Antibody formulations

Abstract

The present disclosure relates to formulations of a pharmaceutically active antigen binding protein, such as a monoclonal antibody. In particular, the present disclosure relates to a stable lyophilized pharmaceutical formulation of an anti-CD38 antibody, a reconstituted liquid formulation of such lyophilized formulation, and to methods of making and using such lyophilized and reconstituted formulations.

Description

(19) *EP004759326A2* (11) EP 4 759 326 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 17.06.2026 Bulletin 2026 / 25 (21) Application number: 26172020.5 (22) Date of filing: 13.12.2019 (51) International Patent Classification (IPC): A61K 39 / 395 (2006.01) (52) Cooperative Patent Classification (CPC): A61K 39 / 39591; A61K 9 / 0019; A61K 9 / 19; A61K 47 / 183; A61K 47 / 26; C07K 16 / 2896 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 14.12.2018 EP 18212591 (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 19820750.8 / 3 893 841 (71) Applicant: MorphoSys AG 82152 Planegg (DE) (72) Inventors: • BROCKS, Bodo 82205 Gilching (DE) • KELLERER, Robert 85283 Wolnzach (DE) (74) Representative: Elkington and Fife LLP Prospect House 8 Pembroke Road Sevenoaks, Kent TN13 1XR (GB) Remarks: The complete document including Reference Table(s) and the Sequence Listing(s) can be downloaded from the EPO website (54) ANTIBODY FORMULATIONS (57) Thepresent disclosure relates to formulations of a pharmaceutically active antigen binding protein, such as a monoclonal antibody. In particular, the present dis- closure relates to a stable lyophilized pharmaceutical formulation of an anti-CD38 antibody, a reconstituted liquid formulation of such lyophilized formulation, and to methods of making and using such lyophilized and reconstituted formulations. EP 4 75 9 32 6 A 2 Processed by Luminess, 75001 PARIS (FR) Description Field of Disclosure

[0001] The present disclosure relates to formulations of a pharmaceutically active antigen binding protein, such as a monoclonal antibody. In particular, the present disclosure relates to a stable lyophilized pharmaceutical formulation of an anti-CD38antibody, a reconstituted liquid formulation of such lyophilized formulation, and tomethodsofmaking andusing such lyophilized and reconstituted formulations. Background

[0002] The pharmaceutical use of antibodies has increased over the past years. Inmany instances such antibodies are injected via the intravenous (IV) route. Alternative administration pathways are subcutaneous or intramuscular injection, which offer potential advantages, e.g. in terms of patient compliance and ease of administration. Very often highly concentrated, stable pharmaceutical formulations are desired. Also very often, for reasons such as storage and handling, lyophilized formulations are prefererred.

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

[0004] Formulations with higher protein concentrations pose yet additional challenges, in particular with respect to protein stabilitiy, protein-protein interactions and viscosity. Viscosity is not only an issue regarding the biophysical and biochemical properties of the therapeutic protein, but also for the delivery and manufacturing of highly concentrated protein solutions. The higher the viscosity of the solution the longer it takes to inject such a viscous solution via syringe and needle.So theaspect of syringability is influencedby the viscosity andneeds tobeconsideredduring thedevelopment of a high-concentration formulation. Certain antibodies also exhibit a tendency for undesired self-interactions, which makes them less suitable for a high concentration formulation. This self-interaction propensity may lead to oligomerization, aggregation and high viscosities at high protein concentrations. Opalescence is one parameter indicating physical instabilityof a formulationbecauseof thepresenceofaggregatesor liquid-liquidphaseseparation insolutionandhasbeen reported for monoclonal antibody (mAb) formulations.

[0005] To address these problems the development of suitable formulation compositions is of utmost importance. In order to avoid stability problems such as the formation of aggregates, protein or antibody formulationsmay be lyophilized.

[0006] CD38 is a type II membrane protein having function in receptor-mediated adhesion and signaling as well as mediating calcium mobilization via its ecto-enzymatic activity, catalyzing formation of cyclic ADP-ribose (cADPR) from NAD+ and also hydrolyzing cADPR into ADP-ribose (ADPR). CD38 mediates cytokine secretion and activation and proliferation of lymphocytes (Funaro et al, J Immunology 145:2390‑6, 1990;Guseet al, Nature 398:70‑3, 1999), and via its NADglycohydrolase activity regulates extracellular NAD+ levels which have been implicated inmodulating the regulatory T-cell compartment (Adriouch et al., 14: 1284‑92, 2012; Chiarugi et al., Nature Reviews 12:741‑52, 2012).

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

[0008] Several antibodies (including bispecific antibodies and other constructs) specific for CD38 are in use or in development, including but not limited to: WO199962526 (Mayo Foundation); WO200206347 (Crucell Holland), WO2005103083 (MorphoSys AG), WO2006125640 (MorphoSys AG), WO2007042309 (MorphoSys); WO2006099875 (Genmab),WO2011154453A1 (Genmab),WO2008047242 (Sanofi-Aventis),WO2015066450 (Sanofi), WO2012092616A1 (Takeda), WO2012092612A1 (Takeda), WO2013059885 (Teva), WO2014178820 (Teva), WO2015149077 (Xencor),WO2017081211A2 (University Hamburg-Eppendorf) andWO2017091656 (Amgen, Xencor).

[0009] Thepresentdisclosure relates to thedevelopmentanduseofahighly stable formulation foranti-CD38antibodies suitable for administration to patients, such as the antibody known as MOR202.

[0010] Pharmaceutical formulations for therapeutic antibodies are known in the prior art. For example,WO2013016648 disclosesapharmaceutical formulation comprisingananti-PCSK9antibody, ahistidinebuffer, anon-ionic surfactant anda stabilizer. However, said document does not disclose an anti-CD38 antibody. WO2018204405 discloses a formulation comprising an anti-TIGITantibody, a histidine buffer, polysorbate‑80 as non-ionic surfactant, a non-reducing sugar and an anti-oxidant, but also does not disclose an anti-CD38 antibody. WO2017079150 discloses subcutaneous formulations 2 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 comprising an anti-CD38 antibody, hyalorunidase, a histidine buffer, methionine and a non-ionic surfactant. This document teaches the addition of hyaluronidase to the composition and does not disclose MOR202 or a freeze-dried, lyophilized composition.

[0011] Thus, there is still need for a stable lyophilized antibody formulation for the preparation of an anti-CD38 medicament, in particular comprising the antibody MOR202. Summary of the Disclosure

[0012] It is anobject of thepresent invention toprovide formulationsof anti-CD38antibodies, inparticular formulationsof anti-CD38 antibodies having a suitable shelf life.

[0013] Suitable formulations for therapeutic antibodies can be aqueous pharmaceutical compositions or lyophilisates, which can be reconstituted to provide a solution for administration to a patient.

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

[0015] Thepresent disclosure providesapharmaceutical formulations for said anti-CD38antibodies, suchasMOR202, comprising that antigen binding protein, a surfactant and a histidine buffer of a pH between 5.5 and 6.5.

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

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

[0018] In certain aspects, said anti-CD38 antibody comprises aHCDR1of SEQ IDNO.: 1, aHCDR2of SEQ IDNO.: 2, a HCDR3 of SEQ ID NO.: 3, a LCDR1 of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6.

[0019] Inotheraspects, saidanti-CD38antibodyhasavariableheavychainofofSEQIDNO.:7andavariable light chain of SEQ ID NO.: 8.

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

[0021] In one aspect, the present disclosure provides a pharmaceutical formulation for said anti-CD38 antibodies, such asMOR202,wherein said pharmaceutical formulation comprises a surfactant. In certain aspects, said surfactant is a non- ionic surfactant. In other aspects, said non-ionic surfactant is polysorbate. In yet other aspects, said polysorbate is polysorbate 20 (PS20) or polysorbate 80 (PS80). In yet other aspects, said polysorbate is polysorbate 20.

[0022] In one aspect, the present disclosure provides a pharmaceutical formulation for said anti-CD38 antibodies, such asMOR202, wherein said pharmaceutical formulation comprises a histidine buffer of a pH between 5.5 and 6.5. In certain aspects, said histidine buffer is a histidine buffer of a pHof between5.9 and6.1. In certain aspects, said histidinebuffer has a pH of about 6.0. In certain aspects, said histidine buffer has a pH of 6.0.

[0023] In one aspect, the present disclosure provides a pharmaceutical formulation for said anti-CD38 antibodies, such asMOR202,wherein said pharmaceutical formulation comprises ahistidine buffer at a concentration of 5mM to15mM. In other aspects, said histidine buffer is at a concentration of 8 mM to 12 mM. In other aspects, said histidine buffer is at a concentration of about 10 mM. In other aspects, said histidine buffer is at a concentration of 10 mM.

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

[0025] In one aspect, the present disclosure provides a lyophilized pharmaceutical formulation for said anti-CD38 antibodies, such as MOR202, prepared by the 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, said method comprising providing the lyophilized pharmaceutical formulation and reconstituting said lyophilized for- mulation. In certain aspects, said liquid formulation is generated via the addition of water or another pharmaceutical acceptable reagent to a lyophilized formulation.

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

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

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

[0030] In other aspects, said anti-CD38 antibody is at a concentration of 62.5‑67.5 mg / ml.

[0031] In yet other aspects, said anti-CD38 antibody is at a concentration of about 65 mg / ml. In yet other aspects, said 3 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 anti-CD38 antibody is at a concentration of 65 mg / ml.

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

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

[0034] In one aspects, the present disclosure provides the use of the pharmaceutical formulations of the present disclosure for the preparation of amedicament. In certain aspects, said use is the use for the preparation of amedicament for the treatment of a disease or a disorder. In certain aspects, said disease or disorder is cancer or an inflammatory disorder. In certain aspects, said cancer is a hematological cancer or a solid cancer. In certain aspects, said hematological cancer is selected from multiple myeloma, lymphoma, leukemia, or any specific type or sub-type thereof. In certain aspects, said said cancer is multiple myeloma. In certain aspects, said disease or disorder is cancer or an inflammatory disorder. Brief description of the drawings

[0035] Figure 1: Overview of the key pre-formulations tested in Example 2. Figure 2: Test schedule during pre-formulation development. Figure 3: Results of the stability testing in the pre-formulation development. Figures 3A - 3B: time point 0 Figures 3C - 3D: time point 2 weeks, 40°C / 75% RH Figure 3E: time point 4 weeks, 40°C / 75% RH Figure 3F: time point 2 weeks, 5°C Figure 3G: time point 4 weeks, 5°C Figure 4: Results of various test of the lead buffer system plus various concentrations of Polysorbate 20. Figures 4A - 4C: Results of the shear tests at T0, T24h and T48h Figures 4D - 4E: Results of the freeze / thaw tests Figure 4F: Results of the saline dilution tests Figure 5: Vials with cakes after initial lyophilization experiments. Figure 6: Stability results and subvisible particles for liquid formulations. Figures 6A - 6C: Appearance of solutions and UV assays Figure 6D: pH and SE-HPLC Figures 6E - 6G: DLS Figure 6H: HIAC Figure 7: Stability results and subvisible particles for lyophilized formulations. Figure 7A: Appearance, UV assays and pH Figures 7B - 7D: DLS, appearance of cake, reconstitution time and moisture content Figure 7E: SE-HPLC and subvisible particles Figure 8: Analytical results of the drug product after the fifth lyophilization optimization. Figure 9: Vials with cakes after the fifth lyophilization optimization. Definitions and Detailed Description

[0036] It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, composi- tions, or biological systems,which can, of course, vary. It is also to beunderstood that the terminologyusedherein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0037] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural 4 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 referents unless the content clearly dictates otherwise. Thus, for example, reference to "a polypeptide" includes a combination of two or more polypeptides, and the like.

