SUBCUTANEOUS DOSAGE FORMS OF ANTI-DIFFERENTIATION GROUP 38 (CD38) ANTIBODIES FOR PHARMACEUTICAL USE IN THE TREATMENT OF A DISEASE CHARACTERIZED BY CD38 EXPRESSION

Abstract

Methods for administering isolated anti-CD38 antibodies subcutaneously at low doses are described. These methods provide effective treatment for autoimmune diseases and certain cancers, including hematological disorders. Unit-dose formulations for anti-CD38 antibodies are also described.

Description

SUBCUTANEOUS DOSAGE OF ΑΝΤΙ ANTIBODIES DIFFERENTIATION GROUP 38 (CD38) Field of Invention Methods for administering isolated anti-CD38 antibodies in low doses and low volumes by subcutaneous (SC) administration are described. Background of the Invention CD38, also known as cyclic ADP ribose hydrolase, is a type II transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. CD38 is a member of a group of related membrane-bound or soluble enzymes comprising CD157 and Aplysia ADPR cyclase. This family of enzymes has the unique ability to convert NAD to cyclic ribose ADP or nicotinic acid-adenine dinucleotide phosphate. CD38 is involved in Ca2+ mobilization and signal transduction through tyrosine phosphorylation of numerous signaling molecules, including phospholipase Cy, ZAP-70, syk, and c-cbl. Based on these observations, CD38 is an important signaling molecule in the maturation and activation of lymphoid cells during their normal development. Among hematopoietic cells, a variety of functional effects have been attributed to cell-mediated signaling. RZfr? nn / nznz / E / YiAi Ref. 309435 by CD38, including lymphocyte proliferation, cytokine release, regulation of B lymphocyte and myeloid cell survival and development, and induction of dendritic cell (DC) maturation. CD38 is expressed on immature hematopoietic cells, is down-regulated on mature hematopoietic cells, and is re-expressed at high levels on plasma cells and activated lymphocytes. For example, high expression of CD38 is observed on activated B cells, plasma cells, activated CD4+ T cells, activated CD8+ T cells, NK cells, NKT cells, mature DCs, and activated monocytes (US Patent No. 8,362,211). CD38 deficiency in mice has been associated with reduced levels of peripheral invariant and regulatory NKT cells, defects in humoral B cell responses and DC trafficking, and an attenuated form of collagen-induced arthritis (CIA) (Chiba et al. (2005) Arthritis Rheum 52:1941-48). The presence of autoantibodies against CD38 has been associated with several diseases, such as diabetes, chronic autoimmune thyroiditis, and Graves' disease (Antonelli et al. (2001) Clin. Exp. Immunol. 126: 426-431; Mallone et al. (2001). ) Diabetes 50: 752 and Antonelli et al (2004) J Endocrinol Invest 27: 695-707). Increased expression of CD38 has been documented in a RZfr? nn / nznz / E / YiAi variety of diseases, including autoimmune diseases and types of cancer. Such diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis (UC), myasthenia gravis (MG) (Yilmaz et al. (2018) Ann. Clin. Trans. Neurol. 5(11):1408-1414), neuromyelitis optica (NMO) (Chihara et al. (2011) Proc. Nati. Acad. Sci. USA 108(9):3701-6), immune thrombocytopenic purpura (ITP), purpura thrombotic thrombocytopenia (TTP) (Behzad et al. (2018) APMIS 126(6):523-532), antiphospholipid syndrome (APS) (Álvarez-Rodríguez et al. (2018) Int. J. Mol. Sci. 19(2 ): pii), pemphigus vulgaris (PV), pemphigus foliaceus (PE), anti-NMDAR encephalitis (NMDR), autoimmune hemolytic anemia (AIHA), Grave's disease, membranous nephropathy, Sjogren's syndrome (SS), ANCA vasculitis, epidermolysis bullous pemphigoid (BP), Hashimoto's thyroiditis, scleroderma, and IgG4-related disease. In RA patients, plasma cells are increased in joint tissue compared to controls. In patients with SLE, plasmablasts are increased in the peripheral blood in patients with more active disease. However, current CD20-based B cell depletion treatments, such as rituximab, effectively deplete CD20+ B cells, but cannot directly and effectively deplete plasma cells or plasmablasts because they do not express CD20. Therefore, RA or SLE patients with high levels of plasma cells or plasmablasts are unlikely to derive substantial clinical benefit from CD20-based therapies. Treatments targeting CD38, which is highly expressed on plasma cells, plasmablasts, NK cells, activated B cells, plasmatoid dendritic cells, and activated T cells, may provide effective treatment for RA and SLE, as well as other diseases characterized by expression. of CD38. The level of CD38-expressing plasmablasts in peripheral blood of adult SLE patients treated with rituximab and oral steroids was the best predictor of time to recurrence. In addition, circulating immunoglobulin (Ig)-secreting cells expressing high levels of CD38 were identified in the peripheral blood of SLE patients with active disease, and the level of this subset was associated with treatment-induced decreases in anti-inflammatory antibody levels. Double-stranded DNA (anti-dsDNA), proteinuria and disease activity ( Grammer et al. (2003) J. Clin. Invest. 112: 1506-1520 ). In addition, plasma cells are sensitive to proteasome inhibition and are reduced in the peripheral blood of highly resistant SLE patients exposed to bortezomib (Alexander et al. (2015) RZfr? nn / nznz / E / YiAi Αηη. rheum. Dis. 74(7): 1474-1478). This reduction corresponded with a decrease in antidsDNA antibodies and a corresponding improvement in disease activity in each patient. Unfortunately, treatment was associated with treatment-emergent adverse events (TEAEs; eg, neuropathy, diarrhoea), which may have resulted from proteasome inhibition in non-lymphoid cells (eg, neurons, epithelium). Taken together, these data indicate that specific reduction of CD38-expressing plasma cells might provide an improved benefit to the risk profile for patients with refractory SLE. As current treatments for both RA and SLE produce significant clinical responses and sustained remission in only a minority of patients, there is an urgent need to explore additional treatment mechanisms. Increased expression of CD38 has been documented in a variety of diseases of hematopoietic origin, as well as in cell lines derived from them, and has been described as a negative prognostic marker in hematological cancers. Such diseases include, but are not limited to, multiple myeloma (MM), chronic lymphoblastic leukemia, B-cell chronic lymphocytic leukemia (B-CLL), including B-cell acute lymphocytic leukemia, B- and T-cell acute lymphocytic leukemia (ALL). , RZfr? nn / nznz / E / YiAi acute lymphoblastic leukemia, Waldenstrom's macroglobulinemia, mantle cell lymphoma, prolymphocytic / myelocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), follicular lymphoma, NK cell leukemia, plasma cells, non-Hodgkin lymphoma (NHL), Burkitt lymphoma (BL), T-cell lymphoma (TCL), hairy cell leukemia (HCL), and Hodgkin lymphoma (HL). In addition, CD38 expression is a prognostic indicator for patients with conditions such as, for example, B-CLL (Dürig et al. (2002) Leukemia 16:30-35; and Morabito et al. (2001) Leukemia Res. 25:927-932) and acute myelogenous leukemia (Keyhani et al. (1999) Leukemia Res. 24:153159). Therefore, CD38 provides a useful target for the treatment of diseases of the hematopoietic system. Several anti-CD38 antibodies are in clinical trials for the treatment of CD38-associated cancers. However, these prior art therapeutic anti-CD38 antibodies bind to red blood cells (RBCs) and platelets, which may explain why a higher required dose is needed to overcome such a capture created by RBC binding. For example, treatment with daratumumab (anti-CD38 IgGl mAb Darzalex®, which is FDA-approved and commercially available from Janssen Oncology) requires a very high dose (>16 mg / kg) and a RZfr? nn / nznz / E / YiAi intensive regimen (8x weekly, 8x biweekly, then monthly) for optimal antitumor activity (Xu et al. (2017) Clin. Pharmacol. Ther. 101(6): 721-724). Daratumumab binding to CD38 on RCBs and platelets results in a positive antiglobulin test (indirect Coombs test), which can persist up to 6 months after the last daratumumab infusion (Sullivan et al. (2017) Blood 129( 22) : 3033-3037). This is an important property of daratumumab and other RBC-binding antibodies. Although CD38 is expressed on RBCs at a level that is approximately 1000-fold lower than on myeloma cells (deWeers et al. (2011) J. Immunol. 186(3):1840-1848), there are approximately 36,000 RBCs per cell. of myeloma in the blood of a MM patient with active disease (Witzig et al. (1993) Cancer 72(1): 108-113). As such, there are 36 times more CD38 molecules expressed by the RBC population compared to a population of humoral cells. Therefore, it has been hypothesized that RBCs bind to a significant amount of whatever anti-CD38 antibody is administered, resulting in the need to administer large doses to have sufficient levels of anti-CD38 antibody to achieve a therapeutic effect on tumor cells. Therefore, treatments using anti-CD38 antibodies are currently focused on intravenous administration. RZfr? nn / nznz / E / YiAi (IV) due to the high volume of antibody required to achieve therapeutic efficacy, as such large volumes are not suitable for subcutaneous administration and there is a limit to how concentrated the antibodies can be formulated. Ab. For example, a 1200 mg dose of daratumumab administered IV over at least 2 hours is approved to treat relapsed and refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM). A subcutaneous (SC) formulation of daratumumab consisting of 1800 mg in 15 mL that is to be a co-formulation with Enhance™ (containing Halozyme, to accelerate absorption) and administered 8X weekly, 8X biweekly, and then once monthly, is found currently in Ph3 trials for RRMM. Another anti-CD38 antibody, isatuximab (commercially available from Sanofi Genzyme and currently in phase 3 clinical trials), is administered at 10 mg / kg and 20 mg / kg, corresponding to 700-1400 mg per dose. 70 kg patient, with a projected injection volume of 3.5 - 14 mL. The higher doses and volumes required of the state-of-the-art anti-CD38 antibodies currently in the clinic can also cause serious side effects such as, for example, hemolytic anemia, a condition in which RBCs are destroyed more rapidly than normal. that can be replaced. In a single-arm, open-label study, isatuximab was administered intravenously to 97 RZfr? nn / nznz / E / YiAi patients total at 3 mg / kg every 2 weeks (Q2W; n=23), 10 mg / kg Q2W for 2 cycles then Q4W (n=25), 10 mg / kg Q2W (n = 24) and 20 mg / kg every week up to 4 doses (1 cycle), then Q2W (n = 25). The most frequent serious adverse event (grade 3 / 4) was anemia, which affected 24% of patients (see http: / / www.onclive.com / conference-coverage / asco2016 / isatuximab-monotherapy-effective-for- heavily-pretreatedmyeloma, 2016 ASCO Annual Meeting, Richter et al (2016) J Clin Oncol 34 (suppl) :abstract 8005). In a study of daratumumab, 45% of all patients experienced anemia (in 19% of Grade 3 cases) and 48% of patients experienced thrombocytopenia (in 10% of Grade 3 cases and 8% of Grade 3 cases). grade 4) (see, for example, https: / / www.rxlist.com / darzalex-side-effects-drug-center.htm; Costello (2017) Ther. Adv. Hematol. 8 (1): 28-37 ) . Therefore, patients treated with isatuximab or daratumumab should be carefully monitored for these life-threatening and other serious side effects. The physical challenges of administering large amounts of anti-CD38 mAb to patients subcutaneously illustrate the need in the art for more potent anti-CD38 antibodies because a more potent antibody could achieve the desired pharmacological effects in a smaller amount / volume and thus allow more effective forms of administration. A more potent antibody could result in the formulation of smaller volumes that would be administered SC more effectively than daratumumab (Darzalex) to patients where depletion of CD38-expressing cells is warranted, such as for treatment of autoimmune diseases and hematologic forms of cancer. Advantages of administering a smaller amount of drug would include delivery taking seconds compared to minutes for SC administration of daratumumab and hours for IV administration of daratumumab, isatuximab, or MOR202, as well as fewer drug reactions. infusion (as seen in the case of SC administration of daratumumab). Reducing the time a patient needs to spend in an infusion center would allow for the option of home treatment, greater management efficiency and higher productivity of infusion centers, lower healthcare costs per patient as a result of greater institutional efficiency , and greater utility if patients could use the drug without access to an infusion center. AB7 9 is a fully human IgG1 immunoglobulin monoclonal antibody that specifically binds to CD38 with high affinity (Kd = 3.5 nM) (US Patent No. 8,362,211, the contents of which are incorporated herein by reference in their entirety). ΆΒ7 9 inhibits the growth of RZfr? nn / nznz / E / YiAi tumor cells expressing CD38 via cellular downregulation by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). AB7 9 also reduces the level of plasma cells and plasmablasts in blood isolated from healthy subjects and patients with systemic lupus erythematosus (SLE). In the case of SLE, there is an 80% reduction in the plasma cell population, which includes short-lived and long-lived plasma cells. In addition, the number of cells producing pathogenic autoantibodies, including anti-VH4-34 9G4+ antibodies (70% reduction), anti-Ro antibody (70% reduction), and anti-dsDNA antibody (80% reduction), was also reduced. The anti-human CD38 mAb daratumumab also decreases CD38-expressing plasmablasts and plasma cells in samples from patients with SLE and RA in a dose-dependent manner in vitro. Unlike daratumumab, AB79 cross-reacts with CD38 expressed by Macaca fascicularis, providing a unique opportunity to determine whether reducing the level of CD38-expressing cells would affect inflammation and tissue damage in a non-primate model of immune disease. humans. In healthy Macaca fascicularis, the depletion efficiency of B and T lymphocytes and NK cells was positively correlated with the expression level of CD38 and the dose level of AB79 (PCT application No. PCT / US2017 / 042128; U.S. Patent No. 8, 362,211). Since many antibodies to CD38 in the clinic are not suitable for low dose or low volume subcutaneous administration and possess dangerous side effects, there remains a need in the art for antibody formulations that are safer, more convenient, and more effective. to treat diseases in which binding to CD38 is indicated, such as autoimmune diseases and haematological forms of cancer. Brief Description of the Invention Provided herein are methods for treating diseases in which CD38 binding is indicated, such as, for example, autoimmune diseases and hematological cancers comprising subcutaneous administration of isolated anti-CD38 antibodies at unexpectedly low doses and / or small volumes. In one aspect, the invention provides a method of treating a disease in which CD38 binding is indicated in a subject, wherein the method comprises the step of administering subcutaneously to a subject having a disease in which CD38 is indicated. binding to CD38 a therapeutically effective amount of an isolated anti-human CD38 antibody that is sufficient to treat the disease, wherein the anti-CD38 antibody comprises a variable heavy (VH) chain region comprising a CDR1 having RZfr? nn / nznz / E / YiAi the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4 and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light chain (VL) region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, RZfr? nn / nznz / E / YiAi a CDR2 having the amino acid sequence of SEQ ID NO:7 and a CDR3 having the amino acid sequence of SEQ ID NO:8. In another aspect, the invention provides a method of treating a disease in which CD38 binding is indicated in a subject, wherein the method comprises the step of administering subcutaneously to a subject having a disease in which CD38 is indicated. binding to CD38 a therapeutically effective amount of an isolated human anti-CD38 antibody that is sufficient to treat the disease, wherein the anti-CD38 antibody comprises a region of the VH chain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4 and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a region of the VL chain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 7. NO:8, wherein the anti-CD38 antibody is administered in a volume of 3 milliliters or less. In another aspect, the invention provides a method of treating a disease in which CD38 binding is indicated in a subject, wherein the method comprises the step of administering subcutaneously to a subject having a disease in which CD38 is indicated. binding to CD38 a therapeutically effective amount of an isolated human anti-CD38 antibody that is sufficient to treat the disease, wherein the anti-CD38 antibody comprises a region of the VH chain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4 and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a region of the VL chain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 7. NO:8, wherein the anti-CD38 antibody is administered at a dose of 0.03 to 0.6 milligrams per kilogram of body weight. In one aspect, the anti-CD38 antibody does not cause hemolytic anemia or thrombocytopenia. In one aspect, administration of the anti-CD38 antibody results in less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10 % or less than 5% grade 3 or 4 incidence of one or more treatment-emergent adverse events (TEAEs) selected from the group consisting of anemia, hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia and lymphopenia. In one aspect, the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40%, or less than 50% decrease in RBC. In one aspect, the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40%, or less than 50% decrease in platelets. In one aspect, the disease is selected from the group consisting of an autoimmune disease and a type of cancer. In one aspect, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis, myasthenia gravis (MG), neuromyelitis optica (NMO), purpura Immune Thrombocytopenia (ITP), Thrombotic Thrombocytopenic Purpura (TTP), Antiphospholipid Syndrome (APS), Pemphigus Vulgaris (PV), Pemphigus Foliaceus (PE), Anti-NMDAR Encephalitis (NMDR), Autoimmune Hemolytic Anemia (AIHA), Grave's Disease, membranous nephropathy, Sjogren's syndrome (SS), ANCA vasculitis, epidermolysis bullosa acquisita (EBA), bullous pemphigoid (BP), Hashimoto's thyroiditis, RZfr? nn / nznz / E / YiAi scleroderma, IgGg-related disease, and graft-versus-host disease. (Yilmaz V, et. al., Ann Clin Transi Neurol. 2018 Sep 22;5(11):1408-1414; Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S, Okamoto T, Ogawa M, Toda T, Yamamura T. Proc Nati Acad Sci U S A. 2011 Mar 1;108(9):3701-6;Behzad MM, et al., APMIS 2018 Jun;126(6):523-53 2;or Alvarez-Rodriguez L., et al., Int J Mol Sci. 16 Feb 2018;19(2). In one aspect, the hematologic cancer is selected from the group consisting of multiple myeloma, NK cell / T cell lymphoma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B cell lymphoma and Burkitt's lymphoma. In one aspect, the hematologic cancer is multiple myeloma. In certain embodiments, multiple myeloma is selected from the group consisting of RRMM and EDMM. In one aspect, the VH chain region has the amino acid sequence of SEQ ID NO:9 and the VL chain region has the amino acid sequence of SEQ ID NO:10. In one aspect, the anti-CD38 antibody comprises a heavy chain amino acid sequence of SEQ ID NO:11 and a light chain amino acid sequence of SEQ ID NO:12. RZfr? nn / nznz / E / YiAi In one aspect, the therapeutically effective amount is a dose of 0.03 to 0.6 milligrams per kilogram of body weight. In one aspect, the therapeutically effective amount has a volume of 3 milliliters or less. In one aspect, the therapeutically effective amount has a volume of 2 milliliters or less. In one aspect, the therapeutically effective amount has a volume of 1 milliliter or less. In one aspect, the anti-human CD38 antibody is administered in the form of a pharmaceutically acceptable composition. In another aspect, the invention provides a method of treating a blood cancer in a subject, wherein the method comprises the step of administering subcutaneously to a subject having a blood cancer a therapeutically effective amount of an isolated anti-human CD38 antibody. which is sufficient to treat hematological cancer, wherein the anti-CD38 antibody comprises a region of the VH chain comprising a CDR1 having the amino acid sequence of SEQ ID NO:3, a CDR2 having the amino acid sequence of SEQ ID NO: 4 and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a region of the VL chain comprising a CDR1 having the amino acid sequence of SEQ ID NO:6, a CDR2 having the amino acid sequence of SEQ ID NO:7 and a CDR3 having RZfr? nn / nznz / E / YiAi has the amino acid sequence of SEQ ID NO:8. In another aspect, the invention provides a method of treating a blood cancer in a subject, wherein the method comprises the step of administering subcutaneously to a subject having a blood cancer a therapeutically effective amount of an isolated anti-human CD38 antibody. which is sufficient to treat hematological cancer, wherein the anti-CD38 antibody comprises a region of the VH chain comprising a CDR1 having the amino acid sequence of SEQ ID NO:3, a CDR2 having the amino acid sequence of SEQ ID NO: 4 and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a region of the VL chain comprising a CDR1 having the amino acid sequence of SEQ ID NO:6, a CDR2 having the amino acid sequence of SEQ ID NO:7 and a CDR3 having the amino acid sequence of SEQ ID NO:7. NO:8, wherein the anti-CD38 antibody is administered in a volume of 3 mL or less, 2 mL or less, or 1 mL or less. In another aspect, the invention provides a method of treating a blood cancer in a subject, wherein the method comprises the step of administering subcutaneously to a subject having a blood cancer a therapeutically effective amount of an isolated anti-human CD38 antibody. that is sufficient to treat blood cancer, wherein the anti-CD38 antibody comprises a RZfr? nn / nznz / E / YiAi region of the VH chain comprising a CDR1 having the amino acid sequence of SEQ ID NO:3, a CDR2 having the amino acid sequence of SEQ ID NO:4 and a CDR3 having the sequence of amino acids of SEQ ID NO: 5; and a region of the VL chain comprising a CDR1 having the amino acid sequence of SEQ ID NO:6, a CDR2 having the amino acid sequence of SEQ ID NO:7 and a CDR3 having the amino acid sequence of SEQ ID NO:7. NO:8, wherein the anti-CD38 antibody is administered at a dose of 0.03 to 0.6 milligrams per kilogram of body weight. In one aspect, the anti-CD38 antibody does not cause hemolytic anemia or thrombocytopenia. In one aspect, administration of the anti-CD38 antibody results in less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10 % or less than 5% grade 3 or 4 incidence of one or more TEAEs selected from the group consisting of anemia, including hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, and lymphopenia. In one aspect, the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40%, or less than 50% decrease in RBC. In one aspect, the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40% or RZfr? nn / nznz / E / YiAi less than 50% decrease in platelets. In one aspect, the hematologic cancer is selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B cell lymphoma, NK cell / T cell lymphoma. and Burkitt's lymphoma. In one aspect, the hematologic cancer is multiple myeloma. In certain embodiments, multiple myeloma is selected from the group consisting of RRMM and EDMM. In one aspect, the VH chain region has the amino acid sequence of SEQ ID NO: 9 and the VL chain region has the amino acid sequence of SEQ ID NO: 10. In one aspect, the anti-CD38 antibody comprises a heavy chain amino acid sequence of SEQ ID NO:11 and a light chain amino acid sequence of SEQ ID NO:12. In one aspect, the therapeutically effective amount is a dose of 0.03 to 0.6 milligrams per kilogram of body weight. In one aspect, the therapeutically effective amount has a volume of 3 milliliters or less. In one aspect, the therapeutically effective amount has a volume of 2 milliliters or less. In one aspect, the therapeutically effective amount has RZfr? nn / nznz / E / YiAi a volume of 1 milliliter or less. In one aspect, the anti-human CD38 antibody is administered in the form of a pharmaceutically acceptable composition. In another aspect, the invention provides a unit dose form comprising an isolated antibody comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 9 and a light chain variable region amino acid sequence. of SEQ ID NO: 10, wherein the isolated antibody binds to CD38, wherein the unit dosage form is formulated for subcutaneous administration of the antibody at a dose of 0.03 to 0.6 milligrams per kilogram of body weight. In one aspect, the heavy chain comprises the amino acid sequence of SEQ ID NO:11 and the light chain comprises the amino acid sequence of SEQ ID NO:12. In one aspect, the unit dosage form has a volume of 3 milliliters or less. In one aspect, the unit dosage form has a volume of 2 milliliters or less. In one aspect, the unit dosage form has a volume of 1 milliliter or less. In one aspect, the unit dosage form is formulated for subcutaneous administration of the antibody in the treatment of a hematologic cancer selected from the group RZfr? nn / nznz / E / YiAi consisting of multiple myeloma, chronic lintoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt's lymphoma. In one aspect, the hematologic cancer is multiple myeloma. In certain embodiments, multiple myeloma is selected from the group consisting of RRMM and EDMM. In one aspect, the anti-CD38 antibody does not cause hemolytic anemia or thrombocytopenia. In one aspect, the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40%, or less than 50% decrease in RBC. In one aspect, the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40%, or less than 50% decrease in platelets. These and other potential embodiments, features, and advantages will become apparent upon reference to the following description and following figures. Brief Description of the Figures The objects and characteristics of the invention can be better understood by referring to the figures described below in which, Figure 1 shows the PK data of Macaca fascicularis from the SC dose groups described in Table 2. Anti-drug antibodies (ADA) were detected with an assay RZfr? nn / nznz / E / YiAi electrochemiluminescent (ECL) qualitative validated. The incidence increased with time and affected the PK when it reached a specific threshold titer of around 1000 Hog(7) ). Figures 2A-2F show PK data for Macaca fascicularis and PK patterns for AB7 9. Figures 2A and 2B show raw PK data from IV data from all 8 monkey studies; Figure 2A shows the first 7 days after the first dose and Figure 2B shows the entire observation period. SC data was omitted (see Figure 1 for SC data). Figure 2C shows the final structure of the PK model, including target-mediated drug disposition (TMDD), marked with a blue box. Vc designates the volume of the central compartment where AB79 concentrations are observed (marked with Conc). VP designates the volume of the peripheral compartment. Rtotai represents the antibody bound and unbound CD38 receptor compartment. KSPn and KDEG designate the receptor production and degradation rate constants and KINT the internalization rate constant (complex removal rate constant). Ksses is the steady state constant, defined as Kss= (KDIS+ Kint) / KFij, where KDIS is the dissociation and KFIJ is the fixation rate constant. Figures 2D-2F show the overlays of the 2-compartment linear model predictions (median, 95% prediction interval) without a TMDD component and the observed data from the 3 lowest doses (Study 8). Note the different time scales between figures 2D, 2E and 2F. Figure 3 shows the effects of ADA and PK in a 13-week toxicology study in Macaca fascicularis. The evaluation refers to the PK model of the final population (Figures 2A-2F, Table 2). The following goodness-of-fit (GOF) plots stratified by dose and route of administration are presented (Keizer et al. (2013) CPT Pharmacometrics Syst. Pharmacol. 2:e50): (1) conditional weighted residuals (CWRES) compared to time; (2) observed concentration compared to the population model prediction; (3) CWRES compared to the population model prediction; and (4) observed concentration compared to individual model prediction. Figures 4A-4J show GOF plots for the final population PK model stratified by dose and route of administration (IV - crosses, SC - triangles). Figure 4A overview; Figure 4B - 0.03 mg / kg dose; Figure 4C - 0.1 mg / kg dose; Figure 4D - 0.3 mg / kg dose; Figure 4E 1.0 mg / kg dose; Figure 4F - 2.0 mg / kg dose; Figure 4G - dose 3.0 mg / kg; Figure 4H - 30 mg / kg dose; Figure 41 80 mg / kg dose; and Figure 4J: 100 mg / kg dose. Figure 5 shows a comparison of the expression of CD38 on the surface of human and monkey NK cells and B and T cells. Flow cytometry measurements were standardized and signals are reported in Molecules of Equivalent Soluble Fluorescence (MOEF). Human and monkey blood lymphocytes bind to similar levels of AB79. A direct comparison of the expression levels of CD38 on NK cells (CD3-, CD159a+), B lymphocytes (CD3-, CD20+) and T lymphocytes (CD3+) of monkey and NK cells (CD3-, CD16+) was evaluated by flow cytometry. / CD56+), human B lymphocytes (CD3-, CD19+) and T lymphocytes (CD3+). The median fluorescence intensity (MFI) for an AB79 stain for each cell population was converted to MOEF units using a standard curve generated with Rainbow Beads (Spherotech; Lake Forest, IL). The data shown are from 3 individuals of each species and show MOEF ± SD for each cell type. There are differences in CD38 expression between blood lymphocytes, with a higher level of AB79 binding in NK cells > B cells > T cells. The pattern of AB7 9 binding is similar in monkey blood cells, but the level of binding to AB79 / expression of CD38 is lower. Figures 6A-6C show the inter-individual and intra-individual variability in the T-lymphocyte, B-lymphocyte and NK cell count data of the animals. RZfr? Placebo-treated nn / nznz / E / YiAi from the study depicted in Figure 5. Figure 6A - NK cells; Figure 6B - B lymphocytes; and Figure 6C - T lymphocytes. Figures 7A-7F show predose NK cell, B cell, and T cell counts (cells per pL) stratified by study (top row) or sex (bottom row). Figure 7A: NK cells per study; Figure 7B B lymphocytes per study; Figure 7C - T lymphocytes per study; Figure 7D - NK cells per male subject / female subject; Figure 7E - B cells per male subject / female subject; and Figure 7F - T cells per male subject / female subject. Figures 8A-8I show the AB79-dependent decrease in NK cells, B cells, and T cells. Graphs focus on changes that occurred within the first 7 days after treatment with the first dose of AB79. It was possible to pool data from single dose and multiple dose studies with a weekly or biweekly dosing schedule. Figure 8A - nadir (lowest point) of cell decline for NK cells; Figure 8B - 1 week after the 1st dose in the case of NK cells; Figure 8C - Mean profile per dose group for NK cells; Figure 8D - nadir decrease in cells in the case of B lymphocytes; Figure 8E - 1 week after the 1st dose in the case of B lymphocytes; Figure 8F - mean RZfr? nn / nznz / E / YiAi profile by dose group for B cells; Figure 8G - nadir cell decrease in the case of T lymphocytes; Figure 8H - 1 week after the 1st dose in the case of T lymphocytes; and Figure 81 - mean profile by dose group for T cells. Graphs A-C show individual trough cell counts (ie, maximum PD effect), individual cell counts 7 days after the first dose, and the profiles of mean cell decline per dose and the structure of the PK-PD model of NK cells, respectively. Figures 8D-8F show the same information regarding B cells and the GI graphs show the same information regarding T cells. Figures 9A and 9B show the effect of AB79 treatment on RBC two days post-dose (Figure 9A) and total lymphocyte count on the first day post-dose in Study 7 (Table 2) (Figure 9B). . Figures 10A-10H show simulated human PK and NK cell, B cell, and T cell depletion profiles of AB79. Based on the monkey-scale PK and PK-PD models, 5 PK and cell decay profiles of single IV and SC doses (0.0003 to 1 mg / kg) were simulated. The graphs on the left show the data after IV administration and the graphs on the right show the RZfr? nn / nznz / E / YiAi data after SC administration. The first row of graphs shows the PK profiles. The lower limit of quantification (LLOQ) of 0.05 pg / mL is indicated by a horizontal dashed line. The PK of the lower dose was completely noise superimposed and only at doses of 0.03 mg / kg did the PK reach levels above the LLOQ. Figure 10A AB79 via IV; Figure 10B - AB79 via SC route; Figure 10C by IV route in NK cells; Figure 10D - via SC in NK cells; Figure 10E - IV in B lymphocytes; Figure 10F - via SC route in B lymphocytes; Figure 10G - by IV route in T lymphocytes; and Figure 10H - by SC route in T lymphocytes. Figure 11 shows the plan for a single escalating dose toxicity study of AB79 in healthy volunteers. A total of 6 IV and 4 SC cohorts in 74 subjects were randomized and received a single dose of AB79. Extensive blinded safety, PK, and PD data were reviewed after each cohort and before dose escalation. Stopping criteria included depletion of target cells to avoid possible immunosuppression of healthy volunteers. Each subject was followed for up to 92 days post-dose. Figures 12A-12C show GOF plots for PK-PD models, stratified by route of administration (IV red; SC - blue), where Figure 12A - NK cells; Figure RZfr? nn / nznz / E / YiAi 12B - B lymphocytes; and Figure 12C - T lymphocytes. Figures 13A-13C show that AB79 mediates the decrease in monkey lymphocytes. Blood NK cells > B cells > T cells decreased in a dose-dependent manner of AB79 in female Macaca fascicularis monkeys (n=4 / dose group) after a single IV dose of AB79 as quantified with Flow-Count™ fluorospheres ( BeckmanCoulter) by flow cytometry. Samples were collected at pretreatment (week -1), on day 1: pre-dose, post-dose at 15, 30 min, 1, 4, 8, 24, 48, 96, and 168 hours, on days 10, 15, 22, 29, 36, 43, 50, and 57. Only 2 weeks of data are shown for clarity. The mean of the cell number values ​​at each time point were calculated and used to calculate the % of initial counts. Figure 13A - T lymphocytes; Figure 13B - B lymphocytes; and Figure 13C - NK cells. Figure 14 shows that human tetanus toxoid (TTd) recovery responses are reduced by AB79 treatment. CB17 / SCID mice were treated with antiasialo GM1 to kill NK cells and then received 25 x 10 6 human peripheral blood lymphocytes. After 7-10 days, serum samples were collected to test for human Ig and the Ig level was the basis for randomization. Mice received TTd to induce the recovery response and were treated with the indicated antibodies twice weekly for 10 days. three days after the RZfr? nn / nznz / E / YiAi last treatment, serum was collected and tested for anti-TTd antibodies. AB79 dose-dependently inhibited the TTd recovery response to a similar degree to Rituxan (Rtx) (isotype (Iso), Rtx and AB79 at 10 mg / kg in all cases). Figure 15 shows that AB79 does not induce cytokine induction. AB79 did not increase IL-6 levels in PBMC collected from 4 different subjects after a 24-h incubation compared to the IgGl isotype control. PHA and anti-CD3 positive controls increased cytokine levels in all subjects, demonstrating that the cells had the ability to produce IL-6. Similar results were observed with PBMC stimulated for 48 hours when IL-2, IL-4, IL-10, GMCSF, IFNγ and TNFα were assessed (data not shown). The bars are as follows for each subject: (i) without Ab; (ii) isotype control; (iii) AB79; (iv) anti-CD3; (v) PHA. Each value is a mean of triplicate wells ± SD measured 24 hours after incubation. Figure 16A shows the setup of the dry fix, wet fix and soluble experiment of Figure 16B (modified from Stebbings et al. (2007) J. Immunol. 