antibody composition

Abstract

This invention provides a pharmaceutical composition that can maintain the activity of a bispecific antibody that binds to both EGFR and LGR5, as well as its analog variants. [Solution] A pharmaceutical composition is provided comprising a polyspecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional portion or derivative thereof, a buffer system including histidine buffer and / or citrate buffer, a sugar component, and a nonionic surfactant.

Description

[Technical Field]

[0001] [introduction] The present invention relates to a (bio)pharmaceutical composition comprising an anti-EGFR / anti-LGR5 bispecific antibody, particularly This relates to liquid (e.g., aqueous) biopharmaceutical compositions, and more particularly to liquid biopharmaceutical compositions. The present invention also includes, among other things, a method for producing a composition, a kit containing a composition, and a composition containing Package, method for manufacturing package, and for example, for the treatment of colorectal cancer , relating to methods of treatment using compositions and / or packages, particularly methods of cancer treatment. ru. [Background technology]

[0002] Recently, the applicants have developed an antimicrobial agent for treating solid tumors, including potential treatment of colorectal cancer. Characterized by enhanced somatic cell-mediated cytotoxicity (ADCC), and containing leucine-rich repeats. It expresses G protein-coupled receptor 5 (LGR5) and epidermal growth factor receptor (EGFR). We have developed Biclonics®, which binds to cancer stem cells. EGFR and Antibodies that bind to both sides of LGR5 are described in International Publication No. 2017069628A2. (MERUS et al) describes this in detail, and the related sequences are shown in Figures 1-4. It is listed. Such antibodies have two different mechanisms of action. The first is cancer stem cells This includes blocking the proliferation and survival pathways of the cells, and secondly, allowing them to remain in the solid tumor and prevent recurrence. and mobilize immune effector cells to directly kill cancer stem cells that cause metastasis. and includes enhancing.

[0003] The object of the present invention is a bispecific antibody that binds to both EGFR and LGR5, and necessary The purpose is to provide a viable pharmaceutical composition of its analogous variants accordingly. And so the unpredictability inherent in the formulation technology of biopharmaceuticals, especially antibodies, is such as the activity of This is hindering the discovery of viable pharmaceutical compositions. The reason is that most of the given biopharmaceuticals Most formulations (if the aforementioned formulations are arbitrarily selected) affect biological formulations, especially aqueous formulations. Due to various physical or chemical factors that can cause stress over long periods of time and / or stress This is because it is unstable under certain conditions. For example, it may be difficult to prevent protein aggregation. Furthermore, the pharmaceutical composition is formulated with the intention of being safe for administration to human subjects. This should be done so that the adverse effects of its administration, such as intravenous injection, are minimized. It means.

[0004] Physical or chemical effects can occur, particularly between different batches of drug products during manufacturing, transportation, and storage. Due to the fluctuating stresses that may be exposed to it (e.g., stirring, heat, frost, light), the active fibers Drug products that cannot be maintained (may not be safe for use in medical procedures) or products that can maintain activity This may result in any drug product whose properties are variable and unpredictable.

[0005] U.S. Patent No. 6,171,586 (Lam et al.) describes stable aqueous antibodies. The formulation is described. The F(ab')2rhuMAb CD18 antibody is sodium acetate. and formulated with histidine-HCl buffer. Preferred production of rhuMAb CD18 The agent contains 10 mM sodium acetate, 8% trehalose, and 0.01% Tween (registered trademark). It was formulated at pH 5.0.

[0006] Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody and is available in different formulation forms depending on whether it is frozen dried or liquid. In the case of the dry form, omalizumab is packaged as a sterile white preservative-free lyophilized powder contained in a single-use vial and is reconstituted with sterile water for injection and administered as a subcutaneous injection. One vial contains 202.5 mg of omalizumab, 145.5 mg of sucrose, 2.8 mg of L-histidine hydrochloride monohydrate, 1.8 mg of L-histidine, and 0.5 mg of polysorbate 20, and after reconstitution with 1.4 mL of sterile water, it is designed to deliver 1.2 mL of omalizumab 150 mg. In the case of the aqueous form, it is available as a prefilled syringe. The injection solution in the syringe contains L-arginine hydrochloride, L-histidine hydrochloride salt, L-histidine, polysorbate 20, and water. The label attached to the prefilled syringe includes instructions for storing the sealed syringe in the outer box in a refrigerator at 2°C to 8°C (36°F to 46°F) and not freezing the product. It is also mentioned that the expiration date is 15 months including potential temperature deviations. This product can be maintained at 25°C for a total of 4 hours and, if necessary, returned to the refrigerator and used later, but this should not be done more than once. In the pamphlet of International Publication No. 2015 / 130173 A1, bispecific antibodies formulated as pharmaceutical compositions having 25 mM of histidine, 220 mM of trehalose, 0.2 g / L of polysorbate 20, or a combination thereof and most preferably set at pH 6 are disclosed.

[0007]

[0008] The present invention suitably addresses one or more of the aforementioned stability problems, thereby providing a pharmaceutically active agent for administration to humans and providing a pharmaceutically active agent that can maintain its activity. Another object of the present invention is to provide a formulation with improved stability and / or preservability. SUMMARY OF THE INVENTION

[0009] According to one aspect of the present invention, there is provided a multispecific antibody, a functional portion or derivative thereof, comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5 (bio)pharmaceutical composition. The pharmaceutical composition of the present invention preferably comprises some or all of any relevant amounts of the components described herein (e.g., buffers, surfactants, sugar components, amino acid components, tonicity agents, antioxidants, or chelating agents), and / or is preferably characterized by any of the parameters described herein (e.g., pH, pI, weight osmolarity concentration). The pharmaceutical composition is preferably a liquid (e.g., aqueous) ​​​​​​​​​​​​​​​​​​​​​​​​Our devices (e.g., vials, ampoules, syringes, pre-filled syringes, injection pens) (For example, something that essentially incorporates a syringe), an auto-injector, or an IV drip machine A package / container containing either a bag or any of the above is provided.

[0012] According to one aspect of the present invention, a drug delivery device, a pharmaceutical composition as defined herein (as necessary) (Included in the package or container), and, if necessary, related to the administration of the pharmaceutical composition The kit of parts includes a set of instructions for use with accompanying instructions. (This is provided.)

[0013] According to one aspect of the present invention, a method for producing a pharmaceutical composition comprising EGFR bonded A multispecific antibody comprising a first binding domain and a second binding domain that binds to LGR5. A body, its functional portion, derivative, or variant is given one or more pharmaceutically acceptable substances. A method is provided which includes mixing with an excipient and / or carrier.

[0014] According to one aspect of the present invention, in patients requiring such treatment, the disease or medical condition A method for treating a disorder, comprising administering a therapeutically effective amount of the pharmaceutical composition specified herein to the said patient A method is provided which includes administering to a person. The administration preferably includes parenteral administration and non-efferent administration. Oral administration is preferable to any other administration method other than enteral and topical administration, usually by injection. The method includes, but more preferably, intravenous delivery of a therapeutically effective amount of the pharmaceutical composition.

[0015] According to one aspect of the present invention, in patients requiring such treatment, the disease or medical condition Pharmaceutical compositions, preferably as defined herein, are provided for use in treating disorders.

[0016] According to one aspect of the present invention, in the manufacture of a pharmaceutical product for treating a disease or disorder, Alternatively, the use of the pharmaceutical compositions specified herein is provided.

[0017] According to further aspects of the present invention, a method for treating a disease or medical disorder, or pharmaceutical compositions for use in the treatment of medical disorders, and diseases or The use of pharmaceutical compositions in the manufacture of pharmaceuticals for treating disorders, diseases, or medicines is provided. The disorders are EGFR-related and LGR5-related diseases. The first binding pathway that binds to EGFR A polyspecific antibody containing a main and a second binding domain that binds to LGR5, and its functional portion. The fraction, derivative, or variant is preferably a leucine-rich repeat-containing G-conjugated receptor. It binds to cancer stem cells that express LGR5 and epidermal growth factor receptor (EGFR). ru.

[0018] According to further aspects of the present invention, a method for treating a disease or medical disorder, or pharmaceutical compositions for use in the treatment of medical disorders, and diseases or The use of pharmaceutical compositions in the manufacture of pharmaceuticals for treating disorders, diseases, or medicines is provided. The proliferative disorder is a proliferative disorder or disorder. The proliferative disorder or disorder is preferably cancer. The cancer preferably manifests as one or more solid tumors. or cancers that express EGFR ligand-responsive, preferably membrane-bound members of the WNT pathway. The cancer is preferably adenocarcinoma. In particular, the cancer is colorectal cancer, pancreatic cancer, and lung cancer. Breast cancer, liver cancer, prostate cancer, ovarian cancer, cervical cancer, endometrial cancer; head and neck cancer melanoma, testicular cancer, urothelial carcinoma, kidney cancer, stomach cancer, carcinoid cancer, and so on. The cancer is selected from the group consisting of all possible combinations of these. Most preferably, the cancer is colorectal cancer. Pancreatic cancer, lung cancer, breast cancer, liver cancer, prostate cancer, ovarian cancer, cervical cancer, endometrial cancer Cancer, head and neck cancer, or melanoma. In a particularly preferred embodiment, the cancer is gastrointestinal cancer. , stomach cancer, or head and neck cancer. The disease or medical disorder in question is preferably international. Choose from any of the options disclosed in Public Notice No. 2017069628 A2 Pamphlet. This document can be selected. This document thus forms part of this specification by reference. The appropriateness of the treatment of the present invention is in light of the present disclosure, International Publication No. 2017069628A. This is further justified by the pamphlet.

[0019] According to further aspects of the present invention, a method for treating a disease or medical disorder, or pharmaceutical compositions for use in the treatment of medical disorders, and diseases or The use of pharmaceutical compositions in the manufacture of pharmaceuticals for treating disorders, diseases, or medicines is provided. The ailments are preferably as specified herein, and the treatment or treatment agent is a pharmaceutical The composition is combined with one or more other pharmaceutical or biopharmaceutical active substances. This includes combination therapy administered by, and the combination therapy involves the simultaneous, sequential, and individual components of the treatment agent. This includes separate medications. In some embodiments, additional pharmaceutical active substances or biopharmaceutical active substances are added. The substance may be present in any of the pharmaceutical compositions specified herein.

[0020] The aforementioned treatment methods, compositions for use, and the use of compositions in the manufacture of pharmaceuticals are all The associated package, drug delivery device, and kit incorporating the composition They are equally applicable.

[0021] In a preferred embodiment, a pharmaceutical formulation with improved stability characteristics is provided. Any suitable preferred features as needed, as described with respect to any particular aspect of The features include features that are suitable and preferred features as needed for any other aspect of the present invention. That's fine. [Brief explanation of the drawing]

[0022] [Figure 1] This figure shows the amino acid sequences of sequence numbers 1-16. [Figure 2] This figure shows the amino acid sequences of sequence numbers 17-52. [Figure 3] This figure shows the amino acid sequences of sequence numbers 53-57. [Figure 4] This figure shows the amino acid sequences of sequence numbers 58-62. [Figure 5] This figure shows the amino acid sequences of sequence numbers 63-68. [Modes for carrying out the invention]

[0023] [Definition] Unless otherwise stated, the following terms used in this specification and in the claims are: It has the meanings shown below.

[0024] Throughout this specification and the claims, the word "comprise" is used. The word "contain" and its variations are used to mean "to include but This means "not limited to those," and does not include other parts, additives, ingredients, integers, or steps. This specification and claims are not intended to exclude (or will not exclude) the following. Through this, unless the situation requires otherwise, the singular encompasses the plural. In particular, when the indefinite article is used If so, unless circumstances require otherwise, this specification intends to be plural as well as singular. It should be understood that they exist.

[0025] Features, integers, characteristics described in relation to specific aspects, embodiments, or examples of the present invention , compounds, chemical parts or groups, unless incompatible with them, any of the compounds, chemical parts or groups described herein. This specification should be understood to be applicable to other aspects, embodiments, or examples. All of the features disclosed in (including any attached claims, abstract, and drawings) , and / or all steps of any method or process disclosed in that manner A combination in which at least some of such features and / or steps are mutually exclusive. Except for the above, it can be combined in any combination. The present invention can be any of the above-mentioned embodiments The present invention is not limited to the details of the state. The present invention is as specified herein (any appended claims, abstract, Any novel features or any novel combination of features disclosed in (including drawings), or any novelty of any method or step of process disclosed in that manner Or it extends to any new combination.

[0026] Reader's attention is drawn to any documents filed concurrently with or prior to this specification in connection with this application. This specification applies to all papers and documents made publicly available for viewing. All such papers and documents shall, by reference, form part of this Specified Publication. .

[0027] To avoid any ambiguity, the following is disclosed at the beginning of this specification under the heading "Background Art". The information relating to the present invention should be read as part of the disclosure of the present invention. This is stated here.

[0028] "Antibody," and "monoclonal," "polyclonal," "IgG," "IgG1" Related nomenclature such as "IgG4" is well-known technical terminology. In this specification, to avoid any doubt, Just to clarify, the term "antibody" refers to one that binds to an antigen's epitope. This is a proteinaceous molecule belonging to the immunoglobulin class of proteins, containing multiple domains. This means that such domains are either variable domains of the antibody or derived from them. or they share sequence homology. Antibodies typically each have two heavy chains and two It is composed of basic structural units including light chains. Antibodies for therapeutic use are preferably used in treatment It is preferable that the antibody is as close as possible to the natural antibody of the target subject (for example, in the case of a human subject, it should be human antibody).

[0029] When used herein, the term “binding domain” includes a variable domain and an antigen This refers to a portion of an antibody that functions in binding or shares sequence homology with a variable domain. Non-exclusive examples of combined domains including mutation domains are in the Fv domain and Fab domain. Yes. Typical variability is found in the complementarity determination region or CDR, the VH domain and VL. It is found in three surface loop-forming regions of the domain.

[0030] The term "heavy chain" or "immunoglobulin heavy chain" is derived from any organism. Includes the constant region sequence of the brin heavy chain, and unless otherwise specified, includes the variable heavy chain domain. The term "variable domain" refers to three heavy-chain CDRs and four FRs unless otherwise specified. Includes regions. Heavy chain fragments include CDR, CDR, and FR, as well as combinations thereof. One example is the heavy chain, which consists of a variable domain followed by a C-terminus. It has an H1 domain, a hinge, a CH2 domain, and a CH3 domain. Functionality of the heavy chain. The fragment is capable of specifically recognizing the antigen and contains at least one CDR. Examples of fragments include: In this specification, the CDR domain of the heavy chain is preferably kabat-attached. Follow the numbering system.

[0031] The term "light chain" refers to the immunoglobulin light chain variable domain derived from any organism or VL (or its functional fragment) sequence and immunoglobulin constant domain or CL (and It contains its functional fragment sequence. Unless otherwise specified, the term light chain refers to a human kappa. It may include light chains selected from lambda, and combinations thereof. Variable light chain (V The L) domain, unless otherwise specified, typically consists of three light chain CDRs and four f Includes the framework (FR) region. Generally, the full-length light chain is FR1 from the N-terminus to the C-terminus. -VL domains including CDR1-FR2-CDR2-FR3-CDR3-FR4 and light It contains a chain constant domain. As a light chain that can be used in the present invention, a heavy chain is selected. Examples include epitopes that bind selectively and those that do not. This is the light chain shown in Figure 3. In this specification, the CDR domain of the light chain is preferably, Follow the IMGT numbering scheme.

[0032] Suitable light chains for use with the antibodies of the present invention include existing antibody libraries (wet-library). The most widely used light chain in braley or in silico is screeni Common light chains that can be identified by pinging, and heavy chain epitones It does not substantially impede the affinity and / or selectivity of the p-binding domain, but when paired with a series of heavy chains Common light chains are also suitable for this purpose. For example, suitable light chains include those that can be incorporated into the genome. Common light chain antibodies, which contain embedded common light chains and exhibit diversity in their heavy chains upon exposure to the antigen, are large-scale common light chain antibodies. Transgenic rodents and other organisms that can be used to generate model panels. One example is the light chain derived from transgenic animals (International Publication No. 2009 / 15777). (Pamphlet No. 1). The present invention relates to light chains, particularly CL, VL, VL-CDR1, and VL-CDR2. The associated sequences of VL-CDR3 and other related sequences are shown in Figure 3.

[0033] The term "common light chain" in this invention may refer to the same or some amino acids. The sequences may have differences, but this does not affect the binding specificity of the antibody of the present invention, that is, The difference refers to light chains that do not substantially affect the formation of functional bonding regions.

[0034] For example, whether pairing with conservative amino acid changes or homogeneous chains does not contribute to binding specificity. By introducing and testing amino acid changes in regions that only partially contribute, For example, variable chains that are not identical but are still functionally equivalent are used herein. It is possible to prepare or find such a common chain within the definition of a common chain. Therefore, such a Riants can also bind to different homologous chains and form functional antigen-binding domains. Therefore, when the term "common light chain" is used herein, it refers to the same thing. It may be or may have differences in some amino acid sequences, but obtained after pairing with the heavy chain. This refers to the light chain that maintains the binding specificity of the antibody. Functionally equivalent combinations of variants are encompassed within the term "common light chain."

[0035] To a person skilled in the art, "common" also refers to functional equivalents of light chains that do not have the same amino acid sequence. They will recognize that the light chain substantially influences the formation of functional bonding regions. Numerous variants exist that contain mutations (deletions, substitutions, additions) that do not occur.

[0036] The terms "full-length IgG" or "full-length antibody" in this invention refer to essentially complete IgG. It is defined as including, but does not necessarily possess all the functions of intact IgG. To avoid any misunderstanding, it should be noted that full-length IgG contains two heavy chains and two light chains. Each chain contains a constant (C) region and a variable (V) region, consisting of CH1, CH2, CH3, and VH. It can be divided into domains called CL and VL. IgG antibodies are divided into the Fab region. It binds to the antigen via the variable region domain contained in the molecule, and after binding, the constant domain, mainly The Fc portion can interact with molecules and cells of the immune system. Long antibodies contain IgG molecules that may contain mutations that provide the desired characteristics. IgG should not have substantial deletions in any of those regions. However, However, without essentially changing the binding properties of the resulting IgG molecules, one or several IgG molecules with deleted amino acid residues are included in the term "full-length IgG." In such cases, the IgG molecule preferably has 1 to 10 amino acid residues in the non-CDR region. The molecule may have a deletion of a group, in which case the deleted amino acid affects the antigen-binding specificity of IgG. It's not required.

[0037] As intended herein, a “bispecific antibody” is one in which one variable domain of the antibody is a first antibody. An antibody that binds to a progenitor, and whose second variable domain binds to a second antigen, wherein the first antibody The protoantigen and the second antigen are not identical; they are antibodies. This term refers to a case where at least one VH is It is capable of specifically recognizing the first antigen, and at least one of the immunoglobulin variable domains VH contains an antibody that, paired with VL, is capable of specifically recognizing the second antigen. The / VL pair will bind to either antigen 1 or antigen 2, resulting in a "two-in-one antibody" This is called a "two-in-one antibody," for example, International Publication No. 2008 Pamphlet No. / 027236, International Publication No. 2010 / 108127, and Schaefer et al (Cancer Cell 20,472-486, It is described in October 2011. The bispecific antibody according to the present invention is preferably is human IgG, more preferably human IgG1. Preferably, as intended herein The two specific antibodies possess binding specificity to LGR5 and EGFR, and further variable It does not include a domain.

[0038] The term "polyspecific antibody" as used herein refers to, for example, a bispecific antibody or a trispecific antibody. In antibodies, one variable domain of the antibody binds to the first antigen, and the second variable domain of the antibody... The third variable domain of the antibody binds to the second antigen, and in the case of a trispecific antibody, the third variable domain of the antibody binds to the third antigen. An antibody that binds to the antigen, wherein the first, second, and third antigens are not identical or are variable. The antibodies are antibodies to which the domains bind are not identical epitopes.

[0039] The term "first binding domain that binds to EGFR and LGR5" as intended herein refers to the first binding domain that binds to EGFR and LGR5. An antibody containing a second binding domain is a polyspecific antibody, preferably a bispecific antibody. This antibody is a BsAb. In this specification, this antibody is referred to as an "anti-EGFR / anti-LGR5 bispecific antibody." It is also simply called "EGFR / LGR5 BsAb". This antibody and its production are For more details, see International Publication No. 2017069628A2 pamphlet (MERUS et al). It is described in detail. The antibody preferably has an anti-EGFR moiety and an anti-LGR5 moiety. It is a full-length human IgG1 heterodimer, and its associated DNA and / or amino acid combination The columns are disclosed in Figures 1-4 of the international publication No. 2017069628A2 brochure. , as referred to herein. The molecular weight is approximately 146 kDa, and this molecular weight is approximately It is used for the purpose of loose molar calculations. Therefore, a 10 mg / mL antibody aqueous solution is 0.068 This corresponds to an mM solution, and a 20 mg / mL aqueous solution corresponds to a 0.137 mM antibody solution, and 50 mg A volume of antibody aqueous solution per mL corresponds to a 0.342 mM solution.

[0040] The "functional portion" of a bispecific antibody is the antigen-binding portion or binding portion of the bispecific antibody. It includes derivatives. The antibody-binding portion is contained within the variable domain.

[0041] Antibody "derivatives" consist of at most 20 amino acids, excluding the CDR region, compared to natural antibodies. These are proteins that deviate from the amino acid sequence. The antibody derivatives disclosed herein include many This antibody also has 20 amino acids that deviate from the aforementioned amino acid sequence.