[0038] "About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of±20% or±10%, including±5%,±1%, and±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosurepertains.Althoughanymethodsandmaterials similar or equivalent to thosedescribedherein canbeused in the practice for testing of the present disclosure, the preferredmaterials andmethods are described herein, in describing and claiming the present disclosure, the following terminology will be used.

[0039] The terms "pharmaceutical formulation" or "formulation" refer to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile. A "sterile" formulation is aseptic or free from all living microorganisms and their spores.

[0040] The term "viscosity" refers to the internal resistance toflowexhibitedbyafluidataspecified temperature; the ratio of shearing stress to rate of shear. A liquid has a viscosity of one poise if a force of 1 dyne / square centimeter causes two parallel liquid surfaces one square centimeter in area and one square centimeter apart to move past one another at a velocity of 1 cm / second. One poise equals one hundred centipoise. In one embodiment, the viscosity of the formulation comprising buffering agent and stabilizer is less than about 50 cP, less than about 45 cP, less than about 40 cP, less than about 35 cP, less thanabout 30 cP, less thanabout 25 cP, less thanabout 20 cP, less thanabout 15 cP, or less thanabout 10 cP.

[0041] When referring to apparent viscosity, it is understood that the value of viscosity is dependent on the conditions under which the measurement was taken, such as temperature, the rate of shear and the shear stress employed. The apparent viscosity is defined as the ratio of the shear stress to the rate of shear applied. There are a number of alternative methods formeasuring apparent viscosity. For example, viscosity canbe tested bya suitable coneandplate, parallel plate or other type of viscometer or rheometer.

[0042] As used herein, "buffer" refers to a buffered solution that resists changes in pH by the action of its acid-base conjugatecomponents.Thebufferof this inventionpreferablyhasapH in the rangeofbetween5.9and6.1,preferablyapH of about 6.0, and more preferably a pH of 6.0. A "histidine buffer" is a buffer comprising the amino acid histidine. Histidine buffers are preferred buffers of the present disclosure. Examples of histidine buffers include histidine hydrochloride, histidine acetate, histidine phosphate, and histidine sulfate.

[0043] As used herein, a "surfactant" refers to a surface-active agent. Examples of surfactants include polysorbate (for example, polysorbate 20 and polysorbate 80), poloxamer (for example, poloxamer 188), Triton, sodium dodecyl sulfate (SDS), sodium laurel sulfate, sodium octyl glycoside, lauryl‑, myristyl‑, linoleyl‑, or stearyl-sulfobetaine, lauryl‑, myristyl‑, linoleyl‑ or stearyl-sarcosine, linoleyl‑, myristyl‑, or cetyl-betaine, lauroamidopropyl‑, cocamidopropyl‑, linoleamidopro- pyl‑, myristamidopropyl‑, palmidopropyl‑, or isostearamidopropyl-betaine (for example lauroamidopropyl,; myristamido- propyl‑, palmidopropyl‑, or isostearamidopropyl‑ dimethylamine,; sodium methyl cocoyl‑, or disodium methyl oleyl- taurate, and the MONAQUAT™ series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (for example Pluronics or PF68). Preferably, the surfactant is a nonionic surfactant. More preferably said nonionic surfactant is polysorbate 20. Polysorbat 20 is also know as PS20 or Tween‑20. Polysorbat 80 is also know as PS80 or Tween‑80.

[0044] Said surfactants may be used in different concentrations. Preferably, said surfactant is at a concentration of 0.05% (w / w) to 0.2% (w / w). More preferably, said surfactant is at a concentration of about 0.1% (w / w). More preferably, said surfactant is at aconcentrationof0.1% (w / w).Preferably, said surfactant ispolysorbate20at a concentrationof 0.05% (w / w) to 0.2% (w / w). More preferably, said surfactant is polysorbate 20 at a concentration of about 0.1% (w / w). More preferably, said surfactant is polysorbate 20 at a concentration of 0.1% (w / w).

[0045] In certain embodiments, the pharmaceutical formulation according to the present disclosure may comprise a stabilizer as further excipient. Stabilizers, include, but are not limited to human serum albumin, bovine serum albumin, α- casein, globulins, α-lactalbumin, LDH, lysozyme, myoglobin, ovalbumin, and RNase A. Stabilizers also include amino acids and their metabolites, such as, glycine, alanine, arginine, betaine, leucine, lysine, glutamic acid, aspartic acid, proline, 4-hydroxyproline, sarcosine, γ-aminobutyric acid (GABA), opines (alanopine, octopine, strombine), and trimethy- lamine N-oxide (TMAO). Stabilizers may also include sugar alcohols and / or mono‑, di‑ or polysaccharides, such as mannitol, sorbitol, trehalose, dextrose, lactose, sucrose, and the like. Preferably, the stabilizer is sucrose.

[0046] The term "reconstituted" as used herein in connection with the pharmaceutical formulations of the present disclosure denotes a formulation which is lyophilized and re-dissolved by addition of reconstitution medium. The reconstitution medium comprise but is not limited to water, in particular water for injection (WFI), bacteriostatic water for injection (BWFI), sodium chloride solutions (e.g. 0.9% (w / v) NaCl), glucose solutions (e.g. 5% glucose), surfactant, containing solutions (e.g. 0.01% polysorbate 20), a pH-buffered solution (e.g. phosphate-buffered solutions).

[0047] In one aspect the pharmaceutical formulation of the present disclosure is stable upon freezing and thawing, A 5 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 "stable" formulation is one in which ail the protein therein essentially retain their physical stability and / or chemical stability and / or biological activity upon storage at the intended storage temperature, e.g. 2‑8°C. It is desired that the for mulation 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 following freezing (to, e.g., ‑70°C) and thawing of the formu lation, for example following 1, 2 or 3 cycles of freezing and thawing. Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery’, 247‑301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. DrugDelivery Rev. 10: 29‑90 (1993), for example. Stability can bemeasured at a selected temperature for a selected timeperiod. Stability can be evaluated qualitatively and / or quantitatively in a variety of different ways, including evaluation of aggregate formation (for example using size exclusion chromatography, by measuring turbidity, and / or by visual inspection); byassessing chargeheterogeneity usingcationexchangechromatographyor capillary zoneelectrophoresis; amino-terminal or earboxy-terminal sequence analysis; mass spectrometric analysis; SDS-PAGE analysis to compare reduced and intact antibody; peptidemap (for example tryptic or LYS-C) analysis; evaluating biological activity or antigen binding function of the antibody.

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

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

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

[0051] The term "antibody" as used herein refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connectedbydisulfidebonds,which interactswithanantigen.Eachheavychain is comprisedofaheavychain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprisedof threedomains,CH1,CH2andCH3.Each light chain is comprisedofa light chainvariable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersedwith regions that aremore conserved, termed framework regions (FR). EachVHandVL is composed of three CDRs and four FR’s arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The term "antibody" includes for example, monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies and chimeric antibodies. The antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. Both the light and heavy chains are divided into regions of structural and functional homology.

[0052] The phrase "antibody fragment", as used herein, refers to one or more portions of an antibody that retain the ability to specifically interactwith (e.g., bybinding, steric hindrance, stabilizing spatial distribution) anantigen.Examples of binding fragments include, but are not limited to, a Fab fragment, amonovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; aFd fragment consistingof theVHandCH1domains; aFv fragment consistingof theVLandVHdomainsofa singlearmofanantibody; adAb fragment (Wardetal., (1989)Nature341:544‑546),whichconsists of aVHdomain; andan isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., (1988) Science 242:423‑426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879‑5883). Such single chain antibodies are also intended to be encompassed within the term "antibody fragment". These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments 6 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 are screened for utility in the same manner as are intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126‑1136). Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies). Antibody fragments can be incorporated into single chain molecules comprising a pair of tandemFv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen-binding sites (Zapata et al., (1995) Protein Eng. 8:1057‑1062; and U.S. Pat. No. 5,641,870).

[0053] A "human antibody" or "human antibody fragment", as used herein, includes antibodies and antibody fragments having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Human antibodies can also be isolated from synthetic libraries or from transgenic mice (e.g. xenomouse) provided the respective systemyield in antibodieshaving variable regions inwhich both the framework andCDRregions areequivalent to the sequences of human origin.

[0054] Furthermore, if theantibodycontainsaconstant region, theconstant regionalso isderived fromsuchsequences. Human origin includes, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik et al., (2000) J Mol Biol 296:57‑86).

[0055] The structures and locations of immunoglobulin variable domains, e.g., CDRs,may be defined usingwell known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia (see, e.g., Sequences of Proteins of Immunological Interest, U.S. 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., NIHPublication no. 91‑3242U.S.Department ofHealth andHumanServices;Chothia et al., (1987) J. Mol. Biol. 196:901‑917; Chothia et al., (1989) Nature 342:877‑883; and Al-Lazikani et al., (1997) J. Mol. Biol. 273:927‑948.

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

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

[0058] The term "isolated antibody" refers to an antibody or antibody fragment that is substantially free of other antibodies or antibody fragments having different antigenic specificities. Moreover, an isolated antibody or antibody fragmentmaybe substantially free of other cellularmaterial and / or chemicals. Thus, in someaspects, antibodies provided are isolated antibodies, which have been separated from antibodies with a different specificity. An isolated antibody may be a monoclonal antibody. An isolated antibody may be a recombinant monoclonal antibody. An isolated antibody that specifically binds to anepitope, isoformor variant of a targetmay, however, have cross-reactivity to other related antigens, e.g., from other species (e.g., species homologs).

[0059] The term "recombinant antibody", as used herein, includes all antibodies that are prepared, expressed, created or segregatedbymeansnot existing innature. Forexample, antibodies isolated fromahost cell transformed toexpress the antibody, antibodies selected and isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of all or a portion of a human immunoglobulin gene, sequences to other DNA sequences or antibodies isolated from an animal (e.g., a mouse) that is transgenicor transchromosomal for human immunoglobulingenesorahybridomaprepared therefrom.Preferably, such recombinant antibodies have variable regions inwhich the framework andCDR regions are derived fromhuman germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VHandVL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. A recombinant antibodymay be amonoclonal antibody. In an embodiment, the antibodies and antibody fragment disclosed herein are isolated from the HuCAL library (Rothe et al, J.Mol.Biol. (2008) 376, 1182‑1200).

[0060] The term "monoclonal antibody" as used herein refers to a preparation of antibodymolecules of singlemolecular composition. A monoclonal antibody composition displays a unique binding site having a unique binding specificity and affinity for particular epitopes.

[0061] In one embodiment, the antigen binding protein of the present disclosure is a monoclonal antibody or fragment thereof. In another embodiment, the antigen binding protein of the present disclosure is amonoclonal antibody. In another 7 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 embodiment, themonoclonal antibody is amouse, a chimeric, ahumanized, or a humanantibody. Inanother embodiment, themonoclonal antibody is a human antibody. In another embodiment, themonoclonal antibody is a humanized antibody. In another embodiment, themonoclonal antibody is a chimeric antibody. In another embodiment, themonoclonal antibody is a mouse antibody.

[0062] In one embodiment, the antigen binding protein of the present disclosure binds toCD38. In another embodiment, the antigen binding protein of the present disclosure binds specifically to CD38. In another embodiment, the antigen binding protein of the present disclosure is specific for CD38. In another embodiment, the antigen binding protein of the present disclosure specifically recognizes CD38.

[0063] "Percent identity" between a query amino acid sequence and a subject amino acid sequence is the "Identities" value, expressed as a percentage, that is calculated by the BLASTP algorithm when a subject amino acid sequence has 100%query coveragewithaqueryaminoacidsequenceafter apair-wiseBLASTPalignment is performed.Suchpair-wise BLASTP alignments between a query amino acid sequence and a subject amino acid sequence are performed by using thedefault settingsof theBLASTPalgorithmavailable on theNationalCenter forBiotechnology Institute’swebsitewith the filter for low complexity regions turned off. Importantly, a query amino acid sequence may be described by an amino acid sequence identified in one or more claims herein.

