Antibody preparations

Abstract

This disclosure relates to formulations of pharmaceutically active antigen-binding proteins, such as monoclonal antibodies. [Solution] In particular, this disclosure relates to a stable lyophilized pharmaceutical formulation of an anti-CD38 antibody, a reconstituted liquid formulation of such a lyophilized formulation, and a method for preparing and using such a lyophilized and reconstituted formulation.

Description

Technical Field

[0001] The present disclosure relates to formulations of pharmaceutically 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 Art

[0002] The pharmaceutical use of antibodies has been increasing over the past several 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 with medication 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 thus formulations of such proteins pose special challenges. For the protein to remain biologically active, the formulation must preserve the conformational integrity of at least the core sequence of the protein's amino acids while protecting multiple functional groups of the protein from degradation. Antibody formulations can have a short shelf life, and the prepared antibodies can lose biological activity due to chemical and physical instabilities during storage. The three most common pathways for proteolysis 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 increase in the patient's immune response, leading to safety concerns and must be minimized or prevented.

[0004] Formulations with higher protein concentrations present further challenges, particularly in relation to protein stability, protein-protein interactions, and viscosity. Viscosity is not only a matter of the biophysical and biochemical properties of therapeutic proteins, but also a matter of 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 syringes and needles. Therefore, aspects of injectability are affected by viscosity and must be considered during the development of high-concentration formulations. Certain antibodies also exhibit undesirable self-interaction tendencies, which makes them relatively unsuitable for high-concentration formulations. This self-interaction tendency can result in oligomerization, aggregation, and high viscosity at high protein concentrations. Opaqueness, one parameter indicating the physical instability of a formulation due to the presence of aggregates or liquid-liquid phase separation in the solution, has been reported for monoclonal antibody (mAb) formulations.

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

[0006] CD38 is a type II membrane protein that functions in receptor-mediated adhesion and signal transduction, mediates calcium mobilization via its ecto-enzyme activity, catalyzes the formation of cyclic ADP-ribose (cADPR) from NAD+, and hydrolyzes cADPR back to ADP-ribose (ADPR). CD38 mediates cytokine secretion and lymphocyte activation and proliferation (Funaro et al, J Immunology 145:2390-6, 1990; Guse et al, Nature 398:70-3, 1999), and regulates extracellular NAD+ levels involved in the regulation of the regulatory T cell compartment via its NAD glycohydrolase activity (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 being studied for other indications, including but not limited to solid tumors, autoimmune disorders, and numerous other diseases.

[0008] International Publication No. 199962526 (Mayo Foundation); International Publication No. 200206347 (Crucell Holland), International Publication No. 2005103083 (MorphoSys AG), International Publication No. 2006125640 (MorphoSys AG), International Publication No. 2007042309 (MorphoSys); International Publication No. 2006099875 (Genmab), International Publication No. 2011154453A1 (Genmab), International Publication No. 2008047242 (Sanofi-Aventis), International Publication No. 2015066450 (Sanofi), International Publication No. 2012092616A1 (Takeda), International Publication No. 2012092612A1 (Takeda), International Publication No. 2013059885 (Teva), International Publication No. 2014178820 (Teva), International Publication No. 2015149077 (Xencor), International Publication No. 2017081211A2 (University Several antibodies specific to CD38 (including bispecific antibodies and other constructs), including but not limited to those described in the Hamburg-Eppendorf publication and International Publication No. 2017091656 (Amgen, Xencor), have been used or developed.

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

[0010] Pharmaceutical formulations for therapeutic antibodies are known in the prior art. For example, International Publication No. 2013016648 discloses a pharmaceutical formulation comprising an anti-PCSK9 antibody, histidine buffer, a nonionic surfactant, and a stabilizer. However, this document does not disclose an anti-CD38 antibody. International Publication No. 2018204405 discloses a formulation comprising an anti-TIGIT antibody, histidine buffer, polysorbate-80 as a nonionic surfactant, a non-reducing sugar, and an antioxidant, but this also does not disclose an anti-CD38 antibody. International Publication No. 2017079150 discloses a subcutaneous formulation comprising an anti-CD38 antibody, hyalorunidase, histidine buffer, methionine, and a nonionic surfactant. This document teaches the addition of hyaluronidase to the composition and does not disclose MOR202 or a lyophilized composition.

[0011] Therefore, there is still a need for stable lyophilized antibody preparations, particularly those containing the antibody MOR202, for the preparation of anti-CD38 drugs. [Overview of the project]

[0012] The object of the present invention is to provide a formulation of anti-CD38 antibody, in particular, a formulation of anti-CD38 antibody having an appropriate shelf life.

[0013] A suitable formulation of a therapeutic antibody may be an aqueous pharmaceutical composition or a lyophilized product that can be reconstituted to provide a solution for administration to a patient.

[0014] This invention provides lyophilized pharmaceutical formulations containing antibodies. In aspects of this disclosure, the pharmaceutical formulation comprises an anti-CD38 antibody. In another aspect of this disclosure, the pharmaceutical formulation comprises an antibody known as MOR202.

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

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

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

[0018] In a particular embodiment, the anti-CD38 antibody includes HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 the variable heavy chain of SEQ ID NO: 7 and the variable light chain of SEQ ID NO: 8.

[0021] In one embodiment, the present disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, wherein the pharmaceutical formulation comprises a surfactant. In a particular embodiment, the surfactant is a nonionic surfactant. In another embodiment, the nonionic surfactant is a polysorbate. In yet another embodiment, the polysorbate is polysorbate 20 (PS20) or polysorbate 80 (PS80). In yet another embodiment, the polysorbate is polysorbate 20.