179: 3325-3331). Figure 16B shows that AB79 has no agonist activity. AB79 was highly concentrated when added RZfr? ηη / ηζηζ / Ε / γίΛΐ to wells in solution and the liquid allowed to evaporate (dry fixation) compared to AB7 9 which was allowed to fix to wells in solution (wet fixation) or added directly to PBMCs (solvable) . AB79 did not stimulate IL-6 or IL-2, IL-4, IL-8, IL-10, GM-CSF, IFNγ, or TNFa in any of the conditions tested after 24 hours. PBMCs constitutively produced IL-8, which was not altered by any treatment (data not shown). Each measurement is a mean of triplicate wells measured 24 hours after incubation from a single subject. Figure 17 shows an assessment of AB79 binding to human RBCs. No binding of AB79 (solid histogram) or isotype control (shaded histogram) to RBCs was observed in whole blood from thirty human volunteers in this study. Representative data from 15 of 30 human volunteers are shown. Figure 18 shows an assessment of AB7 9 binding to Macaca fascicularis RBC. No binding of AB79 (solid histogram) or isotype control (shaded histogram) to RBCs in whole blood of thirty Macaca fascicularis was observed in this study. Representative data from 15 of 30 Macaca fascicularis are shown. Figure 19 shows an assessment of AB79 binding to human platelets. No binding of AB79 (solid histogram) or isotype control (shaded histogram) to CD61+ regulated platelets was observed in this study in whole blood from thirty human volunteers. Representative data from 15 of 30 human volunteers are shown. Figure 20 shows an assessment of AB79 binding to Macaca fascicularis platelets. No binding of AB79 (solid histogram) or isotype control (shaded histogram) to CD61+ regulated platelets in whole blood of thirty Macaca fascicularis was observed in this study. Representative data for 15 of 30 Macaca fascicularis are shown. Figure 21 shows an assessment of AB79 binding to Macaca fascicularis CD45+ lymphocytes. Binding of AB79 to CD45+ lymphocytes in unlysed whole blood of Macaca fascicularis. CD45+ lymphocytes are upregulated and then assessed for AB79 binding (solid histogram) or isotype control binding (shaded histogram). AB7 9 binding was detected in a subset of lymphocytes as illustrated in the cell fraction to the right of the vertical dashed line. Little or no binding of the isotype control to lymphocytes is observed. Figures 22A and 22B show the regulatory hierarchy for (Figure 22A) RBC identification and (Figure 22B) human RBC lymphocyte identification. Figure 23 shows the binding capacity of antibodies to biotin-streptavidin-BV421 AB79 and biotin RZfr? nn / nznz / E / YiAi streptavidin-BV421 daratumumab. Bars represent (i) negative beads, (ii) SavBv421 only negative control, (iü) AB7 9-biotin / Sav-BV421 (5 pg / mL), (iv) daratumumab-biotin / Sav-BV421 (5 pg / mL). mL), (v) AB79-biotin / Sav-BV421 (10 pg / mL), (vi) daratumumab-biotin / SavBV421 (10 pg / mL). MFI = median fluorescence, Sav = streptavidin. A photomultiplier tube (PMT) voltage of 275 was used. Figure 24 shows the binding of biotin-streptavidin-BV421 AB79 and biotin-streptavidin-BV421 daratumumab to CD38+ lymphocytes. Bars represent (i) AB79-biotin-strep-BV421 (0 pg / mL), (ii) unlabeled AB79 and AB79-biotin-strep-BV421 (10 pg / mL), (iii) AB79-biotin-strep-BV421 ( 10 pg / mL), (iv) daratumumab-biotin-estrepBV421 (0 pg / mL), (v) unlabeled daratumumab and daratumumabbiotin-strep-BV421 (10 pg / mL), (vi) daratumumab-biotinestrep-BV421 (10 pg / mL). The vertical lines represent the standard deviation; n = 4 donors (3 donors for unlabeled conditions). MFI = median fluorescence. Figure 25 shows the binding of AB79 and daratumumab to human RBCs (% individual donor positive results). Peripheral blood from four healthy volunteers incubated with biotin-streptavidin-BV421 AB79 (0, 0.1, 10, 100 pg / mL) or biotin-streptavidin-BV421 daratumumab (0.0.1, 1, 10, 100 pg / mL) for 3 hours at RT on a gentle shaker RZfr? nn / nznz / E / YiAi in the presence or absence of unlabeled AB79 (500 pg / mL) or unlabeled daratumumab (500 pg / mL). Key: AB79biotin-strep-BV421; “Cold “W*-*AB79 and AB79-biotin-strep-BV421; daratumumab-biotin-strep-BV421; ““^“cold daratumumab and cold daratumumab-biotin-streptavidin BV421. Figure 26 shows the binding of AB79 and daratumumab to human RBCs (summary of % positive data). Peripheral blood from four healthy volunteers incubated with biotinstreptavidin-BV421 AB79 (0, 0.1, 10, 100 pg / mL) or biotinstreptavidin-BV421 daratumumab (0.0.1, 1, 10, 100 pg / mL) for 3 hours at RT in a gentle shaker in the presence or absence of unlabeled AB79 (500 pg / mL) or unlabeled daratumumab (500 pg / mL). Key: AB79-biotin-strep-BV421 ; ”^“:AB79 and AB79-biotin-strep-BV421 cold; daratumumabbiotin-strep-BV421; daratumumab cold and daratumumabbiotin-strep-BV421 cold. Figure 27 shows the binding of AB79 and daratumumab to human RBCs (median individual donor fluorescence). Peripheral blood from four healthy volunteers incubated with biotin-streptavidin-BV421 AB79 (0, 0.1, 10, 100 pg / mL) or biotin-streptavidin-BV421 daratumumab (0,0.1, 1, 10, 100 pg / mL) for 3 hours at RT on a gentle shaker in the presence or absence of unlabeled AB79 (500 pg / mL) or unlabeled daratumumab (500 pg / mL). Key: AB79bio tina-strep-BV4 21; “·®~”Ζ'\Β7 9 and AB79-biotin-strep-BV421 RZfr? cold nn / nznz / E / YiAi; daratumumab-biotin-strep-BV421; cold daratumumab and cold daratumumab-biotin-strep-BV421. Figure 28 shows the binding of AB7 9 and daratumumab to human RBCs (median summary fluorescence). Peripheral blood from four healthy volunteers incubated with biotinstreptavidin-BV421 AB7 9 (0, 0.1, 10, 100 pg / mL) or biotinstreptavidin-BV421 daratumumab (0.0.1, 1, 10, 100 pg / mL) for 3 hours at RT at a gentle shaker in the presence or absence of unlabeled AB79 (500 pg / mL) or unlabeled daratumumab (500 pg / mL). Key: AB79-biotin-strep-BV421 ; cold AB79 and AB79-biotin-strep-BV421; daratumumab-biotinstrep-BV421; cold daratumumab and cold daratumumab-biotin-strepBV421. Figure 29 shows hemolysis (% normalized) of human red blood cells by: human IgGl isotype control, daratumumab AB79, and saponin control in pg / mL. Each symbol represents the average of 3 human replicates (n=5 donors). Figure 30 shows hemolysis (% normalized) of Macaca fascicularis red blood cells using: human IgGl isotype control, daratumumab AB79, and saponin control in pg / mL. Each symbol represents the average of 3 Macaca fascicularis replicates (n=5 donors). Figures 31A-31D show (Figure 31A) the mean of RZfr? nn / nznz / E / YiAi concentration of AB79 in serum of monkeys infused IV with ΑΒ79 and percent change from pre-dose baseline in mean absolute cell counts of (Figure 31B) CD2 O~ / CD3~ / CD16+ NK cells; (Figure 31C) CD3_ / CD20+ B lymphocytes; and (Figure 31D) CD3+ T cells in peripheral blood of monkeys after IV infusion of AB79. Vehicle Control (open squares), 0.1 mg / kg (open diamonds), 0.3 mg / kg (open triangles), 1.0 mg / kg (open circles), 3.0 mg / kg (closed squares), 30.0 mg / kg (diamonds closed) and 80.0 mg / kg (closed triangles) of AB79. The cohorts indicated with open symbols (n = 7 animals) received weekly doses and the closed symbols (n = 5 animals) biweekly for 3 months. The error bars indicate the standard deviation. Figures 32A-32C show the concentration-dependent binding of AB79 (Figure 32A) to CHO cells expressing recombinant Macaca fascicularis CD38; and (Figure 32B) to endogenous Macaca fascicularis CD3 8 expressed on CD3+ T cells, CD3-CD20+ B cells and CD3 / CD20- / CD16+ NK cells. NK cell levels in Macaca fascicularis whole blood (n=3) are shown in Figure 32C after incubation with AB79 for 48 hours in culture. Figure 33 shows the dosing strategy schedule for Example 7. Figures 34A-34F show the (Figure 34A) measurements RZfr? nn / nznz / E / YiAi of body weights normalized as a function of percent change from the time of enrollment: a non-arthritic control animal (open circles); untreated arthritic animals (closed circles); animals prophylactically treated with AB7 9 (open squares); animals therapeutically treated with AB79 (closed squares); animals therapeutically treated with dexamethasone (open triangles); (Figure 34B) mean clinical arthritis index of 16 joints: untreated arthritic animals (closed circles); animals prophylactically treated with AB7 9 (open squares); animals therapeutically treated with AB79 (closed squares); animals therapeutically treated with dexamethasone (open triangles); (Figure 34C) the number of PIP joints with joint inflammation; and (Figure 34D) the mean oval area of ​​16 PIP joints calculated and reported as the mean joint inflammation for each animal. Radiographic examination after X-ray imaging was performed for each joint of (Figure 34E) DIP and (Figure 34F) MCP. Data are mean ± standard error for each group. * p<0.05 ** p<0.01 compared to the untreated group (Dunn's multiple comparison test\ANOVA one way). Figures 35A-35F show the (Figure 35A) normalized body weight measurements as a function of percentage of RZfr? nn / nznz / E / YiAi change from time of enrollment: one non-arthritic control animal (open circles); untreated arthritic animals (closed circles); animals prophylactically treated with AB7 9 (open squares); animals therapeutically treated with ΆΒ79 (closed squares); animals therapeutically treated with dexamethasone (open triangles). Serum chemistry levels of (Figure 35B) CRP and (Figure 35C) ALP over time: data are mean ± standard error for each group. * p<0.05 ** p<0.01 compared to the untreated group (Dunn's multiple comparison test\ANOVA one way). Figures 36A-36D show quantitative histomorphometry of the joint area and DIP joint surface performed in a blinded manner by a bone histopathologist with toluidine blue stained slides (32 x 22 animals = 704 slides). The individual results for each animal were plotted as the mean ± standard error for each group. Statistical analysis was performed as specified in the table above. (Figure 36A) Total area of ​​articular cartilage; (Figure 36B) thickness of damaged articular cartilage; (Figure 36C) percentage of articular surface damaged; and (Figure 36D) area of ​​osteophytes. Data are mean ± standard error for each group. * p<0.05 ** p<0.01 compared to the untreated group (multiple comparison test of RZfr? nn / nznz / E / YiAi Dunn\ANOVA one way). Figures 37A and 37B show serum chemistry levels of (Figure 37A) CRP and (Figure 37B) ALP over time. A non-arthritic control animal (open circles); untreated arthritic animals (closed circles); animals prophylactically treated with AB79 (open squares); animals therapeutically treated with AB79 (closed squares); animals therapeutically treated with dexamethasone (open triangles). Data are mean ± standard error for each group. * p<0.05 ** p<0.01 compared to the untreated group (Dunn's multiple comparison test\ANOVA one way). Figures 38A-38F show levels of (Figure 38A) red blood cells; (Figure 38B) hematocrit; (Figure 38C) reticulocytes, (Figure 38D) platelets, (Figure 38E) neutrophils, and (Figure 38F) lymphocytes in animals over time: a non-arthritic control animal (open circles); untreated arthritic animals (closed circles); animals prophylactically treated with AB79 (open squares); animals therapeutically treated with AB79 (closed squares); animals therapeutically treated with dexamethasone (open triangles). Data are mean ± standard error for each group. * p<0.05 ** p<0.01 compared to the untreated group (Dunn's multiple comparison test\ANOVA one way). Figures 39A-39D show levels of (Figure 39A) NK cells; (Figure 39B) B lymphocytes; (Figure 39C) T lymphocytes and; (Figure 39D) Peripheral blood monocytes over time: a non-arthritic control animal (open circles); untreated arthritic animals (closed circles); animals prophylactically treated with AB7 9 (open squares); animals therapeutically treated with AB79 (closed squares); animals therapeutically treated with dexamethasone (open triangles). Data are mean ± standard error for each group. * p<0.05 ** p<0.01 compared to the untreated group (Dunn's multiple comparison test\ANOVA one way). Figures 40A-40D show the serum concentrations of AB79 in individual monkeys when administered (Figure 40A) prophylactically or (Figure 40B) therapeutically. Serum concentrations of anti-AB79 antibodies in individual monkeys when administered (Figure 40C) prophylactically or (Figure 40D) therapeutically. Figure 41 shows the mean serum concentration-time profiles of AB79 after a single 2-hour IV infusion of AB79 at 0.03 (squares) and 0.06 (triangles) mg or a single SC injection of AB79 at 0.6 mg kg- 1(circles) in healthy subjects. Error bars represent standard deviation (n = 6). IV, intravenous; SC, RZfr? nn / nznz / E / YiAi subcutaneous . Figures 42A and 42B show peripheral blood NK cell levels of healthy subjects after a single IV or SC administration of AB79. IV, intravenous; SC, subcutaneous. Figure 43 shows levels of plasmablasts, monocytes, B and T lymphocytes, and NK cells in peripheral blood of healthy subjects after a single injection of placebo control, 0.1, 0.3, or 0.6 mg kg-1 of AB79 SC. Absolute monocytes (cells / pL), '“‘NK cells (cells / pL), Total T lymphocytes (lymphocytes / pL), ““'B lymphocytes (lymphocytes / pL), plasmablasts (cells / pL). The centered curves represent the median. NK, natural killer cell; SC, subcutaneous. Figure 44 shows the change from baseline levels of total IgA, IgG, and IgM in serum of healthy subjects after a single administration of placebo or 0.003 to 0.06 mg kg-1 AB79 IV, placebo, or 0.03 to 0.6 mg kg- 1 of AB79 SC. The symbols represent the mean value for the cohort and the error bars represent the standard error of the mean. placebo, AB7 9 0.0003 mg / kg AB79 0.001 mg / kg AB79 0.003 mg / kgAAB79 0.01 mg / kg AB79 0.03 mg / kg V AB7 9 0.06 mg / kg AB7 9 0.1 mg / kg * AB7 9 0.3 mg / kg AB7 9 0.6 mg / kg. Ig, immunoglobulin; IV, intravenous; SC, subcutaneous. RZfr? nn / nznz / E / YiAi Detailed description of the invention The present invention relates to methods of treating CD38-related diseases by subcutaneous administration of low doses (<600 mg) and low volumes (<3 mL) of anti-CD38 antibodies. AB79, daratumumab, isatuximab, and MOR202 are IgGl that kill tumors primarily through antibody-dependent cellular cytotoxicity (ADCC). This mechanism requires effector cells, such as NK cells, to bind to antibodies on target cells and form a lytic synapse to secrete cytotoxic agents in a targeted manner. The frequency of these effector cells in the blood is lower than that of RBCs and platelets by several orders of magnitude. For example, the ratio of RBC to NK cells in blood is 20,000:1. Furthermore, there are approximately 36 times more CD38 molecules expressed on RBC than on myeloma cells from patients with active disease. It has been postulated that the effector activity of daratumumab, isatuximab, and MOR202 is bypassed in tumors because effector cells are primarily bound by anti-CD38 antibodies bound to RBCs and platelets, thus preventing the formation of a lytic synapse with tumors, thus which results in low ADCC efficiency. In contrast, decreased or more transient RBC and platelet binding by AB79 compared to daratumumab RZfr? ηη / ηζηζ / Ε / γίΛΐ may allow effector cells to focus on the tumor, resulting in more efficient ADCC, higher tumoricidal activity, and lower effective dose. Treatment of patients with anti-CD38 antibodies that bind to RBCs and platelets can also cause life-threatening side effects. For example, treatment of RRMM with MOR202 resulted in several serious treatment-emergent adverse events (TEAEs) (see, eg, Raab et al. (2015) Blood 126:3035). The most common TEAEs at any grade were anemia (15 patients, 34%), fatigue (14 patients, 32%), infusion-related reactions (IRRs), and leukopenia (13 patients, 30% each), lymphopenia, and nausea. (11 patients, 25% in each case). TEAE grade >3 was reported in 28 patients (64%); the most common included lymphopenia (8 patients, 18%), leukopenia (5 patients, 11%), and hypertension (4 patients, 9%). IRRs arose mainly during the first infusion; all were grade 1-2 except in the case of one patient (grade 3). Infections were commonly reported (26 patients, 59%), but in most cases they were not considered to be related to treatment. MOR202 has only been used clinically by IV infusion. This is in contrast to the present invention, which allows for subcutaneous administration of AB79 at low doses and in low volumes, as described herein. RZfr? nn / nznz / E / YiAi Other Morphosys antibodies directed to CD38 are known (see, for example, WO 2006 / 125640, which discloses four human antibodies: MOR03077, MOR03079, MOR03080 and MOR03100 and two murine antibodies: OKT10 and IB4). These state of the art antibodies are inferior to AB79 for a variety of reasons. MOR03080 binds to human CD38 and Macaca fascicularis CD38 but with low affinity to human CD38 (Biacore KD=27.5 nm). OKT10 binds to human CD38 and Macaca fascicularis CD38 but with low / moderate affinity to human CD38 (Biacore KD= 8.28 nm). MOR03079 binds to human CD38 with high affinity (Biacore KD= 2.4 nm) but does not bind to Macaca fascicularis CD38. MOR03100 and MOR03077 bind to human CD38 with moderate or low affinity (Biacore KD=10 nm and 56 nm, respectively). In comparison, AB79 binds to human and Macaca fascicularis CD38 with high affinity (to human CD38 with Biacore KD=5.4 nm). In addition, prior art antibodies have poor ADCC and CDC activity. An advantage of more efficient ADCC is the ability to deliver an anti-CD38 therapeutic agent as a low volume injection. If AB7 9 is formulated at a concentration of 135 mg / mL, an effective dose for a 80 kg myeloma patient could be administered as a single SC injection of <2.5 mL. In contrast, the SC dose of daratumumab under evaluation in Ph3 clinical trials is 1800 mg suspended in a 15 mL coformulation of Enhance™ (Halozyme). The safety, tolerability, pharmacokinetics, and pharmacodynamics of IV and SC administered AB79 were initially characterized in monkeys. AB79 was administered as a single dose by IV bolus or SC injection to Macaca fascicularis in sterile saline (IV) or SC dilution solution at 0.03, 0.1 and 0.3 mg / kg (4 females / group). For the IV route, Cmax was approximately dose proportional to 0.03 to 0.3 mg / kg AB79, and AUC(O-t) was greater than dose proportional to 0.03 to 0.1 mg / kg AB79, but was approximately proportional to the dose of 0.1 to 0.3 mg / kg of AB79. For the SC route, Cmax and AUC(O-t) increased with dose, but AUC(O-t) increased more than dose-proportionally after SC dosing over the range of 0.03 to 0.3 mg / kg. The Ik / 2 was estimated to be between 120 and 144 hours. The mean bioavailability for the SC route was approximately 100% (120%, 73%, and 120% for 0.03, 0.1, and 0.3 mg / kg, respectively). Administration of AB7 9 at 0.03, 0.1 or 0.3 mg / kg by single intravenous or subcutaneous injection to female Macaca fascicularis was well tolerated. Anticipated pharmacological effects of mild to moderate decreases in lymphocytes (T cells, B cells) and dose-dependent decreases in NK cell populations were observed at all levels of RZfr? nn / nznz / E / YiAi dose and by both routes; the maximum cell-depleting effects after SC dosing were similar to, or slightly less than, those observed after IV dosing at the same dose level (Roepcke et al. (2018) Pharmacol Res. Perspect. 6(3) : e00402) . Based on the results of this study, the No Observed Adverse Effect Level (NOAEL) was considered to be 0.3 mg / kg for both IV and SC routes. Changes in lymphocytes and NK cells resolved after an AB79-free period of 56 days. The serum AUC and Cmax associated with the NOAEL were 574 h*pg / mL and 7.94 pg / mL for IV and 698 h*pg / mL and 2.15 pg / mL for SC, respectively. The safety, tolerability, pharmacokinetics, and pharmacodynamics of AB79 were then clinically characterized in a randomized, double-blind, placebo-controlled study of a single 1 mL intravenous (IV) infusion or subcutaneous (SC) injection in dose-escalating cohorts of human subjects. healthy. AB79 was well tolerated, all adverse events (AEs) were mild or moderate, and there were no withdrawals due to AEs or infusion reactions (Fedyk et al. (2018) Blood 132:3249). In higher dose cohorts, transient mild to moderate increases in cytokine levels coincided with decreases in cells expressing CD38; clinical symptoms mainly included RZfr? nn / nznz / E / YiAi pyrexia, headache and postural hypotension. No notable findings for laboratory tests, electrocardiograms, vital signs, or physical examinations related to AB79 treatment were reported. AB7 9 reduced plasmablast and natural killer (NK) cell levels at similar doses, with 50% of the maximum effective dose (ED50) of 0.003 mg / kg IV and 0.1 mg / kg SC. Reductions in total immunoglobulins (Ig) M and A occurred with no comparable changes in IgG. Total white blood cell, granulocyte, lymphocyte, red blood cell, and platelet counts were maintained within normal ranges for all dose levels. In summary, AB79 selectively reduced the level of plasmablasts and NK cells in peripheral blood of healthy subjects when administered IV or SC and was generally safe and well tolerated. This plasmacytolytic profile could be useful for treating disorders caused by NK or plasma cells, malignant counterparts (eg, multiple myeloma and NK cell leukemia), and pathogenic Ig or antibodies. AB79 can induce a therapeutic response (eg, disease remission) in Ig- or antibody-mediated diseases relatively quickly because it directly targets plasma cells, unlike treatments that target the B cell progenitors plasmatic (for example, anti-BAFF mAb (for RZfr? nn / nznz / E / YiAi eg belimumab), anti-CD20 mAb (eg rituximab) and BTK inhibitors (eg baricitinib)). These latter strategies indirectly target plasma cells, essentially eliminating de novo generation of plasma cells by inhibiting differentiation from predecessors. Pre-existing pools of plasma cells remain relatively undisturbed and continue to produce pathogenic Ig / antibodies throughout their lifespan. Thus, the lifespan of pre-existing plasma cells, some of which survive for decades, would drive a potential decline in pathogenic Ig / antibodies, which is why indirect strategies may exhibit slower onset of activity and efficacy than AB79. . The only other treatments that have been shown to reduce plasma cells directly are proteasome inhibitors (eg, bortezomib) and this class of agents is relatively poorly tolerated and includes dose-limiting adverse events (eg, neuropathy, diarrhea) that are attributed to inhibition of the proteasome in non-plasma cells (eg, neurons, epithelial cells) because the proteasome is ubiquitously expressed in these tissues. Thus, the specificity of AB79 for CD38, combined with the restricted expression profile of CD38, creates a mechanism of action that directly targets plasma cells, by RZfr? nn / nznz / E / YiAi while minimizing non-plasma cell effects and has the potential to provide rapid efficacy in diseases caused by plasma cells, transformed counterparts, and / or pathogenic Iq / antibodies. The unit doses and anti-CD38 methods of the disclosure provide, for the first time, subcutaneous administration of low volumes and therapeutically effective doses of anti-CD38 antibodies, providing unexpected benefits and avoiding the side effects, inconvenience and expense of administering treatments with systemic and high-dose anti-CD38 antibodies. The present invention provides methods and unit dose forms for the subcutaneous administration of a therapeutically effective amount of an isolated anti-CD38 antibody to a patient in need thereof to treat diseases in which CD38 binding is indicated, including hematologic cancers. . In some embodiments, the antibody for subcutaneous administration comprises a heavy chain variable region comprising SEQ ID NO:9 and a light chain variable region comprising SEQ ID NO:10. The anti-CD38 antibody provided herein is capable of being therapeutically effective when administered at unexpectedly low doses and, as such, can be administered in a surprisingly small volume, which RZfr? nn / nznz / E / YiAi facilitates subcutaneous administration. Another advantage of the anti-CD38 antibodies of the invention is that, unlike other anti-CD38 antibodies in the clinic, the anti-CD38 antibodies of the present invention (eg, AB79) can bind to CD38 from Macaca fascicularis (cyno ), providing a useful animal model for preclinical evaluation of dose tolerability, toxicity and efficacy, etc. Another advantage of the anti-CD38 antibodies of the invention is that they can be used to screen for other antibodies that compete for binding to CD38 at the same epitope and that may be useful in the methods and unit doses of the invention. Another advantage of the anti-CD38 antibodies of the invention is that they can be used to screen for other antibodies with decreased or alternative (eg, more transient) binding to RBCs and / or platelets compared to daratumumab and that may be useful. in the methods and unit doses of the invention, for example, an antibody that competes for or binds to the same epitope as ΆΒ79. Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings ordinarily understood by persons skilled in the art. The meaning and scope of the terms should be made clear. However, if there is any RZfr? ηη / ηζηζ / Ε / γίΛΐ latent ambiguity, the definitions provided herein take precedence over any extrinsic or dictionary definitions. In addition, unless the context otherwise requires, singular terms shall include plural forms and plural terms shall include singular forms. The term or includes and / or unless otherwise indicated. Furthermore, the use of the term including, includes, including or included is not limiting. Terms such as element or component encompass both elements and components that comprise a unit and elements and components that comprise more than one subunit, unless specifically stated otherwise. The methods and techniques of the present invention are generally carried out in accordance with conventional methods known in the art and as described in various general and more specific references which are cited and discussed throughout the present description unless otherwise indicated. otherwise. The nomenclatures used in connection with, and laboratory procedures and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, protein and nucleic acid chemistry and hybridization, analytical chemistry, synthetic organic chemistry, and medicinal chemistry and pharmaceuticals described herein are those known and commonly used in the art. Standard techniques are used for RZfr? nn / nznz / E / YiAi chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, administration and treatment of patients. Purification techniques and commercial enzymatic reactions are carried out according to the manufacturer's instructions, as commonly performed in the art or as described herein. All headings and section designations are used for clarity and reference only and are not to be construed as limiting in any way. For example, those skilled in the art will appreciate the utility of combining various aspects of the description of different headings and sections as appropriate in accordance with the spirit and scope of the invention described herein. Selected terms are defined below in order that the present invention may be more readily understood. The terms human CD38 and human CD38 antigen refer to the amino acid sequence of SEQ ID NO:1, or a functional fraction thereof, such as an epitope, as defined herein (Table 1). In general, CD38 possesses a short intracytoplasmic tail, a transmembrane domain, and an extracellular domain. The expressions Macaca fascicularis CD38 and Macaca fascicularis CD38 antigen refer to the amino acid sequence of SEQ ID NO:2, which is RZfr? nn / nznz / E / YiAi 92% identical to the human CD38 amino acid sequence (Table 1). Synonyms for CD38 include cyclic ADP ribose hydrolase; Cyclic ADP ribose hydrolase 1; ADP ribosyl cyclase; ADP-ribosyl cyclase 1; cADPr hydrolase 1; CD38-rsl; 1-19; NIM-R5 antigen; ADP-ribose transferase 2'phospho-cyclic; 2'-phospho-ADP-ribosyl cyclase; ADP-ribose transferase 2'-phospho-cyclic; 2'-phospho-ADP-ribosyl cyclase; and uncle . RZfr? nn / nznz / E / YiAi Table 1. Amino acid sequence of human CD38 and macaca fascicularis Especie Secuencia de aminoácidos 1234567890123456789012345678901234567890 SEC ID NO CD38 humana MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILWVLAV WPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRH VDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVP CNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLT WCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRF AEAACDWHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKV QTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCK NIYRPDKFLQCVKNPEDSSCTSEI 1 CD38 de Macaca fascicularis MANCEFSPVSGDKPCCRLSRRAQVCLGVCLLVLLILWW AWLPRWRQQWSGSGTTSRFPETVLARCVKYTEVHPEM RHVDCQSVWDAF KGAFISKYPC NI TEEDYQ PLVKLGTQTV PCNKTLLWSRIKDLAHQFTQVQRDMFTLEDMLLGYLADDL TWCGEFNTFEINYQSCPDWRKDCSNNPVSVFWKTVSRR FAETACGWHVMLNGSRSKIFDKNSTFGSVEVHNLQPEK VQALEAWVIHGGREDSRDLCQDPTIKELESIISKRNIRFFC KNIYRPDKFLQCVKNPEDSSCLSGI 2 CD157 humana MAAQGCAASRLLQLLLQLLLLLLLLAAGGARARWRGEGTS AHLRDIFLGRCAEYRALLSPEQRNKNCTAIWEAFKVALDK DPCSVLPSDYDLFINLSRHSIPRDKSLFWENSHLLVNSFAD NTRRFMPLSDVLYGRVADFLSWCRQKNDSGLDYQSCPT SEDCENNPVDSFWKRASIQYSKDSSGVIHVMLNGSEPTG AYPIKGFFADYEIPNLQKEKITRIEIWVMHEIGGPNVESCGE GSMKVLEKRLKDMGFQYSCINDYRPVKLLQCVDHSTHPD CALKSAAAATQRKAPSLYTEQRAGLIIPLFLVLASRTQL 13 The terms "therapeutically effective amount" and "therapeutically effective dose" refer to an amount of a treatment that is sufficient to reduce or ameliorate the severity and / or duration of a disorder or one or more symptoms thereof; prevent the progression of a disorder; cause the regression of a disorder; prevent the recurrence, development, onset, or progression of one or more symptoms associated with a disorder; or potentiate or enhance the prophylactic or therapeutic effects of another treatment (eg, therapeutic or prophylactic agent), at doses and for periods of time necessary to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the drugs to elicit a desired response in the individual. A therapeutically effective amount of an antibody is one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects. A therapeutically effective amount of an antibody for the treatment of a tumor can be measured based on its ability to stabilize the progression of the disease. The ability of a component to inhibit cancer can be assessed in an animal model system to predict efficacy in human cancer. The terms patient and subject include both humans and other animals. Therefore, the compositions, RZfr? nn / nznz / E / YiAi the doses and methods described herein are applicable to both human and veterinary treatment. In one embodiment, the patient is a mammal, eg, a human. The term "disease in which binding to CD38 is indicated" means a disease in which binding of a binding component (eg, an anti-CD38 antibody of the disclosure) to CD38 provides a prophylactic or curative effect, including the improvement of one or more symptoms of the disease. Such binding could result in blocking of other binding factors or components for CD38, neutralization of CD38, ADCC, CDC, complement activation, or some other mechanism by which disease is prevented or treated. Binding factors and components for CD38 include autoantibodies against CD38, which are blocked by the anti-CD38 antibodies of the invention. Such binding may be indicated as a consequence of CD38 expression by cells or a subset of cells, eg, MM cells, whereby providing a CD38-binding component to the subject results in deletion, eg, lysis, of those cells, for example, by hemolysis or apoptosis. Such CD38 expression may, for example, be normal, overexpressed, inappropriately expressed, or a consequence of CD38 activation, compared to normal cells or other cell types, either during a non-pathological state or a pathological state. The term hematologic cancer refers to malignant neoplasms of blood-forming tissues and encompasses leukemias, lymphomas, and multiple myelomas. Non-limiting examples of conditions associated with abnormal CD38 expression include, but are not limited to, multiple myeloma (MM) (Jackson et al. (1988) Clin. Exp. Immunol. 72: 351-356), including relapsed refractory MM (RRMM ) or newly diagnosed MM (NDMM); B-cell chronic lymphocytic leukemia (B-CLL) (Dürig et al. (2002) Leukemia 16: 30-35; Morabito et al. (2001) Leukemia Res. 25: 927-932; Marinov et al. (1993) Neoplasm 40(6): 355-358, and Jelinek et al (2001) Br. J. Haematol. 115: 854-861); acute lymphoblastic leukemia (Keyhani et al. (1999) Leukemia Res. 24: 153-159; and Marinov et al. (1993) Neoplasm 40(6): 355-358); chronic myeloid leukemia (Marinov et al. (1993) Neoplasm 40(6): 355-358); acute myeloid leukemia (Keyhani et al. (1999) Leukemia Res. 24:153-159); chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia or chronic myeloid leukemia (CML); acute myelogenous leukemia or acute myeloid leukemia (AML); acute lymphocytic leukemia (ALL); hairy cell leukemia (HCL); NK-cell / T-cell lymphoma, myelodysplastic syndromes (MDS) (Nurulhuda et al. (2017) Blood 130:2814); and all subtypes and stages (eg, blast phase (BP), chronic phase (CP), or accelerated phase (AP) of CML) of these leukemias and other hematologic diseases, which are defined by known morphologic, histochemical, and immunologic techniques. persons skilled in the art. The terms neoplasia and neoplastic condition refer to a condition associated with cell proliferation characterized by a loss of normal controls resulting in one or more symptoms including unregulated growth, failure to differentiate, dedifferentiate, local tissue invasion, and metastasis. . The term "isolated antibody" refers to an antibody that is substantially free of other antibodies that have different antigenic specificities. For example, an isolated antibody that specifically binds to CD38 is substantially free of antibodies that specifically bind to antigens other than CD38. However, an isolated antibody that specifically binds to an epitope, isoform or variant of human CD38 or Macaca fascicularis CD38 may cross-react with other related antigens, for example from other species, such as species homologues of CD38. In addition, an isolated antibody may be substantially free of other chemicals and / or RZfr? nn / nznz / E / YiAi cellular materials. The terms red blood cells, RBCs, and erythrocytes refer to the bone marrow-derived hemoglobin-containing blood cells that carry oxygen to cells and tissues and carry carbon dioxide back to the respiratory organs. RBCs are also called red blood cells, red corpuscles, red blood cells, and erythroid cells. The terms "specific binding", "binds specifically to" and "is specific for" in reference to the interaction of a particular antibody, protein or peptide with an antigen, epitope or other chemical species mean binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule, which is generally a similarly structured molecule that has no binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target. The anti-CD38 antibodies of the present invention specifically bind to CD38 ligands. The terms "bind specifically", "binds specifically to" and "is specific for" also mean that the interaction depends on the presence of a particular structure (eg, an antigenic determinant or epitope) in the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than proteins in general. If an antibody is specific for the A epitope, the presence of a molecule containing the A epitope (or untagged free A), in a reaction containing tagged A and the antibody, will reduce the amount of tagged A bound to the antibody. Specific binding for a particular antigen or epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about 10~4M, at least about 10-5 pf, and less than about ΙΟ-6M, at least around ΙΟ-7M, at least around ΙΟ-8M, at least around 10~9M, at least around ΙΟ-10M, at least around ΙΟ-11M, at least around ΙΟ- 12M or more, where KD refers to a rate of dissociation of a particular antibody-antigen interaction. Typically, an antibody that specifically binds to an antigen will have a KD that is 20, 50, 100, 500, 1000, 5000, 10,000 or more times greater for a control molecule relative to the antigen or epitope. Furthermore, specific binding to a particular antigen or epitope may be exhibited, for example, by an antibody that has a KA or Ka for an antigen or epitope of at least 20, 50, 100, 500, 1000, 5,000, 10,000 or more fold. greater for the epitope relative to a control, where KA or Ka refer to RZfr? nn / nznz / E / YiAi at a rate of association of a particular antibody-antibody interaction. The term "over a period of time" refers to any period of time, for example, minutes, hours, days, months, or years. For example, during a period of time you can mean at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 105 minutes, at least 120 minutes , at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours , at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least one day, at least two days, at least three days, at least 4 days, at least 5 days, at least 6 days , at least a week, at least a month, at least a year, or any time interval in between. In other words, the antibody in the composition can be absorbed by the individual to whom it is administered over a period of at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 105 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, RZfr? nn / nznz / E / YiAi at least 16 hours, at least 18 hours, at least 20 hours, at least s 22 hours, at least one day, at least two days, at least three days, at least 4 days, at least 5 < days, at least 6 days, at least a week, at least a month, at least one year or any time interval in between. A composition comprising "substantially one component" means that the composition contains more than about 80% by weight, in some modalities more than about 90% by weight, in some modalities more than about 95% by weight, in some embodiments more than about 97% by weight, in some embodiments more than about 98% by weight, in some embodiments more than about 99% by weight of the component. RZfr? nn / nznz / E / YiAi The expression around refers to a close extension in number, degree, volume, time, etc., with only small variations in dimension of up to 10%. The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle that is suitable for administering compounds of the present invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulation materials involved in transporting the compound in question from one organ or body part to another organ or body part. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. In one embodiment, the pharmaceutically acceptable carrier is suitable for intravenous administration. In one embodiment, the pharmaceutically acceptable carrier is suitable for locoregional injection. In one embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous administration. In one embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous injection. The term "pharmaceutical composition" refers to preparations suitable for administration to a subject and treatment of disease. When the anti-CD38 antibodies of the present invention are administered as pharmaceuticals to mammals, for example, humans, they may be administered as such or as a pharmaceutical composition containing the anti-CD38 antibody in combination with a carrier acceptable from the point of view of pharmaceutical and / or other excipients. The pharmaceutical composition may be in the form of a unit dosage form for administration of a particular dose of the anti-CD38 antibody at a particular concentration, a particular amount, or a particular volume. Pharmaceutical compositions comprising the anti-CD38 antibodies are provided, either alone or in combination with agents RZfr? nn / nznz / E / YiAi pharmaceutically acceptable prophylactics, therapeutic agents and / or carriers. In general, traditional antibody structural units comprise a tetramer. In general, each tetramer is made up of two identical pairs of polypeptide chains, each pair having a light chain (generally having a molecular weight of about 25 kDa) and a heavy chain (generally having a molecular weight of about 50-70 kDa). Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including but not limited to IgM1 and IgM2. Thus, isotype refers to any of the immunoglobulin subclasses defined by the chemical and antigenic characteristics of their constant regions. Known human immunoglobulin isotypes are IgG1, IgG2, IgG3, IgG4, IgAl, IgA2, IgM1, IgM2, IgD and IgE. Therapeutic antibodies may also comprise isotype and / or subclass hybrids. Each variable heavy (VH) and variable light (VL) region (about 100 to 110 amino acids long) is composed of three hypervariable regions called complementarity determining regions (CDRs) and four framework regions (FRs) (about 15-30 amino acids), arranged from amino-terminal to carboxy-terminal in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3FR4. Variable refers to the fact that the CDRs differ widely in sequence between antibodies and therefore determines a unique antigen binding site. The hypervariable region generally spans amino acid residues from about amino acid residues 24-34 (LCDR1; L indicates light chain), 50-56 (LCDR2), and 8997 (LCDR3) in the light chain variable region and about 31 -35B (HCDR1; H indicates heavy chain), 50-65 (HCDR2) and 95-102 (HCDR3) in the variable region of the heavy chain (Kabat et al., (1991) Sequences Of Proteins Of Immunological Interest, 5. aed. Public Health Service, National Institutes of Health, Bethesda, MD) and / or those residues that form a hypervariable loop (for example, residues 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3) in the light chain variable region and 26-32 (HCDR1), 53-55 (HCDR2) and 96-101 (HCDR3) in the heavy chain variable region (Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917). The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately, light chain variable region residues 1-107 and heavy chain variable region residues 1-113). (for example, Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest!, 5.aed. Public Health Service, National Institutes of Health, Bethesda, MD) , and the EU numbering system is used for the RZfr? nn / nznz / E / YiAi region Fe. The term "immunoglobulin (Ig) domain" refers to a region of an immunoglobulin that has a distinct tertiary structure. In addition to variable domains, each heavy and light chain has constant domains: constant heavy (CH) domains; constant light domains (CL) and hinge domains. In the context of IgG antibodies, each of the IgG isotypes has three CH regions. The carboxy-terminal portion of each HC and LC defines a constant region responsible primarily for effector function. Therefore, the CH domains in the context of IgG are as follows: CH1 refers to positions 118-220 according to the EU index according to Kabat. CH2 refers to positions 237-340 according to the EU index according to Kabat, and CH3 refers to positions 341-447 according to the EU index according to Kabat. Another type of heavy chain Ig domain is the hinge region. The term "hinge region" refers to the flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody. Structurally, the IgG CH1 domain ends at position 220 EU, and the IgG CH2 domain begins at position 237 EU of the residue. Therefore, for IgG, the antibody hinge is defined herein as including positions 221 (D221 in IgGl) to 236 (G236 in IgGl), where the numbering is according to the Kabat EU index. In some embodiments, for example in the context of an Fe region, the bottom hinge is included, where bottom hinge generally refers to positions 226 or 230. The term Fe region refers to the polypeptide that comprises the constant region of an antibody, not including the first immunoglobulin domain of the constant region and, in some cases, part of the hinge. Thus, Fe refers to the last two immunoglobulin domains of the constant region of IgA, IgD, and IgG, the last three immunoglobulin domains of the constant region of IgE and IgM, and the flexible hinge N-terminus of these. domains. For IgA and IgM, Fe may include the J chain. For IgG, the Fe domain comprises the immunoglobulin domains Cy2 and Cy3 (Cy2 and Cy3) and the lower hinge region between Cyl (Cyl) and Cy2 (Cy2). Although the boundaries of the Fe region may vary, the Fe region of the human IgG heavy chain is, in general, defined to include residues C226 or P230 at its carboxy-terminus, where numbering is according to the EU index according to Kabat. In some embodiments, as described in greater detail below, RZfr? nn / nznz / E / YiAi amino acid modifications in the Fe region, eg, to alter binding to one or more FcyR receptors or to the FcRn receptor. Antibodies against CD38 Accordingly, the present invention provides isolated anti-CD38 antibodies that specifically bind to human and primate CD38 protein and have decreased or less than 10%, less than 20%, less than 30%, less than 40% binding. , less than 50% to human RBCs compared to daratumumab and are therefore useful in subcutaneous delivery methods and unit dose forms. Of particular use in the present invention are antibodies that bind to both human and primate CD38 proteins, particularly from primates used in clinical trials, such as Macaca fascicularis (Crab-eating macaque, also referred to herein as cyno). In some embodiments, the anti-CD38 antibodies of the invention interact with CD38 at various amino acid residues including K121, F135, Q139, D141, M142, D202, V203, H205, Q236, E239, W241, S274, C275, K276, F284, C287, V288, K289, N290, P291, E292 and D293, the epitope of AB79. Any antibodies that interact with these residues also find use in the therapeutic methods and unit doses of the invention. In some embodiments, anti-CD38 antibodies from the RZfr? nn / nznz / E / YiAi invention interact with CD38 at several amino acid residues including K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292 and D293. It should be noted that these residues are identical in both humans and Macaca fascicularis, with the exception that S274 is in fact F274 in Macaca fascicularis. These residues may represent the immunodominant epitope and / or residues within the specific antigen-binding peptide space. In some embodiments, the anti-CD38 antibody comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 4; ID NO: 5; HCDR3 AB79). In some embodiments, the antibody comprises a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 AB79), RDS (SEQ ID NO:7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO:: 8; LCDR3 AB79). In some embodiments, the antibody comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO:3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), and a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 AB79), RDS (SEQ ID NO:7; LCDR2 AB79) and QSYDSSLSGS (SEQ ID NO:: 8;LCDR3 ΑΒ7 9) . In some embodiments, the antibody comprises a heavy chain comprising the variable heavy (VH) chain amino acid sequence of SEQ ID NO:9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYV DSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVS SASTKGPSVFPLA (SEQ ID NO:9). In some embodiments, the antibody comprises a light chain comprising the variable light chain (VL) amino acid sequence of SEQ ID NO:10. