Control of trace metals during the production of anti-CD38 antibodies

Abstract

The present disclosure relates to methods for controlling trace metals during the production of anti-CD38 antibodies, drug substances and pharmaceutical products produced using the methods, and uses of the produced drug substances and pharmaceutical products.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 62 / 760,782, filed November 13, 2018, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THEINVENTION The present disclosure relates to methods for controlling trace metals during the production of anti-CD38 antibodies, drug substances and drug products produced using the methods, and uses of the produced drug substances and drug products.

[0003] (Sequence Listing) This application contains a Sequence Listing submitted via EFS-Web, which is incorporated herein by reference in its entirety. The ASCII text file, created on November 2, 2018, has the file name JBI6023WOPCT_ST25.txt and is 91 kilobytes in size. [Background technology]

[0004] Over the past few decades, much research has focused on the production of recombinant proteins, such as monoclonal antibodies, from cell culture. Serum- or hydrolysate-containing media have been utilized for such cultures, but synthetic media have been developed to minimize lot-to-lot variability in media components (Luo and Chen, Biotechnology and Bioengineering 97(6):1654-59, 2007). A greater understanding of cell culture has made it possible to shift to synthetic media without compromising product quality while maintaining relatively high viability.

[0005] N-glycosylation during the production of an antibody can mediate its antigenicity, in vivo clearance rate, stability, and Fc-mediated effector functions, and can depend on cell culture conditions. Therefore, there is a need to develop methods that can provide predictable glycosylation profiles of therapeutic antibodies obtained from cell culture in defined media. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the antibody being expressed from a polynucleotide encoding a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8, the method comprising: preparing a culture medium containing about 8.5 parts per billion (ppb) or less of manganese (Mn); and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in the culture medium prepared in step a), thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0007] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the concentration of Mn in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0008] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell comprising a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in the culture medium prepared in step a), thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%; and formulating the anti-CD38 antibody as a pharmaceutical. [Brief description of the drawings]

[0009] [Figure 1] 1 shows the correlation of the percentage of G0F oligosaccharides (G0F%) of DARZALEX® (daratumumab) versus the calculated manganese (Mn) concentration of the dry powder medium (DPM) for different manufacturing batches. Y-axis: Mn concentration, parts per billion (ppb); X-axis: G0F%. [Diagram 2] 1 shows the correlation of the percentage of G1F oligosaccharides (G1F%) of DARZALEX® (daratumumab) versus the calculated Mn concentration of DPM for different manufacturing batches. Y-axis: Mn concentration (ppb); X-axis: G1F%. [Diagram 3]1 shows the GOF% of DARZALEX® (daratumumab) versus Mn concentration calculated from DPM bioreactor media components for out of specification (OOS), out of trend (OOT), and passed batches. [Figure 4] 1 shows the G1F% of DARZALEX® (daratumumab) versus Mn concentration calculated from DPM bioreactor media components for out-of-specification, out-of-trend, and passing batches. [Diagram 5] 1 shows the G1F% (shown as G1F% in the figure) and Mn concentrations of DARZALEX® (daratumumab) in various manufacturing batches over time. [Figure 6] Total Mn concentrations (ppb) before, during, and after OOS / OOT batch production are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if fully set forth.

[0011] It should be understood that the terms used herein are used only to describe particular embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0012] Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, exemplary materials and methods are described herein. In describing and claiming the present disclosure, the following terminology is used.

[0013] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0014] "About" means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of the method, i.e., measurement system, by which the value is measured or determined. Unless expressly stated otherwise in the Examples or elsewhere in the specification in the context of a particular assay, result, or embodiment, "about" means within one standard deviation or a range of up to 5%, whichever is greater, according to practice in the art.

[0015] An "antibody" refers to an immunoglobulin molecule having two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region, which is divided into a CH1 region, a hinge region, a CH2 region, and a CH3 region. Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). VH and VL may be further divided into regions of hypervariability called complementarity determining regions (CDRs) interspersed in framework regions (FRs). Each VH and VL is composed of three CDRs and four FR segments, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Antibodies include monoclonal antibodies, including murine, human, humanized, and chimeric antibodies, bispecific or multispecific antibodies. Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG, and IgM, depending on the heavy chain constant region amino acid sequence. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two clearly distinct types, kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0016] "Antigen-binding fragment" refers to a portion of an immunoglobulin molecule that retains the antigen-binding properties of the parent full-length antibody. Exemplary antigen-binding fragments are heavy chain complementarity determining regions (HCDRs) 1, 2 and / or 3, light chain complementarity determining regions (LCDRs) 1, 2 and / or 3, VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, and domain antibodies (dAbs) consisting of either one VH domain or one VL domain. VH and VL domains can be linked together via synthetic linkers to form various types of single chain antibody designs in which the VH / VL domains pair intramolecularly or intermolecularly when the VH and VL domains are expressed by separate chains to form monovalent antigen-binding sites such as single chain Fvs (scFvs) or diabodies. For example, they are described in WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804 and WO 1992 / 01047.

[0017] "Biosimilar" (of an approved reference product / biological product) refers to a biological product that is closely similar to the reference product, with minor differences in clinically inactive ingredients, but with no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency, based on data obtained from: (a) analytical studies that demonstrate that the biological product is closely similar to the reference product, with minor differences in clinically inactive ingredients, (b) animal studies (including evaluation of toxicity), and / or (c) clinical trial(s) (including evaluation of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency under one or more appropriate conditions of use, such as the conditions of use for which the reference product is approved and the conditions for which the reference product is intended to be used, and the conditions for granting approval for the biosimilar. A biosimilar may be an interchangeable product that may substitute for the reference product in the pharmacy without the intervention of a prescribing healthcare professional. To comply with the further criteria of "interchangeability," a biosimilar is required to produce the same clinical outcome in any given patient as the reference product, and, when a biosimilar is administered multiple times to an individual, the risks of reduced safety or efficacy from alternating or switching between the use of the biosimilar and the reference product do not outweigh the risks of using the reference product without such alternation or switching. To the extent that the mechanism of the reference product is known, the biosimilar utilizes the same mechanism of action for the proposed conditions of use. The condition(s) of use defined, recommended, or proposed in the labeling proposed for the biosimilar are already approved for the reference product. The route of administration, dosage form, and / or strength of the biosimilar are the same as those of the reference product, and the biosimilar is manufactured, processed, packaged, or held in facilities that meet standards designed to ensure that the biosimilar continues to maintain its safety, purity, and strength. A biosimilar may contain minor modifications of the amino acid sequence (e.g., N- or C-terminal truncations) that are not expected to alter the performance of the biosimilar when compared to the reference product. The reference product may be approved in at least one of the United States, Europe, or Japan.

[0018] "CD38" refers to the cluster of differentiation 38 protein, a glycoprotein expressed on immune cells including plasma cells, natural killer cells, and a subpopulation of B cells and T cells.

[0019] "Cell culture medium" and "culture medium" refer to a solution containing components or nutrients that nourish growing mammalian cells. Typically, nutrients include essential and non-essential amino acids, vitamins, energy sources, lipids, and trace elements required by cells for minimal growth and / or survival. Such solutions may also contain additional nutrients or supplemental components that enhance growth and / or survival beyond the minimal proportions, including hormones and / or other growth factors, specific ions (such as sodium, chloride, calcium, magnesium, and phosphate), buffers, vitamins, nucleosides or nucleotides, trace elements (inorganic compounds that are usually present at very low final concentrations), inorganic compounds (e.g., iron) that are present at high final concentrations, amino acids, lipids, and / or glucose or other energy sources.

[0020] A "complementarity determining region (CDR)" is a region of an antibody that binds to an antigen. There are three CDRs (HCDR1, HCDR2, and HCDR3) in VH, and three CDRs (LCDR1, LCDR2, and LCDR3) in VL. CDRs can be defined using various descriptions, such as Kabat (Wu et al. (1970) J Exp Med 132:211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., J Mol Biol 196:901-17, 1987), IMGT (Lefranc et al., Dev Comp Immunol 27:55-77, 2003), and AbM (Martin and Thornton, J Bmol Biol 263:800-15, 1996). Correspondence between the various descriptions and numbering of the variable regions has been described (see, for example, Lefranc et al. Dev Comp Immunol 27:55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International ImMunoGeneTics (IMGT) database; web resource, http: / / www_imgt_org). Available programs such as abYsis by UCL Business PLC can be used to delineate CDRs. As used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the methods of Kabat, Chothia, IMGT or AbM as described above, unless otherwise expressly stated in the specification.

[0021] The transitional phrases "comprising," "consisting essentially of," and "consisting" are intended to connote their generally accepted meanings in patent language, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by," is inclusive or open-ended, and does not exclude other unrecited elements or method steps, (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim, and (iii) "consisting essentially of" limits the scope of the claim to the specified materials or steps, and those that do not materially affect the "basic and novel characteristics" of the claimed disclosure. An embodiment described with respect to the phrase "comprising" (or its equivalents) also provides as an embodiment what is described independently with respect to "consisting of" and "consisting essentially of."

[0022] "Culture," "culture," "cultured," and "cell culture" refer to a population of cells suspended in a culture medium under conditions suitable for the survival and / or growth of the cell population. Cell culture includes fed-batch cell culture and perfusion cell culture.

[0023] "Drug Substance" or "DS" refers to any substance or mixture of substances that is intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes the active ingredient of that drug product. Such substances are intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.

[0024] "Drug Product" or "DP" refers to a finished dosage form, e.g., tablet, capsule, or liquid, that contains an active pharmaceutical ingredient (e.g., a drug substance), typically, but not necessarily, along with inactive ingredients.

[0025] An "expression vector" refers to a vector that can be utilized in a biological system or a reconstituted biological system to direct the translation of a polypeptide encoded by a polynucleotide sequence present in the expression vector.

[0026] "G0F" refers to asialo, agalacto core-fucosylated biantennary glycans.

[0027] "G0F oligosaccharide content" refers to the percentage of G0F oligosaccharides in glycoprotein oligosaccharides (G0F%).

[0028] "G1F" refers to an asialo, monogalacto core-fucosylated biantennary glycan.

[0029] "G1F oligosaccharide content" refers to the percentage of G1F oligosaccharides in glycoprotein oligosaccharides (G1F%).

[0030] "G2F" refers to asialo, digalacto core-fucosylated biantennary glycan.

[0031] "G2F oligosaccharide content" refers to the percentage of G2F oligosaccharides in glycoprotein oligosaccharides (G2F%).

[0032] "GMP-compliant conditions" refers to manufacturing under the Current Good Manufacturing Practice (CGMP) regulations enforced by the Food and Drug Administration (FDA). CGMP provides a system to ensure proper design, monitoring, and control of manufacturing processes and facilities. Compliance with CGMP regulations ensures the identity, strength, quality, and purity of drug products by requiring pharmaceutical manufacturers to properly control manufacturing operations. This includes establishing a strong quality control system, obtaining raw materials of appropriate quality, establishing robust operating procedures, detecting and investigating variations in product quality, and maintaining reliable testing laboratories. This formal system of control in pharmaceutical companies, when properly implemented, helps prevent instances of contamination, adulteration, variability, failure, and error. This ensures that drug products meet their quality standards.

[0033] A "humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Humanized antibodies can contain substitutions in the framework, such that the framework may not be an exact copy of an expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0034] "Human antibody" refers to an antibody that is optimized to have a minimal immune response when administered to a human subject. The variable regions of a human antibody are derived from human immunoglobulin sequences. If the human antibody contains a constant region or a portion of a constant region, the constant region is also derived from a human immunoglobulin sequence. A human antibody contains heavy and light chain variable regions that are "derived" from sequences of human origin when the variable regions of the human antibody are derived from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Exemplary such systems include phage-displayed human immunoglobulin gene libraries and transgenic non-human animals, such as mice or rats, carrying human immunoglobulin loci. "Human antibodies" typically contain amino acid differences when compared to immunoglobulins expressed in humans due to differences in the systems used to obtain human antibodies and human immunoglobulin loci, deliberate introduction of somatic mutations or substitutions into frameworks or CDRs, or both. Typically, a "human antibody" is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to the amino acid sequence encoded by a human germline immunoglobulin or rearranged immunoglobulin gene. In some cases, a "human antibody" may comprise a consensus framework sequence obtained from human framework sequence analysis as described, for example, in Knappik et al., J Mol Biol 296:57-86, 2000, or a synthetic HCDR3 incorporated into a phage-displayed human immunoglobulin gene library as described, for example, in Shi et al., J Mol Biol 397:385-96, 2010 and WO 2009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of "human antibody."

