Treatment of warm autoimmune hemolytic anemia

Abstract

The present invention provides compositions and methods of treating and improving the symptoms of warm autoimmune hemolytic anemia using an antibody or antigen-binding fragment thereof that specifically binds human CD19 (e.g., obexelimab).

Description

Attorney Docket No. ZEN-024WO1TREATMENT OF WARM AUTOIMMUNE HEMOLYTIC ANEMIACROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of U.S. Provisional Patent Application No. 63 / 713,867, filed on October 30, 2024, and U.S. Provisional Patent Application No 63 / 726,904 filed on December 2, 2024, each of which are hereby incorporated by reference in their entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 21, 2024, is named “ZEN-024WOl_SL” and is 16,384 bytes.BACKGROUND

[0003] Autoimmune hemolytic anemia (AH4A) is an uncommon, acquired autoimmune disorder, in which autoantibodies directed against self-red blood cell (RBC) membrane antigens lead to accelerated destruction of RBCs. The destruction of the RBCs by immune cells more rapidly than the production rate of production of new cells, leads apatients to develop anemia, generalized fatigue, dizziness, syncope, malaise, chest pressure / pain, cognitive dysfunction, weakness, a pale skin color (pallor), palpitations, shortness of breath (dyspnea), appearance of jaundice and abnormally dark urine (hematouria), usually suggestive of hemolysis. Murine models of AH4A show that reticulocytes are preferentially targeted by anti-RBC autoantibodies and an increase in oxidative stress may trigger autoantibody production. Though not usually fatal, most patients have a reduced health-related quality of life. Among the forms of AH4A, warm AH4A (wAIHA) is the most prevalent. Current therapies used for treatment of wAIHA include steroids, immunosuppressants and splenectomy. Corticosteroids are commonly used as first- line treatment but are not always effective. Additionally, prolonged steroid use carries a significant risk for infection, diabetes, and fracture. Harnessing treatment and defining a risk- adapted efficacious therapy for wAIHA is an emerging unmet need.Attorney Docket No. ZEN-024WO1SUMMARY

[0004] Among other things, the present disclosure provides methods, compositions, and uses of an anti-CD19 antibody such as obexelimab for efficient treatment of a patient with wAIHA and prevention of relapse. In some aspects, the present invention provides a method of treating wAIHA, comprising administering obexelimab at a therapeutically effective dosing regimen to improve hemoglobin (Hgb) as compared to baseline. In some aspects, the present invention provides a method of treating wAIHA, comprising administering obexelimab at a therapeutically effective dosing regimen to reduce anti-RBC autoantibodies as compared to baseline. In some embodiments, the present disclosure is directed to a method of treating of wAIHA using CD 19 antibodies such as obexelimab.

[0005] In some aspects, the present invention provides a method of treating wAIHA, including administering obexelimab subcutaneously to a patient at a therapeutically effective dosing regimen for a treatment period sufficient to result in an increase of Hgb of > 2 g / dL as compared to baseline.

[0006] In some embodiments, a treatment period is at least 8 weeks, at least 10 weeks, at least 15 weeks, at least 20 weeks, or at least 24 weeks.

[0007] In some embodiments, a patient achieves a Hgb level of > 7 g / dL. In some embodiments, a patient achieves a Hgb level of > 8 g / dL. In some embodiments, a patient achieves a Hgb level of > 9 g / dL. In some embodiments, a patient achieves a Hgb level of > 10 g / dL. In some embodiments, a patient maintains the Hgb level for at least 5 weeks, at least 10 weeks, at least 15 weeks, or at least 20 weeks.

[0008] In some embodiments, a patient achieves one or more of the following: (a) a reduction in serum lactate dehydrogenase (LDH) as compared to baseline; (b) a reduction in bilirubin as compared to baseline; and (c) an increase in serum haptoglobin as compared to baseline. In some embodiments, a patient achieves normal values of one or more of the following: (a) LDH; (b) bilirubin; and (c) haptoglobin.

[0009] In some aspects, the present invention provides a method of treating wAIHA including administering obexelimab to a patient at a therapeutically effective dosing regimen for a treatment period sufficient to result in reducing the level of anti-RBC autoantibodies by at least 10% as compared to baseline.Attorney Docket No. ZEN-024WO1

[0010] In some embodiments, a treatment period is at least 8 weeks, at least 10 weeks, at least 15 weeks, at least 20 weeks, or at least 24 weeks.

[0011] In some embodiments, a therapeutically effective dosing regimen is sufficient to reduce the presence of anti-RBC autoantibodies so that the patient is substantially free of anti-RBC autoantibodies. In some embodiments, a therapeutically effective dosing regimen is sufficient to reduce the presence of anti-RBC autoantibodies to an undetectable amount.

[0012] In some embodiments, a patient is direct antiglobulin test (DAT) negative following administration of a therapeutically effective dosing regimen.

[0013] In some embodiments, obexelimab is administered at a dose of 250 mg. In some embodiments, obexelimab is administered at a dose of 250 mg weekly.

[0014] In some embodiments, a patient is DAT-positive for anti-IgG and / or anti-IgA at baseline.

[0015] In some embodiments, a patient, prior to administration of obexelimab, had an Hgb level of < 10 g / dL. In some embodiments, a patient, prior to administration of obexelimab, had an Hgb level of > 7.

[0016] In some embodiments, a patient has primary wAIHA.

[0017] In some embodiments, a patient has secondary wAIHA. In some embodiments, a patient has secondary wAIHA due to systemic lupus erythematous, rheumatoid arthritis, and / or deficiency of the immune system (immunodeficiency).

[0018] In some embodiments, a patient has at least one sign or symptom of anemia.

[0019] In some embodiments, a patient has failed at least 1 prior wAIHA treatment regimen. In some embodiments, a prior wAIHA treatment regimen is a glucocorticoid (GC) or immunosuppression therapy. In some embodiments, a failure of a prior wAIHA treatment regimen includes a reduction in Hgb of > 1 g / dL. In some embodiments, a failure of a prior wAIHA treatment regimen includes an increase in LDH of > 1.5 x upper limit of normal (ULN).

[0020] In some embodiments, obexelimab is administered concurrently with a GC therapy. In some embodiments, a GC therapy is administered at a dose of 1-1.5 mg / kg / day prednisone or equivalent.Attorney Docket No. ZEN-024WO1

[0021] In some embodiments, obexelimab is administered for a treatment period sufficient to improve, stabilize, or reduce one or more symptoms of wAIHA relative to a control.

[0022] In some embodiments, a patient achieves an improvement in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) score compared to the FACIT-F score prior to treatment.

[0023] In some embodiments, a patient achieves improvement in EuroQol 5- dimension 5-level (EQ-5D-5L) index score compared to the EQ-5D-5L index score prior to treatment.

[0024] In some embodiments, a patient achieves one or more of the following: (a) a decrease in circulating absolute T, B, and natural killer cell count, (b) a decrease in Ig levels and ratios (e.g., IgG, IgM, IgA, IgE), (c) an increase in CD 19 target receptor occupancy, (d) a decrease in reticulocyte count, (e) a decrease in LDH, (f) an increase in Haptoglobin, and (g) a decrease in indirect bilirubin, following administration of obexelimab.

[0025] In some embodiments, a patient is relapsed or refractory to rituximab.

[0026] In some embodiments, a patient is 18 years of age or older.

[0027] In some embodiments, a patient does not have cold autoimmune hemolytic anemia (cAIHA).

[0028] In some embodiments, a patient does not have mixed type autoimmune hemolytic anemia.

[0029] In some embodiments, a patient does not have paroxysmal cold hemoglobinuria (PCH).

[0030] In some embodiments, obexelimab is administered in a liquid formulation containing 125 mg / mL obexelimab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid, 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80 at pH 5.5.

[0031] In some embodiments, obexelimab is administered as 2 x 1 mL injections or 1 x 2 mL injection.

[0032] In some embodiments, obexelimab is administered using a prefilled syringe or autoinjector.Attorney Docket No. ZEN-024WO1BRIEF DESCRIPTION OF DRAWINGS

[0033] All drawings are for illustration purposes, not for limitation.

[0034] FIGs. 1A-1H illustrate the results from a study treating diseased and control 2B-KIX mice twice weekly with either PBS or 10 mg / kg XENP8206, a surrogate mAh of obexelimab (* denotes p<0.05). FIG. 1A shows blood immune cell counts assessed at week 3. FIG. IB shows blood immune cell counts assessed at week 6. FIG. 1C shows blood immune cell counts assessed at week 12. FIG. ID shows inguinal lymph node immune cell counts assessed at week 12. FIG. IE shows spleen immune cell counts assessed at week 12. FIG. IF shows bone marrow immune cell counts assessed at week 12. FIG. 1G shows the amount of anti-mouse RBC autoantibody from week 1 to week 12, demonstrating a decrease in the mean anti-mouse RBC autoantibody levels with significant differences in levels compared to the PBS dosed control diseased group at weeks 10 through 12. FIG. 1H shows the hemoglobin levels at weeks 10, 11, and 12.

[0035] FIG. 2 is a schematic showing an exemplary clinical study design described for treating wAIHA.

[0036] FIGs. 3A-3B show the change in Hgb (g / dL) from baseline in wAIHA patients after commencing treatment with obexelimab 250 mg SC weekly. FIG. 3A shows the mean change in Hgb (g / dL) from baseline among 8 patients (7 with primary wAIHA, 1 with secondary wAIHA) from Day 1 to Week 24 after commencing treatment. Error bars at each timepoint show mean + / - standard error. For patients who received rescue medication, the change from baseline is after Week 8 and after 28 day-censoring following cessation of concomitant therapy. FIG. 3B shows the change in Hgb (g / dL) from baseline of a patient with secondary wAIHA due to autoimmune disease.DETAILED DESCRIPTION

[0037] The present invention provides, among other things, methods of treating wAIHA by administering to a patient in need of treatment an anti-CD19 antibody (e.g., obexelimab) at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce one or more symptoms of wAIHA-related autoimmune disease relative to a control (e.g., start of treatment).Attorney Docket No. ZEN-024WO1

[0038] Various aspects of the invention are described in detail in the following sections. The use of sections is not meant to limit the invention. Each section can apply to any aspect of the invention. In this application, the use of “or” means “and / or” unless stated otherwise.

[0039] Any numerical values used in this application are meant to cover any variations within the standard deviation or normal fluctuations appreciated by one of ordinary skill in the relevant art.Definitions

[0040] Described herein are several definitions. Such definitions are meant to encompass grammatical equivalents.

[0041] Antibody. The term “antibody” herein is meant to include a protein consisting of one or more polypeptides substantially encoded by all or part of the recognized immunoglobulin genes. The recognized immunoglobulin genes, for example in humans, include the kappa (K), lambda (1), and heavy chain genetic loci, which together comprise the myriad variable region genes, and the constant region gene gamma (y) which encodes the IgG (IgGl, IgG2, IgG3, and IgG4) isotype. Antibody herein is meant to include full length antibodies and antibody fragments, and may refer to a natural antibody from any organism, an engineered antibody, or an antibody generated recombinantly for experimental, therapeutic, or other purposes.

[0042] Baseline: The term “baseline” is defined as values of a parameter at the time of, or prior to, commencement of treatment with a therapeutic. In some embodiments “baseline” is an initial measurement of a condition that is taken at an early time point and used for comparison over time to look for changes. In some embodiments, the baseline is time “zero”, before the participants in the study receive an experimental agent or intervention, or negative control; drug safety and efficacy may be determined by monitoring changes in baseline values.

[0043] Effector Function: The term “effector function” as used herein is meant a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include FcyR-mediated effector functions such as ADCC and ADCP, and complement-mediated effector functions such as CDC. Further, effector functions include FcyRIlb-mediated effector functions, such as inhibitory functions,Attorney Docket No. ZEN-024WO1 e.g., downregulating, reducing, inhibiting etc., B cell responses (e.g., a humoral immune response).

[0044] Fc or Fc region'. The terms “Fc” or “Fc region,” as used herein is meant the polypeptide comprising the constant region of an antibody excluding the first constant region immunoglobulin domain, and in some cases, part of the hinge. Thus, Fc may refer to the last two constant region immunoglobulin domains of IgG, and the flexible hinge N-terminal to these domains. For IgG, Fc comprises immunoglobulin domains Cgamma2 and Cgamma3 (Cy2 and Cy3) and the hinge between Cgammal (Cyl) and Cgamma2 (Cy2). Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to comprise residues C226 or P230 to its carboxyl-terminus, wherein the numbering is according to the EU index as in Kabat. Fc may refer to this region in isolation, or this region in the context of an Fc polypeptide, as described below.

[0045] Fc gamma receptor, or FcyR'. The terms “Fc gamma receptor” or “FcyR” as used herein is meant any member of the family of proteins that bind the IgG antibody Fc region and are substantially encoded by the FcyR genes. In humans this family includes but is not limited to FcyRI (CD64), including isoforms FcyRIa, FcyRIb, and FcyRIc; FcyRII (CD32), including isoforms FcyRIIa (including allotypes H131 and R131), FcyRIIb (including FcyRIIb-1 and FcyRIIb-2), and FcyRIIc; and FcyRIII (CD16), including isoforms FcyRIIIa (including allotypes VI 58 and Fl 58) and FcyRIIIb (including allotypes FcyRIIIb- NA1 and FcyRIIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, incorporated entirely by reference), as well as any undiscovered human FcyRs or FcyR isoforms or allotypes. An FcyR may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcyRs include but are not limited to FcyRI (CD64), FcyRII (CD32), FcyRIII (CD 16), and FcyRIII-2 (CD 16-2), as well as any undiscovered mouse FcyRs or FcyR isoforms or allotypes.

[0046] Modification'. The term “modification” herein is meant an alteration in the physical, chemical, or sequence properties of a protein, polypeptide, antibody, or immunoglobulin. Modifications described herein include amino acid modifications (including amino acid substitutions) and glycoform modifications.

[0047] Normal Values: The term “normal values” herein is meant to mean the typical or expected values for an individual as if the individual did not have AH4A. Those skilled inAttorney Docket No. ZEN-024WO1 the art will appreciate that normal values may vary from individual to individual based on a multitude of factors including, but not limited to, age, race, sex, and comorbidities depending on the specific context the term is used in. For example, the factors considered when determining a patient’s normal value for Hgb may differ from those factors considered when determining a patient’s normal value for LDH.

[0048] Target Antigen'. The term “target antigen” as used herein is meant the molecule that is bound by the variable region of a given antibody, or the fusion partner of an Fc fusion. A target antigen may be a protein, carbohydrate, lipid, or other chemical compound. An antibody or Fc fusion is said to be “specific” for a given target antigen based on having affinity for the target antigen. In some embodiments, the target antigen for obexelimab is CD 19.

[0049] Target cell'. The term “target cell” as used herein is meant a cell that expresses a target antigen.

[0050] Treat'. The term “treat” or “treating” as used herein is meant to encompass improving, ameliorating, stabilizing, or delaying the onset of one or more symptoms of a disease or disorder.

[0051] Therapeutically Effective Dosing Regimen: The term “therapeutically effective dosing regimen” as used herein is meant to encompass administering a therapeutic (e.g., obexelimab) at a dose and dosing interval sufficient to treat a disease or disorder.

[0052] Obexelimab'. The term “Obexelimab” as used herein, is an Fc engineered humanized monoclonal antibody (mAb) that binds to the human B-cell restricted surface antigen CD19 and has enhanced Fc binding to Fey receptor lib (Fc RIIb). The molecule is an IgGl immunoglobulin with a kappa light chain and 2 amino acid substitutions in the constant portion of the heavy chain. Obexelimab is a mAb with a projected mass of approximately 147,426 Da based on the amino acid sequence. The heavy and light chains of obexelimab are given by SEQ ID NO: 10, and SEQ ID NO: 9, respectively.

[0053] Rescue Therapy. The term “rescue therapy” as used herein refers to use of a therapy to treat a suspected remerging disease or worsening of disease symptoms. In some embodiments, the rescue therapy is a different approved therapy. In some embodiments, the rescue therapy is any therapy that may be used to lessen the symptoms associated with wAIHA. In some embodiments, the rescue therapy for wAIHA is GC rescue therapy. InAttorney Docket No. ZEN-024WO1 some embodiments, the rescue therapy for wAIHA is a blood transfusion. Non-limiting examples of rescue therapies may include splenectomy, blood transfusion, rituximab, and other anti-CD19 antibody therapies.Autoimmune Hemolytic Anemia (AIHA)

[0054] Provided herein are methods of treating AIHA comprising administering obexelimab, or a variant thereof. In some aspects, the present invention provides treating a patient with obexelimab at a therapeutically effective dosing regimen for a treatment period sufficient to stabilize or reduce one or more symptoms (e.g., one or more symptoms of wAIHA). For example, methods described herein can result in a therapeutically effective increase in hemoglobin as compared to baseline or a therapeutically effective decrease in anti-RBC autoantibodies.

