Subcutaneous preparations of anti-CD38 antibodies and their use

Abstract

This invention provides a subcutaneous formulation of an anti-CD38 antibody and its use. [Solution] A pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase is provided. The method for treating cancer in a subject is also provided, comprising subcutaneously administering the pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase to the subject in need of treatment for a period of time sufficient to treat the cancer.

Description

[Technical Field]

[0001] (Sequence Listing) This application includes the sequence listing submitted via EFS-Web, and all of its contents are referenced. This document is incorporated herein by [authorization]. Created on October 28, 2016 by ASCII. The quist file has the filename JBI5070WOPCT_ST25.txt, The size is 26 kilobytes.

[0002] (Field of invention) This invention relates to a subcutaneous formulation of an anti-CD38 antibody and its use. [Background technology]

[0003] CD38 has functions in receptor-mediated adhesion and signal transduction, and its e- It mediates calcium mobilization via type T enzyme activity, and cyclic ADP-ribose (cADPR) and CD38 is a multifunctional protein that catalyzes the formation of ADPR. It mediates secretion and the activation and proliferation of lymphocytes (Funaro et al., J Im munol 145:2390~6,1990;Terhorst et al.,Ce ll 771~80,1981;Guse et al.,Nature 398:70 (~3,1999). CD38 also regulates through its NAD glycohydrase activity. Extracellular NAD is thought to be involved in regulating the T cell compartment. + Adjust the level ( Adriouch et al.,14:1284~92,2012;Chiarugi et al., Nature Reviews 12:741~52, 2012). C a 2+ In addition to signaling via the mediated signaling pathway, CD38 signaling is also transmitted to antigens on T and B cells. Crosstalk with receptor complexes or other types of receptor complexes (e.g., MHC molecules) This occurs, and in this way, CD38 switches several cellular responses as well as IgG1. It is also involved in stimuli and secretion. CD38 is expressed on various malignant cells.

[0004] Anti-CD38 antibodies are being developed for the treatment of multiple myeloma and other heme malignancies. The antibody is administered via intravenous (IV) route. The amount of antibody that can be administered depends on the physicochemical properties of the antibody, particularly its solubility in a suitable liquid formulation, and It is limited by stability and the volume of the injected fluid. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] Therefore, further anti-CD38 antibody preparations and pharmaceutical compositions are needed. [Means for solving the problem]

[0006] This invention provides a pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase.

[0007] The present invention also relates to an anti-CD38 antibody and hyaluronidium having the amino acid sequence of SEQ ID NO: 22. The present invention provides a pharmaceutical composition containing -ze rHuPH20.

[0008] The present invention also relates to a method for treating cancer in a subject, wherein the subject in need of such treatment... A pharmaceutical composition containing an anti-CD38 antibody and hyaluronidase is used to treat cancer when sufficient time is needed. The present invention provides a method that includes subcutaneous administration over a period of time.

[0009] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. administering the pharmaceutical composition of the present invention subcutaneously to a subject to be treated for a time sufficient to treat CD38-positive hematological malignancies to provide a method.

[0010] The present invention also provides a method for treating multiple myeloma, comprising administering to a subject in need thereof the pharmaceutical composition of the present invention subcutaneously for a time sufficient to treat multiple myeloma to provide a method.

[0011] The present invention also provides an amount of about 1,200 mg to about 5,000 mg of an anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5, an amount of about 30,000 U to about 45,000 U of hyaluronidase, a histidine concentration of about 5 mM to about 15 mM, a sorbitol concentration of about 100 mM to about 300 mM, a PS-20 concentration of about 0.01% w / v to about 0.04% w / v, and a methionine concentration of about 1 mg / mL to about 2 mg / mL, having a pH of about 5.5 to provide a unit dosage form.

[0012] The present invention also provides an amount of about 1,800 mg of an anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 and an amount of about 30,000 U of hyaluronidase, a histidine concentration of about 10 mM, a sorbitol concentration of about 300 mM, a PS-20 concentration of about 0.04% w / v, and a methionine concentration of about 1 mg / mL, having a pH of about 5.5, to provide the unit dosage form according to claim 74

[0013] The present invention also provides a container containing the unit dosage form of the present invention.

[0014] The present invention also provides a container for a pharmaceutical composition of the present invention. [Modes for carrying out the invention]

[0015] "CD38" is the human CD38 protein (synonym: ADP-ribosylcyclase 1, c This refers to ADPr hydrolase 1 (cyclic ADP-ribose hydrolase 1). Human CD38 is , as shown in GenBank acceptance number NP 001766 and sequence number 1, ami It has an acid sequence. CD38 consists of amino acid residues 1-21 representing the cytoplasmic domain and transmembrane. Amino acid residues 22-42 represent the domain, and residues 43- represent the extracellular domain of CD38. It is well known that it is a single-pass type II membrane protein having 300.

[0016] Sequence ID 1 MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVL AVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRH VDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPC NKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTW CGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEA ACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLE AWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIY RPDKFLQCVKNPEDSSCTSEI

[0017] The term "antibody" is intended to be used in a broad sense, encompassing mouse, human, humanized, and chimeric monoclonal antibodies. Monoclonal antibodies containing antigen-binding fragments, bispecific antibodies or multispecific antibodies, two quantities Body, tetramer, or macromer antibodies, single-chain antibodies, domain antibodies, and required special This also includes any other modified structures of immunoglobulin molecules that contain heterozygous antigen-binding sites. Contains globulin molecules. "Full-length antibodies" are interconnected by disulfide bonds. It contains two heavy (H) chains and two light (L) chains, as well as their polymers (e.g., IgM). Each heavy chain consists of a variable heavy chain region (VH) and a constant heavy chain region (domain CH1, hinge CH2). It consists of (and CH3). Each light chain has a variable light chain region (VL) and a constant light chain region. It consists of domains (CL). The VH domain and VL domain are composed of the framework domain (FR). These are scattered and can be further classified into hypervariable regions called complementary determination regions (CDRs). VH and VL are in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 – three CDRs and four FRs. It consists of fragments.

[0018] The "complementarity-determining region (CDR)" is the "antigen-binding site" in an antibody. It can be defined using various terms: (i) Three within VH (HCDR1, HCDR2, HC Sequence diversity exists in DR3 and VL, with three variations (LCDR1, LCDR2, LCDR3). Complementarity Determination Region (CDR) based on (Wu and Kabat, J Exp Med) 132:211~50,1970;Kabat et al.,Sequences o f Proteins of Immunological Interest,5th Ed.Public Health Service,National Institute Tutes of Health, Bethesda, Md., 1991). (ii) “ The "highly variable region," or "HVR" or "HV," has three elements within VH (H1, H2, H3) There are three (L1, L2, L3) within the VL, and these are Chothia and Les k(Chothia and Lesk,Mol Biol 196:901~17,1 This refers to the region of the antibody variable domain that is hypervariable in the structure defined by 987). International ImMunoGeneTics (IMGT) Database (http: / / www_imgt_org) standardizes the numbering of antigen binding sites and This provides definitions. For correspondences between CDR, HV, and IMGT notations, see Lef. Ranc et al., Dev Comparat Immunol 27:55~7 As described in 7,2003. When used herein, the terms "CDR" and "HCDR" are used. 1", "HCDR2", "HCDR3", "LCDR1", "LCDR2", and "LC Unless otherwise expressly stated herein, "DR3" refers to the above-mentioned Kabat, Ch Includes CDRs as defined by either othia or the method described by IMGT. nothing.

[0019] Immunoglobulins are classified into five major classes based on the amino acid sequence of their heavy chain constant domain. That is, it can be assigned to IgA, IgD, IgE, IgG, and IgM. IgA and IgG is divided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and Ig It is further classified as G4. The antibody light chains of any vertebrate species have their constant domains Based on the amino acid sequence, there are two distinctly different types: kappa (κ) and lambda ( It can be classified into one of the following categories (λ).

[0020] An "antigen-binding fragment" is the portion of the immunoglobulin molecule that retains the antigen-binding properties of the parent full-length antibody. This refers to the following. Exemplary antigen-binding fragments include heavy chain complementarity-determining regions (HCDRs) 1, 2 and / or 3. Light chain complementarity determination region (LCDR) 1, 2 and / or 3. Heavy chain variable region (VH ), or light chain variable region (VL), Fab, F(ab')2, Fd and Fv fragments, and 1 It is a domain antibody (dAb) consisting of one VH domain or one VL domain. The domain and VL domain are linked together via a synthetic linker, allowing for various It is possible to design various types of single-chain antibodies, where the VH / VL domains are diagonally arranged within the molecule. If the VH domain and VL domain are expressed on separate strands, then Pairs are formed between the offspring, forming monovalent antigen-binding sites such as single-stranded Fv (scFv) or bispecific antigens. Forms a body. For example, see International Publication No. 1998 / 44001 and No. 1988 / 01649. It is listed in issues 1994 / 13804 and 1992 / 01047.

[0021] "Monoclonal antibodies" have potential well-known properties such as the removal of C-terminal lysine from the antibody heavy chain. Except for the substitutes, each heavy chain and each light chain has a single amino acid composition. This refers to a population of antibodies possessed by two or more different antigens or epitopes. Except for the polyspecific monoclonal antibodies that bind, most antibodies typically bind to a single antigenic epitope. A bispecific monoclonal antibody binds to two different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Antibodies can be monospecific or multispecific, or monovalent, bivalent, or polyvalent. Monoclonal antibodies include polyspecific antibodies such as bispecific or trispecific antibodies. Born.

[0022] "Isolated antibodies" are antibodies that substantially do not contain other antibodies with different antigen specificities. This refers to an antigen-binding fragment (for example, an isolated antibody that specifically binds to human CD38). (Substantially contains no antibodies that specifically bind to antigens other than human CD38). Bispecific antibodies In this case, the bispecific antibody specifically binds to two target antigens, and the two target antigens It substantially contains antibodies that specifically bind to antigens other than those specified. "Isolated antibodies" have a purity of 8. 0%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 9 0%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or This includes antibodies isolated to a high purity, such as 100%.

[0023] "Humanized antibodies" are antibodies whose antigen-binding sites originate from species other than humans and whose variable region framework is... The term "humanized antibody" refers to an antibody derived from a human immunoglobulin sequence. Such framework may include mutations that have been intentionally introduced into the region. This does not necessarily have to be a complete replica of the expressed human immunoglobulin or germline gene sequence. .

[0024] "Human antibodies" are those in which both the framework and antigen-binding site are derived from human sequences. This refers to an antibody that has a heavy chain variable region and a light chain variable region. If a portion is included, the constant region also originates from a human-derived sequence.

[0025] Human antibodies are antibodies whose variable region is human germline immunoglobulin or rearranged immunoglobulin. When obtained from a system using the brin gene, the heavy chain variable region derived from a human sequence or It includes a light chain variable region. A typical example of such a system is human phages presented on phages. Immunoglobulin gene library and human immunoglobulin genes described herein This includes non-human genetically modified animals such as mice or rats that possess the locus. Human antibodies This includes, for example, naturally occurring somatic mutations, frameworks, or antigen-binding sites. During the introduction of graphical substitution, and in the process of cloning and VDJ recombination in non-human animals The amino acid changes introduced into the sequence result in a human germline or rearranged immunoglobulin sequence. When compared, differences in amino acids can typically be present. Typically, human antibodies are amino In the acid sequence, encoded by human germline or rearranged immunoglobulin genes The amino acid sequence is at least approximately 80%, 81%, 82%, 83%, 84%, 85%, 8 6%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 9 They are 6%, 97%, 98%, 99%, or 100% identical. In some cases, human antibodies For example, see Knappik et al., J Mol Biol 296:57~8 The consensus framework obtained from human framework sequence analysis described in 6,2000 Mwell sequence, or for example, Shi et al., J Mol Biol 397:38 On the phages described in 5-96, 2010 and International Publication No. 2009 / 085462 The presented human immunoglobulin gene library contains synthetic HCDR3 incorporated into it. obtain.

[0026] Antibodies whose antigen-binding sites originate from species other than humans are not included in the definition of human antibodies.

[0027] "Recombinant" refers to antibodies and other substances prepared, expressed, produced, or isolated by recombinant methods. It contains protein.

[0028] An "epitope" refers to the part of an antigen to which an antibody specifically binds. An epitope is a typical epitope. Specifically, the chemically active (polar, nonpolar, or hydrophobic) sites of amino acids or polysaccharide side chains. It consists of surface groups (such as properties) and may have specific three-dimensional structural properties and specific charge properties. The 'coordinate' is formed from consecutive and / or discontinuous amino acids that form the spatial unit of the conformation. It is possible. In discontinuous epitopes, amino acids in different parts of the linear sequence of the antigen can be tan. The folding of protein molecules brings them into close proximity in three-dimensional space.

[0029] "Polyspecificity" means that there are at least two different antigens, or two different epithets within an antigen. An antibody that specifically binds to a p (for example, three, four, or five different antigens or epitopes). It refers to.

[0030] "Bispecificity" refers to two different antigens, or two different epitopes within the same antigen. This refers to antibodies that specifically bind to other antigens. Bispecific antibodies cross-react to other relevant antigens. It may have sexual properties, or it may bind to epitopes shared between two or more different antigens.

[0031] "Mutant" refers to, for example, one or more modifications such as substitution, insertion, or deletion. Refers to a polypeptide or polynucleotide that is different from the polypeptide or reference polynucleotide. vinegar.

[0032] "Used in combination with ~" means that two or more therapeutic drugs are used together in a mixture form on the target, or together with ~ Each drug may be administered simultaneously as a separate drug, or sequentially in any order. It means to be done.

[0033] "Pharmaceutical composition" refers to a combination of anti-CD38 antibody and hyaluronidase. This refers to the product obtained by [method], and includes both fixed and unfixed combinations. Pharmaceutical composition The substance typically contains a pharmaceutically acceptable carrier. “Fixed combination” refers to anti-CD3 A single pharmaceutical composition containing 8 antibodies and hyaluronidase, in the form of a single entity or in a single dose. This refers to simultaneous administration in the form of the anti-CD38 antibody and Different pharmaceutical compositions or unit dosage forms of hyaluronidase, as different entities, at specific intervening times This refers to administration simultaneously, concurrently, or sequentially without any restrictions in between, and here, This administration provides effective levels of the two compounds in the subject's body.

[0034] A "medically acceptable carrier" is a pharmaceutical composition other than the active ingredient that is non-toxic to the target. This refers to the components inside. Medicinal carriers include buffers, excipients, stabilizers, or preservatives. However, it is not limited to these.

[0035] "To treat" or "to treat" means, with the purpose of treating an undesirable physiological change or the progression of a disease. To slow down (reduce) growth, for example, to slow down the development or spread of a tumor or tumor cells. This may involve providing beneficial or desired clinical outcomes during treatment. It refers to therapeutic procedures, such as those that may have a beneficial or desired clinical outcome, which may be detectable. And, whether undetectable or undetectable, relief of symptoms, reduction of the severity of the disease, stabilization (i.e., worsening) (No progression) Disease state, delayed or slowed progression of disease, absence of metastasis, improvement or mitigation of disease state , and remission (whether partial or complete). "Treatment" also means, To extend survival time compared to the expected survival time if the subject were not receiving treatment. This could mean that the condition requiring treatment is an undesirable physiological change or disease. This includes subjects who already possess the condition, as well as subjects who tend to have physiological changes or diseases. It can be done.

[0036] "A therapeutically effective dose" means the dose and duration required to achieve the desired therapeutic result. This refers to the amount that is effective in achieving the desired result. The therapeutically effective amount depends on the individual's condition, age, sex, and weight. Which factors, and the ability of therapeutic drugs or combinations of therapeutic drugs to elicit the desired response in an individual The effects may vary depending on the force. Examples of indicators showing effective therapeutic drugs or combinations of therapeutic drugs are provided. For example, improvements in the patient's health, reduction in tumor volume, cessation or slowing of tumor growth, This includes the absence of metastasis of cancer cells to other parts of the body and / or other locations.

[0037] "Inhibiting proliferation" (for example, when referring to tumor cells) is the action of a therapeutic agent or combination of therapeutic drugs. Compared to the proliferation of identical tumor cells or tumor tissue in the absence of the combination, the therapeutic agent or therapeutic agent Tumor cell proliferation in vitro or in vivo when in contact with a combination or drug or This refers to a measurable reduction in tumor tissue. This is observed in tumor cells or tumors in vitro or in vivo. Inhibition of tissue proliferation is at least approximately 10%, 20%, 30%, 40%, 50%, 60%. It could be 70%, 80%, 90%, 99%, or 100%.

[0038] "CD38-positive hematological malignancies" include leukemia, lymphoma, and myeloma, as well as CD38-positive hematological malignancies. This refers to hematological malignancies characterized by the presence of tumor cells expressing gene 8. Examples of CD38-positive hematological malignancies include precursor B-cell lymphoblastic leukemia / lymphoma and B-cell non-Hodgkin lymphoma, acute promyelocytic leukemia, acute lymphoblastic leukemia, and mature B Cellular tumors, such as B-cell chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) ), B-cell acute lymphoblastic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma Mantle cell lymphoma (MCL), follicular lymphoma (FL) (low-grade, intermediate-grade and (including high-grade FL), cutaneous follicular lymphoma, marginal zone B-cell lymphoma (MALT type, nodule) hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), - Kitt lymphoma (BL), plasmacytoma, multiple myeloma, plasma cell leukemia, post-transplant lymphoma Proliferative disorders, light chain amyloidosis, Waldenström macroglobulinemia, phenotype Examples include cell leukemia and anaplastic large cell lymphoma (ALCL).

[0039] "Approximately" means that a particular value is within the tolerance range determined by a person skilled in the art. This means that the limits of the measurement system are how the value is measured or determined. Partially dependent on the examples or the specification relating to a particular assay, result, or embodiment. Unless otherwise explicitly stated elsewhere, “about” means “about” in the context of the technical field. This refers to the greater of either one standard deviation or up to 5% of the row.

[0040] Pharmaceutical composition This invention provides a pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase.

[0041] Hyaluronidase breaks down hyaluronic acid (EC3.2.1.35) and extracellular matrix This enzyme increases tissue permeability by reducing the viscosity of hyaluronan in custard. The enzymatic activity of hyaluronidase containing rHuPH20 is as described further below, mL It is defined by the unit per unit (U / mL) or the total enzyme activity (U) in a particular formulation. It is possible.

[0042] rHuPH20 is recombinant hyaluronidase (HYLENEX® recombinant). This is described in International Publication No. 2004 / 078140.

[0043] The standard definition of one unit (U) of enzyme activity is the reaction of a given amount of substrate per unit time. This refers to the amount of catalyzing enzyme, for example, 1 μmole or 1 nmol of substrate per minute. The technique for determining the activity of hyaluronidase preparations is known in the art. Yes, the activity of hyaluronidase preparations is typically measured in USP units or units (hereinafter referred to as "units"). It is expressed as ''). An exemplary method for determining activity is U.S. Patent No. 7,767,429 It is listed in the issue number.

[0044] Hyaluronidase activity refers to the ability to enzymatically catalyze the cleavage of hyaluronic acid. (United States) US Pharmacopoeia (USP) XXII provides assays relating to hyaluronidase, and Luronidase activity is measured by the enzyme's reaction with hyaluronic acid, i.e., hyaluronan (HA), for 30 minutes. By measuring the amount of high molecular weight HA substrate remaining after the reaction at 7°C, it is possible to indirectly determine the amount of high molecular weight HA substrate remaining. It has been determined to be [in a state of emergency]. (USP XXII-NF XVII(1990)644-645) United States Pharmacopeia Convention,In c(Rockville, Md.)). The reference standard solvent is relative to any hyaluronidase. It can be used in assays to determine the target activity (units). Soluble rHu In vitro testing for determining the hyaluronidase activity of hyaluronidases such as PH20 Exemplary examples are known in the art and are described herein. As for the form, it is formed when uncleaved hyaluronic acid binds to serum albumin. By detecting the insoluble precipitate, the cleavage of hyaluronic acid by hyaluronidase can be detected. The microturbidity assay described later, which measures the turbidity indirectly (see, for example, Example 3), For example, the reference standard is used to determine the activity (units) of the hyaluronidase being tested. It can be used to generate a standard curve for determination.