[0042] The term "EGFR" as used herein refers to four receptor tyrosine kinases (RTKs). It refers to the epidermal growth factor receptor, a member of the HER1 family. Human epidermal growth factor (EGF) receptor1) and ErbB1 (erythroblastoma-1) It is also known by various synonyms. EGFR is composed of four subdomains. It has extracellular domains (ECDs), two of which are involved in ligand binding, and two of them It is involved in homodimerization and heterodimerization. EGFR is involved in various ligands It integrates extracellular signals and triggers diverse intracellular responses. Activated by EGFR. The main signaling pathway is Ras mitogen-activated protein kinase (MAPK). It consists of a mitotic signaling cascade. Activation of this pathway is Grb2 This is initiated by the recruitment of tyrosine phosphorylated EGFR. Synthetic Ras Guanine Nucleotide Exchange Factor Sevenless's Son (SOS, Son of Se It is linked to Ras activation via venless. In addition, PI3 kinase Akt The Gunal signaling pathway is also activated by EGFR, but this activation is due to ErbB-3 (HER 3) The effect is even stronger when co-expression of EGFR is present. Malignant tumors, especially breast cancer, bladder cancer, non-small cell lung cancer, lung cancer, colon cancer, ovarian cancer, brain cancer. It is thought to be involved in cervical cancer and brain cancer. This gene is associated with activating mutations, and Overexpression of receptors and their ligands has been found, leading to the formation of an autocrine activation loop. Therefore, RTKs are widely used as targets in cancer therapy. Small molecule inhibitors targeting the extracellular ligand-binding domain, and monoclonal Both antibody (mAb) and mAb formulations have been developed, and so far, they have been used primarily for certain patient groups. However, it has shown some clinical success.

[0043] The database accession number for the human EGFR protein and the gene encoding it is (G enBank NM_005228.3) This accession number is primarily used as a target This was given to provide further methods for identifying EGFR proteins. The actual sequence of the EGFR protein to which the antibody binds is, for example, a genetic factor in some cancers. The results may differ due to mutations in the coding genes, such as those occurring in offspring. Therefore, the words cancer and tumor are used, unless otherwise specified. Typically, both refer to cancer. When EGFR is referred to herein, it refers to a different type of cancer. Unless otherwise specified, the reference refers to human EGFR. The antigen-binding site that binds to EGFR is: EGFR, and its various variants, including those expressed in some EGFR-positive tumors. Combine.

[0044] The term "LGR" refers to a leucine-rich repeat-containing G protein-coupled receptor. This refers to a known family of proteins. Among the members of this family are Roy There is LGR5, a syn-rich repeat-containing G protein-coupled receptor 5. Another name for this protein is leucine-rich repeat-containing G protein-coupled receptor 5. Synrich repeat-containing G protein-coupled receptor 5G protein-coupled receptor HG38, G Protein-coupled receptor 49, G protein-coupled receptor 67, GPR67, GPR49, O - Phan G protein-coupled receptor HG38G, protein-coupled receptor 49, GPR49, HG38, FEX. The protein or antibody of the present invention that binds to LGR5 is human L It binds to GR5. The LGR5-binding protein or antibody of the present invention is used in humans and other mammals. Due to sequence similarity and tertiary structure similarity with orthologues, such orthologues also They can be combined, but it is not necessary to combine them.

[0045] The database accession number for the human LGR5 protein and the gene encoding it is (N C_000012.12, NT_029419.13, NC_018923.2, NP_ 001264155.1, NP_001264156.1, NP_003658.1) Yes, this accession number is primarily used to further identify the LGR5 protein as a target. This is provided to offer a method for binding to the LGR5 protein, and the actual distribution of the LGR5 protein to be bound. The column refers to mutations in coding genes, such as those occurring in the genes of certain cancers. It may differ due to differences. The LGR5 antigen binding site is present in some LGR5-positive tumor cells. It binds to LGR5 and its various variants, including those that are expressed in a specific way.

[0046] Voluntary information, including that disclosed in International Publication No. 2017069628A2 brochure. References herein to specific bispecific antibodies are either commercially available or in the patent literature. Whether described or otherwise in the art, relevant Contains the original raw material.

[0047] The term sequence identity is well known in the art. In this specification, nucleic acid sequences or The "identity percentage (%)" for amino acid sequences is determined by aligning the sequences for optimal comparison. This is the percentage of candidate sequence residues that are identical to the residues of the selected sequence after the selection process. It is stipulated that the sequence identity percentage for comparing nucleic acid sequences is the improved ClustalW Algorithms (Thompson, JD, Higgins, DG, and Gi bson TJ,(1994)Nuc.Acid Res.22(22):4673 -4680), swgapdnamt score matrix, gap open penalty 15, and Vect using the default settings where a gap extension penalty of 6.66 is used. or NTI 30 Advance (registered trademark) 11.5.2 Software Alig Determined using the nX application. The amino acid sequence is modified using ClustalW. Algorithms (Thompson, JD, Higgins, DG, and Gi bson TJ,(1994)Nuc.Acid Res.22(22):4673 -4680), blosum62mt2 score matrix, gap open penalty Using 35 initial settings, a value of 10 and a gap extension penalty of 0.1 are applied. Vector NTI Advance (registered trademark) 11.5.2 software Al Aligned using the ignX application.

[0048] In this specification, the terms “buffer,” “buffer system,” or “buffer solution” refer to an acid (usually) This refers to weak acids, such as acetic acid, citric acid, histidine (imidazolium form), and their conjugates. Bases (e.g., acetate or citrate, e.g., sodium acetate, sodium citrate) , or histidine), or instead a base (usually a weak base, e.g., histidine) and a mixture of its conjugate acid (e.g., protonated histidine salt), generally aqueous It refers to a solution. The pH of a "buffer solution" is due to the "buffering effect" imparted by the buffering system, even in small amounts. Adding a strong acid or strong base would likely result in only a slight change.

[0049] In this specification, “buffering system” refers to one or more buffering agents and / or their conjugates. It contains an acid / base, more preferably one or more buffers and their conjugate acids / bases. It contains, most preferably, only one buffer and its conjugate acid / base. Unless otherwise specified, the concentrations of the "buffer system" as specified herein (i.e., buffer concentrations) are Preferably, this refers to the total concentration of the buffer and / or its conjugate acid / base. In other words, With respect to the "buffer system," the concentrations specified herein preferably include all relevant buffer types. In other words, it refers to the total concentration of species that are in dynamic equilibrium with each other, for example, acetate / acetic acid. The given concentration of the acetate buffer system is generally determined by the acetate (or acetate salt, e.g., sodium acetate). This relates to the total concentration of ammonium and acetic acid. The overall pH of the composition including the associated buffer system is 1 Generally, the equilibrium concentrations of each of the relevant buffer species (i.e., the balance between the buffer and its conjugate acid / base) This reflects the following: Any given "buffer system" can be a single buffer (or buffer system) or multiple buffer systems. It may consist of several buffers (or buffer systems).

[0050] In this specification, the term "buffer" refers to the acidic or base component of a buffer or buffer solution. This refers to a component (usually a weak acid or weak base). A buffer adjusts the pH of a given solution to a predetermined value. Or it helps to maintain a value close to it, and buffers are generally selected to complement a given value. The buffer is selected, preferably in an appropriate amount (depending on the desired predetermined pH). ) when mixed with its corresponding "conjugate acid / base" (and preferably undergoes proton exchange with it) (If possible), or if the required amount of its corresponding "conjugate acid / base" is in sit If it is formed with u, this involves adding a strong acid or strong base until the desired pH is reached. This can be achieved by using a single compound that provides the desired buffering effect. Here are some examples.

[0051] "Acetate buffering agent" preferably consists of acetic acid, which is its conjugate acid / base, and acetic acid that is preferably mixed with acetic acid. A salt, such as sodium acetate. Such a buffer system is provided with a given amount of sodium acetate. It can be formed simply by mixing it with a certain amount of acetic acid. However, instead Such a buffer solution has the desired pH (and therefore the desired balance of sodium acetate / acetic acid). Until the condition is met, a given amount of base, preferably a strong base (e.g., sodium hydroxide), It can be formed by adding it to acetic acid. In this specification, if there are any inconsistencies, Except for the cases mentioned above, any concentrations given for acetate buffer or acetate buffer are preferably This includes buffering agents (e.g., sodium acetate) and / or their conjugate acids / bases (e.g., acetic acid). This refers to the total concentration of ( ). A person skilled in the art can easily calculate such a concentration. Such concentrations are calculated by referring to the total concentration of the buffer and the conjugate acid / base. A buffer system can be formed by simply mixing a buffering agent and a conjugate acid / base together. Instead, either a buffer or a conjugate acid / base is used as a pH adjuster (e.g., a strong When a buffer system is formed by mixing with an acid or a strong base to produce each mixture. Preferably, such concentrations refer to the starting amount / concentration of the buffer or conjugate acid / base, respectively. This can be calculated by adding a pH adjuster until the desired pH is reached. For example, a buffer system is formed using a known amount / concentration of acetic acid mixed with sodium hydroxide. If so, the concentration of the buffer system can be calculated by referring to the initial amount of acetic acid. .

[0052] In this specification, "conjugate acid / base" refers to the conjugate acid or conjugate base of a specific "buffering agent" (specific This refers to the pH-related component, which in the context of this invention typically refers to the conjugate acid. Acetate buffer (for example) The conjugate acid / base of sodium acetate is preferably acetic acid.

[0053] In this specification, the term “buffer species” refers to species that are in a state of dynamic equilibrium with each other (and protons). (to exchange) a specific species of a given buffer system (any associated counter anion or counter cation) This refers to sodium acetate / acetic acid-based sodium ions (excluding those in the acetic acid system, which are ignored). For example, acetic acid. Anions and acetate together constitute the "acetate buffer species" of the "acetate buffer system."

[0054] The amount of the buffer system (whether absolute or relative) is determined by referring to its weight. This is impractical because (the total weight depends on the desired pH, and it depends on the counterions present) (Because it would affect the quantity) this specification instead refers to the theory of relevant "buffer species". The weight-based quantity is determined by referring to the target weight. Any given set of "buffer species" There are at least two species of this (which can be determined simply by referring to pH). In relative amounts, each has a different molecular weight (usually differing by only 1). Therefore, For the purposes of this specification, in order to enable possible weight calculations and references, any given set The weight of the "buffer species" is calculated based on only one buffer species, i.e., the most acidic of the buffer species. (That is, the theoretical weight based on the most protonated form at any given pH) It is given by this. Therefore, the weight of the "buffer species" in a given set is the weight of the acid species equivalent. It is cited as an example. For instance, in an acetate buffer system, the acetate buffer species is the acetate anion (counter-category). It may consist of (ignoring n) and acetic acid. Therefore, the weight of the "buffer species" is It is calculated as if acetic acid were the only species present in the buffer system (even if acetate salts are co-existing with acetic acid). (Even if it is clearly present in) Therefore, the weight or weight of "acetate buffer species" The reference to the ratio preferably refers to the theoretical weight of the acetate equivalent in the buffer system. Therefore, constant The composition is formed by adding a pH adjuster (such as sodium hydroxide) to a certain amount of acetic acid. In this case, regardless of the final pH, the original weight of acetic acid can be considered the weight of the "buffer species". It is possible. Instead, if the concentration of the buffer system (i.e., molar concentration) is known, this is related. The term "buffer species" is defined by referring to the molecular weight of the most acidic form of the buffer species (e.g., acetic acid). The fact that it can be converted to the weight of and that acetate anions also exist is ignored.

[0055] In this specification, any reference to “buffer system” shall preferably be referred to as “buffer solution.” The term "buffer" can be interpreted as encompassing all examples of the term "buffer system". It can be replaced. For example, "acetate buffer system" can preferably be replaced with "acetate buffer solution". It is interpreted as follows: As explained regarding the term "buffer system," a particular "buffer" is generally... It contains an equilibrium mixture of conjugate acid and conjugate base. For example, "acetate buffer" is an acetate Containing ions (such as acetates) and acetic acid, "histidine buffer" generally refers to a solution containing free histidine. n (that is, unprotonated neutral histidine) and histidine imidazoliu This includes the protonated form. As explained regarding the term "buffer system," certain " The concentration of the buffer solution preferably means the total concentration of all relevant conjugate acids and conjugate bases. For example, the concentration of the "acetate buffer solution" is preferably a mixture of acetate anion and acetic acid. This refers to the concentration, and the concentration of the "histidine buffer" is preferably a mixture of free histidine and hi The total concentration of histidine in its imidazolium form (e.g., histidine concentration + histidine.H) This refers to the concentration of Cl. As explained regarding "buffer systems," a "buffer" is a single "buffer." It may consist of a single "liquid," or it may consist of multiple "buffers." Therefore, any reference to “buffer system” in this specification is preferably interpreted as a reference to “buffer solution.” The term "buffer" can replace all instances of the term "buffer system". It is possible to obtain. When the buffer solution contains multiple buffer solutions, the concentrations of the multiple buffer solutions are suitable. This includes the total concentration of the multiple buffers (i.e., all associated conjugate acids and conjugate bases) (Total concentration). For example, it contains both acetate buffer and histidine buffer (or The buffer (or "buffer system") consisting of these preferably comprises acetate anion and acetate ( A combination of (forms an acetate buffer), and further, free histidine and histidine This includes a combination of imidazolium (protonated) form (which forms histidine buffer), The total concentration of the buffer is the acetate anion, acetate, free histidine, and histidine imida. The total number of zolium forms may also be used.

[0056] Preferably, the "buffer system" or "buffer solution" is not the entire composition itself, but rather the components of the composition. It is a matter of minutes. Therefore, preferably, the "buffer composition" or "buffer solution" is the "buffer system". This would include a "buffer."

[0057] Here, in the context of this specification, "strong acid" preferably means pK a is -1.0 or that Some have low levels, and "weak acid" is preferably pK a If it is 2.0 or higher There is. Here, in the context of this specification, “strong base” preferably has a conjugate acid of 12 or A higher pK (preferably 14 or higher) a It has the following characteristics, on the other hand A "weak base" preferably has a conjugate acid with a pK of 10 or lower. a things that have That is the case.

[0058] Those skilled in the art will know that in the context of a buffer system and a composition containing a buffer system, the pH (of the entire composition) (including H), the relative concentrations of the associated conjugate acid and conjugate base, and the pK of the conjugate acid a and related You are probably familiar with the well-known "Henderson-Hasselbalch formula" for connecting them. The following applies:

[0059]

number

[0060] The "amino acid component" is preferably one or more constituent components containing one or more amino acids, but the amino acid component preferably consists of a single amino acid. For clarity, a it is emphasized that the amino acid components contemplated herein are added to pharmaceutical formulations for the purpose of providing buffering functionality. Thus, the amino acid component does not include proteins, antibodies, or active pharmaceutical ingredients. a [[ID=I7]]

[0061] ]] As used herein, the "sugar component" is preferably one or more constituent components containing one or more sugars and / or sugar alcohols, but the sugar component may consist of a single sugar or sugar alcohol, and glycosylation of antibodies or active pharmaceutical ingredients is excluded. As used herein, a "non-reducing sugar" is generally a sugar that does not have any aldehyde moieties or the ability to form aldehyde moieties (e.g., by isomerization).

[0062]

[0064] In this specification, "tonicity modifier" or "isotonic" refers to a substance that is highly sensitive to tension. A tonicifier, when included in a composition, preferably affects the entire composition. This refers to reagents that contribute to (or increase) the gravimetric osmolality and volumetric osmolality. Preferably, the isotonic agent used herein is one that modifies the osmotic properties of the solution to physiological flow. Examples of agents that function in a similar way to the body include those that act in a manner similar to that of the human body.

[0065] In this specification, "antioxidant" or "antioxidant component" preferably refers to one or more antioxidants. It is one or more components containing an oxidizing compound, but the antioxidant component is a single antioxidant compound It may consist of a substance. The antioxidant in the composition of the present invention is preferably such It reduces the oxidation of groups within the fusion protein that may be susceptible to oxidation if they are not present.

[0066] "Chelating agents" preferably have a polydentate coordination mechanism and bind various groups, molecules, atoms, or ions together. This is a technical term referring to compounds that can form complexes and possess antioxidant effects themselves. It can demonstrate its capabilities.

[0067] In this specification, a composition is said to be characterized by the absence of [a specific component]. In any case, preferably, the composition in question is substantially or completely free of the aforementioned component. It means either it is not the case or it is not the case.

[0068] The term "substantially does not contain" means that a given component of the composition (for example, "amino acid component") is not included. When used in relation to a "liquid pharmaceutical composition that substantially does not contain" the said component is essentially an added component. It refers to compositions that have not been subjected to protein structure. As explained above, such references refer to protein structures. This is unrelated to the presence of amino acid residues within the composition. The composition "substantially does not contain" a given component. In this case, the composition preferably contains 0.1% by weight or less of the above component, preferably 0.01% by weight The following components, preferably 0.001% by weight or less, preferably 0.0001% by weight The above component is less than or equal to % of the above component, preferably 0.00001% by weight or less, preferably 0.000001% by weight. % or less, preferably 0.0000001% by weight or less, most preferably 0.0001 parts per billion ( It contains the above components (by weight) or less.

[0069] The term "completely free" means that a given component of the composition (for example, "completely free of amino acid components") is not present. When used in relation to a "liquid pharmaceutical composition that does not qualitatively contain" the above-mentioned component, it means that no such component is added at all. This refers to compositions that are not included in the protein structure. As explained above, such references are within the protein structure. This is unrelated to the presence of the amino acid residue.

[0070] Preferably, unless otherwise stated, the pressure and / or temperature may be dependent. A certain parameter (e.g., pH, pKa, etc.) or the state of a material (e.g., liquid, gas) When references are made to (etc.), preferably, unless there is further clarification, such references are, This refers to the parameters under standard laboratory temperature and pressure conditions.

[0071] In this specification, given components of a composition, particularly buffers or buffering systems, surfactants, sugar components, References to specific amounts of amino acid components, isotonic agents, antioxidants, and / or chelating agents are, Even if such ingredients may be used in a non-anhydrous form when forming a composition In addition, preferably, the amount of the related component in its pure anhydrous form (or the amount of the pure anhydrous form) This relates to compositions formed by using any corresponding non-anhydrous form (for example, one The amount of hydrates, dihydrates, etc. can be easily calculated by simply using the appropriate multiplier. For example, unless otherwise stated (the amount of the example relating to trehalose dihydrate) In this case, the amount of trehalose specified is trehalose in anhydrous form (or specified This refers to a composition formed by using anhydrous trehalose in a specified amount / concentration. Since the molecular weight of trehalose in its form is 342.296 g / mol, it forms the same composition. To calculate the corresponding amount of trehalose dihydrate needed for this purpose (the amount of water added is small) (It will disappear), the molecular weight of trehalose dihydrate is 378.33, therefore the specified amount It is necessary to multiply by 378.33 / 342.296. A person skilled in the art can derive the target concentration. To facilitate this process, a method is provided to carefully adjust the amount of diluent / water depending on the form of the ingredients used. They will understand. This problem does not apply if the amount of moles is specified.

[0072] In this specification, the terms "pharmaceutical composition" or "biopharmaceutical composition" refer to the active components. It makes the biological activity of the drug therapeutically effective, but it is not clear to the target population for which the drug is intended. This refers to a formulation of (bio)pharmaceutical active substance that does not contain other components that are toxic to crabs. In general, references to “compositions” refer to the (bio)pharmaceutical compositions as defined herein.

[0073] In this specification, the term “stable” generally refers to the ingredients during storage / preservation, typically Physical stability and / or chemical stability of the active substance or its composition and / or bioavailability This refers to physical stability. In the case of aqueous compositions of biological products, preferably, storage stability is the biological product. The temperature is 2-8°C for at least 6 months, preferably at least 12 months, preferably up to 24 months. It must remain sufficiently stable even when stored for a month or longer (i.e., patient safety) It can mean (within predetermined limits for performance). However, accelerated stability studies It can be used to provide relevant stability information.

[0074] The act of "treating (treating)" or reference to "treatment (treatment)" implies that the condition has been established. It should be understood that this includes not only alleviating symptoms but also prevention. Therefore, the situation "To treat" or "to treat" a disability or condition, (1) a situation, disability, or They may have the condition or be predisposed to it, but in that situation, If you have not yet experienced or presented any clinical or asymptomatic symptoms of a disorder or condition To prevent or delay the onset of clinical symptoms of a condition, disorder, or state that develops in a person who does not have it. (2) to cause, to impede a situation, disability, or condition, that is, to prevent the onset or The recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom (3) to block, reduce, or delay the disease That is, a situation, disability, or condition, or the low level of its clinical or asymptomatic symptoms. This includes causing at least one regression.

[0075] The terms “effective dose” or “therapeutic effective dose” refer to the desired biological, therapeutic, and / or therapeutic dose. This refers to the amount of an agent or combination of agents that produces a preventive effect. The result is the disease A reduction in one or more signs, symptoms, or causes, or any other desired changes in the biological system. It may be reduced, improved, remission, alleviated, delayed, and / or mitigated. In some embodiments, The effective dose is an amount sufficient to delay tumor development. In some embodiments, the effective dose is This is a sufficient amount to prevent or delay tumor recurrence. The effective dose is one or more doses. It can be administered by administration. An effective amount of the drug or composition (i) reduces the number of cancer cells. (ii) can reduce tumor size, and (iii) can reduce tumors in peripheral organs. It can inhibit, delay, slow, and even stop the invasion of cancer cells to some extent. iv) It can inhibit tumor metastasis, (v) It can inhibit tumor growth, (vi) It can prevent or delay the appearance and / or recurrence of tumors, and / or (vii) It may alleviate to some extent one or more of the symptoms associated with cancer. For example, the "effective dose" is the amount needed to achieve a reduction in cancer (e.g., a reduction in the number of cancer cells). To slow the progression of cancer, or to prevent the regrowth or recurrence of cancer, This refers to the amount of the combination of EGFR / LGR5 antibody and topoisomerase I inhibitor, and cancer is, It is gastrointestinal cancer, preferably colorectal cancer.

[0076] In this specification, the quantities of ingredients and constituent components specified are identified in "parts". It is specified in ppm (parts per million) or as a percentage (%, e.g., by weight) Whether specified by or by ratio, unless otherwise stated. It is intended to be due to weight, to the extent possible.

[0077] The amount or concentration of a particular component of a given composition is expressed as a weight percentage (wt%) or weight / When specified as a weight percentage, the weight percentage refers to the total weight of the composition as a whole. This refers to the weight percentage of the aforementioned component relative to the total amount. Those skilled in the art will know the weight of all components of the composition. The sum of the quantity percentages (whether specified or not) totals 100% by weight. It will be understood that... However, not all components are listed. In cases (for example, when a composition is said to "contain" one or more specific components), The remainder by weight percentage is a dilution of an unspecified component (e.g., water) as needed. It can be made to 100% by weight with an agent or other non-essential but preferred additive.