[0055] Hemolytic anemia occurs when RBCs undergo hemolysis more rapidly than restored. Severe anemia is considered as a Hgb < 10.0 g / dL. AIHAs are acquired haematological disorders caused by increased peripheral erythrocyte destruction mediated by autoantibodies against erythrocyte (RBC) antigens. AIHA may occur with or without complement activation. In fact, critical to the diagnosis of AIHA is the identification of antibodies against RBC antigens. For example, RBCs are initially assessed for the presence of both immunoglobulin and C3 using poly specific antisera. The etiology underlying the pathogenesis of such autoantibodies is still uncertain. Known associations with AIHA include lymphoproliferative neoplasms, autoimmune conditions, drug use and viral infections. The clinical picture is heterogenous and may range from mild / compensated to life-threatening anemia, depending on the antibody's thermal amplitude, isotype and ability to fix complement, as well as on bone marrow compensation. Steroids, immunosuppressants and splenectomy have been the mainstay of treatment. One of the many clinical challenges for the treatment of AIHA is refractory to treatment or recurrence of AIHA. An atypical setting is AIHA after autologous and allogeneic hematopoietic stem cell transplantation. These cases are generally severe and refractory to standard therapy and have high mortality. AIHAs may be primary / idiopathic or secondary to infections, autoimmune diseases, malignancies, particularly lymphoproliferative disorders (LPDs), and drugs, further complicating their clinical picture and management. Regarding new drugs, the false positivity of the Coombs test following daratumumab adds to the list of difficult diagnosis, together with the passenger lymphocyte syndrome after solid organ transplants. AIHA is alsoAttorney Docket No. ZEN-024WO1 increasingly described following therapy of solid cancers with inhibitors of immune checkpoint molecules.

[0056] In embodiments, methods of treating AIHA include methods of treating wAIHA, where the methods comprise administering an anti-CD19 antibody (e.g., obexelimab) according to the methods disclosed herein.Warm Autoimmune Hemolytic Anemia (wAIHA)

[0057] Warm reactive autoantibodies are encountered relatively frequently in tertiary care hospitals. wAIHA is characterized by evidence of RBC hemolysis and a DAT positive for IgG and sometimes complement. While varying with the extent of the compensatory increase in RBC production, symptoms of anemia predominate, as does jaundice, the latter often exacerbated by concurrent Gilbert's syndrome. Rarely, antibodies may be IgA and even less commonly, IgM; these may account for the approximately 5% of patients who have “Coombs-negative” wAIHA.

[0058] More than 95% of patients with wAIHA have an IgG antibody that binds to RBC antigens independently of temperature. The antibodies bind two major RBC antigens - Rhesus (Rh) proteins and glyphorins. Without wishing to be bound by theory, while autoantibodies binding to Rh proteins are not likely to activate complement, due to the number present on RBCs, autoantibodies binding to glyphorins may activate complement. Once bound to an antibody, the RBC can undergo multiple fates. Most will be bound to splenic macrophages via the FcyRIII receptor, resulting in either phagocytosis of the entire RBC or, removal of a significant portion of the RBC membrane-producing spherocytes (also called microspherocytes). Unlike the normal RBC, spherocytes are not deformable and, upon entering the splenic Cords of Billroth, undergo destruction. This may account for some of the increased LDH and depressed haptoglobin. About one-third of patients with wAIHA additionally have complement bound to RBCs, and these C3b-coated RBCs are then cleared by the C3b receptors on hepatic Kupffer cells. In some of these RBCs, C3b is inactivated to C3d, thereby preventing their subsequent destruction and allowing a population of antibody / complement-coated RBCs to persist.

[0059] In summary, wAIHA may be defined by the following: (1) evidence of hemolysis; (2) an IgG antibody binding to protein antigens on the RBC surface at the coreAttorney Docket No. ZEN-024WO1 temperature (warm antibody), demonstrated by a positive Coombs test for IgG in 95% of patients; (3) spherocytes on the peripheral blood smear.

[0060] Patients with wAIHA present with typical symptoms of anemia including shortness of breath with exercise, generalized fatigue, dizziness, syncope, malaise, chest pressure / pain, and cognitive dysfunction. Most patients have a reduced health-related quality of life. Some wAIHA patients have a mild anemia and increased mean corpuscular volume and are referred to hematology for assessment for possible myelodysplastic syndrome. The increased mean corpuscular volume is related to the increased numbers of reticulocytes (which are generally larger than more mature RBCs) and is not due to a primary bone marrow disorder.

[0061] In some embodiments, the patient has primary wAIHA. In some embodiments, the patient has secondary wAIHA. In some embodiments, the patient has secondary wAIHA due to an autoimmune disorder. In some embodiments the secondary wAIHA is due to systemic lupus erythematous, rheumatoid arthritis, or deficiency of the immune system (immunodeficiency). In some embodiments, the patient has secondary wAIHA due to LDP, B-cell lymphoma or chronic lymphocytic leukemia. In some embodiments, the patient has secondary wAIHA due to infection or drug use such as methyldopa or carbamazepine.Patients

[0062] Exemplary patients and patient populations that can benefit from the therapeutically effective methods for treating wAIHA are described herein.

[0063] In some embodiments, a patient has a confirmed diagnosis of wAIHA.

[0064] In some embodiments, a patient has a Hgb level of > 7 g / dL. In some embodiments, a patient has a Hgb level of > 7 g / dL at baseline.

[0065] In some embodiments, a patient has a Hgb level of at or greater than 7 g / dL. In some embodiments, a patient has a Hgb level of at or greater than 8 g / dL. In some embodiments, a patient has a Hgb level of at or greater than 9 g / dL. In some embodiments, a patient has a Hgb level of at or greater than 10 g / dL. In some embodiments, a patient has a Hgb level 7 g / dL or greater at baseline. In some embodiments, a patient has a Hgb level of 8 g / dL or greater at baseline. In some embodiments, a patient has a Hgb level of 9 g / dL orAttorney Docket No. ZEN-024WO1 greater at baseline. In some embodiments, a patient has a Hgb level of 10 g / dL or greater at baseline.

[0066] In some embodiments, a patient has a Hgb level of 11 g / dL or less than 11 g / dL. In some embodiments, a patient has a Hgb level of 10 g / dL or less than 10 g / dL. In some embodiments, a patient has a Hgb level of 9 g / dL or less than 9 g / dL. In some embodiments, a patient has a Hgb level of 8 g / dL or less than 8 g / dL. In some embodiments, a patient has a Hgb level of 7 g / dL or less than 7 g / dL. In some embodiments, a patient has an Hgb level of 11 g / dL or less at baseline. In some embodiments, a patient has an Hgb level of 10 g / dL or less at baseline. In some embodiments, a patient has an Hgb level of 9 g / dL or less at baseline. In some embodiments, a patient has an Hgb level of 8 g / dL or less at baseline. In some embodiments, a patient has an Hgb level of 7 g / dL or less at baseline.

[0067] In some embodiments, a patient has at least one sign or symptom of anemia. In some embodiments, a patient has at least one sign or symptom of anemia, including but not limited to: fatigue, weakness, pallor, chest pain or shortness of breath (at rest or with exertion), headache, dizziness, or lightheadedness, tachycardia or tachypnea.

[0068] In some embodiments, patients also have failed at least 1 prior wAIHA treatment regimen (GC or immunosuppression therapy). In some embodiments, a patient is considered to have failed therapy if, during the course of the disease, there was a reduction in Hgb of 1 g / dL or more and an increase in LDH of > 1.5 x ULN. In some embodiments, failure is assessed after a minimum of 4 weeks of GC therapy. In some embodiments, failure is assessed at after a minimum of 3 months of immunosuppression therapy.

[0069] In some embodiments, patients have failed up to 2 prior wAIHA therapies. In some embodiments, a prior failed therapy may be considered concurrent therapy, if the patient maintains a Hgb level of > 7 g / dL. In some embodiments, a prior failed therapy may be considered concurrent therapy, if the patient maintains a Hgb level of > 8 g / dL. In some embodiments, a prior failed therapy may be considered concurrent therapy, if the patient maintains a Hgb level of > 9 g / dL. In some embodiments, a prior failed therapy may be considered concurrent therapy, if the patient maintains a Hgb level of < 10 g / dL on the therapy.

[0070] In some embodiments, a patient has plasmablast levels greater than 100 cells / mL, greater than 200 cells / mL, greater than 300 cells / mL, greater than 400 cells / mL,Attorney Docket No. ZEN-024WO1 greater than 500 cells / mL, greater than 600 cells / mL, greater than 700 cells / mL, greater than 800 cells / mL, greater than 900 cells / mL, greater than 1000 cells / mL, greater than 2000 cells / mL, greater than 3000 cells / mL, greater than 4000 cells / mL or greater than 5000 cells / mL.

[0071] In some embodiments, a patient is an adult human patient (e.g., a human patient > 18 years of age).

[0072] In some embodiments, a patient has been diagnosed with wAIHA for at least three (3) months.

[0073] In some embodiments, a patient is receiving treatment for wAIHA at the time treatment comprising administering obexelimab commences.

[0074] In some embodiments, a patient is not receiving treatment for wAIHA at the time treatment comprising administering obexelimab commences.

[0075] In some embodiments, a patient has previously received treatment for wAIHA prior to treatment comprising administering obexelimab commences.

[0076] In some embodiments, a patient is diagnosed with primary or secondary wAIHA (e.g., as documented by a positive DAT specific for anti-IgG or anti -IgA). In some embodiments, a patient is diagnosed with primary wAIHA. In some embodiments, a patient is diagnosed with secondary wAIHA. In some embodiments, secondary wAIHA is due to systemic lupus erythematous, rheumatoid arthritis, and / or deficiency of the immune system (immunodefi ci ency ) .

[0077] In some embodiments, a patient received at least one (1) prior wAIHA treatment regimen (e.g., one or more treatment regimens comprising the administration of steroids, rituximab, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, danazol, vincristine, or erythropoiesis-stimulating agents, or wherein the patient previously underwent splenectomy, or any combination thereof).

[0078] In some embodiments, a patient is receiving a steroid (e.g., prednisone / prednisolone) concomitantly with treatment comprising administration of obexelimab as described herein. In some embodiments, a dose of a steroid (e.g., prednisone / prednisolone) may not exceed 20 mg / day, is stable for at least 4 weeks prior to commencing treatment with obexelimab. In some embodiments, a dose of a steroid (e.g.,Attorney Docket No. ZEN-024WO1 prednisone / prednisolone) may not exceed 30 mg / day, and is stable for at least 4 weeks prior to commencing treatment with obexelimab.

[0079] In some embodiments, a patient is receiving an immunosuppressant concomitantly with treatment comprising administration of obexelimab as described herein. In embodiments, an immunosuppressant is selected from the group consisting of azathioprine, mycophenolate mofetil / mycophenolic acid, cyclosporine, and cyclophosphamide, and any combinations thereof. In some embodiments, a patient is on a stable dose during treatment with obexelimab.

[0080] In some embodiments, a patient has Hgb > 7 to < 10 g / dL at baseline.

[0081] In some embodiments, a patient has least one sign or symptom of anemia at baseline.

[0082] In some embodiments, a patient has a platelet count > 50,000 mm3at baseline.

[0083] In some embodiments, a patient has a neutrophil count > 1,000 mm3at baseline.

[0084] In some embodiments, a patient has a serum albumin and serum calcium concentrations within the normal range at baseline.

[0085] In some embodiments, a patient has a total serum IgG of > 400 mg / dL at baseline In some embodiments, a patient has a total serum IgG of > 600 mg / dL at baseline.

[0086] In some embodiments, a patient has a creatine kinase value < 2 x ULN at baseline.

[0087] In some embodiments, a patient who has previously undergone splenectomy is at least 4 months post resection at the time treatment comprising administration of obexelimab as described herein is commenced. In embodiments, the patient is vaccinated as per country-specific immunization schedules.

[0088] In some embodiments, a patient has an autoimmune disorder. In embodiments, an autoimmune disorder is systemic lupus erythematosus or rheumatoid arthritis. In embodiments, an autoimmune disorder is an LPD. In embodiments, a patient with an autoimmune disorder has stable disease with respect to the autoimmune disorder (e.g., a patient has no changes in disease-related concomitant medications and / or the severity of disease has been stable (e.g., for at least 4 months)).Attorney Docket No. ZEN-024WO1

[0089] In some embodiments, a patient has an LPD. In embodiments, a patient with an LPD has stable disease with respect to the LPD (e.g., a patient has no changes in concomitant disease-related medications and / or the severity of disease has been stable (e.g., for at least 4 months)).

[0090] In some embodiments, a patient does not have cAIHA, cold agglutinin syndrome (CAD), mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria.

[0091] In some embodiments, a patient does not have any other associated cause of hereditary or acquired hemolytic anemia.

[0092] In some embodiments, a patient does not have secondary wAIHA that is not due to an autoimmune disorder (e.g., an LPD).

[0093] In some embodiments, a patient has not received a transfusion within 2 weeks prior to commencing treatment comprising administration of obexelimab as described herein.

[0094] In some embodiments, a patient has not received B cell-depleting, B cell- targeted, or other biologic immunomodulatory agents within the 6 months prior to commencing treatment comprising administration of obexelimab as described herein.

[0095] In some embodiments, a patient has received B cell-depleting, B cell- targeted, or other biologic immunomodulatory agents within 6-12 months prior to commencing treatment comprising administration of obexelimab as described herein. In some embodiments, the patient has a B cell count that is within the laboratory reference range at baseline.

[0096] In some embodiments, a patient has not received intravenous immunoglobulin (IVIG) or epoetin alfa within 6 weeks prior to commencing treatment comprising administration of obexelimab as described herein.

[0097] In some embodiments, a patient is not receiving more than two (2) concomitant medications for the treatment of wAIHA at the time treatment comprising administration of obexelimab as described herein is commenced. In some embodiments, the concomitant medications exclude vitamins or other supplements.

[0098] In some embodiments, a patient has not received an investigational treatment or direct medical intervention in another clinical study within 12 weeks or < 5 half-lives ofAttorney Docket No. ZEN-024WO1 the investigational treatment (whichever is shorter) at the time treatment comprising administration of obexelimab as described herein is commenced.

[0099] In some embodiments, a patient has not received live vaccine or live therapeutic infectious agent within the 6 weeks prior to commencing treatment comprising administration of obexelimab as described herein.

[0100] In some embodiments, a patient does not evidence active tuberculosis (TB) or at high risk for TB. In some embodiments, criteria used to assess the patient are selected from:• History of active TB or latent TB, unless completion of treatment is documented;• Positive, indeterminate, or invalid interferon-gamma (IFNy) release assay results at screening, unless treatment is documented (patients with an indeterminate test result can repeat the test once);• Signs of symptoms that could represent active TB; and / or• Chest radiograph, computed tomography scan, or magnetic resonance imaging that suggests possible diagnosis of TB.

[0101] In some embodiments, a patient does not have a history or evidence of a clinically unstable / uncontrolled disorder, condition, or disease (including, but not limited to, cardiopulmonary, oncologic, renal, hepatic, metabolic, hematologic, psychiatric, or active infection).

[0102] In some embodiments, a patient does not have a known allergy to mAb therapy.

[0103] In some embodiments, a patient does not have a known hypersensitivity to dextran or components of dextran.

[0104] In some embodiments, a patient does not have an active infection (e.g., pneumonia, biliary tract infection, diverticulitis, Clostridium difficile infection) that requires parenteral or oral anti-infectives and / or hospitalization, and / or is assessed as serious / clinically significant within eight (8) weeks prior to commencing treatment comprising administration of obexelimab as described herein.

[0105] In some embodiments, a patient does not have a chronic infection (e.g., bronchiectasis, chronic osteomyelitis, chronic pyelonephritis) or requiring chronic treatmentAttorney Docket No. ZEN-024WO1 with anti-infectives (e.g., antibiotics, antivirals) prior to commencing treatment comprising administration of obexelimab as described herein.

[0106] In some embodiments, a patient does not have confirmed or suspected clinical immunodeficiency syndrome not related to treatment of wAIHA, or has a family history of congenital or hereditary immunodeficiency, unless confirmed absent in the patient prior to commencing treatment comprising administration of obexelimab as described herein.

[0107] In some embodiments, a patient does not have an acute hepatitis B infection (hepatitis B surface antigen-positive), active hepatitis C virus (HCV), or HIV infection prior to commencing treatment comprising administration of obexelimab as described herein.

[0108] In some embodiments, a patient does not have a positive test for active hepatitis B through detection of hepatitis B surface antigen prior to commencing treatment comprising administration of obexelimab as described herein.

[0109] In some embodiments, a patient does not have any of the following prior to commencing treatment comprising administration of obexelimab as described herein:• hepatitis B surface antigen,• hepatitis B surface antibody, or• hepatitis B core antibody.

[0110] In some embodiments, a patient does not have a history of HCV prior to commencing treatment comprising administration of obexelimab as described herein. In embodiments, a patient has documented negative HCV ribonucleic acid levels in the serum at 12 weeks or longer after the completion of HCV therapy prior to commencing treatment comprising administration of obexelimab as described herein.Obexelimab[oni] In some embodiments, an anti-CD-19 antibody (e.g., obexelimab, or a variant thereof) is used to treat a patient suffering from wAIHA. In one aspect, the present invention provides a method of administering obexelimab for the treatment of wAIHA.