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPD RFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLF PPSSEEL (SEQ ID NO:10). In some embodiments, the antibody comprises a heavy chain comprising the VH chain amino acid sequence of SEQ ID NO:9 and a light chain comprising the VL chain amino acid sequence of SEQ ID NO:10. As will be appreciated by those skilled in the art, variable heavy and light chains can bind to human IgG constant domain sequences, generally IgG1, IgG2 or IgG4. In some embodiments, the antibody comprises the heavy chain (HC) amino acid sequence of SEQ ID NO:11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYV RZfr? nn / nznz / E / YiAi DSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEC ID NO:11). In some embodiments, the antibody comprises the light chain (LC) amino acid sequence of SEQ ID NO:12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPD RFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLF PPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLS LTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEC ID NO:12). In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO:11 and the LC amino acid sequence of SEQ ID NO:12. The present invention encompasses antibodies that bind to both human and Macaca fascicularis CD38 and interact with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98% or 99% of these amino acid residues. In some embodiments, the antibodies are full length. As used herein, "full-length antibody" means the structure constituting the natural biological form of an antibody, including variable and constant regions, including one or more modifications as described. RZfr? nn / nznz / E / YiAi described herein. Alternatively, antibodies can be a variety of structures, including, but not limited to, antibody fragments, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as antibody mimetics), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to herein as antibody conjugates), and fragments of each, respectively. Specific antibody fragments include, but are not limited to, (i) Fab fragment consisting of VL, VH, CL and CH1 domains, (ii) Fd fragment consisting of VH and CH1 domains, (iii) Fv fragment consisting of consists of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward et al. (1989) Nature 341: 544-546) consisting of a single variable, (v) isolated CDR regions, (vi) F(ab')2 fragments, a bivalent fragment that comprises two linked Fab fragments, (vii) single-chain Fv (scFv) molecules, where a VH domain and a VL domain are linked by a peptide linker that allows the two domains to associate to form an antigen-binding site (Bird et al. al (1988) Science 242: 423426, Huston et al (1988) Proc. Nati. Acad. Sci. USA 85: 5879-5883), (viii) bispecific single-chain Fv (WO 03 / 11161) and (ix) diabodies or triabody, fragments RZfr? nn / nznz / E / YiAi multivalent or multispecific constructed by gene fusion (Tomlinson et al. (2000) Methods Enzymol. 326: 461479; WO94 / 13804; Holliger et al. (1993) Proc. Nati. Acad. Sci. USA 90: 6444-6448). Antibody Modifications The present invention further provides variant anti-CD38 antibodies. That is, there are a number of modifications that can be made to the antibodies of the description, including, among others, amino acid modifications in the CDRs (affinity maturation), amino acid modifications in the Fe region, glycosylation variants, covalent modifications of other kinds, etc. The term "variant" means a polypeptide that differs from that of a parent polypeptide. Amino acid variants can include amino acid substitutions, insertions, and deletions. In general, variants can include any number of modifications, as long as the function of the protein is still present, as described herein. That is, in the case of amino acid variants generated with the CDRs of any AB79, for example, the antibody should still specifically bind to both human and Macaca fascicularis CD38 and not bind to RBCs or have decreased or less than 10% binding. , less than 20%, less than 30%, less than 40%, less than 50% to RBC compared to daratumumab. The term "Fe region variant" means an Fe sequence that differs from a wild-type or parental Fe sequence by at least one amino acid modification. Variant Fe may refer to the Fe polypeptide itself, compositions comprising the variant Fe polypeptide or amino acid sequence. If amino acid variants are generated with the Fc region, for example, the antibody variants must maintain the functions required for the particular application or indication of the antibody. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions can be used, eg, 1-10, 1-5, 1-4, 1-3, and 1- 2 substitutions. Suitable modifications may be made at one or more positions as generally described, for example, in US Pat. Nos. 6,086, 875; 6,737,056; 7,317,091; 7,670,600; 8,084,582; 8,188,231; 8,367,805; 8,937,158; and 9,040,041; all of which are expressly incorporated by reference in their entirety, and in particular for specific amino acid substitutions that increase binding to Fe receptors. It may be desirable to have 1-5 modifications in the F region of wild-type or engineered proteins, as well as 1-5 modifications in the Fv region, for example. A polypeptide sequence variant will preferably possess at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% RZfr? nn / nznz / E / YiAi of identity to parental sequences (eg, variable regions, constant regions, and / or heavy and light chain sequences for AB79). The term "amino acid substitution" means the replacement of an amino acid at a particular position in a parent polypeptide sequence with another amino acid. For example, the S100A substitution refers to a polypeptide variant in which the serine at position 100 is replaced with alanine. The term "amino acid insertion" means the addition of an amino acid at a particular position in a parent polypeptide sequence. The term "amino acid deletion" means the removal of an amino acid at a particular position in a parent polypeptide sequence. The terms parental antibody and precursor antibody mean an unmodified antibody that is subsequently modified to generate a variant. In one embodiment, the parental antibody herein is AB79. Parent antibody can refer to the polypeptide itself, to compositions comprising the parent antibody, or to the amino acid sequence encoding it. Accordingly, the term "parental Fe polypeptide" means an Fe polypeptide that is modified to generate a variant. The expressions wild type, WT and native RZfr? nn / nznz / E / YiAi mean a naturally occurring amino acid sequence or nucleotide sequence, including allelic variations. A protein, polypeptide, antibody, immunoglobulin, IgG, etc., WT has an amino acid sequence or nucleotide sequence that was not intentionally modified. In some embodiments, one or more amino acid modifications are made to one or more of the CDRs of the anti-CD38 antibody. In general, only 1, 2, or 3 amino acids are substituted in any single CDR, and generally no more than 4, 5, 6, 7, 8, 9, or 10 changes are made within a set of CDRs. However, it should be noted that any combination of no substitution, 1, 2 or 3 substitutions in any CDR can be independently and optionally combined with any other substitution. In some cases, amino acid modifications in CDRs are called affinity maturation. An affinity-matured antibody is one that has one or more alterations in one or more CDRs that result in an improvement in the affinity of the antibody for the antigen, compared to a parental antibody that does not possess those alterations. In some cases, it may be desirable to lower the affinity of an antibody for its antigen. Affinity maturation can be performed to increase the binding affinity of the antibody to the antigen. RZfr? ηη / ηζηζ / Ε / γίΛΐ by at least about 10% to 50%, 100%, 150% or more, or 1 to 5-fold compared to the parent antibody. Preferred affinity maturation antibodies will have nanomolar or even picomolar affinities for the target antigen. Affinity maturation antibodies are produced by known procedures (for example, Marks et al. (1992) Biotechnol. 10: 779-783; Barbas et al. (1994) Proc. Nat. Acad. Sci. USA 91: 3809-3813; Shier et al. to the. (1995) Gene 169: 147-155; Yelton et al. (1995) J. Immunol. 155: 1994-2004; Jackson et al., 1995, J. Immunol. 154(7):3310-9; and Hawkins et al. (1992) J. Mol. Biol. 226: 889-896). Alternatively, amino acid modifications can be made in one or more of the CDRs of the antibodies of the invention that are silent, eg, that do not significantly alter the affinity of the antibody for the antigen. These can be done for a number of reasons, including optimizing expression (as can be done in respect of nucleic acids encoding the antibodies of the invention) Therefore, variant CDRs and antibodies are included within the definition of CDRs and antibodies of the invention; that is, the antibodies of the invention may include amino acid modifications in one or more of the AB79 CDRs. In addition, as described below, the RZfr? nn / nznz / E / YiAi amino acid modifications can also be made independently and optionally in any region outside of the CDRs, including the framework and constant regions. In some embodiments, AB79 variant antibodies are described that are specific for human CD38 (SEQ ID NO:1) and Macaca fascicularis CD38 (SEQ ID NO:2). This antibody is composed of six CDRs, where each CDR of this antibody can differ from SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and / or SEQ ID NO:8 at 0, 1, 2 or more amino acid substitutions without significantly altering or inhibiting function. In addition to the modifications described above, other modifications can be made. For example, the molecules can be stabilized by the incorporation of disulfide bridges that link the VH and VL domains (Reiter et al. (1996), Nature Biotech, 14, 1239-1245). In addition, there are a variety of covalent modifications of antibodies that can be performed as described below. Covalent modifications of antibodies are included within the scope of this invention, and are generally, but not always, performed in a post-translational manner. For example, several types of covalent modifications of the antibody are introduced into the molecule by reacting amino acid residues RZfr? nn / nznz / E / YiAi specific to the antibody with an organic derivatizing agent that is capable of reacting with selected side chains or N- or C-terminal residues. In some embodiments, the anti-CD38 antibody of the present invention specifically binds to one or more residues or regions on CD38 but does not cross-react with other proteins with CD38 homology, such as BST-1 ( bone marrow stromal cell antigen 1) and Mo5, also called CD157. Lack of cross-reactivity generally means less than about 5% relative competitive inhibition between the molecules when assessed by ELISA and / or FACS analysis with sufficient amounts of the molecules under suitable assay conditions. Inhibition of CD38 activity and reduction of side effects The described antibodies can be used to block a ligand-receptor interaction or inhibit receptor component interaction. The anti-CD38 antibodies of the invention may be blocking or neutralizing. The term "neutralizing antibody" refers to an antibody whose binding to CD38 results in the inhibition of the biological activity of CD38, for example, its ability to interact with ligands, enzymatic activity, signaling ability, and in particular its ability to cause activated lymphocytes. Inhibition of biological activity RZfr? nn / nznz / E / YiAi of CD38 can be evaluated by one or more of several standard in vitro or in vivo assays known in the art. The terms "inhibits binding" and "blocks binding" (eg, when referring to inhibiting / blocking the binding of an antibody against CD38 to CD38) encompass both partial and complete inhibition / blocking. Inhibiting / blocking the binding of an anti-CD38 antibody to CD38 can reduce or alter the normal level or type of cell signaling that occurs when an anti-CD38 antibody binds to CD38 without inhibition or blockade. Inhibition and blocking are also intended to include any measurable decrease in the binding affinity of an anti-CD38 antibody to CD38 when contacted with an anti-CD38 antibody, compared to ligand not contacted with an anti-CD38 antibody. -CD38, for example, a blockage of binding of an antibody against CD38 to CD38 of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99 % or 100%. The described anti-CD38 antibodies can also inhibit cell growth. The term "inhibits growth" refers to any measurable decrease in cell growth when in contact with an anti-CD38 antibody, compared to the growth of the same cells not in contact with an anti-CD38 antibody, for example, a inhibition of the growth of a RZfr? nn / nznz / E / YiAi cell culture in at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99% or 100%. In some embodiments, the described anti-CD38 antibodies can decrease activated plasma cells and lymphocytes. The term "decrease" in this context means a measurable reduction in the serum levels of plasma cells and / or activated lymphocytes in a subject compared to untreated subjects. In general, decreases of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99% or 100% are observed. As shown in the Examples below, a particular advantage exhibited by the antibodies of the present invention is the ability to recover these cells after dosing; that is, as is known for some treatments (for example, with anti-CD20 antibodies), cell decline can last for long periods of time, leading to unwanted side effects. As shown herein, the effects on plasma cells and / or activated lymphocytes are recoverable. The anti-CD38 antibodies of the present invention allow for reduced side effects compared to anti-CD38 antibodies of the state of the art. In some modalities, AB7 9 does not induce TEAE. In some embodiments, AB7 9 allows for a reduction in TEAE compared to other anti-CD38 antibodies, such as MOR202. It is usually RZfr? nn / nznz / E / YiAi refers to TEAEs based on grades 1, 2, 3, and 5, where grade 1 is the least severe TEAE and grade is the most severe TEAE. Based on EDA guidelines and other guidelines regarding Common Terminology Criteria for Adverse Events (CTCAE) standards for oncology drugs (see, for example, https: / / evs.nci.nih.gov / ftpl / CTCAE / CTCAE 4.03 2010-0614 QuickReference 5x7.pdf, as well as https: / / ctep.cancer.gov / protocoIdevelopment / electronic_applications / ctc.htm, and Nilsson and Koke (2001) Drug Inform. J. 35: 1289-1299) , below is how those ratings are generally determined. Grade 1 is mild: no symptoms or mild symptoms; clinical or diagnostic observations only; no intervention indicated. Grade 2 is moderate: minimal, local or non-invasive intervention is indicated; limits age-appropriate core ADLs. Grade 3 is severe or medically significant, but not immediately life-threatening: hospitalization or prolongation of hospitalization is indicated; disabling; limits personal care ADLs. Grade 4 is a life-threatening consequence: urgent intervention is indicated. Grade 5 is death related to AE. In some modalities, AB79 allows a reduction in the degree of TEAEs compared to other anti- CD38, such as MOR202. In some embodiments, AB79 allows a reduction in the grade of TEAEs compared to other anti-CD38 antibodies from grade 5 to grade 4. In some embodiments, AB7 9 allows a reduction in the grade of TEAEs compared to other anti-CD38 antibodies. -CD38 from grade 4 to grade 3. In some modalities, AB79 allows a reduction in the degree of TEAEs compared to other anti-CD38 antibodies from grade 3 to grade 2. In some modalities, AB79 allows a reduction in the degree of TEAEs compared to other anti-CD38 antibodies from grade 2 to grade 1. In some modalities, AB79 allows for a reduction in grade of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion related reactions (IRRs), leukopenia, lymphopenia, and nausea. In some modalities, AB79 allows a reduction in the occurrence of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion related reactions (IRRs), leukopenia, lymphopenia, and nausea. In some embodiments, a diagnostic test is used to determine the presence and / or degree of anemia, including hemolytic anemia. Diagnostic tests for anemia, including hemolytic anemia, including measuring the level of RZfr? nn / nznz / E / YiAi hemoglobin. In general, hemoglobin levels are interpreted as follows: (i) very mild / absent anemia: ^12.0 g / dL, (ii) mild: 10-12 g / dL, (iii) moderate: 8-10 g / dL, (iv) severe: 6-8 g / dL, and (v) very severe: 56 g / dL. Other diagnostic tests for anemia, including hemolytic anemia, include measuring the haptoglobin level. In general, a haptoglobin level of 525 mg / dL indicates the presence of anemia, including hemolytic anemia. Other diagnostic tests include the direct antiglobulin test (DAT) (also known as the direct Coombs test), which is used to determine whether RBCs have been coated in vivo with immunoglobulin, complement, or both. In some modalities, a diagnostic test is used to determine the presence and / or degree of thrombocytopenia. In general, diagnostic testing for thrombocytopenia includes measuring the number of platelets per microliter (pL) of blood. Normally, there are 150 χ 1 03- 450 χ 103 platelets per pL of blood. In general, thrombocytopenia is diagnosed when there are <150 χ 103 platelets per pL of blood. In general, mild thrombocytopenia is diagnosed if there are 70-150 χ 103 per pL of blood. In general, moderate thrombocytopenia is diagnosed if there are 20-70 χ 103 per pL. In general, severe thrombocytopenia is diagnosed if there is <20 χ 103 per pL of blood. indications of disease The antibodies, methods, and dosage units of the invention find use in a variety of applications, including the treatment or amelioration of CD38-related diseases. CD38 is expressed on immature hematopoietic cells, is down-regulated on mature cells, and is re-expressed at high levels on plasma cells and activated lymphocytes. For example, high expression of CD38 is observed on activated B cells, plasma cells, activated CD4+ T cells, activated CD8+ T cells, NK cells, NKT cells, mature dendritic cells (DC), and activated monocytes. Certain conditions are associated with cells expressing CD38, and certain conditions are associated with overexpression, high-density expression, or upregulated expression of CD38 on cell surfaces. Whether or not a cell population expresses CD38 can be determined by methods known in the art, for example, flow cytometric determination of the percentage of cells in a given population that are labeled with an antibody that specifically binds to CD38 or immunohistochemical assays. , as generally described below for diagnostic applications. For example, a cell population in which CD38 expression is detected on about 10-30% of the cells can be considered to have weak CD38 positivity; and it's possible RZfr? nn / nznz / E / YiAi consider that a population of cells in which CD38 expression is detected on more than about 30% of the cells is definitively CD38 positive (as in Jackson et al. (1988) Clin. Exp Immunol 72: 351-356), although other criteria can be used to determine if a population of cells expresses CD38. Expression density on the surface of cells can be determined by methods known in the art, such as, for example, flow cytometric measurement of the mean fluorescence intensity of cells that have been fluorescently labeled using antibodies. that specifically bind to CD38. The therapeutic anti-CD38 antibodies of the present invention bind to CD38-positive cells, resulting in the depletion of these cells through multiple mechanisms of action, including the CDC and ADCC pathways. It is known in the art that certain conditions are associated with cells expressing CD38, and that certain conditions are associated with overexpression, high-density expression, or upregulated expression of CD38 on cell surfaces. Whether or not a cell population expresses CD38 can be determined by methods known in the art, for example, flow cytometric determination of the percentage of RZfr? nn / nznz / E / YiAi cells in a given population that are labeled with an antibody that specifically binds to CD38 or immunohistochemical assays, as generally described below for diagnostic applications. For example, a cell population in which CD38 expression is detected on about 10-30% of the cells can be considered to have weak CD38 positivity; and a population of cells in which CD38 expression is detected on more than about 30% of the cells can be considered to have definite CD38 positivity (Jackson et al. (1988) Clin. Exp. Iimnunol. 72: 351 -356), although other criteria can be used to determine if a cell population expresses CD38. Expression density on cell surfaces can be determined by methods known in the art, such as, for example, flow cytometric measurement of the mean fluorescence intensity of cells that have been fluorescently labeled using antibodies. that specifically bind to CD38. In one aspect, the invention provides methods of treating a condition associated with the proliferation of CD38-expressing cells, comprising administering to a patient a pharmaceutically effective amount of a disclosed antibody. In some modalities, the condition is cancer, and, in particular modalities, the cancer is a cancer. RZfr? nn / nznz / E / YiAi haematological. In some modalities, the condition is multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia and plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, or lymphoma of Burkitt. In some modalities, the condition is multiple myeloma and the therapeutic anti-CD38 antibody does not bind or has less binding to human RBCs compared to daratumumab. In some modalities, the condition is multiple myeloma and the therapeutic anti-CD38 antibody does not bind or has less binding to Macaca fascicularis RBCs compared to daratumumab. In some embodiments, the condition is multiple myeloma and the therapeutic anti-CD38 antibody does not bind or has less binding to human or Macaca fascicularis RBCs. CLL is the most common adult leukemia in the Western world. CLL involves clonal expansion of mature-appearing lymphocytes involving lymph nodes and other lymphoid tissues with progressive infiltration of the bone marrow and presence in the peripheral blood. The B-lymphocyte form (B-CLL) accounts for the majority of cases. B-lymphocyte form of chronic lymphocytic leukemia (B-CLL) B-CLL is an incurable disease characterized by a RZfr? ηη / ηζηζ / Ε / γίΛΐ progressive increase in anergic monoclonal B-lineage lymphocytes that accumulate in bone marrow and peripheral blood on a prolonged basis over many years. CD38 expression is considered a poor independent prognostic factor for B-CLL (Hamblin et al. (2002) Blood 99: 1023-9). B-CLL is characterized by two subtypes, indolent and aggressive. These clinical phenotypes correlate with the presence or absence of somatic mutations in the immunoglobulin heavy chain variable region (IgVH) gene. As used herein, indolent B-CLL refers to a disorder in a subject who has a mutated IgVH gene and / or who exhibits one or more clinical phenotypes associated with indolent B-CLL. As used herein, the phrase "aggressive B-CLL" refers to a disorder in a subject who has a wild-type IgVH gene and / or who exhibits one or more clinical phenotypes associated with aggressive B-CLL. The current standard of care for B-CLL is palliative and is carried out mainly with the cytostatic agent chlorambucil or fludarabine. When recurrences occur, co-treatment with fludarabine, cyclophosphamide in combination with rituximab (CD20 monoclonal antibody) or alemtuzumab (CD52 monoclonal antibody) is often initiated. In one study, thirty-five patients with relapsed or refractory aggressive B-cell NHL underwent high-dose chemotherapy. (HCT) followed by rituximab 375 mg / m2 weekly for 4 doses beginning on day 40, which was repeated for four more doses beginning on day 180. Rituximab infusions were well tolerated with only one infusion-related toxicity grade 3 / 4. The unexpected adverse event observed in this trial was late-onset neutropenia in more than half of the patients (19 / 35 patients with 46 episodes of grade 3 or 4 neutropenia; Kosmas et al. (2002) Leukemia 16: 2004-2015, which can be found online at https: / / www.nature.com / articles / 2402639). In another study, six patients received alemtuzumab by intravenous infusion every other day three times a week for 12 weeks. The dose was gradually increased daily (3, 10, and then 30 mg) until tolerated by the patient. The main TEAEs were anemia, neutropenia (6 / 6 patients in each case) and thrombocytopenia (5 / 6 patients) in haematological adverse events (Ishizawa et al. (2017) Jpn. J. Clin. Oncol. 47(1) : 54 -60) . Therefore, there is a fundamental unmet medical need for treatment of B-CLL with fewer haematological adverse events. In some embodiments, methods of treating B-CLL with the described anti-CD38 antibodies are provided and, as described below, this can be accomplished with concomitant treatments that optionally and independently include any of the drugs RZfr? previous ηη / ηζηζ / Ε / γΐΛ. Multiple Myeloma (MM) Multiple myeloma is a malignant disorder of the B lymphocyte lineage characterized by neoplastic proliferation of plasma cells in bone marrow and / or extramedullary sites. The proliferation of myeloma cells produces a variety of effects, including bone lytic lesions (holes), organ damage, anemia (decreased number of red blood cells), abnormal protein production (accompanied by damage to the kidneys, nerves and other organs), reduced immune system function, kidney failure and high levels of calcium in the blood (hypercalcaemia). Currently, treatment options include chemotherapy, preferably associated when possible with autologous stem cell transplantation (ASCT). These treatment regimens exhibit moderate response rates. However, only marginal changes in overall survival are seen, and the median survival is approximately 3 years. Therefore, there is a fundamental unmet medical need for treatment of multiple myeloma. In some embodiments, methods of treating multiple myeloma with the described antibodies are provided. Newly diagnosed MM (NDMM) is distinguished from relapsed MM or relapsed and resistant MM (RRMM). the MM RZfr? Relapsed nn / nznz / E / YiAi is considered a recurrence of disease after a prior response, and has been defined based on objective laboratory and radiological criteria: >25% increase in serum monoclonal protein (M protein) or urine or a >25% difference between implicated and uninvolved serum free light chains from their nadir, respectively, or the development of new plasmacytomas or hypercalcemia. In patients with nonsecretory disease, recurrence is defined as an increase in bone marrow plasma cells. In general, an indication for treatment of recurrence has been defined as the appearance or recurrence of one or more symptoms of MM described above or a rapid and constant biochemical recurrence. Relapsed / Refractory MM (RRMM) is defined as disease that becomes unresponsive or progressive on therapy or within 60 days of the last treatment in patients who had achieved a minimal response (MR) or greater on prior treatment. (Sonneveld and Broijl (2016) Haematologica 101(4):396-406). Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic premalignant disorders characterized by the proliferation of monoclonal plasma cells in the bone marrow and RZfr? nn / nznz / E / YiAi no damage to end organs. Smoldering multiple myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells with a high risk of progression to symptomatic or active multiple myeloma (Kyle et al. (2007) N. Engl. J. Med. 356(25) : 25822590 ) . International consensus criteria defining MMS were adopted in 2003, and these require that a patient have an M protein level >30 g / L and / or bone marrow clonal plasma cells >10% (Internat. Myeloma Working Group (2003 ) Br. J. Haematol. 121: 749-757). Patients must not have related organ or tissue impairment, such as skeletal lesions or symptoms. Recent studies have identified two subsets of SMM: i) patients with progressive disease and ii) patients with non-progressive disease (Internat. Myeloma Working Group (2003) Br. J. Haematol. 121: 749-757). SMM resembles monoclonal gammopathy of undetermined significance (MGUS) in that there is no end-organ damage (Kyle et al. (2007) N. Engl. J. Med. 356(25): 2582-2590). However, in clinical terms, SMM is much more likely to progress to active multiple myeloma or amyloidosis by 20 years (78% probability for SMM compared to 21% for MGUS) (Kyle et al. (2007) N. Engl. J. Med. 356(25): 2582-2590). The international consensus criteria that define the RZfr? nn / nznz / E / YiAi MGUS require that a patient have an M protein level <30 g / L, bone marrow plasma cells <10%, and no related organ or tissue impairment, including bone lesions or symptoms (Internat. Myeloma Working Group (2003) Br J. Haematol. 121: 749-757). CD38-related conditions The antibodies, methods, and dosage units of the invention find use in a variety of applications, including the treatment or amelioration of CD38-related diseases, such as inflammation-associated diseases and conditions, and immune diseases, particularly diseases associated with activated lymphocytes. The anti-CD38 antibodies of the present invention bind to CD38-positive cells, resulting in the depletion of these cells, such as activated lymphocytes, through multiple mechanisms of action, including the CDC and ADCC pathways. Therefore, any autoimmune disease showing increased expression of CD38 or an increased number of cells expressing CD38 as a component of the disease can be treated with the antibodies of the invention. These include, but are not limited to, allogeneic islet graft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, cytoplasmic autoantibodies RZfr? nn / nznz / E / YiAi antineutrophils (ANCA), autoimmune adrenal gland diseases, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, autoimmune urticaria, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman syndrome, spruce-related celiac dermatitis, chronic fatigue syndrome and immune dysfunction, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, mixed essential cryoglobulinemia, factor VIII deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré, Goodpasture syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, idiopathic pulmonary fibrosis , purple Idiopathic thrombocytopenia (ITP), IgA neuropathy, IgM polyneuropathies, immune-mediated thrombocytopenia, juvenile arthritis, Kawasaki disease, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 diabetes mellitus, myasthenia severe, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, and RZfr? nn / nznz / E / YiAi dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjógren's syndrome, solid organ transplant rejection, male syndrome rigid, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uveitis, vasculitis such as dermatitis herpetiformis, vitiligo, and Wegener's granulomatosis. Of particular use in some embodiments is the use of the present antibodies in the diagnosis and / or treatment of a number of diseases, including, but not limited to, autoimmune diseases, including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis, and graft-versus-host disease. Thus, by way of example, patients with high plasma cell counts may be treated, such as SLE patients who exhibit high plasma cell counts, as well as RA patients who do not respond to plasma-based treatments. CD20. Antibody compositions for administration in vivo The formulations of the antibodies used in accordance with the present invention are prepared for storage. RZfr? nn / nznz / E / YiAi by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences, 16th Edition (1980) Osol, A. Ed.), in the form of aqueous solutions or lyophilized formulations. The formulations herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide antibodies with other specificities. Alternatively or additionally, the composition may comprise a cytotoxic agent, cytokine, growth inhibitory agent and / or small molecule antagonist. Such molecules are suitably present together in amounts that are effective for their intended purpose. subcutaneous administration The present invention is based on the unexpected discovery that the anti-CD38 antibodies described herein, such as AB79, can be administered at sufficiently low doses that they are therapeutically effective, allowing subcutaneous administration of low volumes of liquid formulations. Subcutaneous administration is a minimally invasive mode of administration and is considered the most versatile and therefore most RZfr? nn / nznz / E / YiAi desirable that can be used for short-term and long-term treatments. In some embodiments, subcutaneous administration can be accomplished by injection. In some modalities, the injection site or device can be rotated when multiple injections or devices are needed. Consequently, subcutaneous formulations are much easier for a patient to administer to himself, especially since the patient may need to take the formulation regularly throughout his life (for example, even from the first year onwards). child's life). In addition, the ease and speed of subcutaneous administration allows for greater patient compliance and faster access to medication when needed. Therefore, the subcutaneous formulations of the anti-CD38 antibodies provided herein provide substantial benefit compared to the prior art and address certain unmet needs. In some embodiments, the antibodies of the invention are administered to a subject in accordance with known methods via a subcutaneous route. In some embodiments, the antibodies of the present invention can be administered by subcutaneous injection. In specific embodiments, the subcutaneous formulation is injected subcutaneously into the same site of a patient (for example, it is administered in the RZfr? nn / nznz / E / YiAi upper arm, anterior thigh, lower abdomen, or upper back) for repeated or continuous injections. In other embodiments, the subcutaneous formulation is injected subcutaneously at a different or rotating site on a patient. Single or multiple administrations of the formulations may be employed. In some embodiments, the subcutaneous unit dose forms described herein can be used for the treatment of cancer. In some embodiments, the subcutaneous unit dose forms described herein can be used for the treatment of a hematologic cancer. In some embodiments, the subcutaneous unit dose forms described herein can be used for the treatment of multiple myeloma. In some embodiments, antibodies of the invention that transiently bind to human RBCs have increased bioavailability. In some embodiments, the bioavailability of the antibodies of the present invention that bind to RBCs is transiently increased by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100 % or more. In some embodiments, the bioavailability of the antibodies of the present invention that transiently bind to human RBCs is 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%. , 200%, 250%, 300% or more. RZfr? ηη / ηζηζ / Ε / γίΛΐ In some modalities, increased bioavailability allows subcutaneous administration. In some embodiments, the increased bioavailability is due to the fact that the antibodies of the invention bind to RBC transiently. In some embodiments, the increased human bioavailability is due to the fact that the antibodies of the invention bind to human RBCs differently. In some embodiments, the antibodies of the invention lead to a decrease in NK cells, B lymphocytes, and / or T lymphocytes. In some embodiments, the antibodies of the invention allow a greater decrease in NK cells compared to the decrease in of B lymphocytes or T lymphocytes. In some embodiments, the antibodies of the invention allow a greater depletion of NK cells compared to B lymphocytes, as well as a greater depletion of NK cells compared to T lymphocytes. In some embodiments, the antibodies of the invention allow for a greater decrease in NK cells compared to B lymphocytes, as well as a greater decrease in B lymphocytes compared to T lymphocytes. In some embodiments, the antibodies of the invention allow a greater decrease in NK cells compared to B cells and a greater decrease in B cells compared to T cells. RZfr? nn / nznz / E / YiAi 100 In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 50% and at least 80% compared to standard intravenous administration for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 60% and at least 80% compared to standard intravenous administration for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 50% and 70% compared to standard intravenous administration for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 55% and 65% compared to standard intravenous administration for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 55% and 70% compared to standard intravenous administration for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after RZfr? nn / nznz / E / YiAi 101 subcutaneous administration is at least 40%, at least 45%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, or at least 85% compared to intravenous administration normalized for the same dose. In some embodiments, the present disclosure provides a method wherein the bioavailability of antibodies of the invention that transiently bind to human RBCs after subcutaneous administration is 50%-80% as compared to standard intravenous administration for same dose. In some embodiments, the present disclosure provides a method wherein the bioavailability of antibodies of the invention that transiently bind to human RBCs after subcutaneous administration is at least 50% compared to standard intravenous administration for the same. dose. In some embodiments, the present disclosure provides a method wherein the bioavailability of the RZfr? nn / nznz / E / YiAi 102 antibodies of the invention transiently binding to human RBCs after subcutaneous administration is at least 55% compared to standard intravenous administration for the same dose. In some embodiments, the present disclosure provides a method wherein the bioavailability of antibodies of the invention that transiently bind to human RBCs after subcutaneous administration is at least 60% compared to standard intravenous administration for the same. dose. In some embodiments, the present disclosure provides a method wherein the bioavailability of antibodies of the invention that transiently bind to human RBCs after subcutaneous administration is at least 65% compared to standard intravenous administration for the same. dose. In some embodiments, the present disclosure provides a method wherein the bioavailability of antibodies of the invention that transiently bind to human RBCs after subcutaneous administration is at least 70% compared to standard intravenous administration for the same. dose. In some embodiments, the present disclosure provides a method wherein the bioavailability of antibodies of the invention that bind to human RBCs of RZfr? nn / nznz / E / YiAi 103 transient manner after subcutaneous administration is at least 75% compared to standardized intravenous administration for the same dose. In some embodiments, the present disclosure provides a method wherein the bioavailability of antibodies of the invention that transiently bind to human RBCs after subcutaneous administration is at least 80% as compared to standard intravenous administration for the same. dose. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously in a single bolus injection. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously on a monthly basis. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously once every three weeks. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously every two weeks. