Antibody formulations

Abstract

To provide formulations of a pharmaceutically active antigen binding protein, such as a monoclonal antibody.SOLUTION: In particular, the present disclosure relates to a stable lyophilized pharmaceutical formulation of an anti-CD38 antibody, a reconstituted liquid formulation of such lyophilized formulation, and to methods of making and using such lyophilized and reconstituted formulations.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure relates to formulations of pharma- ceutically active antigen-binding proteins, such as monoclonal antibodies. In particular, the present disclosure relates to stable lyophilized pharmaceutical formulations of anti-CD38 antibodies, reconstituted liquid formulations of such lyophilized formulations, and methods of making and using such lyophilized and reconstituted formulations. [Background technology]

[0002] The pharmaceutical use of antibodies has increased over the past few years. In many cases, such antibodies are injected via the intravenous (IV) route. Alternative routes of administration are subcutaneous or intramuscular injection, which offer potential advantages, for example, in terms of patient compliance and ease of administration. Highly concentrated and stable pharmaceutical formulations are very often desired. Also, for reasons such as storage and handling, lyophilized formulations are very often preferred.

[0003] Therapeutic antibodies are large and complex molecules, and therefore formulation of such proteins poses special challenges. For a protein to remain biologically active, the formulation must preserve the conformational integrity of at least the core sequence of amino acids of the protein while protecting the protein's multiple functional groups from degradation. Antibody formulations may have a short shelf life, and the prepared antibodies may lose biological activity due to chemical and physical instability during storage. The three most common pathways for protein degradation are protein aggregation, deamidation, and oxidation (Cleland et al., Critical Reviews in Therapeutic Drug Carrier Systems 10(4):307-377(1993)). In particular, aggregation can potentially lead to an increased immune response in patients, leading to safety concerns and must be minimized or prevented.

[0004] Formulations with higher protein concentrations pose even more challenges, especially related to protein stability, protein-protein interactions and viscosity. Viscosity is not only an issue for the biophysical and biochemical properties of therapeutic proteins, but also for the delivery and manufacture of highly concentrated protein solutions. The higher the viscosity of the solution, the longer it takes to inject such a viscous solution through a syringe and needle. Thus, the injectability aspect is affected by viscosity and needs to be considered during the development of high concentration formulations. Certain antibodies also exhibit a tendency for undesirable self-interactions, making them relatively unsuitable for high concentration formulations. This tendency for self-interactions can lead to oligomerization, aggregation and high viscosity at high protein concentrations. Opalescence is one parameter that indicates the physical instability of a formulation due to the presence of aggregates or liquid-liquid phase separation in the solution and has been reported for monoclonal antibody (mAb) formulations.

[0005] To address these issues, the development of appropriate formulation compositions is of utmost importance.To avoid stability issues such as aggregate formation, protein or antibody formulations can be lyophilized.

[0006] CD38 is a type II membrane protein that has functions in receptor-mediated adhesion and signal transduction, as well as mediating calcium mobilization through its ectoenzymatic activity, catalyzing the formation of cyclic ADP-ribose (cADPR) from NAD+, and hydrolyzing cADPR to ADP-ribose (ADPR). CD38 mediates cytokine secretion, as well as lymphocyte activation and proliferation (Funaro et al, J Immunology 145:2390-6, 1990; Guse et al, Nature 398:70-3, 1999), and, through its NAD glycohydrolase activity, regulates extracellular NAD+ levels involved in the regulation of the regulatory T cell compartment (Adriouch et al., 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012).

[0007] CD38 is expressed on malignant plasma cells and other lymphocytes and is therefore a therapeutic target in the treatment of multiple myeloma and other hypergammaglobulinemias. CD38 is also a target used or investigated for other indications, including but not limited to solid tumors, autoimmune disorders, and numerous other diseases.

[0008] WO 199962526 (Mayo Foundation); WO 200206347 (Crucell Holland); WO 2005103083 (MorphoSys AG); WO 2006125640 (MorphoSys AG), WO 2007042309 (MorphoSys); WO 2006099875 (Genmab), WO 2011154453A1 (Genmab), WO 2008047242 (Sanofi-Aventis), WO 2015066450 (Sanofi), WO 2012092616A1 (Takeda), WO 2012092612A1 (Takeda), WO 2013059885 (Teva), WO 2014178820 (Teva), WO 2015149077 (Xencor), WO 2017081211A2 (University of California, Sanofi), Several antibodies (including bispecific antibodies and other constructs) specific for CD38 are in use or under development, including but not limited to: CD38-specific antibodies (Hamburg-Eppendorf) and WO2017091656 (Amgen, Xencor).

[0009] The present disclosure relates to the development and use of highly stable formulations for anti-CD38 antibodies, such as the antibody known as MOR202, suitable for administration to patients.

[0010] Pharmaceutical formulations for therapeutic antibodies are known in the prior art. For example, WO2013016648 discloses a pharmaceutical formulation comprising an anti-PCSK9 antibody, a histidine buffer, a non-ionic surfactant and a stabilizer. However, the document does not disclose an anti-CD38 antibody. WO2018204405 discloses a formulation comprising an anti-TIGIT antibody, a histidine buffer, polysorbate-80 as a non-ionic surfactant, a non-reducing sugar and an antioxidant, but also does not disclose an anti-CD38 antibody. WO2017079150 discloses a subcutaneous formulation comprising an anti-CD38 antibody, hyalorunidase, a histidine buffer, methionine and a non-ionic surfactant. This document teaches the addition of hyaluronidase to the composition and does not disclose MOR202 or a lyophilized lyophilized composition.

[0011] Thus, there remains a need for stable lyophilized antibody formulations for the preparation of anti-CD38 medicaments, including in particular the antibody MOR202. Summary of the Invention

[0012] It is an object of the present invention to provide formulations of anti-CD38 antibodies, particularly formulations of anti-CD38 antibodies that have a suitable shelf life.

[0013] Suitable formulations of therapeutic antibodies may be an aqueous pharmaceutical composition or a lyophilizate that can be reconstituted to provide a solution for administration to a patient.

[0014] Provided herein is a lyophilized pharmaceutical formulation comprising an antibody.In an embodiment of the present disclosure, the pharmaceutical formulation comprises an anti-CD38 antibody.In another embodiment of the present disclosure, the pharmaceutical formulation comprises the antibody known as MOR202.

[0015] The disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, comprising an antigen-binding protein, a surfactant, and a histidine buffer of pH 5.5-6.5.

[0016] In one aspect, the disclosure provides a pharmaceutical formulation for an antigen binding protein, wherein said antigen binding protein is an anti-CD38 antibody.

[0017] In a particular embodiment, the anti-CD38 antibody has an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5 and an LCDR3 of SEQ ID NO:6.

[0018] In a particular embodiment, the anti-CD38 antibody comprises an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5, and an LCDR3 of SEQ ID NO:6.

[0019] In another embodiment, the anti-CD38 antibody has a variable heavy chain of SEQ ID NO:7 and a variable light chain of SEQ ID NO:8.

[0020] In another embodiment, the anti-CD38 antibody comprises a variable heavy chain of SEQ ID NO:7 and a variable light chain of SEQ ID NO:8.

[0021] In one aspect, the disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, wherein the pharmaceutical formulation comprises a surfactant. In certain aspects, the surfactant is a non-ionic surfactant. In other aspects, the non-ionic surfactant is a polysorbate. In yet other aspects, the polysorbate is polysorbate 20 (PS20) or polysorbate 80 (PS80). In yet other aspects, the polysorbate is polysorbate 20.

[0022] In one aspect, the disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, wherein the pharmaceutical formulation comprises a histidine buffer of pH 5.5 to 6.5. In certain aspects, the histidine buffer is a histidine buffer of pH 5.9 to 6.1. In certain aspects, the histidine buffer has a pH of about 6.0. In certain aspects, the histidine buffer has a pH of 6.0.

[0023] In one aspect, the disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, the pharmaceutical formulation comprising a histidine buffer at a concentration of 5 mM to 15 mM. In another aspect, the histidine buffer is at a concentration of 8 mM to 12 mM. In another aspect, the histidine buffer is at a concentration of about 10 mM. In another aspect, the histidine buffer is at a concentration of 10 mM.

[0024] In one aspect, the disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, wherein the pharmaceutical formulation includes a stabilizer. In certain aspects, the stabilizer is a disaccharide. In other aspects, the disaccharide is sucrose. In other aspects, the sucrose is at a concentration of 150 mM to 350 mM. In other aspects, the sucrose is at a concentration of 175 mM to 260 mM. In other aspects, the sucrose is at a concentration of about 260 mM. In other aspects, the sucrose is at a concentration of 260 mM.

