SIRP alpha, beta, gamma antibodies for treatment of epstein–BARR virus infections

Abstract

Provided herein are SIRP antibodies, specific for one or more of SIRPα and SIRPβ, and also specific for SIRPγ, for the treatment of Epstein–Barr virus (EBV) and clinically relevant parameters thereof.

Description

SIRP ALPHA, BETA, GAMMA ANTIBODIES FOR TREATMENT OF EPSTEIN- BARR VIRUS INFECTIONSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional patent application number 63 / 637,314, filed on April 22, 2024, the contents of which is incorporated by reference herein in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (ELTH_007_01WO_SeqList_ST26.xml; Size: 211,386 bytes; and Date of Creation: April 17, 2025) are herein incorporated by reference in its entirety.BACKGROUND

[0003] Epstein-Barr virus (EBV) is a common human virus of the herpesvirus family which infects B cells and also epithelial cells. After infection occurs, EBV can remain dormant for life in the host’s cells and reactivate to produce new virus particles. In many cases EBV may not cause any notable symptoms, especially in young children. However, those individuals that do experience symptoms, experience a wide variety of symptoms ranging from mild to severe. One significant concern with EBV infection is its linkage to several diseases and disorders including a variety of cancers such as lymphoma and immune disorders such as hemophagocytic lymphohistiocytosis (HLH).

[0004] Despite a high prevalence of EBV infection in humans, there is currently no licensed vaccine available, making treatment and management methods highly desirable. Thus, there is a need for novel targets, agents, and protocols for the treatment of EBV infection. Provided herein are methods and compositions that address this need.SUMMARY

[0005] The disclosure provides SIRP antibodies that are specific for one or more of SIRPa and SIRPP, and are also specific for SIRPy, useful in a method of treating an EBV infection in a subject in need thereof.

[0006] In some embodiments of the antibodies of disclosure, the antibody comprises the heavy and light variable chain CDR sequence combination selected from the group consisting of:(a) SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106;(b) SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118;(c) SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 124;(d) SEQ ID NO: 137, SEQ ID NO: 138, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142;(e) SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148;(f) SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154;(g) SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 159, SEQ ID NO: 160;(h) SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166;(i) SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172;0) SEQ ID NO: 173, SEQ ID NO: 174, SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178;(k) SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184; and(l) SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190.

[0007] In some embodiments of the antibodies of the disclosure, the heavy chain variable region sequence and the light chain variable region sequence are selected from the group consisting of:(a) the VH comprises the amino acid sequence of SEQ ID NO: 497, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the aminoacid sequence of SEQ ID NO: 498, or an amino acid sequence with at least 80% sequence identity thereto;(b) the VH comprises the amino acid sequence of SEQ ID NO: 501, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 502, or an amino acid sequence with at least 80% sequence identity thereto;(c) the VH comprises the amino acid sequence of SEQ ID NO: 503, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 504, or an amino acid sequence with at least 80% sequence identity thereto;(d) the VH comprises the amino acid sequence of SEQ ID NO: 509, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 510, or an amino acid sequence with at least 80% sequence identity thereto;(e) the VH comprises the amino acid sequence of SEQ ID NO: 511, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 512, or an amino acid sequence with at least 80% sequence identity thereto;(f) the VH comprises the amino acid sequence of SEQ ID NO: 513, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 514, or an amino acid sequence with at least 80% sequence identity thereto;(g) the VH comprises the amino acid sequence of SEQ ID NO: 515, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence with at least 80% sequence identity thereto;(h) the VH comprises the amino acid sequence of SEQ ID NO: 517, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence with at least 80% sequence identity thereto;(i) the VH comprises the amino acid sequence of SEQ ID NO: 519, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the aminoacid sequence of SEQ ID NO: 520, or an amino acid sequence with at least 80% sequence identity thereto;(j) the VH comprises the amino acid sequence of SEQ ID NO: 521, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence with at least 80% sequence identity thereto;(k) the VH comprises the amino acid sequence of SEQ ID NO: 523, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 524, or an amino acid sequence with at least 80% sequence identity thereto; and(l) the VH comprises the amino acid sequence of SEQ ID NO: 525, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 526, or an amino acid sequence with at least 80% sequence identity thereto.

[0008] In some embodiments of the antibodies of the disclosure, the antibody is a monoclonal antibody. In some embodiments, 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 chimeric antibody. In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is a bispecific antibody.

[0009] In some embodiments of the antibodies of the disclosure, the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4. In some embodiments, the Fc domain comprises the amino acid sequence of any one of SEQ ID NO: 15-46. In some embodiments, the Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 15 or SEQ ID NO: 39. In some embodiments, the at least one amino acid substitution is 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.

[0010] In some embodiments, the EBV infection is acute or chronic. In some embodiments, the subject is infected with an EBV strain selected from the group consisting of type 1 (EBV- 1), type 2 (EBV-2), and an EBV variant strain or subtype thereof. In some embodiments, thesubject suffers from an EBV-associated disease or disorder. In some embodiments, the treatment prevents, delays, or mitigates of the onset of an EBV-associated disease or disorder. In some embodiments, the EBV-associated disease or disorder is selected from the group consisting of a secondary hemophagocytic lymphohistiocytosis (sHLH), cancer, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes (T1D), Macrophage activation syndrome (MAS), chronic NK lymphocytosis, and T cell chronic active EBV (CAEBV). In some embodiments, the subject suffers from one or more additional comorbidities.

[0011] In some embodiments, the treatment reduces the EBV viral load in the subject. In some embodiments, the EBV viral load is reduced at least by 10%. In some embodiments, the EBV viral load is reduced in the blood. In some embodiments, the EBV viral load is reduced in B cells, T cells, NK cells, or myeloid cells. In some embodiments, the EBV viral load is reduced in bone marrow. In some embodiments, the treatment results in the depletion of SIRP-expressing cells. In some embodiments, the SIRP-expressing cells are B cells, T cells, or NK cells. In some embodiments, the method of treatment comprises monitoring EBV viral load, PET-SCANs, C-reactive protein (CRP), sCD25, and / or ferritin peak, minimum, maximum, and reduction prospectively to diagnose and predict prognosis, and / or likelihood of response to therapy for the EBV infection, EBV associated disease or disorder, and / or the one or more additional comorbidities.

[0012] In some embodiments, the SIRP binding antibody is administered to the subject subcutaneously or intravenously. In some embodiments, the administration occurs in a treatment phase (herein referred to interchangeably as a maintenance phase). In some embodiments, the method comprises more than one treatment phase. In some embodiments, the treatment phase comprises a dose of at least about 0.01 mg / kg to about 5.0 mg / kg of the SIRP binding antibody. In some embodiments, the treatment phase comprises a dose about 0.1 mg / kg to about 1.0 mg / kg of the SIRP binding antibody.

[0013] In some embodiments, the SIRP binding antibody is administered in combination with an additional therapy. In some embodiments, the additional therapy is selected from the group consisting of corticosteroids, antiviral agents (e.g., nucleoside analogues), interleukin- 2, interferon alfa, intravenous immunoglobulins, etoposide, and other chemotherapy agents.

[0014] In some embodiments, the SIRP binding antibody is administered in a pharmaceutical composition, wherein the pharmaceutical composition comprises the antibody, and a pharmaceutically acceptable carrier.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIGS. 1A-B shows the PK profile and various HLH markers, PD, and blood count response after IV administration of a SIRP antibody of the disclosure during the first 71+ days of treatment in patient 602-01 with EBV triggered sHLH.

[0016] FIG. 2 shows Ferritin and ALT response to a SIRP antibody of the disclosure during the first 57 days of treatment in patient 601-10 with EBV triggered sHLH in the background of Peripheral T-Cell Lymphoma (PTCL).

[0017] FIG. 3 shows Ferritin, sCD25, CRP, and ALT response to a SIRP antibody of the disclosure during the first 11 days of treatment in patient 609-02 with EBV+ diffuse large B- cell lymphoma (DLBCL),

[0018] FIGS. 4A-B shows an increased frequency of SIRP+ B cells in patient US603- EAP001 with EBV-triggered sHLH. FIG. 4A depicts a flow cytometry analysis of B cells from a normal healthy volunteer (NHV) (left) and EBV-triggered sHLH patient (right). FIG. 4B shows the percentage of SIRP+ B cells in NHV (mean ± SD, n=6) and EBV-triggered sHLH patient.DETAILED DESCRIPTION

[0019] Provided herein are antibodies that bind to one or more of SIRPa and SIRPP, and that are also specific for SIRPy, and methods of treating EBV infections using such antibodies. The antibodies may be useful for treating EBV infections by reducing viral load in infected cell types, involved in EBV pathology.Definitions

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The term “priming dose phase” refers to a phase to prime the subject for a subsequent treatment phase. In some embodiments, the dosing protocol comprises a priming dose phase followed by a subsequent treatment phase. In some embodiments, the protocol comprises multiple treatment phases, each optionally preceded by a priming dose phase. The term “priming dose” or “priming doses” refers to one or more doses within the priming dose phase. In some embodiments, a therapeutic effect may be present during the priming dose phase.

[0024] 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. AntibodiesA. SIRP Antibodies

[0025] Provided herein are antibodies that bind to one or more of SIRPa and SIRPP, and are also specific for SIRPy, and are interchangeably referred to herein as SIRP antibodies, anti- SIRP antibodies, SIRP binding antibodies and the like.

[0026] The skilled artisan will appreciate that, depending on context, a SIRP antibody of the disclosure that has the ability to bind to one or more of SIRPa and SIRPP, and to SIRPy will encounter a binding surface (e.g., a cell) that may express only a subset of the targets towhich the antibody is capable of binding. For example, an antibody that can bind SIRPa and SIRPy, can bind to a cell expressing only SIRPa. Alternatively, a binding surface, such as a cell, may express more than one, or all, of the targets to which the antibody can bind. In such a situation, the antibody is also expected to bind that surface. Thus, although the SIRP antibodies of the disclosure may have binding specificity for one or more of SIRPa and SIRPP, and also for SIRPy, the binding of multiple SIRP isoforms simultaneously is not required for activity.