[0045] The pharmaceutical composition is for subjects requiring anti-CD38 antibody therapy, such as cancer (e.g., CD38 It is useful for subcutaneous administration of anti-CD38 antibodies to subjects with positive hematological malignancies. While not bound by theory, subcutaneous administration of anti-CD38 antibodies is equivalent to intravenous administration of anti-CD38 antibodies. Compared to oral administration, infusion-related reactions are reduced, and an improvement in response rates can be achieved.

[0046] In some embodiments, the pharmaceutical composition is a fixed combination.

[0047] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0048] In some embodiments, the pharmaceutical composition contains approximately 1 mg / mL to approximately 180 mg / mL of anti-C. Contains D38 antibody.

[0049] In some embodiments, the pharmaceutical composition contains approximately 10 mg / mL to approximately 180 mg / mL of antimicrobial agent. Contains CD38 antibody.

[0050] In some embodiments, the pharmaceutical composition contains approximately 20 mg / mL to approximately 160 mg / mL of antimicrobial agent. Contains CD38 antibody.

[0051] In some embodiments, the pharmaceutical composition contains approximately 20 mg / mL to approximately 140 mg / mL of antimicrobial agent. Contains CD38 antibody.

[0052] In some embodiments, the pharmaceutical composition contains approximately 20 mg / mL to approximately 120 mg / mL of antimicrobial agent. Contains CD38 antibody.

[0053] In some embodiments, the pharmaceutical composition contains approximately 40 mg / mL to approximately 120 mg / mL of antimicrobial agent. Contains CD38 antibody.

[0054] In some embodiments, the pharmaceutical composition contains approximately 60 mg / mL to approximately 120 mg / mL of antimicrobial agent. Contains CD38 antibody.

[0055] In some embodiments, the pharmaceutical composition contains approximately 80 mg / mL to approximately 120 mg / mL of antimicrobial agent. Contains CD38 antibody.

[0056] In some embodiments, the pharmaceutical composition is approximately 100 mg / mL to approximately 120 mg / mL Contains anti-CD38 antibody.

[0057] In some embodiments, the pharmaceutical composition is approximately 1 mg / mL, approximately 5 mg / mL, and approximately 10 mg / mL. g / mL, approx. 15 mg / mL, approx. 20 mg / mL, approx. 30 mg / mL, approx. 40 mg / mL , approx. 50 mg / mL, approx. 60 mg / mL, approx. 70 mg / mL, approx. 80 mg / mL, approx. 90 mg / mL, approx. 100 mg / mL, approx. 110 mg / mL, approx. 120 mg / mL, approx. 130 mg / mL, approx. 140 mg / mL, approx. 150 mg / mL, approx. 160 mg / mL, approx. 170 Contains mg / mL or approximately 180 mg / mL of anti-CD38 antibody.

[0058] In some embodiments, the pharmaceutical composition contains approximately 20 mg / mL of anti-CD38 antibody.

[0059] In some embodiments, the pharmaceutical composition contains approximately 100 mg / mL of anti-CD38 antibody. .

[0060] In some embodiments, the pharmaceutical composition comprises approximately 120 mg / mL of anti-CD38 antibody. .

[0061] In some embodiments, the pharmaceutical composition contains approximately 50 U / mL to approximately 5,000 U / mL of hydroxypropyl alcohol. Contains alronidase.

[0062] In some embodiments, the pharmaceutical composition is approximately 500 U / mL to approximately 5,000 U / mL. Contains hyaluronidase.

[0063] In some embodiments, the pharmaceutical composition is approximately 1,000 U / mL to approximately 5,000 U / mL. Contains L-hyaluronidase.

[0064] In some embodiments, the pharmaceutical composition is approximately 2,000 U / mL to approximately 5,000 U / mL. Contains L-hyaluronidase.

[0065] In some embodiments, the pharmaceutical composition contains approximately 50 U / mL to approximately 2,000 U / mL of hyphen. Contains alronidase.

[0066] In some embodiments, the pharmaceutical composition is approximately 500 U / mL to approximately 2,000 U / mL. Contains hyaluronidase.

[0067] In some embodiments, the pharmaceutical composition is approximately 1,000 U / mL to approximately 2,000 U / mL. Contains L-hyaluronidase.

[0068] In some embodiments, the pharmaceutical composition is approximately 500 U / mL, approximately 600 U / mL, and approximately 7 00U / mL, approx. 800U / mL, approx. 900U / mL, approx. 1,000U / mL, approx. 1,1 00U / mL, approximately 1,200U / mL, approximately 1,300U / mL, approximately 1,400U / mL, Approx. 1,500U / mL, Approx. 1,600U / mL, Approx. 1,700U / mL, Approx. 1,800U / mL, approx. 1,900U / mL, approx. 2,000U / mL, approx. 2,100U / mL, approx. 2, 200U / mL, approx. 2,300U / mL, approx. 2,400U / mL, approx. 2,500U / mL , approx. 2,600U / mL, approx. 2,700U / mL, approx. 2,800U / mL, approx. 2,900 U / mL, approx. 3,000U / mL, approx. 3,100U / mL, approx. 3,200U / mL, approx. 3 ,300U / mL, approx. 3,400U / mL, approx. 3,500U / mL, approx. 3,600U / m L, approx. 3,700U / mL, approx. 3,800U / mL, approx. 3,900U / mL, approx. 4,00 0U / mL, approx. 4,100U / mL, approx. 4,200U / mL, approx. 4,300U / mL, approx. 4,400U / mL, approx. 4,500U / mL, approx. 4,600U / mL, approx. 4,700U / hyaluronic acid in mL, approximately 4,800 U / mL, approximately 4,900 U / mL, or approximately 5,000 U / mL Contains lonidase.

[0069] In some embodiments, the pharmaceutical composition contains approximately 500 U / mL of hyaluronidase. .

[0070] In some embodiments, the pharmaceutical composition contains approximately 2,000 U / mL of hyaluronidase. include.

[0071] In some embodiments, the pharmaceutical composition contains approximately 5,000 U / mL of hyaluronidase. include.

[0072] In some embodiments, the pharmaceutical composition contains approximately 1,200 mg to approximately 5,000 mg of anti-C. Contains D38 antibody.

[0073] In some embodiments, the pharmaceutical composition contains approximately 1,200 mg to approximately 2,400 mg of anti-C. Contains D38 antibody.

[0074] In some embodiments, the pharmaceutical composition contains approximately 1,200 mg to approximately 1,800 mg of anti-C Contains D38 antibody.

[0075] In some embodiments, the pharmaceutical composition contains about 1,200 mg of anti-CD38 antibody.

[0076] In some embodiments, the pharmaceutical composition contains about 1,400 mg of anti-CD38 antibody.

[0077] In some embodiments, the pharmaceutical composition contains about 1,600 mg of anti-CD38 antibody.

[0078] In some embodiments, the pharmaceutical composition contains approximately 1,800 mg of anti-CD38 antibody.

[0079] In some embodiments, the pharmaceutical composition contains about 2,000 mg of anti-CD38 antibody.

[0080] In some embodiments, the pharmaceutical composition contains approximately 2,200 mg of anti-CD38 antibody.

[0081] In some embodiments, the pharmaceutical composition contains approximately 2,400 mg of anti-CD38 antibody.

[0082] In some embodiments, the pharmaceutical composition contains approximately 2,600 mg of anti-CD38 antibody.

[0083] In some embodiments, the pharmaceutical composition contains approximately 2,800 mg of anti-CD38 antibody.

[0084] In some embodiments, the pharmaceutical composition contains about 3,000 mg of anti-CD38 antibody.

[0085] In some embodiments, the pharmaceutical composition contains approximately 3,500 mg of anti-CD38 antibody.

[0086] In some embodiments, the pharmaceutical composition contains approximately 4,000 mg of anti-CD38 antibody.

[0087] In some embodiments, the pharmaceutical composition contains approximately 4,500 mg of anti-CD38 antibody.

[0088] In some embodiments, the pharmaceutical composition contains approximately 5,000 mg of anti-CD38 antibody.

[0089] In some embodiments, the pharmaceutical composition contains approximately 750U to approximately 75,000U of hyaluronic acid. Contains dase.

[0090] In some embodiments, the pharmaceutical composition contains hyaluronic acid in a concentration of approximately 7,500 U to approximately 45,000 U. Contains lonidase.

[0091] In some embodiments, the pharmaceutical composition contains approximately 30,000U to approximately 45,000U of hyaluronic acid. Contains luronidase.

[0092] In some embodiments, the pharmaceutical composition contains approximately 7,500 U, approximately 8,000 U, and approximately 8,5 00U, approx. 9,000U, approx. 10,000U, approx. 15,000U, approx. 20,000U, approx. 21,000U, approx. 22,000U, approx. 23,000U, approx. 24,000U, approx. 25,0 00U, approx. 26,000U, approx. 27,000U, approx. 28,000U, approx. 29,000U, Approx. 30,000U, Approx. 31,000U, Approx. 32,000U, Approx. 33,000U, Approx. 34, 000U, approx. 35,000U, approx. 36,000U, approx. 37,000U, approx. 38,000U , approx. 39,000U, approx. 40,000U, approx. 41,000U, approx. 42,000U, approx. 43 ,000U, approx. 44,000U, approx. 45,000U, approx. 46,000U, approx. 47,000 U, approx. 48,000U, approx. 49,000U, approx. 50,000U, approx. 55,000U, approx. 6 Hyaluronic acid at 0,000U, approximately 65,000U, approximately 70,000U, or approximately 75,000U Contains dase.

[0093] In some embodiments, the pharmaceutical composition contains about 5,000 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0094] In some embodiments, the pharmaceutical composition contains about 5,000 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0095] In some embodiments, the pharmaceutical composition contains about 3,000 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0096] In some embodiments, the pharmaceutical composition contains about 3,000 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0097] In some embodiments, the pharmaceutical composition contains about 2,800 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0098] In some embodiments, the pharmaceutical composition contains about 2,800 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0099] In some embodiments, the pharmaceutical composition contains about 2,600 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0100] In some embodiments, the pharmaceutical composition contains about 2,600 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0101] In some embodiments, the pharmaceutical composition contains about 2,400 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0102] In some embodiments, the pharmaceutical composition contains about 2,400 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0103] In some embodiments, the pharmaceutical composition contains about 2,200 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0104] In some embodiments, the pharmaceutical composition contains about 2,200 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0105] In some embodiments, the pharmaceutical composition contains about 2,000 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0106] In some embodiments, the pharmaceutical composition contains about 2,000 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0107] In some embodiments, the pharmaceutical composition contains about 1,800 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0108] In some embodiments, the pharmaceutical composition contains about 1,800 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0109] In some embodiments, the pharmaceutical composition contains about 1,600 mg of anti-CD38 antibody and about 3 Contains 0,000 U of hyaluronidase.

[0110] In some embodiments, the pharmaceutical composition contains about 1,600 mg of anti-CD38 antibody and about 4 It contains 5,000 U of hyaluronidase.

[0111] In some embodiments, the hyaluronidase has the amino acid sequence of SEQ ID NO: 22 It is rHuPH20.

[0112] In some embodiments, the anti-CD38 antibody in the pharmaceutical composition is located in the heavy chain variable region of SEQ ID NO: 4. Antibodies containing the VH region and the VL light chain variable region of SEQ ID NO: 5, and related to binding to CD38. They compete.

[0113] In some embodiments, the anti-CD38 antibody in the pharmaceutical composition is human CD38 (SEQ ID NO: 1) Region SKRNIQFSCKNIYR (SEQ ID NO: 2) and region EKVQTLEAWV It binds to at least IHGG (sequence number 3).

[0114] In some embodiments, the anti-CD38 antibody in the pharmaceutical composition is represented by SEQ ID NOs. 6 and 7, respectively. , 8, 9, 10 and 11, Heavy Chain Complementarity Determination Region 1 (HCDR1), HCDR2, HCD This includes R3, light chain complementarity determination region 1 (LCDR1), LCDR2, and LCDR3.

[0115] In some embodiments, the anti-CD38 antibody in the pharmaceutical composition is the amino acid of SEQ ID NO: 4 The heavy chain variable region (V) is 95%, 96%, 97%, 98%, 99%, or 100% identical to the column. H) and the amino acid sequence of SEQ ID NO: 95%, 96%, 97%, 98%, 99%, or 10% It includes a light chain variable region (VL) that is 0% identical.

[0116] In some embodiments, the anti-CD38 antibody in the pharmaceutical composition is VH of SEQ ID NO: 4 and Includes VL for column number 5.

[0117] In some embodiments, the anti-CD38 antibody in the pharmaceutical composition is the heavy chain of SEQ ID NO: 12 and Includes the light chain of sequence number 13.

[0118] Sequence ID 2 SKRNIQFSCKNIYR

[0119] Sequence ID 3 EKVQTLEAWVIHGG

[0120] Sequence ID 4 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQ APGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYFCAKDK ILWFGEPVFDYWGQGTLVTVSS

[0121] Sequence ID 5 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYD ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQ QRSNWPPTFGQ GTKVEIK

[0122] Sequence ID 6 SFAMS

[0123] Sequence ID 7 AISGSGGGTYYADSVKG

[0124] Sequence ID 8 DKILWFGEPVFDY

[0125] Sequence ID 9 RASQSVSSYLA

[0126] Sequence ID 10 DASNRAT

[0127] Sequence ID 11 QQRSNWPPTF

[0128] Sequence ID 12 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQ APGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK

[0129] Sequence ID 13 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC

[0130] Other exemplary anti-CD38 antibodies that may be used in the pharmaceutical compositions and methods of the present invention include teeth, VH as described in U.S. Patent No. 7,829,693, Sequence IDs 14 and 15, respectively. mAb003 containing the sequence and VL sequence (VH and VL of mAb003 are IgG1 / κ and It can be expressed as follows; VH as described in U.S. Patent No. 7,829,693, Sequence IDs 16 and 17, respectively. mAb024 containing the sequence and VL sequence (the VH and VL of mAb024 are IgG1 / κ and It can be expressed as follows; VH as described in U.S. Patent No. 8,088,896, Sequence ID Nos. 18 and 19, respectively. MOR-202 (MOR-03087) (VH of MOR-202) containing sequence and VL sequence And VL can be expressed as IgG1 / κ); or VH as described in U.S. Patent No. 8,153,765, Sequence IDs 20 and 21, respectively. Isatuximab containing the sequence and VL sequence (VH and VL of isatuximab are IgG1 / (This can be expressed as κ.)

[0131] Sequence ID 14 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQ APGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTA YMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVS SAS

[0132] Sequence ID 15 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQK PEKAPKSLIYAASSLQSGVPSRFSGSGGSGTDFTLTISSLQ PEDFATYYCQQYNSYPRTFGQGTKVEIK

[0133] Sequence ID 16 EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQ MPGKGLEWMGIIYPHSDARYSPSFQGQVTFSADKSISTA YLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVT VSS

[0134] Sequence ID 17 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPGLLIYDASNRASGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPLTFGGGTKVEIK

[0135] Sequence ID 18 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQ APGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVS S

[0136] Sequence ID 19 DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKP GQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQA EDEADYYCQTYTGGASLVFGGGGTKLTVLGQ

[0137] Sequence ID 20 QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQ RPGQGLEWIGT IYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASE DSAVYYCARGD YYGSNSLDYWGQGTSVTVSS

[0138] Sequence ID 21 DIVMTQSHLSMSSTSLGDPVSITCKASQDVSTVVAWYQQK PGQSPRRLIYS ASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQ QHYSPPYTFGG GTKLEIK

[0139] Other exemplary anti-CD38 antibodies that may be used in the pharmaceutical compositions of the present invention include international Publication No. 05 / 103083, Publication No. 06 / 125640, Publication No. 07 / 042309, Some are listed in the same document, No. 08 / 047242 or No. 14 / 178820. .

[0140] An exemplary anti-CD38 antibody that may be used in the pharmaceutical composition of the present invention is daratumumab. Yes. Daratumumab has a heavy chain variable region (VH) amine, as shown in Sequence IDs 4 and 5, respectively. The HC sequences of the anoacid sequence and the light chain variable region (VL) amino acid sequence, respectively, of sequence numbers 6, 7, and 8. LCDs DR1, HCDR2, and HCDR3, and sequence numbers 9, 10, and 11, respectively. It contains R1, LCDR2, and LCDR3, and is of the IgG1 / κ subtype, and is a US special It is described in Permission No. 7,829,693. The amino acid sequence of the daratumumab heavy chain is: The sequence of amino acids in the light chain, shown as number 12, is shown in sequence number 13.

[0141] The present invention also includes an anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5, and sequence A pharmaceutical composition comprising hyaluronidase rHuPH20 of number 22, and the pharmaceutical composition The present invention provides a pharmaceutical composition in which the anti-CD38 antibody concentration is approximately 20 mg / mL.

[0142] The present invention also relates to HCDR1, HCDR2 and HCDR of Sequence IDs 6, 7 and 8, respectively. 3 and LCDR1, LCDR2, and LCDR3 of sequence numbers 9, 10, and 11 respectively A pharmaceutical product containing an anti-CD38 antibody and hyaluronidase rHuPH20 (SEQ ID NO: 22). A composition in which the concentration of anti-CD38 antibody in the pharmaceutical composition is approximately 20 mg / mL. A composition is provided.

[0143] The present invention also includes approximately 1,200 mg to 1, 800 mg of anti-CD38 antibody and approximately 30,000 U to 45,000 U of SEQ ID NO: 22 A pharmaceutical composition comprising arronidase rHuPH20, wherein the pharmaceutical composition contains anti-CD3 The present invention provides a pharmaceutical composition in which the antibody concentration is approximately 20 mg / mL.

[0144] The present invention also provides approximately 1,800 mg of anti-C, including VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5. D38 antibody and approximately 30,000 U of hyaluronidase rHuPH20 (SEQ ID NO: 22), A pharmaceutical composition comprising, wherein the concentration of anti-CD38 antibody in the pharmaceutical composition is approximately 20 mg / mL. A certain pharmaceutical composition is provided.

[0145] The present invention also provides approximately 1,800 mg of anti-C, including VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5. D38 antibody and approximately 45,000 U of hyaluronidase rHuPH20 (SEQ ID NO: 22), A pharmaceutical composition comprising, wherein the concentration of anti-CD38 antibody in the pharmaceutical composition is approximately 20 mg / mL. A certain pharmaceutical composition is provided.

[0146] The present invention also includes approximately 1,600 mg of anti-C, containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5. D38 antibody and approximately 30,000 U of hyaluronidase rHuPH20 (SEQ ID NO: 22), A pharmaceutical composition comprising, wherein the concentration of anti-CD38 antibody in the pharmaceutical composition is approximately 20 mg / mL. A certain pharmaceutical composition is provided.

[0147] The present invention also includes approximately 1,600 mg of anti-C, containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5. D38 antibody and approximately 45,000 U of hyaluronidase rHuPH20 (SEQ ID NO: 22), A pharmaceutical composition comprising an anti-CD38 antibody, wherein the anti-CD38 antibody concentration in the pharmaceutical composition is about 20 mg / mL Provided is a pharmaceutical composition.

[0148] The present invention also provides a pharmaceutical composition comprising about 1,200 mg of an anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 and about 30,000 U of rHuPH20 of SEQ ID NO: 22 A pharmaceutical composition comprising an anti-CD38 antibody, wherein the anti-CD38 antibody concentration in the pharmaceutical composition is about 20 mg / mL Provided is a pharmaceutical composition.

[0149] The present invention also provides a pharmaceutical composition comprising about 1,200 mg of an anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 and about 45,000 U of rHuPH20 of SEQ ID NO: 22 A pharmaceutical composition comprising an anti-CD38 antibody, wherein the anti-CD38 antibody concentration in the pharmaceutical composition is about 20 mg / mL Provided is a pharmaceutical composition.

