, and SEQ ID NO: 287;96331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073l) the three VL CDRs of amino acid sequences of SEQ ID NO: 110, SEQ ID NO:146, SEQ ID NO: 177, and the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 249, and SEQ ID NO: 288;m) the three VL CDRs of amino acid sequences of SEQ ID NO: 111, SEQ ID NO:147, SEQ ID NO: 178, and the three VH CDRs of amino acid sequences of SEQ ID NO: 220, SEQ ID NO: 256, and SEQ ID NO: 289;n) the three VL CDRs of amino acid sequences of SEQ ID NO: 101, SEQ ID NO:139, SEQ ID NO: 168, and the three VH CDRs of amino acid sequences of SEQ ID NO: 210, SEQ ID NO: 246, and SEQ ID NO: 278;o) the three VL CDRs of amino acid sequences of SEQ ID NO: 113, SEQ ID NO:143, SEQ ID NO: 180, and the three VH CDRs of amino acid sequences of SEQ ID NO: 221, SEQ ID NO: 257, and SEQ ID NO: 291;p) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:149, SEQ ID NO: 181, and the three VH CDRs of amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 258, and SEQ ID NO: 292;q) the three VL CDRs of amino acid sequences of SEQ ID NO: 114, SEQ ID NO:150, SEQ ID NO: 182, and the three VH CDRs of amino acid sequences of SEQ ID NO: 223, SEQ ID NO: 250, and SEQ ID NO: 293;r) the three VL CDRs of amino acid sequences of SEQ ID NO: 115, SEQ ID NO:151, SEQ ID NO: 183, and the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 259, and SEQ ID NO: 294;s) the three VL CDRs of amino acid sequences of SEQ ID NO: 116, SEQ ID NO:152, SEQ ID NO: 184, and the three VH CDRs of amino acid sequences of SEQ ID NO: 224, SEQ ID NO: 260, and SEQ ID NO: 295;t) the three VL CDRs of amino acid sequences of SEQ ID NO: 117, SEQ ID NO:153, SEQ ID NO: 185, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 261, and SEQ ID NO: 296;u) the three VL CDRs of amino acid sequences of SEQ ID NO: 118, SEQ ID NO:143, SEQ ID NO: 186, and the three VH CDRs of amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 262, and SEQ ID NO: 297;v) the three VL CDRs of amino acid sequences of SEQ ID NO: 119, SEQ ID NO:154, SEQ ID NO: 187, and the three VH CDRs of amino acid sequences of SEQ ID NO: 225, SEQ ID NO: 250, and SEQ ID NO: 298;97331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073w) the three VL CDRs of amino acid sequences of SEQ ID NO: 120, SEQ ID NO:140, SEQ ID NO: 188, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 263, and SEQ ID NO: 299;x) the three VL CDRs of amino acid sequences of SEQ ID NO: 121, SEQ ID NO:141, SEQ ID NO: 189, and the three VH CDRs of amino acid sequences of SEQ ID NO: 227, SEQ ID NO: 264, and SEQ ID NO: 300;y) the three VL CDRs of amino acid sequences of SEQ ID NO: 122, SEQ ID NO:155, SEQ ID NO: 190, and the three VH CDRs of amino acid sequences of SEQ ID NO: 228, SEQ ID NO: 249, and SEQ ID NO: 301;z) the three VL CDRs of amino acid sequences of SEQ ID NO: 123, SEQ ID NO:143, SEQ ID NO: 186, and the three VH CDRs of amino acid sequences of SEQ ID NO: 229, SEQ ID NO: 265, and SEQ ID NO: 302;aa) the three VL CDRs of amino acid sequences of SEQ ID NO: 124, SEQ ID NO:143, SEQ ID NO: 191, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 266, and SEQ ID NO: 303;bb)the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:156, SEQ ID NO: 192, and the three VH CDRs of amino acid sequences of SEQ ID NO: 230, SEQ ID NO: 249, and SEQ ID NO: 304;cc) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:145, SEQ ID NO: 193, and the three VH CDRs of amino acid sequences of SEQ ID NO: 231, SEQ ID NO: 267, and SEQ ID NO: 305;dd)the three VL CDRs of amino acid sequences of SEQ ID NO: 125, SEQ ID NO:143, SEQ ID NO: 194, and the three VH CDRs of amino acid sequences of SEQ ID NO: 232, SEQ ID NO: 268, and SEQ ID NO: 306;ee) the three VL CDRs of amino acid sequences of SEQ ID NO: 126, SEQ ID NO:157, SEQ ID NO: 195, and the three VH CDRs of amino acid sequences of SEQ ID NO: 233, SEQ ID NO: 269, and SEQ ID NO: 307;ff) the three VL CDRs of amino acid sequences of SEQ ID NO: 127, SEQ ID NO:155, SEQ ID NO: 196, and the three VH CDRs of amino acid sequences of SEQ ID NO: 234, SEQ ID NO: 249, and SEQ ID NO: 308;gg)the three VL CDRs of amino acid sequences of SEQ ID NO: 128, SEQ ID NO:158, SEQ ID NO: 197, and the three VH CDRs of amino acid sequences of SEQ ID NO: 235, SEQ ID NO: 270, and SEQ ID NO: 309;98331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073hh)the three VL CDRs of amino acid sequences of SEQ ID NO: 129, SEQ ID NO:159, SEQ ID NO: 198, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 271, and SEQ ID NO: 310;ii) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:143, SEQ ID NO: 199, and the three VH CDRs of amino acid sequences of SEQ ID NO: 236, SEQ ID NO: 272, and SEQ ID NO: 311;jj) the three VL CDRs of amino acid sequences of SEQ ID NO: 130, SEQ ID NO:155, SEQ ID NO: 200, and the three VH CDRs of amino acid sequences of SEQ ID NO: 237, SEQ ID NO: 249, and SEQ ID NO: 312;kk) the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO:141, SEQ ID NO: 201, and the three VH CDRs of amino acid sequences of SEQ ID NO: 238, SEQ ID NO: 264, and SEQ ID NO: 313;11) the three VL CDRs of amino acid sequences of SEQ ID NO: 132, SEQ ID NO:140, SEQ ID NO: 202, and the three VH CDRs of amino acid sequences of SEQ ID NO: 239, SEQ ID NO: 273, and SEQ ID NO: 314;mm) the three VL CDRs of amino acid sequences of SEQ ID NO: 109, SEQ ID NO: 143, SEQ ID NO: 203, and the three VH CDRs of amino acid sequences of SEQ ID NO: 240, SEQ ID NO: 250, and SEQ ID NO: 315;nn)the three VL CDRs of amino acid sequences of SEQ ID NO: 133, SEQ ID NO:160, SEQ ID NO: 191, and the three VH CDRs of amino acid sequences of SEQ ID NO: 241, SEQ ID NO: 274, and SEQ ID NO: 316;oo)the three VL CDRs of amino acid sequences of SEQ ID NO: 134, SEQ ID NO:161, SEQ ID NO: 204, and the three VH CDRs of amino acid sequences of SEQ ID NO: 242, SEQ ID NO: 275, and SEQ ID NO:pp)the three VL CDRs of amino acid sequences of SEQ ID NO: 135, SEQ ID NO:162, SEQ ID NO: 189, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 249, and SEQ ID NO: 318;qq)the three VL CDRs of amino acid sequences of SEQ ID NO: 129, SEQ ID NO:155, SEQ ID NO: 205, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 276, and SEQ ID NO: 319;rr) the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO:163, SEQ ID NO: 206; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 267, and SEQ ID NO: 320;99331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073ss) the three VL CDRs of amino acid sequences of SEQ ID NO: 100, SEQ ID NO:138, SEQ ID NO: 167, and the three VH CDRs of amino acid sequences of SEQ ID NO: 209, SEQ ID NO: 245, and SEQ ID NO: 277;tt) the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO:165, SEQ ID NO: 208; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 269, and SEQ ID NO: 322; or uu)the three VL CDRs of amino acid sequences of SEQ ID NO: 137, SEQ ID NO:166, SEQ ID NO: 169; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 244, SEQ ID NO: 256, and SEQ ID NO: 323.