[0027] 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.

[0028] In exemplary embodiments, the SIRP antibodies provided herein are monoclonal antibodies (mAbs). In exemplary embodiments, the SIRP antibodies provided herein are human antibodies. In exemplary embodiments, the SIRP antibodies provided herein are humanized antibodies. In exemplary embodiments, the SIRP antibodies provided herein are monoclonal human antibodies. In exemplary embodiments, the SIRP antibodies provided herein are chimeric antibodies. In exemplary embodiments, the SIRP antibodies provided herein are monoclonal chimeric antibodies.

[0029] In some embodiments, the SIRP antibodies provided herein are antibody fragments, retaining SIRPy as well as SIRPP and / or SIRPa antigen binding specificity. In some embodiments, the antibody fragments are 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 (sc Ab) or other antibody variable region fragments, such as Fab’, F(ab’)2, dsFv diabody, and Fd polypeptide fragments.

[0030] The SIRPa protein has been characterized to be highly polymorphic but does not appear to affect ligand binding properties. At least thirteen variants (polymorphs) have been characterized in humans, Variants 1-13, with VI and V2 the most common. (Hatherley et al. JBC 289: 10024-10028, 2014). SIRPa also has at least three isoforms. Accordingly, the term “SIRPa” as used herein is inclusive of all variants and isoforms of SIRPa. Such isoforms are described in greater detail in WO2021226591, the contents of which are incorporated by reference in their entirety herein.

[0031] The amino acid sequence of human SIRPa (hSIRPa) isoform 1, variant 1 (VI) is provided in SEQ ID NO: 9 and referred to herein as hSIRPa VI.1 MEPAGPAPGR LGPLLCLLLA ASCAWSGVAG EEELQVIQPD KSVLVAAGET ATLRCTATSL 61 I PVGPIQWFR GAGPGRELIY NQKEGHFPRV TTVSDLTKRN NMDFSIRIGN ITPADAGTYY 121 CVKFRKGSPD DVEFKSGAGT ELSVRAKPSA PWSGPAARA TPQHTVSFTC ESHGFSPRDI 181 TLKWFKNGNE LSDFQTNVDP VGESVSYSIH STAKWLTRE DVHSQVICEV AHVTLQGDPL 241 RGTANLSETI RVPPTLEVTQ QPVRAENQVN VTCQVRKFYP QRLQLTWLEN GNVSRTETAS 301 TVTENKDGTY NWMSWLLVNV SAHRDDVKLT CQVEHDGQPA VSKSHDLKVS AHPKEQGSNT 361 AAENTGSNER NIYIWGWC TLLVALLMAA LYLVRIRQKK AQGSTSSTRL HEPEKNAREI 421 TQDTNDITYA DLNLPKGKKP APQAAEPNNH TEYASIQTSP QPASEDTLTY ADLDMVHLNR 481 TPKQPAPKPE PSFSEYASVQ VPRK ( SEQ ID NO : 5 )

[0032] The amino acid sequence of hSIRPa isoform 1, variant 2 (V2) is provided in SEQ ID NO: 10 and referred to herein as hSIRPa V2.1 MEPAGPAPGR LGPLLCLLLA ASCAWSGVAG EEELQVIQPD KSVSVAAGES AILHCTVTSL61 I PVGPIQWFR GAGPARELIY NQKEGHFPRV TTVSESTKRE NMDFSI SI SN ITPADAGTYY121 CVKFRKGSPD TEFKSGAGTE LSVRAKPSAP WSGPAARAT PQHTVSFTCE SHGFSPRDIT181 LKWFKNGNEL SDFQTNVDPV GESVSYSIHS TAKWLTRED VHSQVICEVA HVTLQGDPLR241 GTANLSETIR VPPTLEVTQQ PVRAENQVNV TCQVRKFYPQ RLQLTWLENG NVSRTETAST301 VTENKDGTYN WMSWLLVNVS AHRDDVKLTC QVEHDGQPAV SKSHDLKVSA HPKEQGSNTA361 AENTGSNERN IYIWGWCT LLVALLMAAL YLVRIRQKKA QGSTSSTRLH EPEKNAREIT421 QVQSLDTNDI TYADLNLPKG KKPAPQAAEP NNHTEYASIQ TSPQPASEDT LTYADLDMVH481 LNRTPKQPAP KPEPSFSEYA SVQVPRK ( SEQ ID NO : 6 )

[0033] The amino acid sequence of hSIRPa isoform 2 is provided herein as SEQ ID NO: 11.1 MEPAGPAPGR LGPLLCLLLA ASCAWSGVAG EEELQVIQPD KSVLVAAGET ATLRCTATSL61 I PVGPIQWFR GAGPGRELIY NQKEGHFPRV TTVSDLTKRN NMDFSIRIGN ITPADAGTYY121 CVKFRKGSPD DVEFKSGAGT ELSVRAKPSA PWSGPAARA TPQHTVSFTC ESHGFSPRDI181 TLKWFKNGNE LSDFQTNVDP VGESVSYSIH STAKWLTRE DVHSQVICEV AHVTLQGDPL241 RGTANLSETI RVPPTLEVTQ QPVRAENQVN VTCQVRKFYP QRLQLTWLEN GNVSRTETAS301 TVTENKDGTY NWMSWLLVNV SAHRDDVKLT CQVEHDGQPA VSKSHDLKVS AHPKEQGSNT361 AAENTGSNER NIYIWGWC TLLVALLMAA LYLVRIRQKK AQGSTSSTRL HEPEKNAREI421 TQVQSLDTND ITYADLNLPK GKKPAPQAAE PNNHTEYASI QTSPQPASED TLTYADLDMV481 HLNRTPKQPA PKPEPSFSEY ASVQVPRK ( SEQ ID NO : 7 )

[0034] The amino acid sequence of human SIRPa isoform 4 is provided in SEQ ID NO: 12.1 MEPAGPAPGR LGPLLCLLLA ASCAWSGVAG EEELQVIQPD KSVLVAAGET ATLRCTATSL61 I PVGPIQWFR GAGPGRELIY NQKEGHFPRV TTVSDLTKRN NMDFSIRIGN ITPADAGTYY121 CVKFRKGSPD VEFKSGAGTE LSVRAKPSAP WSGPAARAT PQHTVSFTCE SHGFSPRDIT181 LKWFKNGNEL SDFQTNVDPV GESVSYSIHS TAKWLTRED VHSQVICEVA HVTLQGDPLR241 GTANLSETIR VPPTLEVTQQ PVRAENQVNV TCQVRKFYPQ RLQLTWLENG NVSRTETAST301 VTENKDGTYN WMSWLLVNVS AHRDDVKLTC QVEHDGQPAV SKSHDLKVSA HPKEQGSNTA361 AENTGSNERN IYIWGWCT LLVALLMAAL YLVRIRQKKA QGSTSSTRLH EPEKNAREIT421 QDTNDITYAD LNLPKGKKPA PQAAEPNNHT EYASIQTSPQ PASEDTLTYA DLDMVHLNRT481 PKQPAPKPEP SFSEYASVQV PRK ( SEQ ID NO : 8 )

[0035] In some embodiments, the SIRP antibodies also bind to one or more variants or isoforms of a SIRPa of a single species. In some embodiments, the SIRP antibodies also bind to one or more variants or isoforms of a SIRPa of more than one species. In some embodiments, the SIRP antibodies also bind to one or more variants or isoforms of human SIRPa. In some embodiments, the SIRP antibodies also bind to one or more variants or isoforms of a non-human primate SIRPa, e.g. a cynomolgus monkey SIRPa.

[0036] In some embodiments, the SIRP antibodies also bind to a plurality of SIRPa variants found in a particular species, e.g. the SIRP antibodies bind to more than one of SIRPa human variants 1-13. In some embodiments the SIRP antibodies also bind to hSIRPa VI. In some embodiments, the SIRP antibodies also bind to hSIRPa V2. In some embodiments, the SIRP antibodies also bind to hSIRPa VI and V2. In some embodiments, the SIRP antibodies also bind the extracellular domain of SIRPa, e.g. hSIRPa VI (e.g. Metl-Arg370 of VI, Gly27- Arg370 of VI, or Glu31-Arg370 of VI), or e.g. hSIRPa V2 (Metl-Arg369).

[0037] In some embodiments, the SIRP antibodies of the disclosure bind a plurality of SIRPa isoforms. For example, the SIRP antibodies of the disclosure may bind to two or more SIRPa isoforms, or all SIRPa isoforms. In some embodiments, the SIRP antibodies bind to isoform 1, 2 and 4 of SIRPa.

[0038] In some embodiments, the SIRP antibodies also bind specifically to hSIRPa VI. In some embodiments, the SIRP antibodies also bind specifically to hSIRPa V2. In some embodiments, the SIRP antibodies also bind specifically to hSIRPa VI and hSIRPa V2. In some embodiments, the SIRP antibodies also bind specifically to one or more variants of SIRPa, but show little or no binding to SIRPP or SIRPy.