[0078] The composition consists of several specified components (at concentrations specified as necessary). If it is stated that the composition contains, then, if necessary, any additional ingredients other than those specified. It may also contain additional components. However, in certain embodiments, several specified components may be included. A composition that is said to contain the constituent components actually contains the specified amount of as needed. The composition may consist essentially of or consist of all of the specified components. If it is an aqueous composition, water is an implied component, even if not stated. In either situation, each component is itself a subordinate component or one or more subordinate components. Contains, essentially consists of, or may consist of. In this specification, "contains Whenever the term "comprise" is used, it is always appropriate to the situation. "consists essentially of" or "from" It can be replaced with "consists of".

[0079] In this specification, when a composition is said to be "essentially" made up of certain components, the composition The material preferably contains at least 70% by weight of the said component, preferably at least 90% by weight of the said component. Preferably at least 95% by weight of its component, most preferably at least 99% by weight of its component It includes. Preferably, a composition that is said to be "essentially" made up of a particular component is one or It consists of the above components, with the exception of several trace impurities.

[0080] In this specification, unless otherwise incompatible under given circumstances, the components are ionized (e.g., pro Whenever it is stated that a component is (tonic or deprotonate) possible, the definition of that component is always... This preferably includes any suitable salt thereof, preferably a pharmaceutically acceptable salt thereof. For example, this is for buffering agents (e.g., citric acid or citrate) and amino acids, etc. This applies to all references in this specification. Similarly, if it is not incompatible in a given situation, As far as is the case, whenever a neutralizable component is specified, the definition of the said component preferably includes, Its neutralized form, for example, contains citric acid instead of citrate.

[0081] <Pharmaceutical composition> The present invention relates to a pharmaceutical composition, particularly a first binding domain that binds to EGFR and LGR5 A polyspecific antibody containing a second binding domain that binds to, its functional moiety or derivative, his A buffer system including thidine buffer and / or citrate buffer, sugar components, and nonionic components. The present invention provides a pharmaceutical composition containing a surfactant.

[0082] The composition is most preferably a liquid pharmaceutical composition, and more preferably an aqueous pharmaceutical composition. Furthermore, the amounts and concentrations used herein relate to liquid pharmaceutical compositions, but such amounts are calculated Therefore, it can be easily converted to the corresponding amount in the corresponding solid composition. The quantity is expressed as the (weight or mole) ratio between each component, or as the absolute concentration (dilute). (Considering the removal of the solvent) it can be expressed.

[0083] The composition preferably includes a first binding domain that binds to EGFR and a binding domain that binds to LGR5. A polyspecific or bispecific antibody (i.e., EGFR / LGR) containing a second binding domain. 5 BsAb) is included, and is sometimes simply referred to as “antibody” in this specification. The composition is Preferably, it contains a diluent. The composition preferably contains a buffer system, preferably histidine or The composition includes a citrate buffer system, more preferably a histidine buffer system. The composition preferably contains salts, etc. Contains a tensor. The composition preferably contains a sugar component, and the sugar component is preferably sucrose. The composition contains or includes a surfactant, more preferably a polysorbate. The composition contains a nonionic surfactant that is or contains 80. Contains amino acid components.

[0084] The pH of the pharmaceutical composition is preferably 5 to 7, preferably 5.4 to 6.5, more preferably 5.8 to 6.4, most preferably 5.9 or 6.3.

[0085] The antibody present in the pharmaceutical composition of the present invention is 0.5 to 150 mg / mL, preferably 1 to 100 mg / mL, more preferably 1-50 mg / mL, more preferably 1-30 mg / mL, more preferably 5-25 mg / mL, more preferably 15-25 mg / mL, most Preferably, it is present at a concentration of 20 mg / mL.

[0086] The sugar content is preferably 200-400 mM, preferably 250-350 mM, more preferably It is present at a concentration of 270-300 mM, most preferably 280 mM or 290 mM.

[0087] The nonionic surfactant is preferably 0.01 to 2 mg / mL, preferably 0.1 to 1 0.5 mg / mL, more preferably 0.1-0.6 mg / mL or 0.6-1.2 mg / mL, most preferably a concentration of 0.2 mg / mL, 0.5 mg / mL, or 1 mg / mL. It exists.

[0088] The buffer system or combination of buffer systems is preferably 2 to 50 mM, preferably 3 to 20 mM. , more preferably 4-12 mM, more preferably 3-7 mM or 8-12 mM, most preferably It is present at concentrations of 5 mM or 10 mM.

[0089] The molar concentration ratio of sugar component to antibody is preferably 250:1 to 60,000:1, preferably 500:1 to 5000:1, preferably 1460:1 to 2920:1, preferably 182 5:1 to 255:1, more preferably 1970:1 to 2190:1, most preferably about The ratio is 2040:1 or 2117:1.

[0090] The molar concentration ratio of nonionic surfactant to antibody is preferably 1:90 to 224:1. Or 1:50 to 20:1, preferably 1:18 to 11:1, preferably 1:2 to 8:5 :1, preferably 1:2 to 3.5:1 or 3.5:1 to 7:1, most preferably about 1. The ratio is 11:1, approximately 2.79:1, or approximately 5.55:1.

[0091] The molar concentration ratio of buffer system (or combination of buffer systems) versus antibody is preferably 2.9:1~73 00:1, preferably 6:1 to 700:1, preferably 14:1 to 365:1, preferably The ratio is 21:1 to 146:1, preferably 29:1 to 88:1, more preferably 21:1 to 5 The ratio is 1:1 or 58:1 to 88:1, most preferably about 36.5:1 or 73:1. .

[0092] The buffering system preferably includes or consists of a citrate buffering system.

[0093] The composition preferably consists of a single buffer system such as histidine buffer or citrate buffer. Includes only.

[0094] Preferably, the composition does not contain trehalose and / or polysorbate 20 It does not contain a non-buffered salt isotonic agent, and most preferably does not contain sodium chloride.

[0095] The composition preferably does not contain antioxidants and / or chelating agents.

[0096] The composition is preferably such that water is not present or that water is less than 5% by weight. The composition can be characterized by the presence of a (non-buffered) salt isotonic agent. It can be characterized by the absence of. The composition preferably contains antioxidants (or antioxidants). If any of the agents specifically mentioned herein (one or more) are not present This can be characterized by the following. The composition preferably contains a chelating agent (or chelating agent). There is one or more of the drugs specifically mentioned herein. It can be characterized by its absence.

[0097] A) Embodiments of combinations of constituent components to be included The pharmaceutical composition comprises an antibody, a functional part thereof, a derivative, or a variant, and, if necessary, one or more pharmaceutically acceptable excipients and / or carriers.

[0098] The following numbered paragraphs A1 to A127 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, consists of the following together with water for injection, if necessary) and is characterized by the following: A1. EGFR / LGR5 BsAb, and a buffer system. A2. EGFR / LGR5 BsAb, and a salt isotonicity agent. A3. EGFR / LGR5 BsAb, and a sugar component. A4. EGFR / LGR5 BsAb, and a surfactant. A5. EGFR / LGR5 BsAb, and an amino acid component. A6. EGFR / LGR5 BsAb, and an antioxidant. A7. EGFR / LGR5 BsAb, and a chelating agent. A8. EGFR / LGR5 BsAb, a buffer system, and a salt isotonicity agent. A9. EGFR / LGR5 BsAb, a buffer system, and a sugar component. A10. EGFR / LGR5 BsAb, a buffer system, and a surfactant. A11. EGFR / LGR5 BsAb, a buffer system, and an amino acid component. A12. EGFR / LGR5 BsAb, a buffer system, and an antioxidant. A13. EGFR / LGR5 BsAb, a buffer system, and a chelating agent. A14. EGFR / LGR5 BsAb, a salt isotonicity agent, and a sugar component. A15. EGFR / LGR5 BsAb, a salt isotonicity agent, and a surfactant. A16. EGFR / LGR5 BsAb, a salt isotonicity agent, and an amino acid component. A17. EGFR / LGR5 BsAb, a salt isotonicity agent, and an antioxidant. A18. EGFR / LGR5 BsAb, a salt isotonicity agent, and a chelating agent. A19. EGFR / LGR5 BsAb, a sugar component, and a surfactant. A18. EGFR / LGR5 BsAb, salt isotonic agent, and chelating agent. A19. EGFR / LGR5 BsAb, sugar components, and surfactants. A20. EGFR / LGR5 BsAb, sugar components, and amino acid components. A21. EGFR / LGR5 BsAb, sugar components, and antioxidants. A22. EGFR / LGR5 BsAb, sugar components, and chelating agents. A23. EGFR / LGR5 BsAb, surfactants, and amino acid components. A24. EGFR / LGR5 BsAb, surfactant, and antioxidant. A25. EGFR / LGR5 BsAb, surfactants, and chelating agents. A26. EGFR / LGR5 BsAb, amino acid components, and antioxidants. A27. EGFR / LGR5 BsAb, amino acid components, and chelating agents. A28. EGFR / LGR5 BsAb, antioxidant, and chelating agent. A29. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, and sugar component. A30. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, and surfactant. A31. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, and amino acid components . A32. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, and antioxidant. A33. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, and chelating agent. A34. EGFR / LGR5 BsAb, buffering system, sugar components, and surfactants. A35. EGFR / LGR5 BsAb, buffer system, glucose components, and amino acid components. A36. EGFR / LGR5 BsAb, buffering system, sugar components, and antioxidants. A37. EGFR / LGR5 BsAb, buffering system, sugar components, and chelating agents. A38. EGFR / LGR5 BsAb, buffering system, surfactant, and amino acid components . A39. EGFR / LGR5 BsAb, buffering system, surfactant, and antioxidant. A40. EGFR / LGR5 BsAb, buffering systems, surfactants, and chelating agents. A41. EGFR / LGR5 BsAb, buffering system, amino acid components, and antioxidants. A42. EGFR / LGR5 BsAb, buffer system, amino acid components, and chelating agents . A43. EGFR / LGR5 BsAb, buffering system, antioxidant, and chelating agent. A44. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, and surfactant. A45. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, and amino acid component . A46. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, and antioxidant. A47. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, and chelating agent. A48. EGFR / LGR5 BsAb, salt isotonic agents, surfactants, and amino acids component. A49. EGFR / LGR5 BsAb, salt isotonic agents, surfactants, and antioxidants . A50. EGFR / LGR5 BsAb, salt isotonic agents, surfactants, and chelates Agent. A51. EGFR / LGR5 BsAb, salt isotonic agent, amino acid component, and antioxidant Agent. A52. EGFR / LGR5 BsAb, salt isotonic agent, amino acid component, and chlorine Drug. A53. EGFR / LGR5 BsAb, salt isotonic agent, antioxidant, and chelating agent . A54. EGFR / LGR5 BsAb, sugar components, surfactants, and amino acid components 。 A55. EGFR / LGR5 BsAb, sugar component, surfactant, and antioxidant. A56. EGFR / LGR5 BsAb, sugar component, surfactant, and chelating agent. A57. EGFR / LGR5 BsAb, sugar component, amino acid component, and antioxidant. A58. EGFR / LGR5 BsAb, sugar component, amino acid component, and chelating agent 。 A59. EGFR / LGR5 BsAb, sugar component, antioxidant, and chelating agent. A60. EGFR / LGR5 BsAb, surfactant, amino acid component, and antioxidant agent. A61. EGFR / LGR5 BsAb, surfactant, amino acid component, and chelating agent. A62. EGFR / LGR5 BsAb, surfactant, antioxidant, and chelating agent 。 A63. EGFR / LGR5 BsAb, amino acid component, antioxidant, and chelating [[ID=二十九]]agent. A64. EGFR / LGR5 BsAb, buffer system, salt isotonicity agent, sugar component, and surfactant agent. A65. EGFR / LGR5 BsAb, buffer system, salt isotonicity agent, sugar component, and amino acid component A66. EGFR / LGR5 BsAb, buffer system, salt isotonicity agent, sugar component, and antioxidant agent A67. EGFR / LGR5 BsAb, buffer system, salt isotonicity agent, sugar component, and chelating agent. A68. EGFR / LGR5 BsAb, buffer system, salt isotonicity agent, surfactant, and <0000�85>amino acid component. A69. EGFR / LGR5 BsAb, buffer system, salt isotonicity agent, surfactant, and antioxidant. A70. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, surfactant, and Chelating agent. A71. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, amino acid component, and Antioxidants. A72. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, amino acid component, and Chelating agent. A73. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, antioxidant, and Rate-adjusting agent. A74. EGFR / LGR5 BsAb, buffer system, sugar components, surfactants, and amino acids. Acidic components. A75. EGFR / LGR5 BsAb, buffering system, sugar components, surfactants, and acid fasteners. Chemical agent. A76. EGFR / LGR5 BsAb, buffer system, sugar components, surfactant, and sharpness A stimulant. A77. EGFR / LGR5 BsAb, buffer system, glucose components, amino acid components, and anti Oxidizing agent. A78. EGFR / LGR5 BsAb, buffer system, sugar components, amino acid components, and Rate-adjusting agent. A79. EGFR / LGR5 BsAb, buffer system, sugar component, antioxidant, and chelating agent. Drug. A80. EGFR / LGR5 BsAb, buffer system, surfactant, amino acid component, and Antioxidants. A81. EGFR / LGR5 BsAb, buffer system, surfactant, amino acid component, and Chelating agent. A82. EGFR / LGR5 BsAb, buffering systems, surfactants, antioxidants, and Rate-adjusting agent. A83. EGFR / LGR5 BsAb, buffer system, amino acid components, antioxidants, and Chelating agent. A84. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, and Amino acid components. A85. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, and Antioxidant. A86. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, and Chelating agent. A87. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, amino acid component, and Antioxidants. A88. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, amino acid component, and Chelating agent. A89. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, antioxidant, and Rate-adjusting agent. A90. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, amino acid component, And antioxidants. A91. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, amino acid component, and chelating agents. A92. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, antioxidant, and Chelating agent. A93. EGFR / LGR5 BsAb, salt isotonic agent, amino acid component, antioxidant, Also known as a chelating agent. A94. EGFR / LGR5 BsAb, sugar components, surfactants, amino acid components, and Antioxidants. A95. EGFR / LGR5 BsAb, sugar components, surfactants, amino acid components, and Chelating agent. A96. EGFR / LGR5 BsAb, sugar components, surfactants, antioxidants, and Rate-adjusting agent. A97. EGFR / LGR5 BsAb, sugar components, amino acid components, antioxidants, and Chelating agent. A98. EGFR / LGR5 BsAb, surfactant, amino acid component, antioxidant, Also known as a chelating agent. A99. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, sugar component, surfactant , and amino acid components. A100. EGFR / LGR5 BsAb, buffer system, salt tonicity agent, sugar component, surfactant Agents, and antioxidants. A101. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, surfactant Agents, and chelating agents. A102. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, amino acid Ingredients and antioxidants. A103. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, amino acid Ingredients and chelating agents. A104. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, antioxidant , and chelating agents. A105. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, surfactant, amine Acidic components and antioxidants. A106. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, surfactant, amine Acidic components and chelating agents. A107. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, surfactant, acid fastener Chemical agents and chelating agents. A108. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, amino acid component, anti Oxidizing agents and chelating agents. A109. EGFR / LGR5 BsAb, buffer system, sugar component, surfactant, amino acid Ingredients and antioxidants. A110. EGFR / LGR5 BsAb, buffer system, sugar component, surfactant, amino acid Ingredients and chelating agents. A111. EGFR / LGR5 BsAb, buffering system, sugar component, surfactant, antioxidant , and chelating agents. A112. EGFR / LGR5 BsAb, buffer system, sugar component, amino acid component, antioxidant Agents, and chelating agents. A113. EGFR / LGR5 BsAb, buffer system, surfactant, amino acid component, anti Oxidizing agents and chelating agents. A114. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, ammonium compound Acidic components and antioxidants. A115. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, ammonium compound Acidic components and chelating agents. A116. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, acid fastener Chemical agents and chelating agents. A117. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, amino acid component, anti Oxidizing agents and chelating agents. A118. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, amino acid component antioxidants and chelating agents. A119. EGFR / LGR5 BsAb, sugar component, surfactant, amino acid component, anti Oxidizing agents and chelating agents. A120. EGFR / LGR5 BsAb, buffer system, salt tonicity agent, sugar component, surfactant Agents, amino acid components, and antioxidants. A121. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, surfactant Agents, amino acid components, and chelating agents. A122. EGFR / LGR5 BsAb, buffer system, salt tonicity agent, sugar component, surfactant Antioxidants, chelating agents. A123. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, amino acid Ingredients, antioxidants, and chelating agents. A124. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, surfactant, amine Acid components, antioxidants, and chelating agents. A125. EGFR / LGR5 BsAb, buffer system, sugar component, surfactant, amino acid Ingredients, antioxidants, and chelating agents. A126. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, ammonium compound Acid components, antioxidants, and chelating agents. A127. EGFR / LGR5 BsAb, buffer system, salt tonicity agent, sugar component, surfactant Agents, amino acid components, antioxidants, and chelating agents.

[0099] In A1-A127, it is written as EGFR / LGR5 BsAb, EGFR It includes two specific binding domains: a first binding domain that binds and a second binding domain that binds to LGR5. Sex antibodies, their functional portions, derivatives, or variants are preferably full-length IgG antibodies. include.