[0306] Embodiment 11-5. The method of embodiments 11-1 to II-4, wherein:a) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 415, or an amino acid sequence with at least 70% sequence identity thereto;b) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 384, or an amino acid sequence with at least 70% sequence identity thereto;c) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 373, or an amino acid sequence with at least 70% sequence identity thereto;d) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 374, or an amino acid sequence with at least 70% sequence identity thereto;e) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 375, or an amino acid sequence with at least 70% sequence identity thereto;f) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of100331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the antibody comprises the amino acid sequence of SEQ ID NO: 376, or an amino acid sequence with at least 70% sequence identity thereto;g) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 330 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 377, or an amino acid sequence with at least 70% sequence identity thereto;h) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 331 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 378, or an amino acid sequence with at least 70% sequence identity thereto;i) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 332 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 379, or an amino acid sequence with at least 70% sequence identity thereto;j) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 333 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 380, or an amino acid sequence with at least 70% sequence identity thereto;k) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 381, or an amino acid sequence with at least 70% sequence identity thereto;l) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 382, or an amino acid sequence with at least 70% sequence identity thereto;m) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 383, or an amino acid sequence with at least 70% sequence identity thereto;n) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 325 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of101331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the antibody comprises the amino acid sequence of SEQ ID NO: 372, or an amino acid sequence with at least 70% sequence identity thereto;o) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 338 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 385, or an amino acid sequence with at least 70% sequence identity thereto;p) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 339 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 386, or an amino acid sequence with at least 70% sequence identity thereto;q) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 340 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 387, or an amino acid sequence with at least 70% sequence identity thereto;r) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 341 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 388, or an amino acid sequence with at least 70% sequence identity thereto;s) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 389, or an amino acid sequence with at least 70% sequence identity thereto;t) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 390, or an amino acid sequence with at least 70% sequence identity thereto;u) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 391, or an amino acid sequence with at least 70% sequence identity thereto;v) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of102331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the antibody comprises the amino acid sequence of SEQ ID NO: 392, or an amino acid sequence with at least 70% sequence identity thereto;w) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 346 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 393, or an amino acid sequence with at least 70% sequence identity thereto;x) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 347 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 394, or an amino acid sequence with at least 70% sequence identity thereto;y) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 348 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 395, or an amino acid sequence with at least 70% sequence identity thereto;z) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 349 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 396, or an amino acid sequence with at least 70% sequence identity thereto;aa) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 397, or an amino acid sequence with at least 70% sequence identity thereto;bb)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 398, or an amino acid sequence with at least 70% sequence identity thereto;cc) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 399, or an amino acid sequence with at least 70% sequence identity thereto;dd)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of103331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the antibody comprises the amino acid sequence of SEQ ID NO: 400, or an amino acid sequence with at least 70% sequence identity thereto;ee) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 354 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 401, or an amino acid sequence with at least 70% sequence identity thereto;ff) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 355 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 402, or an amino acid sequence with at least 70% sequence identity thereto;gg)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 356 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 403, or an amino acid sequence with at least 70% sequence identity thereto;hh)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 357 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 404, or an amino acid sequence with at least 70% sequence identity thereto;ii) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 405, or an amino acid sequence with at least 70% sequence identity thereto;jj) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 406, or an amino acid sequence with at least 70% sequence identity thereto;kk)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 407, or an amino acid sequence with at least 70% sequence identity thereto;11) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of104331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the antibody comprises the amino acid sequence of SEQ ID NO: 408, or an amino acid sequence with at least 70% sequence identity thereto;mm) the VH of the antibody comprises the amino acid sequence of SEQ ID NO:362 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 409, or an amino acid sequence with at least 70% sequence identity thereto;nn)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 363 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 410, or an amino acid sequence with at least 70% sequence identity thereto;oo)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 364 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 411, or an amino acid sequence with at least 70% sequence identity thereto;pp)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 365 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 412, or an amino acid sequence with at least 70% sequence identity thereto;qq)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 413, or an amino acid sequence with at least 70% sequence identity thereto;rr) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 414, or an amino acid sequence with at least 70% sequence identity thereto;ss) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 324 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 371, or an amino acid sequence with at least 70% sequence identity thereto;tt) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of105331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073the antibody comprises the amino acid sequence of SEQ ID NO: 416, or an amino acid sequence with at least 70% sequence identity thereto; oruu)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 370 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 417, or an amino acid sequence with at least 70% sequence identity thereto.

[0307] Embodiment II-6. The method of any one of embodiments II- 1 to II-5, wherein the antibody is an antibody fragment.

[0308] Embodiment II-7. The method of any one of embodiments II- 1 to II-5, wherein the antibody is a human antibody.

[0309] Embodiment II-8. The method of any one of embodiments II- 1 to II-5, wherein the antibody is a humanized antibody.

[0310] Embodiment II-9. The method of any one of embodiments II- 1 to II-5, wherein the antibody is a full-length antibody.

[0311] Embodiment II- 10. The method of any one of embodiments II- 1 to II-9, wherein the antibody wherein the antibody has low or no affinity for binding SIRPa and / or SIRPpi .

[0312] Embodiment II- 11. The method of any one of embodiments II- 1 to 11-10, wherein the antibody binds to human and non-human primate SIRPy with high affinity.