[0150] SEQ ID NO: 22 MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFR APPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSP RINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKIS LQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTWARNWK PKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDF LVETIKLGKLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCF NVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAATLYVR NRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQD ELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYME TILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYLH LNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYS TLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQ IFYNASPSTLSATMFIVSILFLIISSVASL

[0151] The anti-CD38 antibody used in the pharmaceutical composition of the present invention is, for example, a phage-presenting antibody. A new phage may be selected from Burari, and this phage may be human immunoglobulin or a portion thereof. (For example, Fab, single-chain antibodies (scFv), or unpaired or paired antibodies are acceptable.) The gene has been modified to express the variant region (Knappik et al., J Mol Biol 296:57~86,2000;Krebs et al.,JI mmunol Meth 254:67~84,2001;Vaughan et al .,Nature Biotechnology 14:309~314,1996;S heets et al., PITAS (USA) 95:6157~6162, 1998 ;Hoogenboom and Winter, J Mol Biol 227:38 1,1991;Marks et al.,J Mol Biol 222:581,1 991). The CD38-binding variable domain is, for example, Shi et al., J. Mol. (As described in Biol. 397:385~96, 2010 and International Publication No. 09 / 085462) The antibody heavy chain is a fusion protein with the bacteriophage pIX coated protein that is included. It can also be isolated from phage-presenting libraries expressing the light chain variable region. Antibody library The positive results were screened for binding to the extracellular domain of human CD38. Further characterization of the clone was performed, and Fab was isolated from the clone lysate, followed by full-length antibody It can be cloned as such. Such phage preparations for isolating human antibodies The method is well-established in the art. For example, U.S. Patent No. 5,223,409, No. 5,403,484, No. 5,571,698, No. 5,427,908, No. 5,427,908, No. No. 5,580,717, No. 5,969,108, No. 6,172,197, No. 5 , No. 885,793, No. 6,521,404, No. 6,544,731, No. 6, See also issues 555,313, 6,582,915 and 6,593,081. and.

[0152] The antibody, using a well-known in vitro method, was tested for its binding to CD38 using a reference antibody, for example, We will evaluate the competition with anti-CD38 antibodies, including VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5. This is possible. In an exemplary method, CHO cells that recombinantly express CD38 are unlabeled. After incubation with the reference antibody at 4°C for 15 minutes, add the excess amount of fluorescently labeled test antibody at 4°C. It can be incubated for 45 minutes. After washing in PBS / BSA, use a standard method. Fluorescence can be measured by low cytometry. In another exemplary method, The extracellular portion of human CD38 can be coated on the surface of the ELISA plate. The labeled reference antibody can be added for approximately 15 minutes, after which the biotinylation antibody can be added. After washing in PBS / Tween, the biotinylated antibody was bound to horseradish peroxy HRP-conjugated streptavidin and signals detected using standard methods can be used for detection. In a competitive assay, it is readily apparent that the reference antibody may be labeled and the test antibody may not be labeled. If the reference antibody inhibits the binding of the test antibody, or the test antibody inhibits the binding of the reference antibody by at least 80%, for example, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%, the test antibody competes with the reference antibody. The epitope of the test antibody can be further defined, for example, by peptide mapping, or by a hydrogen / deuterium protection assay using known methods, or by crystal structure determination. 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%, the test antibody competes with the reference antibody. The epitope of the test antibody can be further defined, for example, by peptide mapping, or by a hydrogen / deuterium protection assay using known methods, or by crystal structure determination. Antibodies that bind to the regions SKRNIQFSCKNIYR (SEQ ID NO: 2) and EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1) can be generated, for example, by immunizing mice with peptides having the amino acid sequences shown in SEQ ID NOs: 2 and 3 using standard methods and methods described herein, and characterizing the resulting antibodies for binding to these peptides using, for example, ELISA or mutagenesis experiments.

[0153] The present invention also provides a. the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15, b. the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17, c. the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19, or d. the HCDR1 sequence, the HCDR2 sequence of the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21

[0154] The present invention also provides a. the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15, b. the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17, c. the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19, or d. the HCDR1 sequence, the HCDR2 sequence of the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21 ​​Anti-CD38 containing HCDR3 sequence, LCDR1 sequence, LCDR2 sequence and LCDR3 sequence This invention provides a pharmaceutical composition comprising an antibody and hyaluronidase rHuPH20, which is sequence number 22. ru.

[0155] The present invention also, a. VH of sequence number 14 and VL of sequence number 15, b. VH of sequence number 16 and VL of sequence number 17, c. VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d. Anti-CD38 antibodies including VH of SEQ ID NO: 20 and VL of SEQ ID NO: 2 The present invention provides a pharmaceutical composition comprising hyaluronidase rHuPH20.

[0156] The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier. Exemplary pharmaceutically acceptable... The carriers include physiologically compatible solvents, dispersion media, coating agents, antibacterial and antifungal agents, These include isotonic and absorption retardants, such as salts, buffers, antioxidants, sugars, aqueous or non-aqueous solutions. Aqueous carrier, preservative, wetting agent, surfactant or emulsifier, or a combination thereof. .

[0157] Examples of buffers that can be used include acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, and phosphate. Goic acid, aspartic acid, histidine, boric acid, Tris buffer, HEPPSO and HEP It is ES.

[0158] Examples of antioxidants that may be used include ascorbic acid, methionine, cysteine ​​hydrochloride, Sodium bicarbonate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, These are ethylenediaminetetraacetic acid (EDTA), sorbitol, and tartaric acid.

[0159] Examples of amino acids that can be used include histidine, isoleucine, methionine, and glycine. Arginine, lysine, L-leucine, trileucine, alanine, glutamic acid, L- These are rheonine and 2-phenylamine.

[0160] Exemplary surfactants that may be used include polysorbates (e.g., polysorbate-20) or polysorbate-80); polyoxamer (e.g., poloxamer 188); trito Sodium octyl glycoside; lauryl-, myristyl- , linoleyl- or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl Lu- or stearyl-sarcosine; linoleyl-, myristyl- or cetyl-betaine; Lauroamidopropyl-, Cocamidopropyl-, Linoleamidopropyl-, Myristoami Dopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (for example, Lauroamidopropyl; Myristoamidopropyl-, Palmidopropyl- or Isoste Aramidopropyl-dimethylamine; sodium-methylcocoyl- or disodium- Methyl oleyl taurate; and MONAQUA® series (Mona In Dustries, Inc. (Paterson, NJ), polyethyl glycol , polypropyl glycol, and copolymer of ethylene and propylene glycol (for example) Examples include PLURONICS (trademark), PF68, etc.

[0161] Examples of preservatives that may be used include phenol, m-cresol, p-cresol, o- Cresol, chlorocresol, benzyl alcohol, phenylmercury nitrate, phenoxyethanol Tanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparabens (Methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride It is sodium dehydroacetate and thimerosal, or a mixture thereof.

[0162] Exemplary sugars that may be used include glucose, sucrose, trehalose, lactose, Fructose, maltose, dextran, glycerin, dextran, erythritol Glycerol, arabitol, sylitol, sorbitol, mannitol , melivious, melegithos, raffinose, mannotrious, stachyous, mal Tose, lactulose, maltulose, glucitol, maltitol, lactitol or Monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non- It is a reducing sugar.

[0163] Examples of salts that can be used are acid addition salts and base addition salts. Examples of acid addition salts include Non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorous acid. Origin, and for example, aliphatic mono and dicarboxylic acids, phenyl-substituted alkanes, hydrox Derived from non-toxic organic acids such as sialic acid, aromatic acids, aliphatic and aromatic sulfonic acids. Examples include sodium, potassium, magnesium, and calcium. Alkaline earth metals such as sium, and for example, N,N'-dibenzylethylenediamine Min, N-methylglucamine, chloroprocaine, choline, diethanolamine, etile Examples include those derived from non-toxic organic amines such as diamines and procaine. Exemplary salts It is sodium chloride.

[0164] The amount of pharmaceutically acceptable carriers (one or more) in a pharmaceutical composition is the amount of carriers (one or more) The activity and desired properties of the formulation, such as stability and / or minimal oxidation, are determined experimentally. It can be determined.

[0165] In some embodiments, the pharmaceutical composition contains acetic acid.

[0166] In some embodiments, the pharmaceutical composition contains acetic acid at a concentration of about 1 mM to about 50 mM.

[0167] In some embodiments, the pharmaceutical composition contains acetic acid at a concentration of about 10 mM to about 40 mM. .

[0168] In some embodiments, the pharmaceutical composition is approximately 10 mM, approximately 15 mM, approximately 20 mM, and approximately 2 mM. Acetic acid at concentrations of 5 mM, approximately 30 mM, approximately 35 mM, approximately 40 mM, approximately 45 mM, or approximately 50 mM. Includes.

[0169] In some embodiments, the pharmaceutical composition contains acetic acid at a concentration of about 25 mM.

[0170] In some embodiments, the pharmaceutical composition includes sodium chloride (NaCl).

[0171] In some embodiments, the pharmaceutical composition contains NaCl at a concentration of about 20 mM to about 100 mM. Includes.

[0172] In some embodiments, the pharmaceutical composition contains NaCl at a concentration of about 40 mM to about 80 mM. include.

[0173] In some embodiments, the pharmaceutical composition is approximately 20 mM, approximately 25 mM, approximately 30 mM, and approximately 3 mM. 5mM, about 40mM, about 45mM, about 50mM, about 55mM, about 60mM, about 65mM, Approximately 70mM, approximately 75mM, approximately 80mM, approximately 85mM, approximately 90mM, approximately 95mM, or approximately 10 Contains NaCl at a concentration of 0 mM.

[0174] In some embodiments, the pharmaceutical composition contains NaCl at a concentration of about 60 mM.

[0175] In some embodiments, the pharmaceutical composition includes sugars.

[0176] In some embodiments, the sugar is sucrose.

[0177] In some embodiments, the sugar is sorbitol.

[0178] In some embodiments, the sugar is mannitol.

[0179] In some embodiments, the pharmaceutical composition contains sugars at a concentration of about 50 mM to about 500 mM. nothing.

[0180] In some embodiments, the pharmaceutical composition contains sugars at a concentration of about 50 mM to about 450 mM. nothing.

[0181] In some embodiments, the pharmaceutical composition contains sugars at a concentration of about 50 mM to about 400 mM. nothing.

[0182] In some embodiments, the pharmaceutical composition contains sugars at a concentration of about 50 mM to about 350 mM. nothing.

[0183] In some embodiments, the pharmaceutical composition contains sugars at a concentration of about 100 mM to about 350 mM. include.

[0184] In some embodiments, the pharmaceutical composition contains sugars at a concentration of about 100 mM to about 300 mM. include.

[0185] In some embodiments, the pharmaceutical composition is approximately 100 mM, approximately 110 mM, and approximately 120 mM. , about 130mM, about 140mM, about 150mM, about 160mM, about 170mM, about 180 mM, approx. 190mM, approx. 200mM, approx. 210mM, approx. 220mM, approx. 230mM, approx. 2 40mM, approx. 250mM, approx. 260mM, approx. 270mM, approx. 280mM, approx. 290mM, Approx. 300mM, Approx. 310mM, Approx. 320mM, Approx. 330mM, Approx. 340mM, Approx. 350m M, approx. 360mM, approx. 370mM, approx. 380mM, approx. 390mM, approx. 400mM, approx. 41 0mM, approximately 420mM, approximately 430mM, approximately 440mM, approximately 450mM, approximately 460mM, approximately It contains sugars at concentrations of 470 mM, approximately 480 mM, approximately 490 mM, or approximately 500 mM.

[0186] In some embodiments, the pharmaceutical composition includes mannitol.

[0187] In some embodiments, the pharmaceutical composition contains mannitol at a concentration of about 100 mM to about 180 mM. Includes Thor.

[0188] In some embodiments, the pharmaceutical composition contains mannitol at a concentration of about 120 mM to about 160 mM. Includes Thor.

[0189] In some embodiments, the pharmaceutical composition is approximately 100 mM, approximately 105 mM, and approximately 110 mM. , about 115mM, about 120mM, about 125mM, about 130mM, about 135mM, about 140 mM, approx. 145mM, approx. 150mM, approx. 155mM, approx. 160mM, approx. 165mM, approx. 1 Contains mannitol at concentrations of 70 mM, approximately 175 mM, or approximately 180 mM.

[0190] In some embodiments, the pharmaceutical composition contains mannitol at a concentration of about 140 mM.

[0191] In some embodiments, the pharmaceutical composition includes polysorbate.

[0192] In some embodiments, the pharmaceutical composition comprises polysorbate-20 (PS-20). .

[0193] In some embodiments, the pharmaceutical composition has a concentration of about 0.01% w / v to about 0.1% w / v. Contains polysorbate-20 (PS-20).

[0194] In some embodiments, the pharmaceutical composition contains approximately 0.01% w / v to approximately 0.08% w / v Contains polysorbate-20 (PS-20) at a concentration.

[0195] In some embodiments, the pharmaceutical composition contains approximately 0.01% w / v to approximately 0.04% w / v Contains polysorbate-20 (PS-20) at a concentration.

[0196] In some embodiments, the pharmaceutical composition contains about 0.01% w / v, 0.02% w / v, and 0 .03%w / v, 0.04%w / v, 0.05%w / v, 0.06%w / v, 0.07% Polysorbates at concentrations of w / v, 0.08% w / v, 0.09% w / v, or 0.1% w / v. Includes To-20 (PS-20).

[0197] The present invention also, pH approximately 5.5, approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mM ma In nitrol and polysorbate-20 (PS-20) at approximately 0.04% w / v, sequence number Anti-CD3 formulations containing approximately 20 mg / mL to 120 mg / mL, including VH of product 4 and VL of sequence number 5. 38 antibodies, pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L-histidine Thionine, approximately 30,000U to 45,000U in 0.02% polysorbate 80 The present invention provides a pharmaceutical composition containing hyaluronidase.

[0198] In some embodiments, the hyaluronidase is rHuPH20 (SEQ ID NO: 22). ru.

[0199] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0200] The present invention also, pH approximately 5.5, approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mM ma In nitrol and polysorbate-20 (PS-20) at approximately 0.04% w / v, sequence number A 20 mg / mL anti-CD38 antibody containing VH of product 4 and VL of sequence number 5, pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L-histidine Thionine, approximately 30,000 U of hyaluronidase in 0.02% polysorbate 80. The present invention provides a pharmaceutical composition containing the following:

[0201] In some embodiments, the hyaluronidase is rHuPH20 (SEQ ID NO: 22). ru.

[0202] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0203] The present invention also, pH approximately 5.5, approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mM ma In nitrol and polysorbate-20 (PS-20) at approximately 0.04% w / v, sequence number A 20 mg / mL anti-CD38 antibody containing VH of product 4 and VL of sequence number 5, pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L-histidine Thionine, approximately 45,000 U of hyaluronidase in 0.02% polysorbate 80. The present invention provides a pharmaceutical composition containing the following:

[0204] In some embodiments, the hyaluronidase is rHuPH20 (SEQ ID NO: 22). ru.

[0205] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0206] In some embodiments, the pharmaceutical composition contains histidine.

[0207] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 1 mM to about 50 mM. include.

[0208] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 5 mM to about 50 mM. include.

[0209] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 5 mM to about 30 mM. include.

[0210] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 5 mM to about 20 mM. include.

[0211] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 5 mM to about 15 mM. include.

[0212] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 5 mM to about 10 mM. include.

[0213] In some embodiments, the pharmaceutical composition is approximately 1 mM, approximately 2 mM, approximately 3 mM, approximately 4 mM, Approximately 5mM, approximately 6mM, approximately 7mM, approximately 8mM, approximately 9mM, approximately 10mM, approximately 11mM, approximately 12 mM, approx. 13mM, approx. 14mM, approx. 15mM, approx. 16mM, approx. 17mM, approx. 18mM, approx. 19mM, approx. 20mM, approx. 21mM, approx. 22mM, approx. 23mM, approx. 24mM, approx. 25mM , about 26mM, about 27mM, about 28mM, about 29mM, about 30mM, about 31mM, about 32 mM, approx. 33mM, approx. 34mM, approx. 35mM, approx. 36mM, approx. 37mM, approx. 38mM, approx. 39mM, approx. 40mM, approx. 41mM, approx. 42mM, approx. 43mM, approx. 44mM, approx. 45mM histidine at concentrations of approximately 46 mM, 47 mM, 48 mM, 49 mM, or 50 mM. Includes.

[0214] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 5 mM.

[0215] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 10 mM.

[0216] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 15 mM.

[0217] In some embodiments, the pharmaceutical composition contains histidine at a concentration of about 20 mM.

[0218] In some embodiments, the pharmaceutical composition contains sorbite at a concentration of about 50 mM to about 500 mM. Includes .

[0219] In some embodiments, the pharmaceutical composition contains sorbite at a concentration of about 50 mM to about 450 mM. Includes .

[0220] In some embodiments, the pharmaceutical composition contains sorbite at a concentration of about 50 mM to about 400 mM. Includes .

[0221] In some embodiments, the pharmaceutical composition contains sorbite at a concentration of about 50 mM to about 350 mM. Includes .

[0222] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 100 mM to about 350 mM. Includes Thor.

[0223] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 100 mM to about 300 mM. Includes Thor.

[0224] In some embodiments, the pharmaceutical composition is approximately 100 mM, approximately 110 mM, and approximately 120 mM. , about 130mM, about 140mM, about 150mM, about 160mM, about 170mM, about 180 mM, approx. 190mM, approx. 200mM, approx. 210mM, approx. 220mM, approx. 230mM, approx. 2 40mM, approx. 250mM, approx. 260mM, approx. 270mM, approx. 280mM, approx. 290mM, Approx. 300mM, Approx. 310mM, Approx. 320mM, Approx. 330mM, Approx. 340mM, Approx. 350m M, approx. 360mM, approx. 370mM, approx. 380mM, approx. 390mM, approx. 400mM, approx. 41 0mM, approximately 420mM, approximately 430mM, approximately 440mM, approximately 450mM, approximately 460mM, approximately Contains sorbitol at concentrations of 470 mM, approximately 480 mM, approximately 490 mM, or approximately 500 mM. .

[0225] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 50 mM.

[0226] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 100 mM.

[0227] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 150 mM.

[0228] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 200 mM.

[0229] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 250 mM.

[0230] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 300 mM.

[0231] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 350 mM.

[0232] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 400 mM.

[0233] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 50 mM to about 500 mM. Includes S.

[0234] In some embodiments, the pharmaceutical composition contains sucrose in a concentration of about 50 mM to about 450 mM. Includes S.

[0235] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 50 mM to about 400 mM. Includes S.

[0236] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 50 mM to about 350 mM. Includes S.

[0237] In some embodiments, the pharmaceutical composition is diluted with a slurry at a concentration of about 100 mM to about 350 mM. Includes -.

[0238] In some embodiments, the pharmaceutical composition is diluted with a slurry at a concentration of about 100 mM to about 200 mM. Includes -.

[0239] In some embodiments, the pharmaceutical composition is approximately 100 mM, approximately 110 mM, and approximately 120 mM. , about 130mM, about 140mM, about 150mM, about 160mM, about 170mM, about 180 mM, approx. 190mM, approx. 200mM, approx. 210mM, approx. 220mM, approx. 230mM, approx. 2 40mM, approx. 250mM, approx. 260mM, approx. 270mM, approx. 280mM, approx. 290mM, Approx. 300mM, Approx. 310mM, Approx. 320mM, Approx. 330mM, Approx. 340mM, Approx. 350m M, approx. 360mM, approx. 370mM, approx. 380mM, approx. 390mM, approx. 400mM, approx. 41 0mM, approximately 420mM, approximately 430mM, approximately 440mM, approximately 450mM, approximately 460mM, approximately Contains sucrose at concentrations of 470 mM, approximately 480 mM, approximately 490 mM, or approximately 500 mM.

[0240] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 50 mM.

[0241] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 100 mM.

[0242] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 150 mM.

[0243] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 200 mM.

[0244] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 250 mM.

[0245] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 300 mM.

[0246] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 350 mM.

[0247] In some embodiments, the pharmaceutical composition contains sucrose at a concentration of about 400 mM.

[0248] In some embodiments, the pharmaceutical composition contains methionine.

[0249] In some embodiments, the pharmaceutical composition has a concentration of about 0.1 mg / mL to about 5 mg / mL. It contains methionine.

[0250] In some embodiments, the pharmaceutical composition is approximately 0.1 mg / mL to approximately 2.5 mg / mL Contains a high concentration of methionine.

[0251] In some embodiments, the pharmaceutical composition has a concentration of approximately 1 mg / mL to approximately 2 mg / mL. Contains thionine.