[0025] In one aspect, the disclosure provides a lyophilized pharmaceutical formulation for said anti-CD38 antibody, such as MOR202, prepared by lyophilization of a liquid pharmaceutical formulation.

[0026] In one aspect, the disclosure provides a liquid formulation of an anti-CD38 antibody, such as MOR202, the method comprising providing a lyophilized pharmaceutical formulation and reconstituting the lyophilized formulation, hi certain aspects, the liquid formulation is produced by adding water or another pharma- ceutically acceptable reagent to the lyophilized formulation.

[0027] In one aspect, the disclosure provides a reconstituted pharmaceutical formulation of said anti-CD38 antibody, such as MOR202.

[0028] In one aspect, the disclosure provides a pharmaceutical formulation for said anti-CD38 antibody, such as MOR202, wherein said anti-CD38 antibody is at a concentration of at least 55 mg / ml.

[0029] In one aspect, the disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, wherein the anti-CD38 antibody is at a concentration of 55-75 mg / ml.

[0030] In another embodiment, the anti-CD38 antibody is at a concentration of 62.5 to 67.5 mg / ml.

[0031] In yet another embodiment, the anti-CD38 antibody is at a concentration of about 65 mg / ml.In yet another embodiment, the anti-CD38 antibody is at a concentration of 65 mg / ml.

[0032] In one aspect, the disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, wherein the pharmaceutical formulation comprises a surfactant at a concentration of 0.05% (w / w) to 0.2% (w / w). In another aspect, the surfactant is at a concentration of about 0.1% (w / w). In another aspect, the surfactant is at a concentration of 0.1% (w / w).

[0033] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to said subject an effective amount of a pharmaceutical formulation of the present disclosure.

[0034] In one aspect, the disclosure provides a use of the pharmaceutical formulation of the disclosure for the preparation of a medicament. In certain aspects, the use is for the preparation of a medicament for the treatment of a disease or disorder. In certain aspects, the disease or disorder is cancer or an inflammatory disorder. In certain aspects, the cancer is a hematological cancer or a solid cancer. In certain aspects, the hematological cancer is selected from multiple myeloma, lymphoma, leukemia, or any particular type or subtype thereof. In certain aspects, the cancer is multiple myeloma. In certain aspects, the disease or disorder is cancer or an inflammatory disorder. [Brief description of the drawings]

[0035] [Figure 1] Summary of the main preformulations tested in Example 2. [Diagram 2] Testing schedule during preliminary formulation development. [Figure 3A] Results of stability studies in preliminary formulation development. Time point 0 [Figure 3B] Results of stability studies in preliminary formulation development. Time point 0 [Figure 3C] Stability test results for preliminary formulation development. Time period: 2 weeks, 40℃ / 75% RH [Figure 3D] Stability test results for preliminary formulation development. Time period: 2 weeks, 40℃ / 75% RH [Figure 3E] Stability test results for preliminary formulation development. Time period: 4 weeks, 40℃ / 75% RH [Figure 3F] Results of stability test in preliminary formulation development. Time point: 2 weeks, 5℃ [Figure 3G] Results of stability test in preliminary formulation development. Time point: 4 weeks, 5℃ [Figure 4A] Results of various tests of Reed Buffer System + Polysorbate 20 at various concentrations. Shear test results at T0, T24h and T48h [Figure 4B] Results of various tests of Reed Buffer System + Polysorbate 20 at various concentrations. Shear test results at T0, T24h and T48h [Figure 4C] Results of various tests of Reed Buffer System + Polysorbate 20 at various concentrations. Shear test results at T0, T24h and T48h [Figure 4D] Results of various tests of Reed buffer system + various concentrations of polysorbate 20. Freeze / thaw test results [Figure 4E] Results of various tests of Reed buffer system + various concentrations of polysorbate 20. Freeze / thaw test results [Figure 4F] Results of various tests of Reed Buffer System + various concentrations of Polysorbate 20. Results of saline dilution tests [Diagram 5] Vial with cake after first freeze-drying experiment. [Figure 6A] Stability results and subvisible particles for liquid formulations. Solution appearance and UV assay [Figure 6B]Stability results and subvisible particles for liquid formulations. Solution appearance and UV assay [Figure 6C] Stability results and subvisible particles for liquid formulations. Solution appearance and UV assay [Figure 6D] Stability results and subvisible particles for liquid formulations. pH and SE-HPLC [Figure 6E] Stability results and subvisible particles for liquid formulations. DLS [Figure 6F] Stability results and subvisible particles for liquid formulations. DLS [Figure 6G] Stability results and subvisible particles for liquid formulations. DLS [Figure 6H] Stability Results and Subvisible Particles for Liquid Formulations. HIAC [Figure 7A] Stability results and subvisible particles for lyophilized formulations. Appearance, UV assay and pH [Figure 7B] Stability results and subvisible particles for lyophilized formulations. DLS, cake appearance, reconstitution time and moisture content [Figure 7C] Stability results and subvisible particles for lyophilized formulations. DLS, cake appearance, reconstitution time and moisture content [Figure 7D] Stability results and subvisible particles for lyophilized formulations. DLS, cake appearance, reconstitution time and moisture content [Figure 7E] Stability results and subvisible particles for lyophilized formulations. SE-HPLC and subvisible particles [Figure 8] Analytical results of the drug product after the fifth lyophilization optimization. [Figure 9] Vial with cake after the fifth lyophilization optimization. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Of course, it is to be understood that this disclosure is not limited to particular methods, reagents, compounds, compositions, or biological systems, which can vary. Also, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0037] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a "polypeptide" includes a combination of two or more polypeptides, and the like.

[0038] As used herein, "about" when referring to measurable values ​​such as amounts, time durations, etc., is meant to encompass a variation of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate for carrying out the disclosed methods. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure pertains. Although any methods and materials similar or equivalent to those described herein can be used in carrying out the tests of the present disclosure, the preferred materials and methods are described herein in describing and claiming the present disclosure, and the following terms are used.

[0039] The term "pharmaceutical formulation" or "formulation" refers to a formulation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. Such a formulation is sterile. A "sterile" formulation is aseptic or free of all living microorganisms and their spores.

[0040] The term "viscosity" refers to the internal resistance to flow, i.e., the ratio of shear stress to shear rate, that a fluid exhibits at a particular temperature. A liquid has a viscosity of 1 poise when a force of 1 dyne / square centimeter moves two parallel liquid surfaces, each with an area of ​​1 square centimeter and spaced 1 square centimeter apart, past each other at a speed of 1 cm / sec. 1 poise is equal to 100 centipoise. In one embodiment, the viscosity of the formulation, including the buffer and stabilizer, is less than about 50 cP, less than about 45 cP, less than about 40 cP, less than about 35 cP, less than about 30 cP, less than about 25 cP, less than about 20 cP, less than about 15 cP, or less than about 10 cP.

[0041] When referring to apparent viscosity, it is understood that the viscosity value depends on the conditions under which the measurement is performed, such as the temperature, shear rate and shear stress used. Apparent viscosity is defined as the ratio of the applied shear stress to the shear rate. There are many alternative methods for measuring apparent viscosity. For example, viscosity can be tested by a suitable cone and plate, parallel plate or other type of viscometer or rheometer.

[0042] As used herein, a "buffer" refers to a buffer solution that resists changes in pH by the action of its acid-base conjugate components. The buffer of the present invention preferably has a pH in the range of 5.9 to 6.1, preferably a pH of about 6.0, more preferably a pH of 6.0. A "histidine buffer" is a buffer that contains the amino acid histidine. Histidine buffers are preferred buffers of the present disclosure. Examples of histidine buffers include histidine hydrochloride, histidine acetate, histidine phosphate, and histidine sulfate.

[0043] As used herein, "surfactant" refers to a surface-active agent. Examples of surfactants include polysorbates (e.g., polysorbate 20 and polysorbate 80), poloxamers (e.g., poloxamer 188), Triton, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, sodium octyl glycoside, lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine, lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine, linoleyl-, myristyl-, or cetyl-betaine, lauroamidopropyl-, cocoamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl; myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate, and the MONAQUAT® series (Mona Polysorbate 80 is also known as PS80 or Tween-80. ...

[0044] The surfactant can be used in different concentrations. Preferably, the surfactant is at a concentration of 0.05% (w / w) to 0.2% (w / w). More preferably, the surfactant is at a concentration of about 0.1% (w / w). More preferably, the surfactant is at a concentration of 0.1% (w / w). Preferably, the surfactant is polysorbate 20 at a concentration of 0.05% (w / w) to 0.2% (w / w). More preferably, the surfactant is polysorbate 20 at a concentration of about 0.1% (w / w). More preferably, the surfactant is polysorbate 20 at a concentration of 0.1% (w / w).