[0313] Embodiment 11-12. The method of any one of embodiments II- 1 to 11-10, wherein the antibody does not bind to human and non-human primate SIRPa or SIRPpi .

[0314] Embodiment 11-13. The method of any one of embodiments II- 1 to 11-12, wherein the antibody comprises a Fc domain.

[0315] Embodiment 11-14. The method of embodiment 11-13, wherein the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4 heavy chain sequence.

[0316] Embodiment 11-15. The method of embodiment 11-14, wherein the Fc domain is from the heavy chain IgG amino acid sequences of SEQ ID NO: 5 or SEQ ID NO: 28, optionally with one or more Fc amino acid substitutions.

[0317] Embodiment 11-16. The method of embodiment 11-15, wherein the Fc domain is from the heavy chain IgG amino acid sequences of any one of SEQ ID NOS: 5-36.

[0318] Embodiment 11-17. The method embodiment 11-15, wherein the heavy chain Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 5 or SEQ ID NO: 28 at a position selected from the group consisting of: 215, 221, 222, 228, 234, 235, 236,106331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, and 440 wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0319] Embodiment 11-18. The method of any one of embodiments II- 1 to 11-17, wherein the antibody comprises a light chain constant region that is from the amino acid sequences of any one of SEQ ID NOS: 38-42.

[0320] Embodiment 11-19. The method of any one of embodiments II- 1 to 11-18, wherein the binding of the antibody does not disrupt the interaction between CD47 and SIRPy.

[0321] Embodiment 11-20. The method of any one of embodiments II- 1 to 11-18, wherein the binding of the antibody disrupts the interaction between CD47 and SIRPy.

[0322] Embodiment 11-21. The method of any one of embodiments II- 1 to 11-18, wherein the binding of the antibody stabilizes or promotes the interaction between CD47 and SIRPy.

[0323] Embodiment 11-22. The method comprising of anyone of embodiments II- 1 to II- 21, wherein the antibody comprises a binding affinity to SIRPy lower than about 500 nM.

[0324] Embodiment 11-23. The method of any one of embodiments II- 1 to 11-22, wherein the antibody preferentially depletes of a population of SIRPy-expressing cells.

[0325] Embodiment 11-24. The method of embodiment 11-23, wherein the SIRPy-expressing cells are T cells, B cells and / or NK cells.

[0326] Embodiment 11-25. The method of embodiment 11-23, wherein the SIRPy-expressing cells are T cells.

[0327] Embodiment 11-26. The method of embodiment 11-25, wherein the T cells are activated (stimulated).

[0328] Embodiment 11-27. The method of embodiment 11-25, wherein the T cells are activated (stimulated), and the depletion is preferential for activated (stimulated) T cells.

[0329] Embodiment 11-28. The method of embodiment 11-25, wherein the T cells are exhausted.

[0330] Embodiment 11-29. The method of embodiment 11-25, wherein the T cells are exhausted, and the depletion is preferential for exhausted T cells.

[0331] Embodiment 11-30. The method of embodiment 11-25, wherein the T cells are naive, central memory, effector memory, exhausted, or terminal effector memory cells.107331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0332] Embodiment II-31. The method of embodiment 11-25, wherein the T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosal associated invariant T cells, alpha beta T cells, or gamma delta T cells.

[0333] Embodiment 11-32. The method of embodiment 11-25, wherein the T cells are Thl cells, Th2 cells, Thl7 cells or T follicular helper cells.

[0334] Embodiment 11-33. The method of embodiment 11-25, wherein the T cells are a CD3+ T cell, CD4+ T cell, CD8+ T cell, CD25+ T cell, CD69+ T cell, and / or PD1+ T cell.

[0335] Embodiment 11-34. The method of embodiment 11-33, wherein the T cells are CD4+ / CD8+ T cells.

[0336] Embodiment 11-35. The method of embodiment 11-33, wherein the T cells are CD69+ / CD8+ T cells.

[0337] Embodiment 11-36. The method of embodiment 11-33, wherein the T cells are CD25+ / CD8+ T cells.

[0338] Embodiment 11-37. The method of embodiment 11-33, wherein the T cells are PD1+ T cells.

[0339] Embodiment 11-38. The method of embodiment 11-33, wherein the depletion is preferential for stimulated T cells, as compared to unstimulated T cells.

[0340] Embodiment 11-39. The method of embodiment 11-33, wherein the depletion is preferential for SIRPy-expressing CD8+ T cells.

[0341] Embodiment 11-40. The method of embodiment 11-33, wherein the depletion is preferential for SIRPy-expressing CD4+ T- cells.

[0342] Embodiment 11-41. The method of embodiment 11-33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T- cells.

[0343] Embodiment 11-42. The method of embodiment 11-33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T- cells.

[0344] Embodiment 11-43. The method of embodiment 11-33, wherein the depletion is preferential for SIRPy-expressing CD8+ T cells, when compared to SIRPy-expressing CD4+ T- cells.

[0345] Embodiment 11-44. The method of embodiment 11-33, wherein the depletion is preferential for SIRPy-expressing CD4+ T cells, when compared to SIRPy-expressing CD8+ T- cells.108331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0346] Embodiment 11-45. The method of embodiment 11-33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T cells, when compared to SIRPy-expressing CD8+ / CD69- T- cells.

[0347] Embodiment 11-46. The method of embodiment 11-33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T cells, when compared to SIRPy-expressing CD8+ / CD25- T- cells.

[0348] Embodiment 11-47. The method of embodiment 11-23, wherein the SIRPy-expressing cells are B cells.

[0349] Embodiment 11-48. The method of embodiment 11-23, wherein the SIRPy-expressing cells are NK cells.

[0350] Embodiment 11-49. The method of any one of embodiments 11-23 to 11-48, wherein, the SIRPy-expressing cells are activated.

[0351] Embodiment 11-50. The method any one of embodiments 11-23 to 11-49, wherein the population of SIRPy-expressing cells comprises tissue-resident cells.

[0352] Embodiment 11-51. The method any one of embodiments 11-23 to 11-50, wherein the population of SIRPy-expressing cells comprises circulating cells.

[0353] Embodiment 11-52. The method of any one of embodiments 11-23 to 11-51, wherein the depletion involves one or more of ADCC, ADCP, and CDC.

[0354] Embodiment 11-53. The method of any one of embodiments II- 1 to 11-52, wherein the antibody is administered with a pharmaceutically acceptable carrier.

[0355] Embodiment 11-54. The method of any one of embodiments II- 1 to 11-53, wherein the subject is human.

[0356] Embodiment 11-55. The method of any one of embodiments II- 1 to 11-54, wherein the SIRPy antibody is administered subcutaneously or intravenously.