[0064] The query sequence may be 100% identical to the subject sequence, or it may include up to a certain integer number of amino acid alterations as compared to the subject sequence such that the % identity is less than 100%. For example, the query sequence is at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the subject sequence. Such alterations include at least one of the following: amino acid deletion, substitution (including conservative and non- conservative substitution), or insertion, andwherein saidalterationsmayoccur at theamino‑or carboxy-terminal positions of the query sequence or anywhere between those terminal positions, interspersed either individually among the amino acids in the query sequence or in one or more contiguous groups within the query sequence.

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

[0066] A "therapeutically effective amount" of a compound or combination refers to an amount sufficient to at least partially arrest the clinical manifestations of a given disease or disorder and its complications. The amount that is effective for a particular therapeutic purposewill depend on the severity of the disease or injury aswell as on theweight and general state of the subject. It will be understood that determination of an appropriate dosage may be achieved, using routine experimentation, by constructing a matrix of values and testing different points in the matrix, all of which is within the ordinary skills of a trained physician or clinical scientist.

[0067] "MOR202" is an anti-CD38 antibody, also know as "MOR03087" or "MOR3087". The terms are used inter- changeable in the present disclosure.

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

[0069] The amino acid sequence of the MOR202 HCDR2 as defined by Kabat is: GISGDPSNTYYADSVKG (SEQ ID NO: 2)

[0070] The amino acid sequence of the MOR202 HCDR3 as defined by Kabat is: DLPLVYTGFAY (SEQ ID NO: 3)

[0071] The amino acid sequence of the MOR202 LCDR1 as defined by Kabat is: SGDNLRHYYVY (SEQ ID NO: 4)

[0072] The amino acid sequence of the MOR202 LCDR2 as defined by Kabat is: GDSKRPS (SEQ ID NO: 5)

[0073] The amino acid sequence of the MOR202 LCDR3 is: QTYTGGASL (SEQ ID NO: 6)

[0074] The amino acid sequence of the MOR202 Variable Heavy Domain is:

[0075] The amino acid sequence of the MOR202 Variable Light Domain is: 8 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55

[0076] The DNA sequence encoding the MOR202 Variable Heavy Domain is:

[0077] The DNA sequence encoding the MOR202 Variable Light Domain is:

[0078] MOR202 has an IgG1 Fc region.

[0079] The term "hematological cancer" as used herein refers to a cancer of the blood, and includes leukemia, lymphoma and myeloma among others. "Leukemia" refers to a cancer of the blood in which too many white blood cells that are ineffective infighting infectionaremade, thuscrowdingout theotherparts thatmakeup theblood, suchasplatelets and red blood cells. It is understood that cases of leukemia are classified as acute or chronic. Certain forms of leukemia include, by way of nonlimiting examples, acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); Myeloproliferative disorder / neoplasm (MPDS); and myelodysplasia syndrome. "Lymphoma"may refer toaHodgkin’s lymphoma,both indolent andaggressivenon-Hodgkin’s lymphoma, Burkitt’s lymphoma, and follicular lymphoma (small cell and large cell), among others. Myeloma may refer to multiple myeloma (MM), giant cell myeloma, heavy-chain myeloma, and light chain or Bence-Jones myeloma.

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

[0081] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject comprising administering to said subject an effective amount of the formulation of the present disclosure. In certain embodiments, said disease or disorder is cancer or an inflammatory disorder. In certain embodiments, said cancer is a hematological cancer or a solid cancer. In certain embodiments, said cancer is a hematological cancer is selected from leukemia, lymphoma and myeloma. In certain embodiments, said cancer is multiple myeloma. In certain embodiments, said cancer is a solid cancer selected from sarcomas and carcinomas, such as e.g. 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, said inflammatory disorder is selected from inflammatory bowel disease, rheumatoid arthritis, psoriasis, amyloidosis, systemic lupus erythematosus (SLE), atopic dermatitis, Wegener’s granulomatosis and psoriatic arthritis.

[0083] In certain embodiments, the present disclosure provides the use of a pharmaceutical formulation of the present disclosure for the preparation of a medicament. In certain embodiments, said use is the use for the preparation of a medicament for the treatment of a disease or a disorder. In certain embodiments, said disease or disorder is cancer or an inflammatory disorder. In certain embodiments, said cancer is a hematological cancer or a solid cancer. In certain embodiments, said cancer is a hematological cancer is selected from leukemia, lymphoma and myeloma. In certain embodiments, said cancer is multiple myeloma. In certain embodiments, said cancer is a solid cancer selected from sarcomas and carcinomas, such as e.g. 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 9 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 tumors, liver tumors, thyroid tumors and kidney tumors. In certain embodiments, said 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 oneembodiment, thepresent disclosureprovidesapharmaceutical formulation comprisinganantigenbinding protein, a surfactant and a buffer. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a buffer. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising ananti-CD38antibody, a surfactant and abuffer,wherein said anti-CD38antibody has a HCDR1 of SEQ ID NO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3 of SEQ ID NO.: 3, a LCDR1 of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulationcomprisingananti-CD38antibody, asurfactant andabuffer,wherein, saidanti-CD38antibody has a variable heavy chain of 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 buffer, wherein said anti-CD38 antibody is MOR202.

[0085] In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a buffer, wherein said anti-CD38 antibody is at a concentration of at least 55 mg / ml. In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a buffer, wherein said anti-CD38 antibody is at a concentration of 55‑75 mg / ml. In one embodiment, thepresent disclosureprovidesapharmaceutical formulation comprisingananti-CD38antibody, a surfactant andabuffer, wherein said anti-CD38 antibody is at a concentration of 62.5‑67.5 mg / ml. In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a buffer, wherein said anti- CD38 antibody is at a concentration of about 65 mg / ml. In one embodiment, the present disclosure provides a pharmaceutical formulation comprising ananti-CD38antibody, a surfactant and abuffer,wherein said anti-CD38antibody is at a concentration of 65 mg / ml.

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

[0087] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant and a histidine buffer at a concentration of 5mM to 15mMand of a pHbetween 5.9 and 6.1. In another embodiment, the present 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 of a pH between 5.9 and 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant and a histidine buffer at a concentration of about 10 mM and of a pH between 5.9 and 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant and a histidine buffer at a concentration of 10 mM and of a pH between 5.9 and 6.1.

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

[0089] In another embodiment, the present 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 of a pH of 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant andahistidinebufferat a concentrationof 8mMto12mMandof apHof6.0. Inanother embodiment, thepresent disclosureprovidesapharmaceutical formulation comprisinganantigenbindingprotein, a surfactant andahistidinebuffer at a concentration of about 10 mM and of a pH of 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a surfactant and a histidine buffer at a concentration of 10 mM and of a pH of 6.0.

[0090] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, a non-ionic surfactant and a buffer. In other embodiment, the present disclosure provides a pharma- ceutical formulation comprising an antigen binding protein, a polysorbate and a buffer. In other embodiment, the present 10 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 disclosure provides a pharmaceutical formulation comprising an antigen binding protein, polysorbate 20 and a buffer. In other embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, polysorbate 80 and a buffer. In other embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, polysorbate 20 and a buffer, wherein said polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w). In other embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, polysorbate 20 and a buffer, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w). In other embodiment, the present disclosure provides a pharmaceutical formulation comprising an antigen binding protein, polysorbate 20 and a buffer, wherein said polysorbate 20 is at a concentration of 0.1% (w / w).

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

[0092] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidine buffer, wherein said anti-CD38antibody has aHCDR1of SEQ IDNO.: 1, aHCDR2of SEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 andaLCDR3ofSEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and ahistidine buffer of a pHbetween5.5 and6.5,wherein said anti-CD38antibodyhas aHCDR1of SEQ ID NO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3 of SEQ IDNO.: 3, a LCDR1 of SEQ IDNO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulationcomprisingananti-CD38antibody, asurfactant andahistidinebufferof apHbetween5.9and6.1,wherein said anti-CD38 antibody has aHCDR1 of SEQ IDNO.: 1, a HCDR2 of SEQ IDNO.: 2, a HCDR3 of SEQ IDNO.: 3, a LCDR1 of SEQ IDNO.: 4, a LCDR2of SEQ IDNO.: 5 anda LCDR3of SEQ IDNO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidine buffer of a pH of about 6.0, wherein said anti-CD38antibody has aHCDR1of SEQ IDNO.: 1, aHCDR2of SEQ IDNO.: 2, aHCDR3of SEQ IDNO.: 3, a LCDR1of SEQ IDNO.: 4, a LCDR2of SEQ IDNO.: 5 and a LCDR3of SEQ IDNO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidinebufferof apHof 6.0,wherein saidanti-CD38antibodyhasaHCDR1ofSEQIDNO.: 1, aHCDR2ofSEQ IDNO.: 2, a HCDR3 of SEQ ID NO.: 3, a LCDR1 of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6.

[0093] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant andahistidine buffer, wherein said anti-CD38antibodyhas avariable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ ID NO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulationcomprisingananti-CD38antibody, asurfactant andahistidinebufferof apHbetween5.5and6.5,wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ IDNO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ IDNO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti- CD38 antibody, a surfactant and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8.

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

[0095] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH 11 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 between5.5and6.5. Inanother embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingan anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.9 and 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pHof about 6.0. In another embodiment, the present disclosure provides apharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH of 6.0.

[0096] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer, wherein said anti-CD38 antibody has aHCDR1 of SEQ IDNO.: 1, a HCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQIDNO.: 3, aLCDR1ofSEQ IDNO.: 4, aLCDR2ofSEQ IDNO.: 5andaLCDR3 of SEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, aLCDR1ofSEQ IDNO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody has a HCDR1 of SEQ ID NO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3ofSEQIDNO.: 3,aLCDR1ofSEQIDNO.:4, aLCDR2ofSEQIDNO.: 5andaLCDR3ofSEQIDNO.:6. Inanother embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingananti-CD38antibody, anon-ionic surfactant and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody has a HCDR1 of SEQ ID NO.: 1, a HCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQIDNO.: 3, aLCDR1ofSEQ IDNO.: 4, aLCDR2ofSEQ IDNO.: 5andaLCDR3 of SEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody has a HCDR1ofSEQ IDNO.: 1, aHCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6.

[0097] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ IDNO.: 8. In another embodiment, the present disclosure provides apharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8. In another embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingananti-CD38antibody, anon-ionic surfactant andahistidinebuffer of apHof about 6.0,wherein saidanti-CD38antibodyhasavariable heavy chain of ofSEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH of 6.0, wherein saidanti-CD38antibodyhasavariableheavychainofofSEQIDNO.: 7andavariable light chainofSEQIDNO.: 8.

[0098] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer, wherein said anti-CD38 antibody is MOR202. In another embodi- ment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibody is MOR202. In another embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingananti-CD38antibody, anon-ionic surfactant and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody is MOR202. In another embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingananti-CD38antibody, anon-ionic surfactant andahistidinebufferof a pHof about 6.0,wherein saidanti-CD38antibody isMOR202. Inanother embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody is MOR202.

[0099] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between5.5and6.5. Inanother embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingan anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.9 and 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pHof about 6.0. In another embodiment, the present disclosure provides apharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH of 6.0.