[0252] In some embodiments, the pharmaceutical composition is approximately 0.5 mg / mL, approximately 1 mg / mL, and approximately 1 .1mg / mL, approx. 1.2mg / mL, approx. 1.3mg / mL, approx. 1.4mg / mL, approx. 1 .5mg / mL, approx. 1.6mg / mL, approx. 1 / 7mg / mL, approx. 1.8mg / mL, approx. 1 .9mg / mL, approx. 2.0mg / mL, approx. 2.1mg / mL, approx. 2.2mg / mL, approx. 2 / 3mg / mL, approx. 2.4mg / mL, approx. 2.5mg / mL, approx. 2.6mg / mL, approx. 2 .7mg / mL, approx. 2.8mg / mL, approx. 2.9mg / mL, approx. 3mg / mL, approx. 3.5 Methionine at concentrations of mg / mL, approximately 4 mg / mL, approximately 4.5 mg / mL, or approximately 5 mg / mL. It includes n.

[0253] In some embodiments, the pharmaceutical composition has a pH of 5.0 to 6.0.

[0254] In some embodiments, the pharmaceutical composition has a pH of 5.3 to 5.8.

[0255] In some embodiments, the pharmaceutical composition has a pH of 5.5.

[0256] In some embodiments, the pharmaceutical composition has a pH of 5.6.

[0257] The present invention also, Anti-CD38 antibodies in concentrations of approximately 1 mg / mL to 180 mg / mL, Hyaluronidase at approximately 50 U / mL to approximately 5,000 U / mL, Approximately 5 mM to approximately 50 mM histidine, The present invention provides a pharmaceutical composition containing approximately 50 mM to approximately 400 mM sorbitol.

[0258] In some embodiments, the hyaluronidase is rHuPH20.

[0259] The present invention also, Anti-CD38 antibodies in concentrations of approximately 1 mg / mL to 180 mg / mL, Hyaluronidase at approximately 50 U / mL to approximately 5,000 U / mL, Approximately 5 mM to approximately 50 mM histidine, Sorbitol in concentrations of approximately 50 mM to 400 mM, PS-20 with approximately 0.01% w / v to approximately 0.1%, We provide a pharmaceutical composition containing methionine in an amount of approximately 0.1 mg / mL to approximately 2.5 mg / mL. ru.

[0260] In some embodiments, the hyaluronidase is rHuPH20.

[0261] The present invention also, Anti-CD38 antibody at approximately 100 mg / mL to approximately 120 mg / mL, Hyaluronidase at approximately 50 U / mL to approximately 5,000 U / mL, Approximately 10 mM histidine, The present invention provides a pharmaceutical composition containing approximately 100 mM to approximately 300 mM sorbitol.

[0262] In some embodiments, the hyaluronidase is rHuPH20.

[0263] In some embodiments, the pharmaceutical composition is It also contains PS-20 at approximately 0.01% w / v to 0.04% w / v.

[0264] In some embodiments, the pharmaceutical composition contains about 1 mg / mL to about 2 mg / mL of methionine. It also includes n.

[0265] In some embodiments, the pharmaceutical composition contains about 100 mM to about 200 mM sucrose. It also includes.

[0266] In some embodiments, the anti-CD38 antibody is used. HCDR1, HCDR2, and HCDR, respectively, with sequence numbers 6, 7, 8, 9, 10, and 11. 3. LCDR1, LCDR2 and LCDR3, VH and VL of sequence numbers 4 and 5, respectively, and / or This includes the heavy and light chains of sequence numbers 12 and 13, respectively.

[0267] In some embodiments, the anti-CD38 antibody is used. VH and VL of sequence numbers 14 and 15, respectively. VH and VL of sequence numbers 16 and 17, respectively. VH and VL of sequence numbers 18 and 19, respectively, or These include VH and VL of sequence numbers 20 and 21, respectively.

[0268] In some embodiments, the hyaluronidase contains rHuPH20 (SEQ ID NO: 22). nothing.

[0269] The present invention also, Each contains approximately 1 mg / mL to 180 mg / mL, including VH and VL of SEQ ID NOs. 4 and 5, respectively. The anti-CD38 antibody, Hyaluronidase at approximately 50 U / mL to approximately 5,000 U / mL, Approximately 5 mM to approximately 50 mM histidine, The present invention provides a pharmaceutical composition containing approximately 50 mM to approximately 400 mM sorbitol.

[0270] In some embodiments, the hyaluronidase is rHuPH20.

[0271] The present invention also, Each contains approximately 1 mg / mL to 180 mg / mL, including VH and VL of SEQ ID NOs. 4 and 5, respectively. The anti-CD38 antibody, Hyaluronidase at approximately 50 U / mL to approximately 5,000 U / mL, Approximately 5 mM to approximately 50 mM histidine, Sorbitol in concentrations of approximately 50 mM to 400 mM, PS-20 with approximately 0.01% w / v to approximately 0.1%, We provide a pharmaceutical composition containing methionine in an amount of approximately 0.1 mg / mL to approximately 2.5 mg / mL. ru.

[0272] In some embodiments, the hyaluronidase is rHuPH20.

[0273] The present invention also, Each contains approximately 100 mg / mL to approximately 120 mg / L, including VH and VL of SEQ ID NOs. 4 and 5, respectively. mL of anti-CD38 antibody, rHuPH20 with concentrations ranging from approximately 50 U / mL to approximately 5,000 U / mL, Approximately 10 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, The present invention provides a pharmaceutical composition containing approximately 1 mg / mL to approximately 2 mg / mL of methionine.

[0274] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 500 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.04 w / v, The present invention provides a pharmaceutical composition containing approximately 2 mg / mL of methionine and having a pH of approximately 5.5. .

[0275] The present invention also, Approximately 120 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.04 w / v, The present invention provides a pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6. .

[0276] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 500 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The present invention provides a pharmaceutical composition containing approximately 2 mg / mL of methionine and having a pH of approximately 5.5. .

[0277] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 500 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.01% w / v, The present invention provides a pharmaceutical composition containing approximately 2 mg / mL of methionine and having a pH of approximately 5.5. .

[0278] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 500 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.02% w / v, The present invention provides a pharmaceutical composition containing approximately 2 mg / mL of methionine and having a pH of approximately 5.5. .

[0279] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 500 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.06% w / v, The present invention provides a pharmaceutical composition containing approximately 2 mg / mL of methionine and having a pH of approximately 5.5. .

[0280] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 50 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.04 w / v, The present invention provides a pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.5. .

[0281] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 500 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.04 w / v, The present invention provides a pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.5. .

[0282] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.04 w / v, The present invention provides a pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.5. .

[0283] The present invention also, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 5,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.04 w / v, The present invention provides a pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.5. .

[0284] In some embodiments, the pharmaceutical composition is a fixed combination.

[0285] Preparations intended for in vivo administration are generally sterile. Sterility is achieved, for example, through sterile filtration. This can be easily achieved by filtration through a permeable membrane.

[0286] The pharmaceutical composition of the present invention can be prepared by known methods. For example, the pharmaceutical composition is For example, in a sterile aqueous or oily medium conventionally used for injection, an anti-CD38 antibody It can be prepared by dissolving, suspending, or emulsifying it.

[0287] Administration The pharmaceutical compositions of the present invention can be administered as non-fixed combinations.

[0288] The pharmaceutical compositions of the present invention also have fixed combinations, for example, unit dosage forms (or administration unit forms) and It can be administered in this manner. Fixed combinations are advantageous in terms of ease of administration and uniformity of dosage. This could be advantageous.

[0289] The present invention also contains approximately 1,200 mg to approximately 5 units of VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 0,000 mg of anti-CD38 antibody and approximately 30,000 U to 75,000 U of rH A unit dosage form containing uPH20 is provided.

[0290] The present invention also contains approximately 1,200 mg to approximately 4 units of VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 0,000 mg of anti-CD38 antibody and approximately 30,000 U to 75,000 U of rH A unit dosage form containing uPH20 is provided.

[0291] The present invention also contains approximately 1,200 mg to approximately 2 400 mg of anti-CD38 antibody and approximately 30,000 U to 45,000 U of rH A unit dosage form containing uPH20 is provided.

[0292] The present invention also contains approximately 1,200 mg to approximately 1 800 mg of anti-CD38 antibody and approximately 30,000 U to 45,000 U of rH A unit dosage form containing uPH20 is provided.

[0293] The present invention also, Approximately 1,200 mg to 5,000 mg containing SEQ ID NO: VH and SEQ ID NO: VL A certain amount of anti-CD38 antibody, Approximately 30,000U to approximately 75,000U of rHuPH20, Histidine at concentrations of approximately 5 mM to approximately 15 mM, Sorbitol at a concentration of approximately 100 mM to approximately 300 mM, PS-20 at concentrations of approximately 0.01% w / v to approximately 0.04% w / v, It contains methionine at a concentration of approximately 1 mg / mL to 2 mg / mL and has a pH of approximately 5.5. , provides a unit dosage form.

[0294] The present invention also, Approximately 1,200 mg to 2,400 mg containing SEQ ID NO: 4 (VH) and SEQ ID NO: 5 (VL) A certain amount of anti-CD38 antibody, Approximately 30,000U to approximately 45,000U of rHuPH20, Histidine at a concentration of approximately 10 mM, Sorbitol at a concentration of approximately 300 mM, PS-20 at a concentration of approximately 0.04% w / v, This product provides a single dosage form containing methionine at a concentration of approximately 1 mg / mL and a pH of approximately 5.5. do.

[0295] The present invention also, Approximately 1,200 mg to 1,800 mg of the product containing SEQ ID NO: 4 (VH) and SEQ ID NO: 5 (VL) A certain amount of anti-CD38 antibody, Approximately 30,000U to approximately 45,000U of rHuPH20, Histidine at a concentration of approximately 10 mM, Sorbitol at a concentration of approximately 300 mM, PS-20 at a concentration of approximately 0.04% w / v, This product provides a single dosage form containing methionine at a concentration of approximately 1 mg / mL and a pH of approximately 5.5. do.

[0296] The present invention also, Approximately 1,200 mg to 1,800 mg of the product containing SEQ ID NO: 4 (VH) and SEQ ID NO: 5 (VL) A certain amount of anti-CD38 antibody, Approximately 30,000U to approximately 45,000U of rHuPH20, Histidine at concentrations of approximately 5 mM to approximately 15 mM, Sorbitol at a concentration of approximately 100 mM to approximately 300 mM, PS-20 at concentrations of approximately 0.01% w / v to approximately 0.04% w / v, It contains methionine at a concentration of approximately 1 mg / mL to 2 mg / mL and has a pH of approximately 5.5. , provides a unit dosage form.

[0297] The present invention also, Approximately 1,800 mg of anti-CD38 antibody, including VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 and, Approximately 30,000U of rHuPH20, Histidine at a concentration of approximately 10 mM, Sorbitol at a concentration of approximately 300 mM, PS-20 at a concentration of approximately 0.04% w / v, This product provides a single dosage form containing methionine at a concentration of approximately 1 mg / mL and a pH of approximately 5.5. do.

[0298] The present invention also, Approximately 1,800 mg of anti-CD38 antibody, including VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 and, Approximately 45,000U of rHuPH20, Histidine at a concentration of approximately 10 mM, Sorbitol at a concentration of approximately 300 mM, PS-20 at a concentration of approximately 0.04% w / v, This product provides a single dosage form containing methionine at a concentration of approximately 1 mg / mL and a pH of approximately 5.5. do.

[0299] The pharmaceutical composition of the present invention is available in approximately 80 mL, 90 mL, 100 mL, 110 mL, or 120 mL. It can be administered in a total volume of L.

[0300] The pharmaceutical composition of the present invention is available in approximately 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, and 15 mL. mL, 16mL, 17mL, 18mL, 19mL, 20mL, 25mL, 30mL, 35 mL, 40mL, 45mL, 50mL, 55mL, 60mL, 65mL, 70mL, 75 mL, 80mL, 85mL, 90mL, 95mL, 100mL, 105mL, 110mL It can be administered in a total volume of 115 mL or 120 mL.

[0301] The pharmaceutical composition of the present invention can be administered in a total volume of approximately 10 mL.

[0302] The pharmaceutical composition of the present invention can be administered in a total volume of approximately 15 mL.

[0303] The pharmaceutical composition of the present invention can be administered in a total volume of approximately 20 mL.

[0304] The total volume of administration is typically better with a fixed combination compared to a non-fixed combination. It can be quite small.

[0305] The present invention also provides a container for a pharmaceutical composition of the present invention.

[0306] The present invention also provides a container containing the unit dosage form of the present invention.

[0307] The containers are vials, cartridges, syringes, pre-filled syringes, or disposable pens. That's fine.

[0308] The pharmaceutical composition of the present invention is administered over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, and 2 weeks. 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months It can be repeated later, or even more later. It is also possible to repeat the treatment process. Long-term administration is also possible. Repeated administration may be at the same dose or a different dose. The dosage may also be... For example, the pharmaceutical composition of the present invention is administered once a week for 8 weeks, and then every 2 weeks thereafter... The medication can be administered once for 16 weeks, followed by once every 4 weeks thereafter.

[0309] The pharmaceutical composition of the present invention can be administered subcutaneously.

[0310] The pharmaceutical composition of the present invention can be administered subcutaneously to the abdomen.

[0311] Subcutaneous administration can be achieved using a device. The device is a syringe, pre-filled injection Injectors, disposable or reusable auto injectors, pen injectors, patch injectors A portable syringe injection pump having an ejector, a wearable injector, or a subcutaneous injection set. That's fine.

[0312] For non-fixed combinations, the mixture should be administered to the target at pH 5.5 with a 25 mM solution. Sodium acetate, 60 mM sodium chloride, 140 mM D-mannitol, 0.0 20 mg / mL of anti-CD38 antibody in 4% polysorbate 20, at pH 6.5, 0 mM L-histidine, 130 mM NaCl, 10 mM L-methionine, 0.02 1 mg / mL (75-150 kU / mL) of rHuPH in % polysorbate-80 It may be mixed with 20.

[0313] The pharmaceutical composition of the present invention also reduces the risk of cancer progression and the events in cancer progression. To delay the onset of the disease and / or reduce the risk of recurrence when the cancer is in remission, It may be administered prophylactically. This is known to be present due to other biological factors. This may be particularly useful in patients where it is difficult to pinpoint the location of the tumor.

[0314] Treatment method The present invention also relates to a method for treating cancer, wherein the medical device of the present invention is used on a subject in need of treatment. The present invention provides a method comprising administering a drug composition for a sufficient amount of time to treat cancer. ru.

[0315] In some embodiments, cancer is a CD38-positive hematological malignancy.

[0316] In some embodiments, the CD38-positive hematological malignancy is multiple myeloma.

[0317] In some embodiments, CD38-positive hematological malignancies are diffuse large B-cell leukemia. It is a lymphoma (DLBCL).

[0318] In some embodiments, CD38-positive hematological malignancies are non-Hodgkin lymphomas. .

[0319] In some embodiments, CD38-positive hematological malignancies include acute lymphoblastic leukemia (AL). L) is the answer.

[0320] In some embodiments, CD38-positive hematological malignancies are follicular lymphoma (FL). be.

[0321] In some embodiments, CD38-positive hematological malignancies are defined as Burkitt lymphoma (BL). )

[0322] In some embodiments, CD38-positive hematological malignancies are mantle cell lymphomas (M CL)

[0323] In some embodiments, CD38-positive hematological malignancies include light chain amyloidosis (A L) is the answer.

[0324] In some embodiments, CD38-positive hematological malignancies include multiple myeloma and acute lymphoblastoma. Leukemia malformation (ALL), non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBC) L), Burkitt lymphoma (BL), follicular lymphoma (FL), or mantle cell lymphoma (MCL)

[0325] Examples of B-cell non-Hodgkin lymphoma include lymphomatoid granulomatosis, primary exudative lymphoma, and vascular lymphoma. Internal large B-cell lymphoma, mediastinal large B-cell lymphoma, heavy chain disease (γ, μ, and a disease) Lymphomas induced by immunosuppressant therapy (including), such as cyclosporine-induced lymphomas. These are lymphomas originating from the body and methotrexate-induced lymphomas.

[0326] In some embodiments, cancer is a solid tumor.

[0327] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target population, a pharmaceutical composition containing an anti-CD38 antibody and hyaluronidase is used in CD38-positive blood A pharmaceutical composition comprising subcutaneous administration for a sufficient amount of time to treat a fluid-related malignant disease. This method provides a solution in which the concentration of anti-CD38 antibody is approximately 20 mg / mL.

[0328] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. The target of this study includes anti-CD38 antibodies containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5, and sequence number A pharmaceutical composition containing hyaluronidase rHuPH20 (number 22) is used in CD38-positive blood cells. This includes subcutaneous administration for a sufficient amount of time to treat a malignant disease, and in the pharmaceutical composition This method provides a method in which the anti-CD38 antibody concentration is approximately 20 mg / mL.

[0329] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target group, approximately 1,200 mg to 1,800 mg of the product containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 is recommended. 00 mg of anti-CD38 antibody and approximately 30,000 U to 45,000 U of SEQ ID NO: 22 A pharmaceutical composition containing luronidase rHuPH20 is used to treat CD38-positive hematological malignancies. The pharmaceutical composition contains an anti-CD38 antibody concentration, which is administered over a period of time sufficient for treatment. The present invention provides a method in which the concentration is approximately 20 mg / mL.

[0330] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target group, approximately 1,200 mg to approximately 1, 800 mg of anti-CD38 antibody and approximately 30,000 U of hyaluronidase r of sequence number 22 A pharmaceutical composition containing HuPH20 is sufficient to treat CD38-positive hematological malignancies. The administration includes administering the drug over a period of time, and the concentration of the anti-CD38 antibody in the pharmaceutical composition is approximately 20m This provides a method for determining the concentration in g / mL.

[0331] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target group, approximately 1,200 mg to approximately 1, 800 mg of anti-CD38 antibody and approximately 45,000 U of hyaluronidase r of sequence number 22 A pharmaceutical composition containing HuPH20 is sufficient to treat CD38-positive hematological malignancies. The administration includes administering the drug over a period of time, and the concentration of the anti-CD38 antibody in the pharmaceutical composition is approximately 20m This provides a method for determining the concentration in g / mL.

[0332] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target group, approximately 1,600 mg of anti-CD medication containing VH (SEQ ID NO: 4) and VL (SEQ ID NO: 5) was administered. 38 antibodies and approximately 30,000 U of hyaluronidase rHuPH20 (SEQ ID NO: 22) were used. This includes administering the drug for a sufficient amount of time to treat CD38-positive hematological malignancies. The present invention provides a method in which the concentration of anti-CD38 antibody in the pharmaceutical composition is approximately 20 mg / mL.

[0333] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target group, approximately 1,600 mg of anti-CD medication containing VH (SEQ ID NO: 4) and VL (SEQ ID NO: 5) was administered. 38 antibodies and approximately 45,000 U of hyaluronidase rHuPH20 (SEQ ID NO: 22) were used. This includes administering the drug for a sufficient amount of time to treat CD38-positive hematological malignancies. The present invention provides a method in which the concentration of anti-CD38 antibody in the pharmaceutical composition is approximately 20 mg / mL.

[0334] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. The target group includes anti-CD38 antibodies containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5, and hyaluronic acid. The administration of a pharmaceutical composition containing lonidase, wherein the pharmaceutical composition is a non-fixed combination Therefore, we provide a method.

[0335] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target, pH approximately 5.5, approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mannitol SEQ ID NO: 4 in Thor and approximately 0.04% w / v polysorbate-20 (PS-20) Anti-CD38 formulations containing VH and VL of SEQ ID NO: 5, ranging from approximately 20 mg / mL to approximately 120 mg / mL. Antibodies and pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L-histidine Thionine, approximately 30,000 U to 45,000 U in 0.02% polysorbate-80 The present invention provides a method comprising administering a pharmaceutical composition containing hyaluronidase U.

[0336] In some embodiments, the hyaluronidase is rHuPH20.

[0337] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0338] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target, pH approximately 5.5, approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mannitol SEQ ID NO: 4 in Thor and approximately 0.04% w / v polysorbate-20 (PS-20) Approximately 20 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NO: 5, pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L-histidine Thionine, approximately 30,000 U of hyaluronide in 0.02% polysorbate-80. The present invention provides a method comprising administering a pharmaceutical composition containing ze and .

[0339] In some embodiments, the hyaluronidase is rHuPH20.