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously on a weekly basis. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously twice weekly. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously daily. In certain modalities, the RZfr? nn / nznz / E / YiAi 104 anti-CD38 antibodies described herein are administered subcutaneously every 12 hours. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously every 8 hours. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously every six hours. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously every four hours. In certain embodiments, the anti-CD38 antibodies described herein are administered subcutaneously every two hours. In some embodiments, subcutaneous unit dose forms are administered at a dose of about 0.01 mg per kilogram of body weight to about 0.8 milligrams per kilogram of body weight. In some embodiments, subcutaneous unit dose forms comprise an amount sufficient to administer a dose from about 0.02 mg per kilogram of body weight to about 0.75 milligrams per kilogram of body weight. In some embodiments, subcutaneous unit dose forms comprise an amount sufficient to administer a dose from about 0.02 mg per kilogram of body weight to about 0.7 milligrams per kilogram of body weight. In some embodiments, subcutaneous unit dose forms comprise an amount sufficient to deliver a dose from about 0.03 mg per kilogram of body weight to about 0.6 milligrams. RZfr? nn / nznz / E / YiAi 105 per kilogram of body weight. In some embodiments, the amount is formulated in a volume between about 0.25 milliliters (mL) and about 3.5 milliliters (mL). In some embodiments, the amount is formulated in a volume of between about 0.5 mL and about 3 mL. In some embodiments, the amount is formulated in a volume between about 0.5 mL and about 2.5 mL. In some embodiments, the amount is formulated in a volume of between about 0.5 mL and about 2 mL. In some embodiments, the amount is formulated in a volume of between about 1 mL and about 2 mL. In some embodiments, the amount is formulated in a volume between about 0.25 mL and about 1.25 mL. In some embodiments, the amount is formulated in a volume between about 0.5 mL and about 1.25 mL. In some embodiments, the amount is formulated in a volume between about 0.75 mL and about 1.25 mL. In some embodiments, the amount is formulated in a volume between about 0.75 mL and about 1 mL. In some embodiments, the amount is formulated in a volume between about 0.9 mL and about 1.5 mL. In some embodiments, the amount is formulated in a volume between about 0.9 mL and about 1.1 mL. In some embodiments, the amount is formulated in a volume between about 1 mL and about 1.0 mL. In some 106 modalities, the amount is formulated in a volume between about 0.95 mL and about 1.05 mL. In some embodiments, the amount is formulated in a volume of about 3.5 mL. In some embodiments, the amount is formulated in a volume of about 3 mL. In some embodiments, the amount is formulated in a volume of about 2.5 mL. In some embodiments, the amount is formulated in a volume of about 2 mL. In some embodiments, the amount is formulated in a volume of about 1.5 mL. In some embodiments, the amount is formulated in a volume of about 1 mL. In some embodiments, the amount is formulated in a volume of about 0.5 mL. In some embodiments, the amount is formulated in a volume of about 0.25 mL. Unit Dose Forms In some embodiments, the therapeutic anti-CD38 antibodies are formulated as part of a unit dose form. In some embodiments, the antibody comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO:3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO:: 5; HCDR3 AB79). In some embodiments, the antibody comprises a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 7; LCDR2 AB79). RZfr? nn / nznz / E / YiAi 107 ID NO:8; LCDR3AB79). In some embodiments, the antibody comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), and a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79) and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB7 9). In some embodiments, the antibody comprises a heavy chain comprising the variable heavy (VH) chain amino acid sequence of SEQ ID NO:9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYV DSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVS SASTKGPSVFPLA (SEQ ID NO:9). In some embodiments, the antibody comprises a light chain comprising the variable light chain (VL) amino acid sequence of SEQ ID NO:10. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPD RFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLF PPSSEEL (SEQ ID NO:10). In some embodiments, the antibody comprises a heavy chain comprising the VH chain amino acid sequence of SEQ ID NO:9 and a light chain comprising the VL chain amino acid sequence of SEQ ID NO:10. As those skilled in the art will appreciate, the RZfr? nn / nznz / E / YiAi Variable heavy and light chains can bind to human IgG constant domain sequences, usually IgG1, IgG2 or IgG4. In some embodiments, the antibody comprises the heavy chain (HC) amino acid sequence of SEQ ID NO:11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYV DSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS T YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEC ID NO:11). In some embodiments, the antibody comprises the light chain (LO) amino acid sequence of SEQ ID NO:12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPD RFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLF PPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLS LTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEC ID NO:12). In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO:11 and the LC amino acid sequence of SEQ ID NO:12. In some modalities, the formulation comprising the 109 anti-CD38 antibody is a unit dose form. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose from about 0.01 mg per kilogram of body weight to about 0.8 milligrams per kilogram of body weight. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose from about 0.02 mg per kilogram of body weight to about 0.75 milligrams per kilogram of body weight. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose from about 0.02 mg per kilogram of body weight to about 0.7 milligrams per kilogram of body weight. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dose from about 0.03 mg per kilogram of body weight to about 0.6 milligrams per kilogram of body weight. In some embodiments, the amount is formulated in a volume between about 0.25 milliliters (mL) and about 3.5 milliliters (mL). In some embodiments, the amount is formulated in a volume of between about 0.5 mL and about 3 mL. In some embodiments, the amount is formulated in a volume between about 0.5 mL and about 2.5 mL. In some embodiments, the amount is formulated in a volume between about 0.5 mL and 110 about 2 mL. In some embodiments, the amount is formulated in a volume of between about 1 mL and about 2 mL. In some embodiments, the amount is formulated in a volume between about 0.25 mL and about 1.25 mL. In some embodiments, the amount is formulated in a volume between about 0.5 mL and about 1.25 mL. In some embodiments, the amount is formulated in a volume between about 0.75 mL and about 1.25 mL. In some embodiments, the amount is formulated in a volume between about 0.75 mL and about 1 mL. In some embodiments, the amount is formulated in a volume between about 0.9 mL and about 1.5 mL. In some embodiments, the amount is formulated in a volume between about 0.9 mL and about 1.1 mL. In some embodiments, the amount is formulated in a volume between about 1 mL and about 1.1 mL. In some embodiments, the amount is formulated in a volume between about 0.95 mL and about 1.05 mL. In some embodiments, the amount is formulated in a volume of about 3.5 mL. In some embodiments, the amount is formulated in a volume of about 3 mL. In some embodiments, the amount is formulated in a volume of about 2.5 mL. In some embodiments, the amount is formulated in a volume of about 2 mL. In some embodiments, the quantity is formulated in a volume of 111 about 1.5 mL. In some embodiments, the amount is formulated in a volume of about 1 mL. In some embodiments, the amount is formulated in a volume of about 0.5 mL. In some embodiments, the amount is formulated in a volume of about 0.25 mL. In some embodiments, the anti-CD38 antibody unit dose forms provided herein may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents. Dosage regimens are adjusted to provide the optimal response desired (eg, a therapeutic response). For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be proportionally reduced or increased as dictated by the exigencies of the therapeutic situation. The compositions may be formulated in unit dose form for ease of administration and uniformity of dose. As used herein, unit dosage forms may refer, in some embodiments, to physically separate units useful as unit doses for subjects to be treated, each unit containing a predetermined amount of active compound, calculated to produce the therapeutic effect. desired in combination with the required pharmaceutical carrier. The description for unit dose forms of the RZfr? ηη / ηζηζ / Ε / γίΛΐ 112 The present invention is dictated by, and is directly dependent upon, (a) the unique characteristics of the active compound and the particular therapeutic effect it is desired to achieve, and (b) the limitations inherent in the art of compounding such active compound for the treatment of an individual. Effective doses and dosage regimens for the anti-CD38 antibodies used in the present invention depend on the type and severity of the disease or condition to be treated, and can be determined by persons skilled in the art. The dosage forms provided herein are based on subcutaneous administration which is achieved at least in part based on a decreased ability to bind or remain bound to RBCs compared to daratumumab. Without intending to be limited to any particular theory, such binding activity may be due to the transient nature of AB7 9 binding to RBC. In some embodiments, therapeutic antibodies bind to human RBCs transiently. In some embodiments, therapeutic anti-CD38 antibodies bind to Macaca fascicularis RBC transiently. In some embodiments, therapeutic anti-CD38 antibodies bind to human or Macaca fascicularis RBCs transiently. In some embodiments, therapeutic anti-CD38 antibodies bind to human and Macaca fascicularis RBCs transiently. RZfr? nn / nznz / E / YiAi 113 In one embodiment, the anti-CD38 antibody is administered RZfr? nn / nznz / E / YiAi by subcutaneous administration at a weekly dose of from about 0.01 to about 1 mg / kg, such as from about 0.02 to about 0.8 mg / kg. Such administration can be repeated, for example, 1 to 14 times, such as 3 to 5 times. An exemplary non-limiting range for a therapeutically effective amount of an anti-CD38 antibody used in the present invention is about 0.01-1 mg / kg, such as about 0.01-0.8 mg / kg, about 0.02-0.75 mg / kg, about 0.02-0.7 mg / kg or about 0.03-0.6 mg / kg. As non-limiting examples, the treatment according to the present invention can be provided as a daily dose of an antibody in an amount of about 0.01 to about 1 mg / kg, such as 0.009, 0.01, 0.03, 0.05, 0.07, 0.09 , 0.11, 0.13, 0.15, 0.17, 0.19, 0.21, 0.23, 0.25, 0.27, 0.29, 0.31, 0.33, 0.35, 0.37, 0.39, 0.41, 0.43,0.45, 0.47, 0.49, 0.51, 0.53, 0.55, 0.57, 0.59, 0.61, 0.63,0.65, 0.67, 0.69, 0.71, 0.72, 0.73, 0.75, 0.77, 0.79, 0.81,0.83, 0.85, 0.87, 0.89, 0.91, 0.93, 0.95, 0.97 or 0.99, 1.0, or 1.1 mg / kg, per day, on at least one of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39 or 40, or, alternatively, in at least one of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 114 16, 17, 18, 19, or 20 after the start of treatment, or any combination of these, by single or divided doses to be administered every 24, 18, 12, 8, 6, 4, or 2 hours, or any combination of these. In one embodiment, the anti-CD38 antibody is administered at a weekly dose of from about 0.01 to about 1 mg / kg, such as from about 0.02 to about 0.8 mg / kg. Such administration can be repeated, for example, 1 to 14 times, such as 3 to 5 times. Administration can be by continuous infusion over a period of 2 to 24 hours, such as 2 to 12 hours. Such a regimen can be repeated one or more times as necessary, for example, after 6 months or 12 months. The dose can be determined or adjusted by measuring the amount of the compound of the present invention in the blood after administration, for example, by taking a biological sample and using anti-idiotypic antibodies that target the antigen-binding region of the anti-CD38 antibody. . In a further embodiment, the anti-CD38 antibody is administered once a week for 2 to 12 weeks, such as for 3 to 10 weeks, such as for 4 to 8 weeks. In one embodiment, the anti-CD38 antibody is administered by maintenance treatment, such as, for example, once a week for a period of 6 months or more. RZfr? nn / nznz / E / YiAi 115 In one embodiment, the anti-CD38 antibody is administered by a regimen that includes an infusion of an anti-CD38 antibody followed by an infusion of a radioisotope-conjugated anti-CD38 antibody. The regimen can be repeated, for example, 7 to 9 days later. In some embodiments, the anti-CD38 antibody of the invention is used in combination with one or more additional therapeutic agents, eg, a chemotherapeutic agent. Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (eg, irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (eg, etoposide, teniposide, and daunorubicin); alkylating agents (eg, melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (eg, cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators, such as bleomycin; and nucleoside mimetics (eg, 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea). Chemotherapeutic agents that alter cell replication include: paclitaxel, docetaxel, and RZfr? nn / nznz / E / YiAi 116 related analogues; vincristine, vinblastine and related analogues; thalidomide, lenalidomide and related analogs (eg CC-5013 and CC-4047); protein tyrosine kinase inhibitors (eg, imatinib mesylate and gefitinib); proteasome inhibitors (eg, bortezomib); NF-κΒ inhibitors, including IkB kinase inhibitors; antibodies that bind to overexpressed, underexpressed, or activated proteins in cancers and thereby downregulate cell replication (eg, trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, overexpressed, misexpressed, or activated in cancers, which inhibition downregulates cell replication. In some embodiments, the antibodies of the invention may be used before, concurrently with, or after Velcade® (bortezomib) treatment. treatment modalities In the methods of the invention, the treatment is used to provide a positive therapeutic response in relation to a disease or condition. The term "positive therapeutic response" refers to an improvement in the disease or condition, and / or an improvement in symptoms. RZfr? nn / nznz / E / YiAi 117 associated with the disease or condition. For example, a positive therapeutic response would refer to one or more of the following improvements in disease: (1) a decrease in the number of neoplastic cells; (2) an increase in neoplastic cell death; (3) inhibition of neoplastic cell survival; (5) inhibition (ie, slowing to some extent, preferably stopping) of tumor growth; (6) an increased survival rate of patients; and (7) relief to some extent of one or more symptoms associated with the disease or condition. Positive therapeutic responses in any given disease or condition can be determined using standardized response criteria specific to that disease or condition. Tumor response can be assessed to identify changes in tumor morphology (ie, overall tumor burden, tumor size, and the like) by screening techniques, such as magnetic resonance imaging (MRI) scanning, x-ray imaging, computed tomography (CT), bone scan imaging, endoscopy, and tumor biopsy specimens, including bone marrow aspiration (BMA) and circulating tumor cell counts. In addition to these positive therapeutic responses, the subject undergoing treatment may experience the beneficial effect of an improvement in symptoms associated with the RZfr? nn / nznz / E / YiAi 118 disease. In the case of B-lymphocyte tumors, the subject may experience a decrease in so-called B-symptoms, eg, night sweats, fever, weight loss, and / or hives. In the case of premalignant conditions, treatment with a therapeutic anti-CD38 antibody may block and / or prolong the time before the development of a related malignancy, for example, the development of multiple myeloma in subjects with monoclonal gammopathy of undetermined significance. (MGUS). An improvement in the disease can be characterized as a complete response. The term complete response refers to the absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow and cerebrospinal fluid (CSF), or abnormal monoclonal protein in the case of myeloma. Such a response may persist for at least 4-8 weeks, or at least 6-8 weeks, after treatment according to the methods of the invention. Alternatively, an improvement in the disease may be classified as a partial response. The term partial response refers to a decrease of at least about 50% in the entire measurable tumor burden (ie, the number of malignant cells present in the subject, or the measured volume of tumor masses, or the amount of abnormal monoclonal protein ) in the absence of new lesions, which may persist for RZfr? nn / nznz / E / YiAi 119 to 8 weeks, or 6 to 8 weeks. Treatment according to the present invention includes a therapeutically effective amount of the medicaments used. A "therapeutically effective amount" refers to an effective amount, in doses and for periods of time necessary, to achieve a desired therapeutic result. The terms "therapeutically effective amount" and "therapeutically effective dose" refer to an amount of a treatment that is sufficient to reduce or ameliorate the severity and / or duration of a disorder or one or more symptoms thereof; prevent the progression of a disorder; cause the regression of a disorder; prevent the recurrence, development, onset, or progression of one or more symptoms associated with a disorder; or potentiate or enhance the prophylactic or therapeutic effects of another treatment (eg, therapeutic or prophylactic agent), in doses and for periods of time necessary to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the drugs to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effect of the antibody or portion of RZfr? nn / nznz / E / YiAi 120 antibody is outweighed by the therapeutically beneficial effects. A therapeutically effective amount of an antibody for the treatment of a tumor can be measured based on its ability to stabilize the progression of the disease. The ability of a component to inhibit cancer can be assessed in an animal model system to predict efficacy in human tumors. Alternatively, this property of a composition can be assessed by examining the compound's ability to inhibit cell growth or induce apoptosis by in vitro assays known to those skilled in the art. A therapeutically effective amount of a therapeutic compound can decrease tumor size or otherwise ameliorate symptoms in a subject. One of the mid-level trade could determine such amounts based on factors such as the size of the subject, the severity of the subject's symptoms, and the particular composition or route of administration selected. Anti-CD38 Antibody Kits In another aspect of the invention, kits are provided for the treatment of a disease or condition associated with "hematological" cancers. In one embodiment, the kit comprises a dose of an anti-CD38 antibody described herein, such as AB79. In some embodiments, the kits provided herein may contain one or more doses RZfr? nn / nznz / E / YiAi 121 of a liquid or lyophilized formulation as provided herein. Where the kits comprise a lyophilized formulation of an anti-CD38 antibody described herein, such as AB79, the kits will generally also contain a suitable liquid for reconstitution of the liquid formulation, for example, sterile water or a buffer acceptable from the point of view of from a pharmaceutical point of view. In some embodiments, the kits may comprise an anti-CD38 antibody formulation described herein prepackaged in a syringe for subcutaneous administration by a healthcare professional or for home use. In certain embodiments, the kit will be for a single administration or dose of an anti-CD38 antibody described herein, such as AB7 9. In other embodiments, the kit may contain multiple doses of an anti-CD38 antibody described herein, such as AB79, for subcutaneous administration. In one embodiment, the kit may comprise an anti-CD38 antibody formulation described herein prepackaged in a syringe for subcutaneous administration by a healthcare professional or for home use. manufacturing items In other embodiments, an article of manufacture is provided that contains materials useful for the RZfr? nn / nznz / E / YiAi treatment of the disorders described above. He 122 article of manufacture comprises a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers can be formed from a variety of materials, such as glass or plastic. The container contains a composition that is effective in treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial that has a stopper that can be pierced with a hypodermic injection needle). . The active agent in the composition is the antibody. The label on, or associated with, the container indicates that the composition is used to treat the condition in question. The article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as phosphate buffered saline, Ringer's solution or dextrose solution. It may also include other commercially and user desirable materials, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. EXAMPLES Example 1: Characterization based on the anti-CD38 antibody model in Macaca fascicularis Anti-CD38 antibody AB79 binds to Macaca fascicularis CD38, distinguishing it from daratumumab RZfr? nn / nznz / E / YiAi 123 (Darzalex™), a monoclonal antibody against cytolytic CD38 recently approved for the treatment of multiple myeloma. This unique role supported the use of Macaca fascicularis for preclinical studies to characterize the pharmacokinetics (PK), pharmacodynamics (PD), and safety of AB7 9. To this end, assays were developed to measure immunogenicity and drug concentrations. , and to quantify T, B and NK lymphocytes in the blood of Macaca fascicularis. These parameters were evaluated in 8 preclinical pharmacological and toxicological studies. Regarding the cell populations tested, CD38 is more highly expressed on NK cells; therefore, it is assumed that the pharmacological effect on NK cells is closer to the effect on the considered target cells, plasmablasts, plasma cells and other activated lymphocytes. Data were pooled from 8 studies in healthy monkeys with a dose range of 0.03 - 100 mg / kg and mathematical models were developed describing the pharmacokinetics and exposure-effect relationship of each of the cell types. NK cell depletion was identified as the most sensitive pharmacodynamic effect of AB79. This decrease was described with a turnover model (EC50 = 34.8 pg / mL at the rate of decrease) and a complete decrease was achieved with an IV dose of 0.3 mg / kg. RZfr? ηη / ηζηζ / Ε / γίΛΐ 124 Intermediate effects were also seen on T cell counts using a direct response model (EC50 = 9.43 pg / mL) and on B cell counts using a 4-compartment transit model (EC50 = 19.3 pg / mL at rate of decrease) . These analyzes corroborated the observation that AB7 9 cleared each of the measured lymphocyte subsets at different rates and that each required different periods of time to decrease blood compartment. Mathematical models describing PK and PD data are useful tools for obtaining mechanistic and quantitative information about the relationships between drug exposure and drug effect (Friberg et al. (2002) J. Clin. Oncol. 20: 4713- 4721, Mager et al (2003) Drug Metab Dispos 31:510-518, Han and Zhou (2011) Ther Deliv 2:359-368). The typical PK characteristics of IgG antibodies, including distribution and clearance, physiological and genetic similarities between monkeys and humans, can be exploited to explain the pharmacology of AB79 (Glassman and Balthasar (2014) Cancer Biol. Med. 11:20-33;Kamath (2016) Drug Discov.Today Technol.21-22:75-83). Furthermore, those models have been successfully applied to predict PK concentrations and PD effects in healthy human subjects (Han and Zhou (2011) Ther. Deliv. 2:359-368). RZfr? nn / nznz / E / YiAi 125 Materials and methods A summary of the monkey studies is shown in Table 2 in chronological order. Single dose studies 2, 7 and 8 were performed primarily to assess the PK and PD of AB7 9 administered intravenously (IV) and subcutaneously (SC) (Figure 1). Repeat-dose studies were conducted to assess safety, PK, and PD, and include two 4-week studies (Studies 1 and 3) and three 13-week studies under GLP conditions (Studies 4, 5, and 6). In study 5 of 13 weeks, a dosing error occurred. Animals in the lower dose group received 0.01 mg / kg instead of the planned 0.1 mg / kg on one occasion (the second dose) and then continued with 0.1 mg / kg. These data were added to the data set with the correct reporting of the amounts of doses actually administered. Study 6 replicated the low dose of 0.1 mg / kg QW from Study Group 5. All animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals adopted and promulgated by the National Institutes of US Health RZfr? nn / nznz / E / YiAi Table 2. Studies of AB79 in monkeys in chronological order. RZfr? nn / nznz / E / YiAi Study No. Study Description Number of animals (female, male) Dose (mg / kg) Number of samples per animal (PK / PD) 1 Day 1 (1 mg / kg) + Day 28 (2 mg / kg) , IV, PK, PD 6 (0, 6) Foot, 1.2 10 / 19 2 Single dose, IV, PK, PD 9 (0, 9) foot, 0.3, 3 9 / 14 3 4 weeks of tox, one once a week, IV, PK, PD 12 (4, 8) ft, 1,30, 100 8 / 15 4 13 weeks of tox, q2wk, IV, PK, PD 40 (20, 20) ft, 3, 30, 80 47 / 29 5 13 weeks of tox, once a week, IV, PK, PD 52 (26, 26) foot, 0.1, 0.3, 1 9 / 31 6 13 weeks of tox, once a week, IV, PK , PD 20 (20, 0) ft, 0.1 10 / 31 7 Single dose, IV / SC, PK, PD 12(12, 0) 0.1, 0.3, 1 16 / 16 8 Single dose, IV / SC, PK, PD 24 (24, 0) 0.03, 0.1, 0.3 19 / 19 IV: 30 minute intravenous infusion (studies 1-4) or bolus (studies 5-8), SC: subcutaneous injection (study 7 arm 4 and study 8 arm 3), PK: dense PK sampling, PD: sampling whole blood for flow cytometric analysis producing cell count data for T and B lymphocytes and NK cells. foot - placebo, “4 weeks” or “13 weeks” describes the length of the treatment period, tox: toxicology study, q2wk: biweekly dose schedule. Bioanalysis PK was analyzed by a validated method developed and performed by Charles River Laboratories (Reno, NV). Briefly, the concentration of AB79 in monkey serum was measured with an indirect enzyme-linked immunosorbent assay (ELISA). A 96-well microtiter format was coated with an anti-idiotypic antibody against AB79. Blanks, standards, and quality control (QC) samples containing AB79 at various concentrations were added to the plate and incubated for 55-65 minutes at room temperature (RT). After washing the microtiter plate, peroxidase conjugated Affinipure anti-mouse anti-human IgG (Peroxidase AffiniPure Mouse Anti-Human IgG, Fcy Fragment Specific; Jackson ImmunoResearch) was added and incubated in the plate for 55-65 127 additional minutes. The plate was washed again, and tetramethylbenzidine (TMB) was added to the wells to generate a chromophore, and color development was stopped by adding stop solution (2N sulfuric acid). Absorbance at 450 nm was measured with a SPECTRAmax® 190 microplate reader (Molecular Devices) and AB7 9 concentrations were calculated using a 4-parameter logistic (1 / y2) weighted standard calibration curve. In study 1 (Table 2), the lower limit of quantification (LLOQ) for AB79 in serum was 0.061 pg / mL and in all other studies it was 0.05 pg / mL. Determination of anti-AB79 antibodies (immunogenicity) A screen of monkey serum for anti-drug antibodies (ADA) was analyzed with a validated, qualitative electrochemiluminescent (ECL) method, performed by Charles River Laboratories (Reno, NV). Briefly, undiluted serum samples were incubated with 300 mM acetic acid. Acid-dissociated samples were incubated in a mixture of biotinylated AB79, SULFO-TAG-tagged AB79 (Meso Scale Diagnostics, labeled at Charles River Laboratories), and 1.5 M Trizma base to neutralize the acid and form an immune complex. This complex was then added to a streptavidin-coated MSD plate (Meso Scale Diagnostics) and allowed to set. After washing, the complex was detected by adding the 128 MSD T (Meso Scale Diagnostics) read buffer to the plate and subsequent excitation of the SULFO-TAG™ through an electrochemical reaction of Ru(bpy)3 to generate luminescence (light), which was read with the MSD Sector 6000 (Meso Scale Diagnostics). The amount of luminescence was correlated with the level of monkey anti-AB79 antibodies present in the serum of individual samples. Characterization of blood cells To assess and compare the level of AB79 binding between humans and monkeys, blood samples from each were collected in sodium heparin tubes. An aliquot of blood (100 pL) was mixed with the appropriate volume of a characterizing antibody (Table 3) and incubated for 15-20 minutes at RT in the dark. After incubation, 1 mL of BD FACS lysate (IX; BD Biosciences; San Jose, CA) was added to lyse red blood cells and cells were incubated for 10 min at RT in the dark, then centrifuged, decanted, and they were resuspended in 1 mL of bovine serum albumin staining buffer (BD Biosciences). The cells were centrifuged a second time, decanted, and 250 pL of Flow Fix (1% paraformaldehyde in calcium and PBS) were measured. RZfr? Dulbecco's magnesium-free nn / nznz / E / YiAi (Life Technologies, Carlsbad, CA) ) and fluorescence by flow cytometry analysis with a FACSCanto™ II flow cytometer (BD 129 Biosciences). Monkey NK cells (CD3-, CD159a+), B lymphocytes (CD3-, CD20+) and T lymphocytes (CD3+) and NK cells (CD3-, CD16 / CD56+), B lymphocytes (CD3-, CD19+) and T lymphocytes were measured. (CD3+) humans. The mean fluorescence intensity for AB7 9 staining for each cell population was converted to Molecule Equivalent Soluble Fluorescence (MOEF) units using a standard curve generated with Rainbow Beads (Spherotech; Lake Forest, IL). RZfr? nn / nznz / E / YiAi Table 3. Antibodies used to characterize blood cells. Antibody Antibody volume per sample (pl_ / 100 pL sample) Supplier CD3-APCH7 (SK7)* 5 BD Biosciences CD3-APC Cy7 (SP34-2) 1.25 BD Biosciences CD3-PerCp Cy 5.5 (SP34-2) 5 BD Biosciences AB19- AF647 1 Prepared at Takeda AB79-AF488 2 Prepared at Takeda AB19- AF488 0.42 Prepared at Takeda CD19-PerCp Cy 5.5 (HIB19)* 5 BD Biosciences CD20-PE (2H7) 10 BD Biosciences CD20 -APCH7 (2H7) 2.5 BD Biosciences CD16-PE (B73.1)* 5 BD Biosciences CD16-PerCP-Cy5.5 (3G8) 20 BD Biosciences CD56-PE (B159)* 5 BD Biosciences CD159a-PE (Z199) 5 Beckman Coulter (Brea, CA) CD45-PerCP TruCount (DO58-1283) NA BD Biosciences CD45-PeCy7 (HI30)* 2.5 BD Biosciences CD45-PeCy7 (DO58-1283) 2.5 BD Biosciences mouse lgG1 kappa -AF488 or -AF647 (MOPC-21) 2.5 BioLegend ( San Diego, CA) *used only to stain human cells In the studies described in Table 2, cells were stained and analyzed by a validated method developed and performed by Charles River Laboratories (Reno, NV). HE 130 collected monkey blood samples in sodium heparin tubes before and on multiple occasions after AB79 treatment and specific lymphocyte populations were measured by flow cytometry analysis with a FACSCanto™ II flow cytometer (BD Biosciences). Commercial antibodies and an antibody against CD38 (AB19; Table 3; US Patent No. 8,362,211) were titrated to optimal concentrations for staining. Populations of monkey CD38+ / -, T-lymphocytes (CD3+), B-lymphocytes (CD3- / CD20+) and natural killer (NK) cells (CD3- / CD20- / CD16+) were identified and lymphocytes quantified with CD45TruCount™ tubes. (BD Biosciences). Aliquots of approximately 100 pL of each blood sample were placed in a suitable well of a 96-well plate and antibodies were added in the indicated volume, mixed, and incubated for a minimum of 30 minutes at RT in the dark. After incubation, red blood cells were used and samples were mixed and incubated at RT for an additional 10 minutes in the dark. The plate was centrifuged and the supernatant was decanted. The cell pellet was then resuspended in 1,800 pL of staining buffer, the samples mixed and centrifuged, and the supernatant decanted. The cell pellet was resuspended in 500 pL of fetal bovine serum staining buffer and approximately 300 pL of the suspension 131 cells were transferred to a 96-well V-bottom plate for analysis. Percentages of NK cells, as well as total T cells and B cells, were applied to cell count values ​​obtained with TruCount™ tubes (BD Biosciences; San Jose, CA) and used to determine absolute cell counts. for each cell population. In studies 1-4, subsets of CD38+ lymphocytes, NK cells, B lymphocytes, and T lymphocytes were assessed at baseline with the anti-CD38 antibodies labeled AB79 or AB19. Although AB19 binds to a different epitope, the results were very similar and are therefore not presented separately. The processed samples were immediately analyzed. Development of the PK model During the development of the PK model, one-, two-, and three-compartment model structures were investigated. The two-compartment model was clearly superior to the one-compartment model, as judged by goodness-of-fit (GOF) plots and a decrease in objective function value (OFV). Based on visual inspections of the diagnostic charts, it was not necessary to introduce a third compartment to adequately describe the data. Bioavailability (F) was modeled by logit transformation F=exp(PAR) / (1+exp(PAR)), where PAR designates the model parameter, to ensure that 132 estimates are constrained between 0 and 1. Nonlinear PK at low concentrations was modeled with the quasi-steady-state (QSS) approximation model of the target-mediated drug disposition (TMDD) process (Gibiansky and Gibiansky (2009) Expert Opin. Drug Metab. Toxicol. 5: 803-812). A schematic representation of the model is provided in Figure 2C. For the QSS approximation, it is assumed that the steady-state concentrations of free drug C, target R, and target drug complex RC establish very rapidly compared to all other processes. This implies that the fixation process is balanced by the dissociation and internalization processes and that the following equation holds in the appropriate units: KDts*C*R = (KDis + Kint) * RC, where KDis designates the rate constant of fixation, KDTS the dissociation rate constant, and Kint the internalization rate constant. Between-subject variability (BSV) was investigated for all parameters and modeled with exponential models of the following type: PARi = TVPAR * qEtapar^, where PARi is the individual, TVPAR is the typical parameter estimate, and STAGEi is the estimate of the deviation of the individual i. It was assumed that the values ​​of ETAPARi follow a normal distribution with mean zero. The residuals were described with a combined model of proportional and additive error (Beal and RZfr? nn / nznz / E / YiAi 133 Sheiner (1992) NONMEM User Guides, at the University of California, CA). The following parameters were investigated to identify potential covariate effects on AB79 PK: body weight, gender, dose, route of administration, and study. Development of the PK-PD model For each of the three cell types, the development of the PK-PD model was performed separately. It should be noted that measurements close to drug administration (<8 hours post-dose) were not used for model development because they were influenced by a non-specific drug-independent effect, potentially because multiple blood samples were taken over a short period of time. The PK model and parameter estimates were fixed. Turnover, transit compartment and direct response models were evaluated in various ways (Friberg et al. (2002) J. Clin. Oncol. 20: 4713-4721; Mager et al. (2003) Drug Metab. Dispos. 31: 510 -518). In the turnover models, the pharmacological effect was input into the cell clearance rate in the form of an Emax-like model with or without Hill factors. In the present exchange, an Emax model is a function f of the concentration of drug c as follows: f(c) =EMAX*cH / (cH+C50H), where EMAX denotes the maximum effect, C50 the concentration at which is achieved RZfr? nn / nznz / E / YiAi 134 half of the maximum effect and H the Hill factor. In the transit compartment model (TCM), the pharmacological effect was introduced and evaluated at different positions: on the proliferation rate, on circulating cells, and on the third transit compartment. Combinations of these effects and whether the data support the presence of a feedback mechanism from circulation to proliferation rate were also evaluated. In addition, Emax-type direct response models with and without Hill factors were evaluated to describe the drug concentration-effect curve. Random-effect parameters were introduced to estimate inter-subject variability in baseline cell count, cell production rate (KIN), transit time in the transit compartment model (MTT), C50, and EMAX. Individual baseline cell level means were provided in the data set (column BL). This was used as a typical value in the model. A random effect parameter was added to allow adjustment of the individual's initial estimate based on all the individual's measurements. PD residuals were described with a proportional error model. For model validation during the course of VFO modeling (PK and PK-PD), standard errors, GOF plots, and individual prediction plots were used in RZfr? nn / nznz / E / YiAi 135 comparison with data to evaluate the models and compare them with the alternative ones. The following software packages were used: NONMEM (version 7.2), KIWI (version 1.6), Berkeley Madonna (version 8.3.14), PSN (version 4), and R (version 3.3.0). Data set preparation Data sets from all 8 monkey studies were collected, reorganized into a single format, and merged into three separate NONMEM-readable PK-PD data sets. Each of the three data sets contained individual monkey characteristics (study, ID, group, body weight, sex), dose information, PK, and NK cell, B cell, or T cell data. For animals For control groups, only cell counts were added, but no PK data was added to the data sets, with the implicit assumption that there are no serum levels of AB7 9. Time-resolved information on immunogenicity status antipharmacological (ADA), namely, TITLE containing the result of the quantitative measurement and the variable ADAF marked with 0 / 1 (ADAF = 1 if ADA affects the concentration of AB79, ADAF = 0 if it does not), was added in separate columns for each observation. ADA titers were measured with different method specifications in the different studies and therefore, across studies, the RZfr? nn / nznz / E / YiAi 136 values ​​are not directly comparable in a quantitative way. To use ADA information consistently across studies, the following procedure was applied for each animal separately: ADA titers that increased at time points after 7 days above initially measured levels were considered ADA positive and labeled in the data set (ADAF = 1) . If a sample at one time point was marked ADA positive, all samples taken after that time point were also marked ADA positive in this animal, regardless of the titer measured. Positive ADA observations were not used for parameter estimation during model development. Note that also the PD measurements of the sampling time points of the ADA-affected PK concentrations were labeled with ADAF = 1. For cell count data, individual baseline values ​​for each cell type (NK cells and B and T lymphocytes) were calculated as the mean value of all available pre-dose measurements from a given animal. In most studies, this was a single measurement. The baseline value for each animal was then added as an observation at the time of the first dosing event (TIME=0) and as a constant value in the BL column to each observation for the respective animal. Based on this value RZfr? nn / nznz / E / YiAi 137 baseline, the baseline percentage for each observed cell count was calculated and added to the data set. Expanded Monkey PK Parameters The final PK and PK-PD models were used as the starting point to simulate PK and PK-PD profiles for the first human clinical trial. Although never conclusive, comparative analyzes of therapeutic monoclonal antibody data have shown that PK parameters derived from monkey studies can be extended to help predict human PK profiles with acceptable accuracy (Han and Zhou (2011) Ther Deliv. 