[0112] Obexelimab (XmAb5871) is a humanized anti-CD19 mAb with an Fc portion engineered for increased affinity to FcyRIIb, the only Fc receptor on B-cells. Obexelimab is a mAb specific for CD 19 comprising: a light chain comprising a variable region having:Attorney Docket No. ZEN-024WO1 a CDR1 comprising RSSKSLQNVNGNTYLY (SEQ ID NO: 2), a CDR2 comprising RMSNLNS (SEQ ID NO: 3), and a CDR3 comprising MQHLEYPIT (SEQ ID NO: 4); and a heavy chain comprising a variable region having a CDR1 comprising SYVMH (SEQ ID NO: 5), a CDR2 comprising WIGYINPYNDGTKY (SEQ ID NO: 6), and a CDR3 comprising GTYYYGTRVFDY (SEQ ID NO: 7), wherein the heavy chain comprises amino acid substitutions in the Fc region S267E and L328F as compared to SEQ ID NO: 8: wherein the numbering is according to the EU index, as in Kabat.ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 8)

[0113] In some embodiments, obexelimab comprises: a light chain comprising amino acid sequence:DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMS NLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRT VAAPSVEI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 9); and heavy chain comprising an amino acid sequence:EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDG TKYNEKFQGRVTISSDKS ISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVEHEDPEVKFNWYVDGAttorney Docket No. ZEN-024WO1VEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKAFPAPIEKT I SK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 10).Table 1: Sequence of Heavy chain and Light chain amino acid sequence of obexelimabAttorney Docket No. ZEN-024WO1Table 2: Kabat heavy chain and light chain CDRs of obexelimab.

[0114] In some embodiments, obexelimab comprises a light chain variable region and a heavy chain variable region as given by Table 1. In some embodiments, obexelimab comprises CDRs as given by Table 2.

[0115] In some embodiments, an anti-CD19 antibody comprises a light chain comprising an amino acid sequence of SEQ ID NO: 9. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises an amino acid sequence of SEQ ID NO: 9, and wherein the heavy chain comprises an amino acid sequence of SEQ ID NO: 10.

[0116] In some embodiments, an anti-CD19 antibody comprises a light chain, wherein the light chain comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 11. In some embodiments, an anti-CD19 antibody comprises a heavy chain, wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain, wherein the heavy chain comprises a heavy chain variable region comprising an amino acidAttorney Docket No. ZEN-024WO1 sequence of SEQ ID NO: 12, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 12, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F.

[0117] In some embodiments, an anti-CD19 antibody comprises a light chain comprising a LCDR1 comprising an amino acid sequence of SEQ ID NO: 2, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 3, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 4. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1 comprising an amino acid sequence of SEQ ID NO: 5, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising an amino acid sequence of SEQ ID NO: 7. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1 comprising an amino acid sequence of SEQ ID NO: 5, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising an amino acid sequence of SEQ ID NO: 7, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F. In some embodiments, an anti-CD19 antibody comprises a light chain and heavy chain, wherein the light chain comprises a LCDR1 comprising an amino acid sequence of SEQ ID NO: 2, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 3, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 4, and wherein the heavy chain comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 5, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising an amino acid sequence of SEQ ID NO: 7. In some embodiments, an anti-CD19 antibody comprises a light chain and heavy chain, wherein the light chain comprises a LCDR1 comprising an amino acid sequence of SEQ ID NO: 2, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 3, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 4, and wherein the heavy chain comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 5, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising an amino acid sequence of SEQ ID NO: 7, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F.Attorney Docket No. ZEN-024WO1

[0118] Obexelimab works by exploiting the regulation of B-cell receptor (BCR) signaling by FcyRIIb. Obexelimab binds CD19 of the BCR complex and its Fc is engineered to increase its affinity for the inhibitory FcyRIIb. Since CD19 is associated with the BCR, Obexelimab tethering of CD 19 to FcyRIIb on the same cell poises the BCR complex for inhibition upon antigen-induced BCR aggregation. Obexelimab capitalizes upon the natural inhibitory mechanism of FcyRIIb, the only Fc receptor expressed by B cells, which acts as a negative regulator in conditions of antigen excess and immune complex formation (Chu et al., 2014). Obexelimab may also have an improved safety profile compared to B cell depleting antibodies as it may not mediate B cell killing.Variants

[0119] In some embodiments, a variant of obexelimab is an immunoglobulin specific for CD19 comprises: a light chain comprising a variable region having a CDR1 comprising RSSKSLQNVNGNTYLY, a CDR2 comprising RMSNLNS, and a CDR3 comprising MQHLEYPIT; and a heavy chain comprising a variable region having a CDR1 comprising SYVMH, a CDR2 comprising WIGYINPYNDGTKY, and a CDR3 comprising GTYYYGTRVFDY, wherein the heavy chain comprises amino acid substitutions in the Fc region S267E and L328F as compared to:ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 8) wherein the numbering is according to the EU index, as in Kabat.

[0120] In some embodiments, a variant of obexelimab comprises a heavy chain variable region (VH) and / or a light chain variable region (VL), comprising a CDR1, a CDR2, and a CDR3, each of which differs by no more than 1, 2, 3, 4 or 5 amino acid residues from each of RSSKSLQNVNGNTYLY (SEQ ID NO: 2), RMSNLNS (SEQ ID NO: 3), MQHLEYPIT (SEQ ID NO: 4), SYVMH (SEQ ID NO: 5), WIGYINPYNDGTKY (SEQ ID NO: 6) and / or GTYYYGTRVFDY (SEQ ID NO: 7). In some embodiments, a variant ofAttorney Docket No. ZEN-024WO1 obexelimab comprises a heavy chain, wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F.

[0121] In some embodiments, an anti-CD19 antibody comprises a light chain comprising a LCDR1, LCDR2, and LCDR3, each of which differs by no more than 1 residue from each of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a LCDR1, LCDR2, and LCDR3, each of which differs by no more than 2 residues from each of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a LCDR1, LCDR2, and LCDR3, each of which differs by no more than 3 residues from each of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a LCDR1, LCDR2, and LCDR3, each of which differs by no more than 4 residue from each of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a LCDR1, LCDR2, and LCDR3, each of which differs by no more than 5 residues from each of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4.

[0122] In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 1 residue from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 2 residues from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 3 residues from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 4 residues from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 5 residues from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7.

[0123] In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 1 residue from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F. InAttorney Docket No. ZEN-024WO1 some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 2 residues from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 3 residues from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 4 residues from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a HCDR1, HCDR2, and HCDR3, each of which differs by no more than 5 residues from each of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and wherein the heavy chain comprises an Fc region comprising amino acid substitutions S267E and L328F.

[0124] In some embodiments, the variant of obexelimab comprises: a light chain variable region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the light chain variable region identified in Table 1. In some embodiments, the variant of obexelimab comprises: a heavy chain variable region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the heavy chain variable region as identified in Table 1.

[0125] In some embodiments, an anti-CD19 antibody comprises a light chain comprising a light chain variable region at least 80% identical to SEQ ID NO: 11. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a light chain variable region at least 85% identical to SEQ ID NO: 11. In some embodiments, an antiCD 19 antibody comprises a light chain comprising a light chain variable region at least 90% identical to SEQ ID NO: 11. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a light chain variable region at least 91% identical to SEQ ID NO: 11. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a light chain variable region at least 92% identical to SEQ ID NO: 11. In some embodiments, an anti- CD19 antibody comprises a light chain comprising a light chain variable region at least 93% identical to SEQ ID NO: 11. In some embodiments, an anti-CD19 antibody comprises a lightAttorney Docket No. ZEN-024WO1 chain comprising a light chain variable region at least 94% identical to SEQ ID NO: 11. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a light chain variable region at least 95% identical to SEQ ID NO: 11. In some embodiments, an anti- CD19 antibody comprises a light chain comprising a light chain variable region at least 96% identical to SEQ ID NO: 11. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a light chain variable region at least 97% identical to SEQ ID NO: 11. In some embodiments, an anti-CD19 antibody comprises a light chain comprising a light chain variable region at least 98% identical to SEQ ID NO: 11. In some embodiments, an anti- CD19 antibody comprises a light chain comprising a light chain variable region at least 99% identical to SEQ ID NO: 11.

[0126] In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 80% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 85% identical to SEQ ID NO: 12. In some embodiments, an anti- CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 90% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 91% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 92% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 93% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 94% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 95% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 96% identical to SEQ ID NO: 12. In some embodiments, an anti- CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 97% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 98% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a heavy chain comprising a heavy chain variable region at least 99% identical to SEQ ID NO: 12.Attorney Docket No. ZEN-024WO1

[0127] In some embodiments, the variant of obexelimab comprises: a light chain variable region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the light chain variable region identified in Table 1 and a heavy chain variable region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the heavy chain variable region as identified in Table 1 and further comprises amino acid substitutions in the Fc region S267E and L328F as compared to SEQ ID NO: 8, wherein the numbering is according to the EU index.

[0128] In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 80% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 80% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 85% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 85% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 90% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 90% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 91% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 91% identical to SEQ ID NO: 12. In some embodiments, an anti- CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 92% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 92% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 93% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 93% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 94% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 94% identical to SEQ ID NO: 12. In some embodiments, anAttorney Docket No. ZEN-024WO1 anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 95% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 95% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 96% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 96% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 97% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 97% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 98% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 98% identical to SEQ ID NO: 12. In some embodiments, an anti-CD19 antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region at least 99% identical to SEQ ID NO: 11, and wherein the heavy chain comprises a heavy chain variable region at least 99% identical to SEQ ID NO: 12.

[0129] In some embodiments, the variant of obexelimab comprises: a light chain comprising an amino acid sequence 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the light chain as identified in Table 1. In some embodiments, the variant of obexelimab comprises: a heavy chain comprising an amino acid sequence 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the heavy chain as identified in Table 1.

[0130] In some embodiments, an anti-CD19 antibody comprises a light chain amino acid sequence that is at least 70% identical to SEQ ID NO: 9. In some embodiments, an anti- CD19 antibody comprises a light chain amino acid sequence that is at least 75% identical to SEQ ID NO: 9. In some embodiments, an anti-CD19 antibody comprises a light chain amino acid sequence that is at least 80% identical to SEQ ID NO: 9. In some embodiments, an anti- CD19 antibody comprises a light chain amino acid sequence that is at least 85% identical to SEQ ID NO: 9. In some embodiments, an anti-CD19 antibody comprises a light chain amino acid sequence that is at least 90% identical to SEQ ID NO: 9. In some embodiments, an anti- CD19 antibody comprises a light chain amino acid sequence that is at least 91% identical to SEQ ID NO: 9. In some embodiments, an anti-CD19 antibody comprises a light chain aminoAttorney Docket No. ZEN-024WO1 acid sequence that is at least 92% identical to SEQ ID NO: 9. In some embodiments, an anti- CD19 antibody comprises a light chain amino acid sequence that is at least 93% identical to SEQ ID NO: 9. In some embodiments, an anti-CD19 antibody comprises a light chain amino acid sequence that is at least 94% identical to SEQ ID NO: 9. In some embodiments, an anti- CD19 antibody comprises a light chain amino acid sequence that is at least 95% identical to SEQ ID NO: 9. In some embodiments, an anti-CD19 antibody comprises a light chain amino acid sequence that is at least 96% identical to SEQ ID NO: 9. In some embodiments, an anti- CD19 antibody comprises a light chain amino acid sequence that is at least 97% identical to SEQ ID NO: 9. In some embodiments, an anti-CD19 antibody comprises a light chain amino acid sequence that is at least 98% identical to SEQ ID NO: 9. In some embodiments, an anti- CD19 antibody comprises a light chain amino acid sequence that is at least 99% identical to SEQ ID NO: 9.

[0131] In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 70% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 75% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 80% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 85% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 90% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 91% identical to SEQ ID NO: 10. In some embodiments, an antiCD 19 antibody comprises a heavy chain amino acid sequence that is at least 92% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 93% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 94% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 95% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 96% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acid sequence that is at least 97% identical to SEQ ID NO: 10. In some embodiments, an anti-CD19 antibody comprises a heavy chain amino acidAttorney Docket No. ZEN-024WO1 sequence that is at least 98% identical to SEQ ID NO: 10. In some embodiments, an antiCD 19 antibody comprises a heavy chain amino acid sequence that is at least 99% identical to SEQ ID NO: 10.

[0132] In some embodiments, the variant of obexelimab comprises: a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the light chain sequence as identified in Table 1 and a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the heavy chain sequence as identified in Table 1, and the heavy chain of the variant comprises amino acid substitutions in the Fc region S267E and L328F as compared to SEQ ID NO: 8, wherein the numbering is according to the EU index, as in Kabat.

[0133] In some embodiments, a suitable variant of obexelimab binds to the same epitope on human CD 19, as an antibody comprising a light chain and a heavy chain as identified in Table 1. Epitope binding may be determined by a method known in the art.

[0134] In some embodiments, a suitable variant of obexelimab competes for binding to human CD 19, as an antibody comprising a light chain and heavy chain as identified in Table 1, under a binning assay known in the art. As used herein, a binning assay refers to any method to regionally map the epitope to which the antibody binds. Standard methods for such antibody characterization, also known as epitope binning, typically involve surface plasmon resonance (SPR) technology. Using SPR, mAb candidates are screened pairwise for binding to a target protein. Other standard methods involve ELISA-based screens and may require synthesis of sets of overlapping peptides corresponding to the protein of interest.

[0135] In some embodiments, the human CD 19 comprises an amino acid sequence of SEQ ID NO: 1. In some embodiments, an anti-CD19 antibody binds to the extracellular domain of human CD 19.MPPPRLLFFLLFLTPMEVRPEEPLWKVEEGDNAVLQCLKGTSDGPTQQLTWSRESP LKPFLKLSLGLPGLGIHMRPLAIWLFI FNVSQQMGGFYLCQPGPPSEKAWQPGWTVN VEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEP PCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSL ELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMS FHLE I TARPVLWHWLL RTGGWKVSAVTLAYLI FCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSAttorney Docket No. ZEN-024WO1GPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGV GPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFS NAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYEDMRGILYAAPQL RS IRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRMGTWSTR (SEQ ID NO: 1)Fc Receptor Binding Properties

[0136] Anti-CD19 antibodies (e.g., obexelimab) disclosed herein comprise an Fc variant that has enhanced Fc binding to the inhibitory Fey receptor lib (FcyRIIb). FcyRIIb, the only FcR on B cells, serves as an antibody-sensing down-regulator of humoral immunity that is naturally engaged by immune complexes. When sufficient antibody is raised against a given antigen, specific immune complexes form and co-engage FcyRIIb and BCR with high avidity, selectively suppressing only B cells recognizing cognate antigen. In addition, FcyRIIb regulates the activity of other B cell stimulators including interleukin (IL)-4, LPS, and BAFF that amplify BCR-driven proliferation and differentiation. By simultaneously binding CD 19 and FcyRIIb, obexelimab (and variants described herein) mimics the action of antigen-antibody complexes and down-regulates B cell activity.

[0137] The Fc variants disclosed herein may be optimized for a variety of Fc receptor binding properties. An Fc variant that is engineered or predicted to display one or more optimized properties is herein referred to as an “optimized Fc variant.” Properties that may be optimized include but are not limited to enhanced or reduced affinity for an FcyR. In one embodiment, the Fc variants disclosed herein are optimized to possess enhanced affinity for an inhibitory receptor FcyRIIb. In other embodiments, immunoglobulins disclosed herein provide enhanced affinity for FcyRIIb, yet reduced affinity for one or more activating FcyRs, including for example FcyRI, FcyRIIa, FcyRIIIa, and / or FcyRIIIb. The FcyR receptors may be expressed on cells from any organism, including but not limited to human, cynomolgus monkeys, and mice. The Fc variants disclosed herein may be optimized to possess enhanced affinity for human FcyRIIb.

[0138] An Fc variant comprises one or more amino acid modifications relative to a parent Fc polypeptide, wherein the amino acid modification(s) provide one or more optimized properties. An Fc variant disclosed herein differs in amino acid sequence from its parent by virtue of at least one amino acid modification. Thus, Fc variants disclosed herein have at least one amino acid modification compared to the parent. Alternatively, the FcAttorney Docket No. ZEN-024WO1 variants disclosed herein may have more than one amino acid modification as compared to the parent, for example from two to fifty amino acid modifications, e.g., from two to ten amino acid modifications, from two to five amino acid modifications, etc. compared to the parent. Thus, the sequences of the Fc variants and those of the parent Fc polypeptide are substantially homologous. For example, the variant Fc variant sequences herein will possess at least 80% homology with the parent Fc variant sequence, e.g., at least 90% homology, at least 95% homology, at least 98% homology, at least 99% homology, etc. Modifications disclosed herein include amino acid modifications, including insertions, deletions, and substitutions. Modifications disclosed herein also include glycoform modifications.

[0139] Modifications may be made genetically using molecular biology or may be made enzymatically or chemically.