[0100] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer, wherein said anti-CD38 antibody has aHCDR1 of SEQ IDNO.: 1, a HCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQIDNO.: 3, aLCDR1ofSEQ IDNO.: 4, aLCDR2ofSEQ IDNO.: 5andaLCDR3 of SEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 12 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, aLCDR1ofSEQ IDNO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody has a HCDR1 of SEQ ID NO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3ofSEQIDNO.: 3,aLCDR1ofSEQIDNO.:4, aLCDR2ofSEQIDNO.: 5andaLCDR3ofSEQIDNO.:6. Inanother embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingananti-CD38antibody, anon-ionic surfactant and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody has a HCDR1 of SEQ ID NO.: 1, a HCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQIDNO.: 3, aLCDR1ofSEQ IDNO.: 4, aLCDR2ofSEQ IDNO.: 5andaLCDR3 of SEQ ID NO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody has a HCDR1ofSEQ IDNO.: 1, aHCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6.

[0101] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of 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 polysorbate 20 and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ IDNO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti- CD38antibody, apolysorbate20andahistidinebuffer of a pHbetween5.9and6.1,wherein saidanti-CD38antibodyhasa variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ IDNO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 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 polysorbate 20 and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8.

[0102] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody isMOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody is MOR202. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody is MOR202.

[0103] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7andavariable light chain ofSEQ IDNO.: 8,wherein saidpolysorbate20 is at a concentrationof 0.05%(w / w) to0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibody has a variable heavy chain of ofSEQ IDNO.: 7 anda variable light chain of SEQ IDNO.: 8 andwherein said 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, a polysorbate 20 and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ IDNO.: 8., andwherein saidpolysorbate20 isat aconcentrationof 0.05%(w / w) to0.2%(w / w). Inanotherembodiment, thepresent disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ ID NO.: 8., and wherein said 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, a polysorbate 20 and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7andavariable light chainofSEQIDNO.: 8andwhereinsaidpolysorbate20 isat aconcentrationof0.05%(w / w) to 0.2% (w / w).

[0104] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20andahistidinebuffer, wherein said anti-CD38antibody isMOR202andwherein said 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 ananti-CD38antibody, a polysorbate 20andahistidine buffer of a pHbetween5.5 and6.5,wherein saidanti-CD38antibody isMOR202andwherein saidpolysorbate20 isat a concentrationof 0.05%(w / w) to 0.2% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti- 13 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody is MOR202 andwherein said 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, a polysorbate 20 and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody is MOR202 and wherein said 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, a polysorbate 20 and a histidine buffer of a pH of 6.0, wherein said anti- CD38 antibody is MOR202 and wherein said polysorbate 20 is at a concentration of 0.05% (w / w) to 0.2% (w / w).

[0105] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 andavariable light chain ofSEQ IDNO.: 8,wherein said polysorbate20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ IDNO.: 8 andwherein said polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure providesa pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ IDNO.: 8., and wherein said polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8., and wherein said polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure providesapharmaceutical formulation comprisingananti-CD38antibody, apolysorbate20andahistidinebuffer of apHof 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8, and wherein said polysorbate 20 is at a concentration of about 0.1% (w / w).

[0106] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20andahistidinebuffer, wherein said anti-CD38antibody isMOR202andwherein said polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38antibody isMOR202andwherein said polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.9 and 6.1, wherein said anti-CD38 antibody is MOR202 and wherein said polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure providesapharmaceutical formulation comprisingananti-CD38antibody, apolysorbate20andahistidinebuffer of apHof about 6.0, wherein said anti-CD38 antibody is MOR202 and wherein said polysorbate 20 is at a concentration of about 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti- CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody is MOR202 and wherein said polysorbate 20 is at a concentration of about 0.1% (w / w).

[0107] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8, wherein said polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ IDNO.: 8 andwherein said polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti- CD38antibody, apolysorbate20andahistidinebuffer of a pHbetween5.9and6.1,wherein saidanti-CD38antibodyhasa variableheavychainof ofSEQIDNO.: 7andavariable light chainofSEQ IDNO.: 8, andwherein saidpolysorbate20 isat a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8, and wherein said polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharma- ceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of 6.0, wherein said anti-CD38antibodyhasavariableheavy chainof ofSEQ IDNO.: 7andavariable light chainofSEQ IDNO.: 8, andwherein said polysorbate 20 is at a concentration of 0.1% (w / w).

[0108] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody isMOR202, wherein said polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti- CD38 antibody is MOR202 and wherein said polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a 14 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 histidinebuffer of a pHbetween5.9and6.1,wherein said anti-CD38antibody isMOR202andwherein said polysorbate20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of about 6.0, wherein said anti-CD38 antibody is MOR202 and wherein said polysorbate 20 is at a concentration of 0.1% (w / w). In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a polysorbate 20 and a histidine buffer of a pH of 6.0, wherein said anti-CD38 antibody is MOR202 and wherein said polysorbate 20 is at a concentration of 0.1% (w / w).

[0109] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2 ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 andaLCDR3ofSEQ IDNO.: 6, andwherein said histidine buffer has a pH between 5.9 and 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein saidanti-CD38antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, aLCDR1 of SEQ IDNO.: 4, a LCDR2 of SEQ IDNO.: 5 and a LCDR3of SEQ IDNO.: 6, andwherein said histidine buffer has a pHof about 6.0. Inanother embodiment, thepresent disclosureprovidesapharmaceutical formulation comprisingananti-CD38 antibody, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2 ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 andaLCDR3ofSEQ ID NO.: 6, and wherein said histidine buffer has a pH of 6.0.

[0110] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2 ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 andaLCDR3ofSEQ IDNO.: 6, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w) andwherein said histidine buffer has a pH between5.9and6.1. Inanother embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingan anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has aHCDR1 of SEQ IDNO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3 of SEQ ID NO.: 3, a LCDR1 of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3ofSEQ IDNO.: 6, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w) andwherein said histidine buffer has a pH of about 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprisingananti-CD38antibody, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1of SEQ ID NO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3 of SEQ IDNO.: 3, a LCDR1 of SEQ IDNO.: 4, a LCDR2 of SEQ ID NO.: 5 anda LCDR3ofSEQ IDNO.: 6, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w), andwherein said histidine buffer has a pH of 6.0.

[0111] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2 ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 andaLCDR3ofSEQ ID NO.: 6, wherein said polysorbate 20 is at a concentration of 0.1% (w / w) and wherein said histidine buffer has a pH between5.9and6.1. Inanother embodiment, thepresent disclosureprovidesapharmaceutical formulationcomprisingan anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has aHCDR1 of SEQ IDNO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3 of SEQ ID NO.: 3, a LCDR1 of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3ofSEQ IDNO.: 6,wherein said polysorbate 20 is at a concentration of 0.1% (w / w) andwherein said histidine buffer has a pH of about 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a HCDR1 of SEQ ID NO.: 1, aHCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 and a LCDR3 of SEQ ID NO.: 6, wherein said polysorbate 20 is at a concentration of 0.1% (w / w), and wherein said histidine buffer has a pH of 6.0.

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

[0113] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w) andwherein said histidine buffer has a pHbetween 5.9 and 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti- 15 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ ID NO.: 8, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w) andwherein said histidine buffer has a pHof about 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, poly- sorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a variable heavy chain of of SEQ ID NO.: 7 and a variable light chain of SEQ IDNO.: 8, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w), and wherein said histidine buffer has a pH of 6.0.

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

[0115] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody is MOR202wherein said polysorbate 20 is at a concentration of about 0.1% (w / w) and wherein said histidine buffer has a pH between 5.9 and 6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, poly- sorbate 20 and a histidine buffer, wherein said anti-CD38 antibody is MOR202 wherein said polysorbate 20 is at a concentration of about 0.1% (w / w) and wherein said histidine buffer has a pH of about 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody is MOR202, and wherein said polysorbate 20 is at a concentration of about 0.1% (w / w), and wherein said histidine buffer has a pH of 6.0.

[0116] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody isMOR202, wherein said polysorbate 20 is at a concentration of 0.1% (w / w)andwherein saidhistidinebufferhasapHbetween5.9and6.1. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody is MOR202, wherein said polysorbate 20 is at a concentration of 0.1% (w / w) and wherein said histidine buffer has a pH of about 6.0. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti- CD38 antibody is MOR202, wherein said polysorbate 20 is at a concentration of 0.1% (w / w), and wherein said histidine buffer has a pH of 6.0.

[0117] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2 ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 andaLCDR3ofSEQ ID NO.: 6, wherein said histidine buffer has a pH between 5.9 and 6.1 and wherein said anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38 antibody has a HCDR1 of SEQ IDNO.: 1, aHCDR2of SEQ IDNO.: 2, aHCDR3of SEQ IDNO.: 3, a LCDR1of SEQ IDNO.: 4, a LCDR2of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6, wherein said histidine buffer has a pH of about 6.0, and wherein said anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising ananti-CD38antibody, polysorbate 20andahistidine buffer, wherein said anti-CD38antibody has aHCDR1of SEQ IDNO.: 1, aHCDR2of SEQ IDNO.: 2, aHCDR3of SEQ IDNO.: 3, a LCDR1of SEQ IDNO.: 4, a LCDR2 ofSEQ IDNO.: 5 andaLCDR3ofSEQ IDNO.: 6,wherein said histidine buffer has apHof 6.0, andwherein said anti-CD38 antibody is at a concentration of 65 mg / ml.

[0118] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2 ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 andaLCDR3ofSEQ ID NO.: 6, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w), wherein said histidine buffer has a pH between 5.9 and 6.1, and wherein said anti-CD38 antibody is at a concentration of 65mg / ml. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti-CD38antibody has aHCDR1of SEQ IDNO.: 1, aHCDR2ofSEQ IDNO.: 2, aHCDR3of SEQ ID NO.: 3, a LCDR1 of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w), wherein said histidine buffer has a pH of about 6.0, and wherein said anti-CD38 antibody is at a concentration of 65 mg / ml.. In another embodiment, the present disclosure provides a 16 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20 and a histidine buffer, wherein said anti- CD38 antibody has aHCDR1of SEQ IDNO.: 1, aHCDR2of SEQ IDNO.: 2, aHCDR3of SEQ IDNO.: 3, a LCDR1 of SEQ IDNO.: 4, a LCDR2 of SEQ IDNO.: 5 and a LCDR3 of SEQ IDNO.: 6, wherein said polysorbate 20 is at a concentration of about 0.1% (w / w), wherein said histidine buffer has a pH of 6.0, andwherein said 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, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1ofSEQ IDNO.: 1, aHCDR2 ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a LCDR1ofSEQ IDNO.: 4, a LCDR2ofSEQ IDNO.: 5 andaLCDR3ofSEQ IDNO.: 6, wherein said polysorbate 20 is at a concentration of 0.1% (w / w), wherein said histidine buffer has a pH between 5.9 and 6.1, and wherein said anti-CD38 antibody is at a concentration of 65 mg / ml. In another embodiment, the present disclosureprovidesapharmaceutical formulationcomprisingananti-CD38antibody, polysorbate20andahistidinebuffer, whereinsaidanti-CD38antibodyhasaHCDR1ofSEQIDNO.: 1,aHCDR2ofSEQIDNO.: 2, aHCDR3ofSEQIDNO.: 3, a LCDR1 of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6, wherein said polysorbate 20 is at a concentration of 0.1% (w / w), wherein said histidine buffer has a pHof about 6.0, andwherein said anti-CD38 antibody is at a concentration of 65 mg / ml.. In another embodiment, the present disclosure provides a pharmaceutical formulation comprisingananti-CD38antibody, polysorbate20andahistidinebuffer,wherein saidanti-CD38antibodyhasaHCDR1of SEQ ID NO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3 of SEQ IDNO.: 3, a LCDR1 of SEQ IDNO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6, wherein said polysorbate 20 is at a concentration of 0.1% (w / w), wherein said histidine buffer has a pH of 6.0, and wherein said anti-CD38 antibody is at a concentration of 65 mg / ml.