2: 359-368). The publication indicated that, by using a fixed exponent of 0.85, human monoclonal antibody clearances can be reliably predicted. Therefore, this relationship was applied to scale up human clearance parameters (CL, Q), while volume parameters (VC, VP) were scaled up by a direct relationship between body weights (BW): λ। _p। j BWtwas® | . , , BWlssiss» and ™ V .' ..... human sws: Results Pharmacokinetics of AB79 The PK data set was pooled from the 8 RZfr? ηη / ηζηζ / Ε / γίΛΐ 138 studies in healthy monkeys, excluding placebo groups (Table 2). In total, the set contained data from 140 animals, 58 of which were male and 82 of which were female. The body weights of the animals studied ranged from 2.1 to 4.7 kg and the doses ranged from 0.03 to 100 mg per kg of body weight (mg / kg). In one group from Study 7 and three groups from Study 8, doses of 0.03, 0.1, 0.3 and 1 mg / kg SC (15 animals total) were administered. The pooled data set contained 2,199 measurable PK observations greater than LLOQ (Figures 2A and 2B). PK was sampled more heavily after the first dose and, even in long-term toxicology studies, most animals terminated their participation before day 98. Only study 4 included recovery groups, and only two groups could be collected. PK data from 4 animals, 2 from the 80 mg / kg group and one each from the 30 mg / kg and 3 mg / kg groups (Figure 2B). Parallel to the AB79 concentrations, ADA was evaluated. 229 PK observations were affected by ADA (Figure 3). Initially, for each of the monkey studies, PK analyzes were performed using standard non-compartmental (NCA) techniques. Based on single dose studies (IV bolus injection or 30 minute IV infusion), the volume of distribution during the terminal phase (Vz) was calculated to range from 64 to 116 mL / kg, the clearance of RZfr? nn / nznz / E / YiAi 139 6.04 to 14.7 mL / kg / day and the terminal elimination half-life (Tl / 2) from 4.75 to 11.2 days. Area under the concentration-time curve (AUC) and maximum concentration (Cmax) values ​​were found to increase proportionally with dose over a wide range. Only the PK profiles of the lower dose groups (<1 mg / kg, Figures 2D-2F) provide evidence of non-linearly increased clearance at concentrations less than 0.5 pg / mL, probably due to target-mediated mechanisms (TMDD). (Kamath (2016) Drug Discov. Today Technol. 21-22: 75-83). Based on data from all monkey studies, excluding the two lowest dose groups (dose >0.3 mg / kg), a 2-compartment linear model was created. When the PK of the lower dose groups was simulated and superimposed with the measured concentrations, it was evident that the linear model predicts excess concentrations (Figures 2D-2F). PK data available after administration of a single SC dose revealed that Cmax was 70-80% lower in SC groups compared to IV of the same dose and that AUCs were comparable. No differences in PK parameters were observed between male and female monkeys. The results of these initial analyzes were used as the starting point for model development. Development of the PK model RZfr? nn / nznz / E / YiAi Model development began with IV dose data 140 unique and then the initial model was gradually extended by using more complex data. Similar to other therapeutic antibodies, PK roughly follows a 2-compartment linear model (Kamath (2016) Drug Discov. Today Technol. 21-22: 75-83). The non-linear component elimination (TMDD) describing the accelerated clearance at low concentrations was modeled with the quasi-steady state (QSS) approximation (Gibiansky and Gibiansky (2009) Expert Opin. Drug Metab. Toxicol. 5: 803812). The assumption that the drug-target association process is much faster than the pharmacological dissociation, distribution and elimination processes, and elimination of the drug-target and target complex, leads to the simplified TMDD model (Figures 2A-2I, Table 4). . The amount of data at low concentrations was relatively small, so not all parameters were estimated in a single estimation run of the software program. Therefore, the TMDD model parameters were first estimated by focusing on data from the single low dose studies 7 and 8. The resulting TMDD parameter estimates were then held fixed during the final estimates over the entire set of data (Table 4). RZfr / nn / nznz / B / Yi Table 4. Results of the PK modeling of the population, parameter estimates and standard errors in percentage RZfr? nn / nznz / E / Yi (% of SEM) Final Parameter Estimate Inter-individual Variability / Residual Variability Parameter Typical Value % SEM Magnitude % SEM F 0.227 121 NE - Ka (L / day) 0.399 20.5 42.1% of CV 53.8 CL (L / day) 0.0187 5.17 42.9% of CV 20.1 Ve (L) 0.141 3.23 19.8% of CV 22.5 Q (L / day) 0.127 14.7 NE - VP (L) 0.127 6.45 39.4% of CV 20.8 Kint (1 / day) 0.1 FIXED 49.3% of CV 36.7* Kss (1 / day) 5.68 38.7* NE - Ksin (u / L / day)$ 0.04 FIXED NE - KDEG(1 / day) 0.00452 30.1* NE - ROUT en Ve -0.697 6.51 NE - RV added 3.17E-04 21.2 0.0178 SD - RV prop 0.0677 1.58 26.0% of CV - Minimum value of the objective function = 5748.412 $Ksin is the receptor synthesis rate of CD38. Since actual concentration measurements or information on the in vivo synthesis or degradation rate of CD38 were not available, "u" was used as the unit for some unknown amount of CD38. *Estimates and standard errors for the TMDD parameters were obtained from a separate run that focused on data from the low-dose groups, and then fixed for the final estimate of the other PK parameters. NE: not estimated. Estimates for the KA and F absorption parameters were obtained when the data from the SC groups were added. All SC data are from four lower single dose arms from Studies 7 and 8. These lower doses (di mg / kg) covered the clinically relevant range, but may limit the generalizability of the parameter estimates for doses. higher. Between-subject variability (BSV) regarding PK parameters was described with exponential models. Absorption rate (KA), clearance (CL) and volume 142 peripheral distribution (VP) have an estimated BSV of around 40% and the central volume of distribution (Vc) is around 20% (Table 4). Analysis of covariates identified an effect of route of administration on Vc. The typical value for Vc was 0.141 L if IV was given and 0.043 L (about 70% smaller) if SC was given. No other significant covariate effects were identified. Due to the limited amount of data at low concentrations, inter-subject variability and individual predictions of TMDD parameters were only estimated for the internalization rate KINT(BSV: 49%). Model evaluation based on residual errors, OFV, standard errors, GOF plots, and individual curve fits confirmed that the final model adequately described the PK of AB7 9 in healthy monkeys (Table 4, Figures 4A-4J). pharmacodynamics The level of binding to AB79 in human and monkey blood NK cells, T cells and B cells was compared by flow cytometric analysis. As shown in Figure 5, monkey lymphocytes had CD38 expression levels, based on AB79 molecules of equivalent fluorescence (MOEF), that were slightly lower compared to their human counterparts, but with a similar relationship between cell types, for example, RZfr? nn / nznz / E / YiAi 143 CD38 expression on NK cells > B cells > T cells. These data support the use of this non-human primate species as a relevant model to help predict the potential of ΆΒ7 9 for PD activity in humans. For in-depth quantitative analyzes of the relationships between drug exposure (PK) and the extent and duration of cell depletion (PD), data sets of PK concentrations and NK cell, B cell, and lymphocyte counts were collected. T of 8 studies in monkeys, including placebo-treated animals, where available (Table 2). Initial characterization of the data set showed that, at baseline, T cells had a median value of 3,732 cells per pL (interquartile range (IQR): 2,881 5,176) and were the most abundant lymphocyte subtype compared to B lymphocytes with 1,279 lymphocytes per pL (IQR: 860.8 - 1,890) and NK cells with 685 cells per pL (IQR: 482.8 - 970.1). Initial CD38 expression on these cell populations was assessed in studies 1-4 (Table 2, n=67). 86.7% (SD 11.3) of NK cells expressed CD38 with minor variability. In contrast, 58.7% (SD 27.0) of B lymphocytes and 34.5% (SD 24.5) of T lymphocytes expressed CD38 with greater variability. Data from placebo-treated animals showed that the average number of each of the cell types 144 varied over time between individual animals more than would be expected from within-individual variability (Figures 6A-6C). For example, the average coefficient of variation of the B-lymphocyte counts from the individual placebo curves was 27%, but the individual average B-lymphocyte levels ranged from 436.6 to 4,389. In addition, there were also differences between the mean baseline numbers of lymphocytes from male and female animals and from animals from different studies which added to the variability (Figures 7A-7F). Based on these results, each cell count after treatment was calculated relative to its individual baseline in percentage, rather than the absolute cell numbers at each time point. For example, a value of 33% means that the sample cell count was 1 / 3 of the initial cell count. This provided standardized values ​​that could be compared across the entire data set. The rapid onset of decline in cells binding to AB79 suggests that the initial blood concentration drives the decline in lymphocyte counts (Figures 8A-8I). At 0.3 mg / kg IV doses of AB79, the median maximum effect on NK cells was a 93.9% decrease (ie, 6.1% of initial cell counts remaining). At 0.1 mg / kg, the maximum decrease was 71% (29% of baseline remaining). At doses >0.3 mg / kg, the RZfr? nn / nznz / E / YiAi 145 NK cells were almost completely decreased in the blood compartment (nadir (range): 1.06% of baseline (0.17, 6.23); Figure 8A). Following a single 0.3 mg / kg dose, it took approximately 7 days for NK cells to recover to an average of 50% of baseline, although the kinetics of recovery were highly variable between individuals (Figures 8B and 8C). Consistent with these results, NK function was also assessed in a subset of animals in study 7 (n=3 / group; Table 2). This experiment showed a dose-dependent reduction with minimal changes in blood NK activity at 48 hours post-treatment in animals treated with 0.1 mg / kg of AB79 (% lysis at an effector:target ratio of 100:1 ± SD, 44.5% ± 23.6% compared to 41.4% ± 25.8%) and almost complete loss of NK activity in animals treated with 1.0 mg / kg (% lysis at an effector:target ratio of 100:1 ± SD; 37.4% ± 10.3% compared to 6.8% ± 12.5%). NK cell function showed recovery at 57 days, the next time point measured (% lysis at an effector:target ratio of 100:1 ± SD; 16.0% ± 11.9%). B cells and T cells were decreased to a lesser extent compared to NK cells, which is consistent with their lower levels of CD38 expression (Figure 5). At 0.3 mg / kg IV of AB79, for example, B cells RZfr? nn / nznz / E / YiAi had a median maximum level of 146 decreased to 45% of baseline, and T cells decreased to 43% of baseline (Figures 8D and 8G). At this dose level, a 50% reduction from baseline in B-lymphocyte counts was not achieved in all animals. Only at the highest doses of >30 mg / kg were B lymphocytes almost completely depleted (FIG. 8D). T cells were depleted to a similar degree as B cells, but recovery was more rapid (Figures 8G-8I). In the two studies 7 and 8, the IV and SC doses were compared (Figures 8C, 8F and 81). There were no apparent differences in cell shrinkage between routes of administration. At the lowest doses (Study 8), a sustained (>24 hour) cellular decline of 50% below baseline was only observed in the NK cell population and not with T and B cells; although all cells showed a cell-specific decline at early time points. The timing of onset of NK cell depletion appeared similar between dose groups, regardless of route of administration, and the duration of depletion was dose-dependent. Cell recovery was observed in all test groups at day 57 . PK–PD models Separate PK-PD models were developed for RZfr? nn / nznz / E / YiAi 147 describe the effects of AB79 exposure on NK cells, B cells, and T cells. During PK-PD modeling, PK parameters were held fixed to the final PK model estimates and various PD models were tested. The NK cell population in the peripheral blood was adequately described with a turnover model, and the pharmacological lowering effect of the drug was related by PK concentration with an Emax-to-lowering-rate model. In this model, EMAX represents the maximum rate of NK cell further depletion and C50 the concentration at which NK cell further depletion rate is the mean maximum. The structural model of PK-PD for NK cells had the following form: dA'A' EMÁY € __17 _ _ A? 17.___________ In the formula, NK represents the actual NK cell count, Kin the production rate, and Κουτ the clearance rate when no drug is present. It must be taken into account that, with the initial measurement determined, BLKout is defined by the equation Κουτ = Kin / BL. c represents the concentration of AB79 in the central compartment. When all the parameters were estimated at once, the software program did not produce stable results. KIN Individual Estimates EMAX and C50 were highly 148 correlated. Furthermore, due to the limited differentiation between the maximum effects of different doses (see previous section) and the large inter-individual variability, precise estimates of all parameters could not be expected. In a series of estimates, one or two of the three parameters KIN, EMAX and C50 were set to different values ​​and the others were estimated. Stable performance and reasonable goodness-of-fit were achieved with a fixed KIN of 10,000 and EMAX of 322. The typical estimate of C50 was 29.0 pg / mL (Table 5). In addition, the sensitivity of the selected KIN and EMAX values ​​was evaluated by choosing different combinations of higher and lower values. The inter-subject variability was large with 113% for the NK KIN production rate and with 14 9% for the C50, which is consistent with the large individual differences at baseline and between treated animals. The model was evaluated based on residual errors, OFV, standard errors, GOF plots, and individual curve fits (Table 5, Figures 9A and 9B). RZfr? nn / nznz / E / YiAi 149 Table 5. Results of PD modeling, estimates of RZfr? nn / nznz / E / Yii parameters and standard errors in percent (% of SEM) Final Parameter Estimate Inter-individual Variability / Residual Variability Parameter Typical Value % SEM Magnitude % SEM NK Cells KIN (count / day) 10000 FIXED 113% of CV 19.2 C50 (pg / mL) 29.0 18.8 149% of CV 25.1 EMAX 322 FIXED NE - Baseline (NK cells)* NE - 28.3% of CV 20.8 NK cells residual 0.291 2.42 53.9% of CV - MTT B cells (day) 8.48 15.4 135% of CV 17.4 C50 (pg / mL) 19.5 7.58 NE - EMAX 2.37 FIXED NE - Baseline (B cells)* NE - 24.1% CV 10.7 Residual B cells 0.136 2.20 36.9% CV - C50 T cells (pg / mL) 11.86 7.267 NE - EMAX 0.4656 6.578 69.46% CV 29.50 Value baseline (T cells)* NE - 29.08% of CV 15.50 Residual T cells 0.1343 2.406 36.65% of CV - *For each individual animal, the typical baseline value was calculated as the average of all pre-dose measurements; NE: not estimated The transit compartment model was superior to the direct response or turnover models in describing the AB79-induced decrease in B lymphocytes. Four transit compartments were found to be adequate, and the pharmacological effect was described with an Emax type model on the rate of decline. Similar to the NK cell depletion model, the EMAX represents the maximum rate and the C50 the concentration at which the rate is the mean maximum. Thus, the structural PK-PD model for the 150 B lymphocytes is provided by the following five RZfr? ηη / ηζηζ / Ε / γίΛΐ equations: —' F R ; cover i TRi (1=1-4) represents the four traffic compartments. KTr, KPROl and Kcirc are defined by the following equations Ktr=KRROl=KciRc=4 / MTT, where MTT is the mean transit time (Friberg et al. (2002) J. Clin. Oncol. 20: 4713-4721) . B represents the count of B lymphocytes in the blood and c the concentration of AB7 9 in the central compartment. With a fixed EMAX of 2.37, the typical C50 was 19.5 pg / mL and the typical mean transit time (MTT) was 8.48 days (Table 5). The delay of the maximum effect relative to the maximum concentration of AB79 was well captured. The model indicates that AB79 primarily affects circulating B lymphocytes. No additional effects or feedback loop in progenitor cells were necessary to describe the available monkey B cell data. The between-subject variability in MTT of 135% and in baseline B lymphocyte levels (BASE) of 24.1% indicates large 151 INDIVIDUAL DIFFERENCES BETWEEN ANIMALS. The drug-induced decrease in T cells with rapid recovery was adequately described with a direct response model: T(c) = BLT*(1EMAX*c / (c+C50)), where T represents the actual lymphocyte count. T, BLt the baseline T cell count and c the concentration of AB79 in the central compartment. The typical C50 was estimated to be 11.86 pg / mL and the typical EMAX was estimated to be 0.47, indicating that in this case AB79 can only downregulate about half of the T cells (Table 5). However, it must be taken into account that the variability between subjects in EMAX was close to 70%. In this model, unlike the models of NK cell and B lymphocyte depletion, the C50 represents the concentration at which the T lymphocyte depletion was the mean maximum. For NK cells, model evaluation of the final PK-PD models for B and T cells based on residual errors, OFV, standard errors, GOF plots, and individual curve fits confirmed that they adequately described the data. of mono available (Table 5, Figures 9A and 9B). Simulation of human PK and cell decline The monkey PK and PK-PD models were used as the starting point for simulation based on the human PK model and cell count data to support the design and RZfr? nn / nznz / E / YiAi 152 justify the doses selected for the first human clinical trial (FIH) in healthy volunteers. To this end, it was hypothesized that model structures including TMDD derived from the monkey data also describe the main features of human PK and the consequent decrease in lymphocytes. To obtain predictions for human PK parameters, estimates of the following monkey PK parameters were extended: central and peripheral volume of distribution (Vc, VP), clearance (CL), and intercompartmental clearance (Q) with a direct approach to monoclonal antibodies (Han and Zhou (2011) Ther. Deliv. 2: 359-368). AB79 is a fully human monoclonal antibody and therefore less immunogenicity is expected in humans than seen in monkeys. Consequently, for modeling and simulation, ADA positive samples were excluded from the data set. Using the amplified model, the exposure and depletion profiles of NK cells, B cells, and T cells were simulated for single doses by 2-hour infusion (IV) or by subcutaneous (SC) injection of 0.0003 to 1.0 mg / kg as planned for the FIH study (Figures 10A-10H). Based on simulations, after an IV dose of 0.0003 mg / kg, no observable drug-induced effect on lymphocyte counts and not even measurable PK concentrations would be expected. RZfr? nn / nznz / E / YiAi 153 above LLOQ. Due to the variability and limited size of the dose groups, it was assumed that the minimal detectable pharmacological effect on NK cell counts would be a reduction of at least 10%. At doses of 0.01 mg / kg IV and 0.03 mg / kg SC, NK cells were predicted to decline to less than 90% remaining from baseline. With an IV dose of 0.3 mg / kg, a decline in NK cells to 17% remaining from baseline was predicted within 3 hours of the end of the infusion and a recovery to greater than 50% after 11 days (Figures 10A-10H). At the same dose, the model predicts that B cells decline to a maximum of 67% of baseline after 2.5 days and T cells decline immediately to 86% of baseline. For subcutaneous administration of the same 0.3 mg / kg dose, the model predicted that it leads to a smaller and later maximal decline (nadirs relative to baseline: NK cells 37%, B cells 74%, T cells 94% ). These in vitro and in vivo preclinical studies demonstrate that the monkey is an appropriate animal model for studying the pharmacology of AB7 9. Densely sampled PK and cell count data of NK cells, B cells, and T cells from eight studies in monkeys with various doses and dose regimens provide a rich data source for a comprehensive and quantitative understanding of the relationships RZfr? nn / nznz / E / YiAi 154 between AB79 dose, exposure and cell decline. The generated population PK and PK-PD models adequately describe the observed data and provide a powerful tool for predicting lymphocyte exposure and depletion not only for future studies in monkeys but also for clinical trials in human subjects. The first human escalating single dose (FIH) trial was conducted in healthy volunteers (www.clinicaltrials.gov: NCT02219256) (Figure 11). The expected pharmacological effect of AB79 is the decrease in activated lymphocytes. However, a profound and long-lasting decrease in lymphocytes (enhanced pharmacology) can lead to immune system deficiencies, which would not be tolerable for patients or healthy study participants. Therefore, a safe IV starting dose of 0.0003 mg / kg was chosen for the FIH assay. The monkey data suggested that NK cell depletion was found to be the most sensitive biological effect. The results of the PK-NK simulation helped determine the minimum dose level of 0.01 mg / kg IV at which the most sensitive pharmacological effect (NK cell depletion) would be expected to be detectable in humans. Emerging data from the FIH trial revealed that the general pattern of dose-dependent, cell-type-specific lowering effects of AB7 9 is consistent with the RZfr? nn / nznz / E / YiAi 155 model-based predictions (manuscript in preparation). AB79 appears to be even more efficient than anticipated. For example, at an IV dose of 0.03 mg / kg, NK cells in human subjects decreased to less than 10% of baseline. The median nadir (lowest point of decline) in monkeys at this dose was 20.0% (Figures 8A-8I). Three cytolytic anti-CD38 monoclonal antibodies (daratumumab, SAR650984 and MOR202) are in clinical development for multiple myeloma (van de Donk et al. (2016) Immunol. Rev. 270: 95-112). Daratumumab (Darzalex™, administered as an intravenous infusion) was recently approved for multiple myeloma in the United States and non-Hodgkin lymphoma in Europe. Unlike AB79, daratumumab does not cross-react with monkey CD38. Therefore, a comparison of the present results with AB79 in Macaca fascicularis with daratumumab was not possible. In addition, patients with multiple myeloma have high levels of CD38-positive malignant cells, which might require higher effective antibody concentrations for this indication of cancer (de Weers et al. (2011) J. Immunol. 186:1840-1848). However, it is notable that daratumumab is approved at a weekly IV dose of 16 mg / kg in multiple myeloma, despite the fact that AB79 achieved complete depletion of peripheral NK cells to around 1 mg / kg and B cells to about 3 mg / kg (Figures 8A-8I). RZfr? nn / nznz / E / YiAi 156 Despite the rich database of 8 monkey studies, several limitations were recognized. AB79 effectively depresses NK cells even at the lowest dose studied of 0.03 mg / kg. At such low doses, the PK rapidly declines below the bioanalytical assay limit of quantification, which prevented resolving the exposure-effect relationship at lower doses. In addition, it was recognized during preclinical development that peak cell decline occurs shortly after peak drug concentration, but resolution of the early phase of decline is technically limited by the total number of samples and potentially by non-specific cell decline due to to repeated blood collections (blood draw effect). The blood draw effect was observed as a transient pancytopenia characterized by a decrease in cell types that do not bind to AB79 (eg, red blood cells) and was not dose-dependent, suggesting that it was due to loss of blood volume as a result of multiple blood draws rather than any specific effect of AB79 (Figures 12A-12C). Consequently, the power to accurately estimate the model parameters, especially for NK cell depletion, was limited and typical values ​​of KIN and EMAX required fixation to achieve adequate and stable estimation results. RZfr? nn / nznz / E / YiAi 157 The effect of AB79 on plasmablasts or tissue plasma cells could not be measured. However, like plasma cells and plasmablasts, NK cells have high levels of CD38 on their surface, and the efficiency of cell knockdown of a specific lymphocyte subset depended, at least in part, on the expression levels of CD38. CD38. Therefore, the cytolytic effect of AB79 on plasmablasts and plasma cells may be comparable to the effect on NK cells. At present, information on the long-term effects of AB79 treatment in monkeys is limited. Only a small subset of animals in the 13-week toxicology studies were investigated in a recovery group for a longer period of time, and the majority of animals in all dose groups developed ADA (Figure 3). Furthermore, the baseline values ​​and decline profiles of the different lymphocyte subsets were highly variable between individuals. Therefore, the long-term effects of AB79 cannot be investigated in monkeys and will have to be studied in humans. With the emerging human data, it will be interesting to compare human and monkey PK and PD data in detail. The creation of a PK model based on human data and a comparison with the monkey model will allow the refinement of the TMDD model of AB7 9. The data 158 generated in patient studies will provide information on how the AB79-mediated decline in B-lineage lymphocytes compares between patients with RA and SLE and those with multiple myeloma and healthy subjects. Investigation of subject- or disease-related factors that may influence the efficiency of cell knockdown in addition to CD38 expression levels is also important and could lead to treatment personalization. Furthermore, a comprehensive and direct comparison of AB7 9 with daratumumab and / or the other anti-CD38 antibodies in vitro and in vivo will reveal valuable information about the pharmacology of anti-CD38 antibodies and their optimal application. The rich pharmacological data and the PK and PKPD models allowed the characterization of exposure-effect relationships in Macaca fascicularis. Analyzes based on the NK cell, B cell, and T cell model supported and quantified the finding that antibody decreases each of the blood lymphocyte subsets at different rates and that each requires different periods of time. to refill the blood compartment. The models proved to be excellent means of simulating PK and PD data in different dose scenarios in preparation for clinical trials. RZfr? nn / nznz / E / YiAi 159 Example 2: Decreased CD38+ lymphocytes by AB79 Table 6 shows that AB79 mediates cell depletion by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Cell lines with increased expression of CD38 were more susceptible to ADCC. ADCC was not observed in a human lymphoblast cell line that did not express CD38 (MV-4-11) or with a Chinese hamster ovary cell line transfected with CD157, a molecule closely related to CD38 (data not shown). Unlike other selective B cell treatments that target CD20 and do not directly deplete plasmablasts, which are CD2 low / ne9ative, CD38 is expressed at high levels on both plasmablasts and plasma cells, making these cells a direct target of AB79. In vitro studies with human blood cells and cell lines showed that binding of AB79 to CD38 did not result in cytokine activation of PBMCs, demonstrating that AB7 9 is not an agonist, as discussed below. Rather, AB79 mediated cell downregulation of human B-lineage cell lines by ADCC and CDC and, in most cases, cell lines with increased expression of CD38 were more susceptible to cell lysis. RZfr? nn / nznz / E / YiAi 160 Table 6. AB79 mediates the cell decline of lines of RZfr? nn / nznz / E / YiAi human B cells by ADCC and CDC. CD38 cell line (Receptor No.) ADCC ECso ± SD (nM) CDC ECso ± SD (nM) Molp8 623,891 0.05 ± 0.04 n=9 1.1 ±1.0 n=7 Daudi 417,874 0.03 ± 0.04 n=4 1.6 ±0.4 n= 3 NCI-H929 82,341 0.14 ± 0.11 n=6 na RPM1-8226 98,080 0.46 ± 0.53 n=8 na OPM2 54,556 0.65 ± 0.64 n=4 na ECso, 50% effective concentration; na, not done; SD, standard deviation. This is consistent with the findings in healthy Macaca Fascicularis where the efficiency of the knockdown was correlated with the expression level of CD38 and the dose level of AB79. NK cells, which express high levels of CD38, were decreased to a greater extent than CD20+ B cells and CD3+ T cells, which express less CD38 (Figures 13A-13C). In vivo, ΆΒΊ9 potently inhibited human B cell retrieval responses to antigen in an adoptive blot mouse model (Figure 14). Together, these data support further investigation of AB79 in autoimmune diseases. Human PBMCs were treated with AB7 9 under multiple conditions and the release of inflammatory cytokines was measured. Macaca Fascicularis was used to show the relationship of cell type-specific decrease and dose of AB79 because AB79 cross-reacts with 161 Monkey CD38, which shares 91% protein identity with the human protein. A second animal model, mice adoptively transferred with human PBMCs, was used to determine whether AB79 could target human antibody-producing cells. AB79 binds to CD38 and media ADCC and CDC The number of receptors was determined with the FIKIT (DAKO, Catalog No. K0078) using mouse anti-human CD38 antibody (clone HIT2) and calculated by converting the mean fluorescence intensity (MFI) of the samples stained on a calibration curve generated from the MFI of 5 bead populations fixed with a defined number of antibody molecules. The absolute number of receptors was calculated by subtracting the isotype control MFI (mouse IgG1) from the anti-CD38 antibody MFI. CDC was assessed by plating cell lines at 10,000 cells / well and adding AB79, control IgG, or media. Typically, a 5-point dose-response curve (0.001 - 10 mg / mL) was performed. Rabbit complement (2-15 uL; No. CL 3441 CedarLane Laboratories) was added to each well except control wells. CytoTox-Glo reagent (Promega, G7571 / G7573) was used to detect cytotoxicity by luminescence. Groups evaluated: single cells; cells + complement; cells + RZfr? nn / nznz / E / YiAi 162 IgG control + complement; cells + AB79 + complement. % CDC equation: equation: % CDC = 100- ((RLU (test) / (complement only)) X 100). ADCC was assessed by plating 5000 target cells / well (T, cell lines) with 50 mL of AB79, control IgG, Triton X-100 (1%; Sigma Chemical) or medium alone and 50 mL of effector PBMC ( E) human at a ratio of 1:25 to 1:50 T lymphocytes:E cells. Typically, a 9-point antibody dose-response curve (0.000001 - 100 nM) was performed. Experimental lysis = PBMC + cell line + antibody. Spontaneous lysis = PBMC + cell line without antibody. Maximum lysis = cell line + Triton X-100. Cytotoxicity assessed by CytoTox-Glo™ Luminescence Cytotoxicity Assay (Promega). AB79 has no agonist activity The ability of AB79 treatment to induce cytokine production in human PBMCs was compared with the IgGl isotype negative control and positive controls, PHA, anti-CD3 (clone OKT3) or anti-CD52 (Campath) antibodies (Figures 15). , 16A and 16B). Soluble AB79 did not increase IL-6 levels (mean ± SD) in PBMC collected from 4 different subjects after a 24-h incubation compared to the IgGl isotype control. PHA increased cytokine levels in all subjects, demonstrating that the cells had RZfr? nn / nznz / E / YiAi 163 the ability to produce IL-6 (Figure 15). Similar results were observed with PBMC stimulated for 48 hours and when IL-2, IL-4, IL-10, GM-CSF, IFNγ and TNFα were assessed (data not shown). The method by which an antibody is presented to a cell can contribute to the outcome of the antibody: ligand binding and cellular response ( Stebbings et al. (2007) J. Immunol. 179: 3325-3331). Stebbings et al. showed that the maximum cellular response (cytokine release) to an agonist antibody occurred when the antibody was highly concentrated and adhered to the surface of the well, such as when the antibody was added to a well in solution and the liquid was allowed to evaporate. (dry fixation) compared to antibodies that were allowed to fix to the wells in solution (wet fixation) or added directly to PBMCs (soluble) (Figure 16A). AB79 did not stimulate cytokine production using either of these approaches (Figure 16B). AB79 (100 mg / mL) did not stimulate IL-2, -4, -6, -8, -10, GMCSF, IFNy, or TNFa in any of the conditions tested after 24 hours. AB79 did not induce IL-10 or GM-CSF, but both were induced by anti-CD3 (not shown, all values ​​except anti-CD3 were below LLOQ). PBMCs constitutively produced IL-8, which was not altered by any treatment (data not shown) (Table 7). RZfr? nn / nznz / E / YiAi 164 Table 7. AB79 and cytokine stimulation RZfr? nn / nznz / E / YiAi Presentation of the antibody None Isotype AB79 Anti-CD52 PHA Anti-CD3 IL-2 Soluble LLOQ LLOQ LLOQ LLOQ 14953 ± 3117 nd Wet fixation LLOQ LLOQ LLOQ LLOQ Nd 395.0 ± 64.8 Dry fixation LLOQ LLOQ LLOQ LLOQ Nd 167.9 ± 90.1 IL-4 Soluble 7.3 ±1.4 4.1 ±0.8 6.4 ±3.2 6.9 ±4.0 50.4 ± 8.9 na Moist fixing 5.3 ±0.08 3.8 ±1.5 6.4 ±0.6 8.5 ±3.7 Nd 17.8 ±2.4 Dry fixing 4.4 ±1.8 ±1.7.8 ± 7.8 ± 2.1 ND 16.2 ± 3.1 IL-6 SOLUBLE 325.1 ± 65.3 236.0 ± 98.9 170.5 202.0 ± 48.0 18880 ± 0 ND Wet fixation 216.8 ± 95.1 191.2 ± 47.0 194.6 ± 66.0 207.2 ± 60.2 ND 902.7 ± 114.1 11 143 465.8 ±230 811.1 ± 473.7 Nd 500 ± 17 IFNy Soluble 1190.2 ± 117.5 857.1 ±311.7 770.1 ±203.6 1116.9 ± 330.8 15857 ± 4614.8 nd Fijación en húmedo 1052.8 ± 385.8 657.2 ±222.6 993.4 ±198.1 1138.9 ± 339.1 Nd 5674.6 ± 564.7 Fijación en dry 768.1 ± 110.0 1583.1 ± 418.6 1927.6 ± 517.6 1827.0 ± 281.5 Nd 3513.2 ± 708.3 Soluble TNFa 28.71 ±8.1 11.6 ± 7.1 59.6 ±90.1 790.2 ± 9 178 na Wet fixation 16.5 ±3.4 16.1 ±3.9 14.8 ±8.8 166.1 ± 21.7 Nd 2123.3 ± 239.7 Dry fixation 16.2 ±7.4 919.2 ±77.4 745.1 ± 141 984.4 ± 317.0 ± 22618 Nd A multiplex cytokine assay was used according to the manufacturer's instructions (Bio-Plex ProTM 8-Plex Human Cytokine Standard) to measure the concentrations of IL-2, -4, -6, -8, -10, GM-CSF. , IFNy and TNFa. Abbreviations: LLOQ, lower limit of quantification; na, not done; PHA, phytohemagglutinin; PBMC, peripheral blood mononuclear cells. AB79 decreases CD38+ lymphocytes AB79 binds to CD38 with high affinity and medium CDC and ADCC. AB7 9 is not an agonist and does not induce cytokine release from human PBMCs. AB79 bound to both human and Macaca fascicularis CD38. Lymphocytes from both species had similar cell-specific patterns of expression. 165 CD38 with NK cells > B cells > T cells as a function of median fluorescent intensity of AB79 staining. Treatment with AB79 decreased monkey lymphocytes in a reversible, cell-specific, and dose-dependent manner. AB79 effectively blocked the human antibody retrieval response in an adoptive transfer mouse model. Example 3: Assessment of AB7 9 binding to human and Macaca fascicularis red blood cells and platelets AB79, a non-agonist, high affinity, fully human IgG1 monoclonal Ab directed against human CD38, was tested for its binding to human or Macaca fascicularis red blood cells (RBCs) or platelets. Thirty blood samples from healthy human volunteers and thirty whole blood samples from healthy Macaca fascicularis were evaluated for binding to AB79, compared to an isotype-matched control monoclonal antibody, Palivizumab, of irrelevant specificity that does not bind to AB79. RBC or platelets. methods Blood samples were purchased from 30 normal human subjects (15 male and 15 female) for platelets, 25 male and 5 female for RBC, and 30 Chinese Macaca fascicularis (15 male and 15 female) from Bioreclamation (Long Island, NY ) . It was collected 166 whole blood into sodium citrate tubes and shipped overnight at room temperature. For assessment of AB79 binding to platelets, 50 pL of whole blood was stained with a cross-reactive human anti-CD61 FITC mAb from Macaca fascicularis (BD Biosciences, Catalog No. 555753) to identify platelets in combination with AB79. Alexa Fluor 647-conjugated (AF647) or an isotype-matched control, AF647-conjugated palivizumab (Medlmmune, Catalog No. 60574-4113-1), a humanized monoclonal antibody that is specific against an epitope at the A antigenic site of the F protein of respiratory syncytial virus (RSV), an antigen not present on RBCs or platelets. RBC lysis was performed after staining and samples were analyzed with a BD Canto flow cytometer. CD61+ platelets were separated for analysis. For assessment of AB79 binding to RBC, 50 pL of whole blood was stained with AF647-conjugated AB79 or isotype-matched control, AF647-conjugated palivizumab. In some experiments, a cross-reactive anti-human CD45 PERCP from Macaca fascicularis (BD Biosciences, Catalog No. 552724) was used to stain lymphocytes to provide evidence of AB79 binding to a subset of lymphocytes as described. 167 observed in previous studies. Samples were analyzed with a BD Canto flow cytometer. Data were expressed as the mean fluorescence intensity (MFI) of AB79 or isotype control. Results and analysis The ability of AB79 to bind to RBC of thirty healthy human volunteers and thirty healthy Macaca fascicularis was evaluated by flow cytometry. RBC staining with AB79 was not above the level of staining seen with the isotype control antibody in any of the human blood samples (Figure 17 and Table 8) or the Macaca fascicularis blood samples (Figure 18 and Table 8). 8j No obnoxious fixation was observed in either species and no difference in the MFI ratio for AB79 / isotype control was observed between humans and RZfr? nn / nznz / E / YiAi Macaca fascicularis. Table 8. Relationship of mean fluorescence values ​​of RZfr? nn / nznz / E / YiAi RBC isotype control / AB79 N.