[0140] Fc variants disclosed herein are defined according to the amino acid modifications that compose them. Thus, for example, S267E is an Fc variant with the substitution S267E relative to the parent Fc polypeptide. Likewise, S267E / L328F defines an Fc variant with the substitutions S267E and L328F relative to the parent Fc polypeptide. The identity of the WT amino acid may be unspecified, in which case the aforementioned variant is referred to as 267E / 328F. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, 267E / 328F is the same Fc variant as 328F / 267E, and so on. Unless otherwise noted, positions discussed herein are numbered according to the EU index as described in Kabat (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, hereby entirely incorporated by reference). In brief, EU is the name of the first antibody molecule whose entire amino acid sequence was determined (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated by reference), and its amino acid sequence has become the standard numbering scheme for heavy chain constant regions. The EU protein has become the standard reference for defining numbering. Kabat et al. lists the EU sequence in a set of indices aligning it with other antibody sequences, serving as a necessary tool for aligning antibodies to the EU numbering scheme. Thus, as appreciated by those of skill in the art, the standard way of referencing the EU numbering is to refer to Kabat et al.’s alignment of sequences, because it puts EU in context with antibodies of other variable domain lengths. As such, as used herein, “according to the EU index,” “the EUAttorney Docket No. ZEN-024WO1 index as in Kabat” or “numbering is according to the EU index, as in Kabat” refers to the numbering of the EU antibody as described in Kabat.

[0141] In certain embodiments, the Fc variants disclosed herein are based on human IgG sequences, and thus human IgG sequences are used as the “base” sequences against which other sequences are compared, including but not limited to sequences from other organisms, for example rodent and primate sequences. It is contemplated that, although the Fc variants disclosed herein are engineered in the context of one parent IgG, the variants may be engineered in or “transferred” to the context of another, second parent IgG. This is done by determining the “equivalent” or “corresponding” residues and substitutions between the first and second IgG, typically based on sequence or structural homology between the sequences of the first and second IgGs. In order to establish homology, the amino acid sequence of a first IgG outlined herein is directly compared to the sequence of a second IgG. After aligning the sequences, using one or more of the homology alignment programs known in the art (for example using conserved residues as between species), allowing for necessary insertions and deletions in order to maintain alignment (i.e., avoiding the elimination of conserved residues through arbitrary deletion and insertion), the residues equivalent to particular amino acids in the primary sequence of the first immunoglobulin are defined. Alignment of conserved residues may conserve 100% of such residues. However, alignment of greater than 75% or as little as 50% of conserved residues is also adequate to define equivalent residues. Equivalent residues may also be defined by determining structural homology between a first and second IgG that is at the level of tertiary structure for IgGs whose structures have been determined. In this case, equivalent residues are defined as those for which the atomic coordinates of two or more of the main chain atoms of a particular amino acid residue of the parent or precursor (N on N, CA on CA, C on C and O on O) are within about 0.13 nm, after alignment. In another embodiment, equivalent residues are within about 0.1 nm after alignment. Alignment is achieved after the best model has been oriented and positioned to give the maximum overlap of atomic coordinates of non-hydrogen protein atoms of the proteins. Regardless of how equivalent or corresponding residues are determined, and regardless of the identity of the parent IgG in which the IgGs are made, what is meant to be conveyed is that the Fc variants discovered as disclosed herein may be engineered into any second parent IgG that has significant sequence or structural homology with the Fc variant. Thus, for example, if a variant antibody is generated wherein the parentAttorney Docket No. ZEN-024WO1 antibody is human IgGl, by using the methods described above or other methods for determining equivalent residues, the variant antibody may be engineered in another IgGl parent antibody that binds a different antigen, a human IgG2 parent antibody, a human IgA parent antibody, a mouse IgG2a or IgG2b parent antibody, and the like. Again, as described above, the context of the parent Fc variant does not affect the ability to transfer the Fc variants disclosed herein to other parent IgGs.

[0142] The term “greater affinity” or “improved affinity” or “enhanced affinity” or “better affinity” than a parent Fc polypeptide, as used herein is meant that an Fc variant binds to an Fc receptor with a significantly higher equilibrium constant of association (KA or Ka) or lower equilibrium constant of dissociation (KD or Kd) than the parent Fc polypeptide when the amounts of variant and parent polypeptide in the binding assay are essentially the same. For example, the Fc variant with improved Fc receptor binding affinity may display from 5 fold to 1000 fold, e.g. from 10 fold to 500 fold improvement in Fc receptor binding affinity compared to the parent Fc polypeptide, where Fc receptor binding affinity is determined, for example, by the binding methods disclosed herein, including but not limited to Biacore, by one skilled in the art. Accordingly, by “reduced affinity” as compared to a parent Fc polypeptide as used herein is meant that an Fc variant binds an Fc receptor with significantly lower KA or higher KD than the parent Fc polypeptide. Greater or reduced affinity can also be defined relative to an absolute level of affinity. For example, according to the data herein, WT (native) IgGl binds FcyRIIb with an affinity of 1.5 mM, or 1500 nM. Furthermore, some Fc variants described herein bind FcyRIIb with an affinity 10- fold greater to WT IgGl. As disclosed herein, greater or enhanced affinity means having a KD lower than 100 nM, for example between 10 nM - 100 nM, between 1 - 100 nM, or less than 1 nM.

[0143] In one embodiment, the Fc variants provide selectively enhanced affinity to FcyRIIb relative to one or more activating receptors. Selectively enhanced affinity means either that the Fc variant has improved affinity for FcyRIIb relative to the activating receptor(s) as compared to the parent Fc polypeptide but has reduced affinity for the activating receptor(s) as compared to the parent Fc polypeptide, or it means that the Fc variant has improved affinity for both FcyRIIb and activating receptor(s) as compared to the parent Fc polypeptide, however the improvement in affinity is greater for FcyRIIb than it is for the activating receptor(s). In alternate embodiments, the Fc variants reduce or ablate binding to one or more activating FcyRs, reduce or ablate binding to one or more complementAttorney Docket No. ZEN-024WO1 proteins, reduce or ablate one or more FcyR-mediated effector functions, and / or reduce or ablate one or more complement-mediated effector functions.

[0144] The presence of different polymorphic forms of FcyRs provides yet another parameter that impacts the therapeutic utility of the Fc variants disclosed herein. Whereas the specificity and selectivity of a given Fc variant for the different classes of FcyRs significantly affects the capacity of an Fc variant to target a given antigen for treatment of a given disease, the specificity or selectivity of an Fc variant for different polymorphic forms of these receptors may in part determine which research or pre-clinical experiments may be appropriate for testing, and ultimately which patient populations may or may not respond to treatment. Thus, the specificity or selectivity of Fc variants disclosed herein to Fc receptor polymorphisms, including but not limited to FcyRIIa, FcyRIIIa, and the like, may be used to guide the selection of valid research and pre-clinical experiments, clinical trial design, patient selection, dosing dependence, and / or other aspects concerning clinical trials.

[0145] Fc variants disclosed herein may comprise modifications that modulate interaction with Fc receptors other than FcyRs, including but not limited to complement proteins, FcRn, and Fc receptor homologs (FcRHs). FcRHs include but are not limited to FcRFH, FcRH2, FcRH3, FcRH4, FcRH5, and FcRH6 (Davis et al., 2002, Immunol. Reviews 190: 123-136).

[0146] An important parameter that determines the most beneficial selectivity of a given Fc variant to treat a given disease is the context of the Fc variant. Thus, the Fc receptor selectivity or specificity of a given Fc variant will provide different properties depending on whether it composes an antibody, Fc fusion, or Fc variants with a coupled fusion partner. In one embodiment, an Fc receptor specificity of the Fc variant disclosed herein will determine its therapeutic utility. The utility of a given Fc variant for therapeutic purposes will depend on the epitope or form of the target antigen and the disease or indication being treated. For some targets and indications, greater FcyRIIb affinity and reduced activating FcyR-mediated effector functions may be beneficial. For other target antigens and therapeutic applications, it may be beneficial to increase affinity for FcyRIIb, or increase affinity for both FcyRIIb and activating receptors.Attorney Docket No. ZEN-024WO1Methods of Treating Warm Autoimmune Hemolytic Anemia (wAIHA)Therapeutically Effective Dosing Regimen

[0147] Various therapeutically effective dosing regimens may be used to administering obexelimab to treat wAIHA according to the present invention. Those skilled in the art will appreciate that a dose and dosing interval may be modified to achieve substantially similar result (e.g., administering at 125 mg twice a week may achieve substantially similar results as 250 mg once a week). In some embodiments, administration of obexelimab in a subcutaneous (SC) formulation minimizes the risk of acute admi ni strati on-related reactions.

[0148] Table 3 shows an exemplary dosage regimen and formulation of Obexelimab.Table 3: Obexelimab Pre-filled syringe and dosageAttorney Docket No. ZEN-024WO1

[0149] In some embodiments, a method comprises administering obexelimab at a dose of 125 mg twice a week. In some embodiments, the method comprises administering obexelimab at a dose of 125 mg every 3 days. In some embodiments, the method comprises administering obexelimab at a dose of 250 mg every 7 days.

[0150] In some embodiments, obexelimab is administered at a dose of 100-500 mg per week. In some embodiments, obexelimab is administered at a dose of 100-200 mg per week, 100-300 mg per week, 100-400 mg per week, 200-400 mg per week, 100-300 mg per week, 200-350 mg per week, 150-300 mg per week, 125-275 mg per week, 225-275 mg per week, 230-260 mg per week, 240-260 mg per week, or 245-255 mg per week. In some embodiments, obexelimab is administered at a dose of 100 mg per week, 150 mg per week, 200 mg per week, 250 mg per week, 300 mg per week, 350 mg per week, 400 mg per week, 450 mg per week, or 500 mg per week.

[0151] In some embodiments, the weekly dose may be injected at once or divided into two or more injections throughout a week. In some embodiments, the weekly dose is divided into 2 injections, 3 injections, 4 injections, 5 injections, 6 injections or daily injections. In some embodiments, the weekly dose is divided equally. In some embodiments, the weekly dose is divided unequally. In some embodiments, the weekly dose is divided such that it is administered every other day, every 2 days or every 3 days.

[0152] In some embodiments, a suitable dose ranges from 20-40 mg daily, 25-40 mg daily, or 30-40 mg daily. In some embodiments, a suitable dose is 35 mg daily.

[0153] In some embodiments, obexelimab is administered at a dose of 500 mg every two weeks. In some embodiments, every 2-week dose may be injected at once or divided into two or more injections. In some embodiments, the dose is divided into 2 injections, 3 injections, 4 injections, 5 injections, 6 injections or more injections.

[0154] In some embodiments, the patient receives 1000 mg of obexelimab per month. In some embodiments, the 1000 mg monthly dose may be injected at once or divided into 4 or more injections. In some embodiments, the dose is divided into 4 injections, 5 injections, 6 injections, 7 injections, 8 injections or more injections.

[0155] In some embodiments, obexelimab is administered to a patient 18 years of age or older at a dose of 250 mg per week.Attorney Docket No. ZEN-024WO1

[0156] In some aspects, the present invention provides a method of treating wAIHA, comprising administering obexelimab subcutaneously to a human patient 18 years of age or older at a dose of 250 mg per week.

[0157] In some embodiments, obexelimab is administered at a dose of 200 mg once a week. In some embodiments, obexelimab is administered at a dose of 125 mg twice a week. In some embodiments, obexelimab is administered at a dose of 100 mg twice a week. In some embodiments, obexelimab is administered at a dose of 300 mg once a week. In some embodiments, obexelimab is administered at a dose of 150 mg twice a week.

[0158] In some embodiments, obexelimab is administered at 250 mg per week subcutaneously, at a concentration of 125 mg / ml, as 2 x 1ml injections. In some embodiments, obexelimab is administered at 250 mg per week subcutaneously, at a concentration of 125 mg / ml, as 1 x 2ml injections. In some embodiments, obexelimab is administered at 200 mg per week subcutaneously. In some embodiments, obexelimab is administered at 150 mg per week subcutaneously. In some embodiments, obexelimab is administered at 100 mg per week subcutaneously. In some embodiments, obexelimab is administered as a single injection. In some embodiments, obexelimab is administered as more than 2 injections, for example, obexelimab is administered as 3 injections, or 4 injections or more. In some embodiments, the concentration of obexelimab is 100 mg / ml. In some embodiments, the concentration of obexelimab is 50 mg / ml. In some embodiments, obexelimab is administered at a concentration of 100 mg / ml, as 2 x 1ml injections, subcutaneously. In some embodiments, obexelimab is administered at a concentration of 125 mg / ml, as 2 x 1 ml injections, subcutaneously.

[0159] In some embodiments, obexelimab is administered in a liquid formulation comprising 125 mg / mL obexelimab. In some embodiments, obexelimab is administered as 2 x 1 mL injections. In some embodiments, obexelimab is administered as 2 x 1 mL injections for a total dose of 250 mg. In some embodiments, obexelimab injections are administered concurrently. In some embodiments, obexelimab injections are administered within 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, or within 20 minutes of each other. In some embodiments, obexelimab injections are administered within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 7 hours, within 8 hours, within 9 hours, within 10 hours, within 11 hours, or within 12 hours of each other.Attorney Docket No. ZEN-024WO1

[0160] In some embodiments, obexelimab is administered in a liquid formulation comprising 125 mg / mL obexelimab as 4 x 0.5 mL injections. In some embodiments, obexelimab is administered in a liquid formulation comprising 125 mg / mL obexelimab as 4 x 0.5 mL injections for a total dose of 250 mg. In some embodiments, obexelimab injections are administered concurrently. In some embodiments, obexelimab injections are administered within 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, or within 20 minutes of each other. In some embodiments, obexelimab injections are administered within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 7 hours, within 8 hours, within 9 hours, within 10 hours, within 11 hours, or within 12 hours of each other.

[0161] In some embodiments, obexelimab is administered in a liquid formulation as a single injection. In some embodiments, obexelimab is administered in a liquid formulation as a single injection for a total dose of 250 mg.Treatment Period

[0162] It is contemplated by the present invention that obexelimab may be administer at a therapeutically effective dosing regimen for treatment periods of varying duration. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of at least 1-24, 4-24, 8-24, 12-24, 16-24, or 20-24 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of 1-24, 4-24, 8-24, 12-24, 16-24, or 20-24 weeks.

[0163] In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of at least 4 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of 4 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of at least 8 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of 8 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of at least 12 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of 12 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab)Attorney Docket No. ZEN-024WO1 for a period of at least 16 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of 16 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of at least 20 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of 20 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of at least 24 weeks. In some embodiments, obexelimab is administered to a patient (e.g., once weekly SC administration of obexelimab) for a period of 24 weeks.

[0164] In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 4 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 5 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 6 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 7 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 8 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 9 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 10 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 11 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 12 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 13 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 14 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 15 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 16 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 17 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 18 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 19 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 20 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 21 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 22 weeks. In some embodiments, obexelimab is administered at aAttorney Docket No. ZEN-024WO1 therapeutically effective dose for at least 23 weeks. In some embodiments, obexelimab is administered at a therapeutically effective dose for at least 24 weeks.Patient Outcomes and Efficacy

[0165] In some aspects, the present invention provides treating a patient with obexelimab at a therapeutically effective dosing regimen for a treatment period sufficient to stabilize or reduce one or more symptoms (e.g., one or more symptoms of wAIHA). For example, methods described herein can result in a therapeutically effective increase in hemoglobin as compared to baseline or a therapeutically effective decrease in anti-RBC autoantibodies.

[0166] In some embodiments, treatment with obexelimab generates a durable Hgb response without the need for long-term steroid use that is associated with substantial toxicity and complications.

[0167] In some embodiments, treatment with obexelimab reduces the level of anti- RBC autoantibodies as compared to baseline.

[0168] In some embodiments, methods described herein can attain one or more of the following therapeutic benefits: change from baseline to Week 24 in Hgb concentration; proportion of patients who attain normal values on at least 3 of 4 consecutive available visits, at the earliest on or after Week 12, with no use of blood transfusion or GC rescue therapy prior to attaining durable response in any or all of the following (LDH; haptoglobin, or indirect bilirubin); proportion of patients with a > 3 -point increase in FACIT-F score at Week 24 with no prior use of blood transfusion or GC rescue therapy; time to durable Hgb response in patients who achieve the primary endpoint; and / or percentage of time in Hgb response, on or after Week 4 through Week 24, in patients who achieve the primary endpoint.Attorney Docket No. ZEN-024WO1

[0169] In some embodiments, methods described herein result in a beneficial change in the proportion of patients who do not receive blood transfusion or GC rescue therapy through week 24 of treatment according to methods described herein.

[0170] In some embodiments, methods described herein result in a beneficial change in the cumulative dose of GC rescue therapy through week 24 of treatment according to methods described herein.

[0171] In some embodiments, methods described herein result in a beneficial change in the proportion of patients who do not receive blood transfusions through week 24 of treatment according to methods described herein.

[0172] In some embodiments, methods described herein result in change from baseline to week 24 in FACIT-F Score, EQ-5D-5L index score, Physician’s Global Assessment of Change Disease Activity, Patient’s Global Impression of Change in Daily Activity Impact, and / or Patient’s Global Impression of Change in Fatigue Severity.

[0173] In some embodiments, methods described herein result in change from baseline through week 24 over time in one or more of the following:- Reduction in Circulating absolute T, B, and NK cell count;- Reduction in Ig levels and ratios (e.g., IgG, IgM, IgA, IgE);- Increase in CD 19 target receptor occupancy;- Decrease in reticulocyte count;- Decrease in LDH;- Increase in Haptoglobin; and- Reduction in indirect bilirubin (unconjugated bilirubin).