[0120] In oneembodiment, thepresent disclosureprovidesapharmaceutical formulation comprisinganantigenbinding protein, a surfactant, a buffer and a stabilizer. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer and a stabilizer. In another embodiment, the present disclosureprovidesapharmaceutical formulation comprisingananti-CD38antibody, a surfactant, a bufferandastabilizer, whereinsaidanti-CD38antibodyhasaHCDR1ofSEQIDNO.: 1,aHCDR2ofSEQIDNO.: 2, aHCDR3ofSEQIDNO.: 3, a LCDR1of SEQ IDNO.: 4, a LCDR2 of SEQ IDNO.: 5 and a LCDR3of SEQ IDNO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and a stabilizer, wherein, said anti-CD38 antibody has a variable heavy chain of 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, a buffer, and a stabilizer, wherein said anti-CD38 antibody is MOR202.

[0121] In oneembodiment, thepresent disclosureprovidesapharmaceutical formulation comprisinganantigenbinding protein, a surfactant, a buffer and sucrose. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer and sucrose. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer and sucrose, whereinsaidanti-CD38antibodyhasaHCDR1ofSEQIDNO.: 1,aHCDR2ofSEQIDNO.: 2, aHCDR3ofSEQIDNO.: 3, a LCDR1of SEQ IDNO.: 4, a LCDR2 of SEQ IDNO.: 5 and a LCDR3of SEQ IDNO.: 6. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and sucrose, wherein, said anti-CD38 antibody has a variable heavy chain of of SEQ IDNO.: 7 and a variable light chain of SEQ IDNO.: 8. In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant, a buffer, and sucrose, wherein said anti-CD38 antibody is MOR202.

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

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

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

[0125] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidine buffer and sucrose, wherein said anti-CD38 antibody is MOR202, wherein said polysorbate20 isat a concentrationof 0.1% (w / w),wherein saidhistidinebuffer hasaconcentration of 10mMandhasapH of about 6.0 and wherein said sucrose is at a concentration of 260 nM.

[0126] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidinebuffer andsucrose,wherein said anti-CD38antibody isMOR202at a concentration of about 65mg / mL,wherein said polysorbate 20 is at a concentration of about 0.1% (w / w),wherein said histidine buffer is at a 17 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 concentration of about 10 mM and has a pH between 5.9 and 6.1 and wherein said sucrose is at a concentration of about 260 mM.

[0127] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising an anti-CD38 antibody, polysorbate 20, a histidinebuffer andsucrose,wherein said anti-CD38antibody isMOR202at a concentration of 65 mg / mL, wherein said polysorbate 20 is at a concentration of 0.1% (w / w), wherein said histidine buffer has a concentration of 10 mM and has a pH of about 6.0 and wherein said sucrose is at a concentration of 260 nM.

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

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

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

[0131] In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation of an anti- CD38antibodyobtainedby reconstituting a lyophilized formulationof thepresent disclosure. In certain embodiments, said reconstitution is achieved via the addition of water or pharmaceutical acceptable reagent to a lyophilized solution comprising an anti-CD38 antibody. In certain embodiments, said reconstitution is achieved via the addition of water to a lyophilized solution comprising an anti-CD38 antibody.

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

[0133] In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidine buffer of a pHbetween 5.5 and 6.5, wherein said anti-CD38 antibody is at a concentration of 55‑75 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceu- tical formulation comprisingananti-CD38antibody, a surfactant andahistidinebufferof apHbetween5.5and6.5,wherein said anti-CD38antibody is at a concentration of 62.5‑67.5mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidine buffer of a pH between5.5and6.5,wherein saidanti-CD38antibody isat a concentrationofabout 65mg / ml. In certainembodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising an anti-CD38 antibody, a surfactant and a histidine buffer of a pH between 5.5 and 6.5, wherein said anti-CD38 antibody is at a concentration of 65 mg / ml.

[0134] In certain embodiments, the reconstituted pharmaceutical formulation also comprises a stabilizer. Suitable stabilizers include but are not limited to human serumalbumin, bovine serumalbumin,α-casein, globulins, a-lactalbumin, LDH, lysozyme,myoglobin, ovalbumin, andRNaseA. Stabilizers also include amino acids and theirmetabolites, such as, glycine, alanine, arginine, betaine, leucine, lysine, glutamic acid, aspartic acid, proline, 4-hydroxyproline, sarcosine, γ- aminobutyric acid (GABA), opines (alanopine, octopine, strombine), and trimethylamineN-oxide (TMAO).Stabilizersmay also include sugar alcohols and mono‑, di‑ or polysaccharides, such as, mannitol, sorbitol, trehalose, dextrose, lactose, sucrose, and the like. Preferably, the stabilizer is sucrose.

[0135] In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising ananti-CD38antibody, a surfactant, ahistidinebuffer of apHbetween5.5and6.5, andastabilizer,wherein saidanti-CD38 antibody is at a concentration of 55‑75 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprisingananti-CD38antibody, a surfactant, a histidine buffer of a pHbetween5.5 and6.5, and a stabilizer, wherein said anti-CD38 antibody is at a concentration of 62.5‑67.5 mg / ml. In certain embodiments, the present disclosure provides a reconstituted pharmaceutical formulation comprising ananti-CD38antibody, a surfactant, a histidinebufferof apHbetween5.5and6.5, andastabilizer,wherein saidanti-CD38antibody isat a concentrationof about 65mg / ml. In certainembodiments, thepresentdisclosureprovidesa reconstitutedpharmaceutical formulationcomprising ananti-CD38antibody, a surfactant, ahistidinebuffer of apHbetween5.5and6.5, andastabilizer,wherein saidanti-CD38 antibody is at a concentration of 65 mg / ml.

[0136] In certain embodiments, the pharmaceutical formulations of the present disclosure are for the use in the treatment of a disease or disorder. In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject comprising administering to said subject an effective amount of the pharmaceutical formulations of the present disclosure. In certain embodiments, the present disclosure provides the use of the pharma- ceutical formulations of the present disclosure for the preparation of a medicament for the treatment of a disease or a 18 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 disorder. Examples Example 1: Liquid formulation for an anti-CD38 antibody

[0137] A liquid formulation of the anti-CD38 specific antibody MOR202 was developed which is suitable for long term storage.

[0138] The formulation strategy consisted of a buffer and pH screening based on thermal stability, followed by excipient optimization with emphasis on protective characteristics against aggregate formation. The buffer screening was per- formed by differential scanning calorimetry (DSC) and resulted in two lead buffers: a histidine buffer (10 mM histidine pH 6.8) andaphosphatebuffer (10mMphosphatebufferpH6.6). ThesebufferswerecombinedwithNaClandsucrose ina full factorial design.

[0139] Samples were subjected to freeze-thaw as well as thermo-mechanical stress and were visually inspected for opalescence and particulate formation. Finally, the product was characterized in the different formulations by UV spectrometry, size exclusion chromatography (SEC) and dynamic light scattering (DLS). A weighted ranking of the analytical outcome identified phosphate or histidine buffer with 125mMNaCl asmost favourable compositions. Histidine buffer showed superior protective properties against freeze-thawing and was therefore chosen as basis for the final formulation.

[0140] Based on data from this study and experience from previous pre-formulation work the following formulation was selected (CMC‑1 formulation): 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 study. Example 2: Pre-formuation development for a lyophilized formulation

[0142] A pre-formulation project was initiated to develop a formulation for the drug product for the anti-CD38 specific antibody MOR202 for Phase III clinical trials and for market supply. Objectives of this study included: • Confirmationof thepHofmaximumchemical anyphysical stability and theeffectof protein concentrationonstability of the molecule • Evaluation of the effect of the shear forces (shaking) and freeze-thaw cycles on the physical and chemical stability of the molecule • Determination of the stability of the protein after dilution into 0.9% NaCl saline (normal saline) Example 2.1: Concentration of the bulk drug substance

[0143] MOR202 bulk drug substance was concentrated by tangential flow filtration (Omega Centramate 30 kD 0.02 sqm, Pall) to a final concentration of 80‑90mg / ml. Trans-membrane pressure not exceeding 6 psi was used tomonitor the tangential flow filtration process. The resulting concentrated solution was divided into sub-lots, loaded into Slide-A-Lyzer DialysisFlasksanddialysedagainst the respectivebuffer (2.0 litre, at least 5x buffer exchanges) over 24hours. 0.3%NaCl was added to the citrate buffer matrices to increase the ionic strength and stabilize the MOR202 solutions.

[0144] At the completion of buffer exchange the MOR202 concentration was measured. Subsequently the solutions were diluted with the respective buffer and were filtered using 0.22 µm syringe filters (PVDF, Millipore or PALL). Filtered formulations were then filled into 5 ml glass vials, stoppered and sealed.

[0145] Thekeypre-formulations testedaresummarized inFigure1.TwodifferentMOR202concentrationswere tested:‑ 50 g / l and 75 g / l. Based on pre-experiments and experience two key buffer systems were compared: histidine buffer and citrate buffer. Example 2.2: Stability and stress tests

[0146] The solutions prepared in Example 2.1 were subjected to various stability and stress tests. Main goal was to determine the optimum pH and to study the effect of protein concentration. 19 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55

[0147] Stabilitywas testedby storing the vials at different conditions: 5±3°C, 25±2°C / 60±5%RH,and40±2°C / 75±5 % RH (RH = relative humidty). Samples were investigated at certain time points. Tests perfomed as well as the test intervals are shown in Figure 2.

[0148] Shear and freeze-thaw cycles were used to investigate the concentration of the surfactant needed to effectively address any physical stability issues of the formulation (e.g., aggregation, appearance) and to protection the API during processing (e.g., mixing, pumping). From a previous study it was known that polysorbate 20 offeres protection against degradation andaggregation. The followingpolysorbate 20 concentrations (w / v%)were tested: 0.02%, 0.04%,and0.1%.

[0149] For shear tests the formulation was agitated on a rotary shaker at 40‑60 rpm at room temperature for 24 and 48 hours. Physical appearance (visually), purity (SEC), protein content (UV) and hydrodynamic size / soluble aggregates (DLS) were analysed.

[0150] For freeze-thaw tests the formulations were subjected to three (3) freeze-thaw cycles (‑70°C). Samples were analysed as in the shear tests.

[0151] For saline dilution tests the formulations were diluted 1 : 100 with normal saline. Purity was measured via SEC. Subvisible particles were measure via HIAC. Example 2.3: Results of stability tests

[0152] Results of the stability tests are summarized in Figures 3A‑3G. The following observations were made: • Histidine buffer is superior in stabilizing the API (MOR202). • No significant differences in appearance and pH was observed during the stability study. • No significant differenceswere detected in UV content overtime. There seems to be an increase in protein content for all formulationsat the last check-point. Theprotein concentration increasecanbeascribed to themethodvariability as the same increase is detected for the standard solution. • Analysis bySEC indicates stability of all formulations at 5°C, except for the pH5.5 L-Histidine (75 g / L) formulation that shows an increase of aggregates and contaminants after 2 weeks • There is an increase in the number of particles per ml with increasing pH. • Sizes assessed by DLS remain unchanged over the period of the stability study. Taken together, the following lead buffer system was chosen as a basis for further development: MOR202 75 g / l 10 mM buffer L-Histidine 1.552 g / l HCl q.s. to pH 6.0 ± 0.1 pH 6.0 ± 0.1 Results for this lead buffer system can be described as follows: Appearance: solutions are clear at time point zero and become slightly opalescent during the stability; colour and presence of particles remain constant UV content: constant pH: constant HIAC: thenumber of particles during the stability remain similar for eachdiameter andare the lowest at timepoint zero SEC: %IgG is constant at 5°C; decrease at 40°C %aggregates is constant at 5°C, increases at 40°C %contaminants is constant at 5°C, increase at 40°C This formulation has the lowest value of aggregates and the highest value of IgG at time point zero. DLS: Sizes assessed by DLS remain unchanged over the period of the stability study. Example 2.4: Results of shear tests, freeze / thaw tests and saline dilution tests

[0153] MOR202 solutions were tested in the lead buffer system identified in Example 2.3. The Polysorbate 20 concentration was adjusted to 0.02%, 0.04% and 0.1%.