[0022] In one embodiment, the present disclosure provides a pharmaceutical formulation for the anti-CD38 antibody, such as MOR202, wherein the pharmaceutical formulation comprises a histidine buffer at pH 5.5 to 6.5. In a particular embodiment, the histidine buffer is a histidine buffer at pH 5.9 to 6.1. In a particular embodiment, the histidine buffer has a pH of approximately 6.0. In a particular embodiment, the histidine buffer has a pH of 6.0.

[0023] In one aspect, the present disclosure provides a pharmaceutical formulation for the anti-CD38 antibody such as MOR202, and the pharmaceutical formulation contains a histidine buffer solution with a concentration of 5 mM to 15 mM. In other aspects, the histidine buffer solution has a concentration of 8 mM to 12 mM. In other aspects, the histidine buffer solution has a concentration of about 10 mM. In other aspects, the histidine buffer solution has a concentration of 10 mM.

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

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

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

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

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

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

[0030] In other aspects, the anti-CD38 antibody has a concentration of 62.5 to 67.5 mg / ml.

[0031] In still other aspects, the anti-CD38 antibody has a concentration of about 65 mg / ml. In still other aspects, the anti-CD38 antibody has a concentration of 65 mg / ml.

[0032] In one aspect, the present disclosure provides a pharmaceutical formulation for the anti-CD38 antibody such as MOR202, wherein the pharmaceutical formulation contains a surfactant at a concentration of 0.05% (w / w) to 0.2% (w / w). In other aspects, the surfactant has a concentration of about 0.1% (w / w). In other aspects, the surfactant has 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 the subject an effective amount of the pharmaceutical formulation of the present disclosure.

[0034] In one aspect, the present disclosure provides the use of the pharmaceutical formulation of the present 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 specific 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 pre-formulations tested in Example 2. [Figure 2] Test schedule during pre-formulation development. [Figure 3A] Results of stability testing in preliminary formulation development. Time point 0 [Figure 3B] Results of stability testing in preliminary formulation development. Time point 0 [Figure 3C] Results of stability testing in preliminary formulation development. Tested at 2 weeks at 40°C / 75% RH. [Figure 3D] Results of stability testing in preliminary formulation development. Tested at 2 weeks at 40°C / 75% RH. [Figure 3E] Results of stability testing in preliminary formulation development. Tested at 4 weeks at 40°C / 75% RH. [Figure 3F] Results of stability testing in preliminary formulation development. Tested at 2 weeks and 5°C. [Figure 3G] Results of stability testing in preliminary formulation development. Tested at 4 weeks and 5°C. [Figure 4A] Results of various tests using a Reed buffer system and polysorbate 20 at various concentrations. Results of shear tests at T0, T24h, and T48h. [Figure 4B] Results of various tests using a Reed buffer system and polysorbate 20 at various concentrations. Results of shear tests at T0, T24h, and T48h. [Figure 4C] Results of various tests using a Reed buffer system and polysorbate 20 at various concentrations. Results of shear tests at T0, T24h, and T48h. [Figure 4D] Results of various tests using a Reed buffer system and polysorbate 20 at various concentrations. Freeze / thaw test results. [Figure 4E] Results of various tests using a Reed buffer system and polysorbate 20 at various concentrations. Freeze / thaw test results. [Figure 4F] Results of various tests using a Reed buffer system and polysorbate 20 at various concentrations. Results of the physiological saline dilution test. [Figure 5] Vial containing cake after the initial freeze-drying experiment. [Figure 6A] Stability results and subvisible particles for liquid formulations. Appearance of solutions and UV assay. [Figure 6B]Stability results and invisible particle analysis for liquid formulations. Appearance of solutions and UV assay. [Figure 6C] Stability results and invisible particle analysis for liquid formulations. Appearance of solutions and UV assay. [Figure 6D] Stability results and invisible particles for liquid formulations. pH and SE-HPLC. [Figure 6E] Stability results and invisible particles for liquid formulations. DLS [Figure 6F] Stability results and invisible particles for liquid formulations. DLS [Figure 6G] Stability results and invisible particles for liquid formulations. DLS [Figure 6H] Stability results and invisible particles for liquid formulations. HIAC [Figure 7A] Stability results and invisible particle analysis for lyophilized formulations. Appearance, UV assay, and pH. [Figure 7B] Stability results and invisible particles for freeze-dried formulations. DLS, cake appearance, reconstitution time, and water content. [Figure 7C] Stability results and invisible particles for freeze-dried formulations. DLS, cake appearance, reconstitution time, and water content. [Figure 7D] Stability results and invisible particles for freeze-dried formulations. DLS, cake appearance, reconstitution time, and water content. [Figure 7E] Stability results and invisible particles for lyophilized formulations. SE-HPLC and invisible particles. [Figure 8] Analysis results of the drug product after the fifth freeze-drying optimization. [Figure 9] A vial containing the fifth freeze-dried optimized cake. [Modes for carrying out the invention]

[0036] Naturally, this disclosure is not limited to any particular method, reagent, compound, composition, or biological system, and it should be understood that these may vary. Similarly, it should be understood that the terms used herein are intended to describe only and not limit to any particular embodiment.

[0037] As used herein and in the appended claims, the singular forms "a," "an," and "the" include multiple references unless the content specifically indicates otherwise. Thus, for example, a reference to "polypeptide" includes combinations of two or more polypeptides.