[0035] "Isolated" refers to a homogenous population of molecules (e.g., a protein such as a synthetic polynucleotide or an antibody) that have been substantially separated and / or purified from other components of the system in which the molecule is produced, such as a recombinant cell, as well as to a protein that has been subjected to at least one purification or isolation step. An "isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemicals, and includes antibodies that have been isolated to greater degrees of purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0036] "Label" and "labeling" are used interchangeably herein and refer to all labels and indications of written, printed, or graphic information that are on, in, or attached to a container or package that contains a drug, such as daratumumab, or that are otherwise available electronically or over the internet. "Label" and "labeling" include package inserts and prescribing information.

[0037] "Monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., individual antibodies that make up the population that are identical except for possible well-known alterations, such as removal of the C-terminal lysine from the antibody heavy chain, or post-translational modifications such as isomerization or deamidation of amino acids, oxidation of methionine, or deamidation of asparagine or glutamine. A monoclonal antibody typically binds to one antigenic epitope. A monoclonal antibody may have heterogeneous glycosylation within the antibody population. A monoclonal antibody may be monospecific or multispecific, such as bispecific, and may be monovalent, bivalent, or multivalent.

[0038] "Polynucleotide" refers to a synthetic molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. cDNA is an example of a polynucleotide.

[0039] "ppb" or "parts per billion" refers to the amount of a metal in a solution or solid. When measured in solution, ppb is equal to the μg / L concentration of the metal in the solution. When measured in a solid, ppb is equal to the μg / kg concentration of the metal in the solution.

[0040] "Recombinant" refers to polynucleotides, antibodies, and other proteins that are prepared, expressed, produced, or isolated by recombinant means, when segments of different origins are joined to produce recombinant DNA, antibodies, or proteins. "Recombinant antibodies" includes all antibodies that are prepared, expressed, produced, or isolated by recombinant means, such as antibodies isolated from animals (e.g., mice) that are transgenic or transchromosomal for human immunoglobulin genes or hybridomas prepared therefrom (described further below), antibodies isolated from host cells transformed to express the antibody, antibodies isolated from recombinant combinatorial antibody libraries, and antibodies prepared, expressed, produced, or isolated by any other means that involve splicing human immunoglobulin gene sequences to other DNA sequences, or antibodies generated in vitro using Fab arm exchange, such as bispecific antibodies.

[0041] "Reference product" refers to an approved biological product against which a biosimilar is compared. The reference product is approved based on, among other things, a full complement of safety and efficacy data and is approved in at least one of the United States, the European Union, or Japan.

[0042] "Refractory" refers to a disease that does not respond to treatment. A refractory disease may be resistant to treatment before or at the start of treatment, or a refractory disease may become resistant during treatment.

[0043] "Relapse" refers to the return of a disease or signs and symptoms of a disease after a period of improvement following previous treatment with a therapeutic agent.

[0044] "Specific binding" or "specifically binds" or "binds" refers to an antibody binding to an antigen or an epitope within the antigen with higher affinity than the affinity for other antigens. Typically, an antibody binds to an antigen with a binding affinity of about 1×10 -8 M or less, for example, about 1×10 -9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, or about 1 x 10 -12 The equilibrium dissociation constant (K D ) binds to an antigen or an epitope within the antigen, and this K D is typically the K for binding to non-specific antigens (e.g., BSA, casein) D Dissociation constants are at least 100-fold lower than the . Dissociation constants can be measured using standard techniques. However, antibodies that specifically bind to an antigen or an epitope within an antigen may have cross-reactivity to other related antigens, e.g., the same antigen (homologs) from other species, such as humans or monkeys, e.g., Macaca fascicularis (cynomolgus monkey, cyno), Pan troglodytes (chimp), or Callithrix jacchus (common marmoset, marmoset).

[0045] A "subject" includes any human or non-human animal. A "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, e.g., non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" can be used interchangeably herein.

[0046] "Therapeutically effective amount" refers to an amount effective to achieve a desired therapeutic result at the required dosage and duration. Therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of a therapeutic agent or combination of therapeutic agents to elicit a desired response in an individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved health of the patient.

[0047] "Treating" or "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow down (reduce) undesirable physiological changes or disorders, such as complications resulting from cancer. Beneficial or desired clinical results include alleviation of symptoms, whether detectable or undetectable, reduction in the extent of disease, a stable (i.e., not worsening) disease state, delay or slowing of disease progression, improvement or relief of the disease state, and remission (whether partial or complete). Those in need of treatment include those already with the condition or disease, as well as those prone to having the condition or disease, or those in whom the condition or disease is to be prevented.

[0048] "Vector" refers to a polynucleotide that can replicate in a biological system or can be transferred between such systems. Vector polynucleotides typically contain elements such as an origin of replication, a polyadenylation signal, or a selection marker that function to facilitate the replication or maintenance of these polynucleotides in a biological system. Examples of such biological systems include cells, viruses, animals, plants, and reconstituted biological systems that utilize biological components capable of replicating the vector. The polynucleotides that make up the vector can be DNA or RNA molecules, or hybrid molecules thereof.

[0049] Methods of the Disclosure The present disclosure provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the antibody being expressed from a polynucleotide encoding a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8, the method comprising: preparing a culture medium containing about 8.5 parts per billion (ppb) or less of manganese (Mn); and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0050] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0051] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing an Mn of about 8.5 ppb or less, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27%.

[0052] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0053] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 25%.

[0054] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%.

[0055] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 65% to about 74%.

[0056] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%.

[0057] In some embodiments, preparing the culture medium includes measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 8.5 ppb or less of Mn.

[0058] In some embodiments, the culture medium is formulated to contain about 4.0 ppb to about 8.5 ppb Mn.

[0059] In some embodiments, the culture medium is formulated to contain about 4.0 ppb to about 6.5 ppb Mn.

[0060] In some embodiments, the culture medium is formulated to contain about 5.0 ppb to about 6.5 ppb Mn.

[0061] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 27%, the G0F oligosaccharide content of the anti-CD38 antibody is about 65% to about 74%, and the culture medium is formulated to contain about 4.0 ppb to about 8.5 ppb Mn.

[0062] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 25%, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%, and the culture medium is formulated to contain about 4.0 ppb to about 6.5 ppb Mn.

[0063] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%, and the culture medium is formulated to contain about 5.0 ppb to about 6.5 ppb Mn.

[0064] In some embodiments, an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO:7 and a VL of SEQ ID NO:8 comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:8.

[0065] In some embodiments, the culture medium is a basal medium or a feed medium.

[0066] In some embodiments, the culturing comprises fed-batch or perfusion culturing.

[0067] In some embodiments, the host cell is a eukaryotic cell.

[0068] In some embodiments, the eukaryotic cell is a CHO cell, a PER.C6 cell, an NS0 cell, an Sp2 / 0 cell, or a BHK cell.

[0069] In some embodiments, the CHO cell is a CHO-K1 cell, a CHO-DG44 cell, a CHO-S cell, or a CHO-DXB11 cell.

[0070] In some embodiments, the CHO cells are deficient in glutamine synthetase (GS).

[0071] In some embodiments, the method is carried out under GMP-compliant conditions.

[0072] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:9.

[0073] In some embodiments, the anti-CD38 antibody comprises an IgG1 isotype.

[0074] In some embodiments, the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO:9 and a light chain (LC) of SEQ ID NO:10.

[0075] In some embodiments, the anti-CD38 antibody is a biosimilar.

[0076] In some embodiments, the anti-CD38 antibody is a biosimilar or DARZALEX® (daratumumab).

[0077] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0078] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0079] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0080] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0081] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25%.

[0082] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0083] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 25%.

[0084] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0085] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, said method having a G1F oligosaccharide content of about 21% to about 25%, comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25%.

[0086] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0087] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 21% to about 25%.

[0088] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0089] The present disclosure relates to a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the anti-CD38 antibody being an IgG1 isotype; preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0090] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the anti-CD38 antibody being of the IgG1 isotype, preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0091] The present disclosure relates to a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the anti-CD38 antibody being of the IgG1 isotype; preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing an Mn of about 8.5 ppb or less, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27%.

[0092] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the VH having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, wherein the anti-CD38 antibody is an IgG1 isotype, preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0093] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the anti-CD38 antibody being an IgG1 isotype; Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0094] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the anti-CD38 antibody being of the IgG1 isotype, Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0095] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method having a G1F oligosaccharide content of about 15% to about 27%, wherein the anti-CD38 antibody is an IgG1 isotype; Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0096] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the VH having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, wherein the anti-CD38 antibody is an IgG1 isotype, Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0097] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the anti-CD38 antibody being an IgG1 isotype; Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25%.

[0098] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the anti-CD38 antibody being of the IgG1 isotype, Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0099] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody being of the IgG1 isotype; Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 25%.

[0100] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the VH having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, wherein the anti-CD38 antibody is an IgG1 isotype, Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0101] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the anti-CD38 antibody being an IgG1 isotype; Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25%.

[0102] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the anti-CD38 antibody being of the IgG1 isotype; Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0103] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method having a G1F oligosaccharide content of about 21% to about 25%, wherein the anti-CD38 antibody is an IgG1 isotype; Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 21% to about 25%.

[0104] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the VH having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, wherein the anti-CD38 antibody is an IgG1 isotype; Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0105] The present disclosure provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10, the antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27%.

[0106] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0107] The present disclosure provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 and having a G1F oligosaccharide content of about 15% to about 27%.

[0108] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0109] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27%.

[0110] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 polynucleotides in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0111] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 and having a G1F oligosaccharide content of about 15% to about 27%.

[0112] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell comprising the HC polynucleotide of SEQ ID NO: 9 and the LC polynucleotide of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0113] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, said antibody having a G1F oligosaccharide content of about 15% to about 25%, comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 25%.

[0114] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0115] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 and having a G1F oligosaccharide content of about 15% to about 25%.

[0116] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%, is provided.

[0117] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, said antibody having a G1F oligosaccharide content of about 21% to about 25%, comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 21% to about 25%.

[0118] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0119] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising the steps of: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 and having a G1F oligosaccharide content of about 21% to about 25%.

[0120] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a host cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0121] The present disclosure provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the antibody being expressed from a polynucleotide encoding a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8, the method comprising: preparing a culture medium containing about 8.5 parts per billion (ppb) or less of manganese (Mn); and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing Chinese hamster ovary (CHO) cells containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0122] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0123] The present disclosure provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 and having a G1F oligosaccharide content of about 15% to about 27%.

[0124] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing CHO cells containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0125] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0126] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0127] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 and having a G1F oligosaccharide content of about 15% to about 27%.

[0128] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0129] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25%.

[0130] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0131] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 and having a G1F oligosaccharide content of about 15% to about 25%.

[0132] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%, respectively.

[0133] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, said method having a G1F oligosaccharide content of about 21% to about 25%, comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25%.

[0134] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0135] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 and having a G1F oligosaccharide content of about 21% to about 25%.

[0136] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0137] The present disclosure relates to a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the anti-CD38 antibody being an IgG1 isotype; preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0138] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the anti-CD38 antibody being of the IgG1 isotype, preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0139] The present disclosure relates to a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the anti-CD38 antibody being of the IgG1 isotype; preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 and having a G1F oligosaccharide content of about 15% to about 27%.

[0140] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the VH having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, wherein the anti-CD38 antibody is an IgG1 isotype, preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing CHO cells containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody comprising the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0141] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the anti-CD38 antibody being an IgG1 isotype; Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%.