[0039] Human SIRPP (hSIRPP) has at least 3 isoforms. SIRPP is also known in the literature as SIRPP 1, and these terms are used interchangeably herein. Such isoforms are described in greater detail in WO2021226591, the contents of which are incorporated by reference in their entirety herein. The amino acid sequence of hSIRPP isoform 1 is provided in SEQ ID NO: 131 MPVPASWPHL PSPFLLMTLL LGRLTGVAGE DELQVIQPEK SVSVAAGESA TLRCAMTSLI61 PVGPIMWFRG AGAGRELIYN QKEGHFPRVT TVSELTKRNN LDFSI SI SNI TPADAGTYYC 121 VKFRKGSPDD VEFKSGAGTE LSVRAKPSAP WSGPAVRAT PEHTVSFTCE SHGFSPRDIT 181 LKWFKNGNEL SDFQTNVDPA GDSVSYSIHS TARWLTRGD VHSQVICEIA HITLQGDPLR 241 GTANLSEAIR VPPTLEVTQQ PMRAENQANV TCQVSNFYPR GLQLTWLENG NVSRTETAST301 LIENKDGTYN WMSWLLVNTC AHRDDWLTC QVEHDGQQAV SKSYALEI SA HQKEHGSDIT 361 HEAALAPTAP LLVALLLGPK LLLWGVSAI YICWKQKA ( SEQ ID NO : 9 )

[0040] In some embodiments, the SIRP antibodies also bind to one or more variants or isoforms of a SIRPp of a single species. In some embodiments, the SIRP antibodies also bind to one or more variants or isoforms of a SIRPP of more than one species. In some embodiments, the SIRP antibodies also bind to one or more variants or isoforms of human SIRPp. In some embodiments, the SIRP antibodies also bind to one or more variants or isoforms of a non-human primate SIRPP, e.g. a cynomolgus monkey SIRPp.

[0041] In some embodiments, the SIRP antibodies also bind to a plurality of SIRPP variants or isoforms found in a particular species, e.g. the SIRP antibodies bind to more than one of SIRPP human isoforms 1-3. In some embodiments, the SIRP antibodies also bind the extracellular domain of SIRPP (e.g. amino acids 1-371 of SEQ ID NO: 13). In some embodiments, the SIRP antibodies also bind specifically to one or more variants or isoforms of SIRPP, in addition to binding to SIRPy and / or SIRPa.

[0042] Human SIRPy has at least 4 isoforms. SIRPy is also known as SIRPP2, and SIRPP2 is not to be confused with SIRPP which is referred to as SIRPP and SIRPP 1 interchangeably herein. The amino acid of hSIRPy isoform 1 is provided as SEQ ID NO: 14 (referencing UniProtKB ID Q9P1W8 Isoform 1).1 MPVPASWPHP PGPFLLLTLL LGLTEVAGEE ELQMIQPEKL LLVTVGKTAT LHCTVTSLLP61 VGPVLWFRGV GPGRELIYNQ KEGHFPRVTT VSDLTKRNNM DFSIRI SSIT PADVGTYYCV121 KFRKGSPENV EFKSGPGTEM ALGAKPSAPV VLGPAARTTP EHTVSFTCES HGFSPRDITL181 KWFKNGNELS DFQTNVDPTG QSVAYSIRST ARWLDPWDV RSQVICEVAH VTLQGDPLRG241 TANLSEAIRV PPTLEVTQQP MRVGNQVNVT CQVRKFYPQS LQLTWSENGN VCQRETASTL301 TENKDGTYNW TSWFLVNI SD QRDDWLTCQ VKHDGQLAVS KRLALEVTVH QKDQSSDATP361 GPASSLTALL LIAVLLGPIY VPWKQKT ( SEQ ID NO : 10 )

[0043] The amino acid sequence of a splice variant hSIRPy (isoform 2) is provided as SEQ ID NO: 37. (referencing UniProtKB ID Q9P1W8 Isoform 2).MIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRI SS ITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPSAPWLGPAARTTPEHTVSFTCESHGFSPRDITLKWF KNGNELSDFQTNVDPTGQSVAYSIRSTARWLDPWDVRSQVICEVAHVTLQGDPLRGTANLSEAIRVPPTLEVTQ QPMRVGNQVNVTCQVRKFYPQSLQLTWSENGNVCQRETASTLTENKDGTYNWTSWFLVNI SDQRDDWLTCQVKHDGQLAVSKRLALEVTVHQKDQSSDATPGPASSLTALLLIAVLLGPIYVPWKQKT ( SEQ ID NO : 11 )

[0044] The amino acid sequence of a splice variant hSIRPy (isoform 3) is provided as SEQID NO: 2. (referencing UniProtKB ID Q9P1W8 Isoform 3).MPVPASWPHPPGPFLLLTLLLGLTEVAGEEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRE LIYNQKEGHFPRVTTVSDLTKRNNMDFSIRI SSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGGPASSLT ALLLIAVLLGPIYVPWKQKT ( SEQ ID NO : 12 )

[0045] The amino acid sequence of another splice variant hSIRPy (isoform 4) is provided asSEQ ID NO: 3 (referencing UniProtKB ID Q9P1W8 Isoform 4).MPVPASWPHPPGPFLLLTLLLGLTEVAGEEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRE LIYNQKEGHFPRVTTVSDLTKRNNMDFSIRI SSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPSAPV VLGPAARTTPEHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPTGQSVAYSIRSTARWLDPWDVRSQVI CEVAHVTLQGDPLRGTANLSEAIRGPASSLTALLLIAVLLGPIYVPWKQKT ( SEQ ID NO : 13 )

[0046] The amino acid sequence of cynomolgus monkey SIRPy is provided as SEQ ID NO:4. (referencing GenBank: EHH65481.1).MPVPASWSHPPGPFLLLTLLLGFTEVAGEEELQMIQPEKLLLVAVGESATLNCTVTSLLPVGPVLWFRGVGPGRE LIYNQKEGHFPRVTTVSDLTKRNNMDFSIRI SSITPADAGTYYCVKFRKGSPENVEFKSGPGTEMALRAKPSAPV VSGPAARATPEHTVSFTCKSHGFSPRDITLKWFKNGNELSDFQTNVDPAGQSVSYSIRSTARWLAPWDVRSQVT CEVAHVTLQGDPLRGTANLSEAIRVPPTLEVTQQPMRAGNQVNITYQVRNFYPQNLQLTWLENGNVCRTETASTL TENKDGTYNWTSWLLVNTSDQRDDWLTCQVKHDGQLAVNKSLVLEVSAHQKDQSSDATHGPASSLTVLLLIAVL LGPIYVPWKQKS ( SEQ ID NO : 14 )

[0047] In some embodiments, the SIRP antibodies bind to one or more variants or isoforms of a SIRPy of a single species. In some embodiments, the SIRP antibodies bind to one or more variants or isoforms of a SIRPy of more than one species. In some embodiments, the SIRP antibodies bind to one or more variants or isoforms of human SIRPy. In some embodiments, the SIRP antibodies bind to one or more variants or isoforms of a non-human primate SIRPy, e.g. a cynomolgus monkey SIRPy.

[0048] In some embodiments, the SIRP antibodies bind to a plurality of SIRPy variants or isoforms found in a particular species, e.g. the SIRP antibodies bind to more than one ofSIRPy human isoforms 1-3. In some embodiments, the SIRP antibodies bind the extracellular domain of SIRPy (e.g. amino acids 1-360 of SEQ ID NO: 14). In some embodiments, the SIRP antibodies also bind specifically to one or more variants or isoforms of SIRPy, in addition to binding to SIRPa and / or SIRPp.

[0049] In some embodiments, a SIRP antibody of the disclosure competes with CD47 for binding to SIRPa or SIRPy on a cell or other surface. In some embodiments, a SIRP antibody of the disclosure partially competes with CD47 for binding to SIRPa or SIRPy on a cell or other surface. In other embodiments, a SIRP antibody of the disclosure does not compete with CD47 for binding to SIRPa or SIRPy on a surface, e.g a cell. Exemplary antibodies ofthe disclosure that do not compete with CD47 binding of SIRPa include Antibodies 1, 12, 13, 15, and 28. Exemplary antibodies of the disclosure that partially inhibit the binding of CD47 to SIRPa include Antibodies 3, 4, 7-11, 14, and 24. Exemplary antibodies of the disclosure that do not compete with CD47 binding of SIRPy include Antibodies 1, 12, 13, 15, and 28. Exemplary antibodies of the disclosure that partially inhibit the binding of CD47 to SIRPy include Antibodies 3, 4, 7-11, 14, and 24.

[0050] Also provided herein are Fc-containing SIRP antibodies. In some embodiments, Fc domain of (interchangeably referred to as a Fc sequence, Fc region, or simply Fc) of the SIRP antibody is a human Fc domain. In some embodiments, the Fc domain of a SIRP antibody is human IgGl, human IgG2, human IgG3, or human IgG4. In some embodiments, the Fc domain of a SIRP antibody is that of a mouse. In some embodiments, the Fc domain of a SIRP antibody is mouse IgGl or mouse IgG2a. In some embodiments, the Fc domain of a SIRP antibody is that of a rat. In some embodiments, the Fc domain of a SIRP antibody is rat IgGl or rat IgG2b. In embodiments, the Fc domain of a SIRP antibody is that of a non-human primate, e.g. it is a cynomolgus monkey Fc domain.

[0051] In some embodiments, the SIRP 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 constant region of the full-length SIRP antibodies comprises a human Fc domain. In some embodiments, the Fc domain of a full-length SIRP antibody is from a human IgGl, human IgG2, human IgG3, or human IgG4. In some embodiments, the Fc domain of a full-length SIRP antibody is that of a mouse immunoglobulin. In some embodiments, the Fc domain of a full-length SIRP antibody is that of a mouse IgGl or mouse IgG2a. In some embodiments, the Fc domain of a full-length SIRP antibody is that of a rat. In some embodiments, the Fc domain of a full-length SIRP antibody is from a rat IgGl or rat IgG2b. In embodiments, the Fc domain of a full-length SIRP antibody is that of a non-human primate, e.g. it is a cynomolgus monkey Fc domain.