[0100] B) Embodiments of combinations of constituent components to be included and solution concentration The following numbered paragraphs B1-B128 state that the pharmaceutical composition comprises (or aqueous) the following: In the case of finished products, they consist of the following (and, if necessary, water for injection), and are specially formulated as follows: Specific embodiments of the present invention are disclosed. B1. EGFR / LGR5 BsAb, and pH 4-8.5. B2. EGFR / LGR5 BsAb, 1-100 mM buffer system, and pH 4-8. 5. B3. EGFR / LGR5 BsAb, pH 4-8.5, and 3-200 mM salts, etc. Tensioning agent. B4. EGFR / LGR5 BsAb, pH 4-8.5, and 20-400 mM sugars component. B5. EGFR / LGR5 BsAb, pH 4-8.5, and 0.01-2 mg / mL surfactant. B6. EGFR / LGR5 BsAb, pH 4-8.5, and 5-150 mM ami Acidic components. B7. EGFR / LGR5 BsAb, pH 4-8.5, and 0.1-100 mM Antioxidant. B8. EGFR / LGR5 BsAb, pH 4-8.5, and 0.001-0.5 mM chelating agent. B9. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, Also, 3-200 mM salt isotonic agents. B10. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, and 20-400 mM sugar components. B11. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, and 0.01-2 mg / mL surfactant. B12. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, And 5-150 mM amino acid components. B13. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, and 0.1-100 mM antioxidants. B14. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, and a 0.001-0.5 mM chelating agent. B15. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution Agents, and 20-400 mM sugar components. B16. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution Agents, and surfactants at a concentration of 0.01-2 mg / mL. B17. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution Agents, and 5-150 mM amino acid components. B18. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution Agents, and 0.1-100 mM antioxidants. B19. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution Agents, and 0.001-0.5 mM chelating agents. B20. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content , and 0.01-2 mg / mL surfactant. B21. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar component , and 5-150 mM amino acid components. B22. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar component , and 0.1-100 mM antioxidants. B23. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar component , and a 0.001-0.5 mM chelating agent. B24. EGFR / LGR5 BsAb, pH4~8.5, 0.01~2mg / mL Surfactants and 5-150 mM amino acid components. B25. EGFR / LGR5 BsAb, pH4~8.5, 0.01~2mg / mL Surfactants and 0.1-100 mM antioxidants. B26. EGFR / LGR5 BsAb, pH4~8.5, 0.01~2mg / mL Surfactants and 0.001-0.5 mM chelating agents. B27. EGFR / LGR5 BsAb, pH 4-8.5, 5-150 mM amino acids Ingredients, and 0.1-100 mM antioxidants. B28. EGFR / LGR5 BsAb, pH 4-8.5, 5-150 mM amino acids Ingredients, and 0.001-0.5 mM chelating agent. B29. EGFR / LGR5 BsAb, pH 4-8.5, 0.1-100 mM acid-fast A chemical agent and a 0.001-0.5 mM chelating agent. B30. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, and 20-400 mM sugar component. B31. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, and 0.01-2 mg / mL surfactant. B32. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, and 5-150 mM amino acid component. B33. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, and 0.1-100 mM antioxidant. B34. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, and 0.001-0.5 mM chelating agent. B35. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components and 0.01-2 mg / mL surfactant. B36. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components and 5-150 mM amino acid components. B37. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components and 0.1-100 mM antioxidants. B38. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar component and 0.001-0.5 mM chelating agent. B39. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 0.01-2 mg / mL surfactant and 5-150 mM amino acid components. B40. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 0.01-2 mg / mL surfactant and 0.1-100 mM antioxidant. B41. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 0.01-2 mg / mL surfactant and 0.001-0.5 mM chelating agent. B42. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 5-150 mM amino acid components and 0.1-100 mM antioxidants. B43. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 5-150 mM amino acid components and 0.001-0.5 mM chelating agent. B44. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 0.1-100 mM antioxidant and 0.001-0.5 mM chelating agent. B45. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 20-400 mM sugar component, and 0.01-2 mg / mL surfactant. B46. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. The agent contains 20-400 mM sugar components and 5-150 mM amino acid components. B47. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agents, 20-400 mM sugar components, and 0.1-100 mM antioxidants. B48. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. A chelate containing 20-400 mM sugar components and 0.001-0.5 mM chelating agents. B49. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 0.01-2 mg / mL surfactant, and 5-150 mM amino acid component. B50. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B51. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. B52. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agents, 5-150 mM amino acid components, and 0.1-100 mM antioxidants. B53. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B54. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agents, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agents. B55. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content 0.01-2 mg / mL surfactant and 5-150 mM amino acid components. B56. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content 0.01-2 mg / mL surfactant and 0.1-100 mM antioxidant. B57. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. B58. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content 5-150 mM amino acid components and 0.1-100 mM antioxidants. B59. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content 5-150 mM amino acid components, and 0.001-0.5 mM chelating agents. B60. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B61. EGFR / LGR5 BsAb, pH4~8.5, 0.01~2mg / mL Surfactants, 5-150 mM amino acid components, and 0.1-100 mM antioxidants. B62. EGFR / LGR5 BsAb, pH4~8.5, 0.01~2mg / mL Surfactants, 5-150 mM amino acid components, and 0.001-0.5 mM chelating agents. B63. EGFR / LGR5 BsAb, pH4~8.5, 0.01~2mg / mL Surfactants, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agents. B64. EGFR / LGR5 BsAb, pH 4-8.5, 5-150 mM amino acids Ingredients: 0.1-100 mM antioxidants and 0.001-0.5 mM chelating agents. B65. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 0.01-2 mg / mL saturates. Surfactants. B66. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 5-150 mM amino acid component Minutes. B67. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 0.1-100 mM antioxidant. Agent. B68. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 0.001-0.5 mM ki Rate-adjusting agent. B69. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, and 5-150 mM Amino acid components. B70. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B71. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, and 0.001-0 0.5 mM chelating agent. B72. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 5-150 mM amino acid component, and 0.1-100 mM anti- Oxidizing agent. B73. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 5-150 mM amino acid component, and 0.001-0.5 mM M-chelating agent. B74. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 3-200 mM salt isotonic agent, 0.1-100 mM antioxidant, and 0.001-0.5 mM M-chelating agent. B75. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components, 0.01-2 mg / mL surfactant, and 5-150 mM alpha Mino acid component. B76. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components, 0.01-2 mg / mL surfactant, and 0.1-100 mM M antioxidant. B77. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components, 0.01-2 mg / mL surfactant, and 0.001-0. 5 mM chelating agent. B78. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components, 5-150 mM amino acid components, and 0.1-100 mM antioxidants Chemical agent. B79. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components, 5-150 mM amino acid components, and 0.001-0.5 mM Chelating agent. B80. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 20-400 mM sugar components, 0.1-100 mM antioxidants, and 0.001-0.5 mM Chelating agent. B81. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.1-10 0 mM antioxidant. B82. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001- 0.5 mM chelating agent. B83. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.001- 0.5 mM chelating agent. B84. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5, 5-150 mM amino acid components, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agent. B85. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 5-150 mg M amino acid component. B86. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 0.1-10 0 mM antioxidant. B87. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 0.001- 0.5 mM chelating agent. B88. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 20-400 mM sugar component, 5-150 mM amino acid component, and 0.1-100 mM Antioxidant. B89. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 20-400 mM sugar component, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B90. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 20-400 mM sugar component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B91. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.1- 100 mM antioxidant. B92. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.00 1-0.5 mM chelating agent. B93. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.00 1-0.5 mM chelating agent. B94. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic solution. Agent, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0 0.5 mM chelating agent. B95. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content , 0.01~2 mg / mL surfactant, 5~150 mM amino acid component, and 0.1~1 00 mM antioxidant. B96. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content , 0.01~2 mg / mL surfactant, 5~150 mM amino acid component, and 0.001 ~0.5 mM chelating agent. B97. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content , 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.001 ~0.5 mM chelating agent. B98. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM sugar content , 5-150 mM amino acid components, 0.1-100 mM antioxidants, and 0.001-0. 5 mM chelating agent. B99. EGFR / LGR5 BsAb, pH4~8.5, 0.01~2mg / mL Surfactants, 5-150 mM amino acid components, 0.1-100 mM antioxidants, and 0.0 0.1-0.5 mM chelating agent. B100. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant Aphrodisiacs and 5-150 mM amino acid components. B101. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant Aphrodisiac and 0.1-100 mM antioxidant. B102. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant Aphrodisiac agents, and 0.001-0.5 mM chelating agents. B103. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 5-150 mM amino acid component, and 0.1-100 mM antioxidants. B104. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 5-150 mM amino acid component, and a 0.001-0.5 mM chelating agent. B105. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.1-100 mM antioxidant, and a 0.001-0.5 mM chelating agent. B106. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid Acid components and 0.1-100 mM antioxidants. B107. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid Acid components and 0.001-0.5 mM chelating agents. B108. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, 0.1-100 mM Antioxidant, and 0.001-0.5 mM chelating agent. B109. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 5-150 mM amino acid component, 0.1-100 mM antioxidant Agents, and 0.001-0.5 mM chelating agents. B110. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 20-400 mM sugar components, 0.01-2 mg / mL surfactant, 5-150 mM amino acids Acidic components and 0.1-100 mM antioxidants. B111. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 20-400 mM sugar components, 0.01-2 mg / mL surfactant, 5-150 mM amino acids Acidic components and 0.001-0.5 mM chelating agents. B112. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 20-400 mM sugar components, 0.01-2 mg / mL surfactant, 0.1-100 mM antimicrobial Oxidizing agent, and 0.001-0.5 mM chelating agent. B113. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 20-400 mM sugar components, 5-150 mM amino acid components, 0.1-100 mM antioxidants , and a 0.001-0.5 mM chelating agent. B114. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 0.01-2 mg / mL surfactant, 5-150 mM amino acid components, 0.1-100 mM M antioxidant and 0.001-0.5 mM chelating agent. B115. EGFR / LGR5 BsAb, pH4~8.5, 3~200mM salt isotonic Refining agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM Minoic acid components and 0.1-100 mM antioxidants. B116. EGFR / LGR5 BsAb, pH4~8.5, 3~200mM salt isotonic Refining agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM Minoic acid components and 0.001-0.5 mM chelating agent. B117. EGFR / LGR5 BsAb, pH4~8.5, 3~200mM salt isotonic Refining agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 0.1-100 mM M antioxidant and 0.001-0.5 mM chelating agent. B118. EGFR / LGR5 BsAb, pH4~8.5, 3~200mM salt isotonic Refining agent, 20-400 mM sugar component, 5-150 mM amino acid component, 0.1-100 mM antioxidant A chemical agent and a 0.001-0.5 mM chelating agent. B119. EGFR / LGR5 BsAb, pH 4~8.5, 3~200mM salt isotonic Reacting agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, 0.1-10 0 mM antioxidant and 0.001-0.5 mM chelating agent. B120. EGFR / LGR5 BsAb, pH4~8.5, 20~400mM Glucose Minutes, 0.01-2 mg / mL surfactant, 5-150 mM amino acid components, 0.1-100 mM antioxidants and 0.001-0.5 mM chelating agents. B121. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant Aphrodisiac, 5-150 mM amino acid components, and 0.1-100 mM antioxidants. B122. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant A stimulant, 5-150 mM amino acid components, and 0.001-0.5 mM chelating agents. B123. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant Probiotics, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agents. B124. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 5-150 mM amino acid component, 0.1-100 mM antioxidant and 0.001-0.5 mM chelating agent. B125. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid Acid components, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agents. B126. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 20-400 mM sugar components, 0.01-2 mg / mL surfactant, 5-150 mM amino acids Acidic components, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agents. B127. EGFR / LGR5 BsAb, pH4~8.5, 3~200mM salt isotonic Refining agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM Minoic acid components, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agents. B128. EGFR / LGR5 BsAb; 1~100mM buffer system, pH4~8.5 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant Aphrodisiac, 5-150 mM amino acid components, 0.1-100 mM antioxidants, and 0.001- 0.5 mM chelating agent.

[0101] EGF is indicated as EGFR / LGR5 BsAb in B1-B128. It includes a first binding domain that binds to R and a second binding domain that binds to LGR5. The specific antibody, its functional moiety, derivative, or variant is preferably a full-length IgG antibody. Including the body.

[0102] C) Embodiments of combinations and molar ratios of constituent components to be included The following numbered paragraphs C1-C128 state that a pharmaceutical composition comprises (or an aqueous mixture) the following: In the case of finished products, they consist of the following (and, if necessary, water for injection), and are specially formulated as follows: Specific embodiments of the present invention are disclosed. C1. EGFR / LGR5 BsAb, and pH 4-8.5. C2. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050: A buffer system of 1, and a pH of 4-8.5. C3. EGFR / LGR5 BsAb, pH 4-8.5, and salt isotonic agent counter antibody Salt isotonic agents with a molar ratio of 7:1 to 3000:1. C4. EGFR / LGR5 BsAb, pH 4-8.5, and molars of sugar component versus antibody. Sugar components with a ratio of 100:1 to 5500:1. C5. EGFR / LGR5 BsAb, pH 4-8.5, and surfactant counter antibody A surfactant with a molar ratio of 1:11 to 17:1. C6. EGFR / LGR5 BsAb, pH 4-8.5, and amino acid component counter antibodies. Amino acid components with a molar ratio of 10:1 to 2500:1. C7. EGFR / LGR5 BsAb, pH 4-8.5, and antioxidant counter-antibody Antioxidants with a ratio of 2:1 to 750:1. C8. EGFR / LGR5 BsAb, pH 4-8.5, and chelating agent counter antibody A chelating agent with a molar ratio of 1:420 to 8:1. C9. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050: A buffer system of 1, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000. A salt isotonic agent with a ratio of 1. C10. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-550. A sugar component ratio of 0:1. C11. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17 A surfactant with a ratio of 1. C12. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a molar ratio of amino acid component to antibody of 10:1-2 The amino acid ratio is 500:1. C13. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and an antioxidant-to-antibody molar ratio of 2:1-750: An antioxidant that is 1. C14. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of chelating agent to antibody of 1:420-8 A chelating agent with a ratio of 1. C15. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and a molar ratio of sugar component to antibody of 100:1 The sugar component ratio is approximately 5500:1. C16. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and a surfactant versus antibody molar ratio of 1:1 A surfactant with a ratio of 1 to 17.1. C17. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent counter antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and a molar ratio of amino acid component to antibody of 10 Amino acid components with a ratio of 1 to 2500:1. C18. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and antioxidants with a molar ratio of 2:1 to 2:1. An antioxidant with a ratio of 750:1. C19. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody The molar ratio of the salt isotonic agent and chelating agent to antibody is 1:4, with a ratio of 7:1 to 3000:1. A chelating agent with a ratio of 20 to 8:1. C20. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar components (100:1 to 5500:1) and surfactants to antibodies (1:11 to 5500:1) is 1:11. A surfactant with a ratio of 17:1. C21. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar components and amino acid components to antibodies is 10:1, ranging from 100:1 to 5500:1. The amino acid ratio is approximately 2500:1. C22. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar components is 100:1 to 5500:1, and the molar ratio of antioxidants to antibodies is 2:1 to 75. Antioxidants in a 0:1 ratio. C23. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The sugar component is 100:1 to 5500:1, and the molar ratio of the chelating agent to the antibody is 1:420. A chelating agent with a ratio of approximately 8:1. C24. EGFR / LGR5 BsAb, pH 4-8.5, Molars of surfactant versus antibody Surfactants with a ratio of 1:11 to 17:1, and amino acid component to antibody molar ratio of 10: Amino acid components with a ratio of 1 to 2500:1. C25. EGFR / LGR5 BsAb, pH 4-8.5, Molars of surfactant versus antibody Surfactants with a ratio of 1:11 to 17:1, and antioxidants with a molar ratio of 2:1 to 7 Antioxidants in a 50:1 ratio. C26. EGFR / LGR5 BsAb, pH 4-8.5, Molars of surfactant versus antibody The ratio of surfactants is 1:11 to 17:1, and the molar ratio of chelating agent to antibody is 1:42. A chelating agent with a ratio of 0 to 8.1. C27. EGFR / LGR5 BsAb, pH 4-8.5, amino acid component vs antibody Amino acid components with a molar ratio of 10:1 to 2500:1, and antioxidants with a molar ratio of 2 Antioxidants with a ratio of 1 to 750:1. C28. EGFR / LGR5 BsAb, pH 4-8.5, amino acid component vs antibody The molar ratio of amino acid components is 10:1 to 2500:1, and the molar ratio of chelating agent to antibody is Chelating agents with a ratio of 1:420 to 8:1. C29. EGFR / LGR5 BsAb, pH 4-8.5, molar ratio of antioxidant to antibody Antioxidants with a molar ratio of 2:1 to 750:1, and chelating agents with a molar ratio of 1:420 to 750:1. A chelating agent with an 8:1 ratio. C30. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 A salt isotonic agent, and a sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1. Minutes. C31. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000:1. The isotonic salt agent and the surfactant-to-antibody molar ratio is 1:11 to 17:1. Aphrodisiac. C32. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000:1. The salt isotonic agent and the molar ratio of amino acid component to antibody are 10:1 to 2500:1. Amino acid components. C33. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000:1. A salt isotonic agent, and an antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. . C34. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 The chelating agent is a salt isotonic agent, and the molar ratio of the chelating agent to the antibody is 1:420 to 8:1. Drug. C35. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The sugar component and the surfactant have a molar ratio of surfactant to antibody of 1:11 to 17:1. . C36. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The molar ratio of the sugar component and amino acid component to the antibody is 10:1 to 2500:1. Acidic components. C37. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. A sugar component, and an antioxidant having a molar ratio of antioxidant to antibody of 2:1 to 750:1. C38. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The sugar component and the chelating agent have a molar ratio of 1:420 to 8:1. . C39. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17:1. A certain surfactant and amino acid component versus antibody have a molar ratio of 10:1 to 2500:1. Mino acid component. C40. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17:1. A surfactant and an antioxidant having a molar ratio of antioxidant to antibody of 2:1 to 750:1. C41. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17:1. A chelating agent in which the molar ratio of a certain surfactant to an antibody is 1:420 to 8:1. Agent. C42. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a molar ratio of amino acid component to antibody of 10:1-2500. The amino acid component is :1, and the molar ratio of antioxidant to antibody is 2:1 to 750:1. Oxidizing agent. C43. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a molar ratio of amino acid component to antibody of 10:1-2500. The amino acid component is 1:1, and the molar ratio of the chelating agent to the antibody is 1:420 to 8:1. Chelating agent. C44. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 The buffer system is 1, pH 4-8.5, and the molar ratio of antioxidant to antibody is 2:1-750:1. Antioxidants, and chelating agents having a molar ratio of 1:420 to 8:1 between the chelating agent and the antibody. C45. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 The sugar component is 0:1, and the surfactant to antibody molar ratio is 1:11 to 17:1. Surfactants. C46. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 The molar ratio of sugar components and amino acid components to antibodies is 0:1, and the molar ratio of sugar components to antibodies is 10:1 to 2500:1. A certain amino acid component. C47. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 The sugar component is 0:1, and the molar ratio of antioxidant to antibody is 2:1 to 750:1. Chemical agent. C48. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent counter antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 The sugar component is 0:1, and the molar ratio of the chelating agent to the antibody is 1:420 to 8:1. Rate-adjusting agent. C49. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agent with a ratio of 7:1 to 3000:1, and the molar ratio of surfactant to antibody is 1:11 to 1 The surfactant is in a 7:1 ratio, and the molar ratio of amino acid component to antibody is 10:1 to 2500:1. It is an amino acid component. C50. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agent with a ratio of 7:1 to 3000:1, and the molar ratio of surfactant to antibody is 1:11 to 1 The surfactant has a 7:1 ratio, and the antioxidant has a molar ratio of 2:1 to 750:1. Oxidizing agent. C51. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent counter antibody Salt isotonic agent with a ratio of 7:1 to 3000:1, and the molar ratio of surfactant to antibody is 1:11 to 1 The surfactant is in a 7:1 ratio, and the molar ratio of the chelating agent to the antibody is 1:420 to 8:1. Chelating agent. C52. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent counter antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and amino acid component to antibody molar ratio of 10:1 to The amino acid component ratio is 2500:1, and the molar ratio of antioxidant to antibody is 2:1 to 750:1. It is an antioxidant. C53. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent counter antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and amino acid component to antibody molar ratio of 10:1 to The amino acid component is 2500:1, and the molar ratio of chelating agent to antibody is 1:420-8: A chelating agent that is 1. C54. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent counter antibody The molar ratio of salt isotonic agents and antioxidants to antibodies is 7:1 to 3000:1, and the molar ratio of antioxidants to antibodies is 2:1 to 750. Antioxidant with a molar ratio of 1:1 and chelating agent to antibody with a molar ratio of 1:420 to 8:1 A stimulant. C55. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar component to surfactant to antibody is 1:11 to 17, with a ratio of 100:1 to 5500:1. The surfactant is 1, and the molar ratio of amino acid component to antibody is 10:1 to 2500:1. It contains amino acid components. C56. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar component to surfactant to antibody is 1:11 to 17, with a ratio of 100:1 to 5500:1. A surfactant of 1, and an antioxidant with a molar ratio of 2:1 to 750:1. Agent. C57. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar component to surfactant to antibody is 1:11 to 17, with a ratio of 100:1 to 5500:1. The surfactant is 1, and the molar ratio of the chelating agent to the antibody is 1:420 to 8:1. A stimulant. C58. EGFR / LGR5 BsAb, pH 4~8.5, Molar ratio of sugar component to antibody The molar ratio of sugar components, amino acid components to antibodies is 10:1 to 25, ranging from 100:1 to 5500:1. The amino acid component is 0:1, and the molar ratio of antioxidant to antibody is 2:1 to 750:1. An antioxidant. C59. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar components, amino acid components to antibodies is 10:1 to 25, ranging from 100:1 to 5500:1. The amino acid component is 0:1, and the molar ratio of chelating agent to antibody is 1:420 to 8:1. A chelating agent. C60. EGFR / LGR5 BsAb, pH 4~8.5, Molar ratio of sugar component to antibody The molar ratio of sugar components to antioxidants to antibodies is 100:1 to 5500:1, and the molar ratio of antioxidants to antibodies is 2:1 to 750:1. The antioxidant and the chelating agent have a molar ratio of 1:420 to 8:1. Agent. C61. EGFR / LGR5 BsAb, pH 4-8.5, Molars of surfactant versus antibody Surfactants with a ratio of 1:11 to 17:1, and amino acid component to antibody molar ratio of 10:1 to 2 The amino acid component is 500:1, and the molar ratio of antioxidant to antibody is 2:1 to 750:1. A certain antioxidant. C62. EGFR / LGR5 BsAb, pH 4-8.5, Molars of surfactant versus antibody Surfactants with a ratio of 1:11 to 17:1, and amino acid component to antibody molar ratio of 10:1 to 2 The amino acid component is 500:1, and the molar ratio of chelating agent to antibody is 1:420 to 8:1. It is a chelating agent. C63. EGFR / LGR5 BsAb, pH 4-8.5, Molars of surfactant versus antibody Surfactants with a ratio of 1:11 to 17:1, antioxidants with a molar ratio of 2:1 to 750 antibodies: The molar ratio of the antioxidant (1) to the chelating agent (1) versus the antibody is 1:420 to 8:1. Drug. C64. EGFR / LGR5 BsAb, pH 4-8.5, amino acid component vs antibody The molar ratio of amino acid components is 10:1 to 2500:1, and the molar ratio of antioxidants to antibodies is 2:1. The molar ratio of antioxidants to antibodies is 750:1, and the molar ratio of chelating agents to antibodies is 1:420 to 8:1. A chelating agent. C65. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 A salt isotonic agent, a sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, A surfactant in which the molar ratio of surfactant to antibody is 1:11 to 17:1. C66. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 A salt isotonic agent, a sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, This refers to amino acid components in which the molar ratio of amino acid component to antibody is 10:1 to 2500:1. C67. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 A salt isotonic agent, a sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, Antioxidants with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C68. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 A salt isotonic agent, a sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, A chelating agent in which the molar ratio of chelating agent to antibody is 1:420 to 8:1. C69. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 A salt isotonic agent, a surfactant with a surfactant-to-antibody molar ratio of 1:11 to 17:1, And amino acid components in which the molar ratio of amino acid component to antibody is 10:1 to 2500:1. C70. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 A salt isotonic agent, a surfactant with a surfactant-to-antibody molar ratio of 1:11 to 17:1, And antioxidants with an antioxidant-to-antibody molar ratio of 2:1 to 750:1. C71. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 A salt isotonic agent, a surfactant with a surfactant-to-antibody molar ratio of 1:11 to 17:1, And a chelating agent having a molar ratio of chelating agent to antibody of 1:420 to 8:1. C72. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 The isotonic salt agent, the amino acid component versus antibody molar ratio is 10:1 to 2500:1. Antioxidants having an acidic component and an antioxidant-to-antibody molar ratio of 2:1 to 750:1. C73. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 The isotonic salt agent, the amino acid component versus antibody molar ratio is 10:1 to 2500:1. A chelating agent in which the molar ratio of the acid component to the chelating agent versus the antibody is 1:420 to 8:1. C74. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 Buffer system with a ratio of :1, pH 4-8.5, and molar ratio of salt isotonic agent to antibody of 7:1-3000:1 salt isotonic agents, antioxidants with a molar ratio of antioxidant to antibody of 2:1 to 750:1, and A chelating agent in which the molar ratio of chelating agent to antibody is 1:420 to 8:1. C75. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The sugar component, the surfactant with a surfactant-to-antibody molar ratio of 1:11 to 17:1, and Amino acid components with a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C76. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The sugar component, the surfactant with a surfactant-to-antibody molar ratio of 1:11 to 17:1, and Antioxidants with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C77. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The sugar component, the surfactant with a surfactant-to-antibody molar ratio of 1:11 to 17:1, and A chelating agent in which the molar ratio of chelating agent to antibody is 1:420 to 8:1. C78. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The molar ratio of sugar components and amino acid components to antibodies is 10:1 to 2500:1. Antioxidants with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C79. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The molar ratio of sugar components and amino acid components to antibodies is 10:1 to 2500:1. A chelating agent having a molar ratio of 1:420 to 8:1 between the chelating agent and the antibody. C80. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of 1:1, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500:1. The sugar component, the antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1, and A chelating agent with a molar ratio of 1:420 to 8:1 between the chelating agent and the antibody. C81. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17:1. A certain surfactant, an amino acid component with a molar ratio of 10:1 to 2500:1 compared to an antibody. Antioxidants with a component ratio and an antioxidant-to-antibody molar ratio of 2:1 to 750:1. C82. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17:1. A certain surfactant, an amino acid component with a molar ratio of 10:1 to 2500:1 compared to an antibody. A chelating agent having a molar ratio of 1:420 to 8:1 between its components and the chelating agent to antibody. C83. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17:1. A certain surfactant, an antioxidant with an antioxidant-to-antibody molar ratio of 2:1 to 750:1, and A chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C84. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 1050 A buffer system with a ratio of :1, pH 4-8.5, and a molar ratio of amino acid component to antibody of 10:1-2500. Antioxidants with an amino acid component of :1 and an antioxidant-to-antibody molar ratio of 2:1 to 750:1 , and chelating agents having a molar ratio of chelating agent to antibody of 1:420 to 8:1. C85. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 A surfactant with a sugar component ratio of 0:1 and a surfactant-to-antibody molar ratio of 1:11 to 17:1. The agent, and the amino acid component having a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C86. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 A surfactant with a sugar component ratio of 0:1 and a surfactant-to-antibody molar ratio of 1:11 to 17:1. Antioxidants having a molar ratio of antioxidant to antibody of 2:1 to 750:1. C87. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 A surfactant with a sugar component ratio of 0:1 and a surfactant-to-antibody molar ratio of 1:11 to 17:1. A chelating agent having a molar ratio of 1:420 to 8:1 between the agent and the antibody. C88. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent counter antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 The molar ratio of sugar component, amino acid component to antibody is 0:1 to 10:1 to 2500:1. Antioxidants having a molar ratio of 2:1 to 750:1 between the amino acid component and the antioxidant to antibody. C89. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 The molar ratio of sugar component, amino acid component to antibody is 0:1 to 10:1 to 2500:1. A chelating agent having a molar ratio of 1:420 to 8:1 between the amino acid component and the chelating agent versus antibody. C90. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and sugar component to antibody molar ratio of 100:1 to 55 Sugar component with a ratio of 0:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1, And a chelating agent having a molar ratio of chelating agent to antibody of 1:420 to 8:1. C91. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agent with a ratio of 7:1 to 3000:1, and the molar ratio of surfactant to antibody is 1:11 to 1 The molar ratio of surfactant to amino acid component to antibody is 7:1, and the molar ratio of amino acid component to antibody is 10:1 to 2500:1. Antioxidants having an amino acid component and an antioxidant-to-antibody molar ratio of 2:1 to 750:1. C92. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agent with a ratio of 7:1 to 3000:1, and the molar ratio of surfactant to antibody is 1:11 to 1 The molar ratio of surfactant to amino acid component to antibody is 7:1, and the molar ratio of amino acid component to antibody is 10:1 to 2500:1. Chelating agents having an amino acid component and a molar ratio of chelating agent to antibody of 1:420 to 8:1. . C93. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agent with a ratio of 7:1 to 3000:1, and the molar ratio of surfactant to antibody is 1:11 to 1 Surfactants with a 7:1 ratio, antioxidants with a molar ratio of antioxidant to antibody of 2:1 to 750:1. , and chelating agents having a molar ratio of chelating agent to antibody of 1:420 to 8:1. C94. EGFR / LGR5 BsAb, pH 4-8.5, molars of salt isotonic agent versus antibody Salt isotonic agents with a ratio of 7:1 to 3000:1, and amino acid component to antibody molar ratio of 10:1 to The amino acid component ratio is 2500:1, and the molar ratio of antioxidant to antibody is 2:1 to 750:1. Antioxidants and chelating agents with a molar ratio of 1:420 to 8:1 between the chelating agent and the antibody. C95. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar component to surfactant to antibody is 1:11 to 17, with a ratio of 100:1 to 5500:1. The surfactant is 1, and the molar ratio of amino acid component to antibody is 10:1 to 2500:1. Antioxidants having a molar ratio of 2:1 to 750:1 between the anoacid component and the antioxidant to antibody. C96. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar component to surfactant to antibody is 1:11 to 17, with a ratio of 100:1 to 5500:1. The surfactant is 1, and the molar ratio of amino acid component to antibody is 10:1 to 2500:1. A chelating agent having a molar ratio of 1:420 to 8:1 between the non-acid component and the chelating agent versus antibody. C97. EGFR / LGR5 BsAb, pH 4-8.5, Molar ratio of sugar component to antibody The molar ratio of sugar component to surfactant to antibody is 1:11 to 17, with a ratio of 100:1 to 5500:1. A surfactant with a molar ratio of 1, an antioxidant with a molar ratio of 2:1 to 750:1, A chelating agent in which the molar ratio of chelating agent to antibody is 1:420 to 8:1. C98. EGFR / LGR5 BsAb, pH 4~8.5, Molar ratio of sugar component to antibody The molar ratio of sugar components, amino acid components to antibodies is 10:1 to 25, ranging from 100:1 to 5500:1. The amino acid component is 0:1, and the molar ratio of antioxidant to antibody is 2:1 to 750:1. A chelating agent in which the molar ratio of the chelating agent to the antibody is 1:420 to 8:1. C99. EGFR / LGR5 BsAb, pH 4-8.5, Molars of surfactant versus antibody Surfactants with a ratio of 1:11 to 17:1, and amino acid component to antibody molar ratio of 10:1 to 2 The amino acid component has a molar ratio of 500:1, and the antioxidant to antibody molar ratio is 2:1 to 750:1. A chelating agent in which the molar ratio of oxidizing agent to antibody is 1:420 to 8:1. C100. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio 4:1~10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Surfactants and amino acid components with a surfactant-to-antibody molar ratio of 1:11 to 17:1 Amino acid components with a molar ratio of 10:1 to 2500:1 against the antibody. C101. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Surfactants with a surfactant-to-antibody molar ratio of 1:11 to 17:1, and antioxidants Antioxidants with a molar ratio of 2:1 to 750:1. C102. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Surfactants and chelating agents having a surfactant-to-antibody molar ratio of 1:11 to 17:1 Chelating agents with an antibody molar ratio of 1:420 to 8:1. C103. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Amino acid components and antibody with a molar ratio of 10:1 to 2500:1, and antibody Antioxidants with a molar ratio of oxidizing agent to antibody of 2:1 to 750:1. C104. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Amino acid components with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and sharpness A chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C105. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Antioxidants and chelating agents with an antioxidant-to-antibody molar ratio of 2:1 to 750:1 A chelating agent with a molar ratio of 1:420 to 8:1. C106. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1:11 to 17:1, and a surfactant with a molar ratio of surfactant to antibody. , an amino acid component having a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and an antibody Antioxidants with an oxidant-to-antibody molar ratio of 2:1 to 750:1. C107. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1:11 to 17:1, and a surfactant with a molar ratio of surfactant to antibody. , an amino acid component having a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and A chelating agent with a molar ratio of 1:420 to 8:1 between the chelating agent and the antibody. C108. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio 4:1~10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1:11 to 17:1, and a surfactant with a molar ratio of surfactant to antibody. Antioxidants and chelating agents having an antioxidant-to-antibody molar ratio of 2:1 to 750:1. A chelating agent with a molar ratio of 1:420 to 8:1. C109. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 10:1 to 2500:1 of amino acid component versus antibody. Antioxidants with an antioxidant-to-antibody molar ratio of 2:1 to 750:1, and chlorine A chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C110. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500: A sugar component with a molar ratio of 1:11 to 17:1, a surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, Amino acid components with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and antioxidants Antioxidants with a drug-to-antibody molar ratio of 2:1 to 750:1. C111. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500: A sugar component with a molar ratio of 1:11 to 17:1, a surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, Amino acid components and chlorine are available in an amino acid component to antibody molar ratio of 10:1 to 2500:1. A chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C112. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500: A sugar component with a molar ratio of 1:11 to 17:1, a surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and an antibody Antioxidants and chelating agents with an oxidizing agent to antibody molar ratio of 2:1 to 750:1 A chelating agent with a molar ratio of 1:420 to 8:1. C113. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500: The molar ratio of sugar component (1) to amino acid component (1) to antibody is 10:1 to 2500:1 for amino acids. The components include antioxidants with a molar ratio of antioxidant to antibody of 2:1 to 750:1, and chelating agents. A chelating agent with a molar ratio of 1:420 to 8:1 against the antibody. C114. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17:1. The surfactant is an amino acid component with a molar ratio of 10:1 to 2500:1. Acid component, antioxidant with an antioxidant-to-antibody molar ratio of 2:1 to 750:1, and chelate A chelating agent with a drug-to-antibody molar ratio of 1:420 to 8:1. C115. EGFR / LGR5 BsAb, pH 4-8.5, isotonic salt counter antibody Isotonic salts with a molar ratio of 7:1 to 3000:1, and sugar components with a molar ratio of 100:1 to 5 The sugar component has a molar ratio of 500:1, and the surfactant to antibody molar ratio is 1:11 to 17:1. The amino acid component has a molar ratio of 10:1 to 2500:1, and Antioxidants with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C116. EGFR / LGR5 BsAb, pH 4-8.5, isotonic salt counter antibody Isotonic salts with a molar ratio of 7:1 to 3000:1, and sugar components with a molar ratio of 100:1 to 5 The sugar component has a molar ratio of 500:1, and the surfactant to antibody molar ratio is 1:11 to 17:1. The amino acid component has a molar ratio of 10:1 to 2500:1, and A chelating agent in which the molar ratio of chelating agent to antibody is 1:420 to 8:1. C117. EGFR / LGR5 BsAb, pH 4-8.5, isotonic salt counter antibody Isotonic salts with a molar ratio of 7:1 to 3000:1, and sugar components with a molar ratio of 100:1 to 5 The sugar component has a molar ratio of 500:1, and the surfactant to antibody molar ratio is 1:11 to 17:1. Antioxidants and chelating agents having a molar ratio of antioxidant to antibody of 2:1 to 750:1 A chelating agent with a molar ratio of 1:420 to 8:1 against the antibody. C118. EGFR / LGR5 BsAb, pH 4-8.5, isotonic salt counter antibody Isotonic salts with a molar ratio of 7:1 to 3000:1, and sugar components with a molar ratio of 100:1 to 5 The molar ratio of sugar components, amino acid components to antibodies is 500:1, while the molar ratio is 10:1 to 2500:1. Antioxidants with amino acid components, antioxidant-to-antibody molar ratio of 2:1 to 750:1, and A chelating agent with a molar ratio of 1:420 to 8:1 between the chelating agent and the antibody. C119. EGFR / LGR5 BsAb, pH 4-8.5, isotonic salt counter antibody Isotonic salts with a molar ratio of 7:1 to 3000:1, and isotonic surfactants with a molar ratio of 1:11 to 1. The surfactant has a molar ratio of 17:1, and the amino acid component to antibody molar ratio is 10:1 to 2500:1. The amino acid components, antioxidants with a molar ratio of antioxidant to antibody of 2:1 to 750:1, and A chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C120. EGFR / LGR5 BsAb, pH 4-8.5, molar ratio of sugar component to antibody. The molar ratio of sugar component to surfactant to antibody is 1:11 to 17, with a ratio of 100:1 to 5500:1. A surfactant with a molar ratio of 1:1 to an amino acid component with an antibody molar ratio of 10:1 to 2500:1 Antioxidants with a molar ratio of 2:1 to 750:1, including amino acid components and antioxidants, and sharpness. A chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C121. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Surfactants and amino acid components with a surfactant-to-antibody molar ratio of 1:11 to 17:1 Amino acid components with a molar ratio of 10:1 to 2500:1, and the molar ratio of antioxidants to antibodies. Antioxidants with a ratio of 2:1 to 750:1. C122. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Surfactants and amino acid components with a surfactant-to-antibody molar ratio of 1:11 to 17:1 Amino acid components with a molar ratio of 10:1 to 2500:1, and chelating agent versus antibody molar Chelating agents with a ratio of 1:420 to 8:1. C123. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, The molar ratio of surfactant to antibody is 1:11 to 17:1. Antioxidants with a molar ratio of 2:1 to 750:1, and chelating agents with a molar ratio of 1:42 to 750:1. A chelating agent with a ratio of 0 to 8.1. C124. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Amino acid component to antibody molar ratio is 10:1 to 2500:1. Antioxidants with an antibody molar ratio of 2:1 to 750:1, and chelating agents with an antibody molar ratio of 2:1 to 750:1 Chelating agents with a ratio of 1:420 to 8:1. C125. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1:11 to 17:1, and a surfactant with a molar ratio of surfactant to antibody. Amino acid components and antioxidants, in which the molar ratio of amino acid component to antibody is 10:1 to 2500:1. Antioxidants and chelating agents with a molar ratio of 2:1 to 750:1 against antibodies, and molar ratio of antibodies against antibodies. A chelating agent with a ratio of 1:420 to 8:1. C126. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of sugar component to antibody of 100:1-5500: A sugar component with a molar ratio of 1:11 to 17:1, a surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, Amino acid components and antioxidants with a molar ratio of amino acid component to antibody of 10:1 to 2500:1 Antioxidants with a molar ratio of 2:1 to 750:1, and chelating agents with a molar ratio of 1 A chelating agent with a ratio of 420 to 8:1. C127. EGFR / LGR5 BsAb, pH 4-8.5, isotonic salt counter antibody Isotonic salts with a molar ratio of 7:1 to 3000:1, and sugar components with a molar ratio of 100:1 to 5 The sugar component has a molar ratio of 500:1, and the surfactant to antibody molar ratio is 1:11 to 17:1. Amino acid components and antibody with a molar ratio of 10:1 to 2500:1, antimicrobial agents, amino acid components, antibody Antioxidants and chelating agents with a molar ratio of 2:1 to 750:1 A chelating agent with a ratio of 1:420 to 8:1. C128. EGFR / LGR5 BsAb, buffer system vs. antibody molar ratio of 4:1 to 10⁵ A buffer system with a 0:1 ratio, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000: A salt isotonic agent with a molar ratio of 1 to 5500:1 of sugar components versus antibodies, Surfactants and amino acid components with a surfactant-to-antibody molar ratio of 1:11 to 17:1 The molar ratio of amino acids is 10:1 to 2500:1, and the molar ratio of antioxidants to antibodies is 2: Antioxidant molar ratio is 1-750:1, and chelating agent molar ratio is 1-420-8:1. It is a chelating agent.