[0357] Embodiment 11-56. The method of any one of embodiments II- 1 to 11-55, wherein the antibody is administered in combination with one or more ofa) a glucocorticoid such as dexamethasone, prednisone, prednisolone, or methylprednisolone;b) a cytokine inhibitor, including but not limited to anti-IL-6 receptor inhibitors (e.g., tocilizumab, sarilumab) and anti-IL-ip or IL-1 receptor inhibitors (e.g., canakinumab, anakinra); andc) an immune suppressant or modulator, such as methotrexate.109331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073

[0358] Embodiment 11-57. Use of an antibody for the treatment of a granulomatous disease or disorder in a subject in need thereof, wherein the antibody is specific for SIRPy.

[0359] Embodiment 11-58. Use of an antibody for the manufacture of a medicament for the treatment of granulomatous disease or disorder in a subject in need thereof, wherein the antibody is specific for SIRPy.

[0360] Embodiment 11-59. The use of embodiment 11-57 or 11-58, wherein the disease or disorder is a granulomatous disease or disorder.

[0361] Embodiment 11-60. The use of embodiment 11-59, wherein the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with poly angiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis.

[0362] Embodiment 11-61. The use of embodiment 11-59 or 11-60, wherein the granulomatous disease or disorder is giant cell arteritis (GCA).

[0363] Embodiment 11-62. The use of any one of embodiments 11-57 to 11-61, wherein the subject is a human.

[0364] Embodiment 11-63. A method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an anti-SIRPy antibody, wherein the antibody comprises a means for binding human SIRPy.

[0365] Embodiment 11-64. The method of embodiment 11-63, wherein the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with poly angiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial110331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis.

[0366] Embodiment 11-65. The method of embodiment 11-63 or 11-64, wherein the granulomatous disease or disorder is giant cell arteritis (GCA).

[0367] Embodiment 11-66. The method of any one of embodiments 11-63 to 11-65, wherein the subject is a human.

[0368] Embodiment 11-67. The method of any one of embodiments 11-63 to 11-66, wherein the SIRPy antibody is administered subcutaneously or intravenously.EXAMPLESExample 1: Antibody SIRP binding

[0369] CHO cells were stably transfected with human or non-human primate (NHP) SIRPy (FIG. 1A), SIRPa (FIG. IB) or SIRPp (FIG. 1C). SIRPa transfected CHO cells expressed either human SIRPa splice variant 1 (vl) and variant 2 (v2) (FIG. IB). Approximately 5xl04stably transfected human or NHP SIRP-expressing CHO cells were incubated with an eightpoint 1:4 dilution of an anti-SIRPy specific antibody of the disclosure (ySIRP-Abl) or isotype control (Iso-Ctrl) starting at 200 nM for 1 hour on ice. The ySIRP-Abl antibody is referred to as Antibody 96 in Tables 1 and 2 and its sequences are provided in said tables. After 2 washes, cells were incubated for 0.5 h on ice with 1 : 100 diluted R-Phycoerythrin (PE)-conjugated AffiniPure F(ab’)2 fragment goat anti-human IgG (Jackson ImmunoResearch) and 2 pg / mL of DAPI (Biolegend). Following a further 2 washes, samples were analyzed on an Attune NxT Flow Cytometer (ThermoFisher). Median fluorescence intensity values were obtained and used to calculate ECso values with 95% confidence intervals using GraphPad Prism. FIG. 1A demonstrates high affinity for SIRPy for ySIRP-Abl, while FIGS. 1B-1C demonstrate no affinity SIRPa or SIRPP for ySIRP-Abl . Indicating high specificity and selectivity of ySIRP-Abl for SIRPy.Example 2: GCA disease models

[0370] PBMC from patients with GCA were incubated ex vivo with either anti-SIRPy specific antibody (ySIRP-Ab2), anti-SIRPa / p specific antibody (aP SIRP- Ab) or anti-SIRPa / p / y pan antibody (panSIRP-Ab) and depletion of immune cells (human CD45+cells) was assessed via flow cytometry. The ySIRP-Ab2 antibody is referred to as Antibody 80 in111331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073Tables 1 and 2 and its sequences are provided in said tables. Antibodies with affinity for SIRPy demonstrated a significant depletion of immune cells (FIG. 2A-B).

[0371] In a humanized mouse model of GCA (FIG. 2D), the anti-inflammatory effects of ySIRP-Ab2, apSIRP-Ab, and panSIRP-Ab were also tested. NSG mice were transplanted subcutaneously (s.c.) with small pieces of an artery from GCA patients (Day -7). Seven days later (Day 0), human PBMC from GCA patients were injected intravenously (i.v.) into animals. Treatment with 10 mg / kg of anti-SIRP antibodies or control antibody subcutaneously (s.c.) began 7 days post PBMC injection (Day 7). On day 14 post PBMC injection (Day 14), the human arteries were isolated and analyzed for number of tissueresident T cells and number of cytokine-producing T cells (FIG. 2C-E). Animals dosed with SIRPy binding antibodies had fewer CD4 T cells, while animals that received a SIRPa / p specific antibody, did not exhibit a reduction of immune cells in the artery and levels of proinflammatory cytokines IFNy and IL-21, demonstrating the anti-inflammatory effects of the SIRPy binding antibody.Example 3: SIRPy expression in unstimulated and stimulated T cells

[0372] Approximately 5xl04human resting or activated T cells were incubated with an eight-point 1 :4 dilution of 0X119 (a SIRPy antibody) at 200 nM for 1 hour on ice. After 2 washes, cells were incubated for 0.5 h on ice with 1 : 100 diluted R-Phycoerythrin (PE)-conjugated AffiniPure F(ab’)2 fragment goat anti-mouse IgG (Jackson ImmunoResearch) and 2 pg / mL of DAPI (Biolegend). Following a further 2 washes, samples were analyzed on an Attune NxT Flow Cytometer (ThermoFisher). Median fluorescence intensity values were obtained and used to calculate an ECso values with 95% confidence intervals using GraphPad Prism. SIRPy expression was shown to be higher on activated T cells when compared to unstimulated naive CD3+ T cells (FIG. 3).Example 4: In vitro ADCC reporter assay