[0142] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the anti-CD38 antibody being of the IgG1 isotype, Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0143] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method having a G1F oligosaccharide content of about 15% to about 27%, wherein the anti-CD38 antibody is an IgG1 isotype; Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 and having a G1F oligosaccharide content of about 15% to about 27%.

[0144] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the VH having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, wherein the anti-CD38 antibody is an IgG1 isotype, Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0145] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the anti-CD38 antibody being an IgG1 isotype; Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25%.

[0146] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the anti-CD38 antibody being of the IgG1 isotype, Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0147] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody being of the IgG1 isotype; Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 and having a G1F oligosaccharide content of about 15% to about 25%.

[0148] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the VH having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, wherein the anti-CD38 antibody is an IgG1 isotype, Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%, respectively.

[0149] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the anti-CD38 antibody being an IgG1 isotype; Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25%.

[0150] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the anti-CD38 antibody being of the IgG1 isotype; Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0151] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method having a G1F oligosaccharide content of about 21% to about 25%, wherein the anti-CD38 antibody is an IgG1 isotype; Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 and having a G1F oligosaccharide content of about 21% to about 25%.

[0152] The present disclosure also provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the VH having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, wherein the anti-CD38 antibody is an IgG1 isotype; Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0153] The present disclosure provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10, the antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27%.

[0154] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0155] The present disclosure provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 and having a G1F oligosaccharide content of about 15% to about 27%.

[0156] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: preparing a culture medium containing about 8.5 ppb or less of Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0157] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27%.

[0158] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing CHO cells containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 polynucleotides in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0159] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 and having a G1F oligosaccharide content of about 15% to about 27%.

[0160] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing CHO cells containing the HC polynucleotide of SEQ ID NO: 9 and the LC polynucleotide of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, respectively.

[0161] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, said antibody having a G1F oligosaccharide content of about 15% to about 25%, comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 25%.

[0162] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0163] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 and having a G1F oligosaccharide content of about 15% to about 25%.

[0164] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 66% to about 74%, is provided.

[0165] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, said antibody having a G1F oligosaccharide content of about 21% to about 25%, comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 21% to about 25%.

[0166] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%.

[0167] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising the steps of: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 and having a G1F oligosaccharide content of about 21% to about 25%.

[0168] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; and controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody containing the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 66% to about 74%, is provided.

[0169] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the concentration of Mn in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0170] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 25%.

[0171] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%.

[0172] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 65% to about 74%.

[0173] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%.

[0174] In some embodiments, the concentration of Mn in the culture medium is adjusted to contain about 4.0 ppb to about 8.5 ppb Mn.

[0175] In some embodiments, the concentration of Mn in the culture medium is adjusted to contain about 4.0 ppb to about 6.5 ppb Mn.

[0176] In some embodiments, the concentration of Mn in the culture medium is adjusted to contain about 5.0 ppb to about 6.5 ppb Mn.

[0177] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 27%, the G0F oligosaccharide content of the anti-CD38 antibody is about 65% to about 74%, and the culture medium is adjusted to contain about 4.0 ppb to about 8.5 ppb Mn.

[0178] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 25%, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%, and the culture medium is adjusted to contain about 4.0 ppb to about 6.5 ppb Mn.

[0179] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%, and the culture medium is adjusted to contain about 5.0 ppb to about 6.5 ppb Mn.

[0180] In some embodiments, the culture medium is a basal medium or a feed medium.

[0181] In some embodiments, the culturing comprises fed-batch or perfusion culturing.

[0182] In some embodiments, the host cell is a eukaryotic cell.

[0183] In some embodiments, the eukaryotic cell is a CHO cell, a PER.C6 cell, an NS0 cell, an Sp2 / 0 cell, or a BHK cell.

[0184] In some embodiments, the CHO cell is a CHO-K1 cell, a CHO-DG44 cell, a CHO-S cell, or a CHO-DXB11 cell.

[0185] In some embodiments, the CHO cells are deficient in GS.

[0186] In some embodiments, the method is carried out under GMP-compliant conditions.

[0187] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:9.

[0188] In some embodiments, the anti-CD38 antibody comprises an IgG1 isotype.

[0189] In some embodiments, the anti-CD38 antibody comprises a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10.

[0190] In some embodiments, the anti-CD38 antibody is a biosimilar.

[0191] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which an anti-CD38 antibody is produced; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the concentration of Mn in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 7 and the LC of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27%.

[0192] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0193] The present disclosure provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which an anti-CD38 antibody is produced; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjust the concentration of Mn in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising a HC of SEQ ID NO: 7 and a LC of SEQ ID NO: 8.

[0194] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0195] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 7 and the LC of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27%.

[0196] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0197] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody, thereby adjusting the concentration of Mn in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising a HC of SEQ ID NO: 7 and a LC of SEQ ID NO: 8.

[0198] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0199] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 7 and the LC of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 25%.

[0200] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0201] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, comprising a HC of SEQ ID NO: 7 and a LC of SEQ ID NO: 8.

[0202] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0203] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, said method having a G1F oligosaccharide content of about 21% to about 25%, comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 5.0 to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 7 and the LC of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 21% to about 25%.

[0204] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0205] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions such that an anti-CD38 antibody is produced; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjust the concentration of Mn in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, comprising a HC of SEQ ID NO: 7 and a LC of SEQ ID NO: 8.

[0206] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0207] The present disclosure provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the concentration of Mn in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 27%.

[0208] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0209] The present disclosure provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10.

[0210] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the anti-CD38 antibody comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10.

[0211] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 27%.

[0212] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0213] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, which comprises a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10.

[0214] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the anti-CD38 antibody comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10.

[0215] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, said antibody having a G1F oligosaccharide content of about 15% to about 25%, comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 25%.

[0216] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0217] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, comprising a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10.

[0218] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the anti-CD38 antibody comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10.

[0219] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, said antibody having a G1F oligosaccharide content of about 21% to about 25%, comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 5.0 to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 21% to about 25%.

[0220] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0221] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, which comprises a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10.

[0222] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Culturing a host cell expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions in which an anti-CD38 antibody is produced; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the anti-CD38 antibody comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10.

[0223] The present disclosure provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the concentration of Mn in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 7 and the LC of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27%.

[0224] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0225] The present disclosure provides a method for producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjust the concentration of Mn in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising a HC of SEQ ID NO: 7 and a LC of SEQ ID NO: 8.

[0226] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0227] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 7 and the LC of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27%.

[0228] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0229] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody, thereby adjusting the concentration of Mn in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising a HC of SEQ ID NO: 7 and a LC of SEQ ID NO: 8.

[0230] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0231] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 7 and the LC of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 25%.

[0232] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0233] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, comprising a HC of SEQ ID NO: 7 and a LC of SEQ ID NO: 8.

[0234] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0235] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, said method having a G1F oligosaccharide content of about 21% to about 25%, comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 5.0 to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 7 and the LC of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 21% to about 25%.

[0236] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0237] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjust the concentration of Mn in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, comprising a HC of SEQ ID NO: 7 and a LC of SEQ ID NO: 8.

[0238] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, and having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0239] The present disclosure provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the concentration of Mn in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the concentration of Mn in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 27%.

[0240] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0241] The present disclosure provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10.

[0242] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the anti-CD38 antibody comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10.

[0243] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 27%.

[0244] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%.

[0245] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, which comprises a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10.

[0246] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the anti-CD38 antibody comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10.

[0247] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, said antibody having a G1F oligosaccharide content of about 15% to about 25%, comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 15% to about 25%.

[0248] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0249] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, comprising a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10.

[0250] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the anti-CD38 antibody comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10.

[0251] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, said antibody having a G1F oligosaccharide content of about 21% to about 25%, comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 5.0 to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, and having a G1F oligosaccharide content of about 21% to about 25%.

[0252] The present disclosure also provides a method for producing an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%.

[0253] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content of the anti-CD38 antibody and adjusting the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, which comprises a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10.

[0254] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising the steps of: Culturing CHO cells expressing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 under conditions to produce anti-CD38 antibodies; monitoring the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody, and adjusting the Mn concentration in the culture medium during biosynthesis of the anti-CD38 antibody to control the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody and adjust the Mn concentration in the culture medium to contain about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the anti-CD38 antibody comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10.

[0255] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising culturing a host cell comprising a polynucleotide encoding the anti-CD38 antibody in a culture medium determined to contain about 8.5 ppb Mn or less, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0256] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising culturing a host cell containing a polynucleotide encoding the anti-CD38 antibody in a culture medium controlled to contain about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0257] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising culturing a host cell containing a polynucleotide encoding the anti-CD38 antibody in a culture medium containing about 8.5 ppb or less of Mn, monitoring the concentration of Mn in the culture medium during antibody biosynthesis, and controlling the G1F oligosaccharide content by adjusting the concentration of Mn in the culture medium during antibody biosynthesis, thereby producing the antibody.

[0258] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to 27%, the method comprising culturing a host cell transfected with a polynucleotide encoding the anti-CD38 antibody in a culture medium containing about 8.0 ppb or less Mn, thereby producing the antibody.

[0259] The present disclosure also provides a method for producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising preparing a culture medium containing about 8.5 ppb or less Mn and culturing a host cell containing a polynucleotide encoding the anti-CD38 antibody in the culture medium containing about 8.5 ppb or less Mn, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0260] The present disclosure also provides a method for producing an antibody having a G1F oligosaccharide content of about 15% to about 27%, comprising preparing a culture medium containing about 8.0 ppb or less of Mn, and culturing a host cell transfected with a polynucleotide encoding the antibody in the culture medium containing about 8.0 ppb or less of Mn, thereby producing the antibody.

[0261] The present disclosure provides a method for controlling the G1F oligosaccharide content of an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% during the process of biosynthesizing the antibody in a culture medium, the method comprising monitoring the level of Mn in the culture medium during biosynthesis of the antibody and adjusting the level of Mn in the culture medium during biosynthesis of the antibody or antigen-binding fragment thereof.

[0262] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 26%.

[0263] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 25%.

[0264] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 16% to about 26%.

[0265] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 17% to about 26%.

[0266] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 18% to about 26%.

[0267] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 19% to about 26%.

[0268] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 20% to about 26%.

[0269] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%.

[0270] In some embodiments, the GOF content of the antibody is about 68% to about 74%.

[0271] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 65% to about 74%.

[0272] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 66% to about 74%.

[0273] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 67% to about 74%.

[0274] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%.

[0275] In some embodiments, preparing the culture medium includes measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 8.5 ppb or less of Mn to prepare the culture medium.

[0276] In some embodiments, preparing the culture medium includes measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 8.0 ppb or less of Mn to prepare the culture medium.

[0277] In some embodiments, preparing the culture medium includes measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 6.5 ppb or less of Mn to prepare the culture medium.

[0278] In some embodiments, preparing the culture medium includes measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that, in combination, contain about 4.0 ppb to about 8.5 ppb Mn to prepare the culture medium.

[0279] In some embodiments, preparing the culture medium includes measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 4.0 ppb to about 6.5 ppb Mn to prepare the culture medium.

[0280] In some embodiments, the culture medium is formulated to contain about 8.0 ppb, about 7.5 ppb or less, about 7.0 ppb or less, about 6.5 ppb or less, about 6.0 ppb or less, about 5.5 ppb or less, or about 5.5 ppb or less Mn.

[0281] In some embodiments, the culture medium is formulated to contain no more than about 8.5 ppb Mn.

[0282] In some embodiments, the culture medium is formulated to contain about 8.0 ppb or less of Mn.

[0283] In some embodiments, the culture medium is formulated to contain about 7.5 ppb or less of Mn.

[0284] In some embodiments, the culture medium is formulated to contain about 7.0 ppb or less of Mn.

[0285] In some embodiments, the culture medium is formulated to contain no more than about 6.5 ppb Mn.

[0286] In some embodiments, the culture medium is formulated to contain about 6.0 ppb or less of Mn.

[0287] In some embodiments, the culture medium is formulated to contain about 5.5 ppb or less of Mn.

[0288] In some embodiments, the culture medium is formulated to contain about 5.0 ppb or less of Mn.