[0103] In C1-C128, it is written as EGFR / LGR5 BsAb, EGFR It includes two specific binding domains: a first binding domain that binds and a second binding domain that binds to LGR5. Sex antibodies, their functional portions, derivatives, or variants are preferably full-length IgG antibodies. include.

[0104] <Bispecific antibody> The pharmaceutical composition has a first binding domain that binds to EGFR and a second binding domain that binds to LGR5. A polyspecific antibody or preferably a bispecific antibody containing a binding domain, its functional portion or The derivative preferably has both anti-EGFR binding properties and anti-LGR5 binding properties. Contains heterozygous antibodies (BsAb) (EGFR / LGR5 BsAb).

[0105] EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific monoab. This is a clonal antibody (EGFR / LGR5 BsAb). b is preferably an anti-EGFR / anti-LGR5 heterodimer bispecific antibody. The / LGR5 BsAb is preferably a human monoclonal antibody. EGFR / LG R5 BsAb is preferably an IgG antibody. EGFR / LGR5 BsAb is Preferably, it is an IgG1 antibody. The EGFR / LGR5 BsAb is preferably full-length. It is an antibody. EGFR / LGR5 BsAb is preferably anti-EGFR / anti-LGR5 bi- This is a specific heterodimer IgG1 monoclonal antibody. EGFR / LGR5 BsAb Preferably, an anti-EGFR / anti-LGR5 bispecific heterodimer full-length human IgG1 monocle. This is a ronal antibody.

[0106] The bispecific antibody preferably binds to the extracellular portion of EGFR (or can bind to the extracellular portion). The (variable) domain and the second binding or variable domain that binds to the extracellular portion of LGR5 Includes. The EGFR / LGR5 antibodies described herein preferably have two variable domains. In other words, as described herein, one that binds to EGFR and another that binds to LGR5. It is a bispecific antibody that possesses certain properties.

[0107] The binding (or variable) domain that binds to human EGFR is preferably the one shown in Figure 1. At least the CDR3 sequence of MF3755's VH, or the V of MF3755 shown in Figure 1. The H CDR3 sequence and at most 3, preferably at most 2, preferably 1 or less amines This domain has a heavy chain variable region containing different CDR3 sequences with different no acids.

[0108] The binding (or variable) domain that binds to human EGFR is preferably the one shown in Figure 1. At least the CDR1, CDR2, and CDR3 sequences of the VH of MF3755, or many It has at most 3, preferably at most 2, and preferably at most 1 amino acid substitutions. Figure 1 shows the VH of MF3755, including the CDR1, CDR2, and CDR3 sequences. It is a domain that has a chain variable region.

[0109] The binding (or variable) domain that binds to human EGFR is preferably the one shown in Figure 1. The sequence of the VH chain of MF3755, or at most 15 elements relative to the VH chain of MF3755. Preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 1, 2 Having 3, 4, or 5 amino acid insertions, deletions, substitutions, or combinations thereof, The heavy chain variable region of MF3755, including the amino acid sequence of the VH chain shown in Figure 1, is present. It is.

[0110] The binding (or variable) domain that binds to human EGFR is preferably the one shown in Figure 1. At least the CDR3 sequence of VH of MF4280, or the V of MF4280 shown in Figure 1. The H CDR3 sequence and at most 3, preferably at most 2, preferably 1 or less amines This domain has a heavy chain variable region containing different CDR3 sequences with different no acids.

[0111] The binding (or variable) domain that binds to human EGFR is preferably the one shown in Figure 1. At least the CDR1, CDR2, and CDR3 sequences of the VH of MF4280, or many It has at most 3, preferably at most 2, and preferably at most 1 amino acid substitutions. Figure 1 shows the VH of MF4280, including the CDR1, CDR2, and CDR3 sequences. It is a domain that has a chain variable region.

[0112] The antibodies are preferably MF3370, MF3755, MF4280, as shown in Figure 1. Alternatively, the EGFR binding domain containing the heavy chain variable region (VH) including the VH chain sequence of MF4289 In, or at most 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or This involves 10, preferably 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions. The following are combinations of these, as shown in Figure 1: MF3370, MF3755, MF428 EGFR linkage containing the heavy chain variable region (VH) including the VH chain sequence of 0 or MF4289 Includes combined domains.

[0113] The binding (or variable) domain that binds to human EGFR is preferably the one shown in Figure 1. The sequence of the VH chain of MF4280, or at most 15 elements relative to the VH chain of MF4280. Preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 1, 2 Having 3, 4, or 5 amino acid insertions, deletions, substitutions, or combinations thereof, The heavy chain variable region of MF4280, including the amino acid sequence of the VH chain shown in Figure 1, is present. It is.

[0114] In one embodiment, the present invention relates to a first binding domain that binds to EGFR and LGR5. A pharmaceutical composition comprising an antibody containing a second binding domain, wherein the heavy chain of the domain The variable region is MF3370, MF3755, MF4280, or MF as shown in Figure 1. At least one CDR3 of the EGFR-specific heavy chain variable region selected from a group of 4289 The column, or the heavy chain variable region of the domain, is MF3370, MF as shown in Figure 1. VH CD-R selected from the group consisting of 3755, MF4280, or MF4289 3 sequences and at most 3, preferably at most 2, preferably 1 or fewer amino acids are different The present invention provides a pharmaceutical composition comprising a heavy chain CDR3 sequence. The variable domain is preferably The small number of MF3370, MF3755, MF4280, or MF4289 shown in Figure 1 It contains a heavy chain variable region that includes the CDR3 sequence, if not the CDR3 sequence.

[0115] The binding (or variable) domain is preferably MF3370, MF as shown in Figure 1. EGFR specific selected from the group consisting of 3755, MF4280, or MF4289 The heavy chain variable region includes at least the CDR1, CDR2, and CDR3 sequences. The region, or MF3370, MF3755, MF4280, or MF4 shown in Figure 1. At least CDR1 and C of the EGFR-specific heavy chain variable region selected from a group of 289. DR2 and CDR3 sequences, and at most three, preferably at most two, preferably many It contains at least one different CDR1, CDR2, and CDR3 sequence. It includes a heavy chain variable region. The domain is preferably MF3370, M shown in Figure 1. F3755, MF4280, or MF4289 at least CDR1, CDR2, and It includes a heavy chain variable region containing the CDR3 sequence. The preferred heavy chain variable region is MF3755. Another preferred heavy chain variable region is MF4280.

[0116] Preferably, the pharmaceutical composition contains a first binding domain that binds to EGFR and LGR5. It contains an antibody having a second binding domain, the EGFR binding domain being CDR3, Having CDR1, CDR2, and CDR3, and / or as shown above in this specification The VH sequence is preferably MF5790, MF5803, MF5805 as shown in Figure 2. MF5808, MF5809, MF5814, MF5816, MF5817, or At least the CDR of the LGR5-specific heavy chain variable region selected from the group consisting of MF5818. 3 sequences, or MF5790, MF5803, MF5805, MF58 shown in Figure 2 08, MF5809, MF5814, MF5816, MF5817, or MF581 A VH CDR3 sequence selected from a group of 8, and at most 3, preferably at most A heavy chain CDR3 sequence containing two, preferably one or fewer, different amino acids, bound to LGR5. It has a variable domain. The binding or variable domain is preferably as shown in Figure 2. MF5790, MF5803, MF5805, MF5808, MF5809, MF58 14. Contains at least one CDR3 sequence of MF5816, MF5817, or MF5818 It includes a heavy chain variable region.

[0117] The LGR5 binding (or variable) domain is preferably MF5790 as shown in Figure 2. MF5803, MF5805, MF5808, MF5809, MF5814, MF581 6. LGR5-specific heavy chain selected from the group consisting of MF5817 or MF5818. At least the CDR1, CDR2, and CDR3 sequences of the variable region, or as shown in Figure 2. MF5790, MF5803, MF5805, MF5808, MF5809, MF581 4. LG selected from the group consisting of MF5816, MF5817, or MF5818. The CDR1, CDR2, and CDR3 sequences of the R5-specific heavy chain variable region, and at most three others. Preferably, at most two, preferably at most one, amino acids are different in the heavy chain CDR1,C The heavy chain variable region includes DR2 and CDR3 sequences. The domain is preferably, Figure 2 shows MF5790, MF5803, MF5805, MF5808, and MF580. 9. At least one CD of MF5814, MF5816, MF5817, or MF5818 Includes a heavy chain variable region containing R1, CDR2, and CDR3 sequences. Preferred heavy chain variable region This includes MF5790, MF5803, MF5814, MF5816, MF5817, or MF5818. Particularly preferred heavy chain variable regions are MF5790, MF5814, MF 5816, and MF5818, preferably MF5814, MF5818, and MF 5816 is preferred, and the heavy chain variable region MF5816 is particularly preferred. Another preferred heavy chain variable region It is MF5818.