[0373] To evaluate ADCC activity, an ADCC Reporter Bioassay Core Kit (Promega) was used according to the manufacturer's protocol. SIRPy CHO cells (target cells) were incubated with an eight-point 1:5 dilution of ySIRP-Abl (with a canonical human IgGl Fc), ySIRP-Ab2 (with a human IgGl Fc with increased effector function), or isotype control antibodies starting at 1600 nM for 0.5 h at RT. The ySIRP-Abl antibody is referred to as Antibody 96 and the ySIRP-Ab2 is referred to as Antibody 80 in Tables 1 and 2, and their sequences are provided in said tables. Effector cells were added to each well to achieve an ADCC effector- 112331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073to-target cell ratio of 1.2:1 and incubated for 5 h at 37°C. Bio-Gio™ Luciferase Assay Reagent was added to each well and luminescence measured using a SpectraMax i3x plate reader. The mean and SD of two replicates were graphed in Graphpad Prism. For each antibody, the ECso value and its associated 95% confidence interval were calculated in GraphPad Prism using a 4-parameter binding model. Both antibodies demonstrated ADCC activity, with ySIRP-Ab2 demonstrating a higher potency.Example 5: GCA disease model

[0374] In a humanized mouse model of GCA, the anti-inflammatory effects of two anti-SIRPy specific antibodies containing different Fc regions were determined, with ySIRP-Abl having a canonical human IgGl Fc and ySIRP-Ab2 having a human IgGl Fc with increased effector function. The ySIRP-Abl antibody is referred to as Antibody 96 and the ySIRP-Ab2 is referred to as Antibody 80 in Tables 1 and 2, and their sequences are provided in said tables.

[0375] NSG mice were transplanted subcutaneously (s.c.) with small pieces of an artery from GCA patients (Day -7). Seven days later (Day 0), human PBMC were injected intravenously (i.v.) into animals. Treatment with lOmg / kg of anti- SIRPy antibodies or control antibody (s.c.) began 7 days post PBMC injection (Day 7). On day 14 post PBMC injection (Day 14), the human arteries were isolated and analyzed for number of tissueresident T cells and number of cytokine-producing T cells. As shown in FIGS. 5A-5B, animals dosed with SIRPy binding antibodies had fewer CD4 T cells and reduced levels of proinflammatory cytokines in the artery.Example 6: GCA disease model

[0376] In a humanized mouse model of GCA the dose dependent anti-inflammatory effects of an anti-SIRPy specific antibody of the disclosure (ySIRP-Abl) were determined. The ySIRP-Abl antibody is referred to as Antibody 96 in Tables 1 and 2 and its sequences are provided in said tables. NSG mice were transplanted subcutaneously (s.c.) with small pieces of an artery from GCA patients (Day -7). Seven days later (Day 0), human PBMC were injected intravenously (i.v.) into animals. Treatment with either 3 mg / kg orlOmg / kg of anti-SIRPy antibodies or control antibody (s.c.) began 7 days post PBMC injection (Day 7). On day 14 post PBMC injection (Day 14), the human arteries were isolated and analyzed for number of tissue-resident T cells and number of cytokine-producing T cells. As shown in113331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073FIGS. 6A-6B, animals dosed with either 3 or 10 mg / kg of the SIRPy binding antibody had fewer CD4 T cells and reduced levels of proinflammatory cytokines in the artery.

[0377] From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the invention. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.114331845966

Claims

Attorney Docket No.: ELTH-009 / 01WO 336159-2073CLAIMS1. A method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an antibody that is specific for signal regulatory protein gamma (SIRPy).

2. The method of claim 1, wherein the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with poly angiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis.