[0174] In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in a decrease in circulating absolute T, B and natural killer cell count. In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in a decrease in Ig levels and ratios (e.g., IgG, IgM, IgA, IgE). In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in an increase in CD 19 target receptor occupancy. In some embodiments,Attorney Docket No. ZEN-024WO1 obexelimab is administered at a therapeutically effective dose sufficient to result in a decrease in reticulocyte count.

[0175] In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in a reduction in serum LDH as compared to baseline. In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in a reduction in bilirubin as compared to baseline. In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in an increase in serum haptoglobin as compared to baseline.

[0176] In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in a patient achieving normal values for serum LDH. In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in a patient achieving normal values for bilirubin. In some embodiments, obexelimab is administered at a therapeutically effective dose sufficient to result in a patient achieving normal values for serum haptoglobin.Hemoglobin (Hgb) Response

[0177] In some aspects, the present invention provides administering obexelimab at a therapeutically effective dosing regimen sufficient to improve patient Hgb levels as compared to baseline. In some embodiments, administering obexelimab at a therapeutically effective dosing regimen is sufficient to result in an increase of Hgb of > 2 g / dL as compared to baseline. In some embodiments, obexelimab administered at a therapeutically effective dosing regimen is sufficient to result in Hgb > 10 g / dL. In some embodiments, obexelimab administered at a therapeutically effective dosing regimen is sufficient to result in Hgb > 10 g / dL and an increase of Hgb of > 2 g / dl as compared to baseline. In some embodiments, obexelimab administered at a therapeutically effective dosing regimen is sufficient to result in Hgb > 9 g / dL. In some embodiments, obexelimab administered at a therapeutically effective dosing regimen is sufficient to result in Hgb > 9 g / dL and an increase of Hgb of > 2 g / dL as compared to baseline. In some embodiments, obexelimab administered at a therapeutically effective dosing regimen is sufficient to result in Hgb > 8 g / dL. In some embodiments, obexelimab administered at a therapeutically effective dosing regimen is sufficient to result in Hgb > 8 g / dL and an increase of Hgb of > 2 g / dL as compared to baseline. In some embodiments, obexelimab administered at a therapeutically effective dosing regimen is sufficient to result in Hgb > 7 g / dL. In some embodiments, obexelimab administered at aAttorney Docket No. ZEN-024WO1 therapeutically effective dosing regimen is sufficient to result in Hgb > 7 g / dL and an increase of Hgb of > 2 g / dL as compared to baseline.

[0178] In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 3 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dl, > 10 g / dL) for at least 4 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 5 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 6 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dl, > 9 g / dL, > 10 g / dL) for at least 7 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 8 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 9 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 10 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 11 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 12 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 13 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dl, > 9 g / dL, > 10 g / dL) for at least 14 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 15 weeks after administration ofAttorney Docket No. ZEN-024WO1 obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 16 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 17 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 18 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 19 weeks after administration of obexelimab at a therapeutically effective dosing regimen. In some embodiments, a patient maintains an achieved Hgb level (e.g., > 7 g / dL, > 8 g / dL, > 9 g / dL, > 10 g / dL) for at least 20 weeks after administration of obexelimab at a therapeutically effective dosing regimen.

[0179] In some aspects, the present invention provides a method of treating wAIHA, comprising administering obexelimab subcutaneously to a patient at a therapeutically effective dosing regimen for a treatment period sufficient to result in an increase of Hgb of >2 g / dL as compared to baseline.

[0180] A durable Hgb response can be Hgb > 10 g / dL or > 2 g / dL increase from baseline. In some embodiments, durable Hgb response is achieved after at least 3 of 4 consecutive weeks. In some embodiments, the Hgb values increase at the earliest in less than one week. In some embodiments, the Hgb values increase at the earliest on or after one week. In some embodiments, the Hgb values increase at the earliest on or after 2 weeks. In some embodiments, the Hgb values increase at the earliest on or after 3 weeks. In some embodiments, the Hgb values increase at the earliest on or after 4 weeks, In some embodiments, the Hgb values increase at the earliest on or after 5 weeks, In some embodiments, the Hgb values increase at the earliest on or after 6 weeks, In some embodiments, the Hgb values increase at the earliest on or after 7 weeks, In some embodiments, the Hgb values increase at the earliest on or after 8 weeks, In some embodiments, the Hgb values increase at the earliest on or after 9 weeks, In some embodiments, the Hgb values increase at the earliest on or after 10 weeks, In some embodiments, the Hgb values increase at the earliest on or after 11 weeks, In some embodiments, the Hgb values increase at the earliest on or after 12 weeks. In someAttorney Docket No. ZEN-024WO1 embodiments, patients achieving increase in Hgb did not use of blood transfusion or GC rescue therapy prior to attaining Hgb increase.

[0181] In some embodiments, a patient achieves > 0.5 g / dL increase from baseline on at least 3 of 4 consecutive available visits. In some embodiments, a patient achieves > 1 g / dL increase from baseline on at least 3 of 4 consecutive available visits. In some embodiments, a patient achieves > 1.5 g / dL increase from baseline on at least 3 of 4 consecutive available visits. In some embodiments, a patient achieves > 2 g / dL increase from baseline on at least 3 of 4 consecutive available visits.

[0182] In some embodiments, the increase in Hgb levels is sustained through week 13. In some embodiments, the increase in Hgb levels is sustained through week 14. In some embodiments, the increase in Hgb levels is sustained through week 15. In some embodiments, the increase in Hgb levels is sustained through week 16. In some embodiments, the increase in Hgb levels is sustained through week 17. In some embodiments, the increase in Hgb levels is sustained through week 18. In some embodiments, the increase in Hgb levels is sustained through week 19. In some embodiments, the increase in Hgb levels is sustained through week 20. In some embodiments, the increase in Hgb levels is sustained through week 21. In some embodiments, the increase in Hgb levels is sustained through week 22. In some embodiments, the increase in Hgb levels is sustained through week 23. In some embodiments, the increase in Hgb levels is sustained through week 24.

[0183] In some embodiments, Hgb response is defined as patients who achieve Hgb > 9 g / dL. In some embodiments, Hgb response is defined as patients who achieve Hgb > 10 g / dL. In some embodiments, Hgb response is defined as patients who achieve Hgb > 11 g / dL. In some embodiments, Hgb response is defined as patients who achieve Hgb > 12 g / dL. In some embodiments, Hgb response is defined as patients who achieve Hgb > 13 g / dL. In some embodiments, Hgb response is defined as patients who achieve Hgb > 14 g / dL. In some embodiments, Hgb response is defined as patients who achieve Hgb > 15 g / dL. In some embodiments, Hgb response is defined as patients who achieve Hgb > 16 g / dL. In some embodiments, Hgb response is defined as patients who achieve Hgb > 17 g / dL.Attorney Docket No. ZEN-024WO1

[0184] In some embodiments, a durable Hgb response is defined as patients who achieve > 2 g / dL increase from baseline. In some embodiments, patients may achieve > 0.5 g / dL increase from baseline. In some embodiments, patients may achieve > 1 g / dL increase from baseline. In some embodiments, patients may achieve > 3 g / dL increase from baseline. In some embodiments, patients may achieve > 4 g / dL increase from baseline. In some embodiments, patients may achieve > 5 g / dL increase from baseline. In some embodiments, patients may achieve > 6 g / dL increase from baseline. In some embodiments, patients may achieve > 7 g / dL increase from baseline. In some embodiments, patients may achieve > 8 g / dL increase from baseline.

[0185] In some embodiments, a durable Hgb response maintains Hgb values for at 1 week, at least two weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks at least 14 weeks at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, or at least 25 weeks.

[0186] In some embodiments, the patient achieves an increase in Hgb levels in less than 1 week. In some embodiments, the patient achieves an increase in Hgb levels in 2 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 3 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 4 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 5 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 6 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 7 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 8 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 9 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 10 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 11 weeks or less. In some embodiments, the patient achieves an increase in Hgb levels in 12 weeks or less.

[0187] In some embodiments, the patient maintains Hgb values for at least 3 weeks with no use of blood transfusion or GC rescue therapy prior to attaining durable response.Attorney Docket No. ZEN-024WO1

[0188] In some embodiments, methods described herein result in a durable Hgb response (e.g., Hgb > 10 g / dL and / or > 2 g / dL increase from baseline) in a patient. In embodiments, a durable response is obtained without use of blood transfusion or GC rescue therapy prior to attaining durable response.

[0189] In some embodiments, methods described herein result in significantly improved Hgb levels in a patient (e.g., as compared to baseline Hgb levels). In embodiments, an improvement is in Hgb concentration is observed by week 8 of treatment according to methods described herein. In embodiments, an improvement is in Hgb concentration is observed by week 24 of treatment according to methods described herein. In some embodiments, methods described herein result in a durable Hgb response (e.g., Hgb > 10 g / dL and / or > 2 g / dL increase from baseline) in a patient. In embodiments, a durable response is obtained without use of blood transfusion or GC rescue therapy prior to attaining durable response.

[0190] In some embodiments, methods described herein result in a patient achieves a reduction in serum LDH or bilirubin as compared to baseline. In some embodiments, a reduction in serum LDH is attained on or after Week 4 of treatment. In some embodiments, a reduction in serum LDH is attained on or after Week 5 of treatment. In some embodiments, a reduction in serum LDH is attained on or after Week 6 of treatment. In some embodiments, a reduction in serum LDH is attained on or after Week 7 of treatment. In some embodiments, a reduction in serum LDH is attained on or after Week 8 of treatment. In some embodiments, a reduction in serum LDH is attained on or after Week 9 of treatment. In some embodiments, a reduction in serum LDH is attained on or after Week 10 of treatment. In some embodiments, a reduction in serum LDH is attained on or after Week 11 of treatment. In some embodiments, a reduction in serum LDH is attained on or after Week 12 of treatment. In some embodiments, a reduction in bilirubin is attained on or after Week 4 of treatment. In some embodiments, a reduction in bilirubin is attained on or after Week 5 of treatment. In some embodiments, a reduction in bilirubin is attained on or after Week 6 of treatment. In some embodiments, a reduction in bilirubin is attained on or after Week 7 of treatment. In some embodiments, a reduction in bilirubin is attained on or after Week 8 of treatment. In some embodiments, a reduction in bilirubin is attained on or after Week 9 of treatment. In some embodiments, a reduction in bilirubin is attained on or after Week 10 of treatment. In some embodiments, a reduction in bilirubin is attained on or after Week 11 of treatment. InAttorney Docket No. ZEN-024WO1 some embodiments, a reduction in bilirubin is attained on or after Week 12 of treatment. In some embodiments, methods described herein result in a patient achieves an increase in serum haptoglobin as compared to baseline. In some embodiments, an increase in serum haptoglobin is attained on or after Week 4 of treatment. In some embodiments, an increase in serum haptoglobin is attained on or after Week 5 of treatment. In some embodiments, an increase in serum haptoglobin is attained on or after Week 6 of treatment. In some embodiments, an increase in serum haptoglobin is attained on or after Week 7 of treatment. In some embodiments, an increase in serum haptoglobin is attained on or after Week 8 of treatment. In some embodiments, an increase in serum haptoglobin is attained on or after Week 9 of treatment. In some embodiments, an increase in serum haptoglobin is attained on or after Week 10 of treatment. In some embodiments, an increase in serum haptoglobin is attained on or after Week 11 of treatment. In some embodiments, an increase in serum haptoglobin is attained on or after Week 12 of treatment. In some embodiments, methods described herein result in a patient attaining normal values in LDH, haptoglobin, and / or indirect bilirubin. In some embodiments, methods described herein result in a patient attaining normal values in LDH, haptoglobin, and indirect bilirubin. In some embodiments, a normal value in LDH is achieved on or after Week 4 of treatment. In some embodiments, a normal value in LDH is achieved on or after Week 5 of treatment. In some embodiments, a normal value in LDH is achieved on or after Week 6 of treatment. In some embodiments, a normal value in LDH is achieved on or after Week 7 of treatment. In some embodiments, a normal value in LDH is achieved on or after Week 8 of treatment. In some embodiments, a normal value in LDH is achieved on or after Week 9 of treatment. In some embodiments, a normal value in LDH is achieved on or after Week 10 of treatment. In some embodiments, a normal value in LDH is achieved on or after Week 11 of treatment. In some embodiments, a normal value in LDH is achieved on or after Week 12 of treatment. In some embodiments, a normal value in bilirubin is achieved on or after Week 4 of treatment. In some embodiments, a normal value in bilirubin is achieved on or after Week 5 of treatment. In some embodiments, a normal value in bilirubin is achieved on or after Week 6 of treatment. In some embodiments, a normal value in bilirubin is achieved on or after Week 7 of treatment. In some embodiments, a normal value in bilirubin is achieved on or after Week 8 of treatment. In some embodiments, a normal value in bilirubin is achieved on or after Week 9 of treatment. In some embodiments, a normal value in bilirubin is achieved on or after Week 10 of treatment. In some embodiments, a normal value in bilirubin is achieved on or afterAttorney Docket No. ZEN-024WO1Week 11 of treatment. In some embodiments, a normal value in bilirubin is achieved on or after Week 12 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 4 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 5 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 6 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 7 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 8 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 9 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 10 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 11 of treatment. In some embodiments, a normal value in serum haptoglobin is achieved on or after Week 12 of treatment. In some embodiments, the normal values for LDH, haptoglobin, and / or indirect bilirubin are attained on or after Week 12 of treatment according to methods described herein. In some embodiments, the normal values for LDH, haptoglobin, and / or indirect bilirubin are attained without use of blood transfusion or GC rescue therapy.Reduction in Anti-Red Blood Cell (RBC) Autoantibodies

[0191] In some aspects, the present invention provides administering obexelimab at a therapeutically effective dosing regimen sufficient to reduce the presence of anti-RBC autoantibodies as compared to baseline. In some embodiments, obexelimab is administered at a therapeutically effective dosing regimen for a treatment period sufficient to result in reducing the level of anti-RBC autoantibodies by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, or at least 9% as compared to baseline. In some embodiments, obexelimab is administered at a therapeutically effective dosing regimen for a treatment period sufficient to result in reducing the level of anti-RBC autoantibodies by at least 10% as compared to baseline. In some embodiments, obexelimab is administered at a therapeutically effective dosing regimen for a treatment period sufficient to result in reducing the level of anti-RBC autoantibodies by at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% as compared to baseline. In some embodiments, obexelimab is administered at aAttorney Docket No. ZEN-024WO1 therapeutically effective dosing regimen sufficient to achieve the reduction in anti-RBC autoantibodies within 5 weeks, within 6 weeks, within 7, within 8 weeks, within 9 weeks, within 10 weeks, within 11 weeks, or within 12 weeks of commencing administration. In some embodiments, obexelimab is administered at a therapeutically effective dosing regimen sufficient to achieve the reduction in anti-RBC autoantibodies within 10 weeks of commencing administration. In some embodiments, obexelimab is administered at a therapeutically effective dosing regimen sufficient to achieve the reduction in anti-RBC autoantibodies within 11 weeks of commencing administration. In some embodiments, obexelimab is administered at a therapeutically effective dosing regimen sufficient to achieve the reduction in anti-RBC autoantibodies within 12 weeks of commencing administration.

[0192] In some embodiments, obexelimab is administered at a therapeutically effective dosing regimen for a treatment period so that the patient is substantially free of anti- RBC autoantibodies. In some embodiments, obexelimab is administered at a therapeutically effective dosing regimen for a treatment period sufficient to reduce anti-RBC autoantibodies to an undetectable amount. In some embodiments, a patient is DAT-negative following administration of the therapeutically effective dosing regimen.Quality of Life Assessment

[0193] In some embodiments, methods described herein result in a change in in FACIT-F score from baseline to Week 24 of treatment according to methods described herein.

[0194] In some embodiments, methods described herein result in a patient attaining > 3-point increase in FACIT-F score. In embodiments, a patient attains > 3-point increase in FACIT-F score on or after Week 24 of treatment according to methods described herein. In some embodiments, the increase in FACIT-F score is obtained with no prior use of blood transfusion or GC rescue therapy.

[0195] Quality of life assessments may be performed as part of the treatment methods described herein. In some embodiments, enhanced quality of life is an improvement in one or more characteristics of fatigue or tiredness and its impact on daily activities and functioning. The assessment instrument may include items such as tiredness, weakness, listlessness, lack of energy, and the impact of these feelings on daily functioning (e.g., sleeping, social activities). In some embodiments, the present disclosure provides a methodAttorney Docket No. ZEN-024WO1 of treating wAIHA, measuring the patients FACIT-F Score or EQ-5D-5L index score and administering obexelimab subcutaneously to a human patient at a dose of 250 mg once a week.

[0196] In some embodiments, the quality of life is measured by FACIT-F scale. In some embodiments, the Quality of life is measured by EQ-5D-5L Questionnaire. In some embodiments, the Quality of life is measured by SF-36 survey.Formulation and Pharmaceutical Compositions

[0197] The present invention provides pharmaceutical compositions and formulations of anti-CD19 antibodies (e.g., obexelimab). Formulations of the anti-CD19 antibody disclosed herein are prepared for storage by mixing said antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980, incorporated entirely by reference), in the form of lyophilized formulations or aqueous solutions.