[0045] In certain embodiments, the pharmaceutical formulation according to the present disclosure may include a stabilizer as an additional excipient. The stabilizer includes, but is not limited to, human serum albumin, bovine serum albumin, α-casein, globulin, α-lactalbumin, LDH, lysozyme, myoglobin, ovalbumin, and RNase A. The stabilizer also includes amino acids and their metabolites, such as glycine, alanine, arginine, betaine, leucine, lysine, glutamic acid, aspartic acid, proline, 4-hydroxyproline, sarcosine, γ-aminobutyric acid (GABA), opines (alanopine, octopine, strombin), and trimethylamine N-oxide (TMAO). The stabilizer may also include sugar alcohols and / or monosaccharides, disaccharides, or polysaccharides, such as mannitol, sorbitol, trehalose, dextrose, lactose, and sucrose. Preferably, the stabilizer is sucrose.

[0046] The term "reconstituted" as used herein in connection with the pharmaceutical formulations of the present disclosure refers to a formulation that has been lyophilized and reconstituted by adding a reconstitution medium. Reconstitution media include, but are not limited to, water, particularly water for injection (WFI), bacteriostatic water for injection (BWFI), sodium chloride solution (e.g., 0.9% (w / v) NaCl), glucose solution (e.g., 5% glucose), surfactant, containing solution (e.g., 0.01% polysorbate 20), pH buffer solution (e.g., phosphate buffer solution).

[0047] In one aspect, the pharmaceutical formulations of the present disclosure are stable upon freezing and thawing, a "stable" formulation is one in which all proteins therein essentially retain their physical and / or chemical stability and / or biological activity upon storage at the intended storage temperature, e.g., 2-8°C. It is desired that the formulation essentially retains its physical and chemical stability, as well as its biological activity upon storage. The storage period is generally selected based on the intended shelf life of the formulation. Furthermore, the formulation should be stable after freezing (e.g., to -70°C) and thawing the formulation, e.g., after 1, 2 or 3 cycles of freezing and thawing. A variety of analytical techniques for measuring protein stability are available in the art and are reviewed, for example, in Peptide and Protein Drug Delivery', 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature for a selected time. Stability can be qualitatively and / or quantitatively assessed in a variety of different ways, including assessing aggregate formation (e.g., using size exclusion chromatography, by measuring turbidity, and / or by visual inspection); by assessing charge heterogeneity using cation exchange chromatography or capillary zone electrophoresis; amino-terminal or earboxy-terminal sequence analysis; mass spectrometry; SDS-PAGE analysis to compare reduced and intact antibodies; peptide map (e.g., trypsin or LYS-C) analysis; and assessing the biological activity or antigen-binding function of the antibody.

[0048] In one embodiment, the pharmaceutical formulation of the present disclosure is suitable for intravenous, subcutaneous or intramuscular administration. In another embodiment, the pharmaceutical formulation of the present disclosure is administered subcutaneously. In another embodiment, the pharmaceutical formulation of the present disclosure is administered intravenously.

[0049] The term "CD38" refers to the protein known as CD38, which has the following synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1, T10.

[0050] Human CD38 (UniProt: P28907) has the following amino acid sequence: [ka]

[0051] The term "antibody" as used herein refers to a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds that interact with an antigen. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2 and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region contains one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with an antigen. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The term "antibody" includes, for example, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, and chimeric antibodies. Antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Both the light and heavy chains are divided into regions of structural and functional homology.

[0052] The term "antibody fragment" as used herein refers to one or more portions of an antibody that retain the ability to specifically interact with an antigen (e.g., by binding, steric hindrance, stabilization of spatial distribution). Examples of binding fragments include, but are not limited to, Fab fragments, a monovalent fragment consisting of VL, VH, CL and CH1 domains; F(ab)2 fragments, a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single arm of an antibody; dAb fragments consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity determining regions (CDRs). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be linked using recombinant methods by a synthetic linker that allows them to be made into a single protein chain (known as single-chain Fv (scFv)) in which the VL and VH regions pair to form a monovalent molecule; see, for example, Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879-5883). Such single-chain antibodies are also intended to be encompassed within the term "antibody fragment". These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments can be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies).Antibody fragments can be assembled into single-chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which form a pair of antigen-binding sites together with complementary light chain polypeptides (Zapata et al., (1995) Protein Eng. 8:1057-1062; U.S. Pat. No. 5,641,870).

[0053] "Human antibodies" or "human antibody fragments," as used herein, include antibodies and antibody fragments having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Human antibodies may also be isolated from synthetic libraries or from transgenic mice (e.g., xenomouse), provided that each system provides antibodies with variable regions in which both the framework and CDR regions are equivalent to sequences of human origin.

[0054] Furthermore, if the antibody comprises a constant region, the constant region is also derived from such sequences. Human origin includes, for example, antibodies that contain human germline sequences, or mutated versions of human germline sequences, or consensus framework sequences derived from human framework sequence analysis, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86.

[0055] The structure and location of immunoglobulin variable domains (e.g., CDRs) can be defined using well-known numbering schemes (e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia) (e.g., Sequences of Proteins of Immunological Interest, USDepartment of Health and Human Services (1991), eds. Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948; Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 USDepartment of Health and Human Services; Chothia et al., (1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 199:101-102, 1997). 342:877-883; and Al-Lazikani et al., (1997) J. Mol. Biol. 273:927-948).

[0056] A "humanized antibody" or "humanized antibody fragment" is defined herein as an antibody molecule having constant antibody regions derived from sequences of human origin, and only the variable antibody regions or parts thereof, or CDRs, are derived from another species. For example, a humanized antibody can be CDR-grafted, in which the CDRs of the variable domain are of non-human origin, while one or more frameworks of the variable domain are of human origin, and the constant domains (if present) are of human origin.

[0057] The term "chimeric antibody" or "chimeric antibody fragment" is defined herein as an antibody molecule having constant antibody regions derived from or corresponding to sequences found in one species and variable antibody regions derived from another species. Preferably, the constant antibody regions are derived from or correspond to sequences found in humans and the variable antibody regions (e.g., VH, VL, CDR or FR regions) are derived from sequences found in a non-human animal (e.g., mouse, rat, rabbit or hamster).

[0058] The term "isolated antibody" refers to an antibody or antibody fragment that is substantially free of other antibodies or antibody fragments with different antigen specificities. Furthermore, an isolated antibody or antibody fragment may be substantially free of other cellular material and / or chemicals. Thus, in some aspects, the antibody provided is an isolated antibody that is separated from antibodies with different specificities. An isolated antibody may be a monoclonal antibody. An isolated antibody may be a recombinant monoclonal antibody. However, an isolated antibody that specifically binds to a target epitope, isoform, or variant may have cross-reactivity to other related antigens (e.g., from other species (e.g., species homologs)).

[0059] The term "recombinant antibody" as used herein includes all antibodies prepared, expressed, generated or isolated by non-naturally occurring means, such as antibodies isolated from host cells transformed to express the antibody, antibodies selected and isolated from recombinant combinatorial human antibody libraries, and antibodies prepared, expressed, generated or isolated by any other means involving splicing of all or part of the sequence into human immunoglobulin genes, other DNA sequences, or antibodies isolated from animals (e.g., mice) that are transgenic or transchromosomal for human immunoglobulin genes or hybridomas prepared therefrom. Preferably, such recombinant antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when animals transgenic for human Ig sequences are used) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are sequences that may not naturally occur within the human antibody germline repertoire in vivo. The recombinant antibodies may be monoclonal antibodies. In one embodiment, the antibodies and antibody fragments disclosed herein are isolated from a HuCAL library (Rothe et al, J. Mol. Biol. (2008) 376, 1182-1200).

[0060] The term "monoclonal antibody" as used herein refers to a preparation of antibody molecules of single molecular composition which display a unique binding site having a unique binding specificity and affinity for a particular epitope.

[0061] In one embodiment, the antigen binding protein of the disclosure is a monoclonal antibody or fragment thereof. In another embodiment, the antigen binding protein of the disclosure is a monoclonal antibody. In another embodiment, the monoclonal antibody is a murine, chimeric, humanized, or human antibody. In another embodiment, the monoclonal antibody is a human antibody. In another embodiment, the monoclonal antibody is a humanized antibody. In another embodiment, the monoclonal antibody is a chimeric antibody. In another embodiment, the monoclonal antibody is a murine antibody.