[0154] Results of the shear tests are shown in Figures 4A - 4C. 20 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55

[0155] Results of the freeze / thaw tests are shown in Figures 4D - 4E.

[0156] Results of the saline dilution tests are shown in Figure 4F. Results of the shear tests:

[0157] • The physical appearance only changes in opalescence after shearing for 48h. The formulation containing 0.02% polysorbate 20 contains the highest grade of opalescence. The shape and aspect of the fibers and particles seemnot to be ascribed to the product. It is conceivable that the presence of the fibers and particles is of external origin. • There is a slight decrease in UV content for the formulation with PS20 at concentrations of 0.04% and 0.1%. • SEC results show that all PS20 concentrations are characterised by a small decrease of %IgG and a corresponding small increase of %aggregates. • No major changes in sizes and polydispersity are observed when assessing the samples by DLS. Results of the freeze / thaw tests:

[0158] • The shape and aspect of the fibers and particles seem to not be ascribed to the product. It is conceivable that the presence of the fibers and particles is of external origin. • The slight increase in UV content for all PS20 concentrations can be ascribed to the method variability. • Regarding SEC results, all PS20 concentrations show a small decrease of%IgG and a corresponding small increase of % aggregates. • Sizes assessed by DLS remain unchanged. Results of the saline dilution tests:

[0159] • No significant differences between time point zero and time point 24 hours in all formulations, as assessed by SEC. • An increase in thenumber of particles for all diameter rangeswasobserved by light obscuration. Thehighest increase is detected in solution originally containing 0.04% Polysorbate 20, where for the 2 µm size range the number of particles increases fourfold. Example 2.5: Final outcome of pre-formulation development

[0160] A series of pre-formulation studies was conducted to select the optimal pH and excipients necessary to stabilize MOR202. These studies involved confirming the optimal pH between 5.5 and 6.3, studying the effect of Polysorbate 20 on freeze-thaw and agitation, as well as stability of MOR202 upon dilution in normal saline.

[0161] Themolecule demonstrated good chemical and physical stability in 10mMHistidine buffer, pH6.0. Based on the results of these studies, 10 mM Histidine buffer pH 6.0 was considered to be the optimum matrix for the formulation of MOR202.

[0162] On the basis of the output of the shear, freeze-thaw, and dilution studies it was found that the presence of Polysorbate 20 is important and preferred.

[0163] The following composition was selected as basis for further formulation development: MOR202 75 g / l Polysorbate 20 0.1% 10 mM buffer L-Histidine 1.552 g / l HCl q.s. to pH 6.0 ± 0.1 pH 6.0 ± 0.1 The characteristics of this formulation can be summarized as follows: 21 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 Appearance: solution becomes opalescent only after 48h of shear UV content: shows a decrease after 48h shear and an increase after the 3rd freeze / thawing cycle SEC: small decrease of %IgG and a corresponding small increase of %aggregates after shear and freeze / thawing cycle tests. %IgG and %aggregates remain constant for saline dilution test HIAC: increase of the number of particles for all diameters during saline dilution test. Overall number of particles significantly lower than with 0.04% PS20. DLS: sizes asassessed by DLS remain unchanged Example 3: Formuation development for a lyophilized formulation of MOR202

[0164] Following pre-formulation, a new project was initiated to develop the formulation for the drug product for the anti- CD38 specific antibody MOR202.

[0165] Objectives of this study included: • Preparation of a lyophilizedMOR202 prototype formulations to be evaluated for suitability with freeze drying process; • Analysis of the stability of the lyophilized prototype formulations; • Selection of one lead MOR202 freeze dried formulation based on the stability data; • Develop and optimise the freeze drying cycle based on the selected lead MOR202 formulation; • Recommend lyophilisation cycles suitable for process transfer and scale-up at a fill / finish facility. Example 3.1: Thermal assessment of the prototype formulations

[0166] Based on previous knowledge and the information obtained in the pre-formulation study the following formula- tions were selected to be screened for freeze drying development: Table 1: Prototype formulations to be screenes for freeze drying development: No. Formulation 1 30 mM His, 240 mM Sucrose, 0.1 % PS20, pH 6.0 2 30 mM His, 50 mM Arg, 190 mM Sucrose, 0.1 % PS20, pH 6.0 3 75 mg / mL MOR03087 10 mM His, 260 mM Sucrose, 0.1 % PS20, pH 6.0 4 10 mM His, 50 mM Arg, 210 mM Sucrose, 0.1 % PS20, pH 6.0 5 10 mM His, 50 mM NaCl, 175 mM Sucrose, 0.1 % PS20, pH 6.0

[0167] Theprototype formulationswereevaluated for their thermalproperties, andbasedon theoutputsof theanalysisa freeze drying cycle suitable for the five prototypes was proposed.

[0168] After thermal assessment of the properties of the prototypes formulations of Table 1 the concentration of MOR202 was decreased from 75 mg / mL to 65 mg / mL. The decrease in API concentration did not effect the thermal properties of the prototype formulations. Table 2: New prototype formulations to be screened for freeze drying development: No. Formulation 1 30 mM His, 240 mM Sucrose, 0.1 % PS20, pH 6.0 2 30 mM His, 50 mM Arg, 190 mM Sucrose, 0.1 % PS20, pH 6.0 3 65 mg / mL MOR03087 10 mM His, 260 mM Sucrose, 0.1 % PS20, pH 6.0 4 10 mM His, 50 mM Arg, 210 mM Sucrose, 0.1 % PS20, pH 6.0 5 10 mM His, 50 mM NaCl, 175 mM Sucrose, 0.1 % PS20, pH 6.0

[0169] The new prototype formulations of Table 2 are refered to as F1 - F5.

[0170] An understanding of the parameters that affect the physical chemistry of freezing, freeze-drying, heat andmass transfer is key for the determination of the parameters for lyophilization cycle. Sub-ambient differential scanning calorimetry (DSC) studies were carried out with Pyris 1 Perkin Elmer system. Parameters used are shown in Table 3. 22 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 Table 3: Parameters for DSC studies: Sub-run Temperatures Rate Hold 1 min at +25 °C - Cool +25 °C → ‑60°C 1 °C / min Hold 1 min at ‑60°C - Heat ‑60 °C → +25 °C 10 °C / min

[0171] Main focus was the identification of the temperature at which crystallization occurs (eutectic point, Te) and identification of the glass transition temperature of the maximally freeze-concentrated solution (Tg’). Thermograms (freezing and heating ramps) for all prototype solutions F1-F5 were obtained. All results are summarized in Table 4: Table 4: Results of the DSC studies Formulations Ingredients F1 F2 F3 F4 F5 mg / mL mg / mL mg / mL mg / mL mg / mL API MOR03087 75 75 75 75 75 Excipients PS20 1.0 1.0 1.0 1.0 1.0 Histidine 4.656 4.656 1.552 1.552 1.552 Arginine 8.7 8.7 Sucrose 82 65 89 72 60 NaCl 2.9 HCl q.s. to pH 6.0 q.s. to pH 6.0 q.s. to pH 6.0 q.s. to pH 6.0 q.s. to pH 6.0 Te (°C) Onset ‑21.14 ‑22.02 ‑16.07 ‑21.19 ‑20.1 Tg’ - Relaxation (°C) n.a. ‑27.51 n.a. n.a. n.a.Delta Cp 0.070 J / g*°C Melting Point (°C) 5 5 5 5 5 Osmolality (mOs- mol / kg) 315 349 311 341 310 Appearance Clear Slightly opales- cent Clear Slightly Opale- sent Slightly Opale- sent

[0172] All five formulations have comparable eutectic points suggesting compatibility with one freeze drying cycle. FormulationsF2,F4andF5appearedslightly opalescent, but noprecipitate / aggregatewasobservedbyvisual inspection. Formulations F2 and F4 have an osmolality near 350 mOsmol / kg which is still in the acceptance ranges for i.v. administration. However, if the target osmolality is closer to the standard of 300 mOsmol / kg, then the sucrose content of F2 and F4 could be decreased by 12 and 10mg, respectively. This should bring the osmolality closer to 310mOsmol / kg without affecting the thermal properties of the formulations.

[0173] Based on these considerations the initial lyophilisation parameters were defined for the first lyo run. Example 3.2: Initial freeze-drying of prototype formulations

[0174] TheprototypesolutionsF1-F5 (seeTable2)were freezeddried. The initial parameters arebasedon the results of the DCS studies (see Example 3.1). 23 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55

[0175] The formulated bulk solutions were filtered using a 0.22 pm PVDF filter and filled into 20R vials with a filling volume of 5.00 mL + 0.3 mL overfill.

[0176] The length of the cycle was of approximately 64 hours. The cycle was monitored on real time. Primary and secondary dryingwere reduced from the initially proposed50 hours to 46hours and from20hours to 8 hours, respectively. The recipe is shown in Table 5. Table 5: Lyophilisation recipe for prototype lyophilisation screening Description Step Temperature (°C) Pressure (Capacitative) (mbar) Time (hh:mm) Phase Time* (hh:mm) LOAD 1 20 Atm N.A. LOAD FREEZING 2 20 → ‑50 Atm 1.10 FREEZING 3 ‑50 Atm 5.00 (06:10) EVACUATION 4 ‑50 0.150 mbar 0.10 EVACUATION (00:10) PRIMARY DRYING 5 ‑50 → ‑15 0.150 mbar 2.00 PRIMARY DRYING (48:00)6 ‑15 0.150 mbar 46.00 SECONDARY DRY- ING 7 ‑15 → 30 0.150 mbar 1.40 SECONDARY DRY- ING (10:10)8 30 0.150 mbar 8.00 9 30 → 15 0.150 mbar 0.30 PRE-AERATION (with N2) 10 15 750 mbar N.A. PRE-AERATION (with N2; N.A.) STOPPERING 11 15 750 mbar N.A. STOPPERING (N.A.) AERATION (with N2) 12 15 Atm N.A. AERATION (with N2; N.A.) CONSERVATION 13 5 Atm N.A. CONSERVATION (N.A.) Lyo-Cycle I Total Length (without Stoppering) 64:30

[0177] The cake of all five formulations appeared well dried. Overall, the appearance can be classified as follows (from better to lessgood): F3=F5>F2=F4>F1.This classification takes intoaccount thenumber of cracks in thecake, the level of shrinkage, and the tendency to break. Images of vials of all formulations are shown in Figure 5. Example 3.3: Freezed-dried and liquid prototype formulation testing

[0178] Liquid and freeze-dried prototype formulations were analysed for the following parameters: • Appearance (liquid and lyo) • Moisture content (lyo only) • pH (liquid and lyo) • Size Exclusion Chromatography (liquid and lyo) • Sub-Visible particles (HIAC) (liquid and lyo) • DLS (liquid and lyo) • Reconstitution Time (lyo) • UV (liquid and lyo) 24 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55

[0179] Stability of the formulations were also tested upon storage at various temperatures (2‑8°C, 0% RH; 25°C, 60% RH; 40°C, 75% RH) and for various tim e points (0, 2 and 4 weeks).

[0180] Results for the liquid formulations are shown in Figures 7A‑7H. Results for the lyophilipzed formulations are shown in Figures 8A‑8E. Example 3.4: Final results

[0181] Based on the in depth analysis of the five prototype liquid and freeze-dried formulations, formulation F3waswas selected for the development steps.