3. The method of claim 1 or 2, wherein the granulomatous disease or disorder is giant cell arteritis (GCA).

4. The method of any one of claims 1-3, wherein the antibody comprises:a) the three light chain variable domain (VL) complementary determining regions (CDRs) of amino acid sequences of SEQ ID NO: 136, SEQ ID NO: 164, SEQ ID NO: 207; and comprising the three heavy chain variable domain (VH) CDRs of amino acid sequences of SEQ ID NO: 243, SEQ ID NO: 249, and SEQ ID NO: 321;b) the three VL CDRs of amino acid sequences of SEQ ID NO: 112, SEQ ID NO:148, SEQ ID NO: 179, and the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 290;c) the three VL CDRs of amino acid sequences of SEQ ID NO: 102, SEQ ID NO:140, SEQ ID NO: 169, and the three VH CDRs of amino acid sequences of SEQ ID NO: 211, SEQ ID NO: 247, and SEQ ID NO: 279;d) the three VL CDRs of amino acid sequences of SEQ ID NO: 103, SEQ ID NO:141, SEQ ID NO: 170, and the three VH CDRs of amino acid sequences of SEQ ID NO: 212, SEQ ID NO: 248, and SEQ ID NO: 280;115331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073e) the three VL CDRs of amino acid sequences of SEQ ID NO: 104, SEQ ID NO:141, SEQ ID NO: 171, and the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 249, and SEQ ID NO: 281;f) the three VL CDRs of amino acid sequences of SEQ ID NO: 105, SEQ ID NO:142, SEQ ID NO: 172, and the three VH CDRs of amino acid sequences of SEQ ID NO: 214, SEQ ID NO: 250, and SEQ ID NO: 282;g) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:143, SEQ ID NO: 173, and the three VH CDRs of amino acid sequences of SEQ ID NO: 215, SEQ ID NO: 251, and SEQ ID NO: 283;h) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:144, SEQ ID NO: 174, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 252, and SEQ ID NO: 284;i) the three VL CDRs of amino acid sequences of SEQ ID NO: 107, SEQ ID NO:141, SEQ ID NO: 175, and the three VH CDRs of amino acid sequences of SEQ ID NO: 217, SEQ ID NO: 253, and SEQ ID NO: 285;j) the three VL CDRs of amino acid sequences of SEQ ID NO: 108, SEQ ID NO:144, SEQ ID NO: 176, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 254, and SEQ ID NO: 286;k) the three VL CDRs of amino acid sequences of SEQ ID NO: 109, SEQ ID NO:145, SEQ ID NO: 171, and the three VH CDRs of amino acid sequences of SEQ ID NO: 218, SEQ ID NO: 255, and SEQ ID NO: 287;l) the three VL CDRs of amino acid sequences of SEQ ID NO: 110, SEQ ID NO:146, SEQ ID NO: 177, and the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 249, and SEQ ID NO: 288;m) the three VL CDRs of amino acid sequences of SEQ ID NO: 111, SEQ ID NO:147, SEQ ID NO: 178, and the three VH CDRs of amino acid sequences of SEQ ID NO: 220, SEQ ID NO: 256, and SEQ ID NO: 289;n) the three VL CDRs of amino acid sequences of SEQ ID NO: 101, SEQ ID NO:139, SEQ ID NO: 168, and the three VH CDRs of amino acid sequences of SEQ ID NO: 210, SEQ ID NO: 246, and SEQ ID NO: 278;o) the three VL CDRs of amino acid sequences of SEQ ID NO: 113, SEQ ID NO:143, SEQ ID NO: 180, and the three VH CDRs of amino acid sequences of SEQ ID NO: 221, SEQ ID NO: 257, and SEQ ID NO: 291;116331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073p) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:149, SEQ ID NO: 181, and the three VH CDRs of amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 258, and SEQ ID NO: 292;q) the three VL CDRs of amino acid sequences of SEQ ID NO: 114, SEQ ID NO:150, SEQ ID NO: 182, and the three VH CDRs of amino acid sequences of SEQ ID NO: 223, SEQ ID NO: 250, and SEQ ID NO: 293;r) the three VL CDRs of amino acid sequences of SEQ ID NO: 115, SEQ ID NO:151, SEQ ID NO: 183, and the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 259, and SEQ ID NO: 294;s) the three VL CDRs of amino acid sequences of SEQ ID NO: 116, SEQ ID NO:152, SEQ ID NO: 184, and the three VH CDRs of amino acid sequences of SEQ ID NO: 224, SEQ ID NO: 260, and SEQ ID NO: 295;t) the three VL CDRs of amino acid sequences of SEQ ID NO: 117, SEQ ID NO:153, SEQ ID NO: 185, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 261, and SEQ ID NO: 296;u) the three VL CDRs of amino acid sequences of SEQ ID NO: 118, SEQ ID NO:143, SEQ ID NO: 186, and the three VH CDRs of amino acid sequences of SEQ ID NO: 222, SEQ ID NO: 262, and SEQ ID NO: 297;v) the three VL CDRs of amino acid sequences of SEQ ID NO: 119, SEQ ID NO:154, SEQ ID NO: 187, and the three VH CDRs of amino acid sequences of SEQ ID NO: 225, SEQ ID NO: 250, and SEQ ID NO: 298;w) the three VL CDRs of amino acid sequences of SEQ ID NO: 120, SEQ ID NO:140, SEQ ID NO: 188, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 263, and SEQ ID NO: 299;x) the three VL CDRs of amino acid sequences of SEQ ID NO: 121, SEQ ID NO:141, SEQ ID NO: 189, and the three VH CDRs of amino acid sequences of SEQ ID NO: 227, SEQ ID NO: 264, and SEQ ID NO: 300;y) the three VL CDRs of amino acid sequences of SEQ ID NO: 122, SEQ ID NO:155, SEQ ID NO: 190, and the three VH CDRs of amino acid sequences of SEQ ID NO: 228, SEQ ID NO: 249, and SEQ ID NO: 301;z) the three VL CDRs of amino acid sequences of SEQ ID NO: 123, SEQ ID NO:143, SEQ ID NO: 186, and the three VH CDRs of amino acid sequences of SEQ ID NO: 229, SEQ ID NO: 265, and SEQ ID NO: 302;117331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073aa) the three VL CDRs of amino acid sequences of SEQ ID NO: 124, SEQ ID NO:143, SEQ ID NO: 191, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 266, and SEQ ID NO: 303;bb)the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:156, SEQ ID NO: 192, and the three VH CDRs of amino acid sequences of SEQ ID NO: 230, SEQ ID NO: 249, and SEQ ID NO: 304;cc) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:145, SEQ ID NO: 193, and the three VH CDRs of amino acid sequences of SEQ ID NO: 231, SEQ ID NO: 267, and SEQ ID NO: 305;dd)the three VL CDRs of amino acid sequences of SEQ ID NO: 125, SEQ ID NO:143, SEQ ID NO: 194, and the three VH CDRs of amino acid sequences of SEQ ID NO: 232, SEQ ID NO: 268, and SEQ ID NO: 306;ee) the three VL CDRs of amino acid sequences of SEQ ID NO: 126, SEQ ID NO:157, SEQ ID NO: 195, and the three VH CDRs of amino acid sequences of SEQ ID NO: 233, SEQ ID NO: 269, and SEQ ID NO: 307;ff) the three VL CDRs of amino acid sequences of SEQ ID NO: 127, SEQ ID NO:155, SEQ ID NO: 196, and the three VH CDRs of amino acid sequences of SEQ ID NO: 234, SEQ ID NO: 249, and SEQ ID NO: 308;gg)the three VL CDRs of amino acid sequences of SEQ ID NO: 128, SEQ ID NO:158, SEQ ID NO: 197, and the three VH CDRs of amino acid sequences of SEQ ID NO: 235, SEQ ID NO: 270, and SEQ ID NO: 309;hh)the three VL CDRs of amino acid sequences of SEQ ID NO: 129, SEQ ID NO:159, SEQ ID NO: 198, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 271, and SEQ ID NO: 310;ii) the three VL CDRs of amino acid sequences of SEQ ID NO: 106, SEQ ID NO:143, SEQ ID NO: 199, and the three VH CDRs of amino acid sequences of SEQ ID NO: 236, SEQ ID NO: 272, and SEQ ID NO: 311;jj) the three VL CDRs of amino acid sequences of SEQ ID NO: 130, SEQ ID NO:155, SEQ ID NO: 200, and the three VH CDRs of amino acid sequences of SEQ ID NO: 237, SEQ ID NO: 249, and SEQ ID NO: 312;kk)the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO:141, SEQ ID NO: 201, and the three VH CDRs of amino acid sequences of SEQ ID NO: 238, SEQ ID NO: 264, and SEQ ID NO: 313;118331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207311) the three VL CDRs of amino acid sequences of SEQ ID NO: 132, SEQ ID NO:140, SEQ ID NO: 202, and the three VH CDRs of amino acid sequences of SEQ ID NO: 239, SEQ ID NO: 273, and SEQ ID NO: 314;mm) the three VL CDRs of amino acid sequences of SEQ ID NO: 109, SEQ ID NO: 143, SEQ ID NO: 203, and the three VH CDRs of amino acid sequences of SEQ ID NO: 240, SEQ ID NO: 250, and SEQ ID NO: 315;nn)the three VL CDRs of amino acid sequences of SEQ ID NO: 133, SEQ ID NO:160, SEQ ID NO: 191, and the three VH CDRs of amino acid sequences of SEQ ID NO: 241, SEQ ID NO: 274, and SEQ ID NO: 316;oo)the three VL CDRs of amino acid sequences of SEQ ID NO: 134, SEQ ID NO:161, SEQ ID NO: 204, and the three VH CDRs of amino acid sequences of SEQ ID NO: 242, SEQ ID NO: 275, and SEQ ID NO:pp)the three VL CDRs of amino acid sequences of SEQ ID NO: 135, SEQ ID NO:162, SEQ ID NO: 189, and the three VH CDRs of amino acid sequences of SEQ ID NO: 216, SEQ ID NO: 249, and SEQ ID NO: 318;qq)the three VL CDRs of amino acid sequences of SEQ ID NO: 129, SEQ ID NO:155, SEQ ID NO: 205, and the three VH CDRs of amino acid sequences of SEQ ID NO: 226, SEQ ID NO: 276, and SEQ ID NO: 319;rr) the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO:163, SEQ ID NO: 206; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 219, SEQ ID NO: 267, and SEQ ID NO: 320; ss) the three VL CDRs of amino acid sequences of SEQ ID NO: 100, SEQ ID NO:138, SEQ ID NO: 167, and the three VH CDRs of amino acid sequences of SEQ ID NO: 209, SEQ ID NO: 245, and SEQ ID NO: 277;tt) the three VL CDRs of amino acid sequences of SEQ ID NO: 131, SEQ ID NO:165, SEQ ID NO: 208; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 213, SEQ ID NO: 269, and SEQ ID NO: 322; or uu)the three VL CDRs of amino acid sequences of SEQ ID NO: 137, SEQ ID NO:166, SEQ ID NO: 169; and comprising the three VH CDRs of amino acid sequences of SEQ ID NO: 244, SEQ ID NO: 256, and SEQ ID NO: 323.