[0062] In one embodiment, the antigen binding protein of the present disclosure binds to CD38. In another embodiment, the antigen binding protein of the present disclosure specifically binds to CD38. In another embodiment, the antigen binding protein of the present disclosure is specific for CD38. In another embodiment, the antigen binding protein of the present disclosure specifically recognizes CD38.

[0063] The "percent identity" between a query amino acid sequence and a subject amino acid sequence is the "identity" value expressed as a percentage, which is calculated by the BLASTP algorithm when the subject amino acid sequence has 100% query coverage with the query amino acid sequence after performing a pairwise BLASTP alignment. Such pairwise BLASTP alignment between the query amino acid sequence and the subject amino acid sequence is performed by using the default settings of the BLASTP algorithm available on the National Center for Biotechnology Institute website and turning off the filter for low complexity regions. Importantly, the query amino acid sequence may be described by an amino acid sequence identified in one or more claims herein.

[0064] The query sequence may be 100% identical to the subject sequence, or may contain up to an integer number of amino acid modifications compared to the subject sequence such that the percent identity is less than 100%. For example, the query sequence is at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the subject sequence. Such modifications include at least one of the following: amino acid deletions, substitutions (including conservative and non-conservative substitutions), or insertions; wherein the modifications may occur at the amino or carboxy terminal positions of the query sequence, or at any position between these terminal positions, either individually among the amino acids in the query sequence, or interspersed in one or more contiguous groups in the query sequence.

[0065] "Administered" or "administration" includes, but is not limited to, delivery by injectable forms, such as intravenous, intramuscular, intradermal or subcutaneous routes, or mucosal routes, for example as a nasal spray or aerosol for inhalation, or delivery as an ingestible solution, capsule or tablet.

[0066] A "therapeutically effective amount" of a compound or combination refers to an amount sufficient to at least partially halt the clinical symptoms of a given disease or disorder and its complications. The amount effective for a particular therapeutic purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the subject. It will be understood that the determination of the appropriate dosage can be accomplished using routine experimentation, constructing a matrix of values ​​and testing different points in the matrix, all of which are within the ordinary skill of a trained physician or clinical scientist.

[0067] "MOR202" is an anti-CD38 antibody also known as "MOR03087" or "MOR3087," terms used interchangeably in this disclosure.

[0068] The amino acid sequence of MOR202 HCDR1 as defined by Kabat is: SYYMN (SEQ ID NO: 1).

[0069] The amino acid sequence of MOR202 HCDR2 as defined by Kabat is: GISGDPSNTYYADSVKG (sequence number 2).

[0070] The amino acid sequence of MOR202 HCDR3 as defined by Kabat is: DLPLVYTGFAY (sequence number 3).

[0071] The amino acid sequence of MOR202 LCDR1 as defined by Kabat is: SGDNLRHYYVY (sequence number 4).

[0072] The amino acid sequence of MOR202 LCDR2 as defined by Kabat is: GDSKRPS (sequence number 5).

[0073] The amino acid sequence of MOR202 LCDR3 is: QTYTGGASL (sequence number 6).

[0074] The amino acid sequence of the MOR202 variable heavy domain is: [ka] It is.

[0075] The amino acid sequence of the MOR202 variable light domain is: [ka] It is.

[0076] The DNA sequence encoding the MOR202 variable heavy domain is: [ka] It is.

[0077] The DNA sequence encoding the MOR202 variable light domain is: [ka] It is.

[0078] MOR202 has an IgG1 Fc region.

[0079] The term "blood cancer" as used herein refers to cancer of the blood, including leukemia, lymphoma, and myeloma, among others. "Leukemia" refers to cancer of the blood in which an excess of ineffective white blood cells that fight infection is produced, crowding out other parts of the blood, such as platelets and red blood cells. It is understood that cases of leukemia are classified as acute or chronic. Specific forms of leukemia include, by way of non-limiting examples, acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); myeloproliferative disorders / neoplasms (MPDS); and myelodysplastic syndromes. "Lymphoma" may refer to Hodgkin's lymphoma, both indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, and follicular lymphoma (small cell and large cell), among others. Myeloma refers to multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence-Jones myeloma.

[0080] The term "solid tumor" or "solid cancer" as used herein refers to a tumor that does not usually contain cysts or liquid areas. As used herein, solid tumors include sarcomas and carcinomas, such as breast tumors, ovarian tumors, gastric tumors, lung tumors, pancreatic tumors, prostate tumors, melanoma tumors, colorectal tumors, lung tumors, head and neck tumors, bladder tumors, esophageal tumors, liver tumors, thyroid tumors, and kidney tumors.

[0081] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject an effective amount of a formulation of the present disclosure. In certain embodiments, the disease or disorder is cancer or an inflammatory disorder. In certain embodiments, the cancer is a blood system cancer or a solid cancer. In certain embodiments, the cancer is a blood system cancer selected from leukemia, lymphoma, and myeloma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is a solid cancer selected from sarcoma and carcinoma, such as breast tumor, ovarian tumor, gastric tumor, lung tumor, pancreatic tumor, prostate tumor, melanoma tumor, colorectal tumor, lung tumor, head and neck tumor, bladder tumor, esophageal tumor, liver tumor, thyroid tumor, and kidney tumor.

[0082] In certain embodiments, the inflammatory disorder is selected from inflammatory bowel disease, rheumatoid arthritis, psoriasis, amyloidosis, systemic lupus erythematosus (SLE), atopic dermatitis, Wegener's granulomatosis, and psoriatic arthritis.

[0083] In certain embodiments, the present disclosure provides a use of the pharmaceutical formulation of the present disclosure for the preparation of a medicament. In certain embodiments, the use is for the preparation of a medicament for the treatment of a disease or disorder. In certain embodiments, the disease or disorder is cancer or an inflammatory disorder. In certain embodiments, the cancer is a blood system cancer or a solid cancer. In certain embodiments, the cancer is a blood system cancer selected from leukemia, lymphoma, and myeloma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is a solid cancer selected from sarcoma and carcinoma, such as breast tumor, ovarian tumor, gastric tumor, lung tumor, pancreatic tumor, prostate tumor, melanoma tumor, colorectal tumor, lung tumor, head and neck tumor, bladder tumor, esophageal tumor, liver tumor, thyroid tumor, and kidney tumor. In certain embodiments, the inflammatory disorder is selected from inflammatory bowel disease, rheumatoid arthritis, psoriasis, amyloidosis, systemic lupus erythematosus (SLE), atopic dermatitis, Wegener's granulomatosis, and psoriatic arthritis.

[0084] In one embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody is MOR202.

[0085] In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody is at a concentration of at least 55 mg / ml. In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody is at a concentration of 55-75 mg / ml. In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody is at a concentration of 62.5-67.5 mg / ml. In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody is at a concentration of about 65 mg / ml. In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody is at a concentration of 65 mg / ml.

[0086] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer of pH 5.5-6.5. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer of pH 5.9-6.1. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer of about pH 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer of about pH 6.0.

[0087] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, a surfactant, and a histidine buffer having a concentration of 5 mM to 15 mM and a pH of 5.9 to 6.1. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, a surfactant, and a histidine buffer having a concentration of 8 mM to 12 mM and a pH of 5.9 to 6.1. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, a surfactant, and a histidine buffer having a concentration of about 10 mM and a pH of 5.9 to 6.1. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, a surfactant, and a histidine buffer having a concentration of 10 mM and a pH of 5.9 to 6.1.

[0088] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer at a concentration of 5 mM to 15 mM and a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer at a concentration of 8 mM to 12 mM and a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer at a concentration of about 10 mM and a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer at a concentration of 10 mM and a pH of about 6.0.

[0089] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer at a concentration of 5 mM to 15 mM and at a pH of 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer at a concentration of 8 mM to 12 mM and at a pH of 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer at a concentration of about 10 mM and at a pH of 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, and a histidine buffer at a concentration of 10 mM and at a pH of 6.0.

[0090] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, a non-ionic surfactant, and a buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, a polysorbate, and a buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate 20, and a buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate 80, and a buffer. In another embodiment, the disclosure provides a formulation comprising an antigen-binding protein, polysorbate 20, and a buffer, wherein the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate 20, and a buffer, wherein the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate 20, and a buffer, wherein the polysorbate 20 is at a concentration of 0.1% (w / w).

[0091] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.5-6.5. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.9-6.1. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of about pH 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 6.0.

[0092] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer at a pH of about 6.0, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer at a pH of 6.0, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6.

[0093] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH about 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidine buffer at pH 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO:7 and a variable light chain of SEQ ID NO:8.