[0289] In some embodiments, the culture medium is formulated to contain about 2 ppb to about 8.0 ppb Mn.

[0290] In some embodiments, the culture medium is formulated to contain about 2 ppb to about 8.5 ppb Mn.

[0291] In some embodiments, the culture medium is formulated to contain about 2 ppb to about 6.5 ppb Mn.

[0292] In some embodiments, the culture medium is formulated to contain about 5.0 ppb to about 8.0 ppb Mn.

[0293] In some embodiments, the culture medium is formulated to contain about 5.0 ppb to about 7.5 ppb Mn.

[0294] In some embodiments, the culture medium is formulated to contain about 5.0 ppb to about 7.0 ppb Mn.

[0295] In some embodiments, the culture medium is formulated to contain about 5.0 ppb to about 6.5 ppb Mn.

[0296] In some embodiments, the culture medium is formulated to contain about 4.0 ppb to about 6.5 ppb Mn.

[0297] In some embodiments, the culture medium is formulated to contain about 4.0 ppb to about 8.5 ppb Mn.

[0298] In some embodiments, the culture medium comprises about 8.5 ppb, 8.0 ppb, about 7.5 ppb or less, about 7.0 ppb or less, about 6.5 ppb or less, about 6.0 ppb or less, about 5.5 ppb or less, or about 5.0 ppb or less Mn.

[0299] In some embodiments, the culture medium contains about 8.5 ppb or less of Mn.

[0300] In some embodiments, the culture medium contains about 8.0 ppb or less of Mn.

[0301] In some embodiments, the culture medium contains about 7.5 ppb or less of Mn.

[0302] In some embodiments, the culture medium contains about 7.0 ppb or less of Mn.

[0303] In some embodiments, the culture medium contains about 6.5 ppb or less of Mn.

[0304] In some embodiments, the culture medium contains about 6.0 ppb or less of Mn.

[0305] In some embodiments, the culture medium contains about 5.5 ppb or less of Mn.

[0306] In some embodiments, the culture medium contains about 5.0 ppb or less of Mn.

[0307] In some embodiments, the culture medium contains about 2 ppb to about 8.0 ppb Mn.

[0308] In some embodiments, the culture medium contains about 2 ppb to about 6.5 ppb Mn.

[0309] In some embodiments, the culture medium contains about 5.0 ppb to about 8.0 ppb Mn.

[0310] In some embodiments, the culture medium contains about 5.0 ppb to about 7.5 ppb Mn.

[0311] In some embodiments, the culture medium contains about 5.0 ppb to about 7.0 ppb Mn.

[0312] In some embodiments, the culture medium contains about 5.0 ppb to about 6.5 ppb Mn.

[0313] In some embodiments, the culture medium contains about 4.0 ppb to about 6.5 ppb Mn.

[0314] In some embodiments, the culture medium contains about 4.0 ppb to about 8.5 ppb Mn.

[0315] In some embodiments, the culture medium is controlled to contain about 8.0 ppb, about 7.5 ppb or less, about 7.0 ppb or less, about 6.5 ppb or less, about 6.0 ppb or less, about 5.5 ppb or less, or about 5.5 ppb or less Mn.

[0316] In some embodiments, the culture medium is controlled to contain about 8.5 ppb or less of Mn.

[0317] In some embodiments, the culture medium is controlled to contain about 8.0 ppb or less of Mn.

[0318] In some embodiments, the culture medium is controlled to contain about 7.5 ppb or less of Mn.

[0319] In some embodiments, the culture medium is controlled to contain about 7.0 ppb or less of Mn.

[0320] In some embodiments, the culture medium is controlled to contain about 6.5 ppb or less of Mn.

[0321] In some embodiments, the culture medium is controlled to contain about 6.0 ppb or less of Mn.

[0322] In some embodiments, the culture medium is controlled to contain about 5.5 ppb or less of Mn.

[0323] In some embodiments, the culture medium is controlled to contain about 5.0 ppb or less of Mn.

[0324] In some embodiments, the culture medium is controlled to contain about 2 ppb to about 8.0 ppb Mn.

[0325] In some embodiments, the culture medium is controlled to contain about 2 ppb to about 6.5 ppb Mn.

[0326] In some embodiments, the culture medium is controlled to contain about 5.0 ppb to about 8.0 ppb Mn.

[0327] In some embodiments, the culture medium is controlled to contain about 5.0 ppb to about 7.5 ppb Mn.

[0328] In some embodiments, the culture medium is controlled to contain about 5.0 ppb to about 7.0 ppb Mn.

[0329] In some embodiments, the culture medium is controlled to contain about 5.0 ppb to about 6.5 ppb Mn.

[0330] In some embodiments, the culture medium is controlled to contain about 4.0 ppb to about 6.5 ppb Mn.

[0331] In some embodiments, the culture medium is controlled to contain about 4.0 ppb to about 8.5 ppb Mn.

[0332] In some embodiments, the culture is a fed-batch culture. In some embodiments, the culture is a perfusion culture.

[0333] In some embodiments, the culture medium is a basal medium or a feed medium. In some embodiments, the culture medium is a basal medium. In some embodiments, the culture medium is a feed medium.

[0334] In some embodiments, the method is carried out under GMP-compliant conditions.

[0335] Any one or more culture media or combinations thereof can be used in the methods of the present disclosure. Media are generally known and include Eagle's MEM (Minimum Essential Medium), Ham's F12, F-12 K Medium, Dulbecco's Medium, Dulbecco's Modified Eagle's Medium, DMEM / Ham's F12 1:1, Trowell's T8, A2 Medium, Weymouth's Medium, Williams' Medium E, RPMI 1640, MCDB 104 / 110 Medium, Ventrex Serum-free media such as HL-1 medium, albumin-globulin medium, RPMI-1640 medium, RPMI-1641 medium, Iscove's modified Dulbecco's medium, McCoy's 5A medium, Leibovitz's L-15 medium, and EX-CELL™ 300 series, protamine-zinc-insulin medium (U.S. Pat. No. 4,072,565), biotin-folic acid medium, transferrin-fatty acid medium (U.S. Pat. No. 4,560,655), transferrin-EGF medium (U.S. Pat. No. 4,615,977, U.S. Pat. No. 4,786,599), and other media permutations. permutation) (U.S. Patent Nos. 6,048,728, 7,294,484, 5,122,469, 5,976,833, 6,180,401, 5,856,179, 5,705,364, 7,666,416, 6,528,286, 6,924,124, and 7,429,491), as well as other synthetic media. Media compositions are typically available through commercial suppliers.

[0336] "Synthetic media" refers to synthetic growth media in which the identity and concentration of all components are known. Synthetic media, i.e., chemically defined media, do not contain bacteria, yeast, animal, or plant extracts, animal serum or plasma, but may or may not contain individual plant or animal derived components (e.g., proteins, polypeptides, etc.). Chemically defined media may contain inorganic salts such as phosphates, sulfates, etc., necessary to support growth. The carbon source is defined, usually a sugar such as glucose, lactose, galactose, or other compounds such as glycerol, lactate, acetate, etc. Certain chemically defined media also use phosphate as a buffer, but may use other buffers such as citrate, triethanolamine, etc. Examples of commercially available synthetic media include ThermoFisher's CD Hybridoma Medium and CD Hybridoma AGT™ Medium, various Dulbecco's Modified Eagle (DME) media (Sigma-Aldrich Co; SAFC Bioscienses, Inc), Ham's Nutrient Mix (Sigma-Aldrich Co; SAFC Bioscienses, Inc), combinations thereof, and the like. Methods for preparing synthetic media are known in the art, for example, U.S. Pat. Nos. 6,171,825 and 6,936,441, WO 2007 / 077217, and U.S. Patent Application Publication Nos. 2008 / 0009040 and 2007 / 0212770. The exemplary culture media described herein can be used as basal or feed media. Defined media feeds designed to provide cell culture nutrients for fed-batch processes for culturing CHO cells include those available from IrivneScientific, such as BalanCD® CHO Feed powder or liquid media.

[0337] Exemplary components of the culture medium include essential and non-essential amino acids, vitamins, energy sources, lipids, and trace elements.

[0338] The disclosed methods can be used with any cell culture method suitable for the desired process (e.g., production of recombinant antibodies). Cells can be grown in batch or fed-batch cultures, where the culture is terminated after sufficient expression of the antibody and the expressed antibody is then harvested. Alternatively, cells can be grown in batch-refeed, where the culture is not terminated, but rather new nutrients and other components are added to the culture periodically or continuously, while the expressed antibody is harvested periodically or continuously. Other suitable methods (e.g., spin tube culture) are known in the art and can be used.

[0339] In some embodiments, the culture is a fed-batch culture. In some embodiments, the culture is a batch re-fed-batch culture. "Fed-batch culture" refers to a method of culturing cells in which additional components are provided to the culture, either at once or in several instalments, after the start of the culture process. Such provided components typically include nutritional components of the cells that are depleted during the culture process. Fed-batch cultures are typically stopped at some point, and the cells and / or components in the medium are harvested and optionally purified. In some embodiments, fed-batch cultures include a basal medium supplemented with a fed-batch medium. The cells can be grown in any convenient volume. For example, the cells may be grown in small-scale reaction vessels ranging in volume from a few milliliters to a few liters. Alternatively, the cells may be grown in large scale commercial bioreactors ranging in volume from about at least 1 liter to 10, 50, 100, 250, 500, 1000, 2500, 5000, 8000, 10,000, 12,000, 15000, 20000, or 25000 liters, or more, or any volume range therebetween.

[0340] A culture medium containing about 8.5 ppb or less of manganese can be prepared by analyzing the manganese concentration in various batches of each raw material component of the culture medium and selecting batches of raw material components for making a culture medium having a manganese concentration of about 8.5 ppb or less or that when combined together results in a total manganese concentration in the selected components of about 8.5 ppb or less. A culture medium containing about 8.0 ppb or less of manganese can be prepared by analyzing the manganese concentration in various batches of each raw material component of the culture medium and selecting batches of raw material components for making a culture medium having a manganese concentration of about 8.0 ppb or less or that when combined together results in a total manganese concentration in the selected components of about 8.0 ppb or less. A culture medium containing about 6.5 ppb or less of manganese can be prepared by analyzing the manganese concentration in various batches of each raw material component of the culture medium and selecting batches of raw material components for making a culture medium having a manganese concentration of about 6.5 ppb or less or that when combined together results in a total manganese concentration in the selected components of about 6.5 ppb or less. Manganese concentrations can be measured in the feed ingredients or culture medium using the methods described herein.

[0341] In some embodiments, the host cell is a eukaryotic cell. Exemplary eukaryotic cells may be of mammalian, insect, avian, or other animal origin. Mammalian eukaryotic cells include immortalized cell lines, such as hybridomas, or myeloma cell lines, such as SP2 / 0 (American Type Culture Collection (ATCC), Manassas, VA, CRL-1581), NS0 (European Collection of Cell Cultures (ECACC), Salisbury, Wiltshire, UK, ECACC No. 85110503), FO (ATCC CRL-1646), and Ag653 (ATCC CRL-1580) mouse cell lines. An exemplary human myeloma cell line is U266 (ATTC CRL-TIB-196). Other useful cell lines include those derived from Chinese hamster ovary (CHO) cells, such as HD-BIOP3 GS Null CHO K1 (Horizon Discovery Limited, Cambridge, UK, CHO-K1SV (Lonza Biologics, Walkersville, MD), CHO-K1 (ATCC CRL-61), DG44, CHO-S, or CHO-DXB11.

[0342] In some embodiments, the host cell is a CHO cell, a PER.C6 cell, an NS0 cell, an Sp2 / 0 cell, or a BHK cell.

[0343] In some embodiments, the CHO cell is a CHO-K1 cell, a CHO-DG44 cell, a CHO-S cell, or a CHO-DXB11 cell.

[0344] In some embodiments, the CHO cells are deficient in glutamine synthetase (GS). Methods for using GS as a selectable marker in mammalian cells are known.

[0345] In some embodiments, the methods of the present disclosure are carried out under GMP-compliant conditions.