[0118] Preferably, the antibodies are MF5790, MF5803, MF5805, M shown in Figure 2. F5808, MF5809, MF5814, MF5816, MF5817, or MF A sequence of 5818 VH chains, or at most 15, preferably 1, 2, 3, 4, 5, 6 7, 8, 9, or 10 amino acid insertions, preferably 1, 2, 3, 4, or 5 amino acids. MF5790, MF58 shown in Figure 2, which have deletions, substitutions, or combinations thereof. 03, MF5805, MF5808, MF5809, MF5814, MF5816, MF LG containing the heavy chain variable region, which includes the amino acid sequence of the VH chain of 5817 or MF5818 Includes R5 binding domain.

[0119] The VH chain of the variable domain that binds to EGFR or LGR5 is shown in Figure 1 or Figure 2. The sequence may have one or more amino acid substitutions. The VH chain is preferably, For the VH chain sequence in Figure 1 or Figure 2, there should be at most 15, preferably 1, 2, 3, 4, 5 , 6, 7, 8, 9, or 10, preferably 1, 2, 3, 4, or 5 amino acid inserts EGFR VH in Figure 1 or Figure 2, which has additions, deletions, substitutions, or combinations thereof. It has the amino acid sequence LGR5 VH.

[0120] Preferably, at most 15 of the referenced VH or VL as specified herein. pieces, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 pieces, preferably 1, 2 The three, four, or five amino acid substitutions are preferably conservative amino acid substitutions. The amino acid insertions, deletions, and substitutions in VH or VL specified in the details are preferably: It is not present in the CDR3 region. Furthermore, the amino acid insertions, deletions, and substitutions mentioned are... Preferably, it is not present in the CDR1 region and the CDR2 region. Also mentioned Amino acid insertions, deletions, and substitutions are preferably not present in the FR4 region.

[0121] At most 15 are mentioned, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, Alternatively, 10 amino acid substitutions, preferably 1, 2, 3, 4, or 5, are preferred. This is an ad-hoc amino acid substitution, and insertions, deletions, substitutions, or combinations thereof are preferably V It is not present in the CDR3 region of the H chain, and preferably also in the CDR1 region of the VH chain, and the CDR2 region. It is not present in the CDR3 region, and preferably not in the FR4 region.

[0122] Preferably, the pharmaceutical composition includes a variable domain that binds to the extracellular portion of EGFR and LG An antibody having a variable domain that binds to the extracellular portion of R5, preferably, - The amino acid sequence of VH chain MF3755 shown in Figure 1, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, The amino acids of the VH chain MF3755 shown in Figure 1, which have substitutions or combinations thereof. The VH chain of the variable domain, which contains the sequence and binds to LGR5, - The amino acid sequence of VH chain MF5790 shown in Figure 2, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, Amino acids of the VH chain MF5790 shown in Figure 2, which have substitutions or combinations thereof. Contains an antibody that includes a sequence.

[0123] Preferably, the pharmaceutical composition includes a variable domain that binds to the extracellular portion of EGFR and LG An antibody having a variable domain that binds to the extracellular portion of R5, preferably, - The amino acid sequence of VH chain MF3755 shown in Figure 1, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, The amino acids of the VH chain MF3755 shown in Figure 1, which have substitutions or combinations thereof. The VH chain of the variable domain, which contains the sequence and binds to LGR5, - The amino acid sequence of VH chain MF5816 shown in Figure 2, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, The amino acids of VH chain MF5816 shown in Figure 2, which have substitutions or combinations thereof. Contains an antibody that includes a sequence.

[0124] Preferably, the pharmaceutical composition includes a variable domain that binds to the extracellular portion of EGFR and LG An antibody having a variable domain that binds to the extracellular portion of R5, preferably, - The amino acid sequence of VH chain MF3755 shown in Figure 1, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, The amino acids of the VH chain MF3755 shown in Figure 1, which have substitutions or combinations thereof. The VH chain of the variable domain, which contains the sequence and binds to LGR5, - The amino acid sequence of VH chain MF5818 shown in Figure 2, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, The amino acids of the VH chain MF5818 shown in Figure 2, which have substitutions or combinations thereof. Contains an antibody that includes a sequence.

[0125] Preferably, the pharmaceutical composition includes a variable domain that binds to the extracellular portion of EGFR and LG An antibody having a variable domain that binds to the extracellular portion of R5, preferably, - The amino acid sequence of VH chain MF4280 shown in Figure 1, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, Amino acids of the VH chain MF4280 shown in Figure 1, having substitutions or combinations thereof. The VH chain of the variable domain, which contains the sequence and binds to LGR5, - The amino acid sequence of VH chain MF5790 shown in Figure 2, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, Amino acids of the VH chain MF5790 shown in Figure 2, which have substitutions or combinations thereof. Contains an antibody that includes a sequence.

[0126] Preferably, the pharmaceutical composition includes a variable domain that binds to the extracellular portion of EGFR and LG An antibody having a variable domain that binds to the extracellular portion of R5, preferably, - The amino acid sequence of VH chain MF4280 shown in Figure 1, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, Amino acids of the VH chain MF4280 shown in Figure 1, having substitutions or combinations thereof. The VH chain of the variable domain, which contains the sequence and binds to LGR5, - The amino acid sequence of VH chain MF5816 shown in Figure 2, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, The amino acids of VH chain MF5816 shown in Figure 2, which have substitutions or combinations thereof. Contains an antibody that includes a sequence.

[0127] Preferably, the pharmaceutical composition includes a variable domain that binds to the extracellular portion of EGFR and LG An antibody having a variable domain that binds to the extracellular portion of R5, preferably, - The amino acid sequence of VH chain MF4280 shown in Figure 1, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, Amino acids of the VH chain MF4280 shown in Figure 1, having substitutions or combinations thereof. The VH chain of the variable domain, which contains the sequence and binds to LGR5, - The amino acid sequence of VH chain MF5818 shown in Figure 2, or - At most 15 relative to VH, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, The amino acids of the VH chain MF5818 shown in Figure 2, which have substitutions or combinations thereof. Contains an antibody that includes a sequence.

[0128] VH / VL EGFR / LGR5 antibody light chain responsiveness of EGFR and LGR5 variable domains The variable domains may be the same or they may be different.

[0129] The antibody preferably includes a light chain variable region (VL) containing the VL chain sequence shown in Figure 3. Binding domains, or at most 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 , or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions, deletions, or placements. Light chain variable regions containing the VL chain sequence shown in Figure 3, which have substitutions or combinations thereof. Includes a binding domain containing (VL).

[0130] The antibody is preferably CDR1, CDR2, and / or of the VL chain shown in Figure 3. A binding domain containing the CDR3 amino acid sequence, or at most 15, preferably 1 or 2. 3, 4, 5, 6, 7, 8, 9, or 10, preferably 1, 2, 3, 4, or 5 VL as shown in Figure 3, which has a number of amino acid insertions, deletions, substitutions, or combinations thereof. The binding domain containing the CDR1, CDR2, and / or CDR3 amino acid sequences of the chain include.

[0131] The antibody preferably has a light chain constant region (CL) containing the CL chain sequence shown in Figure 3, and There are at most 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Preferably, 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or similar combinations. It includes a light chain constant region (CL) containing the CL chain sequence shown in Figure 3, having the combination of the above.

[0132] In some embodiments, the VH / VL EGFR variable domain of the EGFR / LGR5 antibody The VL region is similar to the VL region of the VH / VL LGR5 variable domain. In this embodiment, the VL regions of the first and second VH / VL variable domains are identical.

[0133] In certain embodiments, one or both EGFR / LGR5 antibodies are VH / VL variable. The light chain variable region of the domain includes a common light chain variable region. In some embodiments, one or The common light chain variable region of both VH / VL variable domains is the germline IgVκ1-39 variable region. Includes the V segment of the region. In certain embodiments, one or both VH / VL variable domains The variable region of the light chain of IgV includes the kappa light chain V segment IgVκ1~39*01. κ1-39 are abbreviations for the immunoglobulin variable kappa1-39 genes. These genes are Also known as immunoglobulin kappa variable 1-39, IGKV139, and IGKV1-39. The external IDs for this gene are HGNC:5740 and Entrez Gene:28. 930, Ensembl:ENSG00000242371. Suitable V region mesh The no-acid sequence is provided in Figure 2. The V region can be combined with one of the five J regions. Yes, it is possible. The preferred J regions are jk1 and jk5, and the joined sequence is IGKV1~ These are shown as 39 / jk1 and IGKV1~39 / jk5, with alternative names being IgVκ1~ It is either 39*01 / IGJκ1*01 or IgVκ1~39*01 / IGJκ5*01. (The naming convention follows that of the IMGT database World Wide Web at imgt.org) In certain embodiments, the light chain variable region of one or both VH / VL variable domains This is the kappa light chain IgVκ1~39*01 / IGJκ1*01 or IgVκ1~39*0 It includes 1 / IGJκ1*05 (shown in Figure 3).

[0134] In some embodiments, one or both of the EGFR / LGR5 bispecific antibodies are used for VH / VL The variable domain's light chain variable region contains the amino acid sequence QSISSY (shown in Figure 3) LCD R1, LCDR2 including amino acid sequence AAS (shown in Figure 3), and amino acid sequence QQS Includes LCDR3, which includes YSTP (shown in Figure 3) (i.e., IGKV compliant with IMGT) CDRs 1-39). In some embodiments, one or both of the EGFR / LGR5 antibodies are used. The light chain variable region of the VH / VL variable domain is the amino acid sequence QSISSY (shown in Figure 3). LCDR1 contains, LCDR2 contains the amino acid sequence AASLQS (shown in Figure 3), and It contains LCDR3, which includes the mino acid sequence QQSYSTP (shown in Figure 3).

[0135] In some embodiments, the EGFR / LGR5 antibody has the amino acid sequence shown in Figure 3, and a small amount At least 90%, preferably at least 95%, more preferably at least 97%, and more Preferably at least 98%, more preferably at least 99%, identical, or 1 It includes a light chain variable region containing an amino acid sequence that is 00% identical. In some embodiments, EGF The R / LGR5 antibody has the amino acid sequence shown in Figure 3, and at least 90%, preferably a small amount. At least 95%, more preferably at least 97%, more preferably at least 98%, More preferably, amino acid sequences that are at least 99% identical or 100% identical. Includes a light chain variable region.

[0136] For example, in some embodiments, the EGFR / LGR5 antibody is 0- Ten, preferably 0 to 5, amino acid insertions, deletions, substitutions, additions, or combinations thereof. It may have one or both of the EGFR / LGR5 antibodies. The light chain variable region of the / VL variable domain has 0 to 9 amino acids relative to the shown amino acid sequence, and 0 to 8 pieces, 0-7 pieces, 0-6 pieces, 0-5 pieces, 0-4 pieces, preferably 0-3 pieces, preferably 0- Two, preferably 0 to 1, preferably 0 amino acid insertions, deletions, substitutions, additions, or This includes combinations of those.

[0137] In other embodiments, the light chain variable region of the EGFR / LGR5 antibody is the sequence shown in Figure 3. Includes amino acid sequence. In certain embodiments, the EGFR / LGR5 antibody is the same VL region. Includes the region. In one embodiment, the EGFR / LGR5 bispecific antibody is the amino acid shown in Figure 3. Contains acid sequences.

[0138] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755 or MF4280, LGR5 variable heavy chain MF5790, MF58 shown in Figure 2 16 or MF5818, variable light chain (VL) shown in Figure 3, steady light chain shown in Figure 3 ( CL), CH1 domain sequence shown in Figure 4, hinge sequence shown in Figure 4, and shown in Figure 4 The CH2 domain sequence, the CH3-DE domain sequence shown in Figure 4, and the sequence shown in Figure 4 This is a bispecific anti-EGFR / anti-LGR5 antibody containing the CH3-KK domain sequence. A specific anti-EGFR / anti-LGR5 bispecific antibody is preferably as described in the attached claims. Any aspect of the invention as defined in the Specified Description, and / or any aspect of the invention as defined herein It is combined with any of the embodiments. This particular anti-EGFR / anti-LGR5 dual feature The isoantibodies are preferably embodiments A1-A127, B1-B128, C1-C128, D1~D36, E1~E16, F1~F16, G1~G16, H1~H12, I1~I1 6, J1~J24, K1~K32, L1~L64, M1~M1080 and N1~N26 It is combined with any of 86. More preferably, the pharmaceutical composition of this disclosure is about 20 mg This specific anti-EGFR / anti-LGR5 bispecific antibody contains approximately 10 mM histidine buffer at a concentration of / ml. Liquid; approximately 280 mM sucrose; approximately 0.5 mg / mL polysorbate 80; and water Contains or essentially consists of; the composition is 5.8-6.0, preferably about 5.9 It has a pH.

[0139] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM histidine buffer; approximately 280 mM sucrose; approximately 0.5 mg / mL Polysorbate 80; and water, or essentially composed of it; composition 5.8 It has a pH of ~6.0, preferably about 5.9.

[0140] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 15 mM sodium citrate buffer; approximately 270 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 6.7 to 6.9, preferably about 6.8.

[0141] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM histidine buffer; approximately 290 mM maltose; approximately 0.2 mg / mL phosphate Resorbate 80; and water, or essentially composed of it; composition 6.2~ It has a pH of 6.4, preferably about 6.3.

[0142] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM citrate-phosphate buffer; approximately 290 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 6.9 to 7.1, preferably about 7.0.

[0143] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM sodium succinate buffer; approximately 280 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 5.5 to 5.7, preferably about 5.6.

[0144] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM histidine buffer; approximately 280 mM sucrose; approximately 0.5 mg / mL Polysorbate 80; and water, or essentially composed of it; composition 5.8 It has a pH of ~6.0, preferably about 5.9.

[0145] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM histidine buffer; approximately 280 mM sucrose; approximately 0.5 mg / mL Polysorbate 80; and water, or essentially composed of it; composition 5.8 It has a pH of ~6.0, preferably about 5.9.

[0146] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM histidine buffer; approximately 280 mM sucrose; approximately 0.5 mg / mL Polysorbate 80; and water, or essentially composed of it; composition 5.8 It has a pH of ~6.0, preferably about 5.9.

[0147] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 15 mM sodium citrate buffer; approximately 270 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 6.7 to 6.9, preferably about 6.8.

[0148] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM histidine buffer; approximately 290 mM maltose; approximately 0.2 mg / mL phosphate Resorbate 80; and water, or essentially composed of it; composition 6.2~ It has a pH of 6.4, preferably about 6.3.

[0149] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM citrate-phosphate buffer; approximately 290 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 6.9 to 7.1, preferably about 7.0.

[0150] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM sodium succinate buffer; approximately 280 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 5.5 to 5.7, preferably about 5.6.

[0151] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. It is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferred Or, the attached claims, any aspect of the invention as defined herein, and / or in combination with any embodiment of the invention as defined herein This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably, in the embodiment A1~A127, B1~B128, C1~C128, D1~D36, E1~E16, F1 ~F16, G1~G16, H1~H12, I1~I16, J1~J24, K1~K32, It is combined with one of the following: L1-L64, M1-M1080, or N1-N2686. More preferably, the pharmaceutical composition of this disclosure contains about 20 mg / ml of this particular anti-EGFR / anti-EGFR. LGR5 bispecific antibody, approximately 10 mM sodium citrate buffer; approximately 280 mM sodium citrate buffer. Rose; approximately 0.5 mg / mL of polysorbate 80; and water or this The composition is of high quality; it has a pH of 6.9 to 7.1, preferably about 7.0.

[0152] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. It is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferred Or, the attached claims, any aspect of the invention as defined herein, and / or in combination with any embodiment of the invention as defined herein This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably, in the embodiment A1~A127, B1~B128, C1~C128, D1~D36, E1~E16, F1 ~F16, G1~G16, H1~H12, I1~I16, J1~J24, K1~K32, It is combined with one of the following: L1-L64, M1-M1080, or N1-N2686. More preferably, the pharmaceutical composition of this disclosure contains about 20 mg / ml of this particular anti-EGFR / anti-EGFR. LGR5 bispecific antibody, approximately 10 mM sodium citrate buffer; approximately 280 mM sodium citrate buffer. Rose; approximately 0.5 mg / mL of polysorbate 80; and water or this The composition is of high quality; it has a pH of 6.9 to 7.1, preferably about 7.0.

[0153] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 15 mM sodium citrate buffer; approximately 270 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 6.7 to 6.9, preferably about 6.8.

[0154] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM histidine buffer; approximately 290 mM maltose; approximately 0.2 mg / mL phosphate Resorbate 80; and water, or essentially composed of it; composition 6.2~ It has a pH of 6.4, preferably about 6.3.

[0155] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM citrate-phosphate buffer; approximately 290 mM sucrose; approximately 0.2 mg / mL of polysorbate 80; and water, or essentially consisting of it; the composition is It has a pH of 6.9 to 7.1, preferably about 7.0.

[0156] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM sodium succinate buffer; approximately 280 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 5.5 to 5.7, preferably about 5.6.

[0157] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM histidine buffer; approximately 280 mM sucrose; approximately 0.5 mg / mL Polysorbate 80; and water, or essentially composed of it; composition 5.8 It has a pH of ~6.0, preferably about 5.9.

[0158] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. It is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferred Or, the attached claims, any aspect of the invention as defined herein, and / or in combination with any embodiment of the invention as defined herein This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably, in the embodiment A1~A127, B1~B128, C1~C128, D1~D36, E1~E16, F1 ~F16, G1~G16, H1~H12, I1~I16, J1~J24, K1~K32, It is combined with one of the following: L1-L64, M1-M1080, or N1-N2686. More preferably, the pharmaceutical composition of this disclosure contains about 20 mg / ml of this particular anti-EGFR / anti-EGFR. LGR5 bispecific antibody, approximately 10 mM sodium citrate buffer; approximately 280 mM sodium citrate buffer. Rose; approximately 0.5 mg / mL of polysorbate 80; and water or this The composition is of high quality; it has a pH of 6.9 to 7.1, preferably about 7.0.

[0159] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. It is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferred Or, the attached claims, any aspect of the invention as defined herein, and / or in combination with any embodiment of the invention as defined herein This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably, in the embodiment A1~A127, B1~B128, C1~C128, D1~D36, E1~E16, F1 ~F16, G1~G16, H1~H12, I1~I16, J1~J24, K1~K32, It is combined with one of the following: L1-L64, M1-M1080, or N1-N2686. More preferably, the pharmaceutical composition of this disclosure contains about 20 mg / ml of this particular anti-EGFR / anti-EGFR. LGR5 bispecific antibody, approximately 15 mM sodium citrate buffer; approximately 270 mM sodium citrate buffer. Rose; approximately 0.2 mg / mL of polysorbate 80; and water or this The composition has a pH of 6.7 to 6.9, preferably about 6.8.

[0160] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM histidine buffer; approximately 290 mM maltose; approximately 0.2 mg / mL phosphate Resorbate 80; and water, or essentially composed of it; composition 6.2~ It has a pH of 6.4, preferably about 6.3.

[0161] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM citrate-phosphate buffer; approximately 290 mM sucrose; approximately 0.2 mg / mL of polysorbate 80; and water, or essentially consisting of it; the composition is It has a pH of 6.9 to 7.1, preferably about 7.0.

[0162] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5816 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM sodium succinate buffer; approximately 280 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 5.5 to 5.7, preferably about 5.6.

[0163] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 4280, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. It is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferred Or, the attached claims, any aspect of the invention as defined herein, and / or in combination with any embodiment of the invention as defined herein This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably, in the embodiment A1~A127, B1~B128, C1~C128, D1~D36, E1~E16, F1 ~F16, G1~G16, H1~H12, I1~I16, J1~J24, K1~K32, It is combined with one of the following: L1-L64, M1-M1080, or N1-N2686. More preferably, the pharmaceutical composition of this disclosure contains about 20 mg / ml of this particular anti-EGFR / anti-EGFR. LGR5 bispecific antibody, approximately 10 mM sodium citrate buffer; approximately 280 mM sodium citrate buffer. Rose; approximately 0.5 mg / mL of polysorbate 80; and water or this The composition is of high quality; it has a pH of 6.9 to 7.1, preferably about 7.0.

[0164] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. It is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferred Or, the attached claims, any aspect of the invention as defined herein, and / or in combination with any embodiment of the invention as defined herein This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably, in the embodiment A1~A127, B1~B128, C1~C128, D1~D36, E1~E16, F1 ~F16, G1~G16, H1~H12, I1~I16, J1~J24, K1~K32, It is combined with one of the following: L1-L64, M1-M1080, or N1-N2686. More preferably, the pharmaceutical composition of this disclosure contains about 20 mg / ml of this particular anti-EGFR / anti-EGFR. LGR5 bispecific antibody, approximately 15 mM sodium citrate buffer; approximately 270 mM sodium citrate buffer. Rose; approximately 0.2 mg / mL of polysorbate 80; and water or this The composition has a pH of 6.7 to 6.9, preferably about 6.8.

[0165] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. It is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferred Or, the attached claims, any aspect of the invention as defined herein, and / or in combination with any embodiment of the invention as defined herein This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably, in the embodiment A1~A127, B1~B128, C1~C128, D1~D36, E1~E16, F1 ~F16, G1~G16, H1~H12, I1~I16, J1~J24, K1~K32, It is combined with one of the following: L1-L64, M1-M1080, or N1-N2686. More preferably, the pharmaceutical composition of this disclosure contains about 20 mg / ml of this particular anti-EGFR / anti-EGFR. LGR5 bispecific antibody, approximately 10 mM sodium citrate buffer; approximately 280 mM sodium citrate buffer. Rose; approximately 0.5 mg / mL of polysorbate 80; and water or this The composition is of high quality; it has a pH of 6.9 to 7.1, preferably about 7.0.

[0166] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM histidine buffer; approximately 290 mM maltose; approximately 0.2 mg / mL phosphate Resorbate 80; and water, or essentially composed of it; composition 6.2~ It has a pH of 6.4, preferably about 6.3.

[0167] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM citrate-phosphate buffer; approximately 290 mM sucrose; approximately 0.2 mg / mL of polysorbate 80; and water, or essentially consisting of it; the composition is It has a pH of 6.9 to 7.1, preferably about 7.0.

[0168] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM sodium succinate buffer; approximately 280 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 5.5 to 5.7, preferably about 5.6.