[0038] As used herein, “approximately” means, when referring to measurable values ​​such as quantity or temporal duration, to include variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from a given value, because such variations are appropriate for performing the methods disclosed. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to whom this disclosure relates. Any methods and materials similar or equivalent to those described herein may be used to perform the tests of this disclosure, but preferred materials and methods are described herein in describing and claiming this disclosure, and the following terms are used:

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

[0040] The term "viscosity" refers to the internal resistance to flow exhibited by a fluid at a given temperature, i.e., the ratio of shear stress to shear rate. A liquid has a viscosity of 1 poise if a force of 1 dyne / cm² causes two parallel liquid surfaces separated by an area of ​​1cm² and 1cm² to move past each other at a speed of 1cm / s. 1 poise is equal to 100 centipoise. In one embodiment, the viscosity of a formulation containing buffers and stabilizers 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 numerous 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, “buffer solution” refers to a buffer solution that resists changes in pH due to the action of its acid-base conjugated components. The buffer solutions of the present invention preferably have a pH in the range of 5.9 to 6.1, preferably a pH of about 6.0, and more preferably a pH of 6.0. “Histidine buffer solution” is a buffer solution containing the amino acid histidine. Histidine buffer solutions are preferred buffer solutions of this disclosure. Examples of histidine buffer solutions 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 Examples include polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics or PF68), (Paterson Industries, Inc., NJ). Preferably, the surfactant is a nonionic surfactant. More preferably, the nonionic surfactant is polysorbate 20. Polysorbate 20 is also known as PS20 or Tween-20. Polysorbate 80 is also known as PS80 or Tween-80.

[0044] The surfactant can be used at 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 formulations according to this disclosure may include stabilizers as further excipients. Examples of 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), opine (alanopine, octopine, strombine), and trimethylamine N-oxide (TMAO). Stabilizers 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] As used herein in relation to the pharmaceutical formulations of this disclosure, the term “reconstituted” means a formulation that has been lyophilized and redissolved by the addition of a reconstituted medium. The reconstituted medium includes, but is 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), surfactants, containing solutions (e.g., 0.01% polysorbate 20), and pH buffer solutions (e.g., phosphate buffer solution).

[0047] In one embodiment, the pharmaceutical formulations of the present disclosure are stable upon freezing and thawing, and a “stable” formulation is one in which all proteins within it essentially retain their physical and / or chemical stability and / or biological activity when stored at the intended storage temperature, e.g., 2–8°C. It is desirable 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, e.g., after 1, 2, or 3 cycles of freezing and thawing. Various analytical techniques for measuring protein stability are available in the art and are outlined, 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 evaluated qualitatively and / or quantitatively by a variety of different methods, including: assessment of aggregate formation (e.g., by measuring turbidity using size exclusion chromatography and / or by visual inspection); assessment of charge heterogeneity using cation exchange chromatography or capillary zone electrophoresis; amino-terminated or earboxy-terminated sequence analysis; mass spectrometry; SDS-PAGE analysis for comparing reduced and intact antibodies; peptide mapping (e.g., trypsin or LYS-C) analysis; and assessment of the biological activity or antigen-binding function of the antibody.

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

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

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

[0051] As used herein, the term “antibody” refers to a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, which interact with an antigen. Each heavy chain consists of a heavy chain variable region (hereinafter abbreviated as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains, CH1, CH2, and CH3. Each light chain consists of a light chain variable region (hereinafter abbreviated 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 hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl 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 antigens. The constant region of an antibody can mediate the binding of immunoglobulins 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] As used herein, the term "antibody fragment" refers to one or more portions of an antibody that possess the ability to specifically interact with an antigen (e.g., by binding, steric hindrance, or stabilization of spatial distribution). Examples of binding fragments include, but are not limited to, Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; F(ab)2 fragments, bivalent fragments containing two Fab fragments linked by disulfide crosslinks at a hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of VL and VH domains of a single arm of the antibody; dAb fragments consisting of a 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 recombination methods by synthetic linkers, which allow the VL and VH regions to be paired to form a single protein chain (known as single-chain Fv (scFv)) that forms 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 skilled 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, for example, Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments can be transplanted onto polypeptide-based scaffolds such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199 describing fibronectin polypeptide monobodies).Antibody fragments can be incorporated into single-chain molecules containing a pair of tandem Fv segments (VH-CH1-VH-CH1) that form a pair of antigen-binding sites together with a complementary light chain polypeptide (Zapata et al., (1995) Protein Eng. 8:1057-1062; U.S. Patent No. 5,641,870).

[0053] When used herein, "human antibody" or "human antibody fragment" includes antibodies and antibody fragments having a variable region in which both the framework region and the CDR region are derived from human sequences. Human antibodies may also be isolated from synthetic libraries or from transgenic mice (e.g., heterologous mice), provided that each system provides an antibody having a variable region in which both the framework region and the CDR region are equivalent to human sequences.

[0054] Furthermore, if the antibody contains a constant region, the constant region also originates from such a sequence. Human origins include antibodies containing, for example, human germline sequences, mutant versions of human germline sequences, or consensus framework sequences derived from human framework sequence analysis, such as that 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., Kabat numbering scheme, Chothia numbering scheme, or a combination of Kabat and Chothia) (e.g., Sequences of Proteins of Immunological Interest, USD Department 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 USD Department of Health and Human Services; Chothia et al., (1987) J.Mol.Bio.196:901-917; Chothia et al., (1989) Nature See 342:877-883 and Al-Lazikani et al., (1997) J.Mol.Biol.273:927-948).

[0056] In this specification, a "humanized antibody" or "humanized antibody fragment" is defined as an antibody molecule having a constant antibody region derived from a human sequence, with only the variable antibody region, a portion thereof, or the CDR derived from another species. For example, a humanized antibody may be CDR-implanted, where the CDR of the variable domain is of non-human origin, while one or more frameworks of the variable domain are of human origin, and the constant domain (if present) is of human origin.