[0340] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0341] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target, pH approximately 5.5, approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mannitol SEQ ID NO: 4 in Thor and approximately 0.04% w / v polysorbate-20 (PS-20) Approximately 20 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NO: 5, pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L-histidine Thionine, approximately 45,000 U of hyaluronide in 0.02% polysorbate-80. The present invention provides a method comprising administering a pharmaceutical composition containing ze and .

[0342] In some embodiments, the hyaluronidase is rHuPH20.

[0343] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0344] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. The target group includes anti-CD38 antibodies containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5, and hyaluronic acid. The drug comprises administering a pharmaceutical composition containing lonidase, wherein the pharmaceutical composition is a fixed combination It provides a method to achieve this.

[0345] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target, Each contains approximately 1 mg / mL to 180 mg / mL, including VH and VL of SEQ ID NOs. 4 and 5, respectively. The anti-CD38 antibody, Hyaluronidase at approximately 50 U / mL to approximately 5,000 U / mL, Approximately 5 mM to approximately 50 mM histidine, The method includes administering a pharmaceutical composition containing approximately 50 mM to approximately 400 mM sorbitol. , provide a method.

[0346] In some embodiments, the hyaluronidase is rHuPH20.

[0347] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target, Each contains approximately 1 mg / mL to 180 mg / mL, including VH and VL of SEQ ID NOs. 4 and 5, respectively. The anti-CD38 antibody, Hyaluronidase at approximately 50 U / mL to approximately 5,000 U / mL, Approximately 5 mM to approximately 50 mM histidine, Sorbitol in concentrations of approximately 50 mM to 400 mM, PS-20 with approximately 0.01% w / v to approximately 0.1%, A pharmaceutical composition containing approximately 0.1 mg / mL to approximately 2.5 mg / mL of methionine is administered. To provide a method that includes doing so.

[0348] In some embodiments, the hyaluronidase is rHuPH20.

[0349] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target, Each contains approximately 100 mg / mL to approximately 120 mg / L, including VH and VL of SEQ ID NOs. 4 and 5, respectively. mL of anti-CD38 antibody, Hyaluronidase at approximately 50 U / mL to approximately 5,000 U / mL, Approximately 10 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, Administering a pharmaceutical composition containing approximately 1 mg / mL to approximately 2 mg / mL of methionine. To include, to provide a method.

[0350] In some embodiments, the hyaluronidase is rHuPH20.

[0351] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target, Approximately 100 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, Hyaluronidase at approximately 500 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.04 w / v, A pharmaceutical composition containing approximately 2 mg / mL of methionine and having a pH of approximately 5.5 is administered. To provide a method that includes doing so.

[0352] In some embodiments, the hyaluronidase is rHuPH20.

[0353] The present invention also relates to a method for treating CD38-positive hematological malignancies, which require the treatment of such malignancies. For the target, Approximately 120 mg / mL of anti-CD38 antibody containing VH and VL of SEQ ID NOs. 4 and 5, respectively. and, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and The PS-20 has approximately 0.04 w / v, A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. To provide a method that includes doing so.

[0354] In some embodiments, the hyaluronidase is rHuPH20.

[0355] The anti-CD38 antibody in the pharmaceutical composition of the present invention is antibody-dependent cell-mediated cytotoxicity (ADCC). ), antibody-dependent cell phagocytosis (ADCP), complement-dependent cell-mediated cytotoxicity (CDC), apoptosis To induce the killing of CD38-expressing tumor cells by regulating the activity of the CD38 enzyme. The anti-CD38 antibody in the pharmaceutical composition of the present invention also contains CD4 + and CD8 + T cells By inducing proliferation and / or by using bone marrow-derived suppressor cells (MDSCs) and By mitigating the suppression of inflammatory responses mediated by nodal T cells (Tregs), anti-C The immunomodulatory action of the D38 antibody can mediate antitumor effects.

[0356] "Antibody-dependent cytotoxicity", "Antibody-dependent cell-mediated cytotoxicity", or "ADCC" The Fcγ receptor (FcγR) expressed in effector cells, in antibody-coated target cells, F cells, which have lytic activity against natural killer cells, monocytes, macrophages, and neutrophils. It is a mechanism that induces cell death based on interaction with NK cells. For example, NK cells , expresses FcγRIIIa, while monocytes express FcγRI, FcγRII, and FcvRI It expresses IIa. The death of antibody-coated target cells such as CD38-expressing cells is due to membrane pore-forming proteins. It results from effector cell activity through the secretion of chlorine and proteases. To evaluate the ADCC activity of antibodies that specifically bind to 38, the antibodies were used in an immunoeffector. - These can be added to CD38-expressing cells in combination with other cells, but these antigen-antibody complex When activated by fusion, it can lead to cell lysis of target cells. Cell lysis is usually, Labeling from lysed cells (e.g., radioactive substrates, fluorescent dyes, or native intracellular proteins) It is detected by the release of ). Examples of effector cells for such assays include Examples of target cells include peripheral blood mononuclear cells (PBMCs) and NK cells. Exemplary target cells include CD. Examples include Tregs or MDSCs expressing 38. In an exemplary assay, the target molecule The cells are 20 μCuries 51 Labeled with Cr for 2 hours and then extensively washed. The target cell concentration is 1 × 10⁻⁶. 6 It can be adjusted to cells / mL, but the anti-CD38 antibody varies It is added at various concentrations. The assay involves target cells being charged with an effector-to-target cell ratio of 40:1. It is initiated by adding it. After incubation at 37°C for 3 hours, assembling The process is stopped by centrifugation, and the lysed cells are... 51 The release of Cr, scintillation The measurement is performed in a counter tube. The cytotoxicity percentage is determined by adding 3% perchlorate to target cells. This can be calculated as the maximum dissolution percentage that can be induced by this action.

[0357] "Antibody-dependent cell phagocytosis" ("ADCP") refers to, for example, macrophages or dendritic cells. This refers to a mechanism that eliminates antibody-coated target cells through uptake by phagocytic cells such as cysts. CP uses Treg or MDSC expressing CD38 to GFP or other labeled molecules. It can be evaluated by using it as a target cell that has been genetically engineered to express the gene. It can be, for example, 4:1. The effector Cells can be incubated with target cells for 4 hours, with or without an anti-CD38 antibody. After incubation, the cells can be detached using Accutase. Macrophages can be identified by anti-CD11b and anti-CD14 antibodies conjugated with fluorescent labels. However, the phagocytosis rate (%) can be determined based on the rate (%) of GFP fluorescence in macrophages using standard methods for CD11 + and CD14 + It can be determined based on the rate (%) of GFP fluorescence in macrophages.

[0358] "Complement-dependent cytotoxicity" or "CDC" refers to a mechanism of inducing cell death in which the Fc effector domain of a target-binding antibody binds to and activates complement component C1q, and such complement component C1q then activates the complement cascade to induce cell death of target cells. Activation of the complement also results in the deposition of complement components on the surface of target cells, facilitating ADCC by binding of complement receptors (e.g., CR3) to leukocytes. The ability of monoclonal antibodies to induce ADCC can be enhanced by genetically engineering their oligosaccharide components. Human IgG1 or IgG3 is N-glycosylated at Asn297. Here, most of the glycans are in the well-known bifurcated G0, G0F, G1, G1F, G2, or G2F forms. Antibodies produced by non-genetically engineered CHO cells typically have a fucose content of at least about 85% of the glycans. Core fucose from the bifurcated complex-type oligosaccharides bound to the Fc region

[0359] [[ID = 33]] ​​​​​​​​The removal of the sac improves FcγRIIIa without altering antigen binding or CDC activity. The ADCC of antibodies is enhanced via binding. Such mAbs are concentrated in the medium by weight osmolality. Control of degree (Konno et al., Cytotechnology 64:249~) 65, 2012), Application of the mutant CHO lineage Lec13 as a host cell lineage (Shield s et al., J Biol Chem 277:26733~26740,200 2) Application of mutant CHO line EB66 as a host cell line (Olivier et al. .,MAbs;2(4),2010, published electronically prior to print, PMID:205625 82) Application of rat hybridoma cell line YB2 / 0 as a host cell line (Shink awa et al., J Biol Chem 278:3466~3473,200 3) Specific low levels of the α1,6-fucosyltransferase (FUT8) gene Introduction of molecularly interfering RNA (Mori et al., Biotechnol Bioeng 88:901~908,2004), or β-1,4-N-acetylglucosaminyl Transferase III and Golgi α-mannosidase II or potent α-mannosidase Co-expression of the enzyme I inhibitor kifunensin (Ferrara et al., J Biol Chem 281:5032~5036,2006, Ferrara et al. Biotechnol Bioeng 93:851~861,2006, Xhou e t al.,Biotechnol Bioeng 99;652~65,2008) Which of the following is the effect of a relatively highly defucosylated antibody that has a branched complex of Fc oligosaccharides? This can be obtained using various methods that have been reported to lead to specific expression. In the manner of, and of any of the numbered embodiments listed below, ADCC induced by the anti-CD38 antibody used in several embodiments is also The antibody Fc may be enhanced by certain substitutions. Exemplary substitutions include, for example, As described in U.S. Patent No. 6,737,056, amino acid positions 256, 290, 2 98, 312, 356, 330, 333, 334, 360, 378, or 430 (EU) This is a substitution in residue numbering according to the index.

[0360] In some embodiments, the anti-CD38 antibody includes substitutions in the antibody Fc.

[0361] In some embodiments, the anti-CD38 antibody has amino acid position 256 in antibody Fc. , 290, 298, 312, 356, 330, 333, 334, 360, 378, or 4 Includes substitution at 30 (residue numbering according to the EU index).

[0362] In some embodiments, the anti-CD38 antibody is present in a concentration of about 0% to about 15%, for example, 15%. 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3% It has a branched glycan structure with a fucose content of 2%, 1%, or 0%.

[0363] In some embodiments, the anti-CD38 antibody is present in concentrations of approximately 50%, 40%, 45%, 40%, and 3%. 5%, 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9 It has a fucose content of %, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0%. It has a bifurcated glycan structure.

[0364] Substitutions and reduced fucose content in Fc are found in ADCs of antibodies that specifically bind to CD38. It can enhance C activity.

[0365] "Fucose content" refers to the amount of fucose monosaccharides in the sugar chain of Asn297. The relative amount of fucose is the ratio of fucose-containing structures to the total sugar structure. The construction can be done in several ways, for example, 1) as described in International Publication No. 2008 / 077546 In addition, MALDI-TOF (for example, complex, hybrid) of N-glycosidase F treated samples 1) Use of the sugar structure and high mannose structure, 2) Enzyme release of Asn297 glycan , subsequent derivatization, and HPLC (UPLC) and / or HPLC with fluorescence detection. - Detection / quantification by MS (UPLC-MS), 3) First GlcNAc monosaccharide and second G It cleaves the lcNAc monosaccharide and binds fucose to the first GlcNAc, End With or without treatment of the Asn297 glycan with o S or other enzymes , intact protein analysis of natural or reduced mAbs, 4) digestion using enzymes (e.g., After digestion of mAbs into their component peptides by lipinsin or endopeptidase Lys-C) , separation, detection, and quantification by HPLC-MS (UPLC-MC), or 5) Asn2 In 97, specific deglycosylation of mAbs by enzyme using PNGase F was performed. The isolation of ligosaccharides from mAb proteins can be characterized and quantified. These oligosaccharides are labeled with fluorophores, enabling detailed characterization of the glycan structure. These can be separated and identified by various supplementary techniques, and these are experimental masses Matrix-assisted laser-induced fluorescence (MALDI) mass spectrometry by comparison with theoretical mass, Determination of the degree of sialylation by on-exchange HPLC (GlycoSep C), normal-phase HPLC Separation and quantification of oligosaccharide types according to hydrophilicity standards using (GlycoSep N), and Furthermore, high-performance capillary electrophoresis-laser-induced fluorescence (HPCE-LIF) is used to detect oligosaccharides. By separation and quantification.

[0366] As used herein, "low fucose" or "low fucose content" refers to an antibody content of approximately 0%. This refers to a fucose content of 15%.

[0367] As used herein, "normal fucose" or "normal fucose content" means antibody Fucoid with a percentage exceeding approximately 50%, typically exceeding approximately 60%, 70%, 80%, or 85% This refers to having a certain amount of - content.

[0368] In the methods described herein, and in all numbered methods listed below, In some embodiments of the model, the anti-CD38 antibody is IgG1, IgG2 It is either an IgG3 or IgG4 isotype.

[0369] Antibodies that are substantially identical to antibodies containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 are, It may be used in the method of the present invention. As used herein, the term “substantially identical” means The amino acid sequences of the two antibodies VH or VL being compared are identical or "very slight phases" It means having a "difference." A very slight difference does not negatively affect the properties of the antibody. In the antibody heavy chain or light chain, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1 The substitution involves 2, 13, 14, or 15 amino acids. The identity percentage is, for example, V. ctor NTI v.9.0.0(Invitrogen(Carlsbad,CA Determined by pairwise alignment using the default settings of the AlignX module. It can be determined. The protein sequence of the present invention can be used as a query sequence for public or A search of the patent database may be performed to identify relevant sequences, for example. The exemplary program used to perform the search uses default settings, XBLA ST or BLASTP program (http_ / / www_ncbi_nlm / ni h_gov), or GenomeQuest (trademark) (GenomeQuest(Wes tborough,MA)) sweet. Anti-CD3 used in the method of the present invention 8. Illustrative substitutions that may be performed on antibodies include, for example, similar charge, hydrophobicity, and stereochemical properties. This is a conservative substitution using amino acids that have [a certain characteristic]. Conservative substitutions can also be used for, for example, to improve stability or affinity. To improve antibody properties such as sex, or to improve the function of antibody effectors. It can also be done. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Alternatively, 15 amino acid substitutions may be performed, for example, on the heavy or light chain of an anti-CD38 antibody. Furthermore, as has been previously stated regarding the alanine scanning mutation method... (MacLennan et al.,Acta Physiol Scand Sup pl 643:55~67,1998;Sasaki et al.,Adv Biop (hys 35:1~24, 1998), any native residue in the heavy or light chain is replaced with alanine. It is also possible to make substitutions. A desired amino acid substitution can be made by a person skilled in the art at the time such a substitution is desired. It can be determined. Amino acid substitutions can be used, for example, in PCR mutagenesis (U.S. Patent No. 4,683,1 This can be done by (No. 95). A library of mutants can be created using a well-known method, for example. For example, random codons (NNK) or non-random codons, such as 11 amino acids (Ala , Cys, Asp, Glu, Gly, Lys, Asn, Arg, Ser, Tyr, Trp Using the DVK codon that encodes the desired traits, and searching for mutants with the desired characteristics, They may be generated by screening for ri. The generated mutants are used in vitro. Their binding to CD38, inducing ADCC, ADCP, or apoptosis or With regard to their ability to modulate CD38 enzyme activity, using the methods described herein It can be tested.

[0370] In some embodiments, the anti-CD38 antibody has a certain affinity (K D ) Human CD3 It can be coupled to 8. In one embodiment of the present invention, and the following are listed numbers In some of the nominated embodiments, those skilled in the art have put into practice It is determined by the surface plasmon resonance or coupled equilibrium exclusion (Kinexa) method applied. Sea urchin, anti-CD38 antibody, has high affinity, for example, about 10 -7 K below M D So, for example, While not limited to a specific range, it could be 1-9.9 (or 1, 2, 3, 4, 5, 6, 7, 8, or 9, etc.) (any range or value that falls within this) × 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 M, 10 -14 M, 10 -15 M, or within this K is any range or value DThen it binds to CD38. One example of affinity is 1 × 10⁻¹⁶. -8 It is less than or equal to M. Another example of affinity is 1 × 10 -9 It is M or less.

[0371] In some embodiments, the anti-CD38 antibody is a bispecific antibody. The VL and / or VH regions of the 8 antibodies, or newly identified as described herein. The VL and VH regions may be genetically engineered to produce bispecific, full-length antibodies. Such bispecific antibodies are registered under U.S. Patent No. 7,695,936 and International Publication No. 04 / 11. Patent No. 1233, U.S. Patent Application Publication No. 2010 / 0015133, and U.S. Patent Application Publication No. 2007 / 0287 Patent No. 170, International Publication No. 2008 / 119353, U.S. Patent Application Publication No. 2009 / 018 No. 2127, No. 2010 / 0286374, No. 2011 / 0123532, International Publication No. 2011 / 131746, Publication No. 2011 / 143545, or U.S. Patent Application Publication Using techniques such as those described in Publication No. 2012 / 0149876, single-specificity antibody heavy chain By regulating the CH3 interaction between them to form bispecific antibodies, they can be produced. Yes, it is possible. An additional bispecific structure in which the VL and / or VH regions of the antibody of the present invention can be incorporated. For example, the structure is a bivariate variable domain immunoglobulin (International Publication No. 2009 / 134776). ) or different specific domains such as leucine zipper or collagen dimerization domain A structure containing various dimerization domains to bind two antibody arms having properties (International Public Opening No. 2012 / 022811, U.S. Patent No. 5,932,448, U.S. Patent No. 6,833,4 It is No. 41.

[0372] For example, bispecific antibodies are produced according to the method described in International Publication No. 2011 / 131746. In a cell-free environment, in vitro, the CH3 region of two monospecific homodimeric antibodies was analyzed. Under reducing conditions, an asymmetrical mutation is introduced to isomerize the disulfide bond. In this process, a bispecific heterodimer antibody is formed from two parent monospecific homodimer antibodies. It may be produced by doing so. In this method, the first monospecific bivalent antibody (for example For example, the anti-CD38 antibody and the second monospecific bivalent antibody promote the stability of the heterodimer. These antibodies are genetically engineered to have specific substitutions in the CH3 domain, but This is a reducing element sufficient to cause disulfide bond isomerization of cysteine ​​in the hinge region. Under these conditions, they are incubated together, thereby enabling dual specificity through Fab arm replacement. Antibodies are generated. The incubation conditions may be optimally returned to non-reducing conditions. Examples of reducing agents that may be used include 2-mercaptoethylamine (2-MEA) and dithiothre. Itol (DTT), dithioerythritol (DTE), glutathione, tris(2-C) (Tyreboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethano The compounds are preferably 2-mercaptoethylamine, dithiothreitol, and triglycerides. A reducing agent selected from the group consisting of (2-carboxyethyl)phosphine. at a temperature of at least 20°C, in the presence or absence of at least 25 mM 2-MEA At least 0.5 mM dithiothreitol, pH 5-8, for example, pH 7.0 or This can be incubated at pH 7.4 for at least 90 minutes.

[0373] An example of a CH3 mutation that can be used in the first and second heavy chains of a bispecific antibody is K4. It is 09R and / or F405L.

[0374] The method of the present invention can be used to treat animal subjects belonging to any classification. Examples of such animals include mammals such as humans, rodents, dogs, cats, and domesticated animals. It can be done.

[0375] Combination therapy The pharmaceutical composition of the present invention is administered in combination with a second therapeutic agent, or in combination thereof. It is possible.

[0376] The second treatment drugs are melphalan, mechloretamine, thioepane, chlorambucil, and caramel. Stine (BSNU), Lomustine (CCNU), Cyclophosphamide, Busulfan, Di Bromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine , mitomycin C, cisplatin, and other platinum derivatives (e.g., carboplatin, cisplatin) Lidomide or thalidomide analog, lenalidomide, or CC4047), protea Some chromosome inhibitors (e.g., bortezomib) or vinca alkaloids (e.g., vincristi) It may be an anthracycline (for example, doxorubicin).

[0377] In some embodiments, the second therapeutic agent is a proteasome inhibitor.

[0378] In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib Or it is ixazomib.

[0379] In some embodiments, the second therapeutic agent is an alkylating agent.

[0380] In some embodiments, the alkylating agent is busulfan, cyclophosphamide, ben Damstine, chlorambucil, carboplatin, cisplatin, temozolomide, melfa Orchid, busulfan, bendamustine, carmustine, lomustine, dacarbazine, oxy Saliplatin, ifosfamide, mechloretamine, thiotepa, trabectedin, or strep It is putozocin.

[0381] In some embodiments, the second therapeutic agent is a glutamate derivative.

[0382] In some embodiments, the glutamic acid derivative is Revlimid(registered trademark)(Re It is also known as thalidomide or Pomalyst® (Pomalidomide). .