[0169] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5818 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM histidine buffer; approximately 280 mM sucrose; approximately 0.5 mg / mL Polysorbate 80; and water, or essentially composed of it; composition 5.8 It has a pH of ~6.0, preferably about 5.9.

[0170] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 15 mM sodium citrate buffer; approximately 270 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 6.7 to 6.9, preferably about 6.8.

[0171] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. It is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferred Or, the attached claims, any aspect of the invention as defined herein, and / or in combination with any embodiment of the invention as defined herein This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably, in the embodiment A1~A127, B1~B128, C1~C128, D1~D36, E1~E16, F1 ~F16, G1~G16, H1~H12, I1~I16, J1~J24, K1~K32, It is combined with one of the following: L1-L64, M1-M1080, or N1-N2686. More preferably, the pharmaceutical composition of this disclosure contains about 20 mg / ml of this particular anti-EGFR / anti-EGFR. LGR5 bispecific antibody, approximately 10 mM sodium citrate buffer; approximately 280 mM sodium citrate buffer. Rose; approximately 0.5 mg / mL of polysorbate 80; and water or this The composition is of high quality; it has a pH of 6.9 to 7.1, preferably about 7.0.

[0172] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM histidine buffer; approximately 290 mM maltose; approximately 0.2 mg / mL phosphate Resorbate 80; and water, or essentially composed of it; composition 6.2~ It has a pH of 6.4, preferably about 6.3.

[0173] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 5 mM citrate-phosphate buffer; approximately 290 mM sucrose; approximately 0.2 mg / mL of polysorbate 80; and water, or essentially consisting of it; the composition is It has a pH of 6.9 to 7.1, preferably about 7.0.

[0174] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM sodium succinate buffer; approximately 280 mM sucrose; approximately 0.2 mg Polysorbate 80 / mL; containing or essentially consisting of water; composition It has a pH of 5.5 to 5.7, preferably about 5.6.

[0175] EGFR / LGR5 BsAb is preferably the EGFR variable heavy chain MF shown in Figure 1. 3755, LGR5 variable heavy chain MF5790 shown in Figure 2, variable light chain (V) shown in Figure 3 L), the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, and shown in Figure 4. The hinge sequence, the CH2 domain sequence shown in Figure 4, and the CH3-DE domain sequence shown in Figure 4. The anti-EGFR / anti-LG sequence includes the main sequence and the CH3-KK domain sequence shown in Figure 4. This is an R5 bispecific antibody. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably This includes the attached claims, any aspect of the invention as defined herein, and / or This is combined with any embodiment of the invention as defined herein. The specific anti-EGFR / anti-LGR5 bispecific antibody is preferably one of embodiments A1 to A127, B 1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1~G 16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, M1 It is used in combination with either ~M1080 or N1~N2686. More preferably, The disclosed pharmaceutical composition contains approximately 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific anti- Body, approximately 10 mM histidine buffer; approximately 280 mM sucrose; approximately 0.5 mg / mL Polysorbate 80; and water, or essentially composed of it; composition 5.8 It has a pH of ~6.0, preferably about 5.9.

[0176] EGFR / LGR5 BsAb is preferably shown in Figures 5a, 5b, 5c, 5d, 5e, and Alternatively, the heavy chain sequence corresponding to 5f, or Figures 5a, 5b, 5c, 5d, 5e, or 5f Anti-EGFR containing a variant having at least 85% sequence identity with any of the sequences This is a bispecific antibody against LGR5. See the sequence in Figure 5a, 5b, 5c, 5d, 5e, or 5f. Antibodies having at least 88% sequence identity with any of the above are also included herein. Preferably Sequence identity is at least 92%, more preferably at least 93%, and even more preferably The sequences have at least 94 or 95% sequence identity.

[0177] Instead, EGFR / LGR5 BsAb is preferably as shown in Figures 5a, 5b, 5c. Heavy chain sequences corresponding to 5d, 5e, or 5f, and light chain sequences corresponding to Figure 3, or Combined with the sequence in Figure 3, the sequences in Figures 5a, 5b, 5c, 5d, 5e, or 5f The variant containing the anti-EGFR / anti-LG has at least 85% sequence identity with the other variant. This is an R5 bispecific antibody. Combined with the sequence in Figure 3, see Figures 5a, 5b, 5c, 5d, 5e. Antibodies having at least 88% sequence identity with either of the 5f sequences are also specified herein. It is included. Preferably, sequence identity is combined with the sequence in Figure 3, as shown in Figures 5a, 5b, and 5c. , one of the sequences 5d, 5e, or 5f, and at least 92%, more preferably less At least 93%, and more preferably at least 94 or 95%, the sequence identity is consistent. (Figure) When calculating the sequence identity of the sequence combinations in Figures 3 and 5, these sequences are full-length anti-EG The sequence is arranged to generate a bispecific antibody sequence for FR / anti-LGR5. Next, sequence identity is determined. This can be determined using the Vector NTI program mentioned herein. Cut.

[0178] In one embodiment, the pharmaceutical composition contains 1 to 150 mg / mL of EGFR / LGR5BsAb It includes. In one embodiment, the pharmaceutical composition contains 1 to 60 mg / mL of EGFR / LGR5 B Contains sAb. In one embodiment, the pharmaceutical composition contains 1 to 25 mg / mL of EGFR / LGR. 5. Contains BsAb. In one embodiment, the pharmaceutical composition contains 10-60 mg / mL of EGFR / Contains LGR5 BsAb. In one embodiment, the pharmaceutical composition contains 10 to 30 mg / mL Contains EGFR / LGR5 BsAb. In one embodiment, the pharmaceutical composition contains 15-25 mg It contains EGFR / LGR5 BsAb at a concentration of 20 ml / mL. In one embodiment, the pharmaceutical composition is 20 ml Contains g / mL of EGFR / LGR5 BsAb.

[0179] In one embodiment, the pharmaceutical composition contains 1 to 150 molecules that bind to both EGFR and LGR5. It contains a bispecific antibody in mg / mL. In one embodiment, the pharmaceutical composition contains 1 to 60 mg / mL It contains EGFR / LGR5 BSAB. In one embodiment, the pharmaceutical composition contains 1 to 25 mg Contains EGFR / LGR5 BSAB at a concentration of 10 / mL. In one embodiment, the pharmaceutical composition contains 10- The pharmaceutical composition contains 60 mg / mL of EGFR / LGR5 BsAb. In one embodiment, the pharmaceutical composition It contains 10-30 mg / mL of EGFR / LGR5 BSAB. In one embodiment, the pharmaceutical The composition contains 15-25 mg / mL of EGFR / LGR5 BSAB. In one embodiment... The pharmaceutical composition contains 20 mg / mL of EGFR / LGR5 BSAB.

[0180] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. , B1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1 ~G16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, It can be combined with any of the M1-M1080 and N1-N2686.

[0181] The pharmaceutical composition preferably comprises a first binding domain that binds to EGFR and LGR5. A bispecific antibody containing a second binding domain, in a concentration of 1-30 mg / mL, and its functional portion. 3–20 mM containing 1 / 20 ml of ml of 1 / 2 ml of 1 / 2 ml of 1 / 2 ml of 1 / 2 ml The buffer system, 200-400 mM sugar and / or sugar alcohol components, and 0.01 This is an aqueous composition containing a nonionic surfactant at a concentration of approximately 2 mg / mL, and the composition is described in sections 5.4-6. It has a pH of 4.

[0182] The pharmaceutical composition preferably comprises a first binding domain that binds to EGFR and LGR5. A bispecific antibody containing a second binding domain, at a concentration of 15-25 mg / mL, and its functional properties. 4-12 ml of a partial or derivative, histidine buffer and / or citrate buffer. A buffer system of M, 250-350 mM sucrose, and 0.1-1.5 mg / mL of porangium. This is an aqueous composition containing Resorbate 80, and the composition has a pH of 5.4 to 6.4.

[0183] The pharmaceutical composition preferably comprises a first binding domain that binds to EGFR and LGR5. A 20 mg / mL bispecific antibody containing a second binding domain, and its functional portion Or a derivative, 10 mM histidine buffer or citrate buffer, 280 mM sucrose Composition consists of 0.5 mg / mL of polysorbate 80 and water. The substance has a pH of 5.8 to 6.0.

[0184] The pharmaceutical composition preferably comprises a first binding domain that binds to EGFR and LGR5. A bispecific antibody containing a second binding domain, its functional moiety or derivative, and a buffer system. (or combination of buffer systems) The molar concentration ratio of the counter-antibody is 21:1 to 146:1, histidine A buffer system containing a buffer and / or citrate buffer, sugars and / or sugar alcohols Sugars and / or sugar alcohols with a molar concentration ratio of component to antibody of 1460:1 to 2920:1 The molar concentration ratio of the ion component and the nonionic surfactant versus antibody is 1:18 to 11:1. The composition contains a nonionic surfactant and has a pH of 5.4 to 6.4.

[0185] The pharmaceutical composition preferably comprises a first binding domain that binds to EGFR and LGR5. A bispecific antibody containing a second binding domain, its functional moiety or derivative, and a buffer system. (Or a combination of buffer systems) The molar concentration ratio of the antibody to the histidine is 29:1 to 88:1. Buffer system containing buffer and / or citrate buffer, molar concentration ratio of sucrose versus antibody Sucrose with a ratio of 1825:1 to 2555:1, and polysorbate 80 versus antibody The composition contains polysorbate 80 with a concentration ratio of 1:2 to 8.5:1, and the composition is 5.4 to 6. It has a pH of 4.

[0186] The pharmaceutical composition preferably comprises a first binding domain that binds to EGFR and LGR5. A bispecific antibody containing a second binding domain, its functional moiety or derivative, hist Histidine buffer system vs. sucrose antibody with a molar concentration ratio of 73:1 The molar concentration ratio of sucrose and polysorbate 80 versus antibody is 2040:1. 2.79:1 polysorbate 80, and water as needed. The composition has a pH of 5.8 to 6.0.

[0187] Preferably, the pharmaceutical composition of the present invention has a first binding domain that binds to EGFR and L The antibody contains a bispecific antibody that includes a second binding domain that binds to GR5, and the antibody is shown in Figure 1. The VH amino acid sequence of MF3370 and / or the VH amino acid sequence of MF5790 shown in Figure 2 It includes the amino acid sequence and the VL amino acid sequence shown in Figure 3. Preferably, the antibody is as shown in Figure 4. The CH1, hinge, CH2, and CH3-DE and CH3-KK amino acids shown are shown. Includes further arrays.

[0188] Preferably, the pharmaceutical composition of the present invention has a first binding domain that binds to EGFR and L The antibody contains a bispecific antibody that includes a second binding domain that binds to GR5, and the antibody is shown in Figure 1. The VH amino acid sequence of MF3755 and / or the VH amino acid sequence of MF5816 shown in Figure 2 It includes the amino acid sequence and the VL amino acid sequence shown in Figure 3. Preferably, the antibody is as shown in Figure 4. The CH1, hinge, CH2, and CH3-DE and CH3-KK amino acids shown are shown. Includes further arrays.

[0189] Preferably, the pharmaceutical composition of the present invention has a first binding domain that binds to EGFR and L The antibody contains a bispecific antibody that includes a second binding domain that binds to GR5, and the antibody is shown in Figure 1. The VH amino acid sequence of MF4280 and / or the VH amino acid sequence of MF5809 shown in Figure 2 It includes the amino acid sequence and the VL amino acid sequence shown in Figure 3. Preferably, the antibody is as shown in Figure 4. The CH1, hinge, CH2, and CH3-DE and CH3-KK amino acids shown are shown. Includes further arrays.

[0190] Preferably, the pharmaceutical composition of the present invention has a first binding domain that binds to EGFR and L The antibody contains a bispecific antibody that includes a second binding domain that binds to GR5, and the antibody is shown in Figure 1. The VH amino acid sequence of MF4289 and / or the VH amino acid sequence of MF5818 shown in Figure 2 It includes the amino acid sequence and the VL amino acid sequence shown in Figure 3. Preferably, the antibody is as shown in Figure 4. The CH1, hinge, CH2, and CH3-DE and CH3-KK amino acids shown are shown. Includes further arrays.

[0191] <Diluent> The pharmaceutical composition preferably includes a diluent. The composition contains one or more pharmaceutically acceptable substances. It may contain a diluent or a mixture thereof. However, most preferably The composition is an aqueous composition. Most preferably, the diluent is water, preferably water alone. Yes, it is. The water is preferably water for injection (WFI).

[0192] Preferably, the diluent is, for example, a diluent whose total weight percentage of all components is 100%. The remainder of the constituent components in any composition can be made in such a way. Preferably, Any concentration given herein with respect to any component of the product shall not be mixed with any other component. This represents the concentration of the component (preferably dissolved) in the diluted diluent.

[0193] The compositions of the present invention are preferably solutions and preferably (substantially or completely) particles. Or it does not contain precipitate.

[0194] However, in one embodiment, the pharmaceutical composition contains no water, or at most 10 Water by weight %, preferably at most 5% by weight water, preferably at most 2% by weight water, preferably It contains at most 1% by weight of water. Such embodiments include, for example, use It may be possible to reconstitute it before administration or (preferably short-term) storage. Preferably, water and / or other relevant diluents, such as intravenous fluids, such as physiological saline solution. (By addition) it may be a solid pharmaceutical composition or a lyophilized pharmaceutical composition. The dried formulation is reconstituted to obtain the aqueous pharmaceutical composition disclosed herein (e.g., as specified herein). It is possible to obtain whether the constituent components present or absent at the given concentration.

[0195] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. , B1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1 ~G16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, It can be combined with any of the M1-M1080 and N1-N2686.

[0196] <Buffer system> The pharmaceutical composition preferably includes a buffer system. The buffer system preferably contains a small amount of (strong) acid or Even if a (strong) base is added to the pharmaceutical composition (or potentially one of the components of the pharmaceutical composition), One or more, possibly produced internally as a result of the degradation of that antibody, pH It acts as a pH buffer that creates inertia against change. Therefore, a buffer system is preferable. Alternatively, the pH of the composition can be kept substantially constant over time, and in doing so, the pH can be induced. Reduces the biodegradation pathway. Preferably, the pharmaceutical composition is stored under the same conditions at 2-8°C. Preferably, the pH should be 0.5 pH to resist pH changes of 1 pH unit or more during storage for 6 months. To resist pH changes of more than one unit, most preferably a pH change of 0.2 pH units or more. It is well buffered to resist.

[0197] Preferably, the composition contains a buffer (or buffer system), preferably a conjugate acid of the buffer / It is a buffer solution whose pH is stabilized when combined with a base. Therefore, biopharmaceutical compounds The product preferably contains a buffer as specified herein. Preferably, the composition contains a conjugate acid / The buffer further contains a base, wherein the conjugate acid / base is the buffer itself, or Depending on whether it is an acid, it corresponds to the conjugate acid or conjugate base of the buffer. Buffer and its conjugate Acids / bases can be collectively considered as a "buffer system." Therefore, the composition is preferably This includes a "buffer system" (preferably containing a buffering agent and its conjugate acid / base), and relating to the buffer system Any concentrations specified therein generally refer to the buffer and all of its conjugate acids / Regarding the total concentration of bases. Any "buffer system" preferably includes a weak acid and a weak base. (See the definition above.)

[0198] Preferably, the composition contains a conjugate acid / base of the buffer. The buffer system comprises the buffer and its conjugate acid / base. It consists of an acid / base combination. Preferably, the composition contains a buffer and The conjugate acid / base of the two must be at a level sufficient to provide the desired pH in the composition (i.e., absolute). Buffers and their corresponding components exist in both quantity and relative amounts (or concentrations). It contains a conjugate acid / base. The buffer system is formed by simply mixing the buffer and its conjugate acid / base. Alternatively, a buffer and a desired mixture of conjugate acid / base may be formed in To form situ, an acid or base is used as a buffer or either of its conjugate acids / bases. It may be formed by mixing. For example, the buffer system may be an acetate buffer (e.g., sodium acetate (Lium) and its conjugate acid / base (i.e., acetic acid) are preferably used to yield the desired pH. It may be formed simply by mixing in the appropriate ratio. Alternatively, the buffer system may be a base ( For example, sodium hydroxide is used as the conjugate acid / base (e.g., acetic acid) of the acetate buffer, preferably The desired pH as well as a buffer (e.g., sodium acetate) and the corresponding conjugate acid / base ( That is, it may be formed by adding an appropriate amount to produce a mixture of acetic acid. More preferably, in order to obtain a histidine buffer system, the desired pH and buffering agent are preferably Add an appropriate amount of acid (especially HCl or histidine HCl) to the mixture to obtain histidine It contains a histidine buffer system formed by adding it to. Instead, the buffer system Any method may be used to form it, and a further acid (preferably HCl, etc.) may be used. Either a strong acid or a further base (preferably a strong base such as sodium hydroxide) The pH may be carefully adjusted by adding the following. Preferably, the formulation of the present invention contains histamine. Tizidine-acetate buffer is not included.

[0199] The buffer system is preferably a buffer system comprising one or more buffers. Alternatively, it is a buffer system containing at most one buffer. Preferably, the buffer system is a double buffer system. (For example, a phosphate-citrate buffer.) However, in some embodiments, Pharmaceutical compositions include buffer systems (or any buffer systems specifically mentioned herein). A pharmaceutical composition can be characterized by the absence of one or more of the following: For example, if the antibody provides sufficient self-buffering, it is sufficiently stable even without a buffer. Obtain. This preferably occurs with higher concentrations of antibody.

[0200] The buffer system is preferably an inorganic buffer (e.g., ammonium buffer, bicarbonate buffer, Carbonate buffers, borate buffers, phosphate buffers), organic buffers (e.g., carboxylates) Buffers, organic ammonium buffers, alkanol ammonium buffers, zwitterionic buffers (Solutions, amino acid buffers, aromatic nitrogen buffers, sugar buffers), and any combination thereof It is a buffer system that is selected from among others.

[0201] The buffering system is preferably an amphoteric buffering system (e.g., an amino acid buffering system, e.g., histidine). It exists, consists of, or includes.

[0202] The buffer system is preferably a monocarboxylate buffer system (e.g., acetate buffer, formate buffer). (Solution, lactate buffer, salicylate buffer, benzoate buffer) or consists of these. , or including it.

[0203] The buffer system is preferably a dicarboxylate buffer system (e.g., succinate buffer, malein). Acid buffer, malate buffer, fumarate buffer, tartrate buffer, adipine buffer It is a solution (hexanediate buffer), consists of the same, or contains the same.

[0204] The buffer system is preferably a tricarboxylate buffer system (e.g., a citrate buffer system). or consisting of or including it.

[0205] The buffer system is preferably a zwitterionic buffer system (e.g., amino acid buffer, zwitterionic Sulfonate buffer, for example, N-(2-acetamide)-2-aminoethanesulfonic acid ( ACES buffer, 2-aminoethanesulfonic acid (AES) buffer, N-(1,1-dimethyl (AM) 2-hydroxyethyl 3-amino-2-hydroxypropanesulfonic acid PSO) buffer, N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfone Acid (BES) buffer, 3-(cyclohexylamino)-propanesulfonic acid (CAPS) ) or consisting of or including it.

[0206] The buffer system is preferably an amino acid buffer system (e.g., histidine buffer, glycine buffer). Lysine buffer, glycylglycine buffer, N-[Tris(hydroxymethyl)-methicine Lu-glycine (tricine) buffer, glutamate buffer, aspar (aspar ate) buffer, N,N-bis(2-hydroxyethyl)-glycine (bicine) buffer , N-(2-acetamide)-iminodiacetic acid (ADA) buffer, or consisting of the same , or including it.

[0207] The buffer system is preferably an alkanolammonium buffer system (for example, aminomethylpropyl Panol (AMP) buffer, aminomethylpropanediol (AMPD) buffer, Tris (Hydroxymethyl)aminomethane (Tris) buffer, [bis-(2-hydroxyethyl) [Lu)-imino]-tris-(hydroxymethylmethane)(BIS-Tris) buffer, 1 ,3-Bis[tris(hydroxymethyl)-methylamino]propane(bis-trispro It is a buffer solution, consists of one, or contains one.

[0208] The buffering system is preferably a histidine buffering system, an acetate buffering system, a citrate buffering system, or succinate buffering system. Acid buffering system, phosphate buffering system, citrate-phosphate buffering system, tris buffering system, and so It is a buffer system selected from the group consisting of all combinations of these, or it consists of such a system, It includes that.

[0209] The buffer system is preferably a histidine buffer system (preferably a histidine-acetate buffer). (excluding), citrate buffering systems, and any combination thereof, selected from the group. It is an opposition system, consists of one, or contains one.

[0210] The buffering system is preferably a histidine buffering system, consists of one, or contains one. nothing.

[0211] The buffer system is preferably an acetate buffer system, consisting of, or containing an acetate buffer system.

[0212] The buffering system is preferably a citrate buffering system, consists of one, or contains one. nothing.

[0213] The buffering system is preferably a succinate buffering system, consists of one or contains one. nothing.

[0214] The buffering system is preferably a phosphate buffering system, consisting of, or containing a phosphate buffering system. .

[0215] The buffering system is preferably a citrate-phosphate buffering system, or consists of one such system. It includes that.

[0216] The buffering system is preferably a Tris buffering system, consisting of, or including a Tris buffering system. .

[0217] In one embodiment, the pharmaceutical composition contains a buffer system of 1 to 100 mM, particularly a histidine buffer system. In one embodiment, the pharmaceutical composition includes a buffer system of 2 to 70 mM. The pharmaceutical composition contains a buffer system of 3 to 50 mM. In one embodiment, the pharmaceutical composition contains a buffer system of 4 to 30 mM. It includes a buffer system of M. In one embodiment, the pharmaceutical composition includes a buffer system of 5 to 20 mM. In the application form, the pharmaceutical composition contains a buffer system of 5 to 14 mM. In one embodiment, the pharmaceutical composition It contains a 10 mM buffer system. In one embodiment, the pharmaceutical composition contains a 3-12 mM buffer system. Includes. In one embodiment, the pharmaceutical composition includes a 5 mM buffer system.