° de Donante Humano Macaca fascicularis 1 1.047 1.025 2 1.018 0.904 3 1.006 0.912 4 0.867 0.878 5 0.800 0.805 6 0.937 0.980 7 0.900 0.893 8 0.920 0.861 9 0.896 0.839 10 0.958 0.868 11 0.896 0.863 12 0.950 0.866 13 1.016 1.027 14 0.946 0.989 15 0.985 0.969 16 0.829 0.990 11 0.861 0.985 18 0.903 1.022 19 0.914 0.915 20 0.914 0.911 21 0.813 0.882 22 0.859 0.888 23 0.947 0.960 24 0.917 0.940 25 0.976 0.948 26 0.933 0.931 27 0.889 0.967 28 0.938 0.949 29 0.976 0.941 30 0.934 0.951 Media 0.928 0.929 StDev 0.056 0.057 The ability of AB7 9 to bind to CD61+ platelets from thirty healthy human volunteers and thirty healthy Macaca fascicularis (donors 1-15 were male subjects; donors 16-30 were female subjects) was assessed by flow cytometry. AB79 staining of platelets was not above the level of staining observed 169 with the isotype control in none of the human (Figure 19 and Table 9) or Macaca fascicularis (Figure 20 and Table 9) blood samples. No detectable binding was observed in either species and no difference in the MFI ratio for AB79 / isotype control was observed between humans and Macaca fascicularis. Table 9. Ratio of Platelet Isotype Control / AB79 Mean Fluorescence Values No. of Human Donor Macaca Fasculicis 1 1.46 0.96 2 1.10 0.88 3 1.76 0.90 4 1.16 0.88 5 1.21 1.28 6 1.53 1.19 7 2.14 0.85 8 1.14 0.78 9 1.14 0.97 10 0.53 1.37 11 0.38 0.63 12 0.60 0.98 13 1.06 0.71 15 0.78 1.06 16 1.06 1.03 17 0.95 0.83 18 1.25 0.80 19 1.09 1.55 20 0.89 1.28 21 0.95 1.61 22 1.24 1.24 23 0.36 0.99 24 1.34 1.40 25 0.53 1.04 26 0.91 1.29 27 0.85 1.14 28 0.68 1.05 29 1.05 29 1.03 1.03 1.4 1.11 StDev 0.39 0.33 170 As a positive control for AB79 staining, AB79 staining was measured in a portion of the blood samples. Due to the high prevalence of RBC in the blood, 200,000 events were acquired and a small population of CD45+ lymphocytes was separated for further evaluation. No fixation was observed for isotype control; however, AB79 bound to a small population of CD45+ lymphocytes (Figure 21). This confirmed that AB79 was capable of staining blood cells under conditions where no detectable binding of AB79 to RBCs or platelets was observed. Example 4: Evaluation of the binding of AB79 to human and Macaca fascicularis red blood cells and platelets by means of a flow cytometry assay of higher sensitivity A higher sensitivity flow cytometry assay was developed to further assess whether AB79 binds to human or Macaca fascicularis RBCs in case the previous assay was not sensitive enough to detect low level CD38 expression on RBCs. . Blood samples from 4 healthy human volunteers were incubated with fluorescently labeled AB79 or fluorescently labeled daratumumab, another anti-CD38 antibody known to bind CD38 on RBCs. Each sample was preincubated with its respective unlabeled drug product to block CD38 from binding to the fluorescently labeled drug products, thereby RZfr? nn / nznz / E / YiAi 171 serves as the negative control for the assay. Antibodies against CD45 and CD235a were added to the samples to identify positive RBC cells and then analyzed on a flow cytometer. Fluorescently labeled daratumumab was used as the positive control. The results indicated that AB7 9 and daratumumab bind to RBCs from healthy human donors. methods Blood samples were collected from four healthy human donors (Millennium Blood Donor Program) according to company protocol. Briefly, peripheral blood samples were collected for RBC binding determination in sodium heparin tubes and for lymphocyte staining, peripheral blood samples were collected in BD Vacutainer® CPT tubes (BD Biosciences, Franklin Lakes, NJ, USA) . A separate tube was used to collect peripheral blood mononuclear cells (PBMC) to confirm the binding of fluorescently labeled AB79 and fluorescently labeled daratumumab to CD38+ lymphocytes. For RBC binding and lymphocyte staining experiments, peripheral blood samples were stored at RT and processed within 2 hours of collection to maintain cell viability. For RBC binding, peripheral blood samples were first diluted to RZfr? nn / nznz / E / YiAi 172 1:10,000 in staining buffer (BD Biosciences, Franklin Lakes, NJ, USA) to dilute the large number of RBCs present in the sample. Because the normal range of RBC in healthy human blood samples is approximately 5 million cells per microliter, samples must be diluted substantially to have an acceptable amount of RpBC to stain for flow cytometric analysis. Samples were then transferred to a 96-well V-bottom plate and incubated overnight at 4°C on a gentle shaker with 25 pL / well unlabeled AB79 (500 pg / mL), daratumumab without label (500 pg / mL) or BD buffer alone (no drug). A plate shaker was used to prevent sedimentation of the RBCs during the incubation period. Peripheral blood samples were preincubated with the unlabeled drug products to block CD38 antigenic sites on the RBC surface, which served as the negative control for the assay. After this incubation period, clinically relevant concentrations of biotin-streptavidin-BV421 daratumumab (0, 0.1, 1, 10, and 100 pg / mL) or biotin-streptavidin-BV421 AB79 (0, 0.1, 1, 10, and 100 pg / mL) they were added to the samples for 3 hours at RT on a gentle shaker. Samples were then washed several times with BD buffer and stained with cell surface markers CD45 and CD235a for identification of 173 RBC (RBCs are CD45-CD235a+) and streptavidin-BV421 to bind biotinylated antibodies. By using biotin-streptavidin, the low level expression of CD38 in RBC could be amplified. The BV421 fluorescent dye was selected because it is one of the brightest commercially available fluorophores and uses the violet laser in the flow cytometer, which minimizes the amount of spectral overlap with the other channels / labels in the panel. Together, this signal amplification approach provides the opportunity to detect molecules on the cell surface that would otherwise fall within the noise of the instrument. Samples were washed and subsequently acquired on a BD FACSCanto™ II (BD Biosciences, Franklin Lakes, NJ, USA). Target cell acquisition was established at 10,000 CD235a+ events. For binding to lymphocytes, peripheral blood from the same healthy donors collected in CPT tubes was centrifuged and peripheral blood mononuclear cells (PBMC) were isolated by standard techniques. Cells were washed, stained, and processed as described for RBC experiments. To prepare biotinylated antibodies, AB79 (21.4 mg / mL, Takeda, California, USA) and daratumumab (20 mg / mL, Janssen Biotech, Horsham, PA, USA) were concurrently purified on the same day by using a commercial protein A column kit (Abcam, Cambridge, UK). RZfr? nn / nznz / E / YiAi 174 United) to remove substances that could potentially interfere with the biotinylation process. Protein concentrations of the purified products were determined by A280 / 260 and equal amounts of protein from each antibody were conjugated to biotin using a Lightning Link Rapid Biotin Conjugation Kit (Innova Biosciences, Cambridge, UK). At the end of the procedure, protein concentrations were again measured by A280 / 260. Both antibodies were conjugated with commercial polystyrene microspheres that have binding capacity of the antibody to any antibody isotype or to inert microspheres (negative microspheres). After mixing the microspheres with biotin-strepavidin-BV421 AB79 or biotin-strepavidin-BV421 daratumumab, the two mixed components provide a distinct high-signal positive control with a suitable negative population that can be used to estimate the median fluorescence (MFI) of each. Test antibody by flow cytometry. Samples were acquired on a BD Biosciences FACSCANTO™ II instrument with a BD Biosciences FACSDiva™ (BD Biosciences, Franklin Lakes, NJ, USA). Raw data files were transferred to a secure server and then analyzed offline using FlowJo® version 10 (FlowJo, LLC; Ashland, OR, USA). For RBC identification, they first separated RZfr? nn / nznz / E / YiAi 175 CD235a+ lymphocytes. The geometric MFI and biotin-strepavidin-BV421 AB79 and biotin-strepavidin-BV421 daratumumab percentage positive events were then determined for the detached cells and plotted as a histogram (Figures 22A and 22B). This was compared to the isotype control (samples pre-incubated with unlabeled AB79 or unlabeled daratumumab and then incubated with their respective biotin-strepavidin-BV421-labeled drug products). For lymphocyte identification, residues were first excluded by forward vs. side scatter (FSC-A vs. SSC-A). The CD45 positive population was then sorted out and the MFI and percent positive of biotin-strepavidin-BV421 AB79 and biotin-strepavidin-BV421 daratumumab for the sorted cells were determined and plotted as a histogram ( Figures 22A and 22B ). This was compared to the isotype control (samples pre-incubated with unlabeled AB79 or unlabeled daratumumab and then incubated with their respective biotin-strepavidin-BV421-labeled drug products). RZfr? ηη / ηζηζ / Ε / γίΛΐ 176 Table 10. Summary of AB79 and daratumumab binding to RZfr? nn / nznz / E / YiAi red blood cells (geometric median fluorescence) AB79 BIOTINA-ESTREPTAVIDINA-BV421 CONC. (PG / ML) DONOR 1 DONOR 2 DONOR 3 DONOR 4 MEDIA SD 0 138 155 202 284 195 65.37 0.1 175 201 207 355 235 81.53 1 193 224 282 392 273 87.64 10 196 205 557 521 370 196.02 100 143 139 533 445 315 204.11 Cold AB79 and AB79 Biotin-Streptavidin-BV421 Conc. (pg / mL) Donor 1 Donor 2 Donor 3 Donor 4 Mean SD 0 139 143 220 ND 167 45.65 0.3 16 3 4 1318 1318 132 142 223 ND 166 49.90 10 136 148 421 ND 235 161.19 100 133 140 447 ND 240 179.30 Daratumumab Biotin-Streptavid¡na-BV421 Conc. 191 56.98 0.1 227 297 215 411 288 89.92 1 304 394 387 527 403 92.22 10 317 352 556 599 456 142.11 100 162 190 643 493 372 234.74 Daratumab in cold and daratumumab biotin-stavevidin-bv421 Conc. 2 Donor 3 Donor 4 Average SD 0 143 164 180 ND 162 18.56 0.1 133 146 191 ND 157 30.44 1 135 147 216 ND 166 43.71 10 155 170 431 ND 252 155.20 3 100 13 D NA 138 6.36 ND = not determined; SD = standard deviation Results and analysis The amount of biotin in AB7 9 and daratumumab was determined using a highly sensitive flow cytometric assay. As the results in Figure 23 show, biotin-strepavidin-BV421 daratumumab binds 1.6 to 2.0-fold more to antibody-bound microspheres than biotin-177 strepavidin-BV421 AB79. Therefore, biotin-strepavidinBV421 daratumumab is a brighter antibody compared to biotin-strepavidin-BV421 AB79. Consequently, comparisons of MFI intensity must be calibrated for this difference in labeling. Confirmation of the specificity of biotin-labeled drug products was an important step in ensuring that the observed results are the result of specific binding to the target protein. Competition assays were a common way to assess the specificity of antibodies. A flow cytometry assay was used for this competency assessment. Briefly, peripheral blood samples from healthy volunteers were pre-incubated with unlabeled AB79 or unlabeled daratumumab, and then post-stained with biotinylated AB79 or biotinylated daratumumab, respectively. Samples preincubated with the unlabeled drug product were expected to block the binding of the biotinylated drug products. As demonstrated in Figure 24, biotinylated AB79 and biotinylated daratumumab could be blocked in peripheral blood lymphocytes using the unlabeled drug products. The percentage of biotin-strepavidin-BV421 AB79 and biotin-strepavidin-BV421 daratumumab binding to RBCs is RZfr? nn / nznz / E / YiAi 178 determined by using a total of four peripheral blood samples from healthy volunteers. As shown in Figures 25 and 26, AB79 bound to CD38-expressing RBCs in a dose-dependent manner in all four donors tested. Peak RBC binding levels differed between healthy volunteers and were observed between 1 and 10 pg / mL for both drug products. At 10 and 100 pg / mL biotin-strepavidin-BV421 AB79 or biotin-streptavidin-BV421 daratumumab, RBC levels were lower in 3 of 4 donors tested. There are several factors that may explain the decreased level of drug binding to CD38, including increased RBC hemolysis or reversal of the catalytic domain from outside the cell to inside the cell (Yoshiga et al. (2008 ) Int. J. Mol. Med. 22:369-374). In addition, daratumumab reduced CD38 expression levels, at least in part, through trogocytosis (Colé et al. (2018) Arthritis Res. Ther. 20(1):85); CD38 complexes and the accompanying cell membrane were actively transferred from multiple myeloma cells to monocytes and granulocytes (Kraan et al. (1999) Rheumatology (Oxford) 38(11):1074-1080). One donor (donor 3) had RBC levels that increased with increasing amounts of drug, perhaps as a result of having more CD38 expression on the RBC surface. Additional experiments would be needed to understand 179 decreased drug binding better at the highest concentration tested. The RBC binding profiles of AB79 and daratumumab were compared. As shown in Table 10 and Figures 27 and 28, there appeared to be a difference in the magnitude of RBC binding (ie, MFI) between the drug products in 3 of the 4 donors tested; however, this difference may be attributed to differential levels of biotin in each of the antibodies, with daratumumab having 1.6 to 2.0 times more biotin than AB7 9. An alternative analysis, controlling for a possible difference in fluorescent labeling of the antibodies, is to compare the concentration to the binding profile of each antibody, and a useful metric is the concentration at which maximum binding occurs (ie, maximum specific antigen binding (Bmax)). The Bmax is identical for both antibodies in 3 of 4 donors (eg 1 pg / mL for donor 1). Taken together, these data indicate that both antibodies bind with similar affinities, well within the current resolution limit of the assay, which is a factor of 10. In conclusion, both AB79 and daratumumab bound to RBC in this assay with affinities that were within 10 times each other; there was no 10-fold or greater difference in the binding affinity of these antibodies to RBC within this assay system. 180 Example 5: Evaluation of AB79 hemolysis of human or monkey RBCs in vitro Fresh whole blood from healthy normal human volunteers and Macaca fascicularis, five (n=5) individuals per species, was tested for in vitro hemolysis in response to in vitro treatment with AB79 (27.3 mg / mL; Takeda California, USA) , human IgGl isotype control (7.14 mg / mL of Βίο X Cell) and daratumumab (20 mg / mL; Janssen Biotech, Horsham, PA, USA). A dose response was examined for the test articles of interest at 0, 0.03, 0.08, 0.25, 0.74, 2.2, 6.6, and 20 pg / mL. A semi-log dilution of saponin from a higher 1% saponin solution was evaluated as a positive technical control for blood responsiveness. Treatment was performed for 1 hour at 37°C, 5% CO2 for measurement of acute hemolysis. The absorbance was measured at a wavelength of 540 nm with a spectrophotometer and the percentage of hemolysis was calculated as follows: RZfr? nn / nznz / E / YiAi test sample O.D. - Negative control mean of O.D. hemolytic index - ---------------------------:------------------- -=-------------------------- X 100 hemolytic control 100% O.D. - negative control measurements of O.D. The hemolytic index is classified as follows (hemolytic index = hemolytic grade): 0-2 = non-hemolytic; 2-5 = slightly hemolytic, >5 = hemolytic. Results: RBC of all the individuals of each species, human and Macaca fascicularis, exhibited acute hemolysis in 181 vitro in response to a titration of 1% saponin solution with a hemolytic index greater than 5. AB7 9, daratumumab, and the human IgGl isotype control did not induce detectable hemolysis in any red blood cell samples in the species tested with a non-hemolytic index of zero (Figures 29 and 30). Example 6: Evaluation of AB79 in a Macaca fascicularis collagen-induced arthritic model Expression of the CD38 ectoenzyme is increased on lymphocytes in response to antigenic challenge, and it is believed that targeting these activated lymphocytes could enhance pathological activities in autoimmune diseases. Macaca fascicularis is a suitable model for evaluating the potential effects of CD38 targeting in humans because this species exhibits similar CD38 expression profiles and the anti-human CD38 antibody AB79 binds to monkey CD38 with an affinity (EC50 = 4.5 nM) allowing pharmacological intervention. Therefore, the potential activity of AB7 9 was investigated in a monkey collagen-induced arthritis (CIA) autoimmune disease model. Prophylactic administration of AB79 (3 mg / kg i.v. per week) was well tolerated and prevented the development of arthritis, in contrast to vehicle-treated control animals which exhibited progressive disease with radiographic damage and RZfr? ηη / ηζηζ / Ε / γίΛΐ 182 worsening clinical indices during the course of the study. Therapeutic treatment of arthritic monkeys with AB79 (3 mg / kg i.v. per week) was also well tolerated and reduced disease progression and symptoms. Indices of arthritis and joint inflammation were significantly lower than vehicle control and this was accompanied by decreased blood levels of CRP, ALP, NK cells, B lymphocytes, and T lymphocytes. Histopathology, morphometry, and Radiology revealed significantly less joint damage in animals prophylactically exposed to AB79 treatment compared to vehicle-treated animals and significantly (p<0.05) less damage in animals therapeutically treated with AB79 or dexamethasone (0.1 mg / kg p.o. per day ), illustrating the potential disease-modifying activity. In conclusion, these data indicate that the reduction of cells expressing CD38 could be a therapeutic alternative to treat autoimmune diseases without the deleterious effects of steroids. Methods and materials Antibodies AB79 was available internally. Fluorochrome-conjugated anti-mouse IgG was purchased from Jackson Immunoresearch Laboratories (West Grove, PA). the damper RZfr? nn / nznz / E / YiAi 183 Pharmlyse was obtained from BD Biosciences (San Jose, CA). Fluorochrome-conjugated antibodies to monkey proteins were purchased from several sources: CD20 from BD Biosciences (San Jose, CA); mouse anti-CD3 antibody from eBioscience (San Diego, CA); mouse antibody against CD16 from Miltenyi Biotech (Auburn, CA); mouse antibodies against CD4 and CD8 from R&D Systems. Unconjugated antibodies against AB79 and a humanized control antibody with different antigen specificity but the same Fe IgGl were available in-house, in addition to Alexa Fluor 647-conjugated AB79. Primary antibodies for monkey tissue cross-reactivity investigation they were a rabbit anti-AB79 (generated in-house) and a negative control human IgG1 (Millipore Bioscience Research Reagents, Temecula, CA). Immunohistochemistry of tissues The expression profile of the CD38 antigen was compared in 15 different tissue types collected from human donors and healthy Macaca fascicularis by immunohistochemistry. The suitability of each tissue for detecting CD38 was verified using a positive control antibody against CD31 related transmembrane receptor (Dako North America, Inc.). Sections (5 pm) were cut from freshly frozen tissue samples embedded in OCT compound (Sakura Finetek USA, Inc., Torrance, CA) and 184 fixed them in acetone for 10 minutes at RT. Just prior to staining, slides were fixed for 10 seconds in 10% neutral buffered formalin. Acetone / formalin-fixed cryosections were rinsed twice in phosphate-buffered saline (PBS) and incubated for 20 min with protein block (PBS; 0.5% casein; 5% human gamma globulins; 0.02% IgG). goat; 1 mg / mL heat-added human IgG) designed to reduce non-specific binding. Unconjugated AB79 or a negative control human IgG1 (Millipore Bioscience Research Reagents) was applied to sections at 5 or 25 pg / mL, and this was incubated at RT for 1 hour. Slides were rinsed twice with PBS and an indirect immunoperoxidase procedure was performed to detect these primary reagents. The secondary antibody, rabbit anti-AB79, was then applied at 5 pg / mL for 30 minutes and rinsed twice with PBS. Endogenous peroxidase was blocked by incubating the slides for 5 minutes with the peroxidase solution provided in the Dako EnVision+ kit and then rinsing twice with PBS. Slides were then treated for 30 min with the peroxidase-tagged anti-rabbit-goat IgG polymer supplied in the Dako EnVision+ kit, rinsed twice with PBS and treated for 8 min with Substrate Chromogen (DAB+) solution. supplied in the Dako EnVision+ kit. All the RZfr? nn / nznz / E / YiAi 185 slides were rinsed in tap water, counterstained with hematoxylin, washed, blued in saturated lithium carbonate, washed, dehydrated through alcohols, cleared in xylene, and covered according to standard methods. Staining intensity was scored semiquantitatively by a blinded anatomical pathologist certified by the American College of Veterinary Pathologists (ACVP). Binding of AB79 to recombinant CD38 Chinese hamster ovary K1 (CHOKl) cells stably expressing human, mouse or monkey CD38 were generated to study cell surface binding of anti-CD38 antibodies. CHO-K1 cells (Lonza, USA) were transfected with full-length cDNA clones of human, mouse, or Macaca fascicularis CD38 (Origene Technologies, Rockville, MD). After selection, groups were separated by flow cytometry and clones expressing the highest human, mouse or Macaca fascicularis CD38 (top 15% mean fluorescence intensity (MFI)) were used for binding studies. 200,000 cells per well were plated in a 96-well round bottom plate and stained with 66.7 nM Alexa Fluor® 488 directly conjugated to Ab in 50 pL of FACS buffer (1% BSA in PBS) on ice for 30 RZfr? nn / nznz / E / YiAi minutes to 1 hour. Cells were washed 3 to 4 times in a 186 Final volume of 200 to 250 pL of FACS buffer. The final cell pellet was resuspended in 100L of FACS buffer containing 1% paraformaldehyde. Samples were evaluated on FACS Canto II HTS (BD Biosciences) and analyzed with Flojo software (Tree Star, USA). Flow cytometry of cell lines and whole blood For staining of cell lines, cells were resuspended at 2 x 106 / mL in FACS buffer (5% fetal bovine serum and 0.05% sodium azide in D-PBS (Dulbecco's phosphate buffered saline without calcium). and magnesium) (VWR, West Chester, PA) and 200 µL samples were stained with the appropriate monoclonal antibodies at 4°C for 30 minutes.Samples were washed with FACS buffer and analyzed by flow cytometry (FACSCalibur, BD). For whole blood staining, 200 pL samples from monkeys were stained with the appropriate monoclonal antibody at 4°C for 30 min.BD FACS lysis solution red blood cells were used, and the samples were then washed with FACS buffer and they were analyzed by flow cytometry.In all cases, antibodies were used at saturation concentrations and, in many cases, up to four antibodies per sample were used. AB79 activity in whole blood of Macaca fascicularis Whole blood of Macaca fascicularis was obtained from Charles River Laboratories (Wilmington, MA, USA). For For the fixation assays, anticoagulated Macaca fascicularis peripheral whole blood (100 pL) was incubated with increasing concentrations of AB79 antibody (43-690 nM) for 30 min at RT. Binding of AB79 to cells was assayed using a PE-labeled goat anti-human IgG Fe antibody (Thermo Fisher Scientific). After antibody fixation, red blood cells (RBCs) were used by high-performance lysis without fixative (Thermo Fisher Scientific). Cells were washed twice with magnetically activated cell separation buffer (MACS) containing 0.5% BSA (Miltenyi Biotec). Cell staining data was collected by flow cytometry (Attune NxT acoustic focusing cytometer) and analyzed with FlowJo software. For cytolysis assays, 90 pL of whole blood was placed in each well of a 96-well U-bottom plate. Immediately after plating, whole blood was treated with 0.69, 2.06, 6.17, 18.52, 55.56, 166.67, and 500 nM PBS or AB79 control for 6, 24, and 48 hours. At each time point, blood treated with test and control molecules in the 96-well U-bottom plate was transferred to a deep-well plate for RBC lysis. After lysis, cells were resuspended in staining buffer with antibodies against CD16-BV605, CD56-PE and 188 CD38-FITC for surface marker staining. Cells were protected against light and incubated at 4°C for 20 minutes. After incubation, cells were centrifuged at 350 g at RT for 5 minutes and washed with Annexin V binding buffer IX. Cells were resuspended in Annexin V binding buffer IX containing Alexa Fluor 647 at RT for 15 min. Stained cells were analyzed with a BD FACSCelesta flow cytometer and data were recorded using BD FACSDiva software, version 8.0.1. NK cell viability at each test concentration and IC50 values ​​of AB79 NK cell decline at each time point were plotted and fitted with GraphPad Prism 7.04. Dose-Ranging Studies in Healthy Monkeys In a series of investigations, healthy, experimentally bred Macaca fascicularis with no prior experimental treatment received a vehicle control, 0.03, 0.1, 0.3, and 1 mg / kg of AB79 weekly or at 3, 30, or 80 mg / kg biweekly by infusion. 20-minute intravenous (Charles River Laboratories). In all investigations, animals were evaluated for changes in clinical signs (cage-side observations twice daily, post-dose observations, RZfr? nn / nznz / E / YiAi 189 weekly detailed examinations, food consumption and weekly body weight). Pre- and post-dose blood samples were collected in all investigations to assess pharmacokinetics, pharmacodynamics, and primate anti-human antibodies (PAHAs). Investigations were conducted on Macaca fascicularis in accordance with the SOP (Charles River Laboratories) testing center, which adheres to regulations outlined in the USDA Animal Welfare Act (9 CFR, Parts 1, 2, and 3) and conditions specified in the Guide for the Care and Use of Laboratory Animals (ILAR publication, 1996, National Academy Press). Bioanalytical procedure for the determination of AB79 serum concentrations The concentration of AB79 in Macaca fascicularis serum was measured by an enzyme-linked immunosorbent assay (ELISA) method. This method is an indirect ELISA using a 96-well microtiter format. The plate was coated with a mouse anti-idiotypic antibody against AB79. Blanks, standards, and quality control (QC) samples containing AB79 at various concentrations, as well as monkey serum samples, were added to the coated microtiter plate and incubated for 55-65 minutes at RT. After washing the microtiter plate, the detection antibody (peroxidase-conjugated Affinipure mouse anti-human IgG) was added, and RZfr? ηη / ηζηζ / Ε / γίΛΐ 190 plate was incubated for an additional 55-65 minutes. The plate was washed again, and tetramethylbenzidine (TMB) was added to the wells to generate a chromophore, and color development was stopped by adding stop solution (2N sulfuric acid). Absorbance at 450 nm was measured and AB79 concentrations were calculated using a 4 parameter logistic (1 / y 2) weighted standard calibration curve. Bioanalytical procedure for the determination of anti-AB79 antibodies The anti-AB79 antibody screen of Macaca fascicularis serum was measured by an enhanced guimiluminescence (ECL) method. The design of this qualitative ECL method is such that Macaca fascicularis serum samples were incubated undiluted with 300 mM acetic acid. Acid-dissociated samples were incubated in a mixture of biotinylated AB7 9, SULFO-TAG-tagged AB7 9, and 1.5 M Trizma base to neutralize the acid and form an immune complex. This complex was then added to a streptavidin-coated MSD plate and allowed to set. After washing, the complex was detected by addition of MSD T reading buffer to the plate and subsequent excitation of the SULFO-TAG™ via an electrochemical Ru(bpy)3 reaction to generate luminescence, which was read with the MSD Sector 6000. The amount of luminescence is RZfr? nn / nznz / E / YiAi 191 correlates with the level of Macaca fascicularis anti-AB79 antibodies present in the serum of individual samples. The minimum required dilution (MRD) of Macaca fascicularis serum for this assay was set at 1 / 30. For plotting, all animals were individually plotted as a function of antibody titer and day of enrollment (Figures 31A-31D). Serum samples with values ​​at or below the specific plate cut-off point were represented with a nominal titer value for ease of representation. Monkey Collagen-Induced Arthritis Model Ethically responsible use of non-human primates was ensured by modeling the pharmacodynamic responses of Macaca fascicularis to AB79 and then extrapolating the minimum number of animals required per treatment group to obtain statistically significant differences in PD responses. Thirty-four untreated female Macaca fascicularis, 3-4 years old, and 2.5-3.3 kg, were obtained from Biomedical Research (GZ) Ltd (SNBL China). Upon receipt, the contract research organization (PharmaLegacy Laboratories, Inc., China) performed a health inspection on each animal. Animals were housed one per cage and acclimated for a minimum of 14 days prior to commencement of the experimental procedures. The rooms of the RZfr? nn / nznz / E / YiAi 192 animals were kept at a temperature of 20-29°C with a relative humidity of 40-70% and a light / dark cycle of 12 hours. Animals were trained to receive intravenous infusions or oral gavage prior to the start of the study. The monkeys had on-demand access to vegetables, fruits, food (Shanghai Shilin Biologic Science & Technology Co. Ltd., China) and water according to a conventional protocol. The cages were stratified within the racks to reduce the effect of any environmental influences on the study. This experimental design, all study protocols and experimental procedures were reviewed and approved by the host Ethics Committee (PharmaLegacy Laboratories Inc), in accordance with Chinese law on animal testing. Monkeys were selected for the study based on pre-screening criteria. A naïve animal was not administered collagen and was maintained as a negative control for disease induction. The remaining animals were administered type II bovine collagen (Sichuan, China) dissolved in 0.01N acetic acid (SPGC Sinopharm Chemical Reagent Co., Ltd; Shanghai, China) at a final concentration of 4 mg / mL (Mihara M., et al., Clin Immunol. 2001;98(3):319-26; Uchiyama Y., et al., Biol Pharm Bull. 2008;31(6):1159-63; Uchiyama Y, Koike N, Mihara M. Anemia in monkey collagen-induced arthritis is correlated RZfr? nn / nznz / E / YiAi 193 with serum IL-6, but not TNFa. Rheumatol Int 2008 28:879-883; Kato A., et al., Experimental and Molecular Pathology 2008 84:262-270), on day 0 and day 21 by the subcutaneous route (Miñara et al. (2001) Clin. Immunol. 98(3):319-26 Uchiyama et al (2008) Biol Pharm Bull 31(6) :1159-63 Uchiyama et al (2008) Rheumatol Int 28:879-883 Kato et al (2008) Experimental Mol. Path 84:262-270). The collagen was emulsified with an equal volume of Complete Freund's Adjuvant (CFA) (Sigma-Aldrich; St. Louis, USA). Animals were pre-sedated with ketamine (4 mg / kg i.m. and additional anesthesia applied if necessary, such as 1.5-5% isoflurane (inhalation anesthesia machine, Matrix vip3000 isoflurane) to achieve an oxygen flow rate of 0.8 to 1.5 L. Any ulcerative skin lesions that developed at the immunization sites were treated with iodine each time an animal was sedated to prevent infection. Seven animals that received collagen were assigned to the prophylactic AB79 group on day 0 (FIG. 31A). Animals in the prophylactic AB79 group received weekly infusions of 3 mg / kg of AB79 beginning on day 7, with the last dose administered on day 56, for a total of 8 doses (Figure 31A). Animals in this group were euthanized on day 63. The remaining immunized animals were treated as a group and received a weekly intravenous infusion of vehicle (saline) of 30 RZfr? nn / nznz / E / YiAi 194 minutes from day 7 until an animal reached or exceeded >15% of the maximum Clinical Arthritis Index (CIA). At this point, the animal was enrolled in the vehicle control group, therapeutic AB79 group, or therapeutic dexamethasone group, and enrollment continued continuously due to time differences in disease onset (Figure 31A). . In the case of animals enrolled in the vehicle control group, weekly infusions of vehicle were performed for 5 weeks (FIG. 31A). Animals in this group were euthanized 7 days after the last dose. In the case of animals enrolled in the therapeutic AB79 group, weekly infusions were performed for 5 weeks (FIG. 31A). Animals in this group were euthanized 7 days after the last dose. Animals enrolled in the dexamethasone therapeutic group received daily oral gavage for 5 weeks (Figure 31A) and were euthanized 1 day after the last dose. Animals were observed daily for signs of ill health and general reaction to treatments. All exceptions to normal healthy appearance and behavior were recorded and detailed on standard clinical observation forms. Assessment of arthritic activity The body weight of the monkeys was measured once during RZfr? nn / nznz / E / YiAi 195 the acclimatization period (5 days before the start of the experiment), the day before each disease induction cycle, and then once a week until the end of the study. The number of animals in a group with joint inflammation was recorded on day 0 and day 21, and then daily until the end of the study. The number of proximal interphalangeal (PIP) joints (each hand and foot, respectively) with inflammation was recorded for each animal on day 0, day 21, and then once weekly until the end of the study. The longitudinal and transverse axes of the PIP joints of the forelimbs and hindlimbs (without thumb) were measured with calipers on day 0, day 21, and then once a week after disease onset until the end of the study for all subjects. PIP with arthritis. The mean oval area of ​​16 PIP joints was calculated and adopted as individual data. The oval area of ​​each PIP was calculated with the following formula: Oval area = longitudinal axis χ transversal axis * 3.14 * 1 / 4. The percentage change of oval area and joint inflammation was calculated with the following formula: % change of oval area = (mean oval area on day X / mean oval area on day of first sensitization) x 100. Joint inflammation = (mean oval area on day X - mean oval area on day of first sensitization). 196 clinical arthritis index The severity of arthritis of each limb in the monkeys was scored on day 0 and day 21, and then weekly until the end of the study according to these criteria: (0) normal; (1) mild, subtle but definite arthritis; (2) moderate inflammation; (3) severe arthritis with significant inflammation and / or marked deformity of the joints. The following joints in each paw were examined and scored: 15 total joints, including 5 metacarpophalangeal (MCP) joints, 4 joints PIP (proximal interphalangeal); 4 DIP (distal interphalangeal) joints, 1 interphalangeal joint of the first digit; each wrist or ankle was scored as a single compound joint. The knee / elbow of each member was also evaluated to determine the severity of the disease. The arthritic index of each animal was the total index of each individual joint with a maximum index of 192 (16X3x4) (16: total number of joints plus knee / elbow for each limb; 3: maximum index for each individual joint; 4: number of limbs per monkey). Blood collection and analysis Blood samples for CBC, blood chemistry and serum preparation for antibody, PK and ADA measurements were used and collected from animals at the points RZfr? nn / nznz / E / YiAi 197 temporary indicated below. Vehicle control group and prophylactic AB79 group animals: During weeks 1 and 5, blood was collected twice, once pre-dose and once the following day. During weeks 2, 3, 4, 6, 7 and 8, blood samples were collected just prior to AB7 9 administration. During week 9, blood samples were collected when the animals terminated their participation. All other animals had weekly blood collections until the time the disease reached the threshold of 15% of the maximum rate of arthritis. After assignment to the vehicle group, therapeutic AB79 group, or therapeutic dexamethasone group, blood samples were collected weekly just before and at the end of the dose. In addition, samples were collected the day after the first dose of the drug and the day after the fifth dose. For vehicle control, AB79 prophylactic, AB79 therapeutic, and dexamethasone therapeutic groups, blood samples for flow cytometry were collected prior to the first dose (on the day of infusion), the day following the first dose, before the second dose (on the day of dosing), before the fifth dose (on the day of dosing), and on the day of completion. For the therapeutic AB79 group, blood samples for flow cytometry were collected before the first dose of the drug, the day after the 198 first dose, before the eighth dose, before the 29th dose and the day of completion. radiographic examination Examinations for each joint (DIP, PIP, 1.aIP and MCP - sites generally implicated in human RA) were performed on the hands and paws of live and anesthetized animals at the end of the study. Radiographic classification was performed blindly, based on a 0-4 classification system: (0) normal; (1) minor deformity in articular cartilage layers and / or subchondral bone regions; (2) severe deformity in articular cartilage layers and subchondral bone regions, a small number of osteophytes present on periosteal surfaces and joint margins that are blurred but still visible; (3) the same types of changes seen in grade 2, but more advanced, and a large number of osteophytes present on the periosteal surfaces, the joint cavity is indistinguishable or invisible; (4) the same type of changes as in grade 3, but more advanced, the joint cavity becomes undetectable, the bones appear to be sclerotic or ankylosing, and significant disfigurement occurs. Histopathology and histomorphometry of tissue from arthritic monkeys The animals were euthanized by exsanguination. RZfr? nn / nznz / E / YiAi 199 under anesthesia at the end of the study. Paws, spleen, colon, and lymph nodes (mesenteric and inguinal) were collected and fixed in neutral buffered formalin. PIP and DIP joints were decalcified with 15% EDTA, dehydrated and paraffin embedded: (8 blocks / paw x 4 paws x 22 animals = 704 blocks). Frontal coronal sections of the joints were obtained with a rotary microtome. Histopathology scoring was performed by a bone histopathologist on toluidine blue stained sections (32 x 22 animals = 704 slides) in a blind manner. Histology sections were qualitatively evaluated to determine the following histopathological features: cell infiltration, panicle, cartilage lesion, and bone resorption. Quantitative histomorphometry was performed with Osteomeasure software (OsteoMetrics, Inc., Atlanta, GA) interfaced with a Nikon Eclipse E400 light / fluorescent microscope and video subsystem. Histomorphometric measurements of joint surface and joint area were performed in a blind manner by a bone histopathologist using toluidine blue-stained slides (704 slides). Statistic analysis Data are presented as mean ± standard error of the mean (SEM). Statistical analyzes were carried out with GraphPad Prism on each parameter between groups without RZfr? nn / nznz / E / YiAi 200 prior treatment, model, from reference drug (dexamethasone) and from test article, p < 0.05 was considered significantly different. Results CD38 expression profile in Macaca fascicularis To determine whether Macaca fascicularis could be a suitable model for evaluating the potential effects of CD38 targeting in humans, the CD38 antigen expression profile was compared in 15 different types of tissues collected from human donors and healthy Macaca fascicularis. Immunohistochemistry revealed that AB79 bound to mononuclear leukocytes in the colon, stomach, small intestine, bone marrow, and lymph nodes, as well as some endothelium in the lamina propria of the colon, stomach, and small intestine in both. species (Table 11). RZfr? nn / nznz / E / Yi 201 Table 11. Comparison of CD38 expression profiles in RZfr / nn / nznz / B / Yir human and monkey tissues Human Monkey anti-CD38 mAb Human lgG1 control anti-CD38 mAb Human lgG1 control Tissue 5 pg / mL 25 pg / mL 5 pg / mL 25 pg / mL AB79 Comments 5 pg / mL 25 pg / mL 5 pg / mL 25 pg / mL Comments fromAB79 Bone Marrow 3, C / M 2+, M Neg Neg Bone Marrow Cells, Possibly WBCs 1+, C / M 1+, M Neg Neg Few Bone Marrow Cells, Possibly WBCs Heart Neg Neg Neg Neg Neg Neg Neg Neg Colon 3+, C / M 4+, C / M Neg Neg Leukocytes, including lymphocytes, in lamina propria; some endothelium 2+, C / M Neg Neg Neg Cells in lamina propria, possibly lymphocytes, some endothelium Stomach Neg Neg Neg Neg Leukocytes, including lymphocytes, in lamina propria; some endothelium 1 +, C / M 1+, C Neg Neg Spindle cells in lamina propria, apparently endothelium Small intestine 4+, C / M 4+, C / M Neg Neg Leukocytes, including lymphocytes, in lamina propria; some endothelium 2+, C / M 1+, C / M Neg Neg Cells in lamina propria, possibly lymphocytes, some endothelium Renal glomerulus Neg Neg Neg Neg in lamina propria; some endothelium Neg Neg Neg Neg Renal tubule Neg Neg Neg Neg Neg Neg Neg Neg Liver Neg Neg Neg Neg Neg Neg Neg Neg Lymph node 3+, C / M 4+, C / M Neg Neg Cells in cords and medullary sinuses; possibly plasma cells; few in cortex 4+, M 3+, C Neg Neg Cells in cords and medullary sinuses, fewer in cortex Lung 3+, C / M 3+, C / M Neg Neg Interstitial and peribronchial cells Neg Neg Neg Neg Pancreas Neg Neg Neg Neg Neg Neg Neg Neg Prostate 3+, C 3+, C Neg Neg Acinar epithelium; some interstitial leukocytes Neg Neg Neg Neg Skin Neg Neg Neg Neg Neg Neg Neg Neg Ear - cervix 2+, C / M 1 +, C / M Neg Neg Submucosal leukocytes, probably lymphocytes Neg Neg Neg Neg Ear endometrium Neg Neg Neg Neg Neg Neg Neg Neg Staining intensity: 1+ = minimal, 2+ = mild, 3+ = moderate, 4+ = marked, Neg = negative, M = missing. Staining frequency of a particular cell type: very rare (VR: <25% of cells); rare (R: 25-50% of cells); occasional (O: >50-75% of cells); frequent (F: 76-100% of cells). Staining pattern includes cell type or tissue element (details specific to that cell type (for example, epithelium) or tissue element (for example, basement membrane) and subcellular or extracellular (membrane, cytoplasm, cytoplasmic filaments, initial membrane). ). 