[0057] The terms “chimeric antibody” or “chimeric antibody fragment” are defined herein as an antibody molecule having a constant antibody region derived from or corresponding to a sequence found in one species and a variable antibody region derived from another species. Preferably, the constant antibody region is derived from or corresponding to a sequence found in humans, and the variable antibody region (e.g., VH, VL, CDR, or FR region) is derived from a sequence 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 substantially contains no other antibodies or antibody fragments having different antigen specificities. Furthermore, an isolated antibody or antibody fragment may not substantially contain other cellular material and / or chemical substances. Thus, in some embodiments, the antibody provided is an isolated antibody separated from an antibody having 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 cross-reactive to other related antigens (e.g., those from other species (e.g., species homologs)).

[0059] The term “recombinant antibody,” as used herein, includes all antibodies prepared, expressed, produced, or isolated by means not found in nature. For example, antibodies isolated from host cells transformed to express the antibody, antibodies selected and isolated from a recombinant combinatorial human antibody library, and antibodies prepared, expressed, produced, or isolated by any other means involving the splicing of all or part of the human immunoglobulin gene or other DNA sequence, or antibodies isolated from animals (e.g., mice) that are transgenic or transchromosomes with respect to the human immunoglobulin gene, or hybridomas prepared therefrom. Preferably, such recombinant antibodies have a variable region in which the framework and CDR region are derived from a human germline immunoglobulin sequence. However, in certain embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, if transgenic animals for human Ig sequences are used, in vivo somatic mutagenesis), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to human germline VH and VL sequences, but are sequences that cannot naturally exist in vivo within the human antibody germline repertoire. The recombinant antibody may also be a monoclonal antibody. 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] As used herein, the term "monoclonal antibody" refers to a preparation of an antibody molecule with a single-molecule composition. Monoclonal antibody compositions exhibit a unique binding site that has intrinsic binding specificity and affinity for a particular epitope.

[0061] In one embodiment, the antigen-binding protein of the Disclosure is a monoclonal antibody or a fragment thereof. In another embodiment, the antigen-binding protein of the Disclosure is a monoclonal antibody. In another embodiment, the monoclonal antibody is a mouse, 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 mouse antibody.

[0062] In one embodiment, the antigen-binding protein of the Disclosure binds to CD38. In another embodiment, the antigen-binding protein of the Disclosure specifically binds to CD38. In yet another embodiment, the antigen-binding protein of the Disclosure is specific to CD38. In yet another embodiment, the antigen-binding protein of the Disclosure specifically recognizes CD38.

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

[0064] The query sequence may be 100% identical to the target sequence, or may include amino acid modifications up to a certain integer compared to the target sequence such that the percentage identity is less than 100%. For example, the query sequence may be at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the target sequence. Such modifications include at least one of the following: amino acid deletion, substitution (including conserved and non-conservative substitutions), or insertion; where such modifications may occur at the amino or carboxyl terminal positions of the query sequence, or at any position between these terminal positions, individually between amino acids in the query sequence, or scattered across one or more consecutive groups in the query sequence.

[0065] "Administered" or "administered" includes, but is not limited to, delivery in an injectable form such as intravenous, intramuscular, intradermal or subcutaneous routes, or delivery via mucosal routes such as nasal spray or aerosol for inhalation, or delivery as an ingestible solution, capsule or tablet.

[0066] The "therapeutic dose" 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 effective dose for a particular therapeutic purpose will depend on the severity of the disease or injury, as well as the subject's weight and overall condition. Determining the appropriate dosage can be achieved by constructing a matrix of values ​​and testing different points in the matrix using routine experiments, all of which should be understood to be within the normal skill of a trained physician or clinical scientist.

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

[0068] The amino acid sequence of MOR202 HCDR1 as defined by Kabat is: This is SYYMN (sequence number 1).

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

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

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

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

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

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

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

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

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

[0078] MOR202 has an IgG1 Fc region.

[0079] As used herein, the term “hematological cancer” refers to cancer of the blood, including leukemia, lymphoma, and myeloma. “Leukemia” refers to cancer of the blood in which an excess of white blood cells, which are ineffective in fighting infection, are produced, displacing other parts of the blood, such as platelets and red blood cells. Cases of leukemia are understood to be classified as acute or chronic. Specific forms of leukemia, in non-limiting examples, include acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); myeloproliferative disorders / neoplasms (MPDS); and myelodysplastic syndromes. “Lymphoma” may refer, among others, to Hodgkin lymphoma, both mild and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, and follicular lymphoma (small cell and large cell). Myeloma refers to multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence-Jones myeloma.

[0080] As used herein, the terms “solid tumor” or “solid carcinoma” refer to a tumor that does not typically contain cysts or fluid 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 Disclosure provides a method for treating a disease or disorder in a subject, the method comprising administering an effective amount of a formulation of the Disclosure to the subject. In certain embodiments, the disease or disorder is cancer or an inflammatory disorder. In certain embodiments, the cancer is a hematological cancer or a solid tumor. In certain embodiments, the cancer is a hematological cancer selected from leukemia, lymphoma and myeloma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is a solid tumor selected from 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.

[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 Disclosure provides the use of the pharmaceutical formulations of the Disclosure for the preparation of a pharmaceutical. In certain embodiments, the use is for the preparation of a pharmaceutical 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 hematological cancer or a solid tumor. In certain embodiments, the cancer is a hematological cancer selected from leukemia, lymphoma and myeloma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is a solid tumor selected from sarcomas and carcinomas such as, for example, 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. 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 yet another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. In yet 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a buffer, wherein the anti-CD38 antibody is at least 55 mg / ml in concentration. In one embodiment, the 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 to 75 mg / ml. In one embodiment, the 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 to 67.5 mg / ml. In one embodiment, the 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 approximately 65 mg / ml. In one embodiment, the 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 with a pH of 5.5 to 6.5. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, a surfactant, and a histidine buffer with 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 with 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 with a pH of about 6.0.