[0094] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody is MOR202.

[0095] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.5-6.5. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.9-6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of about pH 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 6.0.

[0096] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.5 to 6.5, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.9 to 6.1, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5 and an LCDR3 of SEQ ID NO: 6.

[0097] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH about 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer at pH 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO:7 and a variable light chain of SEQ ID NO:8.

[0098] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody is MOR202.

[0099] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.5-6.5. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.9-6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of about pH 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 6.0.

[0100] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.5 to 6.5, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of pH 5.9 to 6.1, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5 and an LCDR3 of SEQ ID NO: 6.

[0101] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH about 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer at pH 6.0, wherein said anti-CD38 antibody has a variable heavy chain of SEQ ID NO:7 and a variable light chain of SEQ ID NO:8.

[0102] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody is MOR202. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 6.0, wherein said anti-CD38 antibody is MOR202.

[0103] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.5 to 6.5, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w).

[0104] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.5 to 6.5, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH about 6.0, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w).

[0105] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of about 0.1% (w / w).

[0106] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of about 0.1% (w / w).

[0107] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of about pH 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 6.0, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the polysorbate 20 is at a concentration of 0.1% (w / w).

[0108] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 5.9-6.1, wherein the anti-CD38 antibody is MOR202, and the polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of about pH 6.0, wherein said anti-CD38 antibody is MOR202, and said polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer of pH 6.0, wherein said anti-CD38 antibody is MOR202, and said polysorbate 20 is at a concentration of 0.1% (w / w).

[0109] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the histidine buffer has a pH of 5.9 to 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the histidine buffer has a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5 and an LCDR3 of SEQ ID NO: 6, and the histidine buffer has a pH of 6.0.

[0110] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, the polysorbate 20 is at a concentration of about 0.1% (w / w), and the histidine buffer has a pH of 5.9 to 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, the polysorbate 20 is at a concentration of about 0.1% (w / w), and the histidine buffer has a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5 and an LCDR3 of SEQ ID NO:6, the polysorbate 20 is at a concentration of about 0.1% (w / w), and the histidine buffer has a pH of 6.0.

[0111] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, the polysorbate 20 is at a concentration of 0.1% (w / w), and the histidine buffer has a pH of 5.9 to 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, the polysorbate 20 is at a concentration of 0.1% (w / w), and the histidine buffer has a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5 and an LCDR3 of SEQ ID NO:6, the polysorbate 20 is at a concentration of 0.1% (w / w) and the histidine buffer has a pH of 6.0.

[0112] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the histidine buffer has a pH of 5.9 to 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the histidine buffer has a pH of about 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and the histidine buffer has a pH of 6.0.

[0113] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, the polysorbate 20 is at a concentration of about 0.1% (w / w), and the histidine buffer has a pH of 5.9 to 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, the polysorbate 20 is at a concentration of about 0.1% (w / w), and the histidine buffer has a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of SEQ ID NO:7 and a variable light chain of SEQ ID NO:8, said polysorbate 20 is at a concentration of about 0.1% (w / w), and said histidine buffer has a pH of 6.0.

[0114] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, the polysorbate 20 is at a concentration of 0.1% (w / w), and the histidine buffer has a pH of 5.9 to 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, the polysorbate 20 is at a concentration of 0.1% (w / w), and the histidine buffer has a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, said polysorbate 20 is at a concentration of 0.1% (w / w), and said histidine buffer has a pH of 6.0.

[0115] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody is MOR202, the polysorbate 20 is at a concentration of about 0.1% (w / w), and the histidine buffer has a pH of 5.9 to 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody is MOR202, the polysorbate 20 is at a concentration of about 0.1% (w / w), and the histidine buffer has a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody is MOR202, said polysorbate 20 is at a concentration of about 0.1% (w / w), and said histidine buffer has a pH of 6.0.

[0116] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody is MOR202, the polysorbate 20 is at a concentration of 0.1% (w / w), and the histidine buffer has a pH of 5.9 to 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody is MOR202, the polysorbate 20 is at a concentration of 0.1% (w / w), and the histidine buffer has a pH of about 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody is MOR202, said polysorbate 20 is at a concentration of 0.1% (w / w), and said histidine buffer has a pH of 6.0.

[0117] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, the histidine buffer has a pH of 5.9 to 6.1, and the anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, the histidine buffer has a pH of about 6.0, and the anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5 and an LCDR3 of SEQ ID NO:6, the histidine buffer has a pH of 6.0 and the anti-CD38 antibody is at a concentration of 65 mg / ml.

[0118] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5 and an LCDR3 of SEQ ID NO: 6, the polysorbate 20 is at a concentration of about 0.1% (w / w), the histidine buffer has a pH of 5.9 to 6.1, and the anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5 and an LCDR3 of SEQ ID NO:6, the polysorbate 20 is at a concentration of about 0.1% (w / w), the histidine buffer has a pH of about 6.0 and the anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5 and an LCDR3 of SEQ ID NO:6, the polysorbate 20 is at a concentration of about 0.1% (w / w), the histidine buffer has a pH of 6.0 and the anti-CD38 antibody is at a concentration of 65 mg / ml.

[0119] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5 and an LCDR3 of SEQ ID NO: 6, the polysorbate 20 is at a concentration of 0.1% (w / w), the histidine buffer has a pH of 5.9 to 6.1, and the anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5 and an LCDR3 of SEQ ID NO:6, the polysorbate 20 is at a concentration of 0.1% (w / w), the histidine buffer has a pH of about 6.0 and the anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, an LCDR1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5 and an LCDR3 of SEQ ID NO:6, the polysorbate 20 is at a concentration of 0.1% (w / w), the histidine buffer has a pH of 6.0 and the anti-CD38 antibody is at a concentration of 65 mg / ml.

[0120] In one embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, a buffer, and a stabilizer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and a stabilizer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and a stabilizer, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and a stabilizer, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and a stabilizer, wherein the anti-CD38 antibody is MOR202.

[0121] In one embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant, a buffer, and sucrose. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and sucrose. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and sucrose, wherein the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and sucrose, wherein the anti-CD38 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and sucrose, wherein the anti-CD38 antibody is MOR202.

[0122] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidine buffer and sucrose, wherein the anti-CD38 antibody is MOR202, the polysorbate 20 is at a concentration of about 0.1% (w / w), the histidine buffer is at a concentration of about 10 mM and has a pH of 5.9-6.1, and the sucrose is at a concentration of 150-350 mM.

[0123] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidine buffer and sucrose, wherein the anti-CD38 antibody is MOR202, the polysorbate 20 is at a concentration of about 0.1% (w / w), the histidine buffer is at a concentration of about 10 mM and has a pH of 5.9-6.1, and the sucrose is at a concentration of 175-300 mM.

[0124] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidine buffer, and sucrose, wherein the anti-CD38 antibody is MOR202, the polysorbate 20 is at a concentration of about 0.1% (w / w), the histidine buffer is at a concentration of about 10 mM and has a pH of 5.9 to 6.1, and the sucrose is at a concentration of about 260 mM.

[0125] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidine buffer and sucrose, wherein the anti-CD38 antibody is MOR202, the polysorbate 20 is at a concentration of 0.1% (w / w), the histidine buffer has a concentration of 10 mM and has a pH of about 6.0, and the sucrose is at a concentration of 260 nM.

[0126] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidine buffer, and sucrose, wherein the anti-CD38 antibody is MOR202 at a concentration of about 65 mg / ml, the polysorbate 20 is at a concentration of about 0.1% (w / w), the histidine buffer is at a concentration of about 10 mM and has a pH of 5.9 to 6.1, and the sucrose is at a concentration of about 260 mM.

[0127] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidine buffer and sucrose, wherein the anti-CD38 antibody is MOR202 at a concentration of about 65 mg / ml, the polysorbate 20 is at a concentration of 0.1% (w / w), the histidine buffer has a concentration of 10 mM and has a pH of about 6.0, and the sucrose is at a concentration of 260 nM.

[0128] In certain embodiments, the present disclosure provides a lyophilized pharmaceutical formulation prepared from any of the pharmaceutical formulations disclosed herein, hi certain embodiments, the present disclosure provides a lyophilized pharmaceutical formulation of an anti-CD38 antibody prepared by lyophilization of the pharmaceutical formulation of an anti-CD38 antibody described in this disclosure.

[0129] In certain embodiments, the present disclosure provides a method for preparing a liquid formulation of an anti-CD38 antibody, the method comprising providing a lyophilized pharmaceutical formulation according to the present disclosure and reconstituting the lyophilized formulation.