[0182] Formulation F3 showed the lowest degree of opalescence. Also, and in contrast to the other four formulations tested, no increase of sub-visible particles for the liquid formulation was seen during the stability study. Moreover, formulation F3 also showed the lowest degree of opalescense for the freeze dried formulation after reconstitution, and no increase of aggregates was observed during the stability study. Example 4: Optimization of lyophilization

[0183] In several subsequent steps the lyophilizationprocesswasoptimized.Eachsubsequent processmadeuseof the results and the experience gained during the preceeding experiments. Crucial process parameters whichwere evaluated in the lyophilization process are temperature, pressure and time. Example 4.1: First optimization

[0184] Based on the results collected in the first lyophilisation experiments (see Example 3), the process wasmodified. One of the main goals was to shorten the secondary drying process and to adapt the ramp rates for the different freezing / heating steps. The lyophilization recipe of the first optimization is shown in Table 6. The length of the total cycle was about 72 hours. Table 6: Lyophilisation recipe for the first optimization No. Phase Lyo Temperature °C Pressure (Capacitative) Time hh:mm Ramp rate applied for F1-F5 formulations New ramp rate for P711‑01 (°C / min) (°C / min) 01 Load 20 Atmospheric N.A X 02 Freezing 20 → ‑50 Atmospheric 02:20 1 0.50 03 ‑50 Atmospheric 05:00 04 Evacuation ‑50 0.150 mbar 00:10 05 Primary drying - 50→ ‑15 0. 150 mbar 04:00 0.3 0.15 06 ‑15 0.150 mbar 46:00 07 Secondary drying ‑15→ 30 0.150 mbar 05:00 0.45 0.15 08*. 30 0.150 mbar 08:00 : 09 30→ 15 0.150 mbar 00:30 0.50 0.50 10 Pre-Aeration (with N2) 15 750 mbar N.A. 11 Stoppering 15 750 mbar N.A. 12 Aeration (with N2) 15 Atmospheric N.A. 13 Conservation 5 Atmospheric N.A. Lyo-Cycle / Total length (without Stoppering) 71:00

[0185] Analytical results confirmed that the lyophilized drug product showed the expected properties and did not show any anomalities. 25 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55

[0186] After 5 hours of secondary drying (step 8) the residualmoisture content was 0.9%w / w, so that this step had to be extended for anadditional 3hours. After 8hours the residualmoisture contentwas0.3%w / w, i.e. below the target of <0.5% w / w.

[0187] Itwasalsoobserved that primarydryingand the follwoing rampingupof the secondary dryingstepcanpotentially be shortened. This could lead to an additional savings of about 4 hours of the entire process.

[0188] All cakes were well dried.

[0189] The appearance of the cake was classified taking into account the number of cracks in the cake, the level of shrinkage and the tendency to break.

[0190] The 24 vials tested were classified as follows: 9 vials are fine 13 vials with very slight shrinkage 2 vials with crack

[0191] Freeze-dryingmicroscopy (FDM)was used to determine the critical temperatures of the drug product. FDMwas carried out using a BTL Lyostat freeze-drying microscope (ID PDS 250).

[0192] Sample solutions of 1.5 pL were analyzed to allow the real time observation of freeze-drying of the sample. Information obtained from FDM are the collapse point (Tc) and the eutectic (Teu) point of the formulation.

[0193] Some sample display a collapse zone behaviour, i.e. the structure of the drying sample is gradually lost over a temperature range, rather than at a distinct point.

[0194] Thefirst signof collapsewasobservedat ‑26.8°C.With theprogressionof the sublimationand the increaseof the temperature, also the collapse became more evident. Table summarizes the lower collapse zone temperature and recommens primary drying temperature and pressure. Table 7: Summary of FDM analysis of the first optimization Formulation Tc (start of collapse, °C) Primary drying temperature of the product (°C) Primary drying temperature of the shelves (°C) Primary drying pressure (µbar) API (MOR202) 344.50 mg / vial ‑26.8 ‑28.8 to ‑33.8 ‑15 150

[0195] The following conclusions were drawn: • the temperature should be ideallymaintained below its respective lower collapse zone limit throughout primary drying in order to prevent product collapse • for additional product safety and quality, a safety margin of between 2°C and 7°C, should be envisaged. This accommodates for slight variations thatmayoccur during scale up, technology transfer and theuseof different freeze- dryer • temperature of primary drying should not be increased Example 4.2: Second optimization

[0196] Compared to the first optimization, in the second optimization the ramp rate for the primary and the secondary drying were increased.The primary temperature was maintained at ‑15°C. Table 8: Lyophilisation recipe for the second optimization No. Phase Lyo Temperature °C Pressure (Capacitative) Time hh:mm Ramp (°C / min) 01 Load 20 Atmospheric N.A. N.A 02 Freezing 20 → ‑50 Atmospheric 02:20 0.50 03 ‑50 Atmospheric 05:00 N.A. 04 Evacuation ‑50 0.150 mbar 00:10 N.A. 05 Primary drying - 50→ ‑15 0.150 mbar 02:00 0.3 06* ‑15 0.150 mbar 46:00 N.A. 26 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) No. Phase Lyo Temperature °C Pressure (Capacitative) Time hh:mm Ramp (°C / min) 07 Secondary drying ‑15→ 30 0.150 mbar 01:40 0.45 08 30 0.150 mbar 08:00 N.A. 09 30→ 15 0.150 mbar 00:30 N.A. 10 Pre-Aeration (with N2) 15 750 mbar N.A. N.A. 11 Stoppering 15 750 mbar N.A. N.A. 12 Aeration (with N2) 15 Atmospheric N.A. N.A. 13 Conservation 5 Atmospheric N.A. N.A. Lyo-Cycle / Total length (without Stoppering) 65:40

[0197] The length of the total cycle was about 66 hours, i.e. considerably shorter than in the first optimization.

[0198] Analytical results confirmed that the lyophilized drug product showed the expected properties and did not show any anomalities.

[0199] All cakes were well dried.

[0200] Again, theappearanceof the cakewasclassified taking into account the number of cracks in the cake, the level of shrinkage and the tendency to break.

[0201] The 29 vials tested were classified as follows: 27 vials with very slight shrinkage 2 vials with very slight shrinkage and cracks on the surface

[0202] Observations made and possible changes for the next optimization round: • the lyophilization cakes did not improve by applying different ramps and conditions; the cake appearance is probably due to excipients and the drug product • the ramp of 1°C / min in the freezing step is not po ssible with all commonly used freeze driers and it is therefore recommended to work with a safety margin and use a freezing ramp of 0.5°C / min Example 4.3: Third optimization

[0203] Themain focusof thisoptimizationwas toensure that thequalityof thedrugproduct is notaffectedby thepossible variations in temperature and pressure that can occur during the scale up to commercial scale. In order to test worst case conditions, temperature variations of ±3°C and pressure variations of ±30 µbars were evaluated.

[0204] Two lyophilisation experiments, HT / HP and LT / LP, were performed for the robustness study and the trials were performedat lab-scale (0.5m2 lyophilizationunit) asameansof bridgingbetween theextrapolationat laboratory scale and GMP production.

[0205] This optimization aimed to investigate high temperature and high pressure conditions. Table 9: Lyophilisation recipe for the third optimization No. Phase Lyo Temperature °C Pressure (Capacitative) Time hh:mm Ramp (°C / min) 01 Load 20 Atmospheric N.A. N.A 02 Freezing 20 → ‑50 Atmospheric 02:20 0.50 03 ‑50 Atmospheric 05:00 N.A. 04 Evacuation ‑50 0.180mbar 00:10 N.A. 05 Primary drying - 50→ ‑12 0.180 mbar 02:07 0.3 06 ‑12 0.180 mbar 44:00 N.A. 27 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) No. Phase Lyo Temperature °C Pressure (Capacitative) Time hh:mm Ramp (°C / min) 07 Secondary drying ‑12 → 33 0.180 mbar 01:40 0.45 08 33 0.180 mbar 08:00 N.A. 09 33→ 18 0.180 mbar 00:30 N.A. 10 Pre-Aeration (with N2) 18 750 mbar N.A. N.A. 11 Stoppering 18 750 mbar N.A. N.A. 12 Aeration (with N2) 18 Atmospheric N.A. N.A. 13 Conservation 5 Atmospheric N.A. N.A. Lyo-Cycle / Total length (without Stoppering) 63:47

[0206] The length of the total cycle was about 64 hours, i.e. again shorter than in the last optimization.

[0207] Analytical results confirmed that the lyophilized drug product showed the expected properties and did not show any anomalities.

[0208] All cakes were well dried.

[0209] Again, theappearanceof the cakewasclassified taking into account the number of cracks in the cake, the level of shrinkage and the tendency to break.

[0210] The 29 vials tested were classified as follows: 24 vials had a cohesive and white cake with very slight shrinkage 5 vials with very slight shrinkage and cracks on the surface Example 4.4: Fourth optimization

[0211] This optimization aimed to investigate low temperature and low pressure conditions. Table 10: Lyophilisation recipe for the fourth optimization No. Phase Lyo Temperature °C Pressure (Capacitative) Time hh:mm Ramp (°C / min) 01 Load 20 Atmospheric N.A. N.A 02 Freezing 20 → ‑50 Atmospheric 02:20 0.50 03 ‑50 Atmospheric 05:00 N.A. 04 Evacuation ‑50 0.120mbar 00:10 N.A. 05 Primary drying - 50→ ‑18 0.120 mbar 01:47 0.3 06 ‑18 0.120mbar 44:00 N.A. 07 Secondary drying ‑18 → 27 0.120 mbar 01:40 0.45 08 27 0.120mbar 08:00 N.A. 09 27→ 12 0.120 mbar 00:30 N.A. 10 Pre-Aeration (with N2) 12 750 mbar N.A. N.A. 11 Stoppering 12 750 mbar N.A. N.A. 12 Aeration (with N2) 12 Atmospheric N.A. N.A. 13 Conservation 5 Atmospheric N.A. N.A. Lyo-Cycle / Total length (without Stoppering) 63:27

[0212] The length of the total cycle was again about 64 hours.

[0213] Analytical results confirmed that the lyophilized drug product showed the expected properties and did not show 28 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 any anomalities.

[0214] All 26 cakeswerewell dried and cohesive. 3 vials out of the 26 showed a slight shrinkage that is not considered a defect.

[0215] The results of these runshaveproven that the chosen formulation cansuccessfully be lyophilizedevenwith small variations of the temperature and pressure during the lyophilization process steps.

[0216] This guaratnees a robust process for large-scale routine manufacturing. Example 4.5: Fifth optimization

[0217] Based on all experience gather so far, a fifth optimization was performed. Table 11: Lyophilisation recipe for the fifth optimization No. Phase Lyo Temperature °C Pressure (Capacitative) Time hh:mm Ramp (°C / min) 01 Load 20 Atmospheric N.A. N.A 02 Freezing 20 → ‑50 Atmospheric 02:20 0.50 03 ‑50 Atmospheric 05:00 N.A. 04 Evacuation ‑50 0.150 mbar 00:10 N.A. 05 Primary drying - 50→ ‑15 0.150 mbar 02:00 0.3 06 ‑15 0.150mbar 46:00 N.A. 07 Secondary drying ‑15 → 30 0.150 mbar 01:40 0.45 08 30 0.150 mbar 08:00 N.A. 09 30→ 15 0.150 mbar 00:30 0.50 10 Pre-Aeration (with N2) 15 750 mbar N.A. N.A. 11 Stoppering 15 750 mbar N.A. N.A. 12 Aeration (with N2) 15 Atmospheric N.A. N.A. 13 Conservation 5 Atmospheric N.A. N.A. Lyo-Cycle / Total length (without Stoppering) 65:40

[0218] The length of the total cycle was about 66 hours.