[0087] 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 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 at 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 at a concentration of approximately 10 mM and a pH of 5.9 to 6.1. In yet 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 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 approximately 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 approximately 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 approximately 10 mM and a pH of approximately 6.0. In yet 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 approximately 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 pH 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 pH 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 approximately 10 mM and pH 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 pH 6.0.

[0090] In another embodiment, the Disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, a nonionic surfactant, and a buffer. In yet another embodiment, the Disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate, and a buffer. In yet another embodiment, the Disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate 20, and a buffer. In yet another embodiment, the Disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate 80, and a buffer. In yet another embodiment, the Disclosure provides a formulation comprising an antigen-binding protein, polysorbate 20, and a buffer, wherein the polysorbate 20 is concentrated at a concentration of 0.05% (w / w) to 0.2% (w / w). In yet another embodiment, the Disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate 20, and a buffer, wherein the polysorbate 20 is concentrated at a concentration of about 0.1% (w / w). In yet another embodiment, the Disclosure provides a pharmaceutical formulation comprising an antigen-binding protein, polysorbate 20, and a buffer, wherein the polysorbate 20 is concentrated 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 with a pH of 5.5 to 6.5. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of 5.9 to 6.1. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of approximately 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of 6.0.

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

[0093] In another embodiment, the 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of 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. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of 5.9 to 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of approximately 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 present 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 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of 5.5 to 6.5, wherein the anti-CD38 antibody is MOR202. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of 5.9 to 6.1, wherein the anti-CD38 antibody is MOR202. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of approximately 6.0, wherein the anti-CD38 antibody is MOR202. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer with a pH of 6.0, wherein the anti-CD38 antibody is MOR202.

[0095] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 5.5 to 6.5. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 5.9 to 6.1. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of approximately 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 6.0.

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

[0097] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 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. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 5.9 to 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of approximately 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer, wherein the anti-CD38 antibody is MOR202. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 5.5 to 6.5, wherein the anti-CD38 antibody is MOR202. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 5.9 to 6.1, wherein the anti-CD38 antibody is MOR202. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of approximately 6.0, wherein the anti-CD38 antibody is MOR202. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 6.0, wherein the anti-CD38 antibody is MOR202.

[0099] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 5.5 to 6.5. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 5.9 to 6.1. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of approximately 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 6.0.

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

[0101] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at 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. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at pH 5.9 to 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at pH approximately 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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.

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

[0103] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 concentrated at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at 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 concentrated at a concentration of 0.05% (w / w) to 0.2% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at pH 5.9 to 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at pH approximately 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 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, and the polysorbate 20 is present in a concentration of 0.05% (w / w) to 0.2% (w / w).

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

[0105] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 present in 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 histidine buffer at 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 present in 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 histidine buffer at pH 5.9 to 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 present in 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 histidine buffer at pH approximately 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 present in a concentration of approximately 0.1% (w / w).

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

[0107] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 present in a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at 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 present in a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at pH 5.9 to 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 present in a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at pH approximately 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody is MOR202 and the polysorbate 20 is present in a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer with a pH of 5.5 to 6.5, wherein the anti-CD38 antibody is MOR202 and the polysorbate 20 is present in a concentration of 0.1% (w / w). In yet another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer with a pH of 5.9 to 6.1, wherein the anti-CD38 antibody is MOR202 and the polysorbate 20 is present in a concentration of 0.1% (w / w). In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer at pH approximately 6.0, wherein the anti-CD38 antibody is MOR202 and the polysorbate 20 is at a concentration of 0.1% (w / w).

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

[0110] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 approximately 6.0. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 6.0.

[0114] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 6.0.

[0115] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 6.0.

[0116] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and 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 6.0.

[0117] In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, the histidine buffer has a pH of 5.9 to 6.1, and the anti-CD38 antibody is concentrated at a concentration of 65 mg / ml. In another embodiment, the disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, the histidine buffer has a pH of approximately 6.0, and the anti-CD38 antibody is concentrated 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 histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, the histidine buffer has a pH of 6.0, and the anti-CD38 antibody is present 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 histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, the polysorbate 20 is at a concentration of approximately 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, and histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 approximately 6.0, 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 histidine buffer, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and 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 yet 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 HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. In yet 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 yet 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 yet 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 HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. In yet 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 yet 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, 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 150 to 350 mM.

[0123] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, 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 175 to 300 mM.

[0124] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, 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, 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 a pH of about 6.0, and the sucrose has a concentration of 260 nM.

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

[0127] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, histidine buffer, and sucrose, wherein the anti-CD38 antibody is MOR202 at a concentration of approximately 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 a pH of approximately 6.0, and the sucrose has a concentration of 260 nM.

[0128] In certain embodiments, the Disclosure provides a lyophilized pharmaceutical preparation prepared from any of the pharmaceutical preparations disclosed in the Invention. In certain embodiments, the Disclosure provides a lyophilized pharmaceutical preparation of an anti-CD38 antibody prepared by lyophilization of an anti-CD38 antibody pharmaceutical preparation described in the Disclosure.

[0129] 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.

[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, the reconstitution being achieved via the addition of water or a pharmaceutically acceptable reagent.

[0131] In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation of an anti-CD38 antibody obtained by reconstitutement of a lyophilized formulation of the present disclosure. In certain embodiments, the reconstitutement is achieved by adding water or a pharmaceutically acceptable reagent to a lyophilized solution containing the anti-CD38 antibody. In certain embodiments, the reconstitutement is achieved by adding water to a lyophilized solution containing the anti-CD38 antibody.