[0346] In some embodiments, the anti-CD38 antibody comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

[0347] In some embodiments, the anti-CD38 antibody is expressed from a polynucleotide encoding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

[0348] In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (VH) of SEQ ID NO:7 and a light chain variable region (VL) of SEQ ID NO:8.

[0349] In some embodiments, the anti-CD38 antibody is expressed from a polynucleotide encoding the VH of SEQ ID NO:7 and the VL of SEQ ID NO:8.

[0350] In some embodiments, the anti-CD38 antibody is an IgG1 isotype. In some embodiments, the anti-CD38 antibody is an IgG2 isotype. In some embodiments, the anti-CD38 antibody is an IgG4 isotype.

[0351] In some embodiments, the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO:9 and a light chain (LC) of SEQ ID NO:10.

[0352] In some embodiments, the anti-CD38 antibody is expressed from a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10.

[0353] In some embodiments, the anti-CD38 antibody is DARZALEX® (daratumumab).

[0354] In some embodiments, the anti-CD38 antibody is a biosimilar to DARZALEX® (daratumumab).

[0355] In some embodiments, the anti-CD38 antibody is MOR-202 (MOR-03087) comprising the VH and VL of SEQ ID NOs: 11 and 12, respectively, as described in U.S. Patent No. 8,088,896. The VH and VL of MOR-202 may be expressed as IgG1 / κ.

[0356] In some embodiments, the anti-CD38 antibody is isatuximab, comprising the VH and VL of SEQ ID NOs: 13 and 14, respectively, as described in U.S. Patent No. 8,153,765. The VH and VL of isatuximab can be expressed as IgG1 / κ.

[0357] SEQ ID NO:1 SFAMS SEQ ID NO:2 AISGSGGGTYYADSVKG SEQ ID NO:3 DKILWFGEPVFDY SEQ ID NO:4 RASQSVSSYLA SEQ ID NO:5 DASNRAT SEQ ID NO:6 QQRSNWPPTF SEQ ID NO:7 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDK ILWFGEPVFDYWGQGTLVTVSS SEQ ID NO:8 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQ GTKVEIK SEQ ID NO:9 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:10 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:11 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS SEQ ID NO:12 DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ SEQ ID NO:13 QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGT IYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGD YYGSNSLDYWGQGTSVTVSS SEQ ID NO:14 DIVMTQSHLSMSSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYS ASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGG GTKLEIK

[0358] Method for measuring the oligosaccharide composition of an antibody The oligosaccharide composition of the antibodies can be determined using HPLC methods using an Agilent 1100 / 1200 Series HPLC System with Chemstation / Chemstore software. To quantify the relative amount of glycans, N-linked oligosaccharides are first cleaved from the reduced and denatured test material using N-glycanase (PNGase F). The released glycans are labeled with anthranilic acid, purified by filtration using a 0.45 μm nylon filter, and analyzed by HPLC with fluorescence detection. The HPLC chromatogram serves as a map that can be used to identify and quantify the relative amounts of N-linked oligosaccharides present in the sample. Glycans are identified by co-elution with oligosaccharide standards and retention time.

[0359] The amount of each glycan is quantified by peak area integration and expressed as a percentage of the total glycan peak area (Peak Area %). Results can be reported for G0F, G1F, G2F, total neutral glycans, and total charged glycans. Other neutral glycans can also be analyzed and are the sum of all integrated peaks eluting in the system between 17-35 min, excluding peaks corresponding to G0F, G1F, and G2F. Total neutral glycans are the sum of G0F, G1F, G2F, and other neutralized glycans. Total charged glycans are the sum of all monosialyl oxidized glycan peaks eluting in the system between 42-55 min and all disialyl oxidized glycan peaks eluting in the system between 78-90 min.

[0360] A mixture of oligosaccharide standards (G0F, G2F, G2F + N-acetylneuraminic acid (NANA), and G2F + 2NANA) is analyzed in parallel as a positive control for the labeling reaction, as a standard for peak identification, and as a measure of system suitability. Reconstituted oligosaccharides from Prozyme, G0F (Cat. No. GKC-004301), G2F (Cat. No. GKC-024301), SA1F (Cat. No. GKC-124301), and SA2F (Cat. No. GKC-224301), or equivalent, are used as reference standards. A method blank negative control and a pre-labeled G0F standard are also run for system suitability purposes.

[0361] Method for measuring manganese concentration in culture medium and dry powder Manganese concentrations in materials and solutions can be measured using known methods and those described herein. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) can be used to quantify trace metal concentrations in test samples in parts per billion (ppb, μg / liter). An acid digestion procedure can be used to digest carbon-rich sources to carbon dioxide and water before injecting the sample into an ICP-MS instrument such as the NexION® 350X ICP-MS (PerkinElmer). Wet chemical digestion can utilize a variety of acids and oxidizing agents such as nitric acid (HNO3), hydrogen peroxide (H2O2), and hydrochloric acid (HCl).

[0362] Methods for generating antibodies Methods for producing antibodies on a large scale are known. Antibodies can be produced, for example, in cultured CHO cells using known methods. Antibodies can be isolated and / or purified from the culture medium by removing solids by centrifugation or filtration as a first step in the purification process. Antibodies can be further purified by standard methods including chromatography (e.g., ion exchange, affinity, size exclusion, and hydroxyapatite chromatography), gel filtration, centrifugation, or differential solubility, ethanol precipitation, or any other available technique for the purification of antibodies. To reduce or eliminate antibody degradation during the purification process, protease inhibitors such as phenylmethylsulfonyl fluoride (PMSF), leupeptin, pepstatin, or aprotinin may be added at any or all stages. Those skilled in the art will understand that the exact purification technique will vary depending on the characteristics of the polypeptide or protein to be purified, the characteristics of the cells in which the polypeptide or protein is expressed, and the composition of the medium in which the cells are grown.

[0363] How pharmaceuticals are manufactured The methods disclosed herein also include methods for producing a medicament. For example, the present disclosure provides a method for producing a medicament, comprising carrying out the steps of the method for producing an antibody disclosed herein above.

[0364] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell comprising a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in the culture medium prepared in step a), thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0365] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 25%.

[0366] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%.

[0367] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 65% to about 74%.

[0368] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%.

[0369] In some embodiments, preparing the culture medium includes measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 8.5 ppb or less of Mn.

[0370] In some embodiments, the culture medium is formulated to contain about 4.0 ppb to about 8.5 ppb Mn.

[0371] In some embodiments, the culture medium is formulated to contain about 4.0 ppb to about 6.5 ppb Mn.

[0372] In some embodiments, the culture medium is formulated to contain about 5.0 ppb to about 6.5 ppb Mn.

[0373] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 27%, the G0F oligosaccharide content of the anti-CD38 antibody is about 65% to about 74%, and the culture medium is formulated to contain about 4.0 ppb to about 8.5 ppb Mn.

[0374] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 15% to about 25%, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%, and the culture medium is formulated to contain about 4.0 ppb to about 6.5 ppb Mn.

[0375] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%, and the culture medium is formulated to contain about 5.0 ppb to about 6.5 ppb Mn.

[0376] In some embodiments, the culture medium is a basal medium or a feed medium.

[0377] In some embodiments, the culturing comprises fed-batch or perfusion culturing.

[0378] In some embodiments, the host cell is a eukaryotic cell.

[0379] In some embodiments, the eukaryotic cell is a CHO cell, a PER.C6 cell, an NS0 cell, an Sp2 / 0 cell, or a BHK cell.

[0380] In some embodiments, the CHO cell is a CHO-K1 cell, a CHO-DG44 cell, a CHO-S cell, or a CHO-DXB11 cell.

[0381] In some embodiments, the CHO cells are deficient in glutamine synthetase (GS).

[0382] In some embodiments, the method is carried out under GMP-compliant conditions.

[0383] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:9.

[0384] In some embodiments, the anti-CD38 antibody comprises an IgG1 isotype.

[0385] In some embodiments, the anti-CD38 antibody comprises a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10.

[0386] In some embodiments, the anti-CD38 antibody is a biosimilar.

[0387] In some embodiments, formulating the pharmaceutical product comprises formulating about 120 mg / mL of anti-CD38 antibody in about 2,000 U / mL recombinant human hyaluronidase (rHuPH20), about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol, about 0.01% w / v to about 0.04% w / v PS-20, and about 1 mg / mL to about 2 mg / mL methionine at a pH of about 5.6.

[0388] In some embodiments, formulating the medicament comprises formulating an anti-CD38 antibody at 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0389] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell comprising a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0390] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: preparing a culture medium containing about 8.5 ppb or less of Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 8.5 ppb or less of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0391] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 15% to about 27%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0392] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0393] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 15% to about 25%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0394] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0395] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 21% to about 25%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0396] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0397] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby controlling the G1F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0398] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0399] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 25%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0400] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0401] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, which has a G1F oligosaccharide content of about 21% to about 25%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0402] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating the anti-CD38 antibody as a pharmaceutical.

[0403] In some embodiments, formulating the anti-CD38 antibody as a pharmaceutical comprises formulating about 20 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0404] In some embodiments, the step of formulating the anti-CD38 antibody as a pharmaceutical comprises formulating from about 20 mg / mL to about 180 mg / mL of the anti-CD38 antibody with recombinant human hyaluronidase (rHuPH20) in an amount of from about 30,000 U to about 45,000 U.

[0405] In some embodiments, formulating the anti-CD38 antibody as a pharmaceutical comprises formulating about 120 mg / mL of the anti-CD38 antibody with about 30,000 U of rHuPH20.

[0406] In some embodiments, the step of formulating the anti-CD38 antibody as a pharmaceutical comprises formulating about 120 mg / mL of the anti-CD38 antibody with about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL at a pH of about 5.6.

[0407] In some embodiments, the step of formulating the anti-CD38 antibody as a pharmaceutical comprises formulating about 120 mg / mL of the anti-CD38 antibody with about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL at a pH of about 5.5.

[0408] In some embodiments, the step of formulating the anti-CD38 antibody as a pharmaceutical comprises formulating the anti-CD38 antibody at about 20 mg / mL to about 180 mg / mL using recombinant human hyaluronidase (rHuPH20) in an amount of about 30,000 U to about 45,000 U, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, PS-20 at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL at a pH of about 5.6.

[0409] In some embodiments, the step of formulating the anti-CD38 antibody as a pharmaceutical comprises formulating the anti-CD38 antibody at about 20 mg / mL to about 180 mg / mL using recombinant human hyaluronidase (rHuPH20) in an amount of about 30,000 U to about 45,000 U, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, PS-20 at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL at a pH of about 5.5.

[0410] In some embodiments, formulating the anti-CD38 antibody as a pharmaceutical comprises formulating about 120 mg / mL of the anti-CD38 antibody with about 2,000 U / mL of rHuPH20, 10 mM histidine, about 300 mM sorbitol, about 1 mg / mL of methionine, about 0.04% polysorbate 20, and about 2000 U / mL rHuPH20 at pH 5.6.

[0411] In some embodiments, formulating the anti-CD38 antibody as a pharmaceutical comprises formulating about 120 mg / mL of the anti-CD38 antibody with about 2,000 U / mL of rHuPH20, 10 mM histidine, about 300 mM sorbitol, about 1 mg / mL of methionine, about 0.04% polysorbate 20, and about 2000 U / mL of rHuPH20 at pH 5.5.

[0412] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 15% to about 27%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0413] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0414] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 15% to about 25%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0415] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0416] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 21% to about 25%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0417] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0418] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby controlling the G1F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0419] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0420] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 25%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0421] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0422] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, which has a G1F oligosaccharide content of about 21% to about 25%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0423] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating an anti-CD38 antibody at about 20 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0424] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 15% to about 27%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0425] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0426] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 15% to about 25%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0427] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0428] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, which has a G1F oligosaccharide content of about 21% to about 25%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0429] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0430] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby controlling the G1F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0431] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 8.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 8.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27% and a G0F oligosaccharide content of about 65% to about 74%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0432] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 25%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0433] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 4.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 4.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0434] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a CHO cell containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, which has a G1F oligosaccharide content of about 21% to about 25%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0435] The present disclosure also provides a method for producing a pharmaceutical comprising an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, the anti-CD38 antibody having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%, the method comprising: Preparing a culture medium containing about 5.0 ppb to about 6.5 ppb Mn; Culturing CHO cells containing a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 5.0 ppb to about 6.5 ppb of Mn, thereby controlling the G1F oligosaccharide content and the G0F oligosaccharide content of the anti-CD38 antibody, thereby producing an anti-CD38 antibody expressed from the polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 21% to about 25% and a G0F oligosaccharide content of about 68% to about 74%; and formulating about 120 mg / mL of an anti-CD38 antibody using about 2,000 U / mL of rHuPH20, histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.6.