[0198] In some embodiments, pharmaceutical compositions of interest comprise an anti-CD19 antibody (e.g., obexelimab) at various concentrations. In some embodiments, suitable formulations may comprise the antibody of interest at a concentration up to 250 mg / ml (e.g., up to 225 mg / ml, up to 200 mg / ml, up to 150 mg / ml, up to 140 mg / ml, up to 130 mg / ml, up to 125 mg / ml, up to 120 mg / ml, up to 115 mg / ml, up to 110 mg / ml, up to 105 mg / ml, up to 100 mg / ml, up to 90 mg / ml, up to 80 mg / ml, up to 70 mg / ml, up to 60 mg / ml, up to 50 mg / ml, up to 40 mg / ml, up to 30 mg / ml, up to 25 mg / ml, up to 20 mg / ml, up to 10 mg / ml).

[0199] In some embodiments, suitable formulations may contain the anti-CD19 antibody at a concentration ranging between 10-300 mg / ml (e.g., 10-250 mg / ml, 10-200 mg / ml, 10-180 mg / ml, 10-160 mg / ml, 10-150 mg / ml, 10-140 mg / ml, 10-130 mg / ml, 10-125 mg / ml, 100-125 mg / ml, 100-180 mg / ml, 100-150 mg / ml, 100-130 mg / ml, 100-125 mg / ml, 100-170 mg / ml, 100-160 mg / ml, 100-150 mg / ml, 100-200 mg / ml, or 120-130 mg / ml).

[0200] In some embodiments, a formulation suitable for SC administration contains a protein of interest at a concentration of approximately 100 mg / ml, 115 mg / ml, 120 mg / ml, 125 mg / ml, 130 mg / ml, 135 mg / ml, 140 mg / ml, 145 mg / ml, 150 mg / ml, 200 mg / ml, or 300 mg / ml.Attorney Docket No. ZEN-024WO1

[0201] In some embodiments, isotonic solutions are used. In some embodiments, slightly hypertonic solutions (e.g., up to 300 mM (e.g., up to 250 mM, 200 mM, 175mM, 150 mM, 125 mM) sodium chloride in 5mM sodium phosphate at pH 7.0) and sugar-containing solutions (e.g., up to 3% (e.g., up to 2.4%, 2.0%, 1.5%, 1.0%) sucrose in 5 mM sodium phosphate at pH 7.0). In some embodiments, a suitable formulation composition is saline (e.g., 150 mM NaCl in water).

[0202] Many therapeutic agents, and in particular the antibodies of the present invention, require controlled pH and specific excipients to maintain their solubility and stability in the pharmaceutical compositions of the present invention.

[0203] The pH of the pharmaceutical composition is an additional factor which is capable of altering the solubility of an anti-CD19 antibody (e.g., obexelimab) in an aqueous pharmaceutical composition. In some embodiments, pharmaceutical compositions of the present invention contain one or more buffers. In some embodiments, compositions according to the invention contain an amount of buffer sufficient to maintain the optimal pH of said composition, e.g., between 4.0-8.0, between 5.0-7.5, between 5.5-7.0, between 6.0-7.0 or between 6.0-7.5. In other embodiments, the buffer comprises up to 50 mM (e.g., up to 45 mM, 40 mM, 35 mM, 30 mM, 25 mM, 20 mM, 15 mM, 10 mM, 5 mM) of sodium phosphate. Suitable buffers include, for example acetate, succinate, citrate, phosphate, other organic acids and tris (hydroxymethyl) aminomethane (“Tris”).

[0204] Suitable buffer concentrations can be from 1 mM to 100 mM, or from 3 mM to 20 mM, depending, for example, on the buffer and the desired isotonicity of the formulation. In some embodiments, a suitable buffering agent is present at a concentration of approximately 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, or 100 mM.

[0205] In some embodiments, formulations contain an isotonicity agent to keep the formulations isotonic. Exemplary isotonicity agents include, but are not limited to, glycine, sorbitol, mannitol, sodium chloride and arginine. In some embodiments, suitable isotonic agents may be present in formulations at a concentration from 0.01 - 5 % (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0 or 5.0%) by weight.Attorney Docket No. ZEN-024WO1

[0206] In some embodiments, formulations may contain a stabilizing agent to protect the antibody. Typically, a suitable stabilizing agent is a non-reducing sugar such as sucrose, raffinose, trehalose, or amino acids such as glycine, arginine and methionine. The amount of stabilizing agent in a formulation is generally such that the formulation will be isotonic. However, hypertonic formulations may also be suitable. In addition, the amount of stabilizing agent must not be too low such that an unacceptable amount of degradation / aggregation of the antibody occurs. Exemplary stabilizing agent concentrations in the formulation may range from 1 mM to 400 mM (e.g., from 30 mM to 300 mM, and from 50 mM to 100 mM), or alternatively, from 0.1% to 15% (e.g., from 1% to 10%, from 5% to 15%, from 5% to 10%) by weight. In some embodiments, the ratio of the mass amount of the stabilizing agent and the therapeutic agent is 1 : 1. In other embodiments, the ratio of the mass amount of the stabilizing agent and the therapeutic agent can be 0.1 : 1, 0.2: 1, 0.25: 1, 0.4: 1, 0.5: 1, 1 : 1, 2: 1, 2.6: 1, 3: 1, 4: 1, 5: 1, 10: 1, or 20: 1. In some embodiments, suitable for lyophilization, the stabilizing agent is also a lyoprotectants.

[0207] The pharmaceutical compositions, formulations and related methods of the invention are useful for delivering anti-CD19 antibodies (e.g., subcutaneously) and for the treatment of the associated diseases. The pharmaceutical compositions of the present invention are particularly useful for delivering anti-CD19 antibodies (e.g., obexelimab) to patients suffering from wAIHA.

[0208] In some embodiments, it is desirable to add a surfactant to formulations. Exemplary surfactants include nonionic surfactants such as Polysorbates (e.g., Polysorbates 20 or 80); pol oxamers (e.g., pol oxamer 188); Triton; sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine;1 auroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl ofeyl-taurate; and the MONAQUATTM series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics, PF68, etc). Typically, the amount of surfactant added is such that it reduces aggregation of the protein and minimizes the formation of particulates or effervescences. For example, a surfactant may be present in a formulation at a concentrationAttorney Docket No. ZEN-024WO1 from 0.001 - 0.5% (e.g., 0.005 - 0.05%, or 0.005 - 0.01%). In particular, a surfactant may be present in a formulation at a concentration of approximately 0.005%, 0.01%, 0.02%, 0.1%, 0.2%, 0.3%, 0.4%, or 0.5%, etc.

[0209] In some embodiments, suitable formulations may further include one or more bulking agents, in particular, for lyophilized formylations. A “bulking agent” is a compound which adds mass to the lyophilized mixture and contributes to the physical structure of the lyophilized cake. For example, a bulking agent may improve the appearance of lyophilized cake (e.g., essentially uniform lyophilized cake). Suitable bulking agents include, but are not limited to, sodium chloride, lactose, mannitol, glycine, sucrose, trehalose, hydroxyethyl starch. Exemplary concentrations of bulking agents are from 1% to 10% (e.g., 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, and 10.0%).

[0210] Formulations in accordance with the present invention can be assessed based on product quality analysis, reconstitution time (if lyophilized), quality of reconstitution (if lyophilized), high molecular weight, moisture, and glass transition temperature. Typically, protein quality and product analysis include product degradation rate analysis using methods including, but not limited to, size exclusion HPLC (SE-HPLC), cation exchange-HPLC (CEX- HPLC), X-ray diffraction (XRD), modulated differential scanning calorimetry (mDSC), reversed phase HPLC (RP-HPLC), multi-angle light scattering (MALS), fluorescence, ultraviolet absorption, nephelometry, capillary electrophoresis (CE), SDS- PAGE, and combinations thereof. In some embodiments, evaluation of product in accordance with the present invention may include a step of evaluating appearance (either liquid or cake appearance).

[0211] Generally, formulations (lyophilized or aqueous) can be stored for extended periods of time at room temperature. Storage temperature may typically range from 0°C to 45°C (e.g., 4°C, 20°C, 25°C, 45°C etc.). Formulations may be stored for a period of months to a period of years. Storage time generally will be 24 months, 12 months, 6 months, 4.5 months, 3 months, 2 months or 1 month. Formulations can be stored directly in the container used for administration, eliminating transfer steps.

[0212] Formulations can be stored directly in the lyophilization container (if lyophilized), which may also function as the reconstitution vessel, eliminating transfer steps.Attomey Docket No. ZEN-024WO1Alternatively, lyophilized product formulations may be measured into smaller increments for storage. Storage should generally avoid circumstances that lead to degradation of the proteins, including but not limited to exposure to sunlight, UV radiation, other forms of electromagnetic radiation, excessive heat or cold, rapid thermal shock, and mechanical shock.

[0213] In some embodiments, formulations according to the present invention are in a liquid or aqueous form. In some embodiments, formulations of the present invention are lyophilized. Such lyophilized formulations may be reconstituted by adding one or more diluents thereto prior to administration to a patient. Suitable diluents include, but are not limited to, sterile water, bacteriostatic water for injection and sterile saline solution.Preferably, upon reconstitution, the antibody contained therein is stable, soluble and demonstrates tolerability upon administration to a patient.

[0214] The pharmaceutical compositions of the present invention are characterized by their tolerability. As used herein, the terms “tolerable” and “tolerability” refer to the ability of the pharmaceutical compositions of the present invention to not elicit an adverse reaction in the patient to whom such composition is administered, or alternatively not to elicit a serious adverse reaction in the patient to whom such composition is administered. In some embodiments, the pharmaceutical compositions of the present invention are well tolerated by the patient to whom such compositions is administered.

[0215] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl orbenzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol ; and m-cresol); low molecular weight (less than 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; sweeteners and other flavoring agents; fillers such as microcrystalline cellulose, lactose, com and other starches; binding agents; additives; coloring agents; salt-Attorney Docket No. ZEN-024WO1 forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0216] In some embodiments, the pharmaceutical composition that comprises the antibody disclosed herein may be in a water-soluble form, such as being present as pharmaceutically acceptable salts, which is meant to include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0217] “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Some embodiments include at least one of the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0218] The formulations to be used for in vivo administration (e.g., SC administration) may be sterile. In some embodiments, the formulation is sterilized by filtration through sterile filtration membranes.

[0219] In some embodiments, the anti-CD19 antibodies (e.g., obexelimab) disclosed herein are formulated for SC administration. In some embodiments, the anti -CD 19 antibody (e.g., obexelimab) formulation for SC administration comprises one or more buffers, one or more tonicity modifiers, one or more solvents, and one or more surfactants. Nonlimiting examples of buffers include phosphate, citrate, acetate, glutamate, carbonate, tartrate, triethanolamine (TRIS), glycylglycine, histidine, glycine, lysine, arginine, and other organic acids. More specifically, non-limiting examples of buffers include HEPES sodium, MES, potassium phosphate, potassium thiocyanate, sterilant, TAE, TBE, ammoniumAttorney Docket No. ZEN-024WO1 sulfate / HEPES, BuffAR, sodium acetate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate, di sodium hydrogen phosphate, and sodium phosphate. Additionally, the buffer may be various hydrate forms. For example, the buffer may be a monohydrate, a dihydrate, a trihydrate, a tetrahydate, a pentahydrate, a hexahydrate, a heptahydrate, an octahydrate, a nonahydrate, a decahydrate, an undecahydrate, and a dodecahydrate. Occasionally, a hydrate may be fractional such as a hemihydrate or a sequihydrate. Nonlimiting examples of tonicity modifies include sodium chloride, acetic acid, L-proline, dextrose, mannitol, potassium chloride, glycerin, and glycerol. Non-limiting example of solvents include water, propylene glycol, polyethylene glycols, ethanol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycofurol, Solketal™, glycerol formal, acetone, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, and ethyl lactate. Non-limiting examples of solvents include polysorbates (e.g. polysorbate-20, polysorbate-80), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan trioleate (span 85), lecithin, and polyoxyethylene polyoxypropylene copolymers (Pluronics, Pluronic F-68).

[0220] The amounts of anti-CD19 antibody (e.g., obexelimab), buffer, tonicity modifier, solvent, and surfactants may vary. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is formulated at a concentration of 125 mg / mL obexelimab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid (at density 1.053 g / mL), 30 mg / mL L- proline, 0.1 mg / mL polysorbate 80, pH 5.5. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is formulated at a concentration of 80-200 mg / mL obexelimab, 1.5-3 mg / mL sodium acetate trihydrate, 0. 1-0.2 mg / mL acetic acid (at density 1.053 g / mL), 10-50 mg / mL L-proline, 0.05-0.2 mg / mL polysorbate 80, pH 5.0-6.0. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is formulated at a concentration of 122-127 mg / mL obexelimab, 2.0-2.5 mg / mL sodium acetate trihydrate, 0.15-0.19 mg / mL acetic acid (at density 1.053 g / mL), 25-35 mg / mL L-proline, 0.05-0.15 mg / mL polysorbate 80, pH 5.0-6.0.

[0221] In certain embodiments, a SC formulation comprises the anti-CD19 antibody (e.g., obexelimab), one or more buffers, one or more tonicity modifiers, one or more solvents, and one or more surfactants. In some embodiments, the buffer can be a sodium acetate buffer. For example, the buffer can be sodium acetate trihydrate. In an embodiment, the tonicity modifier can be acetic acid, L-proline, and combinations thereof. In another embodiment, the solvent is water.Attorney Docket No. ZEN-024WO1

[0222] In some embodiments, the surfactant is a polysorbate. In some embodiments, the polysorbate is polysorbate-80. In some embodiments, a SC formulation comprises the anti-CD19 antibody (e.g., obexelimab), sodium acetate trihydrate, acetic acid and L-proline, water, and polysorbate-80.

[0223] In some embodiments, a SC formulation comprises the anti-CD19 antibody (e.g., obexelimab) in an amount from 1 mg to 500 mg per mL or 50 mg to 250 mg per mL or 100 mg to 250 mg per mL, sodium acetate trihydrate in an amount from 1 to 1 0 mg per mL or 1 to 5 mg per mL or 1 to 2.5 mg per mL, acetic acid and L-proline in an amount from 5 to 50 mg per mL or 10 to 50 mg per mL or 20 to 40 mg per mL, water up to about 1 mL, and polysorbate-80 in an amount from 0.01 mg to 1 mg per mL or 0.01 to 0.5 mg / ml or 0.05 to 0.2 mg / ml. Specifically, a SC formulation comprises the anti-CD19 antibody (e.g., obexelimab) in an amount from 100 mg to 250 mg / ml, sodium acetate trihydrate in an amount from 1 to 2.5 mg / ml, acetic acid and L-proline in an amount from 20 to 40 mg / ml, water up to 1 mg / ml, and polysorbate-80 in an amount from 0.05 to 0.2 mg per ml.

[0224] In some embodiments, a SC formulation comprises obexelimab, a buffer, and a tonicity modifier. In some embodiments, a SC formulation comprises 100 mg / mL to 250 mg / mL obexelimab, an acetate buffer, and proline. In some embodiments, a SC formulation comprises 125 mg / mL obexelimab, an acetate buffer, and proline. In some embodiments, a SC formulation comprises 100 mg / mL to 250 mg / mL obexelimab, 5 to 40 mM acetate buffer, and 1% to 5% (w / v) proline. In some embodiments, a SC formulation comprises 125 mg / mL obexelimab, 20 mM acetate buffer, and 3% (w / v) proline, at pH 5 to 6. In some embodiments, a SC formulation comprises 125 mg / mL obexelimab, 20 mM acetate buffer, and 3% (w / v) proline at pH 5.5.

[0225] In some embodiments, a SC formulation comprises obexelimab, a buffer, a tonicity modifier, and a surfactant.

[0226] In some embodiments, a SC formulation comprises 100 mg / mL to 250 mg / mL obexelimab, an acetate buffer, proline, and polysorbate 80.

[0227] In some embodiments, a SC formulation comprises 100 mg / mL to 250 mg / mL obexelimab, 5 to 40 mM acetate buffer, 1% to 5% (w / v) proline, and 0.002% to 0.02% (w / v) polysorbate 80.Attorney Docket No. ZEN-024WO1

[0228] In some embodiments, a SC formulation comprises 125 mg / mL obexelimab, 20 mM acetate buffer, 3% (w / v) proline, and 0.01% (w / v) polysorbate 80, at pH 5 to 6.

[0229] In some embodiments, a SC formulation comprises 125 mg / mL obexelimab, 20 mM acetate buffer, 3% (w / v) proline, and 0.01% (w / v) polysorbate 80 at pH of 5.5.

[0230] In some embodiments, a SC formulation comprises 125 mg / mL obexelimab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid (at density 1.053 g / mL), 30 mg / mL L-proline, and 0.1 mg / mL polysorbate 80. In some embodiments, a SC formulation has a pH of 5.5.

[0231] In some embodiments, a SC formulation has a unit dose strength(s) / dosage level(s) that is 125.0 (± 10%) mg / mL of obexelimab.

