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

[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 some embodiments, 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, 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 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 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, 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 some embodiments, 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. monoclonal antibody.

[0136] Embodiment 1-3. antibody fragment.

[0137] Embodiment 1-4. human antibody.

[0138] Embodiment 1-5. humanized antibody.

[0139] Embodiment 1-6. chimeric antibody.

[0140] Embodiment 1-7. length antibody.

[0141] Embodiment 1-8. The method of Embodiment 1-1, wherein the antibody is a The method of Embodiment 1-1, wherein the antibody is an The method of Embodiment 1-1, wherein the antibody is a The method of Embodiment 1-1, wherein the antibody is a The method of Embodiment 1-1, wherein the antibody is a The method of Embodiment 1-1, wherein the antibody is a full- 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. is reduced at least by 10%.

[0154] Embodiment 1-21. is reduced in the blood. The method of Embodiment 1-19, wherein the EBV viral load The method of Embodiment 1-20, wherein the EBV viral load

[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, wherein the 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 1. 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 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 1. 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 I-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 need thereof, 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. EXAMPLES Example 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 Dose (mg / kg) Frequency Route Duration Priming dose phase 0.01 to 5 Daily, up to Twice Daily IV or SC Up to 7 days Treatment phase 0.01 to 5 Daily, up to Twice Daily IV or SC 1 week to indefinitely

[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 study drug 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

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.

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, SEQ ID 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), whereina. 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; and1. 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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