[0383] In some embodiments, the subjects are further administered corticosteroids.

[0384] In some embodiments, the corticosteroid is dexamethasone or prednisone (pr It is edisone.

[0385] The second treatment, or a combination thereof, is typically administered at the dose recommended for that drug. To be given.

[0386] The pharmaceutical composition of the present invention is administered simultaneously with, or sequentially with, a second therapeutic agent, or in combination thereof. Therefore, it can be administered.

[0387] The present invention has been described in general terms, but each embodiment of the present invention is described below, without limiting the scope of the claims. Further disclosures in the following embodiments are not intended to be interpreted as defining the subject. [Examples]

[0388] Example 1. Recombinant human hyaluronidase PH20(rHuP) in a miniature pig model. Subcutaneous delivery of 2% human immunoglobulin G (IgG) with H2O overview Miniature pigs have anatomical similarities to human skin and clinical potential (clinical t (Ranslatability) makes it suitable for evaluating the conditions for subcutaneous (SC) administration of biopharmaceuticals. This is a floor model (Mahj et al., Exp Toxicol Path 57: 341-5, 2006). The purpose of this study was to compare two different flow rates (2 and 4 mL / min) 20 mg / mL containing rHuPH20 at 200, 500, or 800 U / mL. The objective was to evaluate and assess the conditions for administering 100 mL of human IgG solution. The injection point involves quantitative measurement and qualitative evaluation of the injection pressure at the local injection site (e.g., swelling). (Its size and hardness) were included.

[0389] For Yucatan miniature pigs, administer 200, 500, or 800 U at a flow rate of 2 or 4 mL / min. It contains 20 mg / mL of immunoglobulin G (IgG) along with rHuPH20. A 100 mL solution was administered subcutaneously. Real-time in-line pressure was measured during the injection. After the injection was completed, the volume and area of ​​any visible swelling (if any), the presence or absence of erythema, and Severity, size and hardness of swelling / bleb, and qualitative score of the injection site based on rough observation. Regarding the ring, the local injection site was measured. The injection pressure was generally low, and both flow rates were... The pressure range was approximately 5.3 to 8.0 kPa (approximately 40 to 60 mmHg (approximately 1 PSI)). .

[0390] The statistical differences in pressure between various concentrations of rHuPH20 and between two different flow rates are not shown. The overall pressure was slightly lower than expected, at a flow rate of 2 mL / min.

[0391] An unexpected finding was visible and measurable swelling at the injection site at the slower flow rate of 2 mL / min. The number of injections that exhibited this characteristic was 10 out of 12. This observation is related to the 3 Observed at all concentrations. In contrast, at the faster flow rate of 4 mL / min, it was visible. Furthermore, measurable localized swelling occurred in only 3 out of 12 injections. As shown, these observations were observed at various concentrations of rHuPH20.

[0392] In all cases where localized swelling was visible, the swelling subsided within one hour. In addition, localized swelling / hardening at the injection site, as indicated by the swelling / hardening index (average score less than 2). The swelling was generally soft to the touch and not hardened. Erythema appeared at a rate of 2 mL / min. It was more frequently observed with injections at a certain flow rate, but overall, the severity of the erythema was mild and the following day The symptoms completely subsided. Other minor observations of the injection site are not mentioned in this study.

[0393] This test uses three different concentrations of rHuPH20 (200, 500, or 800 U / m³). L) was evaluated, and there were no statistically significant differences between these concentrations based on the endpoints of this study. Overall, the faster flow rate of 4 mL / min was more effective than the flow rate of 2 mL / min in reducing erythema. The frequency was low, visible swelling was minimal, and the local injection sites were soft.

[0394] Test articles and methods Test item Substances in the formulation buffer: 25 mM sodium acetate (Spectrum; PN#S0104; Lot#1DI) 0271) • 60 mM sodium chloride (Spectrum; PN#S0155; Lot#1CE) 0421) • 140 mM D-mannitol (Spectrum; PN#MA165; Lot#1 EB0316) • 0.04% polysorbate 20 (JT Baker; PN#4116-04; Lo t#0000017659) • pH 5.5 (Glacial acetic acid relative to pH; Fisher Scientific; PN#A) 491-212; Lot#080972)

[0395] Substances in drug raw materials: • Human gamma globulin (BioMed Supply; PN#HGG-1005; L) ot#BMS31309013) ·rHuPH20[(Manufactured by Cook Pharmaca for use in Halozymes; Halozyme Lot#462- ·021B (Published, Cook Lot#104-001-HSTFIL-9054) )]

[0396] formulation Four days before the start of the study, administer 20 mg / mL of IgG, or 200, 500, or 800 U / mL. It was co-mixed with rHuPH20. The solution was divided equally into separate glass bottles and sealed with stoppers. The containers were sealed and the lids were pressed shut. All solutions were stored at 2-8°C until the start of the test, but note Prior to entry, the samples were allowed to acclimate to room temperature. In addition, each formulation was subjected to an rHuPH20 enzyme activity test. Samples were collected from [location]. Based on the enzyme activity assay results, all administered solutions were at the target concentration of 10. It was confirmed that it was within a certain percentage (data is not shown).

[0397] Animal description • Species: Pig (Sus scrofa domestica) • Breed: Yucatan Miniature Pig • Sex: Female • Age: 3 months and older • Weight: Approximately 12 kg • Number of animals: 12 ·Supplier: S&S Farms (Ramona, CA)

[0398] Animal husbandry The animals were housed in iron enclosures equipped with automatic water dispensers as needed. (Test day: afternoon only) Except for the animals mentioned above, the animals were fed twice a day (morning and afternoon). The animals' health status was assessed. Therefore, the weight of the animals was measured and recorded from the day of delivery until the day after the end of the test. During this period, All animals maintained their weight (data not shown). The indoor environment was approximately 17-27°C. Maintain a temperature of 40-70% relative humidity and a 12-hour lighting / 12-hour dark cycle. The animals were allowed to acclimate to the facility for seven days prior to the start of the experiment.

[0399] Test materials • High-pressure syringe pump (KD Scientific (Holliston, MA)) • 23ga x 1.9cm (23) tube set with 30cm (12 inch) tubes. Winged injection needle (ga x 3 / 4 inch) (Terumo Medical) Corporation (Somerset, NJ) • 140cc Luer Lock Syringe (Covid-Free (Mansfield, MA)) • 18cm (7 inch) extension set (B / Braun (Bethlehe) m,PA)) ·PowerLab 4 / 30(AD Instruments(Colorado) Springs, CO) • Deltran-1 disposable pressure transducer (Utah Medical P products(Midvale,UT)) • Digital calipers (Preisser Messtechnik (Gammertin) Gen, Germany)) • Isoflurane (Minrad International Company (Or Chard Park, NY) • Isoflurane vaporizer (VetEquip (Pleasanton, CA))

[0400] Experimental Design The experimental design is summarized in the cohort description (Table 1) and the infusion description for each animal (Table 2). In short, it is mixed with rHuPH20 at 200, 500, or 800 U / mL. A 100 mL solution containing 20 mg / mL of IgG is administered at a flow rate of 2 or 4 mL / min. It was administered into the abdomen of anesthetized Yucatan miniature pigs. The endpoint of the study was Line pressure transducer and volume and area of ​​swelling (bleb) after local injection (possible) This includes measuring the injection pressure using (if possible) and qualitative evaluation of the injection site, including photography. It was

[0401] [Table 1]

[0402] [Table 2]

[0403] Test Procedure Before starting the trial, the animals were assessed for their overall health and their weight was recorded. On the day of the procedure, the animals were anesthetized with isoflurane gas and placed supine on a heated surgical table. The patient was positioned and maintained under isoflurane gas throughout the entire procedure. The abdomen was treated with isopropan The area was cleaned with gauze, wiped with clean gauze, and dried. The injection sites were the upper left and right sides of the abdomen (inguinal groove). It is located approximately 3-4 cm from the head end toward the midline, and then approximately 6 cm further forward. The injection site was marked with an oil-based marker and then photographed. The test material was... Prior to introduction, the sample was allowed to acclimate to room temperature. The test sample was placed in a 140cc syringe (priming water was added to the line). Considering the volume required for the procedure, the solution was drawn up to 100 mL or more. A pressure transformer was used in the syringe. Deucer was attached. Next, 23ga x 1.9cm (23ga x 3 / 4 inch) A line extension set with a winged injection needle was attached to the transducer. Then, the injection needle The doctor's coat was primed onto the tip of the needle. The syringe was loaded into the syringe pump. The process was repeated for each syringe containing a different test item. The needles were marked. The inline pressure transducer was placed subcutaneously at the injection sites on both sides of the animal's abdomen. The pressure was set to zero. After starting the inline pressure recording, the two syringe pumps were operated simultaneously. The system was started, and 100 mL of the test material was injected at a flow rate of 2 or 4 mL / min. Injection complete. Then, stop collecting inline pressure data, remove the needle, and reinsert the needle to prevent leakage. The holes were sealed with VetBond liquid adhesive. Swelling at the local injection site was measured using a digital caliper. The area and volume of the bleb were measured. The local injection site was also scored using a 5-point scoring system. Using this method, the appearance (erythema), size of the swelling / bleb, and hardness (induration) were qualitatively evaluated. The values ​​were determined (Tables 3, 4, and 5, respectively). Finally, photographs were taken of the injection sites.

[0404] [Table 3]

[0405] [Table 4]

[0406] [Table 5]

[0407] Computational and statistical methods Evaluation of injection pressure: The injection pressure measured via the inline transducer was obtained using LabChart7. The data was recorded, and the average pressure over the entire injection period was calculated.

[0408] Evaluation of localized swelling volume and area: The volume and area of ​​swelling after injection were measured using a digital caliper and recorded manually. The constant values ​​were recorded as length, width, and height. The volume was calculated using the equation of the ellipsoid. = 4 / 3πABC (where A is the radius of length, B is the radius of width, and C is the radius of height) The area was calculated using a simple formula: length × width.

[0409] Evaluation of local injection sites: The local injection site was independently evaluated by three different evaluators after the injection was completed. The person will evaluate the skin at each injection site for the presence or absence of erythema, the size of localized swelling, and its hardness. We evaluated three assessment areas using scores on a scale with grades from 0 to 4. (A score of 0 indicates no effect, and a score of 4 indicates severe effect). In addition, formula PII = square The primary irritation index is calculated using the formula [(Σ of erythema grade + Σ of swelling grade) ÷ 2]. To calculate (PII), erythema and swelling scores were used. Furthermore, the formula SII = mean [ Swelling / hardening index (S) using (Swelling grade Σ + Hardness grade Σ) ÷ 2] II) was calculated using swelling and stiffness scores. An SII score of 2 or less indicates stiffness. It was not considered to have transformed.

[0410] Statistical analysis: For statistical comparisons between cohorts, Tukey's multiple comparison test was used for continuous variables. One-way analysis of variance (ANOVA), using Dunn's multiple comparison test for categorical variables. The analysis was performed using a non-parametric Krusal-Wallis test. The intrinsic effect was determined to be p<0.05.

[0411] result Evaluation of injection pressure: 20 mg / mL of I mixed with rHuPH20 at 200, 500, or 800 U / mL gG was administered to the abdomen of Yucatan miniature pigs at a flow rate of 2 or 4 mL / min in 100 mL. Injection at a flow rate of mL / min is performed with rHuPH20 at 200, 500, and 800 U / mL. The average injection pressures for the mixed IgG were 40.5±0.1 and 40.0±0, respectively. The values ​​were 1 and 37.1±0.1 mmHg±SEM. When injected at a flow rate of 4 mL / min, 2 Average injection of IgG co-mixed with rHuPH20 at concentrations of 00, 500, and 800 U / mL The pressures were 49.9±0.1, 55.5±0.1, and 61.9±0.2 mmHg, respectively. The result was ±SEM. The injection pressure showed a statistically significant difference between the various concentrations of rHuPH20 at each flow rate. There was no difference, and there was no statistically significant difference between the two flow rates.

[0412] Evaluation of localized swelling volume and area: After each injection is complete, if any local swelling at the injection site is visible, mark it and digitally... Measurements were taken using a caliper. For injection at a flow rate of 2 mL / min, 200, 500 and For IgG co-mixed with 800 U / mL of rHuPH20, the values ​​were 36.6±1 each. The average swelling volumes were 4.4, 19.5±6.5, and 31.4±6.0 cm³±SEM. Visual and measurable results were obtained in 10 out of 12 injections. In contrast, the flow rate was 4 mL / min. In terms of volume, the volume of swelling was measured once for each concentration of rHuPH20, and 3 out of 12 times. It was only detected during the injection of [a certain substance]. The volume of local swelling was [a certain amount] of rHuPH2 at each flow rate. There was no statistical difference between the various concentrations of 0, and there was no statistical difference between the two flow rates. .

[0413] In addition to volume calculations, the local area of ​​visible swelling after injection was measured at a flow rate of 2 mL / min. For the injection, I was mixed with rHuPH20 at concentrations of 200, 500, and 800 U / mL. For gG, the values ​​were 78.2±26.4, 59.7±20.0, and 94.9±9, respectively. The average swelling area was 7 cm² ± SEM. For injection at a flow rate of 4 mL / min, rH Swelling measurable only once for each uPH20 concentration, in 3 out of 12 injections. The area was determined by the number of localized swellings. The area of ​​localized swelling was statistically determined between the various concentrations of rHuPH20 at each flow rate. There were no significant differences, and there were no statistical differences between the two flow rates.

[0414] Evaluation of local injection sites: After the injection is complete, the local injection site will be assessed by three other evaluators for the presence and severity of erythema. The score incorporated the degree of visible swelling, the physical firmness of the skin, and scores for erythema and swelling. Primary irritation index (PII), and swelling to determine whether or not hardening was present. And qualitatively regarding the swelling / hardening index (SII) incorporating the hardness score I asked about it.

[0415] The presence and severity of erythema were evaluated. For infusion at a flow rate of 2 mL / min, 200, 5 For IgG mixed with rHuPH20 at concentrations of 00 and 800 U / mL, 0. The mean erythema scores were 8±0.2, 0.4±0.1, and 1.0±0.3 (±SEM). At a flow rate of 4 mL / min, rHuPH2 was injected at 200, 500, and 800 U / mL. For IgG mixed with 0, the values ​​were 0.3±0.1, 0.3±0.1, and 0.2, respectively. The mean erythema score (±SEM) was ±0.1. The score for local erythema was calculated using rHu for each flow rate. There is no statistical difference between the various concentrations of pH20, and there is no statistical difference between the two flow rates. There was none. The size of the visible localized swelling was evaluated. Injection at a flow rate of 2 mL / min Therefore, IgG mixed with rHuPH20 at concentrations of 200, 500, and 800 U / mL was treated with The average swelling scores were 1.9±0.4, 1.4±0.3, and 2.0±0.2, respectively. (±SEM) was observed. With an injection flow rate of 4 mL / min, the visible swelling was less. For IgG co-mixed with rHuPH20 at concentrations of 200, 500, and 800 U / mL, These are the mean erythema scores (±SEM) of 0.6±0.3, 0.9±0.4, and 0.9±0.4, respectively. The local swelling score was IgG+ 800U / mL at a flow rate of 2mL / min. rHuPH20 vs. rHuPH20 with IgG+ 200U / mL at a flow rate of 4 mL / min (p< Except for 0.05), there were no statistically significant differences between the various concentrations of rHuPH20 at each flow rate. Furthermore, there was no statistically significant difference between the two flow rates. Stiffness was evaluated. For injection at a flow rate of 2 mL / min, 200, 500 and 800 U / For IgG mixed with mL of rHuPH20, the values ​​were 1.5±0.3 and 1.0, respectively. The mean hardness scores (±SEM) were ±0.2 and 1.4±0.2. The flow rate was 4 mL / min. In the injection, the degree of hardness at the local injection site was small, and the concentrations of 200, 500, and 800 U / mL were low. When IgG was mixed with rHuPH20, the values ​​were 0.5±0.3 and 0.7±0, respectively. The average hardness scores (±SEM) were 2 and 0.7±0.3. The core showed no statistically significant difference between the various concentrations of rHuPH20 at each flow rate, and two There were no statistically significant differences in flow rates. The primary irritation index was the score for erythema and swelling. Calculations were based on the following: Infusion at 2 mL / min corresponds to rH of 200, 500, and 800 U / mL. For IgG mixed with uPH20, the values ​​were 1.4±0.3, 0.9±0.2, and respectively. The average PII score (±SEM) was 1.5 ± 0.2. The PII score is lower, and rHuPH20 is 200, 500 and 800 U / mL. For the co-mixed IgG, the values ​​were 0.4±0.2, 0.6±0.3, and 0.5±0, respectively. The average score was 0.3 (±SEM). The PII score was calculated using IgG at a flow rate of 2 mL / min. +800 U / mL rHuPH20 vs. IgG +200 U / mL r at a flow rate of 4 mL / min Except for HuPH20 (p<0.05), the various concentrations of rHuPH20 at each flow rate are combined. There was no statistical difference, and there was no statistical difference between the two flow rates. Swelling / hardness index The score was calculated based on swelling and hardness. Injection at 2 mL / min was 200. For IgG mixed with 500 and 800 U / mL of rHuPH20, 1 The mean SII scores (±SEM) were 0.7±0.3, 1.2±0.2, and 1.7±0.2. At a flow rate of 4 mL / min, the SII score was lower, at 200, 500, and 8. For IgG mixed with rHuPH20 at 00 U / mL, the respective values ​​were 0.6 ± 0.3. The average scores were 0.8±0.3 and 0.8±0.3(±SEM). SII score There is no statistically significant difference between the various concentrations of rHuPH20 at each flow rate, and the two flow rates There was no statistically significant difference between them. Based on the mean SII value (score of 2 or less), local injection The area was not considered to have hardened. Finally, photographs were taken before and after the completion of each injection. We took photos.

[0416] Example 2. Recombinant human hyaline for the treatment of subjects with relapsed or refractory multiple myeloma. Safety and pharmacokinetics of subcutaneous delivery of daratumumab supplemented with luronidase (rHuPH20) A multicenter, open-label, dose-escalation Phase 1b trial to evaluate the condition. The objective of the trial was to evaluate daratumumab in participants with relapsed or refractory multiple myeloma. To evaluate the safety, pharmacokinetics, and antitumor activity of subcutaneous (SC) or intravenous (IV) delivery of the drug. This study involved participants with relapsed or refractory multiple myeloma, and the treatment of Daratz A multicenter study to evaluate the safety, pharmacokinetics, and antitumor activity of mumab delivered via submucosal or intravenous (IV) delivery. This is a collaborative, open-label, two-part Phase Ib dose-escalation / expansion study. In Part 1: Part 1 will include a maximum of approximately 48 participants, and Part 2 will include a maximum of approximately 80 participants. The dose escalation phase is recommended based on the safety and pharmacokinetic (PK) data of daratumumab. It is designed to determine the two-phase dose (RP2D). Each part of the study is screened. The study consists of three phases: the treatment phase, the open-label treatment phase, and the post-treatment phase (from the last dose of the study drug to 8 weeks post-treatment). It has two phases. In Part 1, participants are in a continuous cohort consisting of approximately 8 participants in each cohort. - Assigned to a horse. Participants will be assigned to cycle 1 (each cycle is 28 days) and cycle 2 (weekly). Once, once every two weeks in cycles 3-6, and once every four weeks in subsequent cycles for each cohort. Multiple times, by SC injection, DARA PH20 (recombinant human hyaluronidase [rHuPH Administer daratumumab (with

[20] added). The last participant in each cohort is 20%. After completing day one of Crew 3, the Safety Assessment Team (SET) followed the protocol definition criteria. We will evaluate the safety and pharmacokinetic data and decide whether to escalate the dose in the new cohort. To determine whether or not to proceed, SET will verify all safety and PK data from Part 1. Before the start of Part 2, RP2D will be determined. In Part 2, participants will be randomly assigned in a 1:1 ratio. The recommended Phase 2 dose of DARA PH20 or 1200 mg of DARA delivered intravenously was used. The study will evaluate the safety, pharmacokinetics, and antitumor activity of daratumumab via SC and IV delivery. The safety of participants will be monitored throughout the examination.