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

[0133] In certain embodiments, the Disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer at pH 5.5 to 6.5, wherein the anti-CD38 antibody is concentrated at a concentration of 55 to 75 mg / ml. In certain embodiments, the Disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer at pH 5.5 to 6.5, wherein the anti-CD38 antibody is concentrated at a concentration of 62.5 to 67.5 mg / ml. In certain embodiments, the Disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer at pH 5.5 to 6.5, wherein the anti-CD38 antibody is concentrated at a concentration of approximately 65 mg / ml. In certain embodiments, the Disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, and a histidine buffer at pH 5.5 to 6.5, wherein the anti-CD38 antibody is concentrated 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), opine (aranopine, octopine, strombine), and trimethylamine N-oxide (TMAO). Stabilizers may also include sugar alcohols and monosaccharides, disaccharides, or polysaccharides, such as mannitol, sorbitol, trehalose, dextrorotonic acid, lactose, and sucrose. Preferably, the stabilizer is sucrose.

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

[0136] In certain embodiments, the pharmaceutical formulations of the Disclosure are for use in the treatment of a disease or disorder. In certain embodiments, the Disclosure provides a method for treating a disease or disorder in a subject, the method comprising administering an effective amount of the pharmaceutical formulation of the Disclosure to the subject. In certain embodiments, the Disclosure provides the use of the pharmaceutical formulations of the 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 have developed a liquid formulation of the anti-CD38 specific antibody MOR202 that is suitable for long-term storage.

[0138] The formulation strategy consisted of buffer and pH screening based on thermal stability, followed by excipient optimization with a focus on protective properties against aggregate formation. Buffer screening was performed using differential scanning calorimetry (DSC), yielding 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 fully factorial design.

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

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

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

[0142] Example 2: Development of preliminary formulations for lyophilized formulations We initiated a preliminary formulation project and developed a formulation for the drug product of the anti-CD38 specific antibody MOR202 for Phase III clinical trials and market supply.

[0143] The objectives of this test included the following: • Confirmation of the pH at which maximum chemical and physical stability is achieved, and the effect of protein concentration on molecular stability. • Evaluation of the effects of shear force (shaking) and freeze-thaw cycles on the physical and chemical stability of molecules. • Measurement of protein stability after dilution with 0.9% NaCl saline (normal saline solution).

[0144] Example 2.1 Concentration of the active pharmaceutical ingredient The MOR202 active pharmaceutical ingredient was concentrated to a final concentration of 80-90 mg / ml by tangential flow filtration (Omega Centramate 30kD 0.02 sqm, Pall). The tangential flow filtration process was monitored using an intermembrane pressure not exceeding 6 psi. The resulting concentrated solutions were divided into sublots, loaded into Slide-A-Lyzer dialysis flasks, and dialyzed over 24 hours against their respective buffers (2.0 liters, at least 5 × buffer exchanges). 0.3% NaCl was added to the citrate buffer matrix to increase the ionic strength and stabilize the MOR202 solution.

[0145] The MOR202 concentration was measured upon completion of the buffer exchange. Subsequently, the solutions were diluted with their respective buffers and filtered using a 0.22 μm syringe filter (PVDF, Millipore, or PALL). The filtered formulations were 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 objectives were to determine the optimal pH and to study the effect of protein concentration.

[0148] Stability was tested by storing vials under 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 points in time. The tests performed and the test intervals are shown in Figure 2.

[0149] Using shear and freeze-thaw cycles, we investigated the surfactant concentrations 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, pump transport). Previous studies have shown that polysorbate 20 provides 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, the formulations were stirred on a rotary shaker at 40–60 rpm at room temperature for 24 and 48 hours. Physical appearance (visual), purity (SEC), protein content (UV), and hydrodynamic size / soluble aggregates (DLS) were analyzed.

[0151] For the freeze-thaw test, the formulation was subjected to three freeze-thaw cycles (-70°C). The samples were analyzed in the same manner as in the shear test.

[0152] For the saline dilution test, the formulation was diluted 1:100 with standard saline solution. Purity was measured by SEC. Invisible particles were measured by HIAC.

[0153] Example 2.3: Results of Stability Test The results of the stability tests are summarized in Figures 3A-3G. The following observations were made: Histidine buffer is excellent for stabilizing API (MOR202). • No significant differences in appearance or pH were observed during the stability test. • No significant differences in UV content were detected over time. At the final checkpoint, an increase in protein content appeared to be observed in all formulations. This increase in protein concentration can be attributed to method variability, as the same increase was detected in the standard solution. • Analysis by SEC shows the stability of all formulations at 5°C, with the exception of the pH 5.5 L-histidine (75 g / L) formulation, which showed an increase in aggregates and contaminants after two weeks. • As pH increases, the number of particles per ml increases. • The size assessed by DLS remains unchanged throughout the stability test period.

[0154] Based on these considerations, the following reed buffer systems were selected as the foundation for further development: MOR202 75g / l 10mM buffer L-histidine 1.552 g / l HCl pH 6.0 ± 0.1 qs pH 6.0±0.1

[0155] The results of this Reed buffer system can be described as follows: Appearance: The solution is clear at time zero, becoming slightly milky white during stabilization; the color and presence of particles remain constant. UV content: constant pH: constant HIAC: During stability testing, the number of particles remains similar for each diameter and is lowest at time zero. SEC:%IgG is constant at 5°C and decreases at 40°C. The percentage of aggregates remains constant at 5°C and increases at 40°C. The percentage of pollutants remains constant at 5°C and increases at 40°C. This formulation has the lowest aggregate levels and the highest IgG levels at time zero. DLS: The size assessed by DLS remains unchanged throughout the stability test period.