5. The method of claims 1-4, wherein:119331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073a) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 415, or an amino acid sequence with at least 70% sequence identity thereto;b) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 384, or an amino acid sequence with at least 70% sequence identity thereto;c) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 373, or an amino acid sequence with at least 70% sequence identity thereto;d) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 374, or an amino acid sequence with at least 70% sequence identity thereto;e) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 375, or an amino acid sequence with at least 70% sequence identity thereto;f) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 376, or an amino acid sequence with at least 70% sequence identity thereto;g) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 330 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 377, or an amino acid sequence with at least 70% sequence identity thereto;h) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 331 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 378, or an amino acid sequence with at least 70% sequence identity thereto;120331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073i) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 332 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 379, or an amino acid sequence with at least 70% sequence identity thereto;j) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 333 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 380, or an amino acid sequence with at least 70% sequence identity thereto;k) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 381, or an amino acid sequence with at least 70% sequence identity thereto;l) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 382, or an amino acid sequence with at least 70% sequence identity thereto;m) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 383, or an amino acid sequence with at least 70% sequence identity thereto;n) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 325 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 372, or an amino acid sequence with at least 70% sequence identity thereto;o) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 338 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 385, or an amino acid sequence with at least 70% sequence identity thereto;p) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 339 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 386, or an amino acid sequence with at least 70% sequence identity thereto;121331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073q) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 340 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 387, or an amino acid sequence with at least 70% sequence identity thereto;r) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 341 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 388, or an amino acid sequence with at least 70% sequence identity thereto;s) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 389, or an amino acid sequence with at least 70% sequence identity thereto;t) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 390, or an amino acid sequence with at least 70% sequence identity thereto;u) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 391, or an amino acid sequence with at least 70% sequence identity thereto;v) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 392, or an amino acid sequence with at least 70% sequence identity thereto;w) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 346 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 393, or an amino acid sequence with at least 70% sequence identity thereto;x) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 347 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 394, or an amino acid sequence with at least 70% sequence identity thereto;122331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073y) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 348 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 395, or an amino acid sequence with at least 70% sequence identity thereto;z) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 349 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 396, or an amino acid sequence with at least 70% sequence identity thereto;aa) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 397, or an amino acid sequence with at least 70% sequence identity thereto;bb)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 398, or an amino acid sequence with at least 70% sequence identity thereto;cc) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 399, or an amino acid sequence with at least 70% sequence identity thereto;dd)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 400, or an amino acid sequence with at least 70% sequence identity thereto;ee) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 354 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 401, or an amino acid sequence with at least 70% sequence identity thereto;ff) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 355 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 402, or an amino acid sequence with at least 70% sequence identity thereto;123331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073gg)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 356 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 403, or an amino acid sequence with at least 70% sequence identity thereto;hh)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 357 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 404, or an amino acid sequence with at least 70% sequence identity thereto;ii) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 405, or an amino acid sequence with at least 70% sequence identity thereto;jj) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 406, or an amino acid sequence with at least 70% sequence identity thereto;kk)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 407, or an amino acid sequence with at least 70% sequence identity thereto;11) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 408, or an amino acid sequence with at least 70% sequence identity thereto;mm) the VH of the antibody comprises the amino acid sequence of SEQ ID NO:362 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 409, or an amino acid sequence with at least 70% sequence identity thereto;nn)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 363 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 410, or an amino acid sequence with at least 70% sequence identity thereto;124331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073oo)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 364 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 411, or an amino acid sequence with at least 70% sequence identity thereto;pp)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 365 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 412, or an amino acid sequence with at least 70% sequence identity thereto;qq)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 413, or an amino acid sequence with at least 70% sequence identity thereto;rr) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 414, or an amino acid sequence with at least 70% sequence identity thereto;ss) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 324 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 371, or an amino acid sequence with at least 70% sequence identity thereto;tt) the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 416, or an amino acid sequence with at least 70% sequence identity thereto; oruu)the VH of the antibody comprises the amino acid sequence of SEQ ID NO: 370 or an amino acid sequence with at least 70% sequence identity thereto, and the VL of the antibody comprises the amino acid sequence of SEQ ID NO: 417, or an amino acid sequence with at least 70% sequence identity thereto.

6. The method of any one of claims 1-5, wherein the antibody is an antibody fragment.

7. The method of any one of claims 1-5, wherein the antibody is a human antibody.

8. The method of any one of claims 1-5, wherein the antibody is a humanized antibody.125331845966Attorney Docket No.: ELTH-009 / 01WO 336159-20739. The method of any one of claims 1-5, wherein the antibody is a full-length antibody.

10. The method of any one of claims 1-9, wherein the antibody wherein the antibody has low or no affinity for binding SIRPa and / or SIRPpi .

11. The method of any one of claims 1-10, wherein the antibody binds to human and nonhuman primate SIRPy with high affinity.

12. The method of any one of claims 1-10, wherein the antibody does not bind to human and non-human primate SIRPa or SIRPpi .

13. The method of any one of claims 1-12, wherein the antibody comprises a Fc domain.

14. The method of claim 13, wherein the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4 heavy chain sequence.

15. The method of claim 14, wherein the Fc domain is from the heavy chain IgG amino acid sequences of SEQ ID NO: 5 or SEQ ID NO: 28, optionally with one or more Fc amino acid substitutions.

16. The method of claim 15, wherein the Fc domain is from the heavy chain IgG amino acid sequences of any one of SEQ ID NOS: 5-36.

17. The method claim 15, wherein the heavy chain Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 5 or SEQ ID NO: 28 at a position selected from the group consisting of: 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, and 440 wherein the position numbers of the amino acid residues are of the EU numbering scheme.