[0232] Anti-CD19 antibodies (e.g., obexelimab) as disclosed herein may also be formulated as immunoliposomes. A liposome is a small vesicle comprising various types of lipids, phospholipids and / or surfactant that is useful for delivery of an anti-CD19 antibody (e.g., obexelimab) to a mammal. Liposomes containing the anti-CD19 antibody (e.g., obexelimab) are prepared by methods known in the art. Liposomes with enhanced circulation time are disclosed in US 5,013,556, incorporated entirely by reference. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is formulated in liposomes generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0233] In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is entrapped in microcapsules prepared by methods including but not limited to coacervation techniques, interfacial polymerization (for example using hydroxymethylcellulose or gelatinmicrocapsules, or poly-(methylmethacylate) microcapsules), colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), and macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16thedition, Osol, A. Ed., 1980, incorporated entirely by reference.

[0234] In some embodiments, sustained-release preparations may be prepared to deliver the anti-CD19 antibody (e.g., obexelimab). Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymer, which matricesAttorney Docket No. ZEN-024WO1 are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained- release matrices include polyesters, hydrogels (for example poly(2- hydroxyethylmethacrylate), or poly(vinylalcohol)), polylactides (US 3,773,919, incorporated entirely by reference), copolymers of L-glutamic acid and gamma ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the Lupron Depot® (which are injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), poly-D-(-)-3 -hydroxybutyric acid, and ProLease® (commercially available from Alkermes), which is a microsphere-based delivery system composed of the desired bioactive molecule incorporated into a matrix of poly-DL-lactide-co- glycolide (PLG).Containers for Injection

[0235] The present invention provides containers for injecting pharmaceutical compositions and formulations of anti-CD19 antibodies (e.g., obexelimab). In one aspect, a container comprises a liquid pharmaceutical composition comprising obexelimab. Suitable containers include, without limitation, a syringe, an autoinjector, vial, infusion bottle, ampoule, carpoule, a syringe equipped with a needle protection system, and a carpoule within an injection pen.

[0236] In some embodiments, a container comprising the liquid pharmaceutical composition is a prefilled syringe, a vial, or an autoinjector. In some embodiments, a container is a prefilled syringe. In some embodiments a container is an autoinjector. In some embodiments, an autoinjector administers a 2.0 mL fixed injection dose volume. In some embodiments, an autoinjector administers a 2.0 mL fixed injection dose volume using a 27- gauge needle. In some embodiments, an autoinjector is suitable for once weekly administration of an effective amount of the obexelimab composition to a patient (e.g., any formulation described herein).

[0237] In some embodiments, a container is a prefilled syringe or autoinjector comprising a liquid pharmaceutical composition comprising: a. 122-127 mg / mL obexelimab, b. 2.0-2.5 mg / mL sodium acetate trihydrate, at a pH 5.0-6.0. c. 0.15-0.19 mg / mL acetic acid (at density 1.053 g / mL),Attorney Docket No. ZEN-024WO1 d. 25-35 mg / mL L-proline, e. 0.05-0.15 mg / mL polysorbate 80.

[0238] In some embodiments, a prefilled syringe or autoinjector comprises a liquid pharmaceutical composition comprising: a liquid pharmaceutical composition comprises 125 mg / mL obexelimab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid, 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80 at pH 5.5.

[0239] In some embodiments, a prefilled syringe or autoinjector comprises a liquid pharmaceutical composition having a unit dose strength of 125.0 (± 10%) mg / mL of obexelimab.

[0240] In some embodiments, a prefilled syringe or autoinjector comprises a liquid pharmaceutical composition comprising: 125 mg / mL obexelimab, 20 mM acetate buffer, 3% (w / v) proline, 0.01% (w / v) polysorbate 80, at pH 5.5.

[0241] In some embodiments, a prefilled syringe or autoinjector facilitates SC or intradermal delivery of the pharmaceutical composition. In some embodiments, a method of treating wAIHA described herein comprises, administering a formulation comprising obexelimab into the patient’s bloodstream following a single or multiple SC injection to the abdomen of the patient using the prefilled syringe or autoinjector.

[0242] In some embodiments, a method of treating wAIHA comprises administering a single weekly injection of a 2.0 mL fixed injection dose. In some embodiments, a method of treating wAIHA comprises administering a single weekly injection of a 2.0 mL of 125 mg / mL obexelimab, 20 mM acetate buffer, 3% (w / v) proline, 0.01% (w / v) polysorbate 80, at pH 5.5.

[0243] In some embodiments, a composition in the prefilled syringe is stable for at least 3 months when stored at 2-8° C. In some embodiments, a composition in a pre-filled syringe is stable for at least 6 months when stored at 2-8° C. In some embodiments, a composition in a pre-filled syringe is stable for at least 6 months when stored at 2-8° C. In some embodiments, a composition in a pre-filled syringe is stable for at least 1 year when stored at 2-8° C. In some embodiments, a composition in a pre-filled syringe is stable for at least 2 years when stored at 2-8° C.Attorney Docket No. ZEN-024WO1Combination Therapies

[0244] In some embodiments of the present invention, obexelimab is administered as part of a combination therapy. The present invention also provides methods of treating wAIHA comprising administering a rescue therapy. In some embodiments, a rescue therapy comprises administration of GC therapy or blood transfusion. In some embodiments, a rescue therapy is any therapy given for the treatment of wAIHA, due to a reduction in Hgb compared to previous Hgb level and / or an increase in LDH, with new or worsening anemia.

[0245] In some embodiments, a GC therapy is administered at a dose of 1 - 1.5 mg / kg. In some embodiments, a GC therapy is administered at a dose of 0.5 - 2 mg / kg. In some embodiments, a GC therapy is administered at a dose of 0.6 mg / kg. In some embodiments, a GC therapy is administered at a dose of 0.7 mg / kg. In some embodiments the GC therapy is administered at a dose of 0.8 mg / kg. In some embodiments, a GC therapy is administered at a dose of 0.9 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.1 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.2 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.3 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.4 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.5 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.6 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.7 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.8 mg / kg. In some embodiments, a GC therapy is administered at a dose of 1.9 mg / kg. In some embodiments, a GC therapy is administered at a dose of 2.0 mg / kg.

[0246] In some embodiments, a GC therapy is administered at a dose of 20-60 mg / day prednisone or equivalent. In some embodiments, a GC therapy is administered at a dose of 10-100 mg / day prednisone or equivalent. In some embodiments, a GC therapy is administered at a dose of 1-70 mg / day, 5-70 mg / day, 10-70 mg / day, 15-70 mg / day, 20-70 mg / day, 25-70 mg / day, 30-70 mg / day, 35-70 mg / day, 40-70 mg / day prednisone or equivalent. In some embodiments, a GC therapy is administered at a dose of 1-60 mg / day, 5- 60 mg / day, 10-60 mg / day, 15-60 mg / day, 20-60 mg / day, 25-60 mg / day, 30-60 mg / day, 35-60 mg / day, 40-60 mg / day prednisone or equivalent.Attorney Docket No. ZEN-024WO1

[0247] In some embodiments, a GC therapy is administered at a dose of 1-150 mg / day, 5-150 mg / day, 10-150 mg / day, 15-150 mg / day, 20-150 mg / day, 25-150 mg / day, 30- 150 mg / day, 35-150 mg / day, 40-150 mg / day, 45-150 mg / day, 50-150 mg / day, 55-150 mg / day, 60-150 mg / day, 65-150 mg / day, 70-150 mg / day, 75-150 mg / day, 80-150 mg / day, 90-150 mg / day, or 100-150 mg / day, prednisone or equivalent. In some embodiments, a GC therapy is administered at a dose of 5-120 mg / day, 5-110 mg / day, 10-90 mg / day, 15-100 mg / day, 20-100 mg / day, 25-100 mg / day, 30-100 mg / day, 35-100 mg / day, 40-100 mg / day, 45-100 mg / day, 50-100 mg / day, 55-100 mg / day, 60-100 mg / day, 65-100 mg / day, 70-100 mg / day, 75-100 mg / day, 80-100 mg / day, or 90-100 mg / day prednisone or equivalent.

[0248] In some embodiments, a GC therapy is administered at a dose of up to 150 mg / day, up to 120 mg / day, up to 110 mg / day, up to 100 mg / day, up to 90 mg / day, up to 80 mg / day, up to 70 mg / day, up to 60 mg / day, up to 50 mg / day, up to 40 mg / day, up to 30 mg / day, up to 20 mg / day, up to 15 mg / day, up to 10 mg / day, up to 5 mg / day, or up to 1 mg / day prednisone or equivalent.

[0249] In some embodiments, a GC therapy is administered at a dose of 0.1-1 mg / kg / day, a dose of 0.1 -0.8 mg / kg / day, a dose of 0.1 -0.7 mg / kg / day, a dose of 0.1 -0.6 mg / kg / day, a dose of 0.1-0.5 mg / kg / day, a dose of 0.1-0.4 mg / kg / day, a dose of 0.1-0.3 mg / kg / day, a dose of 0.1-0.2 mg / kg / day or a dose of 0.05-0.1 mg / kg / day prednisone or equivalent.

[0250] In some embodiments, a GC therapy is administered at a dose of up to Img / kg / day prednisone or equivalent. In some embodiments, a GC therapy is administered at a dose of up to 0.9 mg / kg / day, a dose of up to 0.8 mg / kg / day, a dose of up to 0.7 mg / kg / day, a dose of up to 0.6 mg / kg / day, a dose of up to 0.5 mg / kg / day, a dose of up to 0.4 mg / kg / day, a dose of up to 0.3 mg / kg / day, a dose of up to 0.2 mg / kg / day or dose of up to 0.1 mg / kg / day prednisone or equivalent.

[0251] In some embodiments, a GC therapy is administered at a high dose of prednisone or equivalent. In some embodiments, a patient has been administered a high dose of GC therapy and is unlikely to respond to any treatment therapy. In some embodiments, a patient has not responded to prior therapies before administration of the anti-CD19 antibody (e.g., obexelimab).Attorney Docket No. ZEN-024WO1

[0252] In some embodiments, a GC therapy continues during the treatment with obexelimab. In some embodiments, a GC therapy is tapered during treatment with obexelimab. In some embodiments, a GC therapy is tapered prior to treatment with obexelimab. In some embodiments, a GC therapy is tapered to complete discontinuation. In some embodiments, obexelimab is administered in combination with a GC therapy.

[0253] In some embodiments, patients receiving GCs must be on a stable dose, not to exceed 30 mg / day of prednisone or prednisolone, for 4 weeks prior to the start of treatment with obexelimab. In some embodiments, patients receiving GCs must be on a stable dose, not to exceed 20 mg / day of prednisone or prednisolone, for 4 weeks prior to the start of treatment with obexelimab. In some embodiments, patients receiving immunosuppressants are on a stable dose for 12 weeks and remain on a stable dose of immunosuppressants. Exemplary immunosuppressants include azathioprine, mycophenolate mofetil / mycophenolic acid, cyclosporine, and cyclophosphamide.

[0254] In some embodiments, a prior therapy is GC therapy and / or an increase in background long-term GC therapy.

[0255] In some embodiments, a GC therapy is administered along with obexelimab. In some embodiments, a GC treatment is tapered before the start of obexelimab therapy. Exemplary taper protocols involve administration of corticosteroids at 0.6 - 1.0 mg / kg daily for 2 - 4 weeks followed by a gradual taper. In some embodiments, a GC treatment is completely tapered to discontinuation within 8 - 12 weeks. In some embodiments the tapering takes less than 8 weeks. In some embodiments, the tapering takes more than 12 weeks. In some embodiments, a GC treatment is allowed to continue at a low to moderate dose of 2.5-10.0 mg daily for up to several years.

[0256] In some embodiments, a patient receives at least 2 weeks of GC treatment. In some embodiments, a patient receives at least 3 weeks of GC treatment. In some embodiments, a patient receives more than 3 weeks of GC treatment. In some embodiments, a patient receives up to 6 weeks of GC treatment. In some embodiments, a GC treatment is administered at a dose of 30-50mg / day prednisone or equivalent. In some embodiments, a GC treatment is administered at a dose of 10-70mg / day prednisone or equivalent. In some embodiments, a GC treatment is administered at a dose of 20-60mg / day prednisone or equivalent.Attorney Docket No. ZEN-024WO1EXAMPLESExample 1: Obexelimab Surrogate AIHA Mouse Model Study

[0257] This example describes a study examining the ability of a surrogate mAb of obexelimab, XENP8206, to inhibit AIHA induction in mice.

[0258] To determine whether obexelimab can inhibit anti-RBC autoantibodies in AIHA and improve markers of anemia, the pharmacological activity of XENP8206 was tested in an experimental murine model of AIHA. The Playfair-Marshall Clarke AIHA mouse model (Cox, K.O. & Keast, D., 17 Clin. Exp. Immunol. 319, 1974) involves repeated immunization with rat RBCs resulting in the induction of anti-mouse RBC autoantibodies and development of anemia. Human FcyRIIb transgenic C57BL / 6 mice (called 2B-KIX mice) were injected with leukoreduced rat RBCs (2 x 108per mouse) intraperitoneally on a weekly basis for 11 weeks to induce anemia. XENP8206 mAb, which binds mouse CD 19 and human FcyRIIb, was administered twice weekly IP from week -1 through week 11 at a dose of 10 mg / kg (n=16 mice). Control groups included disease-induced mice dosed with PBS (n=16 mice), and non-diseased mice dosed with XENP8206 (n=3 mice) or PBS (n=3 mice). Immune cell subsets and levels of mouse IgG autoantibodies were measured by flow cytometry. Hemoglobin levels were determined by a hematology analyzer.

[0259] Within the first 3 weeks, bi-weekly dosing with XENP8206 significantly reduced mean circulating B cell counts in the blood (p<0.05) while no effect was observed on non-B lineage cell populations (FIGs. 1A-1C). XENP8206 decreased mean anti-mouse RBC autoantibody levels with significant differences in levels compared to the PBS dosed control diseased group at weeks 10 through 12 (p<0.05) (FIG. 1G). Mean B cell frequencies and absolute counts of splenic transitional (B220+CD93+), marginal zone (B220+CD21 / 35+IgM+), germinal center (GL7+CD95+), plasmablast (B220+CD138+) and plasma cells (B220-CD138++) at termination (week 12) also were reduced in the XENP8206 treated disease mice (p<0.05) (FIG. IE). Unlike the spleen, inguinal lymph node B220+ B cell counts were not affected by treatment (FIG. ID). In the bone marrow, a trend toward lower numbers of total B220+ B cells with an increase in pre-pro B cells (B220+CD43+BP- 1-CD24-CD93+) and early pro-B cells (B220+CD43+BP-1-CD24+) but a decrease in immature (B220+CD43+ / -IgM+IgD-), transitional (B220+CD43+ / - IgMhilgD-), and recirculating B cells (B220+CD43+ / -IgM+ / hiIgD+) were observed (FIG. IF). These dataAttorney Docket No. ZEN-024WO1 suggest a block in B cell development (or compensatory mechanism to increase B cell production). Further, the mean levels of hemoglobin were higher in XENP8206 treated disease mice when compared to levels in the PBS treated disease mice at weeks 11 and 12 (p<0.05) (FIG. 1H)

[0260] Taken together, the current study demonstrated in vivo pharmacological activities of obexelimab surrogate mAb XENP8206 in a relevant disease model, and support obexelimab as a treatment for AIHA.Example 2: Administration of Obexelimab for treating wAIHA

[0261] This Example describes exemplary patient selection criteria for administration of an anti-CD19 antibody (e.g., obexelimab) to patients enrolled in a Phase 2 / 3, multicenter, randomized, double-blind, placebo-controlled study. As shown in FIG. 2, the study included an open-label safety and dose confirmation run-in period (SRP), to evaluate the safety and efficacy of obexelimab in patients with wAIHA. Patients selected for the randomized-control period (RCP) using the inclusion and exclusion criteria described below will receive placebo formulation or obexelimab.

[0262] Placebo without active substance will be supplied also as a solution for SC injection. The placebo formulation is: 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid (at density 1.053 g / mL), 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80, 115 mg / mL Dextran-40 at pH 5.5. The SC formulation of the placebo is a sterile liquid product supplied in single-use glass vials. Each 2-mL glass vial is filled with 1.2 mL of placebo. The single-use glass vial is masked to make it indistinguishable from obexelimab. Table 3 shows the dosage regimen and formulation of obexelimab.