[0156] Example 2.4 Results of shear test, freeze-thaw test, and physiological saline dilution test The MOR202 solution was tested in the reed buffer system identified in Example 2.3. The concentration of polysorbate 20 was adjusted to 0.02%, 0.04%, and 0.1%.

[0157] The results of the shear test are shown in Figures 4A to 4C. The results of the freeze / thaw test are shown in Figures 4D to 4E. The results of the physiological saline dilution test are shown in Figure 4F.

[0158] Results of the shear test: • The physical appearance is only altered by a change in opacity after 48 hours of shearing. Formulations containing 0.02% polysorbate 20 exhibit the highest grade of opacity. 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 considered to be of external origin. • Formulations using PS20 at concentrations of 0.04% and 0.1% show a slight decrease in UV content. The SEC results show that all PS20 concentrations are characterized by a slight decrease in %IgG and a corresponding slight increase in % aggregates. When samples are evaluated using DLS, no significant changes in size or polydispersity are observed.

[0159] Results of the freeze-thaw test: 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 thought to be of external origin. • Any slight increase in UV content across all PS20 concentrations can be attributed to method variability. Regarding the SEC results, all PS20 concentrations show a slight decrease in %IgG and a slight increase in the corresponding % aggregates. The size evaluated by DLS remains unchanged.

[0160] Results of the saline dilution test: • As evaluated by SEC, there was no significant difference between time point zero and time point 24 hours for any of the formulations. An increase in the number of particles across all diameter ranges was observed by light shielding. The highest increase was detected in a solution originally containing 0.04% polysorbate 20, where the number of particles increased fourfold for the 2 μm size range.

[0161] Example 2.5: Final results of preliminary formulation development A series of preliminary formulation tests were conducted to select the optimal pH and excipients necessary to stabilize MOR202. These tests included confirming the optimal pH of 5.5–6.3, the effect of polysorbate 20 on freeze-thaw and agitation, and testing the stability of MOR202 after dilution with normal physiological saline.

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

[0163] Based on the outputs of shear, freeze-thaw, and dilution tests, the presence of polysorbate 20 was found to be important and preferable.

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

[0165] The characteristics of this formulation can be summarized as follows: Appearance: The solution becomes milky white only after 48 hours of shearing. UV content: Shows a decrease after 48 hours of shearing and an increase after the third freeze / thaw cycle. SEC: A slight decrease in %IgG and a slight increase in the corresponding % aggregates after shear and freeze / thaw cycle tests. %IgG and % aggregates remain constant during the saline dilution test. HIAC: Increase in particle count for all diameters during the saline dilution test. The total number of particles was significantly lower than when using 0.04% PS20. DLS: The size evaluated by DLS remains unchanged.

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

[0167] The objectives of this test included the following: • Preparation of lyophilized MOR202 prototype formulations to be evaluated for compatibility with the lyophilization process; • Analysis of the stability of the lyophilized prototype formulation; • Selection of a single lead MOR202 lyophilized formulation based on stability data; • Development and optimization of lyophilization cycles based on selected lead MOR202 formulations; • Recommendations for freeze-drying cycles suitable for process transfer and scale-up in filling / finishing facilities.

[0168] Example 3.1: Thermal evaluation of prototype formulation 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 analysis results, five suitable freeze-drying cycles were proposed for each prototype formulation.

[0170] After thermal evaluation of the properties of the prototype formulation shown 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 referred to as F1 to F5.

[0172] Understanding the parameters that affect the physicochemistry of freezing, freeze-drying, heat, and mass transfer is crucial for determining the parameters of the freeze-drying cycle. Subambient differential scanning calorimetry (DSC) tests 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 (freeze and heating lamp) were obtained for all prototype solutions F1-F5. All results are summarized in Table 4: [Table 4]

[0174] All five formulations possessed equivalent eutectic points, suggesting compatibility with a single freeze-drying cycle. Formulations F2, F4, and F5 appeared slightly milky, but no precipitates / aggregates were observed by visual inspection. Formulations F2 and F4 had osmotic pressures close to 350 mOsmol / kg, which remains within the acceptable range for intravenous administration. However, if the target osmotic pressure is closer to the standard of 300 mOsmol / kg, the sucrose content of F2 and F4 may be reduced by 12 and 10 mg, respectively. This should bring the osmotic pressure closer to 310 mOsmol / kg without affecting the thermal properties of the formulations.

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

[0176] Example 3.2: Initial lyophilization of the prototype formulation Prototype solutions F1-F5 (see Table 2) were freeze-dried. Initial parameters were based on the results of DCS testing (see Example 3.1).

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

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

[0179] The cakes of all five formulations appeared sufficiently dry. Overall, the appearance can be classified as follows (from 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: Freeze-drying and liquid prototype formulation testing Liquid and lyophilized prototype formulations were analyzed for the following parameters: • Appearance (liquid and freeze-dried) • Moisture content (freeze-dried only) • pH (liquid and freeze-dried) • Size exclusion chromatography (liquid and lyophilized) • Invisible particles (HIAC) (liquid and freeze-dried) • DLS (Liquid and Freeze-Dried) ·Reconstitution time (lyophilization) • UV (liquid and freeze-drying)

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

[0182] The results for liquid formulations are shown in Figures 7A to 7H. The results for lyophilized formulations are shown in Figures 8A to 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 exhibited the lowest degree of opalescense. Furthermore, in contrast to the other four formulations tested, no increase in invisible particles was observed in the liquid formulation during the stability test. Additionally, formulation F3 also showed the lowest degree of opalescense in the reconstituted lyophilized formulation, and no increase in aggregates was observed during the stability test.