[0130] In certain embodiments, the present disclosure provides a method for preparing a liquid formulation of an anti-CD38 antibody, the method comprising the steps of providing a lyophilized pharmaceutical formulation according to the present disclosure and reconstituting the lyophilized formulation, wherein the reconstitution is achieved via the addition of water or a pharma- ceutically acceptable reagent. In certain embodiments, the present disclosure provides a method for preparing a liquid formulation of an anti-CD38 antibody, the method comprising the steps of providing a lyophilized pharmaceutical formulation according to the present disclosure and reconstituting the lyophilized formulation, wherein the reconstitution is achieved via the addition of water.

[0131] In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation of an anti-CD38 antibody obtained by reconstitution of a lyophilized formulation of the present disclosure. In certain embodiments, the reconstitution is achieved via addition of water or a pharma- ceutically acceptable reagent to a lyophilized solution comprising the anti-CD38 antibody. In certain embodiments, the reconstitution is achieved via addition of water to a lyophilized solution comprising the anti-CD38 antibody.

[0132] In certain embodiments, the disclosure provides a liquid formulation or a lyophilized formulation, or a liquid formulation reconstituted from a lyophilized formulation.

[0133] In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is at a concentration of 55-75 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is at a concentration of 62.5-67.5 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is at a concentration of about 65 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer of pH 5.5-6.5, wherein the anti-CD38 antibody is at a concentration of 65 mg / ml.

[0134] In certain embodiments, the reconstituted pharmaceutical formulation also includes a stabilizer. Suitable stabilizers include, but are not limited to, human serum albumin, bovine serum albumin, α-casein, globulin, α-lactalbumin, LDH, lysozyme, myoglobin, ovalbumin, and RNase A. Stabilizers also include amino acids and their metabolites, such as glycine, alanine, arginine, betaine, leucine, lysine, glutamic acid, aspartic acid, proline, 4-hydroxyproline, sarcosine, γ-aminobutyric acid (GABA), opines (alanopine, octopine, strombin), and trimethylamine N-oxide (TMAO). Stabilizers may include sugar alcohols and monosaccharides, disaccharides, or polysaccharides, such as mannitol, sorbitol, trehalose, dextrose, lactose, sucrose, and the like. Preferably, the stabilizer is sucrose.

[0135] In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a histidine buffer of pH 5.5-6.5, and a stabilizer, wherein the anti-CD38 antibody is at a concentration of 55-75 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a histidine buffer of pH 5.5-6.5, and a stabilizer, wherein the anti-CD38 antibody is at a concentration of 62.5-67.5 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a histidine buffer of pH 5.5-6.5, and a stabilizer, wherein the anti-CD38 antibody is at a concentration of about 65 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a histidine buffer of pH 5.5-6.5, and a stabilizer, wherein the anti-CD38 antibody is at a concentration of 65 mg / ml.

[0136] In certain embodiments, the pharmaceutical formulations of the present disclosure are for use in the treatment of a disease or disorder. In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to said subject an effective amount of a pharmaceutical formulation of the present disclosure. In certain embodiments, the present disclosure provides the use of a pharmaceutical formulation of the present disclosure for the preparation of a medicament for the treatment of a disease or disorder. EXAMPLES

[0137] Example 1: Liquid formulation for anti-CD38 antibody We developed a liquid formulation of the anti-CD38 specific antibody MOR202 that is suitable for long-term storage.

[0138] The formulation strategy consisted of a buffer and pH screen based on thermal stability, followed by excipient optimization with emphasis on protective properties against aggregate formation. Buffer screening was performed by Differential Scanning Calorimetry (DSC) to yield two lead buffers: histidine buffer (10 mM histidine pH 6.8) and phosphate buffer (10 mM phosphate buffer pH 6.6). These buffers were combined with NaCl and sucrose in a full factorial design.

[0139] Samples were subjected to freeze-thaw and thermomechanical stress and visually inspected for opalescence and particle formation. Finally, the products were characterized in different formulations by UV spectroscopy, size exclusion chromatography (SEC) and dynamic light scattering (DLS). Weighted ranking of the analytical results identified phosphate or histidine buffer with 125 mM NaCl as the most preferred composition. Histidine buffer showed excellent protection properties against freeze-thaw and was therefore selected as the basis for the final formulation.

[0140] Based on the data from this study and experience from previous preformulation work, the following formulation (CMC-1 formulation) was selected: 10mM L-histidine, pH 6.8 140mM NaCl 0.02% Tween 20

[0141] The CMC-1 formulation was used in a Phase I / IIa clinical trial.

[0142] Example 2: Preformulation development of lyophilized formulation A pre-formulation project was initiated to develop a formulation for drug product for anti-CD38 specific antibody MOR202 for Phase III clinical trials and market supply.

[0143] The objectives of this study included: Identifying the pH of maximum chemical and physical stability, and the effect of protein concentration on the stability of the molecule Evaluating the effect of shear forces (shaking) and freeze-thaw cycles on the physical and chemical stability of molecules Determining protein stability after dilution in 0.9% NaCl saline (normal saline)

[0144] Example 2.1 Drug Substance Concentration MOR202 drug substance was concentrated by tangential flow filtration (Omega Centramate 30kD 0.02sqm, Pall) to a final concentration of 80-90mg / ml. A transmembrane pressure not exceeding 6psi was used to monitor the tangential flow filtration process. The resulting concentrated solution was divided into sublots, loaded into Slide-A-Lyzer dialysis flasks, and dialyzed against each buffer (2.0 liters, at least 5x buffer exchange) over 24 hours. 0.3% NaCl was added to the citrate buffer matrix to increase the ionic strength and stabilize the MOR202 solution.

[0145] Upon completion of the buffer exchange, the MOR202 concentration was measured. The solution was then diluted with each buffer and filtered using a 0.22 μm syringe filter (PVDF, Millipore or PALL). The filtered formulation was then filled into 5 ml glass vials, stoppered and sealed.

[0146] The main preliminary formulations tested are summarized in Figure 1. Two different MOR202 concentrations were tested:- 50 g / l and 75 g / l. Based on preliminary experiments and experience, two main buffer systems were compared: histidine buffer and citrate buffer.

[0147] Example 2.2: Stability and Stress Testing The solutions prepared in Example 2.1 were subjected to various stability and stress tests. The main goals were to determine the optimum pH and to study the effect of protein concentration.

[0148] Stability was tested by storing vials at different conditions: 5±3°C, 25±2°C / 60±5% RH, and 40±2°C / 75±5% RH (RH=relative humidity). Samples were examined at specific time points. The tests performed and the test intervals are shown in Figure 2.

[0149] Shear and freeze-thaw cycles were used to determine the concentration of surfactant required to effectively address any physical stability issues of the formulation (e.g., aggregation, appearance) and to protect the API during processing (e.g., mixing, pumping). From previous studies, polysorbate 20 was known to provide protection against degradation and aggregation. The following polysorbate 20 concentrations (w / v %) were tested: 0.02%, 0.04%, and 0.1%.

[0150] For shear testing, formulations were agitated on a rotary shaker at 40-60 rpm at room temperature for 24 and 48 h. Physical appearance (visual), purity (SEC), protein content (UV) and hydrodynamic size / soluble aggregates (DLS) were analyzed.

[0151] For the freeze-thaw test, the formulations were subjected to three freeze-thaw cycles (-70°C). Samples were analyzed similarly to the shear test.

[0152] For saline dilution study, formulations were diluted 1:100 with normal saline. Purity was measured by SEC. Subvisible particles were measured by HIAC.

[0153] Example 2.3: Stability Study Results The results of the stability study are summarized in Figures 3A-3G. The following observations were made: Histidine buffer is excellent at stabilizing the API (MOR202). No significant differences in appearance and pH were observed during the stability study. No significant differences were detected in the UV content over time. At the last checkpoint, there appeared to be an increase in protein content for all formulations. The increase in protein concentration can be attributed to method variability, since the same increase is detected for the standard solution. Analysis by SEC indicates stability of all formulations at 5°C, except for the pH 5.5 L-histidine (75g / L) formulation, which shows an increase in aggregates and contaminants after 2 weeks. · As the pH increases, the number of particles per ml increases. The size assessed by DLS remains unchanged over the duration of the stability study.

[0154] Taking these together, the following lead buffer system was selected as the basis for further development: MOR202 75g / l 10mM buffer L-histidine 1.552g / l HCl pH6.0±0.1 qs pH 6.0±0.1

[0155] The result of this lead buffer system can be described as follows: Appearance: The solution is clear at time zero and becomes slightly milky during stabilization; the color and presence of particles remain constant. UV content: constant pH: constant HIAC: Particle counts during stability testing remain similar for each diameter and are lowest at time zero SEC: % IgG remains constant at 5°C and decreases at 40°C % aggregates remains constant at 5°C and increases at 40°C % Contaminant is constant at 5°C and increases at 40°C This formulation has the lowest levels of aggregates and the highest levels of IgG at time zero. DLS: The size assessed by DLS remains unchanged over the duration of the stability study.