[0052] In some embodiments, the binding of the Fc-containing antibody to a SIRP- expressing cell can mediate effector cell-mediated depletion of the SIRP-expressing cell. In some embodiments, the Fc domain of a SIRP antibody is a human IgGl Fc. Exemplary, but non-limiting, sequences of heavy chain constant regions (CH) of human IgGl encompassingFc domains of interest are provided as SEQ ID NO: 15-38. SEQ ID NO: 15 provides the canonical human IgGl heavy chain constant region (CH) sequence.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 15 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 16 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTI S 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 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 18 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PDVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 19 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 20 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PDVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 21 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 22 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV LHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 23 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHSHYT QKSLSLSPGK ( SEQ ID NO : 24 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV LHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 25 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHSHYT QKSLSLSPGK ( SEQ ID NO : 26 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 27 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSREE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 28 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSREE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 29 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 30 )ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 31 )1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKAEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 32 )

[0053] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 33, wherein XI is V or A.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKXiEP KSCDKTHTCP PCPAPELLAG 121 PDVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPEEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 33 )

[0054] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 34, 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 HTFPAVLQSS61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKXiEP KSCDKTHTCP PCPAPELLX2G 121 PX3VFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPX4EKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 34 )

[0055] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 35, wherein XI is V or A.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKXiEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV LHEALHSHYT QKSLSLSPGK ( SEQ ID NO : 35 )

[0056] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 36, wherein XI is V or A; X2 is M or L; and X3 is N or S.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKXiEP KSCDKTHTCP PCPAPELLGG121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW301 QQGNVFSCSV X2HEALHX3HYT QKSLSLSPGK ( SEQ ID NO : 36 )

[0057] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 37, wherein XI is K or R; X2 is D or E; and X3 is L or M.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKXiVEP KSCDKTHTCP PCPAPELLGG121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRX2E241 X3TKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 37 )

[0058] In some embodiments, the constant region of human IgGl heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 38, and comprises L234A, L235A, P329G substitutions (referred to as LALA-PG substitutions).ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTI SKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK ( SEQ ID NO : 38 )

[0059] In some embodiments, the Fc domain of a Fc-containing SIRP antibody is a humanIgG4 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: 39-46. SEQID NO: 39 provides the canonical human IgG4 heavy chain constant region (CH) sequence.ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 39 )ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 40 )ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFEGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 41 )ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 42 )ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEALGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 43 )ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 44 )ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFAGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 45 )

[0060] In some embodiments, the constant region of human IgG4 heavy chain sequence encompassing a Fc domain of interest is SEQ ID NO: 46, wherein XI is S or P; AND X2 is L or E.ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPX1CPAPEFX2GGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 46 )

[0061] In some embodiments, the SIRP antibodies provided herein are chimeric and comprise a variable region from one species, and a constant region from another species, e.g. comprise a human variable region and a mouse constant region. In some embodiments, the mouse constant region is mouse IgGl, or mouse IgG2a. In some embodiments, the antibodies 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.

[0062] 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 SIRP antibodies of the disclosure. For example, if a SIRP antibody of the disclosure comprises a V215A substitution in the Fc, 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 SIRP 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 SIRP antibody of the disclosure. The EUnumbering system for antibodies is known in the art and is described, for example, at imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html.

[0063] In some embodiments, the Fc domain of a SIRP antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 15), 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).

[0064] In some embodiments, the Fc domain of a SIRP antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 15), and heavy chain Fc substitutions are introduced to decrease effector function (e.g. silence).

[0065] In some embodiments, the Fc domain of a SIRP antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 15), and heavy chain Fc substitutions are introduced to increase antibody half-life.

[0066] In some embodiments, the Fc domain of a SIRP antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 39), 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).

[0067] In some embodiments, the Fc domain of a SIRP antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 39), and heavy chain Fc substitutions are introduced to decrease effector function (e.g. silence).

[0068] In some embodiments, the Fc domain of a SIRP antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 39), and heavy chain Fc substitutions are introduced to increase antibody half-life.

[0069] In some embodiments, the Fc domain of a SIRP 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: 15-38) 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: 39-46).

[0070] In some embodiments, the Fc domain of a SIRP 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: 15-38) 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: 39, 40, or 46), 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, and440 wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0071] In some embodiments, the Fc domain of a SIRP antibody is from heavy chain SEQ ID NOS: 15-38, 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.

[0072] In some embodiments, the Fc domain of a SIRP antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 15-38), 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,L234 Y / L235 Q / G236W / S239M / H268D / D270E / S298 A, and D270E / K326D / A330M / K334E wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0073] In some embodiments, the Fc domain of a SIRP antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 15-38), 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.

[0074] In some embodiments, the Fc domain of a SIRP antibody is from a human IgGl constant heavy chain (e.g. SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 38), 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.

[0075] In some embodiments, the Fc domain of a SIRP antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NOS: 39, 40 or 46), 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.

[0076] In some embodiments, the Fc domain of a SIRP antibody is from a human IgG2 constant heavy chain, and heavy chain Fc substitutions are introduced to reduce effector function, including H268Q / V309L / A330S / P33 IS and V234A / G237A / P238S / H268A / V309L / A330S / P331S, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0077] In some embodiments, the Fc domain of a SIRP antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 39), 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.

[0078] In some embodiments, the Fc domain of a SIRP antibody is from a human IgG4 constant heavy chain (e.g. SEQ ID NO: 39, 40 or 46), 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.

[0079] In other embodiments, the Fc domain of a SIRP antibody is altered to increase its serum half-life. Such alterations include heavy chain Fc substitutions of a human IgGl, IgG2, IgG3 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.i. Exemplary SIRP Antibodies - Complementarity Determining Region (CDR) Sequences

[0080] Provided herein are sequences for exemplary SIRP antibodies of the disclosure. As referred below, a light chain variable (VL) domain 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 (VH) domain 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 exemplary CDR triplets for the light chains and heavy chains of SIRP antibodies of the disclosure. In some embodiments, the antibodies of the disclosure bind specifically to SIRPa and SIRPy. In some embodiments, the antibodies of the disclosure bind specifically to SIRPP and SIRPy. In some embodiments, the antibodies of the disclosure bind specifically to SIRPa, SIRPP, and SIRPy. In some embodiments, the antibodies of the disclosure comprise, 1, 2, 3, or 4 modifications to any CDR sequence of Table 1.Table 1: Exemplary SIRP antibody CDR Combinations

[0081] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 101, 102, 103, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 104, 105, 106.

[0082] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 113, 114, 115, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 116, 117, 118.

[0083] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 119, 120, 121, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 122, 123, 124.

[0084] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 137, 138, 139, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 140, 141, 142.

[0085] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 143, 144, 145, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 146, 147, 148.

[0086] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 149, 150, 151, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 152, 153, 154.

[0087] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 155, 156, 157, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 158, 159, 160.

[0088] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 161, 162, 163, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 164, 165, 166.

[0089] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 167, 168, 169, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 170, 171, 172.

[0090] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 173, 174, 175, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 176, 177, 178.

[0091] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 179, 180, 181, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 182, 183, 184.

[0092] In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 185, 186, 187, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 188, 189, 190. ii. Exemplary SIRP Antibodies - Variable Region SequencesTable 2: Exemplary SIRP antibody VH / VL Combinations

[0093] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 497 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 498, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 497, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 498. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 497, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 498. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 101, 102, 103, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 104, 105, 106.

[0094] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 501 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 502, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 501, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 502. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 501, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 502. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 113, 114, 115, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 116, 117, 118.

[0095] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 503 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 504, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 503, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 504. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 503, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 504. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 119, 120, 121, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 122, 123, 124.

[0096] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 509 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 510, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 509, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 510. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 509, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 510. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 137, 138, 139, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 140, 141, 142.

[0097] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 511 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 512, or an amino acid sequence with at least 80%, 81%, 82%, 83%,84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 511, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 512. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 511, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 512. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 143, 144, 145, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 146, 147, 148.

[0098] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 513 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 514, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 513, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 514. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 513, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 514. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 149, 150, 151, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 152, 153, 154.

[0099] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 515 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 515, and the light chain variabledomain of the antibody comprises the amino acid sequence of SEQ ID NO: 516. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 515, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 516. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 155, 156, 157, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 158, 159, 160.

[0100] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 517 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 517, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 518. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 517, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 518. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 161, 162, 163, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 164, 165, 166.

[0101] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 519 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 519, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 520. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 519, and the light chain variable domain of the antibody comprisesthe amino acid sequence of SEQ ID NO: 520. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 167, 168, 169, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 170, 171, 172.

[0102] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 521 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 521, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 522. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 521, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 522. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 173, 174, 175, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 176, 177, 178.

[0103] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 523 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 524, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 523, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 524. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 523, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 524. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 179, 180, 181, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 182, 183, 184.

[0104] In some embodiments, provided herein is a SIRP antibody, wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 525 or an amino acid sequence with at least 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 wherein the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 526, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 525, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 526. In some embodiments, the heavy chain variable domain of the antibody consists of the amino acid sequence of SEQ ID NO: 525, and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO: 526. In some embodiments, the light chain variable domain comprises CDR sequences of SEQ ID NOS: 185, 186, 187, and the heavy chain variable domain comprises CDR sequences of SEQ ID NOS: 188, 189, 190.

[0105] Table 3 provides full-length exemplary SIRP antibodies of the disclosure.Table 3: Exemplary Combinations of Amino Acid with Fc Regions of SIRP AntibodiesII. Treatment of EBV infection using SIRP Antibodies

[0106] Provided herein are antibodies that recognize and bind to SIRPy, in combination with SIRPa and / or SIRPp. The antibodies disclosed herein may be used for the treatment of an EBV infection in a subject. In some embodiments, the subject is human. The subject can be of any age. e.g., infant, pediatric, adolescent, or adult (e.g. as per FDA guidelines). In some embodiments, the subject is treatment-naive. In some embodiments, the subject has received one or more previous EBV treatments. In some embodiments, the subject is suffering from one or more EBV-associated diseases or disorders. In some embodiments, the subject is suffering from one or more additional comorbidities. These embodiments are discussed in further detail below.A. Epstein-Barr Virus (EBV) and Associated Disorders

[0107] In some embodiments, the EBV infection is an acute infection. In some embodiments, the EBV infection is a chronic infection. In some embodiments, the subject is infected with an EBV strain selected from the group consisting of type 1 (EBV-1), type 2 (EBV-2), and anEBV variant strain or subtype thereof. In some embodiments, the subject is infected with EBV-1. In some embodiments, the subject is infected with EBV-2. In some embodiments, the subject is infected with a variant or subtype strain of EBV-1 or EBV-2. In some embodiments, the subject is infected with multiple EBV strains.