202 In contrast, in humans, but not monkeys, AB79 also binds to mononuclear leukocytes in the liver, lung, prostate, and uterus (cervix), and to the prostatic acinar epithelium. AB79 binding was not observed in the heart, kidney, pancreas, skin and endometrium of the uterus of any of the species. AB7 9 staining was generally moderate to strong intensity (3+ to 4+) in human tissues and minimal to mild intensity (1+ to 2+) in Macaca fascicularis tissues (Table 11), which could reflect the difference in affinities of AB79 to human CD38 compared to monkey and / or to differences in the magnitude of CD38 expression. The staining pattern was mainly cytoplasmic and cell membranes were stained in some cells (Table 11). Overall, it was concluded that the monkey was a suitable model species for evaluating the potential pharmacological effects of targeting CD38 in a model of autoimmune disease. AB79 binds to CD38 expressed by Macaca fascicularis The amino acid sequence of the human CD38 protein exhibits 91% amino acid identity with its Macaca fascicularis ortholog, 59% with mouse and rat, and 54% with rabbit. A comparison of the AB79 binding epitope on human CD38 with the corresponding sequence on monkey CD38 revealed a single amino acid substitution of a lysine with a glutamate at position 274. To determine whether AB79 RZfr? nn / nznz / E / Yi 203 could be used to assess the possible effects of targeting to CD38 in monkeys, monkey CD38 was expressed in Chinese hamster ovary (CHO) cells and AB79 bound to monkey CD38 with a mean maximum effective concentration (EC50) of 4.5 nM (FIG. 32A). This value is approximately 10-fold lower than the binding affinity of AB7 9 to human CD38 expressed by CHO cells (KD = 0.7 nM), indicating that AB79 binds to monkey CD38 less potently in Macaca fascicularis than in its counterparts. human counterparts. AB79 also bound to monkey B and T cells and NK cells in whole blood, and NK cells exhibited a higher mean fluorescent intensity than B cells and T cells (Figure 32B), indicating that monkey NK cells express a higher density of CD38 per cell. After incubation with monkey whole blood in vitro, AB79 cytolyzed NK cells in a dose-dependent manner (Figure 32C) and exhibited a mean EC50 of 29.6 nM, which was approximately 30-fold less potent than NK cell cytolysis. of human peripheral blood by AB79 (data not shown). Taken together, these data indicate that Macaca fascicularis may be less sensitive to the pharmacological effects of AB79 than humans. However, this cross-reactivity profile, as well as the similarity in the CD38 expression profiles, suggest that Macaca fascicularis is a suitable model species for RZfr? nn / nznz / E / Yi 204 to investigate the possible pharmacological effects of AB7 9 in RZfr? nn / nznz / E / Yi live. Pharmacological effects of AB79 in healthy monkeys To characterize the pharmacological effects of AB7 9 in vivo, healthy Macaca fascicularis were infused IV with AB79 at 0.03, 0.1, 0.3, and 1 mg / kg weekly and at 3, 30, and 80 mg / kg biweekly for 3 months, and a subset of the Animals were monitored for 3 months after the last dose (Figure 31A). Peak AB79 concentrations generally occurred at the end of the infusion and were generally dose proportional (Table 12). Table 12. Mean serum pharmacokinetic parameters of AB79 after intravenous infusion in female Macaca fascicularis Dose (mg / kg) 0.1 Schedule Dose sampling time Weekly Week 1 Week 13 Cmax (pg / mL) 1.77 2.49 AUC366 (h*pg / mL) 104 218 T1 / 2 (h) NC NC 0.3 Weekly Week 1 Week 13 4.32 7.78 327 665 NC NC 1.0 Weekly Week 1 Week 13 21.1 28.6 1630 2700 NC NC 3 Qual -year week 1 week 13 62.1 90.1 7600 18,400 NC 237 30 WINDP 220,000 456,000 NA 415 Exposure generally increased dose-proportionally at steady state in animals that did not display anti-AB79 antibodies and accumulated from 1.7 to 205 2.4-fold at week 13 (Table 12), which is consistent with decreased clearance due to AB7 target-mediated drug disposition 9. The half-life after the last dose of animals in cohorts 3 and 80 mg / kg that did not exhibit anti-AB79 antibodies was 237 and 415 hours, respectively (Table 12). No gender differences were observed in PK characteristics. The NK cell population expressed CD38 at a uniformly high density (Figure 32B) and was reduced in peripheral blood after the first AB79 infusion with an ED50 of 0.3 mg / kg (Figure 31B), a corresponding Cmax of 7.63 ug / mL. and a mean overall exposure of 665 h*pg / mL at week 13 (Table 12). In contrast, the B cell population expressed CD38 heterogeneously, with a lower median NK cell density (Figure 32B), and it was reduced in peripheral blood after the initial infusion of AB7 9 with an ED50 of 1.0 mg / kg ( Figure 31C), a Crax of 21.1 ug / mL and a mean overall exposure of 2700 h*pg / mL at week 13 (Table 12). The T cell population also heterogeneously expressed CD38 with an even lower median density than B cells (data not shown), and it was reduced in peripheral blood after the first infusion of AB79 with an ED50 of 30 mg. / kg (Figure 31D), a Cmax of 62.1 ug / mL and a mean overall exposure RZfr? nn / nznz / E / Yii of 18400 h*pg / mL at week 13 (Table 12). Collectively, 206 These dose range finding data indicated that a weekly dose of 3 mg / kg would maintain total NK cell, B cell, and T cell populations at greater than 80, 60, and 20% of baseline peripheral blood levels, respectively. . Profile of AB7 9 in collagen-induced arthritis The potential efficacy of AB79 was investigated with a model of CIA in Macaca fascicularis, a species whose immune system, joints, and skeletal anatomy are similar enough to their human counterparts to allow the use of clinical indices. To induce arthritis, the monkeys were treated intradermally on day 0 and day 21 with type II collagen (Figure 33), and the appearance of anti-collagen antibodies confirmed the successful immunization of each animal (data not shown). One group of animals was treated on day 7 with a 3 mg / kg prophylactic AB7 9 treatment regimen that continued for 8 weeks. In all 3 therapeutic groups, monkeys with overt disease were randomized and given a vehicle control, TAK 079 3 mg / kg or dexamethasone 0.1 mg / kg. Therapeutic treatment continued for 5 weeks after the initiation of treatment ( Figure 33 ). AB79 was well tolerated in both prophylactic and therapeutic regimens. The healthy control monkey gained body weight RZfr? nn / nznz / E / Yi 207 over time, whereas collagen-immunized monkeys in the other four groups began to lose body weight from day 7 (FIG. 34A), indicating a systemic impact associated with the development of arthritis. Based on the percent change in body weight with RZfr? nn / nznz / E / Yi relative to baseline body weight at enrollment, animals in the prophylactic AB79 group, the therapeutic AB79 group, and the therapeutic dexamethasone group were found to regain their body weight from the age of 14 days after initiation of treatment, suggesting a therapeutic benefit of both AB7 9 and dexamethasone positive control treatment. Weight gain approached near normal levels in monkeys treated with AB79 and dexamethasone compared with a healthy, untreated control; vehicle-treated arthritic animals lost weight (FIG. 34A). Arthritis severity was assessed using the Clinical Arthritis Index, which is a global assessment of disease activity that considers each measurable joint in the animal over the course of the study using a 192-point scoring system. Vehicle-treated animals exhibited progressive disease, with increasing clinical indices over the course of the study (Figure 34B). Prophylactic exposure to AB79 prevented the development of arthritis 208 significantly (p < 0.01) compared to the vehicle control. Similarly, therapeutic treatment with AB79 or dexamethasone inhibited the development of arthritis significantly (p<0.05) compared to vehicle control and reduced arthritis indices from pretreatment baselines (Figure 34B). Similar effects were observed in the PIP joint subset, both with respect to the number of PIP joints inflamed (Figure 34C) and the mean overall inflammation of all PIP joints (Figure 34D). To obtain a comprehensive assessment of arthritic joints and the possibility that AB79 has disease-modifying activity in human arthritis, radiographic examination was performed for each IP and MCP joint. Prophylactic exposure to AB79 prevented damage to PIP (data not shown), DIP (Figure 34E), and MCP (Figure 34F) joints significantly (p < 0.01) compared to vehicle control. Similarly, therapeutic exposure to AB79 or dexamethasone resulted in significantly less damage (p < 0.05) in PIP (data not shown), DIP (Figure 34E) and MCP (Figure 34F) joints than in vehicle control animals. . To characterize the components of progressive arthritis, DIP and PIP joints were analyzed histologically with respect to cellular infiltration, panniculus severity, RZfr / nn / nznz / B / Yi 209 cartilage damage, bone resorption, and osteophyte formation. Prophylactic challenge to AB79 resulted in composite indices that were significantly (p<0.01) less than the vehicle control value and of comparable magnitude with collagen non-immunized animals (FIG. 35A). AB79 had a similar effect on each component; indices were significantly lower (p < 0.01) than the vehicle control value for panicle (Figure 35B), infiltrating leukocytes (Figure 35C), cartilage lesions (Figure 35D), bone resorption (Figure 35E), and osteophyte formation. (Figure 35F). Similar differences of lesser magnitude were also observed for therapeutic treatment with AB79 or dexamethasone (Figures 35A-35E), although not all differences reached statistical significance. Quantitative histomorphometry was performed on all DIP and PIP joints in blinded studies by a board-certified veterinary pathologist, including articular cartilage area (Figure 36A), thickness of articular cartilage damaged (Figure 36B), percentage of articular surface damaged (Figure 36C) and osteophyte area compared to the total periosteal surface (Figure 36D). All parameters illustrate that prophylactic exposure to AB79 significantly prevented the development of joint damage. RZfr? nn / nznz / E / Yi Therapeutic treatment with AB79 reduced the severity of the 210 disease, although some histomorphometric measurements did not reach statistical significance. The therapeutic effects of AB79 were similar to therapeutically administered dexamethasone. C-reactive protein (CRP) (Figure 37A), alkaline phosphatase (ALP) (Figure 37B) and albumin (ALB) levels (data not shown) correlated with disease severity. Prophylactic treatment with AB79 prevented the inflammation-associated increases in CRP (Figure 37A) and ALP (Figure 37B) observed in the vehicle control animal. Therapeutic treatment with AB79 caused a rapid decrease in CRP and ALP, while prolonged treatment with dexamethasone was required to reduce CRP and ALP levels (Figures 37A and 37B, respectively). No evidence of liver damage was found in serum chemistry parameters (eg, increased ALT or AST), suggesting that the increased ALP was due to the development of bone disease in CIA animals, and that the decreased of ALP was due to reduced bone damage in animals exposed to AB79. Serum chemistry values ​​for creatinine, blood urea nitrogen, glucose, and total protein varied with time but did not show a consistent correlation with arthritis severity or treatment regimen (data not available). RZfr? nn / nznz / E / YiAi shown). 211 Hematology, complete blood count, and differential analysis were performed during the study and key parameters were reported. No changes in RBC levels were observed after exposure to AB79 or dexamethasone (FIG. 38A). In addition, the hematocrit count decreased after the development of arthritis and increased back toward naïve control levels after treatment with AB79 or dexamethasone (FIG. 38B). Reticulocytes were elevated after the development of arthritis and both AB79 treatment and dexamethasone treatment reduced the reticulocyte count towards the normal level found in the naïve control (FIG. 38C). Both platelet and neutrophil levels were increased with arthritis and AB79 treatment reduced both platelet and neutrophil levels toward no-treatment control, whereas dexamethasone had no effect (Figures 38D and 38E, respectively). In contrast, total lymphocyte levels decreased with disease relative to no-pretreatment control and AB79 treatment, as expected, and further reduced lymphocyte levels, while dexamethasone treatment had no effect (Figure 38F). ). Among peripheral blood lymphocyte subsets, NK cells were reduced >95% below baseline levels (Figure 39A) within 24 hours. RZfr? nn / nznz / E / YiAi 212 post-AB79 exposure, whereas baseline levels of B lymphocytes (Figure 39B), T lymphocytes (Figure 39C), and monocytes (Figure 39D) were reduced by a maximum of 60%, 55%, and 50%, respectively. NK cell and B cell reductions were maintained during dosing, while T cell and monocyte reductions were transient and only observed after the first infusion. A similar pattern of reduction was observed in each cell population after treatment with prophylactic AB79, except that this group of animals had lower monocyte levels before treatment, and monocyte levels did not change in response to treatment. No differences in B cell, T cell, NK cell or monocyte counts were observed between vehicle and dexamethasone treated animals (Figures 39A, 29D and 29F, respectively). A serum bioassay was performed to measure the concentrations of AB79 and anti-AB79 antibodies. Substantial exposure was achieved in each animal dosed prophylactically (Figure 40A) or therapeutically (Figure 40B), and Cmax ranged from 24-97 ug / mL. All animals challenged with AB79 exhibited trough concentrations that exceeded the EC50 for CD38 saturation (Figure 32A) and NK cell lysis (Figure 32C) in vitro. Anti-AB79 antibodies were detected in 4 of 7 animals in the group RZfr? nn / nznz / E / YiAi 213 prophylactic (Figure 40C) between 14 and 30 days after the initial dose and until the end of the study. Two animals exhibited high titers corresponding to low concentrations of AB79 in these animals at day 31 (Figure 40A), indicating that these anti-AB79 antibodies may be affecting clearance. Anti-AB79 antibodies were also detected in 4 of 5 animals in the therapeutic group (Figure 40D) from 21 days after the initial dose to the end of the study, and two animals also exhibited high titers corresponding to low concentrations. of AB79 in these animals at the end of the study ( Figure 40B ). However, all animals were included in the data analyzes because most of the target cells remained reduced from baseline levels throughout the study (Figures 39E and 39F), with the exception of T cells after the second dose. therapeutic (Figure 39G). Analysis CD38 efficiency in mice was reported to result in attenuated forms of CIA, illustrating non-redundant roles for this molecule in an autoimmune disease model; however, the function of CD38 cells in primate models has not been investigated. In addition, numerous studies have indicated that the overall level of CD38 expression on peripheral blood cells correlates RZfr? nn / nznz / E / YiAi 214 positively with disease activity in human patients with RA and SLE (Colé S., et al., Arthritis Res Ther. 2018 May 02;20(1):85; Kraan M.C., et al., Rheumatology (Oxford) 1999 Nov;38(11):1074-80;Vital E.M., et al., Arthritis Rheum.2011 Oct;63(10):3038-47;or Banchereau R., et al., Cell 2016 Apr 21;165(3):55165) . The anti-CD38 mAb AB79 decreased plasma cells in blood or bone marrow samples from patients with RA or SLE in vitro (Smithson et al. (2017) J. Immunol. 198 (1 supplement) 224.20; Colé et al. (2018 ) Arthrit Res Ther 20(1):85 Wang et al (2016) Arthrit Rheumatol 68(Supplement 10) 2016 ACR / ARHP Annual Meeting 1085 Mihara M. et al. Clin Immunol 2001;98(3):319-26 and Uchiyama Y., et al., Biol Pharm Bull 2008;31(6):1159-63). Unlike other anti-CD38 mAbs in development (eg, daratumumab, isatuximab, and MOR202), AB79 binds to CD38 expressed by Macaca fascicularis and provided a unique opportunity to determine whether reducing the level of CD38-expressing cells would prevent and / or would ameliorate inflammation and tissue damage in a non-human primate model of autoimmunity. AB7 9 is a high-affinity monoclonal antibody that effectively mediates CD38+ lymphocyte depletion (Smithson, G., et al., J Immunol 2017 May 01, 198 (1 supplement) 224.20). Comprehensive analysis reveals that CD38 is a cell-rich pre-disease therapeutic target 215 established rheumatoid arthritis and systemic lupus erythematosus (Colé S., et al., Arthrltls Res Ther. 2018 May 02;20(l):85). Macaca fascicularis was determined to be a suitable model for evaluating the possible effects of AB79 on an autoimmune disease because ASD in these monkeys presents a symmetrical small articular polyarthritis resembling human RA (Mihara et al. (2001) Clin. Immunol 98(3):319-26 Uchiyama et al (2008) Biol Pharm Bull 31(6):1159-63 Uchiyama et al (2008) Rheumatol Int 28:879883 Kato et al al (2008) Experimental Mol Path 84: 262-270 Expression profiles for CD38 are similar between these species (Table 11), and AB79 bound to monkey CD38 with 10-fold lower affinity than CD38. (Figures 32A32C) It was concluded that a weekly dose of 3 mg / kg of AB79 would be adequate to assess the potential role of CD38 in ASD because dose-ranging studies in healthy monkeys indicated that a weekly dose of 3 mg / kg kg of AB79 would reduce total NK cell, B cell, and T cell populations by more than 80, 60, and 20% of initial levels. cials in peripheral blood, respectively (Figures 31B, 31C and 31D). Similar reductions in NK cells, B cells, and T cells were achieved in the CIA model for the prophylactic dose (Figures 37E, 37F, and 37G) despite the appearance of anti-AB79 antibodies in some animals (Figures 39C and 37G). RZfr? ηη / ηζηζ / Ε / γίΛΐ 216 39D) . The decrease in AB7 9 concentration over time in 3 prophylactically challenged animals (Figure 39A) indicates that these antibodies may have increased clearance; however, B and T lymphocytes and NK cells had not recovered to baseline levels at study completion (Figures 37E, 37F, and 37G), indicating that AB79 exposures were sufficient to maintain the effects of PD for all the research. Therefore, these animals were included in all analyses. This was also generally true for AB79 therapeutic treatment. B lymphocytes and NK cells had not recovered to baseline levels at study completion (Figures 37E, 37F and 37G), indicating that AB79 exposures were sufficient to maintain PD effects throughout the investigation. In contrast, T-lymphocyte counts had recovered to baseline levels by study completion (Figure 37G), suggesting that anti-AB79 antibodies might partially confound the interpretation of therapeutic data (ie, underestimate the contribution of T cells). CD38-expressing T cells in monkey CIA). Prophylactic administration of AB7 9 prevented the development of arthritis, as consistently illustrated in all evaluations, whereas therapeutic treatment with AB79 inhibited the development of arthritis and damage. 217 articular (Figures 34A-36F). Histological evaluation of the joints demonstrated that AB79 exerted relatively broad effects, preventing panicle formation (Figure 35B), infiltration (Figure 35C), cartilage lesions (Figure 35D), bone erosion (Figure 35E), and osteophyte formation (Figure 35E). 35F). Of note, therapeutic treatment with AB79 and dexamethasone also inhibited these progressive histologic changes, although to a lesser extent than prophylactic administration. Arthritis indices decreased over time with therapeutic treatment (Figures 34B, 34C and 34D), indicating a possible reversal of damage. Collectively, these data demonstrated disease-modifying effects consistent with prophylactic and therapeutic exposure to AB79. The effect of these therapeutic treatments with AB79 and dexamethasone appear comparable to each other for the regimens investigated. The therapeutic use of steroids, such as dexamethasone, is highly effective in the treatment of human autoimmune diseases, including RA and SLE; however, detrimental side effects (eg, osteoporosis, hypertension, diabetes, weight gain, cataracts, glaucoma, thinning of the skin, and bruising) restrict the chronic use of these therapeutic agents. The potential of targeted CD38 cell knockdown to provide comparable efficacy in diseases RZfr? nn / nznz / E / YiAi 218 human autoimmune without the deleterious side effects of steroids warrants future clinical investigation. The prophylactic and therapeutic effects of AB7 9 were associated with sustained reductions in the blood level of total lymphocytes (Figure 38F), NK cells, B and T lymphocytes (Figures 37C-37E), a transient reduction in monocytes (Figure 37F), and no changes in red blood cells (Figure 38A), platelets (Figure 38D) and neutrophils (Figure 38E). These pharmacodynamic data illustrate that there are differences in the sensitivity of cells expressing CD38 to knockdown by AB79. The reduction generally correlated with the density of CD38 expression per cell; the NK cell population uniformly expressed the highest median CD38 density of all cell types examined (Figure 32B) and was the most sensitive to AB7 9 (Figures 31B and 37C). The highest density of CD38 expressed on B cells was approximately 3-fold lower than on NK cells (Figure 32B) and the B cell population was less sensitive to AB79 than on NK cells (Figures 31C and 37C). CD38 is generally expressed at lower median densities on T cells than on B cells (Figure 32B), and T cells were less sensitive to knockdown by AB79 than were B cells and NK cells (Figures 31D and 37D). . Cells expressing low densities of CD38 (for 219 example, red blood cells) or do not express CD38 (eg, neutrophils) were not affected by AB79 (Figures 37A, 37D and 37E). An exception is monocytes, which express CD38 uniformly at intermediate densities and were only transiently reduced by AB79 (Figure 37F). The kinetics of the transient reduction in monocytes is different from the sustained reduction observed for B cells, T cells, and NK cells and indicates different mechanisms. Direct cytolysis of NK cells by AB79 was observed in vitro (Figure 32C) and a sustained reduction in NK cells, B cells, and T cells occurs after a single dose of AB7 9 in vivo (data not shown), which indicating that CDC and / or ADCC mediate these depletions of B, T, and NK cells in vivo. In contrast, monocytes were not cytolyzed in vitro (data not shown) and do not exhibit sustained reduction in vivo ( Figure 37F ), indicating that an alternative mechanism (eg, margination) mediates transient reductions in vivo. Resistance of human monocytes to cytolysis by AB79 has also been observed in healthy subjects (unpublished) and has been described for daratumumab in patients with multiple myeloma (Nijhof et al. (2016) Blood 128(7):959-70 ). Expression of CDC and ADCC inhibitors by human monocytes did not significantly correlate with resistance to cytolysis by daratumumab and it is not known why monocytes are 220 relatively insensitive to daratumumab and AB7 9. While the reduction in NK cells observed with AB79 is qualitatively consistent with the depletion of NK cells by daratumumab in patients with resistant myeloma, there are quantitative differences. The IV infusion dose (0.3 mg / kg), maximum concentration (Cmax= 4.32 ug / mL), and exposure (AUC366 = 327 pg-h / mL) of AB79 required to maintain peripheral blood NK cells at 50% below baseline levels in monkeys (Figure 31B) were approximately 80, 116, and 297-fold lower than the corresponding IV infusion dose (24 mg / kg), peak concentration (Craax-573 ug / mL), and exposure (AUCinf- 97175 pg-h / mL) required for comparable NK cell reductions by daratumumab in patients with resistant myeloma (Casneuf et al. (2017) Blood Adv. 1 (23):2105-2114; Clemens et al. (2017) Clin. Pharmacokinet 56(8):915-924. Of note, AB79 binds to monkey lymphocytes with an affinity (KD = 4 nM) that is similar to the binding of daratumumab to cells expressing human CD38 (KD = 4 nM) (Center for Evaluation and Research Application Number). Drugs: 761036origls00 Pharmacology Reviews); however, it is unknown whether these differences are the result of a potential difference between species, disease states, and / or the potency of the respective antibodies. However, a more definitive comparison RZfr? nn / nznz / E / Yi 221 requires pharmacokinetic and dynamic data for AB7 9 in patients with resistant myeloma because daratumumab does not cross-react with CD38 from mouse, rat, rabbit, pig, Macaca fascicularis and Macaca mulatta (April 1, 2016 EMA / 278085 / 2016, evaluation report of the Committee for Medicinal Products for Human Use, Darzalex International non-proprietary name: daratumumab, procedure No. EMEA / H / C / 004077 / 0000). In conclusion, a reduction in cells expressing CD38 with the cytolytic antibody AB79 prevented the development of CIA in monkeys when administered prophylactically and reversed disease progression when administered therapeutically. A previous study using blood and bone marrow samples from SLE patients demonstrated that AB79 decreased 80% of short- and long-lived plasma cells and reduced autoantibodies (eg, VH4-34 9G4+, anti-Ro, and anti-dsDNA). ) in vitro (Wang et al. (2016) Arthritis Rheumatol. 68(Supplement 10). 2016 ACR / ARHP Annual Meeting, 1085). These collective data suggest that this therapeutic strategy may be effective in the treatment of human RA, SLE, and other autoimmune diseases. Example 7: Evaluation of ΆΒ7 9 in healthy human volunteers This investigation characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of AB79 using a randomized, double-blind, controlled trial with RZfr? nn / nznz / E / Yi 222 placebo of an intravenous (IV) infusion or subcutaneous (SC) injection of AB79 at increasing doses in healthy subjects. Results AB79 was well tolerated. All adverse events (AEs) were mild or moderate and there were no withdrawals due to AEs or infusion or injection site reactions during tested IV and SC doses up to 0.06 and 0.6 mg kg-1, respectively. At higher doses, transient increases in cytokine levels, mainly after IV administration, coincided with the reduction in CD38-expressing cells; clinical symptoms mainly included mild pyrexia, headache, and postural hypotension. No notable findings for laboratory tests, electrocardiograms, vital signs, or physical examinations related to AB79 treatment were reported. AB79 reduced plasmablast and natural killer (NK) cell levels at similar doses, with 50% of the maximum effective dose of approximately 0.003 and 0.1 mg kg-1 for IV and SC administration, respectively. Reductions in immunoglobulin (Ig)M and IgA occurred without comparable changes in IgG. Total white blood cell, granulocyte, lymphocyte, red blood cell, and platelet counts were maintained within normal ranges for all dose levels. conclusions AB79 reduced the levels of plasmablasts and NK cells in RZfr / nn / nznz / B / Yi 223 peripheral blood from healthy subjects when administered IV or SC and was generally safe and well tolerated. The SC dose was better tolerated with a longer lasting decrease in target cells than the IV dose. This plasmadtolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts (eg, multiple myeloma and NK cell leukemia), and pathogenic immunoglobulins. Study design and objectives This was a phase 1, randomized, double-blind, placebo-controlled, single-dose first-in-human study (FIH) of AB79 in healthy adult subjects. The primary objective of the study was to evaluate the safety and tolerability of increasing single doses of AB79 after IV infusion or SC injection. Secondary objectives were to assess PK and PD in blood cell populations and immunogenicity. A total of 74 subjects were enrolled in this study. After two screening visits, separated by a minimum of five days within a 28-day window prior to randomization, subjects were admitted on pre-dose day -2 for baseline assessments. AB79 was administered on day 1 via a 2-hour IV infusion at sequential ascending doses of 0.0003, 0.001, 0.003, 0.01, 0.03, or 0.06 mgkg~1 in six cohorts, or by SC injection at a dose of 0.03, RZfr? nn / nznz / E / Yi 224 0.1, 0.3 or 0.6 mgkg-1 in four other cohorts. Dose selection was based on a PK / PD model derived from a series of studies in Macaca fascicularis (Roepcke et al. (2018) Pharmacol Res Perspect. 6(3):e00402). At each dose level, six to eight subjects were randomized to AB79 (n=4 to 6) or matched placebo (n=2). A sentinel dose was used for each cohort with two baseline subjects receiving AB79 or placebo (1:1). The 24-hour post-dose safety and tolerability data for these two subjects were reviewed before the remaining subjects in each cohort were dosed. Participants were confined to an inpatient Clinical Pharmacology Unit (CPU) until day 8, followed by weekly or biweekly follow-up visits, where the last planned clinical visit was on day 78 for a general safety assessment and analysis of PK, PD and immunogenicity. A final follow-up phone call occurred on day 92. Dose escalation was based primarily on AE severity as classified using the Common Terminology Criteria for Adverse Events classification criteria. Dose escalation was to be stopped if at least two subjects in a cohort experienced cytokine release syndrome (CRS) leading to mild clinical syndromes or reactions of RZfr / nn / nznz / B / Yi 225 administration moderate to severe. Since AB79 is a lymphocyte depleting antibody, no further dose escalation was allowed if clinically relevant reductions in total or subtypes of lymphocyte counts were observed (nominally >50% reduction from pre-dose plus subject and below the lower limit of normal reference intervals (NRRs)) and these were maintained for >29 days. The investigator and sponsor reviewed all blinded safety data for all participants at each dose level before proceeding to the next higher dose. The study was conducted in accordance with Good Clinical Practice guidelines in the Parexel International Phase 1 CPU located at Northwick Park Hospital, Harrow, UK. The protocol was reviewed and approved (approval number 16 / LO / 2067) by an independent local ethics committee, the LondonBrent Research Ethics Committee (London, UK). All subjects signed the informed consent form before starting any study procedure. study participants Eligible participants were healthy men or women (without childbearing potential) between the ages of 18 to 55 years, weighing 50 to 100 kg, and with a body mass index (BMI) of 18.5 to 30 kg m~2. RZfr? nn / nznz / E / Yi 226 Flow cytometry-based counts of CD45+, T-cells, CD4+ T-cells, and B-cells were required to be above the lower limit of the NRR and NK cell counts within the upper 50th percentile of the NRR given that CD38 it is highly expressed in NK cells. The NRRs were defined by Takeda, which performed the flow cytometry analyses. Participants were excluded if they met the exclusion criteria defined in the protocol, such as known immunodeficiency, high risk of infection, history of malignancy, or taking another experimental drug prior to the study that could affect the effect of the experimental drug. To measure AB7 9 serum concentrations, serial blood samples were collected pre-dose and up to 168 hours post-dose, with additional blood samples collected at intermediate time points post-dose or at early termination. (ET) . Serum concentrations of AB79 were determined by an enzyme-linked immunosorbent assay validated at ICON (Whitesboro, NY). To assess AB79 PD response, peripheral blood samples were collected at screening visits, on days -1, 1, 2 (SC only), 3 (SC only), 4 (IV only), 5 (SC only), SC), 6, 8, 15, 22, 29, 50, and 78 post-dose or at RZfr? nn / nznz / E / Yi 227 ET. Primary and secondary PD endpoints were plasmablast and NK cell counts measured in blood, respectively. Additional assessments included total white blood cell count and differential total T cell counts, CD4 and CD8 T cell subsets, B cells, monocytes, and granulocytes. Lymphocyte, monocyte and plasmablast subsets were measured by flow cytometry at Covance (Brussels, Belgium). An electrochemiluminescent assay was validated for the detection of anti-AB79 antibodies in human serum at ICON. Routine safety parameters such as AE, clinical laboratory parameters, physical examinations, electrocardiograms (ECGs), and vital signs were monitored at screening, predose, and throughout the confinement period and visits. of follow up. Infusion reactions have been reported in clinical studies of other anti-CD38 antibodies administered to MM patients after IV infusion (Voorhees et al. (2015) Blood 126:1829). Although ex vivo experiments showed no evidence of AB79 agonist activity in human blood cells, and AB79 infusion did not induce observable findings that are indicative of an infusion reaction in nonclinical studies in monkeys, signs were closely monitored. of reaction to the infusion or CRS (pain of RZfr? nn / nznz / E / Yi 228 head, fever, chills, hypotension, nausea and vomiting). Inflammatory mediators including serum C-reactive protein (CRP) and tumor necrosis factor (TNF) α and interleukin 1 (IL-1) and 6 (IL-6) levels were assessed at various time points on days 1 and 2 and on day 4 (SC cohorts only). Decreasing the infusion rate and / or oral prophylactic medications with paracetamol (acetaminophen) and antihistamines (anti-Hl and anti-H2) allowed to minimize side effects, if necessary. For SC cohorts, signs of injection site reactions (ISRs) such as pain, burning, redness, itching, swelling, or induration at the injection site were monitored. Summary statistics and data analysis were performed with SAS version 9.2 and R version 3.5.1. PK parameters were calculated by non-compartmental analysis. PD variables were assessed and compared between the active dose groups and between each dose level of AB79 and placebo. Results Seventy-four subjects enrolled and received a single dose of AB79 (n=54) or placebo (n=20). Six IV cohorts receiving AB79 at doses of 0.0003, 0.001, 0.003, 0.01, 0.03, or 0.06 mg kg-1 or placebo-matched and four SC cohorts receiving AB79 at doses of 0.03, 0.1, 0.3, or RZfr? nn / nznz / E / Yi 229 0.6 mg kg-1 or matched placebo were monitored for 92 days; all completed the study. The participants were all men, except for one woman in the SC placebo group. The study population consisted of Caucasian (n = 51), Asian (n = 13), African (n = 4), and multiracial (n = 6) ethnicities. Mean age (34.4 years, with a range of 19 to 55 years) and BMI (24 to 25 kg m~2) were similar between IV and SC cohorts, and between AB79 and placebo groups. . All doses of AB79 were well tolerated in this study. The AEs were mild to moderate in intensity and the majority of the AEs were mild and well balanced between the placebo and AB79 treated groups (Table 13). There were no serious AEs (SAEs) or deaths, and no AEs led to discontinuation of the study or visits. No notable findings for laboratory tests, ECG, vital signs, or physical examinations that were related to AB79 treatment were reported. RZfr? nn / nznz / E / Yi 230 Table 13. Total TEAE and AE reported in two or more subjects in any treatment group RZfr? nn / nznz / E / Yi AB79 IV Infusion (mg kg1) Number of Subjects (%) Pooled Placebo (n=12) 0.0003 (n=4) 0.001 (n=4) 0.003 (n=4) 0.01 (n=6) 0.03 (n=6) 0.06 (n = 6) Subjects with any TEAE 11 (91.7) 3 (75.0) 3 (75.0) 3 (75.0) 6 (100.0) 6 (100.0) 6 (100.0) Pyrexia 0 0 0 0 1 (16.7) 1 (16.7 ) 3 (50.0) Chills 0 0 0 0 0 0 2 (33.3) Nasopharyngitis 2 (16.7) 0 1 (25.0) 0 0 0 2 (33.3) Headache 4 (33.3) 0 0 1 (25.0) 2 (33.3) 3 (50.0) 5 (83.3) Postural dizziness 0 0 0 0 0 1 (16.7) 5 (83.3) Somnolence 0 0 0 0 0 1 (16.7) 2 (33.3) SC AB79 Injection (mg kg1) Number of Subjects (% ) Pooled Placebo (n = 8) 0.03 (n = 6) 0.1 (n = 6) 0.3 (n = 6) 0.6 (n = 6) Subjects with any TEAE 6 (75.0) 6 (100.0) 6 (100.0) 5 ( 83.3) 5 (83.3) Erythema at the injection site 1 (12.5) 5 (83.3) 0 1 (16.7) 1 (16.7) Pain at the injection site 0 3 (50.0) 3 (50.0) 0 0 Sensation of heat 0 0 1 (16.7) 1 (16.7) 2 (33.3) Nasopharyngitis 1 (12.5) 2 (33.3) 3 (50.0) 1 (16.7) 3 (50.0) Headache 2 (25.0) 2 (33.3) 1 (16.7) 1 (16.7) 3 (50.0) Oropharyngeal pain 1 (12.5) 0 2 (33.3) 0 1 (16.7) A TEAE was defined as an AE that occurs or worsens after receiving the first dose of study drug and within 94 days of the last dose of study drug. Subjects with one or more AEs within a treatment group and MedDRA term level were counted only once at that level. Percentages are based on the number of subjects in the safety set per treatment. MedDRA (version 18.0) was used to code AE. AE, adverse event; IV, intravenous; MedDRA, Medical Dictionary for Regulatory Activities; SC, subcutaneous; TEAE, treatment emergent adverse event. As shown in Table 13, most AEs were sporadic with no dose-related trend, except for headache, dizziness, and chills, which were more frequently observed in the IV dose groups. 231 higher than AB79, which is consistent with a higher incidence of CRS. These effects (Table 14) were observed primarily in subjects receiving the highest doses (one subject and six subjects at 0.03 and 0.06 mg kg-1IV, respectively; one subject and two subjects at 0.3 and 0.6 mgkg-1SC, respectively). These subjects exhibited reductions in plasmablasts and NK cells, suggesting that these symptoms are the result of decreased CD3-expressing cells 8 . Table 14. Number and percentage of subjects with clinical CRS. RZfr? nn / nznz / E / Yi AB79 IV Infusion (mg kg1) Number of Subjects (%) Pooled Placebo (n=12) 0.0003 (n=4) 0.001 (n=4) 0.003 (n=4) 0.01 (n=6) 0.03 (n=6) 0.06 (n = 6) CRS 0 0 0 0 0 1 (16.7) 6 (100) Severity Mild All Mild SC Injection AB79 (mg kg1) Number of Subjects (%) Pooled Placebo (n = 8) 0.03 (n = 6) 0.1 (n = 6) 0.3 (n = 6) 0.6 (n=6) CRS 0 0 0 1 (16.7) 2 (33.3) Severity Mild All mild Only mild transient ISRs were observed after SC injections, most of which resolved within 7 days. These reactions exhibited an inverse dose-effect relationship, as five of six subjects treated with the lower SC dose and only one subject in each of the two higher dose cohorts had reactions. The serum concentrations of AB79 at all points 232 PK sampling times from IV cohorts 1 (0.0003 mgkg-1) to 4 (0.01 mgkg-1) were below the lower limit of quantification (LLOQ) of the detection assay (ie, 10 ngmlr1), presumably due to at low doses and in the absence of anti-drug antibodies (data not shown). After an IV infusion of 0.03 and 0.06 mg kg-1 of AB79, the maximum observed serum concentration (Cmax) was 21.4 and 100.4 ng mL-1, respectively, and occurred 5 minutes after the end of the infusion (Table 15 and Figure 41). Subsequently, serum concentrations rapidly declined below the LLOQ within 1 or 4 hours after the end of the infusion, respectively, and exposures could not be accurately calculated. Cmax appeared to increase approximately five-fold over a two-fold dose increase from 0.03 to 0.06 mg kg-1. Due to the limited serum concentrations of AB79 (at one to three time points per subject) available in 0.03 and 0.06 mg kg-1 IV cohorts, PK parameters other than time to maximum serum concentration (tmax) and QáXcouldn't RZfr? nn / nznz / E / Yi can be estimated reliably. 233 Table 15. Summary of AB79 PK parameters following a single 2-hour IV infusion of AB79 at 0.03 and 0.06 mg kg-1 or a single SC injection of AB79 at 0.6 mg kg-1 in healthy subjects RZfr? nn / nznz / E / Yi Route Dose n fmax (h) n = 6 Cmax (ngmL 1) n = 6 AUClast (ng day* 1 mL1) n = 6 IV 0.03 mg kg1 6 2.09 (2.07, 2.67) 21.4 (39) NA 0.06 mg kg1 6 2.09 (2.07, 2.13) 100.4 (52) NA SC 0.6 mg kg-1 6 23.87 (7.98, 96.02)a 23.0 (67) 90.4 (92) an = 5. Values ​​represent the mean (%CV), except for tmax where the median (min, max) is presented. AUCúiüma, area under the serum concentration-time curve from time 0 to the time of the last measurable concentration; Cmax, maximum observed serum concentration; CV, coefficient of variance; IV, intravenous; NA, not applicable; PK, pharmacokinetics; SC, subcutaneous; ¿max, time to maximum serum concentration. Serum AB79 concentrations of all subjects in SC cohorts 1 (0.03 mg kg-1) to 3 (0.3 mg kg-1) were below the LLOQ of the screening assay at all time points. Following a single SC injection of 0.6 mg kg-1 of AB79, five subjects in this cohort exhibited a median tmax at approximately 24 hours post-injection. The Craax mean of all six subjects (including one subject with serum concentrations below the LLOQ) in this cohort was 23.0 ng mL-1, which was approximately 23% of the Cmax value after a 2-hour IV fusion at 0.06 mg kg-1 (one tenth of the SC dose in this cohort). Serum concentrations of AB79 gradually decreased below the LLOQ between 3 and 14 days after injection (Figure 41). One subject in the 0.6 mg kg-1 SC cohort did not exhibit a detectable level of AB79 throughout the entire period. 234 PK Sampling. Compared to the PK parameters of the IV cohorts, greater intersubject variability was observed after SC injection at 0.6 mg kg-1. Individual tmax ranged from approximately 8 to 96 hours (0.33 to 4 days) after injection for the five subjects with measurable concentrations in this cohort. In cohorts administered AB79 by IV infusion, dose-dependent reductions in NK cells were observed at doses >0.003 mg kg-1, with >90% reduction in all subjects receiving a 0.06 mg infusion. kg-1 (Figures 42A and 42B) . An effective concentration occurred at 50% of the maximum response (EC50) below the LLOQ of the PK assay (ie, 10 ng mL-1); however, 75% of the maximum effective concentration (EC75) for the RZfr? nn / nznz / E / Yi NK cell reduction by IV administration of AB79 was 21.4 ng mlr1 (Table 15). Although the NK cell level was consistently reduced from baseline to the end of the infusion, the duration of recovery to baseline levels (<—20%) was variable and generally dose-related; recovery to initial levels for the 0.003, 0.01, 0.03, and 0.06 mg kg-1 doses required a mean of 4, 4, 6, and 8 days, respectively (Figure 43). No clinically significant reductions were observed for total lymphocytes, B and T lymphocytes, helper T lymphocytes, and cytotoxic T lymphocytes, 235 granulocytes, red blood cells or platelets with one IV administration of AB79 (data not shown). In the cohorts treated with AB79 by SC injection, a dose-dependent reduction in NK cells (Figures 42A and 42B) and plasmablasts (Figure 43) was observed at doses >0.1 mg kg-1 with a >90% reduction in plasmablasts at all subjects who received an injection of 0.6 mg kg-1. A 75% reduction in NK cells occurred at 0.6 mg kg-1 (data not shown) with a Cmax of 23.0 ng mlr1 (Table 15). Plasmablast and NK cell levels decreased from baseline within 8 hours of injection and exhibited a tmax of 48 hours. The duration of recovery to baseline levels was variable; recovery to baseline (ie, within -20% of baseline levels) for the 0.1, 0.3, and 0.6 mg kg-1 doses required a mean of 4, 78, and 50 days, respectively (data not shown). Minimal or no reductions were observed for total lymphocytes, B and T lymphocytes, cytotoxic T lymphocytes, helper T lymphocytes, monocytes (Figure 43), and granulocytes, red blood cells, and platelets (data not shown). While total Ig levels remained within the NRRs, total IgM levels were reduced in the 0.03 and 0.06 mg kg-1 AB79 IV cohorts and were significantly (F<0.05) lower than RZfr? nn / nznz / E / Yii 236 a synchronized placebo control cohort on days 15-64 (Figure 44, top). Significant reductions (P<0.01) in total IgM levels were also observed on days 15-64 for AB79 administered at 0.3 and 0.6 mg kg-1SC (Figure 44, bottom). IgM levels exhibited a trend toward recovery to baseline at day 78. No significant effect on IgA and IgG levels was observed for AB79 administered IV or SC (data not shown). Of the 54 subjects who received AB79, one subject in the 0.03 mg kg-1 SC cohort exhibited a persistent (ie, on days 15, 29, and 78), hi...