[0436] Material composition The disclosure also provides a drug substance comprising an anti-CD38 antibody comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising culturing a host cell comprising a polynucleotide encoding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, in a culture medium determined to contain no more than about 8.5 ppb Mn, thereby producing a drug substance comprising an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0437] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, having a G1F oligosaccharide content of about 15%-27%, wherein the drug substance is manufactured using a process comprising culturing CHO cells transfected with polynucleotides encoding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, in a culture medium containing about 8.0 ppb or less Mn, thereby producing the drug substance.

[0438] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, having a G1F oligosaccharide content of about 15% to about 27%, the drug substance being manufactured using a process comprising: preparing a culture medium comprising an Mn of about 8.5 ppb or less; and culturing a host cell comprising a polynucleotide encoding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, in a culture medium comprising an Mn of about 8.5 ppb or less, thereby producing a drug substance comprising an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0439] The disclosure also provides a drug substance comprising an anti-CD38 antibody comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, having a G1F oligosaccharide content of about 15%-27%, wherein the drug substance is manufactured using a process comprising preparing a culture medium comprising an Mn of about 8.0 ppb or less; and culturing a host cell comprising a polynucleotide encoding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, in the culture medium comprising an Mn of about 8.0 ppb or less, thereby producing the drug substance.

[0440] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:8, and the host cell comprises a polynucleotide encoding the VH of SEQ ID NO:7 and the VL of SEQ ID NO:8.

[0441] In some embodiments, the anti-CD38 antibody comprises a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10, and the host cell comprises a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10.

[0442] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 16% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 17% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 18% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 19% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 20% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%.

[0443] In some embodiments, the G0F content of the anti-CD38 antibody is about 65% to about 74%.

[0444] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 66% to about 74%. In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 67% to about 74%. In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%.

[0445] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%, the drug substance being manufactured using a process comprising culturing a host cell transfected with a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium determined to contain no more than about 8.5 ppb Mn, thereby producing a drug substance comprising an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0446] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising preparing a culture medium comprising an Mn of about 8.0 ppb or less, and culturing a host cell comprising a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium comprising an Mn of about 8.5 ppb or less, thereby producing the drug substance.

[0447] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, having a G1F oligosaccharide content of about 15% to about 27%, the drug substance being manufactured using a process comprising: preparing a culture medium comprising an Mn of about 8.5 ppb or less; and culturing a host cell transfected with a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in a culture medium comprising an Mn of about 8.5 ppb or less, thereby producing a drug substance comprising an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0448] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, each having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising preparing a culture medium comprising an Mn of about 8.0 ppb or less; and culturing a host cell comprising a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in the culture medium comprising an Mn of about 8.0 ppb or less, thereby producing the drug substance.

[0449] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a HC of SEQ ID NO: 9 and a LC of SEQ ID NO: 10, having a G1F oligosaccharide content of about 15% to about 27%, the drug substance being manufactured using a process comprising culturing a host cell transfected with a polynucleotide encoding the HC of SEQ ID NO: 9 and the LC of SEQ ID NO: 10, in a culture medium determined to contain no more than about 8.5 ppb Mn, thereby producing a drug substance comprising an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0450] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising culturing a CHO cell transfected with a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 8.0 ppb or less Mn, thereby producing the drug substance.

[0451] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27%, the drug substance being manufactured using a process comprising: preparing a culture medium comprising an Mn of about 8.5 ppb or less; and culturing a host cell transfected with a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium comprising an Mn of about 8.5 ppb or less, thereby producing a drug substance comprising an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0452] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising preparing a culture medium comprising an Mn of about 8.0 ppb or less, and culturing a host cell comprising a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium comprising an Mn of about 6.5 ppb or less, thereby producing the drug substance.

[0453] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, having a G1F oligosaccharide content of about 15%-27%, wherein the drug substance is manufactured using a process comprising culturing CHO cells transfected with polynucleotides encoding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, in a culture medium containing about 6.5 ppb or less Mn, thereby producing the drug substance.

[0454] The disclosure also provides a drug substance comprising an anti-CD38 antibody comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, having a G1F oligosaccharide content of about 15%-27%, the drug substance being manufactured using a process comprising preparing a culture medium comprising about 6.5 ppb or less of Mn; and culturing a host cell transfected with a polynucleotide encoding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, in the culture medium comprising about 6.5 ppb or less of Mn, thereby producing the drug substance.

[0455] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, each having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising culturing a CHO cell transfected with a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8, in a culture medium containing about 6.5 ppb or less Mn, thereby producing the drug substance.

[0456] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, each having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising preparing a culture medium comprising an Mn of about 6.5 ppb or less, and culturing a host cell transfected with a polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in the culture medium comprising an Mn of about 6.5 ppb or less, thereby producing the drug substance.

[0457] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising culturing a CHO cell transfected with a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in a culture medium containing about 6.5 ppb or less Mn, thereby producing the drug substance.

[0458] The present disclosure also provides a drug substance comprising an anti-CD38 antibody comprising a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10, having a G1F oligosaccharide content of about 15% to about 27%, wherein the drug substance is manufactured using a process comprising preparing a culture medium comprising an Mn of about 6.5 ppb or less, and culturing a host cell transfected with a polynucleotide encoding the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10 in the culture medium comprising an Mn of about 6.5 ppb or less, thereby producing the drug substance.

[0459] In some embodiments, the culture medium is prepared by measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 8.5 ppb or less of Mn to prepare the culture medium.

[0460] In some embodiments, the culture medium is prepared by measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 8.0 ppb or less of Mn to prepare the culture medium.

[0461] In some embodiments, the culture medium comprises Mn at about 8.0 ppb, about 7.5 ppb or less, about 7.0 ppb or less, about 6.5 ppb or less, about 6.0 ppb or less, about 5.5 ppb or less, or about 5.0 ppb or less.

[0462] In some embodiments, the culture medium contains about 8.0 ppb or less of Mn.

[0463] In some embodiments, the culture medium contains about 7.5 ppb or less of Mn.

[0464] In some embodiments, the culture medium contains about 7.0 ppb or less of Mn.

[0465] In some embodiments, the culture medium contains about 6.5 ppb or less of Mn.

[0466] In some embodiments, the culture medium contains about 6.0 ppb or less of Mn.

[0467] In some embodiments, the culture medium contains about 5.5 ppb or less of Mn.

[0468] In some embodiments, the culture medium contains about 5.0 ppb or less of Mn.

[0469] In some embodiments, the culture medium contains about 2 ppb to about 8.0 ppb Mn.

[0470] In some embodiments, the culture medium contains about 2 ppb to about 6.5 ppb Mn.

[0471] In some embodiments, the culture medium contains about 5.0 ppb to about 8.0 ppb Mn.

[0472] In some embodiments, the culture medium contains about 5.0 ppb to about 7.5 ppb Mn.

[0473] In some embodiments, the culture medium contains about 5.0 ppb to about 7.0 ppb Mn.

[0474] In some embodiments, the culture medium contains about 5.0 ppb to about 6.5 ppb Mn.

[0475] In some embodiments, the culture medium is a basal medium or a feed medium. In some embodiments, the culture medium is a basal medium. In some embodiments, the culture medium is a feed medium.

[0476] In some embodiments, the culture is a fed-batch culture. In some embodiments, the culture is a perfusion culture.

[0477] In some embodiments, the host cell is a eukaryotic cell.

[0478] In some embodiments, the eukaryotic cell is a CHO cell, a PER.C6 cell, an NS0 cell, an Sp2 / 0 cell, or a BHK cell.

[0479] In some embodiments, the CHO cells are deficient in glutamine synthetase (GS).

[0480] In some embodiments, the CHO cell is a CHO-K1 cell, a CHO-DG44 cell, a CHO-S cell, or a CHO-DXB11 cell.

[0481] In some embodiments, the drug substance is manufactured under GMP-compliant conditions.

[0482] The present disclosure also provides a pharmaceutical product produced by the method of the present disclosure.

[0483] The present disclosure also provides a pharmaceutical product comprising a drug substance of the present disclosure.

[0484] The disclosure also provides a pharmaceutical comprising an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%, wherein the anti-CD38 antibody is produced by a process comprising culturing a host cell comprising a polynucleotide encoding the anti-CD38 antibody in a culture medium determined to contain about 8.5 ppb Mn or less, thereby producing an anti-CD38 antibody having a G1F oligosaccharide content of about 15% to about 27%.

[0485] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 16% to about 26%.

[0486] In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 17% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 18% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 19% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 20% to about 26%. In some embodiments, the G1F oligosaccharide content of the anti-CD38 antibody is about 21% to about 25%.

[0487] In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 65% to about 74%. In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 66% to about 74%. In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 67% to about 74%. In some embodiments, the G0F oligosaccharide content of the anti-CD38 antibody is about 68% to about 74%.

[0488] In some embodiments, the culture medium is prepared by measuring the Mn concentration in one or more batches of raw material components used to prepare the culture medium, and selecting one or more batches of raw material components that in combination contain about 8.5 ppb or less of Mn to prepare the culture medium.

[0489] In some embodiments, the culture medium comprises Mn at about 8.0 ppb, about 7.5 ppb or less, about 7.0 ppb or less, about 6.5 ppb or less, about 6.0 ppb or less, about 5.5 ppb or less, or about 5.0 ppb or less.

[0490] In some embodiments, the culture medium contains about 8.0 ppb or less of Mn.

[0491] In some embodiments, the culture medium contains about 7.5 ppb or less of Mn.

[0492] In some embodiments, the culture medium contains about 7.0 ppb or less of Mn.

[0493] In some embodiments, the culture medium contains about 6.5 ppb or less of Mn.

[0494] In some embodiments, the culture medium contains about 6.0 ppb or less of Mn.

[0495] In some embodiments, the culture medium contains about 5.5 ppb or less of Mn.

[0496] In some embodiments, the culture medium contains about 5.0 ppb or less of Mn.

[0497] In some embodiments, the culture medium contains about 2 ppb to about 8.0 ppb Mn.

[0498] In some embodiments, the culture medium contains about 2 ppb to about 6.5 ppb Mn.

[0499] In some embodiments, the culture medium contains about 5.0 ppb to about 8.0 ppb manganese.

[0500] In some embodiments, the culture medium contains about 5.0 ppb to about 7.5 ppb manganese.

[0501] In some embodiments, the culture medium contains about 5.0 ppb to about 7.0 ppb manganese.

[0502] In some embodiments, the culture medium contains about 5.0 ppb to about 6.5 ppb manganese.

[0503] In some embodiments, the culture medium is a basal medium or a feed medium. In some embodiments, the culture medium is a basal medium. In some embodiments, the culture medium is a feed medium.

[0504] In some embodiments, the culture is a fed-batch culture. In some embodiments, the culture is a perfusion culture.

[0505] In some embodiments, the host cell is a eukaryotic cell.

[0506] In some embodiments, the eukaryotic cell is a CHO cell, a PER.C6 cell, an NS0 cell, an Sp2 / 0 cell, or a BHK cell.

[0507] In some embodiments, the CHO cells are deficient in glutamine synthetase (GS).

[0508] In some embodiments, the CHO cell is a CHO-K1 cell, a CHO-DG44 cell, a CHO-S cell, or a CHO-DXB11 cell.

[0509] In some embodiments, the pharmaceutical product is manufactured under GMP-compliant conditions.