[0263] During the RCP, patients will undergo assessments for efficacy, safety, pharmacokinetic (PK), pharmacodynamics (PD), and immunogenicity at study visits specified in the Schedule of Assessments. Adverse events (AE), serious adverse events (SAE) and treatment-emergent adverse events (TEAEs) or clinically significant safety laboratory abnormalities will be evaluated.Inclusion Criteria

[0264] Patients are selected for treatment based on the following criteria:1. Males and females > 18 years of age.Attorney Docket No. ZEN-024WO12. Diagnosed with wAIHA for at least 3 months and currently receiving treatment for wAIHA or have previously received treatment for wAIHA (treatment-naive patients are not eligible)3. Diagnosis of primary or secondary wAIHA as documented by a positive DAT specific for anti-IgG or anti-IgA4. Failed at least 1 prior wAIHA treatment regimen, including steroids, rituximab, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, danazol, vincristine, erythropoiesis-stimulating agents, or splenectomy (folate, iron, or other supplements do not fulfill this criterion)5. For the SRP, if on prednisone / prednisolone, the dose may not exceed 30 mg / day and must have been stable for at least 4 weeks prior to randomization and remain stable throughout the SRP and RCP, except for patients on doses of > 20 mg to < 30 mg / day who may taper to no less than 20 mg / dayFor the RCP if on prednisone / prednisolone, the dose may not exceed 20 mg / day and must have been stable for at least 4 weeks prior to randomization and remain stable throughout the RCP.6. If receiving immunosuppressants, must have been on a stable dose for at least 12 weeks prior to randomization and remain on a stable dose throughout the SRP and RCP. Allowed concomitant immunosuppressants are azathioprine, mycophenolate mofetil / mycophenolic acid, cyclosporine, and cyclophosphamide7. Hgb > 7 to < 10 g / dL8. At least one sign or symptom of anemia as assessed by the investigator at baseline9. Screening platelet count > 50,000 mm310. Screening neutrophil count > 1,000 mm311. Screening serum albumin and serum calcium concentrations within the normal range12. Screening total serum IgG of > 400 mg / dL13. Screening creatine kinase value < 2 x ULN14. Patients with a history of splenectomy must be at least 4 months post resection prior to randomization and must be vaccinated as per country-specific immunization schedulesAttorney Docket No. ZEN-024WO115. Patients with autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis) may be eligible if they are receiving stable treatment (no changes in disease- related concomitant medications), and the severity of disease has been stable for at least 4 months prior to randomizationExclusion Criteria

[0265] Patients may be selected for treatment with obexelimab based on the exclusion criteria:1. Have cAIHA, CAD, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria2. Have any other associated cause of hereditary or acquired hemolytic anemia3. Received a transfusion within 2 weeks prior to enrollment or randomization4. Use of B cell-depleting, B cell-targeted, or other biologic immunomodulatory agents within the 6 months prior to enrollment or randomization. Patients who received B cell- targeted therapy within 6 to 12 months prior to enrollment or randomization must have a B cell count at screening that is within the laboratory reference range, as measured by the central laboratory.5. Received IVIG or epoetin alfa within 6 weeks prior to enrollment or randomization. The patient may be re-screened after the exclusionary period of 6 weeks has passed6. Receiving more than 2 concomitant medications for the treatment of wAIHA, excluding vitamins or other supplements, at the time of screening7. Received an investigational treatment or direct medical intervention in another clinical study within 12 weeks or < 5 half-lives of the investigational treatment, whichever is shorter, prior to screening8. Received live vaccine or live therapeutic infectious agent within the 6 weeks prior to enrollment or randomization9. Evidence of active TB or at high risk for TB based on at least one of the following: a. History of active TB or latent TB, unless completion of treatment according to local guidelines is documentedAttorney Docket No. ZEN-024WO1 b. Positive, indeterminate, or invalid IFNy release assay results at screening, unless treatment is documented. Patients with an indeterminate test result can repeat the test once either centrally or locally, but if the repeat test is also indeterminate, the patient is excluded c. Signs of symptoms that could represent active TB d. Chest radiograph, computed tomography scan, or magnetic resonance imaging that suggests possible diagnosis of TB10. History or evidence of a clinically unstable / uncontrolled disorder, condition, or disease (including, but not limited to, cardiopulmonary, oncologic, renal, hepatic, metabolic, hematologic, psychiatric, active infection), that, in the opinion of the investigator, would pose a risk to patient safety or interfere with the study evaluations, procedures, or completion11. Known allergy to mAb therapy12. Known hypersensitivity to dextran or components of dextran13. Active infection (e.g., pneumonia, biliary tract infection, diverticulitis, Clostridium difficile infection) that requires parenteral or oral anti-infectives and / or hospitalization, and / or is assessed as serious / clinically significant by the investigator, within 8 weeks prior to screening. Patients may be re-screened after the 8-week exclusionary period has passed14. Chronic infection (e.g., bronchiectasis, chronic osteomyelitis, chronic pyelonephritis) or requiring chronic treatment with anti-infectives (e.g., antibiotics, antivirals)15. Confirmed or suspected clinical immunodeficiency syndrome not related to treatment of wAIHA, or has a family history of congenital or hereditary immunodeficiency, unless confirmed absent in the patient16. Acute hepatitis B infection (hepatitis B surface antigen-positive), active HCV, or HIV infection. Patients may be excluded from treatment if they have a positive test for active hepatitis B through detection of hepatitis B surface antigen. In Japan, patients will be excluded if there is detection of (a) hepatitis B surface antigen or (b) hepatitis B surface antibody orAttorney Docket No. ZEN-024WO1(c) hepatitis B core antibody. Patients with a history of HCV may be excluded in the study unless there is documentation of a negative HCV ribonucleic acid level in the serum at 12 weeks or longer after the completion of HCV therapy.

[0266] Patients receiving obexelimab experience significantly improved Hgb levels, compared to patients receiving placebo.Example 3: Efficacy Analyses and Endpoints

[0267] This Example demonstrates efficacy analysis of the clinical trial described in Example 2. The primary efficacy endpoint is the proportion of patients with a Hgb response.

[0268] Samples are collected at baseline and at weekly study visits. Assessment parameters include evaluating patients who achieve a durable Hgb response (defined as Hgb > 10 g / dL and / or > 2 g / dL increase from baseline) and measuring LDH levels. Blood chemistry and hematology panels are assessed to determine Hgb levels in response to treatment with obexelimab. If a patient demonstrates reappearance of prior sign / symptoms or new signs / symptoms of wAIHA, a physical examination, imaging, and / or biochemical parameters are obtained.

[0269] Secondary assessment parameters include evaluating quality of life improvements using, for example, change from baseline to week 24 in FACIT-F Score, EQ- 5D-5L index score, Physician’s Global Assessment of Change Disease Activity, Patient’s Global Impression of Change in Daily Activity Impact, and / or Patient’s Global Impression of Change in Fatigue Severity.

[0270] Additional assessment parameters include change from baseline through week 24 over time in the following:- Reduction in circulating absolute T, B, and NK cell count- Reduction in Ig levels and ratios (e.g., IgG, IgM, IgA, IgE)- Increase in CD 19 target receptor occupancy- Decrease in reticulocyte count- Decrease in LDH- Increase in Haptoglobin- Reduction in indirect bilirubin (unconjugated bilirubin)Attorney Docket No. ZEN-024WO1- Change from baseline in Hgb concentration

[0271] Secondary assessments of disease activity in the SRP include the change from baseline in FACIT-F score through week 24, change in Hgb from baseline to week 24, proportion of patients with no use of blood transfusion or GC rescue therapy through week 24, cumulative dose of GC rescue therapy through week 24, proportion of patients with a durable Hgb response, and the number of patients who attain normal specified hematologic parameters.

[0272] In Part A (for safety and dose confirmation run-in period): Approximately 20 patients are enrolled. Cohort 1 will consist of patients with primary wAIHA or secondary wAIHA due to auto-immune disorders (e.g., systemic lupus erythematous). Outcomes from this part will provide preliminary safety, tolerability, PK / PD, and efficacy data in a similar wAIHA population as the population intended to be enrolled in the randomized control period. The RCP (Part B) is initiated once all 14 patients with primary wAIHA or secondary wAIHA due to underlying autoimmune disorder (Cohort 1) have reached Week 8-12 (or withdrawn from the study) and at least 5 have met the primary endpoint, in the absence of TEAEs Grade 4 or above no significant safety events in Cohort 1, and PK and PD data that are comparable to PK / PD data in other clinical studies and PK modelling of obexelimab.

[0273] The primary analysis of Hgb response is performed in Cohort 1 and is based on the point estimate of Hgb response rate on or after week 8 and the corresponding 90% exact confidence interval. Demonstrating that the lower confidence bound is greater than 15% for the Hgb response rate is considered clinically meaningful and represents the likelihood a patient who has failed prior wAIHA treatment would achieve the endpoint without any additional treatment.

[0274] The order of testing primary and key secondary efficacy endpoints is as follows:1. The proportion of patients who achieve a durable Hgb response (defined as Hgb > 10 g / dL and > 2 g / dL increase from baseline on at least 3 of 4 consecutive available visits), at the earliest on or after Week 12, with no use of blood transfusion or GC rescue therapy prior to attaining durable response (primary endpoint).2. Change in FACIT-F score from baseline to week 24 (key secondary endpoint).3. Proportion of patients with no use of blood transfusion or GC rescue therapy throughAttorney Docket No. ZEN-024WO1 week 24 (key secondary endpoint).4. Cumulative dose of GC rescue therapy through week 24 (key secondary endpoint).5. Proportion of patients with no use of blood transfusions through week 24 (key secondary endpoint).Example 4: Treatment with Obexelimab Improves Hgb in Patients with Primary wAIHA

[0275] This example describes a data read out of the clinical trial described inExample 2.

[0276] Six patients were enrolled in the clinical study as previously described, with a median age at the time of enrollment of 70.5 years. Other demographics include: 5 / 6 (83.3%) of patients were female; 5 / 6 (83.3%) were white; 1 / 6 (16.7%) was Asian. All patients had a diagnosis of primary wAIHA, and the median disease duration was approximately 3 years. Median Hgb at baseline was 9.50 g / dL, and 4 patients were on background therapy (including glucocorticoids, erythropoietin, and / or mycophenolate) at the time they entered the study.

[0277] All 6 patients completed at least 10 weeks of the study, with 3 of the 6 patients achieving a response in Hgb (> 10 g / dL and / or > 2 g / dL increase from baseline). All three patients achieving an Hgb response did so after week 8 of the study. Four out of 6 patients (67%) experienced a total of 18 TEAEs. Three TEAEs were considered related, and all these were grade 1.

[0278] These results is further evidence that obexelimab is well-tolerated and may provide improvement in Hgb and other biomarkers of anemia in patients with wAIHA, including patients who have failed at least one prior therapy.Example 5: Obexelimab Demonstrated Improvement in Hgb, LDH and Total Bilirubin

[0279] This example describes a further data read out of the clinical trial described in Example 2.

[0280] Eight patients with wAIHA (Hgb > 7 to < 10 g / dL at baseline) were treated with obexelimab 250 mg SC weekly. Seven of the patients had primary wAIHA, while one patient had secondary wAIHA due to autoimmune disease. Of the eight patients, five achieved an Hgb increase of > 1 g / dL over baseline during Week 8 to Week 24, without the influence of concomitant medication (FIG. 3A). A Hgb increase of > 2 g / dL measured from Hgb nadir to peak was observed in 5 of 8 patients, none of whom received transfusions.Attorney Docket No. ZEN-024WO1LDH and total bilirubin levels both decreased overall during Week 8 to Week 24. Of the three related TAEs experienced by patients, all were Grade 1 and no discontinuations occurred. For the patient with secondary wAIHA, Hgb increase 3 g / dL from baseline over 14 Weeks (FIG. 3B). Serum LDH in the patient also decreased from 316 U / L to 200 U / L, while total bilirubin also decreased from 2.17 mg / dL to 1.07 mg / dL.

[0281] Taken together, the data further demonstrates the ability of obexelimab 250 mg SC weekly to improve anemia and corresponding markers in patients with wAIHA.Other Embodiments

[0282] While a number of embodiments of this invention are described herein, the present disclosure and examples may be altered to provide other methods and compositions of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims in addition to the specific embodiments that have been represented by way of example. All references cited herein are hereby incorporated by reference.

Claims

Attorney Docket No. ZEN-024WO1CLAIMS1. A method of treating warm autoimmune hemolytic anemia (wAIHA), comprising administering obexelimab subcutaneously to a human patient at a therapeutically effective dosing regimen for a treatment period sufficient to result in at least an increase of hemoglobin (Hgb) of > 2 g / dL as compared to baseline.

2. The method of claim 1, wherein the treatment period is at least 8 weeks, at least 10 weeks, at least 15 weeks, at least 20 weeks, or at least 24 weeks.

3. The method of any one of the preceding claims, wherein the patient achieves a Hgb level of > 7 g / dL.

4. The method of any one of the preceding claims, wherein the patient achieves a Hgb level of > 10 g / dL.

5. The method of claim 3 or 4, wherein the patient maintains the Hgb level for at least 3 weeks.

6. The method of claim 5, wherein the patient maintains the Hgb level for at least 5 weeks, at least 10 weeks, at least 15 weeks, or at least 20 weeks.

7. The method of any one of the preceding claims, wherein the patient achieves one or more of the following: a) a reduction in serum lactate dehydrogenase (LDH) as compared to baseline; b) a reduction in bilirubin as compared to baseline; c) an increase in serum haptoglobin as compared to baseline.

8. The method of claim 7, wherein a patient achieves normal values of one or more of the following: a) LDH; b) bilirubin; c) haptoglobin.Attorney Docket No. ZEN-024WO19. A method of treating wAIHA comprising administering obexelimab to a patient at a therapeutically effective dosing regimen for a treatment period sufficient to result in reducing the level of anti-RBC autoantibodies by at least 10% as compared to baseline.

10. The method of claim 9, wherein the treatment period is at least 10 weeks, at least 15 weeks, at least 20 weeks, or at least 24 weeks.

11. The method of claim 9 or 10, wherein the therapeutically effective dosing regimen is sufficient to reduce the presence of anti-red blood cell (RBC) autoantibodies so that the patient is substantially free of anti-RBC autoantibodies.

12. The method of any one of claims 10-11, wherein the therapeutically effective dosing regimen is sufficient to reduce the presence of anti-RBC autoantibodies to an undetectable amount.

13. The method of any one of claims 10-12, wherein the patient direct anti globulin test (DAT) negative following administration of the therapeutically effective dosing regimen.

14. The method of any one of claims 10-13, comprising administering obexelimab at a dose of 250 mg.

15. The method of claim 14, comprising administering obexelimab at a dose of 250 mg weekly.

16. The method of any one of the preceding claims, wherein the patient is DAT -positive for anti-IgG and / or anti-IgA at baseline.

17. The method of any one of the preceding claims, wherein the patient, prior to administration of obexelimab, had an Hgb level of < 10 g / dL.

18. The method of any one of the preceding claims, wherein the patient, prior to administration of obexelimab, had an Hgb level of > 7.Attorney Docket No. ZEN-024WO119. The method of any one of the preceding claims, wherein the patient has primary wAIHA.

20. The method of any one of claims 1-18, wherein the patient has secondary wAIHA.

21. The method of claim 20, wherein the secondary wAIHA is due to systemic lupus erythematous, rheumatoid arthritis, and / or deficiency of the immune system (immunodefi ci ency ) .

22. The method of any one of the preceding claims, wherein the patient has at least one sign or symptom of anemia.

23. The method of any one of the preceding claims, wherein the patient also has failed at least 1 prior wAIHA treatment regimen.

24. The method of claim 23, wherein the prior wAIHA treatment regimen is a glucocorticoid (GC) or immunosuppression therapy.

25. The method of claim 23, wherein the failure of the prior wAIHA treatment regimen comprises reduction in Hgb of > 1 g / dL.

26. The method of claim 23, wherein the failure of the prior wAIHA treatment regimen comprises an increase in LDH of > 1.5 x upper limit of normal (ULN).

27. The method of any one of the preceding claims, wherein obexelimab is administered concurrently with a GC therapy.

28. The method of claim 27, wherein the GC therapy is administered at a dose of 1-1.5 mg / kg / day prednisone or equivalent.

29. The method of any one of the preceding claims, wherein obexelimab is administered for a time period sufficient to improve, stabilize or reduce one or more symptoms of wAIHA relative to a control.Attorney Docket No. ZEN-024WO130. The method of any one of the preceding claims, wherein the patient achieves improvement in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) score compared to the FACIT-F score prior to treatment.

31. The method of any one of the preceding claims, wherein the patient achieves improvement in EuroQol 5-dimension 5-level (EQ-5D-5L) index score compared to the EQ- 5D-5L index score prior to treatment.

32. The method of any one of the preceding claims, wherein the patient achieves one or more of the following: a) Decrease in Circulating absolute T, B, and natural killer cell count, b) Decrease in Ig levels and ratios (e.g., IgG, IgM, IgA, IgE), c) Increase in CD 19 target receptor occupancy, d) Decrease in reticulocyte count, e) Decrease in LDH, f) Increase in Haptoglobin, g) Decrease in indirect bilirubin following administration obexelimab.

33. The method of any one of the preceding claims, wherein the human patient is relapsed or refractory to rituximab.

34. The method of any one of the preceding claims, wherein the patient 18 years of age or older.

35. The method of any one of the preceding claims, wherein the patient does not have cold autoimmune hemolytic amenia (cAIHA).

36. The method of any one of the preceding claims, wherein the patient does not have mixed type autoimmune hemolytic amenia.

37. The method of any one of the preceding claims, wherein the patient does not have paroxysmal cold hemoglobinuria (PCH).Attorney Docket No. ZEN-024WO138. The method of any one of the preceding claims, wherein obexelimab is administered in a liquid formulation comprising 125 mg / mL obexelimab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid, 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80 at pH 5.5.

39. The method of claim 38, wherein obexelimab is administered as 2 x 1 mL injections or 1 x 2 mL injection.

40. The method of claim 38 or 39, wherein obexelimab is administered using a prefilled syringe or autoinjector.

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