[0108] In some embodiment, the subject suffers from an EBV-associated disease or disorder. In some embodiments, the EBV-associated disease or disorder is selected from the group consisting of a secondary hemophagocytic lymphohistiocytosis (sHLH), cancer, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes (T1D), Macrophage activation syndrome (MAS), chronic NK lymphocytosis, and T cell chronic active EBV (CAEBV). In some embodiment, the cancer is a heme-based cancer. In some embodiment, the heme-based cancer is selected from the group consisting of lymphoma, leukemia, and myeloma. In some embodiment, the lymphoma is NK cell lymphoma, optionally nasal-type NK cell lymphoma. In some embodiment, the leukemia is NK cell leukemia. In some embodiments, treatment with a SIRP antibody of the disclosure prevents, delays, or mitigates of the onset of an EBV-associated disease or disorder.

[0109] In some embodiments, subject suffers from one or more additional comorbidities, associated with EBV infection. In some embodiments, the one or more additional comorbidities involves neurological symptoms. In some embodiments, the one or more additional comorbidities involves liver dysfunction neutropenia.B. Administration of Therapeutic SIRP antibodies

[0110] As contemplated herein, the SIRP antibodies of the present disclosure, and pharmaceutical compositions comprising the SIRP antibodies of the present disclosure are administered for EBV infection treatment in therapeutically effective amounts in at least one treatment phase. In some embodiments, the treatment phase is preceded by a priming dose phase. In some embodiments the subject is administered the antibody in one or more treatment phases. In some embodiments, the SIRP antibodies comprise the VH / VL amino acid sequence combinations of Table 2 or an amino acid sequence combination with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In exemplary embodiments, the SIRP antibodies comprise the CDR combinations of Table 1. In other embodiments, the SIRPantibodies of the disclosure comprise, 1, 2, 3, or 4 modifications to the CDR combinations of Table 1.

[0111] In some embodiments, the SIRP antibodies of the present disclosure are administered daily during the treatment phase where one or more treatment doses (or maintenance doses) are administered. In some embodiments, the SIRP antibodies of the present disclosure are administered at least two times per week during the treatment phase. In some embodiments, the SIRP antibodies of the present disclosure are administered at least three times per week during the treatment phase. In some embodiments, the SIRP antibodies of the present disclosure are administered weekly during the treatment phase. In some embodiments, the SIRP antibodies of the present disclosure are administered every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks during the treatment phase.

[0112] In some embodiments, the treatment phase lasts for a duration of at least 1 week. In some embodiments, the treatment phase lasts for a duration of at least 2 weeks. In some embodiments, the treatment phase lasts for a duration of at least 3 weeks. In some embodiments, the treatment phase lasts for a duration of at least 4 weeks. In some embodiments, the treatment phase lasts for a duration of at least 5 weeks. In some embodiments, the treatment phase lasts for a duration of at least 6 weeks. In some embodiments, the treatment phase lasts for a duration of at least 7 weeks. In some embodiments, the treatment phase lasts for a duration of at least 8 weeks. In some embodiments, the treatment phase lasts for a duration of at least 9 weeks. In some embodiments, the treatment phase lasts for a duration of at least 10 weeks. In some embodiments, the treatment phase lasts for a duration of at least 11 weeks. In some embodiments, the treatment phase lasts for a duration of at least 12 weeks. In some embodiments, the treatment phase lasts for a duration of at least 13 weeks. In some embodiments, the treatment phase lasts for a duration of at least 14 weeks. In some embodiments, the treatment phase lasts for a duration of at least 15 weeks. In some embodiments, the treatment phase lasts for a duration of at least 16 weeks. In some embodiments, the treatment phase lasts for a duration of at least 17 weeks. In some embodiments, the treatment phase lasts for a duration of at least 18 weeks. In some embodiments, the treatment phase lasts for a duration of at least 19 weeks. In some embodiments, the treatment phase lasts for a duration of at least 20 weeks. In some embodiments, the treatment phase lasts for a duration of at least 21 weeks. In some embodiments, the treatment phase lasts for a duration of at least 22 weeks. In someembodiments, the treatment phase lasts for a duration of at least 23 weeks. In some embodiments, the treatment phase lasts for a duration of at least 24 weeks. In some embodiments, the treatment phase lasts for a duration of 24 weeks or more. In some embodiments, the treatment phase lasts indefinitely, e.g. until symptoms or vial load have significantly decreased. In some embodiments, the treatment phase is terminated and recommenced at a later time.

[0113] The administration of the therapeutic SIRP antibodies during the treatment phase as 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 exemplary embodiments, the SIRP antibodies of the disclosure are administered intravenously. In other exemplary embodiments, the SIRP antibodies of the disclosure are administered subcutaneously. In yet other exemplary embodiments, the treatment phase comprises both intravenous and subcutaneous administration of the SIRP antibodies.

[0114] Administration of the therapeutic SIRP antibodies may be performed with any suitable pharmaceutically acceptable excipients, carriers, or other agents to provide suitable or improved tolerance, transfer, delivery, and the like.

[0115] In some embodiments the treatment phase comprises administering one or more doses of a SIRP antibody of the disclosure at a concentration of at least about 0.01 mg / kg, of at least about 0.03 mg / kg, of at least about 0.05 mg / kg, of at least about 0.1 mg / kg, of at least about 0.3 mg / kg, of at least about 0.5 mg / kg, of at least about 1.0 mg / kg, of at least about 3.0 mg / kg, of at least 5.0 mg / kg, of at least about 10 mg / kg per dose, of at least about 20 mg / kg per dose, of at least about 30 mg / kg per dose, of at least about 40 mg / kg per dose, of at least about 50 mg / kg per dose, of at least about 60 mg / kg per dose, of at least about 70 mg / kg per dose, of at least about 80 mg / kg per dose, of at least about 90 mg / kg per dose, of at least about 100 mg / kg per dose. In some embodiments the treatment phase comprises administering one or more doses of a SIRP antibody of the disclosure at a concentration of about 0.01 mg / kg to about 0.03 mg / kg, of about 0.03 mg / kg to about 0.05 mg / kg, of about 0.05 mg / kg to about 0.1 mg / kg, of about 0.1 mg / kg to about 0.3 mg / kg, of about 0.3 mg / kg to about 0.5 mg / kg, of about 0.5 mg / kg to about 1.0 mg / kg, of about 1.0 mg / kg to about 3.0 mg / kg, of about 3.0 mg / kg to about 5.0 mg / kg, of about 5.0 mg / kg to about 10 mg / kg, ofabout 0.1 mg / kg to about 1 mg / kg, of about 0.3 mg / kg to about 3 mg / kg, of about 0.5 mg / kg to about 0.5 mg / kg, of about 0.5 mg / kg to about 5 mg / kg, of about 0.1 mg / kg to about 0.3 mg / kg, of about 0.01 mg / kg to about 0.05 mg / kg, of about 0.01 mg / kg to about 0.3 mg / kg, of about 0.03 mg / kg to about 0.1 mg / kg, of about 0.03 mg / kg to about 0.3 mg / kg, of about 0.05 mg / kg to about 0.5 mg / kg, of about 0.05 mg / kg to about 0.3 mg / kg, of about 0.05 mg / kg to about 3 mg / kg, of about 0.05 mg / kg to about 5 mg / kg, of about 0.1 mg / kg to about 3 mg / kg, 0.1 mg / kg to about 5 mg / kg, 0.3 mg / kg to about 1 mg / kg, 0.3 mg / kg to about 3 mg / kg, 0.3 mg / kg to about 5 mg / kg, about 3.0 mg / kg to about 10 mg / kg, about lOmg / kg to about 20mg / kg, about 20mg / kg to about 30mg / kg, about 30mg / kg to about 40mg / kg, about 40mg / kg to about 50mg / kg, about 50mg / kg to about 60mg / kg, about 60mg / kg to about 70mg / kg, about 70mg / kg to about 80mg / kg, about 80mg / kg to about 90mg / kg, or about 90mg / kg to about lOOmg / kg. In exemplary embodiments, the route of administration is intravenous or subcutaneous.

[0116] As noted above, in some embodiments the subject is administered one or more priming doses during the one or more priming dose phases prior to the one or more treatment phases. Without being held to theory or mechanism, the priming dose may sever several roles, e.g., may reduce infusion reaction severity, improve the responsiveness of the subject during the treatment phase and / or allow for the target concentration of the antibody treatment to be achieved rapidly.

[0117] In some embodiments, the SIRP antibodies of the present disclosure are administered for a period of 1 day during the priming dose phase. In some embodiments, the SIRP antibodies of the present disclosure are administered daily for a period of 2 days or at least 2 days during the priming dose phase. In some embodiments, the SIRP antibodies of the present disclosure are administered daily for a period of 3 days, or at least 3 days during the priming dose phase. In some embodiments, the SIRP antibodies of the present disclosure are administered daily for a period of 4 days, or at least 4 days during the priming dose phase. In some embodiments, the SIRP antibodies of the present disclosure are administered daily for a period of 5 days, or at least 5 days during the priming dose phase. In some embodiments, the SIRP antibodies of the present disclosure are administered daily for a period of more than 5 days during the priming dose phase.

[0118] In some embodiments, one or more additional priming dose phases may be administered after the first treatment phase is terminated and before a subsequent treatment phase is recommenced.