[0510] In some embodiments, the medicament comprises an anti-CD38 antibody comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

[0511] In some embodiments, the medicament comprises an anti-CD38 antibody comprising a VH of SEQ ID NO:7 and a VL of SEQ ID NO:8.

[0512] In some embodiments, the medicament comprises an anti-CD38 antibody comprising a HC of SEQ ID NO:9 and a LC of SEQ ID NO:10.

[0513] In some embodiments, the pharmaceutical product is a reference product.

[0514] In some embodiments, the pharmaceutical product is a biosimilar.

[0515] In some embodiments, the pharmaceutical agent is a biosimilar to DARZALEX® (daratumumab).

[0516] In some embodiments, the pharmaceutical preparation comprises about 20 mg / mL of an anti-CD38 antibody formulated in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0517] In some embodiments, the medicament comprises about 20 mg / mL to about 180 mg / mL of an anti-CD38 antibody and recombinant human hyaluronidase (rHuPH20) in an amount of about 30,000 U to about 45,000 U.

[0518] In some embodiments, the medicament comprises from about 1 mg / mL to about 180 mg / mL of an anti-CD38 antibody.

[0519] In some embodiments, the medicament comprises from about 10 mg / mL to about 180 mg / mL of an anti-CD38 antibody.

[0520] In some embodiments, the medicament comprises from about 20 mg / mL to about 160 mg / mL of an anti-CD38 antibody.

[0521] In some embodiments, the medicament comprises from about 20 mg / mL to about 140 mg / mL of an anti-CD38 antibody.

[0522] In some embodiments, the medicament comprises from about 20 mg / mL to about 120 mg / mL of an anti-CD38 antibody.

[0523] In some embodiments, the medicament comprises from about 40 mg / mL to about 120 mg / mL of an anti-CD38 antibody.

[0524] In some embodiments, the medicament comprises about 60 mg / mL to about 120 mg / mL of an anti-CD38 antibody.

[0525] In some embodiments, the medicament comprises about 80 mg / mL to about 120 mg / mL of an anti-CD38 antibody.

[0526] In some embodiments, the medicament comprises about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody.

[0527] In some embodiments, the medicament comprises about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, or about 180 mg / mL of an anti-CD38 antibody.

[0528] In some embodiments, the medicament comprises about 20 mg / mL of an anti-CD38 antibody.

[0529] In some embodiments, the medicament comprises about 100 mg / mL of an anti-CD38 antibody.

[0530] In some embodiments, the medicament comprises about 120 mg / mL of an anti-CD38 antibody.

[0531] In some embodiments, the medicament contains about 50 U / mL to about 5,000 U / mL of rHuPH20.

[0532] In some embodiments, the medicament contains about 500 U / mL to about 5,000 U / mL of rHuPH20.

[0533] In some embodiments, the medicament contains about 1,000 U / mL to about 5,000 U / mL of rHuPH20.

[0534] In some embodiments, the medicament contains about 2,000 U / mL to about 5,000 U / mL of rHuPH20.

[0535] In some embodiments, the medicament contains about 50 U / mL to about 2,000 U / mL of rHuPH20.

[0536] In some embodiments, the medicament contains about 500 U / mL to about 2,000 U / mL of rHuPH20.

[0537] In some embodiments, the medicament contains about 1,000 U / mL to about 2,000 U / mL of rHuPH20.

[0538] In some embodiments, the pharmaceutical agent is a medicament having a concentration of about 500 U / mL, about 600 U / mL, about 700 U / mL, about 800 U / mL, about 900 U / mL, about 1,000 U / mL, about 1,100 U / mL, about 1,200 U / mL, about 1,300 U / mL, about 1,400 U / mL, about 1,500 U / mL, about 1,600 U / mL, about 1,700 U / mL, about 1,800 U / mL, about 1,900 U / mL, about 2,000 U / mL, about 2,100 U / mL, about 2,200 U / mL, about 2,300 U / mL, about 2,400 U / mL, about 2,500 U / mL, about 2,600 U / mL, about 2,700 U / mL, or about 2,800 U / mL. 800 U / mL, about 2,900 U / mL, about 3,000 U / mL, about 3,100 U / mL, about 3,200 U / mL, about 3,300 U / mL, about 3,400 U / mL, about 3,500 U / mL, about 3,600 U / mL, about 3,700 U / mL, about 3,800 U / mL, about 3,900 U / mL, about 4,000 U / mL, about 4,100 U / mL, about 4,200 U / mL, about 4,300 U / mL, about 4,400 U / mL, about 4,500 U / mL, about 4,600 U / mL, about 4,700 U / mL, about 4,800 U / mL, about 4,900 U / mL, or about 5,000 U / mL of rHuPH20.

[0539] In some embodiments, the medicament comprises about 500 U / mL of rHuPH20.

[0540] In some embodiments, the medicament comprises about 2,000 U / mL of rHuPH20.

[0541] In some embodiments, the medicament comprises about 5,000 U / mL of rHuPH20.

[0542] In some embodiments, the medicament comprises from about 1,200 mg to about 5,000 mg of an anti-CD38 antibody.

[0543] In some embodiments, the medicament comprises from about 1,200 mg to about 2,400 mg of an anti-CD38 antibody.

[0544] In some embodiments, the medicament comprises about 1,200 mg to about 1,800 mg of an anti-CD38 antibody.

[0545] In some embodiments, the medicament comprises about 1,200 mg of an anti-CD38 antibody.

[0546] In some embodiments, the medicament comprises about 1,400 mg of an anti-CD38 antibody.

[0547] In some embodiments, the medicament comprises about 1,600 mg of an anti-CD38 antibody.

[0548] In some embodiments, the medicament comprises about 1,800 mg of an anti-CD38 antibody.

[0549] In some embodiments, the medicament comprises about 2,000 mg of an anti-CD38 antibody.

[0550] In some embodiments, the medicament comprises about 2,200 mg of an anti-CD38 antibody.

[0551] In some embodiments, the medicament comprises about 2,400 mg of an anti-CD38 antibody.

[0552] In some embodiments, the medicament comprises about 2,600 mg of an anti-CD38 antibody.

[0553] In some embodiments, the medicament comprises about 2,800 mg of an anti-CD38 antibody.

[0554] In some embodiments, the medicament comprises about 3,000 mg of an anti-CD38 antibody.

[0555] In some embodiments, the medicament comprises about 3,500 mg of an anti-CD38 antibody.

[0556] In some embodiments, the medicament comprises about 4,000 mg of an anti-CD38 antibody.

[0557] In some embodiments, the medicament comprises about 4,500 mg of an anti-CD38 antibody.

[0558] In some embodiments, the medicament comprises about 5,000 mg of an anti-CD38 antibody.

[0559] In some embodiments, the pharmaceutical comprises about 750 U to about 75,000 U of rHuPH20.

[0560] In some embodiments, the pharmaceutical comprises about 7,500 U to about 45,000 U of rHuPH20.

[0561] In some embodiments, the pharmaceutical comprises about 30,000 U to about 45,000 U of rHuPH20.

[0562] In some embodiments, the pharmaceutical agent is about 7,500 U, about 8,000 U, about 8,500 U, about 9,000 U, about 10,000 U, about 15,000 U, about 20,000 U, about 21,000 U, about 22,000 U, about 23,000 U, about 24,000 U, about 25,000 U, about 26,000 U, about 27,000 U, about 28,000 U, about 29,000 U, about 30,000 U, about 31,000 U, about 32,000 U, about 33,000 U, about 34,000 U, About 35,000 U, about 36,000 U, about 37,000 U, about 38,000 U, about 39,000 U, about 40,000 U, about 41,000 U, about 42,000 U, about 43,000 U, about 44,000 U, about 45,000 U, about 46,000 U, about 47,000 U, about 48,000 U, about 49,000 U, about 50,000 U, about 55,000 U, about 60,000 U, about 65,000 U, about 70,000 U, or about 75,000 U of rHuPH20.

[0563] In some embodiments, the medicament comprises about 5,000 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0564] In some embodiments, the medicament comprises about 5,000 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0565] In some embodiments, the medicament comprises about 3,000 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0566] In some embodiments, the medicament comprises about 3,000 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0567] In some embodiments, the medicament comprises about 2,800 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0568] In some embodiments, the medicament comprises about 2,800 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0569] In some embodiments, the medicament comprises about 2,600 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0570] In some embodiments, the medicament comprises about 2,600 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0571] In some embodiments, the medicament comprises about 2,400 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0572] In some embodiments, the medicament comprises about 2,400 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0573] In some embodiments, the medicament comprises about 2,200 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0574] In some embodiments, the medicament comprises about 2,200 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0575] In some embodiments, the medicament comprises about 2,000 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0576] In some embodiments, the medicament comprises about 2,000 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0577] In some embodiments, the medicament comprises about 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0578] In some embodiments, the medicament comprises about 1,800 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0579] In some embodiments, the medicament comprises about 1,600 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0580] In some embodiments, the medicament comprises about 1,600 mg of an anti-CD38 antibody and about 45,000 U of rHuPH20.

[0581] In some embodiments, the rHuPH20 is an rHuPH20 having the amino acid sequence of SEQ ID NO:22.

[0582] rHuPH20 is recombinant rHuPH20 (HYLENEX® recombinant) and is described in WO 2004 / 078140. rHuPH20 is an enzyme that degrades hyaluronic acid (EC 3.2.1.35) and reduces the viscosity of hyaluronan in the extracellular matrix, thereby increasing tissue permeability. The enzyme activity of rHuPH20, including rHuPH20, can be defined by units per mL (U / mL) or total enzyme activity (U) in a particular formulation. The standard definition of 1 unit (U) of enzyme activity is the amount of enzyme that catalyzes the reaction of 1 nmol of substrate per minute.

[0583] In some embodiments, the medicament comprises about 120 mg / mL of an anti-CD38 antibody and about 30,000 U / mL of rHuPH20.

[0584] In some embodiments, the pharmaceutical comprises histidine at a concentration of about 1 mM to about 50 mM.

[0585] In some embodiments, the pharmaceutical comprises histidine at a concentration of about 5 mM to about 50 mM.

[0586] In some embodiments, the pharmaceutical comprises histidine at a concentration of about 5 mM to about 30 mM.

[0587] In some embodiments, the pharmaceutical comprises histidine at a concentration of about 5 mM to about 20 mM.

[0588] In some embodiments, the pharmaceutical agent is at about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM, about 30 mM, about 31 mM, about 32 mM, about 33 mM, about 34 mM, about 35 mM, about 36 mM, about 37 mM, about 38 mM, about 39 mM, about 40 mM, about 41 mM, about 42 mM, about 43 mM, about 44 mM, about 45 mM, about 46 mM, about 47 mM, about 48 mM, about 49 mM, about 50 mM, about 51 mM, about 52 mM, about 53 mM, about 54 mM, about 55 mM, about 56 mM, about 57 mM, about 58 mM, about 59 mM, about 60 mM, about 61 mM, about 62 mM, about 63 mM, about 64 mM, about 65 mM, about 66 mM, about 67 mM, about 68 mM, about 69 mM, about 70 mM, about 71 mM, about 72 mM, about 73 mM, about 74 mM, about 75 mM, about 76 mM, about 77 mM, about 78 mM, about 79 mM, about 80 mM, about 81 mM, about 82 mM, about 83 mM, about 84 mM, about 85 mM, about In some embodiments, the histidine is at a concentration of about 27 mM, about 28 mM, about 29 mM, about 30 mM, about 31 mM, about 32 mM, about 33 mM, about 34 mM, about 35 mM, about 36 mM, about 37 mM, about 38 mM, about 39 mM, about 40 mM, about 41 mM, about 42 mM, about 43 mM, about 44 mM, about 45 mM, about 46 mM, about 47 mM, about 48 mM, about 49 mM, or about 50 mM.

[0589] In some embodiments, the pharmaceutical comprises sorbitol at a concentration of about 50 mM to about 500 mM.

[0590] In some embodiments, the pharmaceutical comprises sorbitol at a concentration of about 50 mM to about 450 mM.

[0591] In some embodiments, the pharmaceutical comprises sorbitol at a concentration of about 50 mM to about 400 mM.