[0417] Primary outcome measure: Daratumumab serum trough concentration (time frame: Part 2 cycle) 3 (28 days per cycle) up to day 1). Ctrough: Concentration of the test drug before administration.

[0418] Parts 1 and 2: Number of participants experiencing adverse events (AEs) and serious AEs (time frame) Screening until follow-up (30 days after final dose administration)

[0419] Adverse events (AEs) are defined as events that occur in participants who receive the study drug, regardless of the possibility of causality. A serious adverse event (SAE) is any undesirable medical event. A serious adverse event (SAE) is one of the following outcomes. An AE that is considered serious for any of the following reasons: death , the length of hospital stay for initial or extended hospitalized patients, life-threatening experiences (immediate risk of death), Persistent or significant disability / inability, congenital abnormality.

[0420] Secondary outcome measures: Parts 1 and 2: Daratumumab and recombinant human hyaluronidase (rHuPH20) (Plasma) Antibody serum concentration (time frame: approximately 2 years). For evaluation of potential immunogenicity. Serum levels of antibodies against daratumumab and rHuPH20. • Parts 1 and 2: Percentage of participants achieving complete remission (CR) (timeframe: approximately 2 years). CR Participants who achieved complete response (including sustained complete response) according to the International Myeloma Working Group (IMWG) criteria. It is defined as the proportion of people. • Parts 1 and 2: Participant ratio relative to overall response rate (ORR) (Time frame: approximately 2 years) The overall response rate is defined as complete remission during or after the study treatment, according to the International Myeloma Working Group criteria. This is defined as the proportion of participants who achieved a complete remission or partial remission. • Parts 1 and 2: Response Period (DR) (Timeframe: approximately 2 years). DR is based on IMWG standards. As defined by the standard, from the date of the first record of remission (CR or PR), PD first This is the time elapsed up to the date recorded. • Parts 1 and 2: Time to remission (timeframe: approximately 2 years). The time to remission is based on the trial. The first observed remission (CR or PR) was recorded from the day of the first administration of the investigational treatment. It is defined as the time until a specific date.

[0421] Table 6 shows the test plan. Table 7 shows the interventions.

[0422] [Table 6]

[0423] [Table 7]

[0424] Eligibility Participants will undergo a diagnostic assessment for multiple myeloma (MM) according to the International Myeloma Working Group (IMWG) diagnostic criteria. It has been proven that there are signs (symptoms): - Measurable disease as defined by any of the following: (a) Immunoglobulin (I g) G myeloma (serum monoclonal paraprotein [M protein] level is 1.0 gram / day) 100 mg / dL or higher, or urinary M protein level of 200 mg / 24 (b) IgA, IgD or IgE multiple myeloma (serum M protein (White level 0.5 g / dL or higher, or urinary M protein level 200 mg / 24hrs or higher) ; or (c) multiple light chain myeloma (serum immunoglobulin free light chain is 10 mg / dL or higher and Abnormal serum immunoglobulin kappa-lambda free light chain ratio) - Participants were from the Eastern Cooperation Group (Eastern Cooperation Group). If the general health status score of the Oncology Group (ECOG) is 0, 1, or 2 It needs to exist. - Pre-treatment laboratory values ​​meet the protocol-defined parameters during the screening phase. It needs to be added. -Men who are sexually active with women of childbearing age and have not undergone vasectomy, and who are being investigated. I agree to use an appropriate method of contraception that the person deems suitable, and during the trial and the trial You must agree not to donate sperm for four months after your last dose of mumab.

[0425] Exclusion criteria: - Previously received daratumumab or other anticluster therapy with differentiated CD38 (anti-CD38) A participant - Participants who received anti-myeloma treatment within two weeks prior to day 1 of cycle 1. - Participants who have previously received allogeneic stem cell transplantation, or those who have had a transplant on day 1 of cycle 1. Participants who underwent autologous stem cell transplantation (ASCT) within the past two weeks - History of malignant disease (excluding multiple myeloma) within 5 years prior to Cycle 1, Day 1 Participants (squamous and basal cell carcinoma of the skin and cervical intraepithelial neoplasia, or sponsor's medical treatment) Consistent with Nita's opinion, researchers believe that malignant diseases that are considered curable with minimal risk of recurrence are likely to be treated. (Patients are an exception.) - Participants showing clinical signs of intramedullary damage in multiple myeloma Gender: Both Age limit: 18 years old Acceptance of healthy volunteers: None

[0426] Intermediate readout from Part 1 (Data cutoff: Safety / Demographics / Medical history is 2016) (July 21st, effect data is from July 28th, 2016) method The patient has RRMM and is receiving proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). They had a history of two or more prior treatments, including [specific example]. In Part 1 of the two-part trial, [specific example] To determine the recommended SC dose for 2, 1200 mg and 1800 mg DAR A continuous cohort at dose A was included. DARA-PH20 was administered over a 4-week treatment period. Administered with Ikul (once a week for 8 weeks, once every two weeks for 16 weeks, and then every four weeks thereafter) (1 dose). DARA-PH20 is administered via a syringe pump at the rotational site of the abdomen, 120 60 mL of 0 mg over 20 minutes, or 90 mL of 1800 mg over 30 minutes. It was injected over time. The drugs before and / or after injection included paracetamol and diphenhydride. The drugs included lamin, montelukast, and methylprednisolone. In Part 2, the participants Participants were randomized in a 1:1 ratio to receive the recommended Phase 2 dose (RP2D) of SC DARA-PH20. Alternatively, receive IV DARA (16 mg / kg). DARA-PH20 RP2D is... Selected and approved based on a cumulative review of pharmacokinetic and safety data obtained from Et1. With respect to the 16 mg / kg IV dose, the observed weekly duration of administration was equivalent to or greater than that observed. Maximum serum Ctrough should be achieved. The primary endpoint is 1 in cycle 3. The clinical trial and safety of DARA up to day [number] were observed. The secondary endpoint was all The ORR (Order of Response Rate) was included.

[0427] result To date, in Part 1, 1200 mg (n=8) and 1800 mg (n=33) 41 participants were treated with SC DARA-PH20 at the dose level of ) associated with the infusion. Internal response rates (IRRs) were reported in 9 out of 41 participants (22%), and were mostly negative. Severity includes chills, fever, rigidity, vomiting, itching, tongue edema, noncardiac chest pain, and wheezing. It was rated as Grade 1 / 2. After the first infusion, one participant developed Grade 3 dyspnea. One participant required hospitalization due to fever and chills (both grade 2). All RRs occurred during or within 6 hours after the first SC infusion, and were caused by antihistamines and colitis. It was controlled with treatment with tycosteroids, antiemetics, or bronchodilators. Subsequent infusion In this case, no IRR was reported. Overall, the adverse event profile for DARA-PH20 was positive. The file matched IV DARA. Grade 3 or higher drug-related adverse events were fatigue. Of the 41 people, 2 had labor, influenza, hypertension, dyspnea, and oncolytic syndrome. This was reported in 5 participants (12%). SC administration of DARA-PH20 was via abdominal wall injection. The following cases were well tolerated at the application site, and grade 1 erythema, hardening, or burning sensation was reported: Three out of 41 participants (7%) were included. The analysis was performed on IV DARA (16 mg / kg). Compared to the subsequent highest Ctrough achieved, in the 1800mg cohort... It showed a very high maximum Ctrough.

[0428] A 1200mg cohort consisting of 8 participants (median of 5 lines of prior treatment history [range]) 2-10]; Before ASCT, 63%; Treatment resistance to PI only, 0%; For IMiD Treatment resistance only, 13%; treatment resistance to both PI and IMiD, 63% A 25% ORR was observed, including two patients with partial remission (PR). The interval was 14 weeks (range 8-20). At the evaluation of day 1 of cycle 3, 1800m 17 participants in the G cohort who were evaluable as being in remission (median of 4 lines of prior treatment history) Values ​​[[Range 2~7]; Before ASCT, 76%; Treatment resistance to PI only, 6%; IMi Treatment resistance to D only: 12%; Treatment resistance to both PI and IMiD: 65% Of these, 41% ORR was observed, including 3 patients with very good partial remission and 4 patients with partial remission (PR). The median time to remission was 4 weeks (range 4-8).

[0429] Conclusion: SC DARA-PH20 is well tolerated and allows for significantly shorter infusion times during IV DAR. Compared to A, it shows a lower IRR rate and is equivalent to or better than IV DARA in serum thrombocytopenia. The required concentration was achieved. Preliminary data shows that in this participant population, SC DARA-PH20 This suggests that it enables response rates similar to IV DARA monotherapy. For RP2D for T2, we selected DARA-PH20 at a dose level of 1800 mg. These early data support further trials of SC DARA in clinical trials. .

[0430] Example 3. Development of a co-formulation of daratumumab and hyaluronidase. The overall physicochemical stability and delivery of daratumumab and rHuPH20 in combination products. To establish this, various combination formulations were evaluated. The influence of the concentrations of the active ingredient and / or excipients in the formulation. The Hibiki was subjected to stability tests and / or animal tests (storage stability, shaking stability and injection in pigs). The formulations were evaluated in several of the trials. Table 8 provides an overview of the formulations used in the various trials. Present.

[0431] [Table 8]

[0432] The range of excipients and active ingredients in the tested formulations is shown in Table 9.

[0433] [Table 9]

[0434] The generated formulations include subvisible particles, microflow imaging (MFI), and cyanomorphic imaging. Exclusion chromatography (SEC), capillary isoelectric focusing (cIEF), SD S-PAGE (non-reducing and reduced), peptide mapping, sample volume, turbidity, gravimetric osmolality. The formulation was tested in various assays to assess its properties, including concentration and pH.

[0435] Sub-visible particles (Sub-vis): Sub-visible particles 10 μm or larger, or 25 μm or larger. The number of particle sizes is generally an aggregate of protein molecules, and light obscuration (light obscuration) (scuration) can be analyzed by the HIAC method. In the light-deciphered HIAC method, small By passing the solution through a small opening and blocking out light, information about the size of the particles passing through is obtained. To provide.

[0436] MFI: This is orthogonal to optical obscuration, and is related to microflow imaging (MFI ) captures a snapshot image of flowing particles and presents them in a specific amount of liquid. Convert back to the number of particles. This method relates to large aggregates of proteins present in solution. Provide information.

[0437] SEC: Size exclusion chromatography is a separation method that uses a column to separate the flowing solution. The molecules are distributed according to their wide size range. Monomers, aggregates, and fragments are separated by column or Since they elute at different times, a standard UV detector is used to determine their relative positions in the sample. The proportion can be quantified.

[0438] cIEF: Capillary isoelectric focusing is a method of distributing molecules according to their charge, and the whole It is a good indicator of chemical stability. For example, deamidation involves a change in the charge of the molecule. Therefore, it will be collected by this method. This method allows for the collection of molecules present in the solution. This provides a concept of the overall acidity, basicity, and intact percentage.

[0439] SDS (reducing and non-reducing conditions): The SDS method provides information about the physical stability of molecules. Provided. SDS measures intact, aggregated, and fragmented species present in solution. It provides: SDS under non-reducing conditions is aggregated and fragmented with the corresponding antibody intact. It provides information on the components, and the SDS (post-disulfide splitting) under reduction is the heavy chain of the antibody and Provides the same information regarding light chains.

[0440] Peptide mapping: Peptide mapping is used to test the primary structure of proteins. It is an essential technology. Regarding recombinant protein pharmaceuticals, peptide mapping is used to determine structural characteristics. It is used as an initial clue for determination. Peptide mapping is also used for deamidation and oxidation. This provides information about post-translation modifications such as those mentioned above.

[0441] Collection volume: This method refers to the amount of liquid that can be extracted from the vial after each time point. This provides information about the product.

[0442] Turbidity: A light scattering-based method for evaluating the physical stability of a solution. An increase in isp leads to an increase in the light scattering signal, which in turn is obtained as turbidity (milky light) of the solution. Turbidity is measured in turbidimetric units (NTU).

[0443] Osmolality by weight: A measure of overall osmotic activity that depends on the true overall activity of the molecule. The solution provides an activity coefficient multiplied by the concentration. It needs to be an approximation.

[0444] pH: Provides the concept of overall stability, and it is important that the pH remains constant throughout the shelf life. That is the case.

[0445] rHuPH20 enzyme activity: Determination of hyaluronidase activity is based on whether hyaluronic acid (HA) is acidic. Based on the formation of precipitate when bound with sexualized serum. Hyaluronidase is treated with HA for 30 minutes, 9 After culturing in a 6-well plate at 37°C, acidified serum was added to remove undigested HA. The activity is measured by precipitation. The obtained turbidity is measured at 640 nm, and the HA substrate A decrease in turbidity resulting from enzymatic cleavage is an indicator of hyaluronidase activity.

[0446] Formulation 1 (100 mg / mL daratumumab, 10 mM histidine, 300 mM sol) Bitol, 0.04% PS20, 2 mg / mL methionine, 500 U / mL PrH The storage stability of UH20 (pH 5.5) was evaluated using the assay described. The sample was: In 25R vials (filled with a 16 mL dose), at different temperatures (5, 25, and 40°C) Stabilize the vials at different time points (0, 1, 2, 3, 4, 5 and / or 6 months). The samples were extracted for analysis using various assays. The data were shown by various assays. As such, the combination product, in both daratumumab and rHuPH20, under the storage conditions It is shown to be stable under these conditions. Observations regarding particles, color, turbidity, sec, etc. The file is very similar to a stable antibody that behaves well, and the data is similar to several quotients. The stability data is equivalent to that of the mAb formulation used.

[0447] Table 10 shows the number of particles in formulation 1 over time, as evaluated using HIAC.

[0448] Table 11 shows the number of particles in formulation 1 over time, as evaluated using MFI.

[0449] Table 12 shows the pH of formulation 1 over time.

[0450] Table 13 shows the turbidity of Formulation 1 over time.

[0451] Table 14 shows the ratio of high molecular weight aggregates and low molecular weight fragments in formulation 1 over time.

[0452] Table 15 shows the acidic and basic species in Formulation 1, as evaluated using cIEF, over time. .

[0453] Table 16 shows the purity percentage (%) of Formulation 1 as evaluated using reduced SDS-PAGE. This will be shown over time.

[0454] Table 17 shows the purity percentage (%) of Formulation 1 as evaluated using non-reducing SDS-PAGE. This is shown over time.

[0455] Table 18 shows the percentage of biological activity (%) of daratumumab in formulation 1 and the enzyme activity of rhPH20. It shows the nature over time.

[0456] [Table 10]

[0457] [Table 11]

[0458] [Table 12]

[0459] [Table 13]

[0460] [Table 14]

[0461] [Table 15]

[0462] [Table 16]

[0463] [Table 17]

[0464] [Table 18]

[0465] The stirring (shaking) stability of formulation 1 was also evaluated using the assay described above to determine the characteristics of the formulation. This is done by changing only the PS20 concentration in the formulation (PS20 is set to 0, 0.01, 0 Formulations 1, 3, 4, 5, and 6) PS shown in Table 8, with concentrations changed to 0.02, 0.04, and 0.06%. The effect of concentration was tested. The data, as shown by various assays, shows that the combination drug... Both latumumab and the enzyme were shown to be stable under shaking conditions. The observed profiles for color, turbidity, sec, etc., were all concentrations of PS other than 0%. Regarding the degree, it is very similar to a stable antibody that behaves well (a formulation with 0% PS20 is (It had particles and was not stable), the data showed that some commercial mAb formulations have stability data It was equivalent to the data (data not shown).

[0466] Formulation 2 (120 mg / mL daratumumab, 10 mM histidine, 300 mM sol) Bitol, 0.04% PS20, 1 mg / mL methionine, 2000 U / mL rh The storage stability of the sample (uPH20, pH5.5) was evaluated using the assay described. , filled with an overfill (1500 mg dose) to a dose of 13.27 mL 25 Stabilization at different temperatures in R vials and analysis using various assays as described below. The vial was removed for this purpose. The collected data showed that the combination product contained daratumumab and rH It was shown to be stable under storage conditions at both uPH2O. Particle size, color, turbidity, s The profiles observed for EC, etc., were very similar to those of well-behaving, stable antibodies. The data was comparable to the stability data of several commercial mAb formulations. H2O is highly susceptible to high temperatures, and if stored at 40°C, it deteriorates very rapidly. It loses all activity at a certain temperature. Table 19 shows the characteristics of the formulation.

[0467] [Table 19]

[0468] Formulations 3-8 were tested for storage stability or vibration using some or all of the assays described. The stability of formulations 3-8 was tested. The data showed that formulations 3-8 were stable with daratumumab and HuPH20. Both demonstrated stability under the evaluated conditions (formulations 7 and 8 were rHu (It did not have a pH of 20). To provide additional oxidative stability, formulations 1-6 and Methionine was added to samples 9-12. Particle size, color, turbidity, and sec were observed. The file is very similar to a stable antibody that behaves well, and the data is similar to several quotients. The stability data was equivalent to that of the mAb formulation used (data not shown).

[0469] The stirring (shaking) stability of formulation 1 was also evaluated using the assay described above to determine the characteristics of the formulation. This is done by changing only the PS20 concentration in the formulation (PS20 is set to 0, 0.01, 0 Formulations 1, 3, 4, 5, and 6) PS shown in Table 8, with concentrations changed to 0.02, 0.04, and 0.06%. The effects of 20 concentrations were tested. The data showed that the combination drug was effective, as demonstrated by various assays. Both daratumumab and rHuPH20 were stable under shaking conditions. The observed profiles for particles, color, turbidity, sec, etc., were all P values ​​other than 0%. For all concentrations of S, the results are very similar to those of a stable antibody that behaves well, and the data The stability data was comparable to that of several commercial mAb formulations (data not shown).

[0470] Formulations 9-12 also varied the enzyme concentration in the pig model described in Example 2. We investigated the evaluation of subcutaneous administration of daratumumab by conducting these studies. The appropriate rhPH20 concentration for delivering 16 mL of daratumumab was determined. The key points are injection pressure, the area of ​​swelling or bleb (if measurable), and a qualitative assessment of the site. A dose-dependent increase in injection pressure was observed. All rhPH20 tested Concentrations (50, 500, 2000, 5000 U / mL) deliver 16 mL of daratumumab. It was enough to do so.

Claims

1. A pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase.

2. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 1 or 2, which is a fixed combination or a non-fixed combination.

4. The following are claims 1 to 3, each containing the anti-CD38 antibody in a concentration of approximately 1 mg / mL to approximately 180 mg / mL. Any of the pharmaceutical compositions described below.

5. a) The anti-CD38 antibody in a concentration of approximately 10 mg / mL to approximately 180 mg / mL, b) The anti-CD38 antibody in a concentration of approximately 20 mg / mL to approximately 160 mg / mL, c) The anti-CD38 antibody in a concentration of approximately 20 mg / mL to approximately 140 mg / mL, d) The anti-CD38 antibody in a concentration of approximately 20 mg / mL to approximately 120 mg / mL, e) The anti-CD38 antibody in a concentration of approximately 40 mg / mL to approximately 120 mg / mL, f) The anti-CD38 antibody in a concentration of approximately 60 mg / mL to approximately 120 mg / mL, g) The anti-CD38 antibody in an amount of approximately 80 mg / mL to approximately 120 mg / mL, or h) Claim 1, comprising approximately 100 mg / mL to approximately 120 mg / mL of the anti-CD38 antibody. A pharmaceutical composition as described in any of the four items.

6. a) The anti-CD38 antibody at approximately 20 mg / mL, b) The anti-CD38 antibody in an amount of approximately 100 mg / mL, or c) The present invention according to any one of claims 1 to 5, comprising approximately 120 mg / mL of the anti-CD38 antibody. A pharmaceutical composition.

7. Claims 1 to 6, each containing the hyaluronidase in an amount of approximately 50 U / mL to approximately 5,000 U / mL. A pharmaceutical composition as described in any of the following.

8. a) Hyaluronidase in a concentration of approximately 50 U / mL to approximately 5,000 U / mL, b) The hyaluronidase in a concentration of approximately 500 U / mL to approximately 5,000 U / mL, c) The hyaluronidase in a concentration of approximately 1,000 U / mL to approximately 5,000 U / mL, d) The hyaluronidase in a concentration of approximately 2,000 U / mL to approximately 5,000 U / mL e) Hyaluronidase in a concentration of approximately 50 U / mL to approximately 2,000 U / mL, f) The hyaluronidase in an amount of approximately 500 U / mL to approximately 2,000 U / mL, g) Containing the hyaluronidase in an amount of approximately 1,000 U / mL to approximately 2,000 U / mL, A pharmaceutical composition as described in any of the requests 1 to 7.