[0119] The administration of the therapeutic SIRP antibodies during the priming dose phase as 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 during the priming dose phase may be carried out via injection or infusion. In exemplary embodiments, the SIRP antibodies of the disclosure are administered intravenously during the priming dose phase. In exemplary embodiments, the SIRP antibodies of the disclosure are administered subcutaneously during the priming dose phase. In exemplary embodiments the SIRP antibodies of the disclosure are administered subcutaneously and intravenously during the priming dose phase. Administration of the therapeutic SIRP antibodies during the priming dose phase may be performed with any suitable excipients, carriers, or other agents to provide suitable or improved tolerance, transfer, delivery, and the like.

[0120] In some embodiments the priming dose phase comprises administering one or more doses of a SIRP antibody of the disclosure at a concentration of about 0.01 mg / kg, of about 0.03 mg / kg, of about 0.05 mg / kg, of about 0.1 mg / kg, of about 0.3 mg / kg, of about 0.5 mg / kg, of about 1.0 mg / kg, of about 3.0 mg / kg, or of about 5.0 mg / kg per dose. In some embodiments the treatment phase comprises administering one or more doses of a SIRP antibody of the disclosure at a concentration of at least about 0.01 mg / kg, of at least about 0.03 mg / kg, of at least about 0.05 mg / kg, of at least about 0.1 mg / kg, of at least about 0.3 mg / kg, of at least about 0.5 mg / kg, of at least about 1.0 mg / kg, of at least about 3.0 mg / kg, of at least 5.0 mg / kg or of at least about 10 mg / kg per dose. In some embodiments the treatment phase comprises administering one or more doses of a SIRP antibody of the disclosure at a concentration of about 0.01 mg / kg to about 0.03 mg / kg, of about 0.03 mg / kg to about 0.05 mg / kg, of about 0.05 mg / kg to about 0.1 mg / kg, of about 0.1 mg / kg to about 0.3 mg / kg, of about 0.3 mg / kg to about 0.5 mg / kg, of about 0.5 mg / kg to about 1.0 mg / kg, of about 1.0 mg / kg to about 3.0 mg / kg, of about 3.0 mg / kg to about 5.0 mg / kg, of about 5.0 mg / kg to about 10 mg / kg, of about 0.1 mg / kg to about 1 mg / kg, of about 0.3 mg / kg to about 3 mg / kg, of about 0.5 mg / kg to about 0.5 mg / kg, of about 0.5 mg / kg to about 5 mg / kg, of about 0.1 mg / kg to about 0.3 mg / kg, of about 0.01 mg / kg to about 0.05 mg / kg, of about 0.01 mg / kg toabout 0.3 mg / kg, of about 0.03 mg / kg to about 0.1 mg / kg, of about 0.03 mg / kg to about 0.3 mg / kg, of about 0.05 mg / kg to about 0.5 mg / kg, of about 0.05 mg / kg to about 0.3 mg / kg, of about 0.05 mg / kg to about 3 mg / kg, of about 0.05 mg / kg to about 5 mg / kg, of about 0.1 mg / kg to about 3 mg / kg, 0.1 mg / kg to about 5 mg / kg, 0.3 mg / kg to about 1 mg / kg, 0.3 mg / kg to about 3 mg / kg, 0.3 mg / kg to about 5 mg / kg, or about 3.0 mg / kg to about 10 mg / kg. In exemplary embodiments, the route of administration is intravenous or subcutaneous.C. Pharmaceutical Compositions

[0121] The disclosure also provides pharmaceutical compositions comprising any one of the SIRP antibodies disclosed herein, and optionally a pharmaceutical acceptable excipient or carrier. In some embodiments, the pharmaceutical composition is sterile. The pharmaceutical compositions may be formulated to be compatible with their intended routes of administration. In some embodiments, the pharmaceutical compositions of the disclosure are suitable for administration to a human subject.D. Combination Therapies

[0122] The administration of any one of the therapeutic SIRP antibodies provided herein may be in combination with any other known drugs or treatments for diseases or conditions. In some embodiments, the disease or condition is associated with overactivation and / or hyperproliferation of myeloid cells, lymphocytes, or other cells expressing SIRPa, SIRPP, or SIRPy. In some embodiments, the disease or condition is an autoimmune disease or condition. In some embodiments, the disease or condition is a neoplastic disorder or malignancy.

[0123] In some embodiments, a therapeutic SIRP antibody may be used in combination with corticosteroids (e.g. - dexamethasone).

[0124] In some embodiments, a therapeutic SIRP antibody provided herein, is used in combination with one or more additional therapeutic or investigational agents is selected from the group consisting of: a chemotherapeutic agent, an immunotherapeutic agent, a CAR T therapeutic agent, a JAK inhibitor, a radiotherapeutic agent, methotrexate, azathioprine, dexamethasone, a biological therapeutic agent, a TNF inhibitor, anakinra, antimicrobials, etoposide, tocilizumab, emapalumab, alemtuzumab, cyclosporin, intravenous immunoglobulin (IVIG), rituximab, other corticosteroids, any combination chemotherapy regimens, antiviral agents (e.g., nucleoside analogues), interleukin-2, interferon alfa, intravenous immunoglobulins, and etoposide.

[0125] In some embodiments, one or more therapeutic agents are administered as a premedication therapy. In some embodiments, the therapeutic agent used as a premedication therapy is one or more of dexamethasone, etoposide, emapalumab, and CHOEP chemotherapy.E. Evaluation of SIRP Antibody Therapy

[0126] In some embodiments, a predicted prognosis and / or likelihood of response to treatment is obtained by evaluating EBV viral load.

[0127] In some embodiments, response to treatment is monitored by improvement in signs and symptoms of EBV infection, such as fever, fatigue, anorexia, headache, neurological symptoms, confusion, depression, abdominal pain, spleen abnormalities, liver abnormalities, skin changes, pain, myalgias, bone pain, and general wellbeing.

[0128] In some embodiments, a predicted prognosis and / or likelihood of response to treatment is obtained by evaluating a ratio of sCD25 / ferritin.

[0129] In some embodiments, a predicted prognosis and / or likelihood of response to treatment is obtained by measuring circulating monocyte and lymphocyte counts.

[0130] In some embodiments, evaluation of the SIRP antibody therapy in a subject is comprised of measuring or monitoring one or more biomarkers from a biological sample obtained from the subject which may include EBV viral load, ferritin, sCD25, sCD25 / ferritin ratio, C-reactive protein (CRP), fibrinogen, CXCL9, CXCL10, sCD163, LDH, IFN-gamma, IL-6, TNF-alpha, IL-8, IL-10, IL-18, GDF-15, IL-IRA, MDC, ST2, Alanine aminotransferase (ALT), and IL-16. In some embodiments, evaluation of the SIRP antibody therapy in a subject is comprised of monitoring positron emission tomography (PET)- SCANs.

[0131] In some embodiments, treatment with a SIRP antibody of the disclosure reduces the EBV viral load in the subject. In some embodiments, the viral load is reduced in the hematopoietic system (bone marrow or blood cells including stem and progenitor cells). In some embodiments, the viral load is reduced in the blood. In some embodiments, the viral load is reduced in the bone marrow. In some embodiments, the viral load is reduced in B cells, T cells, or myeloid cells. In some embodiments, the EBV viral load is reduced at least by 5% to 100%. In some embodiments, the EBV viral load is reduced at least by 5% to about 10%. In some embodiments, the EBV viral load is reduced at least by 10% to about 20%. In some embodiments, the EBV viral load is reduced at least by 20% to about 30%. In someembodiments, the EBV viral load is reduced at least by 30% to about 40%. In some embodiments, the EBV viral load is reduced at least by 40% to about 50%. In some embodiments, the EBV viral load is reduced at least by 50% to about 60%. In some embodiments, the EBV viral load is reduced at least by 60% to about 70%. In some embodiments, the EBV viral load is reduced at least by 70% to about 80%. In some embodiments, the EBV viral load is reduced at least by 80% to about 90%. In some embodiments, the EBV viral load is reduced at least by 90% to about 100%.

[0132] In some embodiments, treatment with a SIRP antibody of the disclosure results in the depletion of SIRP expressing cells (including SIRPa and / or SIRPP and / or SIRPy). In some embodiments, the SIRP expressing cells are B cells.III. Exemplary Enumerated Embodiments

[0133] The following non-limiting enumerated embodiments are provided as exemplary.

[0134] Embodiment 1-1. A method of treating an Epstein-Barr virus (EBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRP binding antibody, wherein the SIRP binding antibody is specific for one or more of SIRPa and SIRPP, and is also specific for SIRPy.

[0135] Embodiment 1-2. The method of Embodiment 1-1, wherein the antibody is a monoclonal antibody.

[0136] Embodiment 1-3. The method of Embodiment 1-1, wherein the antibody is an antibody fragment.

[0137] Embodiment 1-4. The method of Embodiment 1-1, wherein the antibody is a human antibody.

[0138] Embodiment 1-5. The method of Embodiment 1-1, wherein the antibody is a humanized antibody.

[0139] Embodiment 1-6. The method of Embodiment 1-1, wherein the antibody is a chimeric antibody.

[0140] Embodiment 1-7. The method of Embodiment 1-1, wherein the antibody is a full- length antibody.

[0141] Embodiment 1-8. The method of Embodiment 1-1, wherein the antibody is bispecific for an additional target.

[0142] Embodiment 1-9. The method of any one of Embodiment I- 1 -Embodiment 1-8, wherein the EBV infection is acute or chronic.

[0143] Embodiment 1-10. The method of any one of Embodiment I- 1 -Embodiment 1-9, wherein the subject is infected with an EBV strain selected from the group consisting of type 1 (EBV-1), type 2 (EBV-2), and an EBV variant strain or subtype thereof.

[0144] Embodiment 1-11. The method of any one of Embodiment I- 1 -Embodiment 1-10, wherein the subject suffers from an EBV-associated disease or disorder.