[0156] Example 2.4 Results of shear test, freeze-thaw test and saline dilution test MOR202 solutions were tested in the lead buffer system identified in Example 2.3. The polysorbate 20 concentrations were adjusted to 0.02%, 0.04% and 0.1%.

[0157] The results of the shear tests are shown in Figures 4A-4C. The results of the freeze / thaw test are shown in Figures 4D-4E. The results of the saline dilution study are shown in FIG. 4F.

[0158] Shear test results: Physical appearance changes only to opalescence after 48 hours of shear. Formulations containing 0.02% Polysorbate 20 contain the highest grade of opalescence. The shape and aspect of the fibers and particles do not appear to be attributable to the product. The presence of fibers and particles is believed to be of extraneous origin. There is a slight decrease in UV content in formulations using PS20 at concentrations of 0.04% and 0.1%. · SEC results show that all PS20 concentrations are characterized by a slight decrease in % IgG and a corresponding slight increase in % aggregates. No significant changes in size and polydispersity are observed when the samples are evaluated by DLS.

[0159] Freeze-thaw test results: The shape and aspect of the fibres and particles do not appear to be attributable to the product. The presence of fibres and particles is believed to be of external origin. The slight increase in UV content for all PS20 concentrations can be attributed to method variability. Regarding the SEC results, all PS20 concentrations show a slight decrease in % IgG and a corresponding slight increase in % aggregates. · The size estimated by DLS remains unchanged.

[0160] Saline dilution test results: There are no significant differences between time point zero and time point 24 hours for all formulations as assessed by SEC. An increase in the number of particles for all diameter ranges was observed with light obscuration. The highest increase was detected in solutions originally containing 0.04% polysorbate 20, where for the 2 μm size range there was a four-fold increase in the number of particles.

[0161] Example 2.5: Final results of preformulation development A series of preformulation studies were performed to select the optimal pH and excipients required to stabilize MOR202. These studies included identifying an optimal pH of 5.5-6.3, examining the effect of polysorbate 20 on freeze-thaw and agitation, and testing the stability of MOR202 after dilution with normal saline.

[0162] The molecule exhibited good chemical and physical stability in 10 mM histidine buffer (pH 6.0). Based on the results of these studies, 10 mM histidine buffer (pH 6.0) was considered to be the optimal matrix for the formulation of MOR202.

[0163] Based on the output of shear, freeze-thaw, and dilution studies, the presence of Polysorbate 20 was found to be important and preferred.

[0164] The following compositions were selected as the basis for further formulation development: MOR202 75g / l Polysorbate 20 0.1% 10mM buffer L-histidine 1.552g / l HCl pH6.0±0.1 qs pH 6.0±0.1

[0165] The characteristics of this formulation can be summarized as follows: Appearance: The solution becomes milky only after 48 hours of shearing UV content: Shows a decrease after 48 hours of shear and an increase after the third freeze / thaw cycle SEC: slight decrease in %IgG and corresponding slight increase in %aggregate after shear and freeze / thaw cycle testing. %IgG and %aggregate remain constant during saline dilution testing. HIAC: Increase in particle counts for all diameters during saline dilution testing. Total particle counts are significantly lower than with 0.04% PS20. DLS: Size as assessed by DLS remains unchanged

[0166] Example 3: Formulation development for lyophilized formulation of MOR202 Following pre-formulation, a new project was initiated to develop a formulation for a drug product for the anti-CD38 specific antibody MOR202.

[0167] The objectives of this study included: · Preparation of lyophilized MOR202 prototype formulations to be evaluated for compatibility with the lyophilization process; · Stability analysis of lyophilized prototype formulations; · Selection of one lead MOR202 lyophilized formulation based on stability data; · Development and optimization of a lyophilization cycle based on the selected lead MOR202 formulation; Recommending suitable lyophilization cycles for process transfer and scale-up in fill / finish facilities.

[0168] Example 3.1: Thermal evaluation of prototype formulations Based on previous knowledge and information obtained from preliminary formulation studies, the following formulations were selected for screening for lyophilization development: [Table 1]

[0169] The thermal properties of the prototype formulations were evaluated and based on the analytical results, suitable lyophilization cycles were proposed for the five prototype formulations.

[0170] After thermal evaluation of the properties of the prototype formulation in Table 1, the concentration of MOR202 was reduced from 75 mg / mL to 65 mg / mL. The reduction in API concentration did not affect the thermal properties of the prototype formulation. [Table 2]

[0171] The new prototype formulations in Table 2 are designated F1-F5.

[0172] Understanding the parameters that affect the physicochemistry of freezing, lyophilization, heat and mass transfer is important for determining the parameters of the lyophilization cycle. Sub-ambient differential scanning calorimetry (DSC) studies were performed using a Pyris 1 Perkin Elmer system. The parameters used are shown in Table 3. [Table 3]

[0173] The main focus was on identifying the temperature at which crystallization occurs (eutectic point, Te) and the glass transition temperature (Tg') of the maximum freeze-concentrated solution. Thermograms (freezing and heat ramp) were obtained for all prototype solutions F1-F5. All results are summarized in Table 4: [Table 4]

[0174] All five formulations have comparable eutectic points, suggesting compatibility with one lyophilization cycle. Formulations F2, F4, and F5 appeared slightly milky, but no precipitate / aggregate was observed by visual inspection. Formulations F2 and F4 have osmolalities close to 350 mOsmol / kg, which is still within the acceptable range for intravenous administration. However, if the target osmolality is closer to the standard of 300 mOsmol / kg, the sucrose content of F2 and F4 can be reduced by 12 and 10 mg, respectively. This should bring the osmolality closer to 310 mOsmol / kg without affecting the thermal properties of the formulation.

[0175] Based on these considerations, initial freeze-drying parameters were defined for the first freezing experiment.

[0176] Example 3.2: Initial lyophilization of prototype formulations Prototype solutions F1-F5 (see Table 2) were lyophilized, with initial parameters based on the results of the DCS test (see Example 3.1).

[0177] The prepared bulk solution was filtered using a 0.22 pm PVDF filter and filled into 20R vials with a fill volume of 5.00 mL + 0.3 mL overfill.

[0178] The cycle length was approximately 64 hours. The cycle was monitored in real time. Primary and secondary drying were reduced from the originally proposed 50 hours to 46 hours and 20 hours to 8 hours, respectively. The recipe is shown in Table 5. [Table 5]

[0179] The cakes of all five formulations appeared to be sufficiently dry. Overall, the appearance can be classified as follows (good to poor): F3=F5>F2=F4>F1. This classification takes into account the number of cracks in the cake, the level of shrinkage, and the tendency to break. Images of the vials of all formulations are shown in Figure 5.

[0180] Example 3.3: Lyophilized and Liquid Prototype Formulation Testing The liquid and lyophilized prototype formulations were analyzed for the following parameters: Appearance (liquid and freeze-dried) Water content (freeze-dried only) pH (liquid and freeze-dried) Size Exclusion Chromatography (liquid and freeze-dried) ·Hypervisible particles (HIAC) (liquid and freeze-dried) DLS (liquid and freeze-dried) ·Reconstitution time (lyophilization) ·UV (liquid and freeze drying)

[0181] The stability of the formulations was also studied after storage at different temperatures (2-8°C, 0% RH; 25°C, 60% RH; 40°C, 75% RH) and at different time points (0, 2 and 4 weeks).

[0182] The results for the liquid formulations are shown in Figures 7A-7H, and the results for the lyophilized formulations are shown in Figures 8A-8E.

[0183] Example 3.4: Final Results Based on a thorough analysis of five prototype liquid and lyophilized formulations, formulation F3 was selected for the development step.

[0184] Formulation F3 had the lowest degree of opalescense and, in contrast to the other four formulations tested, no increase in subvisible particles was observed for the liquid formulation during the stability study. Furthermore, Formulation F3 also showed the lowest degree of opalescense for the lyophilized formulations after reconstitution and no increase in aggregates was observed during the stability study.

[0185] Example 4: Optimization of freeze-drying The freeze-drying process was optimized in several subsequent steps, each of which utilized the results and experience gained during the previous experiments. The critical process parameters evaluated in the freeze-drying process were temperature, pressure and time.