9. a) The hyaluronidase at approximately 50 U / mL, b) The hyaluronidase at approximately 500 U / mL, c) The hyaluronidase in a concentration of approximately 2,000 U / mL, or d) The present invention relates to any one of claims 1 to 8, comprising approximately 5,000 U / mL of the hyaluronidase. The pharmaceutical composition described.

10. The following are claims 1 to 9, each containing approximately 1,200 mg to approximately 5,000 mg of the anti-CD38 antibody. Any of the pharmaceutical compositions described below.

11. A hyaluronidase comprising approximately 750 U to approximately 75,000 U of the hyaluronidase, according to any of claims 1 to 10. A pharmaceutical composition as described in any of the following.

12. Claims 1 to 11, comprising approximately 30,000 U to approximately 45,000 U of the hyaluronidase. A pharmaceutical composition as described in any of the following.

13. a) Approximately 2,400 mg of the anti-CD38 antibody and approximately 30,000 U of the hyaluronida -ze, b) Approximately 2,400 mg of the anti-CD38 antibody and approximately 45,000 U of the hyaluronida -ze, c) Approximately 2,200 mg of the anti-CD38 antibody and approximately 30,000 U of the hyaluronida -ze, d) Approximately 2,200 mg of the anti-CD38 antibody and approximately 45,000 U of the hyaluronida -ze, e) Approximately 2,000 mg of the anti-CD38 antibody and approximately 30,000 U of the hyaluronida -ze, f) Approximately 2,000 mg of the anti-CD38 antibody and approximately 45,000 U of the hyaluronida -ze, g) Approximately 1,800 mg of the anti-CD38 antibody and approximately 30,000 U of the hyaluronida -ze, h) Approximately 1,800 mg of the anti-CD38 antibody and approximately 45,000 U of the hyaluronidium -ze, i) Approximately 1,600 mg of the anti-CD38 antibody and approximately 30,000 U of the hyaluronidium -ze, j) Approximately 1,600 mg of the anti-CD38 antibody and approximately 45,000 U of the hyaluronidium -ze, k) Approximately 1,200 mg of the anti-CD38 antibody and approximately 30,000 U of the hyaluronidium -ze, or l) Approximately 1,200 mg of the anti-CD38 antibody and approximately 45,000 U of the hyaluronidium A pharmaceutical composition according to any one of claims 1 to 12, comprising -se.

14. The aforementioned anti-CD38 antibody is a) Heavy chain variable region 1 (HCDR1) of sequence numbers 6, 7, 8, 9, 10, and 11, respectively. Sequence, HCDR2 sequence, HCDR3 sequence, light chain variable region 1 (LCDR1) sequence, LCDR Two sequences and three LCDR sequences, b) The heavy chain variable region (VH) of Sequence ID No. 4 and the light chain variable region (VL) of Sequence ID No. 5, and to / or c) any one of claims 1 to 13, comprising the heavy chain of SEQ ID NO: 12 and the light chain of SEQ ID NO: 13 The pharmaceutical composition described.

15. The aforementioned anti-CD38 antibody is a) Sequence IDs 14 and 15, respectively b) Sequence IDs 16 and 17, respectively c) Sequence IDs 18 and 19, respectively, or d) The respective claims 1 to 13, each including VH and VL of Sequence ID No. 20 and 21. A pharmaceutical composition as described in any of the following.

16. a) Approximately 25 mM acetic acid with a pH of approximately 5.5, approximately 60 mM sodium chloride, and approximately 140 ml of acetic acid. Initol and in approximately 0.04% w / v polysorbate-20 (PS-20), the sequence Approximately 20 mg / mL to approximately 120 mg / m², including the aforementioned VH (number 4) and VL (sequence number 5). The aforementioned anti-CD38 antibody of L, b) pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L - Methionine, approximately 30,000 U to approximately 45,000 U in 0.02% polysorbate-80 A pharmaceutical composition according to any one of claims 1 to 14, comprising 00U of the hyaluronidase. thing.

17. The hyaluronidase is rHuPH20 (SEQ ID NO: 22), as described in claim 16. A pharmaceutical composition.

18. The pharmaceutical composition according to claim 17, which is a non-fixed combination.

19. a) Approximately 25 mM acetic acid with a pH of approximately 5.5, approximately 60 mM sodium chloride, and approximately 140 ml of acetic acid. Initol and in approximately 0.04% w / v polysorbate-20 (PS-20), the sequence Approximately 20 mg / mL of the anti-CD38 anti- Body and, b) pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L - Methionine, approximately 30,000 U of the hyaluronic acid in 0.02% polysorbate-80 A pharmaceutical composition according to any one of claims 1 to 14, comprising lonidase.

20. The hyaluronidase is rHuPH20 (SEQ ID NO: 22), as described in claim 19. A pharmaceutical composition.

21. The pharmaceutical composition according to claim 20, which is a non-fixed combination.

22. a) Approximately 25 mM acetic acid with a pH of approximately 5.5, approximately 60 mM sodium chloride, and approximately 140 ml of acetic acid. Initol and in approximately 0.04% w / v polysorbate-20 (PS-20), the sequence Approximately 20 mg / mL of the anti-CD38 anti- Body and, b) pH 6.5, 10 mM L-histidine, 130 mM NaCl, 10 mM L - Methionine, approximately 45,000 U of the hyaluronic acid in 0.02% polysorbate-80 A pharmaceutical composition according to any one of claims 1 to 14, comprising lonidase.

23. The hyaluronidase is rHuPH20 (SEQ ID NO: 22), as described in claim 22. A pharmaceutical composition.

24. The pharmaceutical composition according to claim 23, which is a non-fixed combination.

25. a) Approximately 1 mg / mL to approximately 180 mg including the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 The anti-CD38 antibody in mg / mL, b) The hyaluronidase in a concentration of approximately 50 U / mL to approximately 5,000 U / mL, c) Histidine at approximately 5 mM to approximately 50 mM, d) any one of claims 1 to 14, comprising approximately 50 mM to approximately 400 mM sorbitol. The pharmaceutical composition described above.

26. a) PS-20 in an amount of approximately 0.01% w / v to approximately 0.1%, and / or b) The present invention further comprises approximately 0.1 mg / mL to approximately 2.5 mg / mL of methionine, according to claim 25. The pharmaceutical composition described.

27. The hyaluronidase is rHuPH20, according to claim 25 or 26. A finished product.

28. a) Approximately 100 mg / mL to approximately 1 The anti-CD38 antibody at 20 mg / mL, b) The hyaluronidase in a concentration of approximately 50 U / mL to approximately 5,000 U / mL, c) Approximately 10 mM histidine, d) The pharmaceutical product according to claim 25, comprising approximately 100 mM to approximately 300 mM sorbitol. composition.

29. a) PS-20 with a concentration of approximately 0.01% w / v to approximately 0.04% w / v, b) The claim 28 further comprises about 1 mg / mL to about 2 mg / mL of methionine. A pharmaceutical composition.

30. The hyaluronidase is rHuPH20, as described in any one of claims 25 to 29. A pharmaceutical composition.

31. a) Approximately 120 mg / mL of the above, including VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH2O at approximately 2,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.04% w / v, f) A solution comprising approximately 1 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

32. a) Approximately 100 mg / mL of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH2O at approximately 500 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.04% w / v, f) A solution comprising approximately 2 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

33. a) Approximately 100 mg / mL of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH2O at approximately 500 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.01% w / v, f) A solution comprising approximately 2 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

34. a) Approximately 100 mg / mL of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH2O at approximately 500 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.02% w / v, f) A solution comprising approximately 2 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

35. a) Approximately 100 mg / mL of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH2O at approximately 500 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.06% w / v, f) A solution comprising approximately 2 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

36. a) Approximately 100 mg / mL of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH20 at approximately 50 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.04% w / v, f) A solution comprising approximately 1 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

37. a) Approximately 100 mg / mL of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH2O at approximately 500 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.04% w / v, f) A solution comprising approximately 1 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

38. a) Approximately 100 mg / mL of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH2O at approximately 2,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.04% w / v, f) A solution comprising approximately 1 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

39. a) Approximately 100 mg / mL of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) rHuPH2O at approximately 5,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 with approximately 0.04% w / v, f) A solution comprising approximately 1 mg / mL of methionine and having a pH of approximately 5.5, according to claims 1 to 14. The pharmaceutical composition is one of the descriptions in 25 to 30.

40. The hyaluronidase is rHuPH20 (SEQ ID NO: 22), according to claims 1 to 39. A pharmaceutical composition as described in any of the following.

41. A pharmaceutical composition according to any one of claims 1 to 40, in the form of an administration unit.

42. A method for treating cancer in a subject, wherein the subject requiring the treatment is given anti-CD3 A pharmaceutical composition containing 8 antibodies and hyaluronidase is administered for a sufficient amount of time to treat the cancer. A method including subcutaneous administration while standing.

43. The pharmaceutical composition is a fixed combination or a non-fixed combination as described in claim 42. method.

44. The anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5, claim 42 or This is the method described in 43.

45. The pharmaceutical composition is approximately 10 mg / mL to approximately 180 mg / mL, and approximately 20 mg / mL to approximately 1 60mg / mL, about 20mg / mL to about 140mg / mL, about 20mg / mL to about 120 mg / mL, about 40 mg / mL to about 120 mg / mL, about 60 mg / mL to about 120 mg / mL, about 80 mg / mL to about 120 mg / mL, about 100 mg / mL to about 120 mg / mL mL, approximately 20 mg / mL, approximately 100 mg / mL, or approximately 120 mg / mL of the anti-CD38 The method according to any one of claims 42 to 44, comprising an antibody.

46. The pharmaceutical composition is approximately 50 U / mL to approximately 5,000 U / mL, and approximately 500 U / mL to approximately 5 ,000U / mL, about 1,000U / mL to about 5,000U / mL, about 2,000U / m L ~ approx. 5,000 U / mL, approx. 50 U / mL ~ approx. 2,000 U / mL, approx. 500 U / mL ~about 2,000U / mL, about 1,000U / mL~about 2,000U / mL, about 50U / m L, approximately 500 U / mL, approximately 2,000 U / mL, or approximately 5,000 U / mL of the hyaluronic acid The method according to any one of claims 42 to 45, comprising nidase.

47. The aforementioned pharmaceutical composition is approximately 1,200 mg to approximately 5,000 mg, approximately 1,200 mg to approximately 4, 000 mg, approximately 1,200 mg to approximately 3,000 mg, approximately 1,200 mg to approximately 2,400 mg g, about 1,200 mg to about 1,800 mg, about 1,200 mg, about 1,400 mg, about 1 , 600mg, about 1,800mg, about 2,000mg, about 2,200mg, about 2,400 mg, about 2,600 mg, about 2,800 mg, about 3,000 mg, about 3,200 mg, about 3,400 mg, approximately 3,600 mg, approximately 3,800 mg, approximately 4,000 mg, approximately 4.20 0 mg, approximately 4,400 mg, approximately 4,600 mg, approximately 4,800 mg, or approximately 5,000 mg The method according to any one of claims 42 to 46, comprising the anti-CD38 antibody.

48. The aforementioned pharmaceutical composition contains approximately 750U to approximately 75,000U, and approximately 30,000U to approximately 45,000U. Claim 4, comprising 0 U, about 30,000 U, or about 45,000 U of the hyaluronidase. The method described in any of 2 to 47.

49. The pharmaceutical composition comprises approximately 2,400 mg of the anti-CD38 antibody and approximately 30,000 U of the pre- The method according to any one of claims 42 to 48, comprising the hyaluronidase described above.

50. The pharmaceutical composition comprises approximately 2,400 mg of the anti-CD38 antibody and approximately 45,000 U of the pre- The method according to any one of claims 42 to 48, comprising the hyaluronidase described above.

51. The pharmaceutical composition comprises approximately 2,200 mg of the anti-CD38 antibody and approximately 30,000 U of the pre- The method according to any one of claims 42 to 48, comprising the hyaluronidase described above.

52. The pharmaceutical composition comprises approximately 2,200 mg of the anti-CD38 antibody and approximately 45,000 U of the pre- The method according to any one of claims 42 to 48, comprising the hyaluronidase described above.

53. The pharmaceutical composition comprises approximately 1,800 mg of the anti-CD38 antibody and approximately 30,000 U of the pre- The method according to any one of claims 42 to 48, comprising the hyaluronidase described above.

54. The aforementioned pharmaceutical composition comprises approximately 1,800 mg of the anti-CD38 antibody and approximately 45,000 U of the pre- The method according to any one of claims 42 to 48, comprising the hyaluronidase described above.

55. The pharmaceutical composition comprises approximately 1,600 mg of the anti-CD38 antibody and approximately 30,000 U of the pre- The method according to any one of claims 42 to 48, comprising the hyaluronidase described above.

56. The pharmaceutical composition comprises approximately 1,600 mg of the anti-CD38 antibody and approximately 45,000 U of the pre- The method according to any one of claims 42 to 48, comprising the hyaluronidase described above.

57. The aforementioned anti-CD38 antibody is a) Sequence IDs 14 and 15, respectively b) Sequence IDs 16 and 17, respectively c) Sequence IDs 18 and 19, respectively, or d) Claim 42, 43, or 45, each comprising VH and VL of Sequence ID No. 20 and 21, respectively. The method described in any of the following 56.

58. The pharmaceutical composition contains approximately 20 mg of VH of SEQ ID NO: 4 and VL of SEQ ID NO:

5. The anti-CD38 antibody in a concentration of 1 / mL and the hyaluronic acid in a concentration of approximately 30,000 U to approximately 45,000 U. Dase, approximately 25 mM acetic acid, approximately 60 mM sodium chloride, and approximately 140 mM mannidine It contains toll and approximately 0.04% w / v polysorbate-20 (PS-20), p The method according to any one of claims 42 to 44 or 46 to 56, wherein H is approximately 5.

5.

59. The pharmaceutical composition contains approximately 1 mg / The aforementioned anti-CD38 antibody in a concentration of approximately 180 mg / mL and approximately 50 U / mL to approximately 5,000 U / mL of the aforementioned hyaluronidase, approximately 5 mM to approximately 50 mM histidine, and approximately 50 mM to approximately It contains 400 mM sorbitol and approximately 0.01% w / v to approximately 0.1% w / v P S-20 and / or methionine in an optional dose of approximately 0.1 mg / mL to approximately 2.5 mg / mL The method according to any one of claims 42 to 44 or 46 to 56, further comprising:

60. The pharmaceutical composition comprises approximately 100 ml of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO:

5. The aforementioned anti-CD38 antibody in a concentration of g / mL to approximately 120 mg / mL, and approximately 50 U / mL to approximately 5,000 The hyaluronidase in U / mL, approximately 10 mM histidine, and approximately 100 mM to approximately 30 It contains 0 mM sorbitol and approximately 0.01% w / v to approximately 0.04% w / v PS -20 and / or optionally further containing about 1 mg / mL to about 2 mg / mL of methionine The method according to any one of claims 42 to 44, 46 to 56, or 59.

61. The pharmaceutical composition contains approximately 120 ml of VH of SEQ ID NO: 4 and VL of SEQ ID NO:

5. The anti-CD38 antibody in g / mL, the hyaluronidase in approximately 2,000 U / mL, and 10 mM histidine, approximately 300 mM sorbitol, and approximately 0.04% w / v PS Claims 42- The method described in any of 44, 46-56, or 59-60.

62. The pharmaceutical composition comprises approximately 100 ml of the VH of SEQ ID NO: 4 and the VL of SEQ ID NO:

5. The anti-CD38 antibody in g / mL, the hyaluronidase in approximately 500 U / mL, and approximately 10 mM histidine, approximately 300 mM sorbitol, and approximately 0.04% w / v PS-2 Claims 42-44, which contain 0 and approximately 2 mg / mL of methionine, and have a pH of approximately 5.

5. , the method described in either 46-56 or 59-60.

63. The hyaluronidase is rHuPH20 (SEQ ID NO: 22), claims 42-62. One of the methods described above.

64. The cancer is a CD38-positive hematological malignancy, as described in any one of claims 42 to 63. method.

65. The aforementioned CD38-positive hematological malignancies include multiple myeloma, follicular lymphoma, and diffuse large cell myeloma. B-cell lymphoma, light chain amyloidosis, non-Hodgkin lymphoma, acute lymphoblastic leukemia, Claim 64, which is mantle cell lymphoma, acute myeloid leukemia, or chronic lymphocytic leukemia. Method of description.

66. The method according to claim 65, wherein the CD38-positive hematological malignancy is multiple myeloma.

67. The method according to any one of claims 42 to 63, wherein the cancer is a solid tumor.

68. The method according to any one of claims 42 to 67, further comprising administering a second therapeutic agent.

69. The second therapeutic agent is a proteasome inhibitor, an alkylating agent, or a glutamate inducer. The method according to claim 68, wherein the body is a combination thereof.

70. a) The proteasome inhibitor is bortezomib, carfilzomib, or ixazomib And, b) The alkylating agent is busulfan, cyclophosphamide, bendamustine, chlorophosphamide. Rambucil, carboplatin, cisplatin, temozolomide, melphalan, carmust N, Lomustine, Dacarbazine, Oxaliplatin, Ifosfamide, Mechloretamine, Thiotepa, trabectedin, or streptozocin, c) The glutamic acid derivative is lenalidomide, thalidomide, or pomalidomide. The method according to claim 69.

71. The method according to any one of claims 42 to 70, further comprising administering a corticosteroid.

72. The corticosteroid is dexamethasone or prednisone, as described in claim 71. Method of loading.

73. The method according to claim 72, wherein the corticosteroid is dexamethasone.

74. a) Approximately 1,200 mg to approximately 5,000 mg containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 A quantity of anti-CD38 antibody in grams, b) Hyaluronidase in an amount of approximately 30,000 U to approximately 45,000 U, c) Histidine at a concentration of approximately 5 mM to approximately 15 mM, d) Sorbitol at a concentration of approximately 100 mM to approximately 300 mM, e) PS-20 at concentrations of approximately 0.01% w / v to approximately 0.04% w / v, f) Contains methionine at a concentration of approximately 1 mg / mL to approximately 2 mg / mL, with a pH of approximately 5.

5. A certain unit dosage form.

75. The aforementioned anti-CD38 antibody is available in doses of approximately 1,200 mg, 1,400 mg, 1,600 mg, and 1,8 00mg, 2,000mg, 2,200mg, 2,400mg, 2,600mg, 2,8 00 mg, 3,000 mg, 3,200 mg, 3,400 mg, 3,600 mg or 4, The unit dosage form according to claim 74, which exists in an amount of 000 mg.

76. The hyaluronidase is present in an amount of approximately 30,000 U as described in claim 74 or 75. The listed unit dosage form.

77. Histidine is present at a concentration of approximately 10 mM, as described in any one of claims 74 to 76. dosage form.

78. Sorbitol is present at a concentration of approximately 300 mM, as described in any one of claims 74 to 78. The unit dosage form.

79. The polysorbate is present at a concentration of approximately 0.04% w / v, according to claims 74 to 79. The unit dosage form listed below.

80. The methionine is present at a concentration of approximately 1 mg / mL, as described in any one of claims 74 to 80. The unit dosage form.

81. Claims 74-8 optionally contain sucrose at a concentration of approximately 100 mM to approximately 200 mM. The unit dosage form listed in any of the following:

82. The hyaluronidase is rHuPH20 (SEQ ID NO: 22), claims 74-81. The unit dosage form described in any of the following.

83. A container containing the unit dosage form according to any one of claims 74 to 82.

84. a) A quantity of approximately 1,800 mg containing the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 Anti-CD38 antibody, b) Hyaluronidase in an amount of approximately 30,000 U, c) Histidine at a concentration of approximately 10 mM, d) Sorbitol at a concentration of approximately 300 mM, e) PS-20 at a concentration of approximately 0.04% w / v, f) A solution comprising methionine at a concentration of approximately 1 mg / mL and having a pH of approximately 5.5, claim 74 The unit dosage form as described above.

85. A container containing the unit dosage form described in claim 84.

Images