[0145] Embodiment 1-12. The method of any one of Embodiment I- 1 -Embodiment 1-10, wherein the treatment prevents, delays, or mitigates of the onset of an EBV-associated disease or disorder.

[0146] Embodiment 1-13. The method of Embodiment 1-11 or Embodiment 1-12, wherein the EBV-associated disease or disorder is selected from the group consisting of a secondary hemophagocytic lymphohistiocytosis (sHLH), cancer, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes (T1D), Macrophage activation syndrome (MAS), chronic NK lymphocytosis, and T cell chronic active EBV (CAEBV).

[0147] Embodiment 1-14. The method of Embodiment 1-13, wherein the cancer is a heme-based cancer.

[0148] Embodiment 1-15. The method of Embodiment 1-14, wherein the heme-based cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.

[0149] Embodiment 1-16. The method of Embodiment 1-15, wherein the lymphoma is NK cell lymphoma, optionally nasal-type NK cell lymphoma.

[0150] Embodiment 1-17. The method of claim Embodiment 1-15, wherein the leukemia is NK cell leukemia.

[0151] Embodiment 1-18. The method of any one of Embodiment I- 1 -Embodiment 1-17, wherein the subject suffers from one or more additional comorbidities.

[0152] Embodiment 1-19. The method of any one of Embodiment I- 1 -Embodiment 1-18, wherein the treatment reduces the EBV viral load in the subject.

[0153] Embodiment 1-20. The method of Embodiment 1-19, wherein the EBV viral load is reduced at least by 10%

[0154] Embodiment 1-21. The method of Embodiment 1-20, wherein the EBV viral load is reduced in the blood.

[0155] Embodiment 1-22. The method of Embodiment 1-20, wherein the EBV viral load is reduced in B cells, T cells, NK cells, or myeloid cells.

[0156] Embodiment 1-23. The method of Embodiment 1-20, wherein the EBV viral load is reduced in bone marrow.

[0157] Embodiment 1-24. The method of any one of Embodiment I- 1 -Embodiment 1-23, wherein the treatment results in the depletion of SIRP-expressing cells.

[0158] Embodiment 1-25. The method of Embodiment 1-24, wherein the SIRP-expressing cells are B cells, T cells, or NK cells.

[0159] Embodiment 1-26. The method of any one of Embodiment I- 1 -Embodiment 1-25, wherein the method comprises monitoring EBV viral load, PET-SCANs, C-reactive protein (CRP), sCD25, and / or ferritin peak, minimum, maximum, and reduction prospectively to diagnose and predict prognosis, and / or likelihood of response to therapy for the EBV infection, EBV associated disease or disorder, and / or the one or more additional comorbidities.

[0160] Embodiment 1-27. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein the SIRP binding antibody is administered to the subject subcutaneously or intravenously.

[0161] Embodiment 1-28. The method of any one of Embodiment I- 1 -Embodiment 1-27, wherein the administration occurs in a treatment phase.

[0162] Embodiment 1-29. The method of Embodiment 1-28, wherein the method comprises more than one treatment phase.

[0163] Embodiment 1-30. The method of any one of of Embodiment I- 1 -Embodiment I- 29, wherein the treatment phase comprises a dose of at least about 0.01 mg / kg to about 5.0 mg / kg of the SIRP binding antibody.

[0164] Embodiment 1-31. The method of Embodiment 1-30, wherein the treatment phase comprises a dose about 0.1 mg / kg to about 1.0 mg / kg of the SIRP binding antibody.

[0165] Embodiment 1-32. The method of any one of Embodiment I- 1 -Embodiment 1-31, wherein the SIRP binding antibody is administered in combination with an additional therapy.

[0166] Embodiment 1-33. The method of Embodiment 1-32, wherein the additional therapy is selected from the group consisting of corticosteroids, antiviral agents (e.g., nucleoside analogues), interleukin-2, interferon alfa, intravenous immunoglobulins, etoposide, and other chemotherapy agents.

[0167] Embodiment 1-34. The method of any one of Embodiment I- 1 -Embodiment 1-33, wherein the SIRP binding antibody is administered in a pharmaceutical composition, whereinthe pharmaceutical composition comprises the antibody, and a pharmaceutically acceptable carrier.

[0168] Embodiment 1-35. The method of any one of Embodiment I- 1 -Embodiment 1-34, wherein the antibody comprises a complementarity determining region (CDR) sequence combination selected from the group consisting of: a. SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106; b. SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118; c. SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 124; d. SEQ ID NO: 137, SEQ ID NO: 138, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142; e. SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148; f. SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154; g. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 159, SEQ ID NO: 160; h. SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166; i. SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172; j. SEQ ID NO: 173, SEQ ID NO: 174, SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178; k. SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184; and l. SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190.

[0169] Embodiment 1-36. The method of any one of Embodiment I- 1 -Embodiment 1-35, wherein the SIRP binding antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein a. the VH comprises the amino acid sequence of SEQ ID NO: 497, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises theamino acid sequence of SEQ ID NO: 498, or an amino acid sequence with at least 80% sequence identity thereto; b. the VH comprises the amino acid sequence of SEQ ID NO: 501, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 502, or an amino acid sequence with at least 80% sequence identity thereto; c. the VH comprises the amino acid sequence of SEQ ID NO: 503, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 504, or an amino acid sequence with at least 80% sequence identity thereto; d. the VH comprises the amino acid sequence of SEQ ID NO: 509, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 510, or an amino acid sequence with at least 80% sequence identity thereto; e. the VH comprises the amino acid sequence of SEQ ID NO: 511, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 512, or an amino acid sequence with at least 80% sequence identity thereto; f. the VH comprises the amino acid sequence of SEQ ID NO: 513, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 514, or an amino acid sequence with at least 80% sequence identity thereto; g. the VH comprises the amino acid sequence of SEQ ID NO: 515, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence with at least 80% sequence identity thereto; h. the VH comprises the amino acid sequence of SEQ ID NO: 517, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence with at least 80% sequence identity thereto; i. the VH comprises the amino acid sequence of SEQ ID NO: 519, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises theamino acid sequence of SEQ ID NO: 520, or an amino acid sequence with at least 80% sequence identity thereto; j . the VH comprises the amino acid sequence of SEQ ID NO: 521, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence with at least 80% sequence identity thereto; k. the VH comprises the amino acid sequence of SEQ ID NO: 523, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 524, or an amino acid sequence with at least 80% sequence identity thereto; and l. the VH comprises the amino acid sequence of SEQ ID NO: 525, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 526, or an amino acid sequence with at least 80% sequence identity thereto.

[0170] Embodiment 1-37. The method of any one of Embodiment 1-1 -Embodiment 1-36, wherein the SIRP binding antibody comprises an Fc domain.

[0171] Embodiment 1-38. The method of Embodiment 1-37, wherein the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4.

[0172] Embodiment 1-39. The method of Embodiment 1-38, wherein the Fc domain is from the heavy chain IgG amino acid sequences of any one of SEQ ID NOS: 15-46.

[0173] Embodiment 1-40. The method of Embodiment 1-39, wherein the heavy chain Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 15 or SEQ ID NO: 39 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.

[0174] Embodiment 1-41. Use of a SIRP binding antibody for the treatment of an Epstein- Barr virus (EBV) infection in a subject in need thereof, wherein the SIRP binding antibody binds to one or more of SIRPa and SIRPP, and is also specific for SIRPy.

[0175] Embodiment 1-42. Use of a SIRP binding antibody for the manufacture of a medicament for the treatment of an Epstein-Barr virus (EBV) infection in a subject in needthereof, wherein the SIRP binding antibody binds to one or more of SIRPa and SIRPP, and is also specific for SIRPy.

[0176] Embodiment 1-43. A method of treating an Epstein-Barr virus (EBV) infection in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-SIRP antibody, wherein the antibody comprises a means for binding human SIRPa and / or SIRPP, and SIRPy.The following Examples are merely illustrative and are not meant to limit any aspects of the present disclosure in any way.EXAMPLESExample 1: Reduction of Viral Load after SIRPa / p / y Antibody Treatment

[0177] The following examples describes clinical efficacy signals in EBV-infected patients. Patient 602-01 has EBV-triggered sHLH; patients 601-10 and 609-02 have EBV-triggered sHLH in the setting of a malignancy. As these patients were not receiving chemotherapy or had residual effects of chemotherapy at the time of the key events described, these patients provide valuable opportunities to better assess SIRP antibody effects on response and PD markers for EBV infection and sHLH, not confounded by chemotherapy. All patients entered the study sHLH treatment naive. The SIRP antibody assessed was Antibody 28.

[0178] Dose administrations occurred as priming doses or maintenance doses (Table El). The dose regimen, including the priming doses to reduce infusion reactions.Table El: Antibody 28 Dose Regimen

[0179] Participants received dexamethasone as background therapy (initially 10 mg / m2) and premedication. After Day 15, a dexamethasone tapering regimen may be considered upon HLH disease control to the minimum effective dose to prevent infusion reactions (typically 4-8 mg of dexamethasone, however, some patients did not receive any dexamethasone premedication).

[0180] Patient 602-01 with EBV-triggered sHLH presenting with neutropenia, neurological symptoms and liver dysfunction. Patient received background dexamethasone with Antibody 28. There was rapid improvement of HLH markers and symptoms (FIG. IB). The PD effects were noted on monocytes and lymphocytes. Upon improvement of HLH activity, there was a recovery of blood counts (healthy blood cells). Patient completed 12-week course of treatment.

[0181] Patient 601-10 with Peripheral T-Cell Lymphoma (PTCL)-triggered HLH. Patient had an initial response to Antibody 28 with background dexamethasone and CHOEP chemotherapy. There was an acute rise in HLH activity (e.g., ferritin and ALT) beginning on Day 38 (FIG. 2). Work-up identified that this was triggered by a concurrent acute EBV infection (bone marrow viral load ~3.9 million lU / mL). Antibody 28 had been interrupted twice for unrelated adverse effects. Without any added therapies for the HLH or for the PTCL, the patient restarted Antibody 28 at maintenance dosing, twice weekly and there was rapid control of HLH activity and reduction of EBV viral load. The investigator could not attribute the rapid resolution of HLH activity to any added therapies or lingering chemotherapy effects.