18. The method of any one of claims 1-17, wherein the antibody comprises a light chain constant region that is from the amino acid sequences of any one of SEQ ID NOS: 38-42.

19. The method of any one of claims 1-18, wherein the binding of the antibody does not disrupt the interaction between CD47 and SIRPy.126331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207320. The method of any one of claims 1-18, wherein the binding of the antibody disrupts the interaction between CD47 and SIRPy.

21. The method of any one of claims 1-18, wherein the binding of the antibody stabilizes or promotes the interaction between CD47 and SIRPy.

22. The method comprising of anyone of claims 1-21, wherein the antibody comprises a binding affinity to SIRPy lower than about 500 nM.

23. The method of any one of claims 1-22, wherein the antibody preferentially depletes of a population of SIRPy-expressing cells.

24. The method of claim 23, wherein the SIRPy-expressing cells are T cells, B cells and / or NK cells.

25. The method of claim 23, wherein the SIRPy-expressing cells are T cells.

26. The method of claim 25, wherein the T cells are activated (stimulated).

27. The method of claim 25, wherein the T cells are activated (stimulated), and the depletion is preferential for activated (stimulated) T cells.

28. The method of claim 25, wherein the T cells are exhausted.

29. The method of claim 25, wherein the T cells are exhausted, and the depletion is preferential for exhausted T cells.

30. The method of claim 25, wherein the T cells are naive, central memory, effector memory, exhausted, or terminal effector memory cells.

31. The method of claim 25, wherein the T cells are cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, natural killer T cells, mucosal associated invariant T cells, alpha beta T cells, or gamma delta T cells.

32. The method of claim 25, wherein the T cells are Thl cells, Th2 cells, Thl7 cells or T follicular helper cells.127331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073 33. The method of claim 25, wherein the T cells are a CD3+ T cell, CD4+ T cell, CD8+ T cell, CD25+ T cell, CD69+ T cell, and / or PD1+ T cell.

34. The method of claim 33, wherein the T cells are CD4+ / CD8+ T cells.

35. The method of claim 33, wherein the T cells are CD69+ / CD8+ T cells.

36. The method of claim 33, wherein the T cells are CD25+ / CD8+ T cells.

37. The method of claim 33, wherein the T cells are PD1+ T cells.

38. The method of claim 33, wherein the depletion is preferential for stimulated T cells, as compared to unstimulated T cells.

39. The method of claim 33, wherein the depletion is preferential for SIRPy-expressing CD8+ T cells.

40. The method of claim 33, wherein the depletion is preferential for SIRPy-expressing CD4+ T- cells.

41. The method of claim 33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T- cells.

42. The method of claim 33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T- cells.

43. The method of claim 33, wherein the depletion is preferential for SIRPy-expressing CD8+ T cells, when compared to SIRPy-expressing CD4+ T- cells.

44. The method of claim 33, wherein the depletion is preferential for SIRPy-expressing CD4+ T cells, when compared to SIRPy-expressing CD8+ T- cells.

45. The method of claim 33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD69+ T cells, when compared to SIRPy-expressing CD8+ / CD69- T- cells.

46. The method of claim 33, wherein the depletion is preferential for SIRPy-expressing CD8+ / CD25+ T cells, when compared to SIRPy-expressing CD8+ / CD25- T- cells.128331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207347. The method of claim 23, wherein the SIRPy-expressing cells are B cells.

48. The method of claim 23, wherein the SIRPy-expressing cells are NK cells.

49. The method of any one of claims 23-48, wherein, the SIRPy-expressing cells are activated.

50. The method any one of claims 23-49, wherein the population of SIRPy-expressing cells comprises tissue-resident cells.

51. The method any one of claims 23-50, wherein the population of SIRPy-expressing cells comprises circulating cells.

52. The method of any one of claims 23-51, wherein the depletion involves one or more of ADCC, ADCP, and CDC.

53. The method of any one of claims 1-52, wherein the antibody is administered with a pharmaceutically acceptable carrier.

54. The method of any one of claims 1-53, wherein the subject is human.

55. The method of any one of claims 1-54, wherein the SIRPy antibody is administered subcutaneously or intravenously.

56. The method of any one of claims 1-55, wherein the antibody is administered in combination with one or more ofa) a glucocorticoid such as dexamethasone, prednisone, prednisolone, or methylprednisolone;b) a cytokine inhibitor, including but not limited to anti-IL-6 receptor inhibitors (e.g., tocilizumab, sarilumab) and anti-IL-ip or IL-1 receptor inhibitors (e.g., canakinumab, anakinra); andc) an immune suppressant or modulator, such as methotrexate.

57. Use of an antibody for the treatment of a granulomatous disease or disorder in a subject in need thereof, wherein the antibody is specific for SIRPy.129331845966Attorney Docket No.: ELTH-009 / 01WO 336159-207358. Use of an antibody for the manufacture of a medicament for the treatment of granulomatous disease or disorder in a subject in need thereof, wherein the antibody is specific for SIRPy.

59. The use of claim 57 or claim 58, wherein the disease or disorder is a granulomatous disease or disorder.

60. The use of claim 59, wherein the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with poly angiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis.

61. The use of claim 59 or claim 60, wherein the granulomatous disease or disorder is giant cell arteritis (GCA).

62. The use of any one of claims 57-61, wherein the subject is a human.

63. A method of treating a granulomatous disease or disorder in subject in need thereof, comprising administering to the subject an anti -SIRPy antibody, wherein the antibody comprises a means for binding human SIRPy.

64. The method of claim 63, wherein the granulomatous disease or disorder is selected from the group consisting of giant cell arteritis (GCA), sarcoidosis, Crohn’s disease, metastatic Crohn’s Disease, chronic granulomatous disease, granuloma annulare, Granulomatous Pyoderma, Necrobiosis lipoidica, Granulomatous vasculitis, Wegener's granulomatosis (granulomatosis with poly angiitis), Eosinophilic granulomatosis with polyangiitis, classic polyarteritis nodosa, Granuloma Annulare, Annular Elastolytic Giant Cell Granuloma, Methotrexate-induced Accelerated Rheumatoid Nodulosis, Necrobiotic Xanthogranuloma, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug 130331845966Attorney Docket No.: ELTH-009 / 01WO 336159-2073Reaction, Berylliosis (chronic beryllium disease), and Palisaded Neutrophilic Granulomatous Dermatitis.

65. The method of claim 63 or claim 64, wherein the granulomatous disease or disorder is giant cell arteritis (GCA).

66. The method of any one of claims 63-65, wherein the subject is a human.

67. The method of any one of claims 63-66, wherein the SIRPy antibody is administered subcutaneously or intravenously.131331845966

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