[0186] Example 4.1: First optimization Based on the results collected in the first freeze-drying experiment (see Example 3), the process was modified. One of the main goals was to shorten the secondary drying process and adapt the ramp rates for the different freezing / heating steps. The first optimized freeze-drying recipe is shown in Table 6. The total cycle length was about 72 hours. [Table 6]

[0187] Analytical results confirmed that the lyophilized drug product exhibited the expected properties and did not exhibit any abnormalities.

[0188] After 5 hours of secondary drying (step 8), the residual moisture content was 0.9% w / w, so this step had to be extended for another 3 hours. After 8 hours, the residual moisture content was 0.3% w / w, i.e. below the target of <0.5% w / w.

[0189] It was also observed that the ramping up of the primary drying and subsequent secondary drying steps could potentially be shortened, which could translate into an additional savings of about 4 hours in the overall process.

[0190] All cakes were thoroughly dried.

[0191] The appearance of the cakes was graded taking into account the number of cracks in the cake, the level of shrinkage and the tendency to break.

[0192] The 24 vials tested were classified as follows: 9 vials is fine 13 vials with very little shrinkage 2 vials with cracks

[0193] Freeze-drying microscopy (FDM) was used to determine the critical temperature of the drug product. FDM was performed using a BTL Lyostat freeze-drying microscope (ID PDS 250).

[0194] 1.5 pL of sample solution was analyzed, allowing real-time observation of the freeze-drying of the sample. Information obtained from FDM is the collapse point (Tc) and eutectic point (Teu) of the formulation.

[0195] Some samples exhibit collapse zone behavior, ie, the structure of the dried sample is lost gradually over a temperature range, rather than at a distinct point.

[0196] The first signs of collapse were observed at -26.8°C. As sublimation progressed and the temperature increased, collapse became more evident. The table summarizes the lower collapse zone temperatures and resumes the primary drying temperatures and pressures. [Table 7]

[0197] The following conclusions were drawn: To prevent product collapse, temperatures should ideally be maintained below the lower limit of each collapse zone during primary drying. For additional safety and quality of the product, a safety margin between 2°C and 7°C should be considered. This allows for slight variations that may occur during scale-up, technology transfer, and use of different freeze-dryers. Do not increase the primary drying temperature.

[0198] Example 4.2: Second optimization Compared to the first optimization, the ramp rates for primary and secondary drying were increased in the second optimization. The primary temperature was maintained at -15°C. [Table 8]

[0199] The total cycle length was approximately 66 hours, ie significantly shorter than in the first optimization.

[0200] Analytical results confirmed that the lyophilized drug product exhibited the expected properties and did not exhibit any abnormalities.

[0201] All cakes were thoroughly dried.

[0202] Again, the appearance of the cakes was graded taking into account the number of cracks in the cake, the level of shrinkage, and the tendency to break.

[0203] The 29 vials tested were classified as follows: 27 vials with very little shrinkage 2 vials with very little shrinkage and superficial cracks

[0204] Observations made and possible changes for the next optimization round: The lyophilized cake does not improve by applying different lamps and conditions; the appearance of the cake is probably due to the excipients and drug product. A 1°C / min ramp in the freezing step is not possible with all commonly used freeze dryers, therefore it is recommended to work within the safety limits and use a 0.5°C / min freezing ramp.

[0205] Example 4.3: Third optimization The main focus of this optimization was to ensure that the quality of the drug product was not affected by possible variations in temperature and pressure that may occur during scale-up to commercial scale. To test worst-case conditions, temperature variations of ±3°C and pressure variations of ±30 μbar were evaluated.

[0206] Two freeze-drying experiments, HT / HP and LT / LP, were performed for robustness testing, and a laboratory-scale (0.5 m 2 The test was carried out in a freeze-drying unit.

[0207] The optimization was aimed at investigating high temperature and pressure conditions. [Table 9]

[0208] The total cycle length was approximately 64 hours, ie again shorter than the last optimization.

[0209] Analytical results confirmed that the lyophilized drug product exhibited the expected properties and did not exhibit any abnormalities.

[0210] All cakes were thoroughly dried.

[0211] Again, the appearance of the cakes was graded taking into account the number of cracks in the cake, the level of shrinkage, and the tendency to break.

[0212] The 29 vials tested were classified as follows: 24 vials had a sticky white cake with very little shrinkage 5 vials with very little shrinkage and superficial cracks

[0213] Example 4.4: Fourth optimization The optimization was aimed at investigating low temperature and low pressure conditions. [Table 10]

[0214] The total cycle length was again approximately 64 hours.

[0215] Analytical results confirmed that the lyophilized drug product exhibited the expected properties and did not exhibit any abnormalities.

[0216] All 26 cakes were thoroughly dried and sticky. Three of the 26 vials showed slight shrinkage that was not considered a defect.

[0217] The results of these experiments demonstrated that the selected formulations could be successfully lyophilized even with minor variations in temperature and pressure during the lyophilization process steps.

[0218] This ensures a robust process for large scale routine manufacturing.

[0219] Example 4.5: Fifth optimization A fifth optimization was performed based on all the experience collected so far. [Table 11]

[0220] The total cycle length was approximately 66 hours.

[0221] The analytical results confirmed that the lyophilized drug product exhibited the expected properties and did not exhibit any abnormalities. Figure 8 shows the results of the analysis of the lyophilized drug product. The reconstitution volume was 4.8 ml. All cakes were sticky.

[0222] 215 vials were conforming. Three of the 215 conforming vials showed cosmetic cracks that were not considered defects. 60 vials were rejected due to drug product between the stopper and the neck. This defect is related to the filling process and not the lyophilization process. 44 vials either showed a stain on the vial near the stopper or there was a very small amount of product between the stopper and the rack. This defect is likely caused during the lyophilizer load. A photograph of an exemplary cake is shown in FIG. 9.

[0223] The fifth optimization result showed that the process was robust and suitable for application in the production of GMP materials.

Claims

1. A lyophilized pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer solution having a pH of 5.5 to 6.

5.

2. 2. The freeze-dried pharmaceutical formulation according to claim 1, wherein the non-ionic surfactant is polysorbate 20.

3. 3. The lyophilized pharmaceutical formulation according to claim 1 or 2, wherein the histidine buffer has a pH of about 6.

0.

4. The freeze-dried pharmaceutical preparation according to any one of claims 1 to 3, characterized in that the anti-CD38 antibody has an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5 and an LCDR3 of SEQ ID NO:

6.

5. The freeze-dried pharmaceutical formulation according to any one of claims 1 to 4, further comprising sucrose.

6. 6. A method for preparing a liquid formulation of an anti-CD38 antibody, comprising the steps of providing a lyophilized pharmaceutical formulation according to any one of claims 1 to 5 and reconstituting the lyophilized formulation by the addition of water.

7. A reconstituted pharmaceutical preparation of an anti-CD38 antibody obtained by the method according to claim 6.

8. 8. A reconstituted pharmaceutical formulation according to claim 7, characterized in that the non-ionic surfactant is in a concentration of 0.05% (w / w) to 0.2% (w / w), preferably about 0.1% (w / w).

9. 9. The reconstituted pharmaceutical formulation according to claim 7 or 8, characterized in that the histidine buffer is at a concentration of 5 mM to 15 mM, preferably about 10 mM.

10. 10. The reconstituted pharmaceutical formulation according to any one of claims 7 to 9, characterized in that the sucrose is at a concentration of 150 to 350 mM, preferably about 260 mM.

11. The reconstituted pharmaceutical formulation according to any one of claims 7 to 10, characterized in that the anti-CD38 antibody is in a concentration of 55 to 75 mg / ml, preferably about 65 mg / ml.

12. 12. A pharmaceutical formulation according to any one of claims 1 to 5 or 7 to 11 for use in the treatment of a disease or disorder.

13. 13. The use of the pharmaceutical preparation according to claim 12, wherein the disease or disorder is cancer.

14. 14. Use of the pharmaceutical preparation according to claim 13, characterized in that the cancer is a blood cancer selected from leukemia, lymphoma and myeloma, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and multiple myeloma (MM), or a solid cancer selected from sarcoma and carcinoma, such as breast cancer, ovarian cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma tumor, colorectal cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, thyroid cancer and kidney cancer.

15. 13. Use of the pharmaceutical preparation according to claim 12, wherein the disease or disorder is an inflammatory disorder.

16. 16. The use of the pharmaceutical preparation of claim 15, wherein the inflammatory disorder is selected from inflammatory bowel disease, rheumatoid arthritis, psoriasis, amyloidosis, systemic lupus erythematosus (SLE), atopic dermatitis, Wegener's granulomatosis, and psoriatic arthritis.

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