[0182] Patient 609-02 with EBV+ diffuse large B-cell lymphoma (DLBCL). The patient developed a brisk onset of HLH secondary to lymphoma progression and EBV presence in the blood. Ferritin was 8,791 ng / mL with sIL2R >80,000 pg / mL, fibrinogen of 104 mg / dL, TG of 326 mg / dL, and with progressive pancytopenia and splenomegaly (FIG. 3). Other than background dexamethasone, at 20 mg on Day 1, there was no additional HLH-directed or cancer-directed therapies including chemotherapy through Day 11. The biomarker responses summarized in FIG. 2, especially sCD25 and CRP can be attributed to Antibody 28 which includes a reduction of blood EBV viral load on day 11.Example 2: SIRP Expression on B Cells from EBV triggered sHLH Patient

[0183] Patient US603-EAP001 was a 15-year-old female with EBV-triggered sHLH. Patient was previously treated with etoposide and with emapalumab twice weekly. Patient had completed the priming regimen but her first weekly dose of Antibody 28 was held due to increased platelet transfusion requirement for menstrual bleeding (in addition to ongoing mucosal and GI bleeding), progressive EBV infection, and progressive sHLH. Because studydrug had been held, Patient was required to restart the priming regimen and received 0.1 mg / kg. In total Patient received 5 infusions of Antibody 28 (cumulative dose of 1.1 mg / kg). However, prior to resumption of Antibody 28, Patient’s clinical condition worsened. Patient had a fever followed by persistent hypotension, and became too critically ill to receive more Antibody 28 and died due to bacterial sepsis, likely from a GI source as been the patient’s prior sepsis episodes. A pre- Antibody 28 treatment blood sample was sent for flow analysis of SIRP expression. Using a SIRPa / p / y specific antibody (Sequence Combination 2 of Tables 1 and 2 with no Fc effector function), the data showed that >90% of the patient’s B-cells had high expression of SIRP compared with normal healthy controls (FIG. 4A-B). This is the first example of B-cells overexpressing SIRPs in the setting of EBV infection, which suggests SIRP as a therapeutic target for the treatment of EBV infection.

Claims

CLAIMS1. A method of treating an Epstein-Barr virus (EBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRP binding antibody, wherein the SIRP binding antibody is specific for one or more of SIRPa and SIRPP, and is also specific for SIRPy.

2. The method of claim 1, wherein the antibody is a monoclonal antibody.

3. The method of claim 1, wherein the antibody is an antibody fragment.

4. The method of claim 1, wherein the antibody is a human antibody.

5. The method of claim 1, wherein the antibody is a humanized antibody.

6. The method of claim 1, wherein the antibody is a chimeric antibody.

7. The method of claim 1, wherein the antibody is a full-length antibody.

8. The method of claim 1, wherein the antibody is bispecific for an additional target.

9. The method of any one of claims 1-8, wherein the EBV infection is acute or chronic.

10. The method of any one of claims 1-9, wherein the subject is infected with an EBV strain selected from the group consisting of type 1 (EBV-1), type 2 (EBV-2), and an EBV variant strain or subtype thereof.

11. The method of any one of claims 1-10, wherein the subject suffers from an EBV- associated disease or disorder.

12. The method of any one of claims 1-10, wherein the treatment prevents, delays, or mitigates of the onset of an EBV-associated disease or disorder.

13. The method of claim 11 or 12, wherein the EBV-associated disease or disorder is selected from the group consisting of a secondary hemophagocytic lymphohistiocytosis (sHLH), cancer, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes (T1D), Macrophage activation syndrome (MAS), chronic NK lymphocytosis, and T cell chronic active EBV (CAEBV).

14. The method of claim 13, wherein the cancer is a heme-based cancer.

15. The method of claim 14, wherein the heme-based cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.

16. The method of claim 15, wherein the lymphoma is NK cell lymphoma, optionally nasal-type NK cell lymphoma.

17. The method of claim 15, wherein the leukemia is NK cell leukemia.

18. The method of any one of claims 1-17, wherein the subject suffers from one or more additional comorbidities.

19. The method of any one of claims 1-18, wherein the treatment reduces the EBV viral load in the subject.

20. The method of claim 19, wherein the EBV viral load is reduced at least by 10%.

21. The method of claim 20, wherein the EBV viral load is reduced in the blood.

22. The method of claim 20, wherein the EBV viral load is reduced in B cells, T cells, NK cells, or myeloid cells.

23. The method of claim 20, wherein the EBV viral load is reduced in bone marrow.

24. The method of any one of claims 1-23, wherein the treatment results in the depletion of SIRP-expressing cells.

25. The method of claim 24, wherein the SIRP-expressing cells are B cells, T cells, or NK cells.

26. The method of any one of claims 1-25, wherein the method comprises monitoring EBV viral load, PET-SCANs, C-reactive protein (CRP), sCD25, and / or ferritin peak, minimum, maximum, and reduction prospectively to diagnose and predict prognosis, and / or likelihood of response to therapy for the EBV infection, EBV associated disease or disorder, and / or the one or more additional comorbidities.

27. The method of any one of claims 1-26, wherein the SIRP binding antibody is administered to the subject subcutaneously or intravenously.

28. The method of any one of claims 1-27, wherein the administration occurs in a treatment phase.

29. The method of claim 28, wherein the method comprises more than one treatment phase.

30. The method of any one of claims of 1-29, wherein the treatment phase comprises a dose of at least about 0.01 mg / kg to about 5.0 mg / kg of the SIRP binding antibody.

31. The method of any claim 30, wherein the treatment phase comprises a dose about 0.1 mg / kg to about 1.0 mg / kg of the SIRP binding antibody.

32. The method of any one of claims 1-31, wherein the SIRP binding antibody is administered in combination with an additional therapy.

33. The method of claim 32, wherein the additional therapy is selected from the group consisting of corticosteroids, antiviral agents (e.g., nucleoside analogues), interleukin- 2, interferon alfa, intravenous immunoglobulins, etoposide, and other chemotherapy agents.

34. The method of any one of claims 1-33, wherein the SIRP binding antibody is administered in a pharmaceutical composition, wherein the pharmaceutical composition comprises the antibody, and a pharmaceutically acceptable carrier.

35. The method of any one of claims 1-34, wherein the antibody comprises a complementarity determining region (CDR) sequence combination selected from the group consisting of: a. SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106; b. SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118; c. SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 124; d. SEQ ID NO: 137, SEQ ID NO: 138, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142; e. SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148; f. SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154; g. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 159, SEQ ID NO: 160; h. SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166; i. SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172; j. SEQ ID NO: 173, SEQ ID NO: 174, SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178; k. SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184; and1. SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQID NO: 189, SEQ ID NO: 190.

36. The method of any one of claims 1-35, wherein the SIRP binding antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein a. the VH comprises the amino acid sequence of SEQ ID NO: 497, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 498, or an amino acid sequence with at least 80% sequence identity thereto; b. the VH comprises the amino acid sequence of SEQ ID NO: 501, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 502, or an amino acid sequence with at least 80% sequence identity thereto; c. the VH comprises the amino acid sequence of SEQ ID NO: 503, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 504, or an amino acid sequence with at least 80% sequence identity thereto; d. the VH comprises the amino acid sequence of SEQ ID NO: 509, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 510, or an amino acid sequence with at least 80% sequence identity thereto; e. the VH comprises the amino acid sequence of SEQ ID NO: 511, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 512, or an amino acid sequence with at least 80% sequence identity thereto; f. the VH comprises the amino acid sequence of SEQ ID NO: 513, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 514, or an amino acid sequence with at least 80% sequence identity thereto; g. the VH comprises the amino acid sequence of SEQ ID NO: 515, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence with at least 80% sequence identity thereto;h. the VH comprises the amino acid sequence of SEQ ID NO: 517, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence with at least 80% sequence identity thereto; i. the VH comprises the amino acid sequence of SEQ ID NO: 519, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence with at least 80% sequence identity thereto; j . the VH comprises the amino acid sequence of SEQ ID NO: 521, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence with at least 80% sequence identity thereto; k. the VH comprises the amino acid sequence of SEQ ID NO: 523, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 524, or an amino acid sequence with at least 80% sequence identity thereto; and l. the VH comprises the amino acid sequence of SEQ ID NO: 525, or an amino acid sequence with at least 80% sequence identity thereto, and the VL comprises the amino acid sequence of SEQ ID NO: 526, or an amino acid sequence with at least 80% sequence identity thereto.

37. The method of any one of claims 1-36, wherein the SIRP binding antibody comprises an Fc domain.

38. The method of claim 37, wherein the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4.

39. The method of claim 38, wherein the Fc domain is from the heavy chain IgG amino acid sequences of any one of SEQ ID NOS: 15-46.

40. The method of 39, wherein the heavy chain Fc domain comprises one or more amino acid substitutions relative to SEQ ID NO: 15 or SEQ ID NO: 39 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.

41. Use of a SIRP binding antibody for the treatment of an Epstein-Barr virus (EBV) infection in a subject in need thereof, wherein the SIRP binding antibody binds to one or more of SIRPa and SIRPP, and is also specific for SIRPy.

42. Use of a SIRP binding antibody for the manufacture of a medicament for the treatment of an Epstein-Barr virus (EBV) infection in a subject in need thereof, wherein the SIRP binding antibody binds to one or more of SIRPa and SIRPP, and is also specific for SIRPy.

43. A method of treating an Epstein-Barr virus (EBV) infection in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-SIRP antibody, wherein the antibody comprises a means for binding human SIRPa and / or SIRPP, and SIRPy.

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