[0185] Example 4: Optimization of freeze-drying In several subsequent steps, the freeze-drying process was optimized. Each subsequent step utilized the results and experience obtained during the preceding experiments. The key 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), this process was modified. One of the main goals was to shorten the secondary drying process and adapt the ramp rate to different freeze / heat steps. The first optimized freeze-drying recipe is shown in Table 6. The total cycle length was approximately 72 hours. [Table 6]

[0187] The analysis results confirmed that the freeze-dried drug product exhibited the expected properties and showed no abnormalities.

[0188] Five hours after the secondary drying (step 8), the residual moisture content was 0.9% w / w, and therefore this step had to be extended for a further three hours. After eight hours, the residual moisture content was 0.3% w / w, which was below the target of <0.5% w / w.

[0189] Furthermore, it was observed that the ramping up of the primary and subsequent secondary drying steps could be potentially shortened. This could lead to an additional saving of approximately 4 hours in the overall process.

[0190] All the cakes were thoroughly dried.

[0191] The appearance of the cakes was classified considering 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: The 9 vials are fine. 13 vials with very slight contraction Two vials with cracks

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

[0194] Analysis of a 1.5 pL sample solution enabled real-time observation of the sample's lyophilization. The information obtained from FDM includes the disintegration point (Tc) and eutectic point (Teu) of the formulation.

[0195] Some samples exhibited disintegration zone behavior, meaning that the structure of the dried sample was gradually lost over a certain temperature range, rather than being lost at a distinct point.

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

[0197] The following conclusions were reached: To prevent the breakdown of the product, the temperature should ideally be kept below the lower limit of each breakdown zone during the primary drying period. • For additional safety and quality of the product, a safety margin between 2°C and 7°C should be assumed. This accommodates slight variations that may occur during scale-up, technology transfer, and the use of different freeze dryers. • The primary drying temperature must not be increased.

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

[0199] The total cycle length was approximately 66 hours, which was considerably shorter than the first optimization.

[0200] The analysis results confirmed that the freeze-dried drug product exhibited the expected properties and showed no abnormalities.

[0201] All the cakes were thoroughly dried.

[0202] Again, the appearance of the cakes was classified considering 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 slight contraction Two vials with very slight shrinkage and surface cracks.

[0204] Observations and possible changes made for the next optimization round: • Freeze-dried cakes cannot be improved by applying different lamps and conditions; the appearance of the cakes is likely due to excipients and drug products. • A 1°C / min freezing lamp during the freezing step is not possible with all commonly used freeze dryers; therefore, it is recommended to work within safe limits and use a 0.5°C / min freezing lamp.

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

[0206] Two freeze-drying experiments, HT / HP and LT / LP, were conducted for robustness testing, and to bridge the gap between laboratory-scale extrapolation and GMP production, laboratory-scale (0.5m²) tests were performed. 2 The test was conducted using a freeze-drying unit.

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

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

[0209] The analysis results confirmed that the freeze-dried drug product exhibited the expected properties and showed no abnormalities.

[0210] All the cakes were dried sufficiently.

[0211] Again, the appearance of the cakes was classified considering the number of cracks in the cakes, the level of shrinkage, and the tendency to break.

[0212] The 29 vials tested were classified as follows: Twenty-four vials had sticky white cakes with very slight shrinkage. Five vials with very slight shrinkage and surface cracks

[0213] Example 4.4: Fourth Optimization This optimization aimed to investigate low-temperature and low-pressure conditions. [Table 10]

[0214] The length of the entire cycle was again approximately 64 hours.

[0215] From the analysis results, it was confirmed that the lyophilized drug product exhibited the expected characteristics and showed no abnormalities.

[0216] Twenty-six cakes were all dried sufficiently and were 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 formulation could be successfully lyophilized even if the temperature and pressure fluctuated slightly during the lyophilization process steps.

[0218] This guarantees a robust process for large-scale regular production.

[0219] Example 4.5: Fifth Optimization Based on all the experiences collected so far, the fifth optimization was carried out. [Table 11]

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

[0221] The analysis results confirmed that the lyophilized drug product exhibited the expected properties and showed no abnormalities. Figure 8 shows the results of the analysis of the lyophilized drug product. The reconstituted volume was 4.8 ml. All cakes were sticky.

[0222] 215 vials were fitted. Of the 215 fitted vials, 3 showed surface cracks that were not considered defects. 60 vials were rejected due to drug product between the stopper and neck. This defect is related to the filling process, not the freeze-drying process. 44 vials either showed staining on the vial near the stopper or had a very small amount of product between the stopper and the rack. This defect is thought to have occurred during freeze-drying loading. A photograph of an exemplary cake is shown in Figure 9.

[0223] The results of the fifth optimization demonstrated that this process is robust and suitable for application in the manufacture of GMP materials.

Claims

1. A lyophilized pharmaceutical preparation containing an anti-CD38 antibody, a nonionic surfactant, and a histidine buffer with a pH of 5.5 to 6.

5.

2. A lyophilized pharmaceutical preparation according to claim 1, characterized in that the nonionic surfactant is polysorbate 20.

3. A lyophilized pharmaceutical preparation according to claim 1 or 2, characterized in that the histidine buffer solution has a pH of approximately 6.

0.

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

6.

5. A lyophilized pharmaceutical preparation according to any one of claims 1 to 4, further characterized by containing sucrose.

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 adding water.

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

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

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

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

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

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

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

14. The use of the pharmaceutical preparation according to claim 13 is characterized in that the cancer is a hematological cancer selected from leukemias, lymphomas and myelomas such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML) and multiple myeloma (MM), or a solid tumor selected from sarcomas and carcinomas 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. The use of the pharmaceutical preparation according to claim 12, characterized in that the disease or disorder is an inflammatory disorder.

16. The use of the pharmaceutical preparation according to claim 15, characterized in that 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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