[0219] Analytical results confirmed that the lyophilized drug product showed the expected properties and did not show any anomalities. Figure 8 shows the results of the analysis of the lyophilized drug product. Reconstitution volumewas 4.8 ml. All cakes were cohesive.

[0220] 215 vialswere conform. 3 out of the 215 conformvials showed cracks on the surface that is not to be considereda defect. 60 vials were rejected because of drug product between the stopper and the neck. This defect is not related to the lyophilization process but to the filling process. 44 vials either showed stains on the vials near the stopper or the presence of very small ammunts of product between the stopper and the rack. This defect was probably caused during the freeze- dryer loading. Pictures of exemplary cakes are shown in Figure 9.

[0221] The results of the fifth optimization showed that theprocess is robust andsuited tobeapplied for theproductionof GMP material.

[0222] The disclosure includes at least the following numbered embodiments: 1. A lyophilized pharmaceutical formulation comprising an anti-CD38 antibody, a non-ionic surfactant and a histidine buffer of a pH between 5.5 and 6.5. 2. The lyophilized pharmaceutical formulation of embodiment 1, wherein said non-ionic surfactant is polysorbate 20. 3. The lyophilized pharmaceutical formulation according to embodiment 1 or 2, wherein said histidine buffer has a pH of about 6.0. 4. The lyophilized pharmaceutical formulation according to any oneof the preceding embodiments, wherein said anti- 29 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 CD38 antibody has aHCDR1 of SEQ IDNO.: 1, a HCDR2 of SEQ IDNO.: 2, a HCDR3 of SEQ IDNO.: 3, a LCDR1 of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6. 5. The lyophilizedpharmaceutical formulationaccording toanyoneof theprecedingembodiments, further comprising sucrose. 6. A method for preparing a liquid formulation of an anti-CD38 antibody, said method comprising providing the lyophilized pharmaceutical formulation of any of the preceding embodiments, and reconstituting said lyophilized formulation via the addition of water. 7. A reconstituted pharmaceutical formulation of an anti-CD38 antibody obtained by the method of embodiment 6. 8. A reconstituted pharmaceutical formulation according to embodiment 7, wherein said non-ionic surfactant is at a concentration of 0.05% (w / w) to 0.2% (w / w), preferably of about 0.1% (w / w). 9. A reconstituted pharmaceutical formulation according to any one of embodiments 7 to 8, wherein said histidine buffer is at a concentration of 5 mM to 15 mM, preferaby of about 10 mM. 10.A reconstitutedpharmaceutical formulationaccording toanyoneof embodiments7 to9,wherein said sucrose isat a concentration of 150 to 350 mM, preferably of about 260 mM. 11. A reconstituted pharmaceutical formulation according to any one of embodiments 7 to 10, wherein said anti-CD38 antibody is at a concentration of 55 to 75 mg / ml, preferably of about 65 mg / ml. 12. A pharmaceutical formulation of any one of embodiments 1‑5 or 7‑11 for use in the treatment of a disease or disorder. 13. The use of a pharmaceutical formulation according to embodiment 12, wherein said disease or disorder is cancer. 14. The use of a pharmaceutical formulation according to embodiment 13, wherein said cancer is a hematological cancer is selected from leukemia, lymphomaandmyeloma, suchasacute lymphocytic leukemia (ALL), acutemyeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and multiple myeloma (MM) or a solid cancer selected from sarcoma and carcinoma, such as breast cancer, ovarian cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer,melanoma tumors, colorectal cancer, headandneck cancer, bladder cancer, esophageal cancer, liver cancer, thyroid cancer and kidney cancer. 15. The use of a pharmaceutical formulation according to embodiment 12, wherein said disease or disorder is an inflammatory disorder. 16. The use of a pharmaceutical formulation according to embodiment 15, wherein said inflammatory disorder is selected from inflammatory bowel disease, rheumatoid arthritis, psoriasis, amyloidosis, systemic lupus erythema- tosus (SLE), atopic dermatitis, Wegener’s granulomatosis, psoriatic arthritis. Claims 1. A method of reducing formation of aggregates of an anti-CD38 antibody in a composition containing the anti-CD38 antibody, the method comprising combining: a) the anti-CD38 antibody, wherein the anti-CD38 antibody comprises a first heavy chain complementarity determining region (HCDR1)ofSEQ IDNO.: 1, aHCDR2ofSEQ IDNO.: 2, aHCDR3ofSEQ IDNO.: 3, a first light chain complementarity determining region (LCDR1)ofSEQ IDNO.: 4, aLCDR2ofSEQIDNO.: 5andaLCDR3of SEQ ID NO.: 6; b) a non-ionic surfactant; c) stabilizer; and d) histidine buffer. 2. The method of claim 1, wherein the composition contains 55 to 75 mg / mL of the anti-CD38 antibody, preferably 65 30 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 mg / mL of the anti-CD38 antibody. 3. The method of claim 1, wherein said non-ionic surfactant is polysorbate 20 or polysorbate 80. 4. The method of claim 3, wherein said non-ionic surfactant is 0.05 to 0.2% w / w polysorbate 20, preferably 0.1% w / w polysorbate 20. 5. The method of claim 1, wherein the composition has a pH of 5.5 to 6.5, preferably a pH of about 6. 6. The method of claim 1, wherein the stabilizer is a sugar alcohol, a monosaccharide, a disaccharide, or a poly- saccharide, preferably a disaccharide. 7. The method of claim 6, wherein the stabilizer is mannitol, sorbitol, trehalose, dextrose, lactose, or sucrose. 8. The method of claim 7, wherein the composition comprises 150 mM to 350 mM sucrose, preferably about 260 mM sucrose. 9. The method of claim 1, wherein the composition comprises 5 mM to 15 mM histidine buffer. 10. The method of claim 1, wherein the anti-CD38 antibody comprises a variable heavy chain (VH) domain of SEQ ID NO:7. 11. Themethodof claim11,wherein theanti-CD38antibodycomprisesavariable light chain (VL)domainofSEQIDNO:8. 12. The method of claim 1, wherein said non-ionic surfactant is 0.05 to 0.2% w / w polysorbate 20, and wherein the composition comprises 150 mM to 350 mM sucrose. 13. Themethod of claim 1, wherein the composition elicits long term storage stability as characterized by size exclusion highperformance liquid chromatography (SE-HPLC)analysis at 4weeksof storageat 25°Cand60%relativehumidity of monomer content greater than 90%. 14. Themethod of claim 1, wherein the composition elicits long term storage stability as characterized by size exclusion highperformance liquid chromatography (SE-HPLC)analysis at 4weeksof storageat 40°Cand70%relativehumidity of monomer content greater than 90%. 15. A composition obtained or obtainable by the method of any of claims 1 to 14, optionally wherein the composition is a pharmaceutical composition, an aqueous pharmaceutical composition, a lyophilizate or a reconstituted lyophilizate. 31 EP 4 759 326 A2 5 10 15 20 25 30 35 40 45 50 55 32 EP 4 759 326 A2 33 EP 4 759 326 A2 34 EP 4 759 326 A2 35 EP 4 759 326 A2 36 EP 4 759 326 A2 37 EP 4 759 326 A2 38 EP 4 759 326 A2 39 EP 4 759 326 A2 40 EP 4 759 326 A2 41 EP 4 759 326 A2 42 EP 4 759 326 A2 43 EP 4 759 326 A2 44 EP 4 759 326 A2 45 EP 4 759 326 A2 46 EP 4 759 326 A2 47 EP 4 759 326 A2 48 EP 4 759 326 A2 49 EP 4 759 326 A2 50 EP 4 759 326 A2 51 EP 4 759 326 A2 52 EP 4 759 326 A2 53 EP 4 759 326 A2 54 EP 4 759 326 A2 55 EP 4 759 326 A2 56 EP 4 759 326 A2 57 EP 4 759 326 A2 58 EP 4 759 326 A2 59 EP 4 759 326 A2 60 EP 4 759 326 A2 61 EP 4 759 326 A2 62 EP 4 759 326 A2 63 EP 4 759 326 A2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • WO 199962526 A

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[0052] • HUSTON et al. Proc. Natl. Acad. Sci., 1988, vol. 85, 5879-5883

[0052] • HOLLINGER ; HUDSON. Nature Biotechnology, 2005, vol. 23, 1126-1136

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[0052] • KNAPPIK et al. J Mol Biol, 2000, vol. 296, 57-86

[0054] • Sequences of Proteins of Immunological Interest. U.S. Department of Health and Human Services, 1991

[0055] • LAZIKANI et al. J. Mol. Bio., 1997, vol. 273, 927-948

[0055] • Sequences of Proteins of Immunological Interest. KABAT et al. NIH Publication no. 91‑3242. U.S. Department of Health and Human Services, 1991

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[0059] 摘 要 本發明涉及具有藥物活性的抗原結合蛋白質（例如單克隆抗體）的製劑。 具體地，本發明涉及抗CD38抗體的穩定的凍乾藥物製劑、這種凍乾製劑的 複溶液體製劑、並涉及製造和使用這種凍乾製劑和複溶製劑的方法。

Claims

1. A method of reducing formation of aggregates of an anti-CD38 antibody in a composition containing the anti-CD38 antibody, the method comprising combining: a) the anti-CD38 antibody, wherein the anti-CD38 antibody comprises a first heavy chain complementarity determining region (HCDR1) of SEQ ID NO.: 1, a HCDR2 of SEQ ID NO.: 2, a HCDR3 of SEQ ID NO.: 3, a first light chain complementarity determining region (LCDR1) of SEQ ID NO.: 4, a LCDR2 of SEQ ID NO.: 5 and a LCDR3 of SEQ ID NO.: 6; b) a non-ionic surfactant; c) stabilizer; and d) histidine buffer.

2. The method of claim 1, wherein the composition contains 55 to 75 mg / mL of the anti-CD38 antibody, preferably 65 mg / mL of the anti-CD38 antibody.

3. The method of claim 1, wherein said non-ionic surfactant is polysorbate 20 or polysorbate 80.

4. The method of claim 3, wherein said non-ionic surfactant is 0.05 to 0.2% w / w polysorbate 20, preferably 0.1% w / w polysorbate 20.

5. The method of claim 1, wherein the composition has a pH of 5.5 to 6.5, preferably a pH of about 6.

6. The method of claim 1, wherein the stabilizer is a sugar alcohol, a monosaccharide, a disaccharide, or a polysaccharide, preferably a disaccharide.

7. The method of claim 6, wherein the stabilizer is mannitol, sorbitol, trehalose, dextrose, lactose, or sucrose.

8. The method of claim 7, wherein the composition comprises 150 mM to 350 mM sucrose, preferably about 260 mM sucrose.

9. The method of claim 1, wherein the composition comprises 5 mM to 15 mM histidine buffer.

10. The method of claim 1, wherein the anti-CD38 antibody comprises a variable heavy chain (VH) domain of SEQ ID NO:7.

11. The method of claim 11, wherein the anti-CD38 antibody comprises a variable light chain (VL) domain of SEQ ID NO:8.

12. The method of claim 1, wherein said non-ionic surfactant is 0.05 to 0.2% w / w polysorbate 20, and wherein the composition comprises 150 mM to 350 mM sucrose.

13. The method of claim 1, wherein the composition elicits long term storage stability as characterized by size exclusion high performance liquid chromatography (SE-HPLC) analysis at 4 weeks of storage at 25°C and 60% relative humidity of monomer content greater than 90%.

14. The method of claim 1, wherein the composition elicits long term storage stability as characterized by size exclusion high performance liquid chromatography (SE-HPLC) analysis at 4 weeks of storage at 40°C and 70% relative humidity of monomer content greater than 90%.

15. A composition obtained or obtainable by the method of any of claims 1 to 14, optionally wherein the composition is a pharmaceutical composition, an aqueous pharmaceutical composition, a lyophilizate or a reconstituted lyophilizate.

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