Claims

Having described the invention as above, the following claims are claimed as property:

1. An isolated human anti-CD38 antibody, administered subcutaneously in a unit-dose form, wherein the anti-CD38 antibody comprises a variable heavy chain (VH) region comprising a CDR1 having the amino acid sequence of SEC ID NO: 3, a CDR2 having the amino acid sequence of SEC ID NO: 4 and a CDR3 having the amino acid sequence of SEC ID NO: 5; and a variable light chain (VL) region comprising a CDR1 having the amino acid sequence of SEC ID NO: 6, a CDR2 having the amino acid sequence of SEC ID NO: 7 and a CDR3 having the amino acid sequence of SEC ID NO: 8, for use in the treatment of a disease in a subject for whom CD38 binding is indicated, wherein the unit-dose form has a volume of 3 mL or less.

2. The isolated human anti-CD38 antibody for use in accordance with any of the preceding claims, wherein the antibody is administered at a dose of 0.03 to 0.6 milligrams per kilogram of body weight.

3. The isolated human anti-CD38 antibody for use according to claim 1 or 2, characterized in that the VH chain region has the RZfr? nn / nznz / E / Yii 247 amino acid sequence of SEC ID NO:9 and the VL chain region has the amino acid sequence of SEC ID NO:

10.

4. The isolated human anti-CD38 antibody for use in accordance with any of claims 1-3, wherein the anti-CD38 antibody comprises a heavy chain amino acid sequence of SEC ID NO: 11 and a light chain amino acid sequence of SEC ID NO:

12.

5. The isolated human anti-CD38 antibody for use in accordance with any of claims 1-4, wherein the unit dose form has a volume of 2 mL or less.

6. The isolated human anti-CD38 antibody for use in accordance with any of claims 1-4, wherein the unit dose form has a volume of 1 mL or less.

7. The isolated human anti-CD38 antibody for use in accordance with any of the preceding claims, wherein administration of the anti-CD38 antibody does not cause hemolytic anemia or thrombocytopenia.

8. The isolated human anti-CD38 antibody for use according to any of claims 1-6, wherein administration of the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40% or less than 50% incidence of grade 3 or 4 of one or more RZfr? nn / nznz / E / Yi 248 treatment-emergent adverse events (TEAEs) selected from the group consisting of anemia, hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia and lymphopenia.

9. The isolated human anti-CD38 antibody for use in accordance with any of the preceding claims, wherein administration of the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40% or less than 50% decrease in RBCs.

10. The isolated human anti-CD38 antibody for use in accordance with any of the preceding claims, wherein administration of the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40% or less than 50% decrease in platelets.

11. The isolated human anti-CD38 antibody for use in accordance with any of the preceding claims, wherein the disease is an autoimmune disease or a cancer.

12. The isolated human anti-CD38 antibody for use according to any of claims 1-10, wherein the disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), RZfr colitis? ulcerative colitis (UC), myasthenia gravis (MG), neuromyelitis optica (NMOD), immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), antiphospholipid syndrome (APS), pemphigus vulgaris (PV), pemphigus foliaceus (PF), anti-NMDAR encephalitis (NMDR), autoimmune hemolytic anemia (AIHA), Graves' disease, membranous nephropathy, Sjogren's syndrome (SS), ANCA-associated vasculitis, acquired epidermolysis bullosa (EBA), bullous pemphigoid (BP), Hashimoto's thyroiditis, scleroderma, IgG4-related disease, and graft-versus-host disease.

13. The human anti-CD38 antibody isolated for use according to claim 11, wherein the disease is selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

14. The isolated human anti-CD38 antibody for use according to claim 11, wherein the disease is multiple myeloma.

15. The human anti-CD38 antibody isolated for use according to claim 14, wherein the disease is selected from the group consisting of relapsing multiple myeloma (RMM), relapsing and resistant multiple myeloma (RRMM) or newly diagnosed multiple myeloma RZfr? nn / nznz / E / Yi 250 (NSMM).

16. The isolated human anti-CD38 antibody for use in accordance with any of the preceding claims, wherein the human anti-CD38 antibody is administered in the form of a pharmaceutically acceptable composition.

17. A unit dose form characterized in that it comprises an isolated antibody comprising a variable heavy chain region comprising SEC ID NO:9 and a variable light chain region comprising SEC ID NO: 10, wherein the isolated antibody is attached to CD38 and wherein the unit dose form is formulated for subcutaneous administration of the antibody at a dose of 0.03 to 0.6 milligrams per kilogram of body weight.

18. The unit dose form according to claim 17, characterized in that the isolated antibody comprises a heavy chain comprising SEC ID NO:11 and a light chain comprising SEC ID NO:

12.

19. The unit dose form according to claim 17 or 18, characterized in that the unit dose form has a volume of 3 mL or less.

20. The unit dose form according to claim 17 or 18, characterized in that the unit dose form has a volume of 2 mL or less. RZfr? nn / nznz / E / Yi 21. The unit dose form according to claim 17 or 18, characterized in that the unit dose form has a volume of 1 mL or less.

22. The unit dose form according to any of claims 17-21, characterized in that the unit dose form is formulated for subcutaneous administration of the antibody in the treatment of a hematological cancer selected from the group consisting of multiple myeloma, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, plasma cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

23. The unit dose form according to claim 22, characterized in that the hematological cancer is multiple myeloma.

24. The unit dose form according to claim 23, characterized in that the disease is selected from the group consisting of relapsing multiple myeloma (RMM), relapsing and resistant multiple myeloma (RRMM), or newly diagnosed multiple myeloma (NSMM).

25. The unit dose form according to any of claims 17-24, characterized in that administration of the anti-CD38 antibody does not cause hemolytic anemia or thrombocytopenia.

26. The unit-dose form according to any of claims 17-24, characterized in that administration of the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40% or less than 50% incidence of grade 3 or 4 of one or more treatment-emergent adverse events (TEAEs) selected from the group consisting of anemia, hemolytic anemia, thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia and lymphopenia.

27. The unit dose form according to any of claims 17-24, characterized in that administration of the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40% or less than 50% decrease in RBCs.

28. The unit dose form according to any of claims 17-24, characterized in that administration of the anti-CD38 antibody results in less than 10%, less than 20%, less than 30%, less than 40% or less than 50% decrease in platelets.