[0592] In some embodiments, the pharmaceutical comprises sorbitol at a concentration of about 50 mM to about 350 mM.

[0593] In some embodiments, the pharmaceutical comprises sorbitol at a concentration of about 100 mM to about 350 mM.

[0594] In some embodiments, the pharmaceutical comprises sorbitol at a concentration of about 100 mM to about 300 mM.

[0595] In some embodiments, the pharmaceutical agent is at about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, about 250 mM, about 260 mM, about 270 mM, about 280 mM, about 290 mM, about 300 mM, about 310 mM, about 320 mM, about 330 mM, about 340 mM, about 350 mM, about 360 mM, about 370 mM, about 380 mM, about 390 mM, about 400 mM, about 410 mM, about 420 mM, about 430 mM, about 440 mM, about 450 mM, about 460 mM, about 470 mM, about 480 mM, about 490 mM, about 500 mM, about 510 mM, about 520 mM, about 530 mM, about 540 mM, about 550 mM, about 560 mM, about 570 mM, about 580 mM, about 590 mM, about 600 mM, about 610 mM, about 620 mM, about 630 mM, about 640 mM, about 650 mM, about 660 mM, about 670 mM, about 680 mM, about 690 mM, about 700 mM, about 710 mM, about 720 mM, about 730 mM, about 740 mM, about 750 mM, about 760 mM, about 770 mM, about 780 mM, about 790 mM, about 800 mM, about 810 In some embodiments, the sorbitol may be present in a concentration of about 300 mM, about 310 mM, about 320 mM, about 330 mM, about 340 mM, about 350 mM, about 360 mM, about 370 mM, about 380 mM, about 390 mM, about 400 mM, about 410 mM, about 420 mM, about 430 mM, about 440 mM, about 450 mM, about 460 mM, about 470 mM, about 480 mM, about 490 mM, or about 500 mM.

[0596] In some embodiments, the pharmaceutical comprises polysorbate-20 (PS-20) at a concentration of about 0.01% w / v to about 0.1% w / v.

[0597] In some embodiments, the pharmaceutical comprises polysorbate-20 (PS-20) at a concentration of about 0.01% w / v to about 0.08% w / v.

[0598] In some embodiments, the pharmaceutical comprises polysorbate-20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v.

[0599] In some embodiments, the medicament comprises polysorbate-20 (PS-20) at a concentration of about 0.01% w / v, 0.02% w / v, 0.03% w / v, 0.04% w / v, 0.05% w / v, 0.06% w / v, 0.07% w / v, 0.08% w / v, 0.09% w / v, or 0.1% w / v.

[0600] In some embodiments, the medicament comprises methionine at a concentration of about 0.1 mg / mL to about 5 mg / mL.

[0601] In some embodiments, the medicament comprises methionine at a concentration of about 0.1 mg / mL to about 2.5 mg / mL.

[0602] In some embodiments, the medicament comprises methionine at a concentration of about 1 mg / mL to about 2 mg / mL.

[0603] In some embodiments, the medicament comprises a methionine concentration of about 0.5 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1 / 7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2 / 3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, or about 5 mg / mL.

[0604] In some embodiments, the pharmaceutical has a pH of 5.0 to 6.0.

[0605] In some embodiments, the pharmaceutical has a pH of 5.3 to 5.8.

[0606] In some embodiments, the pharmaceutical agent has a pH of 5.5.

[0607] In some embodiments, the pharmaceutical agent has a pH of 5.6.

[0608] In some embodiments, the pharmaceutical comprises histidine at a concentration of about 5 mM to about 15 mM, sorbitol at a concentration of about 100 mM to about 300 mM, polysorbate 20 (PS-20) at a concentration of about 0.01% w / v to about 0.04% w / v, and methionine at a concentration of about 1 mg / mL to about 2 mg / mL, at a pH of about 5.5.

[0609] In some embodiments, the pharmaceutical formulation comprises about 100 mg / mL of an anti-CD38 antibody comprising the VH and VL of SEQ ID NOs: 4 and 5, respectively, about 500 U / mL of rHuPH20, about 10 mM histidine, about 300 mM sorbitol, about 0.04% w / v PS-20, and about 2 mg / mL of methionine, at a pH of about 5.5.

[0610] In some embodiments, the pharmaceutical formulation comprises about 120 mg / mL of an anti-CD38 antibody comprising a VH and VL of SEQ ID NOs: 4 and 5, respectively, about 2,000 U / mL of rHuPH20, about 10 mM histidine, about 300 mM sorbitol, about 0.04% w / v PS-20, and about 1 mg / mL of methionine, at a pH of about 5.6.

[0611] In some embodiments, the pharmaceutical formulation comprises about 100 mg / mL of an anti-CD38 antibody comprising a VH and VL of SEQ ID NOs: 4 and 5, respectively, about 500 U / mL of rHuPH20, about 10 mM histidine, about 300 mM sorbitol, and about 2 mg / mL of methionine, at a pH of about 5.5.

[0612] In some embodiments, the pharmaceutical formulation comprises about 100 mg / mL of an anti-CD38 antibody comprising the VH and VL of SEQ ID NOs: 4 and 5, respectively, about 500 U / mL of rHuPH20, about 10 mM histidine, about 300 mM sorbitol, about 0.01% w / v PS-20, and about 2 mg / mL of methionine, at a pH of about 5.5.

[0613] In some embodiments, the pharmaceutical formulation comprises about 100 mg / mL of an anti-CD38 antibody comprising the VH and VL of SEQ ID NOs: 4 and 5, respectively, about 500 U / mL of rHuPH20, about 1...

Claims

1. 1. A method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8, said antibody having an asialo, monogalacto core-fucosylated biantennary glycan (G1F) oligosaccharide content of 15% to 27%, comprising: a) preparing a culture medium containing between 2 parts per billion (ppb) and 8.5 ppb of manganese (Mn); b) controlling the G1F oligosaccharide content of the anti-CD38 antibody by culturing a host cell comprising the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 in the culture medium prepared in step a), thereby producing the anti-CD38 antibody expressed from the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 having a G1F oligosaccharide content of 15% to 27%; Including, The method, wherein the host cell is a CHO cell.

2. A method for producing a pharmaceutical product, comprising: a) producing an anti-CD38 antibody according to the method of claim 1; b) formulating said anti-CD38 antibody as a pharmaceutical; and The method includes:

3. 3. The method of claim 2, wherein formulating the medicament comprises formulating the anti-CD38 antibody at 20 mg / mL to 180 mg / mL with recombinant human hyaluronidase (rHuPH20) in an amount of 30,000 U to 45,000 U, histidine at a concentration of 5 mM to 15 mM, sorbitol at a concentration of 100 mM to 300 mM, PS-20 at a concentration of 0.01% w / v to 0.04% w / v, and methionine at a concentration of 1 mg / mL to 2 mg / mL, at a pH of 5.0 to 6.

0.

4. 4. The method of claim 3, wherein formulating the medicament comprises formulating the anti-CD38 antibody at 120 mg / mL in 2,000 U / mL recombinant human hyaluronidase (rHuPH20), 5 mM to 15 mM histidine, 100 mM to 300 mM sorbitol, 0.01% w / v to 0.04% w / v PS-20, and 1 mg / mL to 2 mg / mL methionine at pH 5.

6.

5. 3. The method of claim 2, wherein formulating the medicament comprises formulating the anti-CD38 antibody at 20 mg / mL in 25 mM acetic acid, 60 mM sodium chloride, 140 mM mannitol, and 0.04% w / v polysorbate-20 (PS-20) at pH 5.

5.

6. 1. A method for producing an anti-CD38 antibody expressed from a polynucleotide encoding a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8, said antibody having a G1F oligosaccharide content of between 15% and 27%, comprising: a) culturing a host cell expressing the polynucleotide encoding the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8 under conditions in which the anti-CD38 antibody is produced; b) monitoring the concentration of Mn in the culture medium during the biosynthesis of the anti-CD38 antibody and controlling the G1F oligosaccharide content of the anti-CD38 antibody by adjusting the concentration of Mn in the culture medium during the biosynthesis of the anti-CD38 antibody, adjusting the concentration of Mn in the culture medium to contain 2 ppb to 8.5 ppb or less of Mn, thereby producing the anti-CD38 antibody having a G1F oligosaccharide content of 15% to 27%; Including, The method, wherein the host cell is a CHO cell.

7. The method of claim 6, wherein the G1F oligosaccharide content of the anti-CD38 antibody is between 15% and 25%.

8. The method of claim 7, wherein the G1F oligosaccharide content of the anti-CD38 antibody is between 21% and 25%.

9. The method of claim 6, wherein the anti-CD38 antibody has an asialo, agalacto core-fucosylated biantennary glycan (G0F) oligosaccharide content of 65% to 74%.

10. The method of claim 7, wherein the anti-CD38 antibody has an asialo, agalacto core-fucosylated biantennary glycan (G0F) oligosaccharide content of 68% to 74%.

11. Preparing the culture medium comprises: Measuring the Mn concentration in one or more batches of feedstock components; selecting one or more batches of feedstock components that in combination contain between 2 ppb and 8.5 ppb Mn; using one or more batches of said selected raw material components to prepare a culture medium; The method of claim 1 , comprising:

12. 2. The method of claim 1, wherein the culture medium is controlled to contain 2 ppb to 6.5 pppb of Mn.

13. 12. The method of claim 11, wherein the culture medium is formulated to contain 4.0 ppb to 8.5 ppb Mn.

14. 14. The method of claim 13, wherein the culture medium is formulated to contain 4.0 ppb to 6.5 ppb Mn.

15. 15. The method of claim 14, wherein the culture medium is formulated to contain 5.0 ppb to 6.5 ppb Mn.

16. 7. The method of claim 6, wherein the culture medium is controlled to contain 2 ppb to 6.5 pppb of Mn.

17. 7. The method of claim 6, wherein the culture medium is controlled to contain 4.0 ppb to 8.5 ppb Mn.

18. 18. The method of claim 17, wherein the culture medium is controlled to contain 4.0 ppb to 6.5 ppb Mn.

19. 20. The method of claim 18, wherein the culture medium is controlled to contain 5.0 ppb to 6.5 ppb Mn.

20. The method of claim 1, wherein the anti-CD38 antibody has an asialo, agalacto core-fucosylated biantennary glycan (G0F) oligosaccharide content of 65% to 74%.

21. 21. The method of claim 20, wherein the culture medium is formulated to contain 4.0 ppb to 8.5 ppb Mn.

22. The method of claim 1, wherein the G1F oligosaccharide content of the anti-CD38 antibody is between 15% and 25%.

23. The method of claim 22, wherein the G0F oligosaccharide content of the anti-CD38 antibody is between 68% and 74%.

24. 24. The method of claim 23, wherein the culture medium is formulated to contain 4.0 ppb to 8.5 ppb Mn.

25. The method of claim 1, wherein the G1F oligosaccharide content of the anti-CD38 antibody is between 21% and 25%.

26. The method of claim 25, wherein the G0F oligosaccharide content of the anti-CD38 antibody is from about 68% to about 74%.

27. 27. The method of claim 26, wherein the culture medium is formulated to contain 5.0 ppb to 6.5 ppb Mn.

28. The method of claim 1 , wherein the culture medium is a basal medium or a feed medium.

29. 29. The method of claim 28, wherein the culturing comprises fed-batch culturing or perfusion culturing.

30. 2. The method of claim 1, wherein the CHO cell is a CHO-K1 cell, a CHO-DG44 cell, a CHO-S cell, or a CHO-DXB11 cell.

31. 31. The method of claim 30, wherein the CHO cells are deficient in glutamine synthetase (GS).

32. 10. The method of claim 1, carried out under GMP-compliant conditions.

33. The method of claim 32, wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:7 and the VL of SEQ ID NO:

8.

34. 34. The method of claim 33, wherein the anti-CD38 antibody comprises an IgG1 isotype.

35. The method of claim 34, wherein the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO:

10.

36. The method of claim 1 , wherein the anti-CD38 antibody is a biosimilar.

37. 2. The method of claim 1, wherein the anti-CD38 antibody is daratumumab.

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