[0218] In one embodiment, the pharmaceutical composition has a molar ratio of buffer system versus antibody of 4:1 to 1050:1. It includes a buffer system. In one embodiment, the pharmaceutical composition has a buffer system versus antibody molar ratio of 14:1 to 52. It includes a buffer system with a 0:1 ratio. In one embodiment, the pharmaceutical composition has a buffer system versus antibody molar ratio of 7 It includes a buffer system with a ratio of 1 to 180:1. In one embodiment, the pharmaceutical composition is a buffer system counter antibody. This includes buffer systems with molar ratios of 20:1 to 90:1.

[0219] In one embodiment, the pharmaceutical composition, histidine buffer system, acetate buffer system, citrate buffer system succinate buffer system, phosphate buffer system, citrate-phosphate buffer system, tris buffer system, This includes a buffer system of 3–25 mM selected from the group consisting of all combinations thereof. In one embodiment, the pharmaceutical composition includes a histidine buffer system, an acetate buffer system, and a citrate buffer system. succinate buffer system, phosphate buffer system, citrate-phosphate buffer system, tris buffer system, This includes a buffer system of 3–12 mM selected from the group consisting of all combinations thereof.

[0220] In one embodiment, the pharmaceutical composition is selected from a histidine buffer system or a citrate buffer system. It contains a buffer system of 3 to 25 mM. In one embodiment, the pharmaceutical composition contains a histidine buffer system. Alternatively, it includes a 3-12 mM buffer system selected from citrate buffer systems.

[0221] In one embodiment, the pharmaceutical composition contains a 3-25 mM histidine buffer system. The pharmaceutical composition contains a 3-12 mM histidine buffer system. In one embodiment, the pharmaceutical composition The product contains a 5 mM histidine buffer system. In one embodiment, the pharmaceutical composition contains a 10 mM histidine buffer system. Includes a histidine buffer system.

[0222] In one embodiment, the pharmaceutical composition has a molar ratio of histidine buffer system versus antibody of 4:1 to 1050 It contains a histidine buffer system which is :1. In one embodiment, the pharmaceutical composition contains a histidine buffer system It includes a histidine buffer system with a molar ratio of 14:1 to 520:1 of the antibody against it. In one embodiment, The pharmaceutical composition is a histidine buffer system with a molar ratio of 7:1 to 180:1. It contains a buffer system. In one embodiment, the pharmaceutical composition has a molar ratio of histidine buffer system versus antibody of 2 It includes a histidine buffer system with a ratio of 0:1 to 90:1.

[0223] In one embodiment, the pharmaceutical composition contains a 3-25 mM acetate buffer system. The pharmaceutical composition contains a 3-12 mM acetate buffer system.

[0224] In one embodiment, the pharmaceutical composition has a molar ratio of acetate buffer system versus antibody of 4:1 to 1050:1 It contains an acetate buffer system. In one embodiment, the pharmaceutical composition is an acetate buffer system versus an antibody. It contains an acetate buffer system with a ratio of 14:1 to 520:1. In one embodiment, the pharmaceutical composition is Includes an acetate buffer system with an acetate buffer system-to-antibody molar ratio of 7:1 to 180:1. In this state, the pharmaceutical composition is an acetate buffer system with a molar ratio of 20:1 to 90:1. Includes a buffer system.

[0225] In one embodiment, the pharmaceutical composition contains a 3-25 mM citrate buffer system. The pharmaceutical composition contains a 3-12 mM citrate buffer system. In one embodiment, the pharmaceutical composition The product contains a 5 mM citrate buffer system. In one embodiment, the pharmaceutical composition contains a 10 mM citrate buffer system. Includes a citrate buffer system.

[0226] In one embodiment, the pharmaceutical composition has a molar ratio of citrate buffer system versus antibody of 4:1 to 1050 It contains a citrate buffer system which is 1:1. In one embodiment, the pharmaceutical composition contains a citrate buffer system It includes a citrate buffer system with a counter-antibody molar ratio of 14:1 to 520:1. In one embodiment, The pharmaceutical composition is a citrate buffer system with a molar ratio of 7:1 to 180:1. It contains a salt buffer system. In one embodiment, the pharmaceutical composition has a molar ratio of citrate buffer system to antibody of 2 Includes citrate buffer systems ranging from 0:1 to 90:1.

[0227] In one embodiment, the pharmaceutical composition contains a 3-25 mM succinate buffer system. The pharmaceutical composition contains a 3-12 mM succinate buffer system.

[0228] In one embodiment, the pharmaceutical composition has a molar ratio of succinate buffer system versus antibody of 4:1 to 1050. It contains a succinate buffer system which is 1. In one embodiment, the pharmaceutical composition contains a succinate buffer system It includes a succinate buffer system with a molar ratio of 14:1 to 520:1 of the counter-antibody. In one embodiment, The pharmaceutical composition is succinate, in which the molar ratio of succinate buffer system versus antibody is 7:1 to 180:1. It contains a salt buffer system. In one embodiment, the pharmaceutical composition has a molar ratio of succinate buffer system to antibody of 2 It includes succinate buffer systems with a ratio of 0:1 to 90:1.

[0229] In one embodiment, the pharmaceutical composition contains a 3-25 mM phosphate buffer system. The pharmaceutical composition contains a phosphate buffer system of 3 to 12 mM.

[0230] In one embodiment, the pharmaceutical composition has a molar ratio of phosphate buffer system versus antibody of 4:1 to 1050: It contains a phosphate buffer system, which is 1. In one embodiment, the pharmaceutical composition is a phosphate buffer system counter antibody. It includes a phosphate buffer system with a molar ratio of 14:1 to 520:1. In one embodiment, the pharmaceutical compound The product contains a phosphate buffer system with a molar ratio of phosphate buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition has a molar ratio of phosphate buffer system versus antibody of 20:1 to 90: It includes a phosphate buffer system of 1.

[0231] In one embodiment, the pharmaceutical composition contains a 3-25 mM citrate-phosphate buffer system. In one embodiment, the pharmaceutical composition contains a 3-12 mM citrate-phosphate buffer system.

[0232] In one embodiment, the pharmaceutical composition has a molar ratio of citrate-phosphate buffer system versus antibody of 4:1 It contains a citrate-phosphate buffer system with a ratio of ~1050:1. In one embodiment, the pharmaceutical composition This refers to citrate-phosphate buffer system with a molar ratio of 14:1 to 520:1. It contains a salt-phosphate buffer system. In one embodiment, the pharmaceutical composition is citrate-phosphate buffer system. It includes a citrate-phosphate buffer system with a molar ratio of system to antibody of 7:1 to 180:1. In the application form, the pharmaceutical composition has a molar ratio of citrate-phosphate buffer system versus antibody of 20:1 to 9 It includes a citrate-phosphate buffer system with a 0:1 ratio.

[0233] In one embodiment, the pharmaceutical composition contains a 3-25 mM Tris buffer system. The pharmaceutical composition contains a 3-12 mM Tris buffer system.

[0234] In one embodiment, the pharmaceutical composition has a molar ratio of Tris buffer system versus antibody of 4:1 to 1050: It contains a Tris buffer system, which is 1. In one embodiment, the pharmaceutical composition is a Tris buffer system counter antibody. It includes a Tris buffer system with a molar ratio of 14:1 to 520:1. In one embodiment, the pharmaceutical compound The product contains a Tris buffer system with a molar ratio of Tris buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition has a molar ratio of Tris buffer system versus antibody of 20:1 to 90: It includes the Tris buffer system, which is 1.

[0235] In one embodiment, the pharmaceutical composition yields a pH of 5.4 to 7.1, with a pH of 3 to 25 m. It contains a histidine buffer system of M. In one embodiment, the pharmaceutical composition is a composition of 5.7 to 6.5. It contains a 3-25 mM histidine buffer system that provides the pH.

[0236] In one embodiment, the pharmaceutical composition is provided with a 3-25 mM solution that yields a pH of 4-5.6 for the composition. Includes an acetate buffer system.

[0237] In one embodiment, the pharmaceutical composition yields a pH of 4.5 to 7.5 in a 3 to 25 ml solution. It contains a citrate buffer system of M. In one embodiment, the pharmaceutical composition is composed of 6 to 7.5 of the composition p It contains a 3-25 mM citrate buffer system that provides H. In one embodiment, the pharmaceutical composition is It contains a 3-25 mM citrate buffer system that results in a pH of 6.5-7.5 for the composition.

[0238] In one embodiment, the pharmaceutical composition is provided with a 3-25 mM solution that yields a pH of 4-6.6 of the composition. Includes succinate buffering system.

[0239] In one embodiment, the pharmaceutical composition yields a pH of 3 to 25 m², resulting in a composition pH of 5.8 to 8.1. Includes M phosphate buffer system

[0240] In one embodiment, the pharmaceutical composition is provided with a 3-25 mM solution that yields a pH of 4-7.1 for the composition. Includes a citrate-phosphate buffer system.

[0241] In one embodiment, the pharmaceutical composition is provided with a 3-25 mM solution that yields a pH of 7-8.6 for the composition. Includes the Tris buffer system.

[0242] The quantities and concentrations related to buffer systems should be specified for all buffer systems unless only a single buffer system is specified. This relates to the total volume and concentration of the buffer system. The concentration of the buffer system or any particular buffer system is... It can be replaced with a ratio.

[0243] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. , B1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1 ~G16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, It can be combined with any of the M1-M1080 and N1-N2686.

[0244] <ph> The pharmaceutical composition preferably has a pH of 4 to 8.5. The antibody in the pharmaceutical composition has a pH value It is resistant over a wide range and can maintain a moderate level of stability, but in particular, the present invention In some cases, in the presence of certain excipients or combinations thereof, a particular pH is particularly advantageous. be.

[0245] In one embodiment, the pharmaceutical composition has a pH of 4.5 to 7.5. The composition has a pH of 5.0 to 6.7. In one embodiment, the pharmaceutical composition has a pH of 5.4 to 6.0 It has a pH of 5.4 to 5.6. In form, the pharmaceutical composition has a pH of 5.8 to 6.0. In one embodiment, the pharmaceutical composition It has a pH of 5.9 to 6.1. In one embodiment, the pharmaceutical composition has a pH of 6.2 to 6.4. It has. In one embodiment, the pharmaceutical composition has a pH of 6 to 7.5. In one embodiment, the The pharmaceutical composition has a pH of 6.5 to 7.5. In one embodiment, the pharmaceutical composition has a pH of 6.8 to 7. It has a pH of 2.

[0246] In a preferred embodiment, the pharmaceutical composition has a pH of 5.4 to 6.5 and is histidine buffered. Includes a system. In another preferred embodiment, the pharmaceutical composition has a pH of 5.8 to 6.4 and It contains a stidine buffer system. In a more preferred embodiment, the pharmaceutical composition has a p of 5.8 to 6.0. It contains H and includes a histidine buffer system. In another preferred embodiment, the pharmaceutical composition is 6.2~ It has a pH of 6.4 and contains a histidine buffer system.

[0247] In a preferred embodiment, the pharmaceutical composition has a pH of 6 to 7.5 and a citrate buffer system. Includes. In another preferred embodiment, the pharmaceutical composition has a pH of 6.5 to 7.5 and contains citric acid. It includes an acid salt buffer system. In another preferred embodiment, the pharmaceutical composition has a pH of 6.8 to 7.2. and includes a citrate buffer system. In another preferred embodiment, the pharmaceutical composition is 6.9-7.1 It has a pH and contains a citrate buffer system.

[0248] In one embodiment, the buffer system has a pH of 4 to 8.5. It has a pH of 8.5. In one embodiment, the buffer system has a pH of 4.5 to 7.5. In the application configuration, the buffer system has a pH of 5.0 to 6.7. In one embodiment, the buffer system has a pH of 5.4 It has a pH of ~6.5. In one embodiment, the buffer system has a pH of 5.4~6.0. In one embodiment, the buffer system has a pH of 5.4 to 5.6. In another embodiment, the buffer system has a pH of 5. It has a pH of 8 to 6.4. In one embodiment, the buffer system has a pH of 5.8 to 6.0. In one embodiment, the buffer system has a pH of 5.9 to 6.1. In one embodiment, the buffer system has a pH of 6 It has a pH of 0.2 to 6.4.

[0249] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. , B1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1 ~G16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, It can be combined with any of the M1-M1080 and N1-N2686.

[0250] <Salt isotonic agent> The pharmaceutical composition preferably contains a salt isotonic agent (e.g., NaCl or other such salts), Preferably, a non-buffered isotonic agent (i.e., one that contributes to the overall tension to some extent) is used. Unlike buffer salts, this product may contain an isotonic agent that does not provide a pH buffering effect. In the context of the invention, the salt isotonic agent is used to adjust the weight osmolality of the pharmaceutical composition. This can be done, for example, by bringing the gravimetric osmolality within a preferred range (for example, in the case of isotonicity, for example). , 200-400 mOsmol / L, preferably 250-350 mOsmol / L, most Preferably, the gravimetric osmolality can be set to 270-310 mOsmol / L. The weight osmolality may not be as important for intravenous compositions as it is for subcutaneous compositions. Yes. Furthermore, salt isotonic agents improve the solubility of antibodies and / or other excipients in pharmaceutical compositions. It can be promoted. In addition, salt isotonic agents have a stabilizing effect on antibodies in pharmaceutical compositions. For example, improving three-dimensional stability (for example, potentially increasing the likelihood of final aggregation) (Reduction of protein unfolding events), reduction of aggregation, and / or fragmentation A reduction can be applied.

[0251] However, the pharmaceutical composition is (non-buffered) salt isotonic agent (or salt isotonic agent as described above). (One or more of the items specifically mentioned in the details are not present.) It can be marked. In particular, the pharmaceutical composition is characterized by the absence of sodium chloride. It can be marked, and most preferably is not present. Sodium chloride or salt isotonic agent is present. If not present, other components in the pharmaceutical composition such as sugar components, buffers, or other tonic components However, it may contribute to the tension of the composition.

[0252] The salt isotonic agent is preferably sodium chloride, potassium chloride, magnesium chloride, or chloride Isotonic salts selected from the group consisting of calcium, zinc chloride, or any combination thereof. It is a nitrifying agent, consists of them, or contains them. The salt isotonic nitrifying agent is preferably a chloride It is sodium, consists of sodium, or contains sodium. The salt isotonic agent is preferably, The salt isotonic agent is preferably potassium chloride, consisting of potassium chloride, or containing potassium chloride. The salt isotonic agent is preferably magnesium chloride, consisting of or containing magnesium chloride. Alternatively, it is calcium chloride, consists of it, or contains it. Salt isotonic agents are Preferably, it is zinc chloride, consists of, or contains zinc chloride.

[0253] In one embodiment, the pharmaceutical composition contains 3 to 200 mM of a salt isotonic agent. The pharmaceutical composition contains a 3-7 mM salt isotonic agent. In one embodiment, the pharmaceutical composition contains 5- It contains a 100 mM salt isotonic agent. In one embodiment, the pharmaceutical composition contains a 5-50 mM salt isotonic agent. It contains a tonifying agent. In one embodiment, the pharmaceutical composition contains 100 to 200 mM of a salt isotonic agent. In one embodiment, the pharmaceutical composition contains 130-170 mM of a salt isotonic agent. The pharmaceutical composition contains 140-160 mM of a salt isotonic agent. In one embodiment, the pharmaceutical composition The substance contains a salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1. In terms of application, the pharmaceutical composition has a molar ratio of salt isotonic agent to antibody of 21:1 to 1500:1. Contains a salt isotonic agent. In one embodiment, the pharmaceutical composition has a molar ratio of salt isotonic agent to antibody of 340 It contains a salt isotonic agent in a ratio of 1 to 2500. In one embodiment, the pharmaceutical composition is salt isotonic It contains a salt isotonic agent with a drug-to-antibody molar ratio of 900:1 to 1300:1.

[0254] In one embodiment, the pharmaceutical composition is sodium chloride, potassium chloride, magnesium chloride, Four selected from the group consisting of calcium chloride, zinc chloride, or any combination thereof. Contains ~160 mM salt isotonic agent. In one embodiment, the pharmaceutical composition contains 10~180 mM Contains sodium chloride.

[0255] In one embodiment, the pharmaceutical composition contains 50 to 170 mM sodium chloride. In this state, the pharmaceutical composition contains 140 to 160 mM sodium chloride. In one embodiment, The pharmaceutical composition is sodium chloride with an antibody molar ratio of 7:1 to 3000:1. Contains um. In one embodiment, the pharmaceutical composition has a molar ratio of sodium chloride to antibody of 21:1 It contains sodium chloride in a ratio of ~1500:1. In one embodiment, the pharmaceutical composition contains sodium chloride Contains sodium chloride with a molar ratio of lium to antibody of 340:1 to 2500:1. In terms of form, the pharmaceutical composition has a sodium chloride to antibody molar ratio of 900:1 to 1300:1. It contains a certain amount of sodium chloride. In one embodiment, the pharmaceutical composition is 200-400 mOsmo It contains sodium chloride at a concentration sufficient to produce a 1 / L composition. In one embodiment, The drug composition contains a concentration of chloride sufficient to produce a composition of 250-350 mOsmol / L. Contains sodium. In one embodiment, the pharmaceutical composition is 270-310 mOsmol / L It contains sodium chloride at a concentration sufficient to produce the composition.

[0256] The amount and concentration of salt isotonic agents shall be as follows, unless only a single salt isotonic agent is specified. The total amount and concentration of all salt isotonic agents. The salt isotonic agents or any specific The concentration of the salt isotonic agent can be expressed as a molar ratio.

[0257] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. , B1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1 ~G16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, It can be combined with any of the M1-M1080 and N1-N2686.

[0258] <Sugar component> The pharmaceutical composition preferably contains a sugar component, preferably a non-reducing sugar component. The sugar component can perform one or more roles within the pharmaceutical composition. For example, These can act as freeze-protectants during freeze-drying. Sugar components, for example, Tension can be imparted to bring the gravimetric osmolality within a desired range (e.g., For Zhang, for example, 200-400 mOsmol / L, more preferably 250-350 mO smol / L, most preferably 270-310 mOsmol / L (osmolality). Sugar Using components to contribute to tonicity is particularly desirable when high ionic strength is not desirable. It may be useful. Sugar components improve the solubility of antibodies and / or other excipients in pharmaceutical compositions. It can be promoted. In addition, sugar components have a stabilizing effect on antibodies in pharmaceutical compositions, for example. Furthermore, improved three-dimensional structural stability (for example, potentially increasing the likelihood of final aggregation) Reduction of protein unfolding events, reduction of aggregation, and / or reduction of fragmentation. It can bring about.

[0259] Preferably, the sugar component is a single compound. Preferably, the sugar component is one or more It is a sugar and / or sugar alcohol, consists of them, or contains them.

[0260] Preferably, the sugar component is one or more sugars, most preferably a single sugar (i.e., at most It consists of, contains, or contains only one sugar. Preferably, the sugar component is It is a sugar, consists of a sugar, or contains a sugar. Preferably, the sugar component is a monosaccharide, disaccharide, A sugar selected from the group consisting of polysaccharides and complex carbohydrates, or consisting of such sugars, It includes it. Preferably, the sugar component is a monosaccharide, consists of one, or contains one. Hmm. More preferably, the sugar component is a disaccharide, consists of a disaccharide, or contains a disaccharide. In short, the sugar components consist of sucrose, trehalose, maltose, and lactose. A disaccharide selected from the group, consisting of, or containing a disaccharide. Preferably, sugar The components are disaccharides selected from maltose, trehalose, and / or sucrose. It consists of, or includes, most preferably the sugar component is sucrose. It consists of, or includes.

[0261] Preferably, the sugar component is one or more sugar alcohols, or consists of them. or containing them. Preferably, the sugar component is a sugar alcohol or consists of a sugar alcohol. or containing thereof. Preferably, the sugar component is a (3-12C) sugar alcohol, or It consists of or contains the sugar component, preferably a (3-6C) sugar alcohol. It consists of, or contains, either the sugar component or (5-6C) sugar alcohol. Preferably, the sugar component is (5-6C) sugar alcohol. It is, consists of, or contains corn. Preferably, the sugar component is mannitol A sugar alcohol selected from or consisting of, or That includes it.

[0262] Most preferably, the sugar component is sucrose, consists of it, or contains it. Preferably, the sugar component is sucrose, and only sucrose. In certain embodiments The pharmaceutical composition is available in concentrations of 20-400 mM, 50-350 mM, 100-320 mM, and 170 mM. Sucrose in an amount of ~310 mM, or 220~320 mM, more preferably 250~3 Contains 00 mM sucrose. In certain embodiments, the pharmaceutical composition contains 275-295 mM It contains sucrose. Most preferably, the pharmaceutical composition contains 280 mM sucrose.

[0263] In certain embodiments, the pharmaceutical composition has a molar ratio of sugar components, particularly sucrose versus antibody, of 100. It contains sugar components in a ratio of 1 to 5500:1. In certain embodiments, the pharmaceutical composition contains sugar components in a ratio of 1 to 5500. It contains a sugar component with an antibody molar ratio of 300:1 to 2600:1. In certain embodiments, The drug composition contains a sugar component in which the molar ratio of sugar component to antibody is 600:1 to 4500:1. In a specific embodiment, the pharmaceutical composition has a molar ratio of sugar component to antibody of 1800:1 to 2200:1. It contains sugar components.

[0264] In certain embodiments, the pharmaceutical composition includes sucrose, trehalose, mannitol, and sol. From vitol, glucose, maltose, lactose, and any combination thereof. It contains 100-400 mM of sugar components selected from the group. In a specific embodiment, the pharmaceutical composition The substance is selected from the group consisting of sucrose, trehalose, mannitol, and sorbitol. It contains a selected sugar component of 100-400 mM. In a particular embodiment, the pharmaceutical composition is sucrose. Selected from the group consisting of rose, mannitol, sorbitol, and maltose, most It preferably contains a sugar component of 100-400 mM, which is sucrose.

[0265] In certain embodiments, the pharmaceutical composition contains 150 to 350 mM sucrose. In the embodiment, the pharmaceutical composition contains 250-300 mM sucrose. Specific Embodiment The pharmaceutical composition contains 280 mM sucrose. In a particular embodiment, the pharmaceutical composition It contains 290 mM sucrose. In certain embodiments, the pharmaceutical composition contains sucrose versus It contains sucrose with an antibody molar ratio of 100:1 to 5500:1. In certain embodiments, The pharmaceutical composition is a sucrose with a molar ratio of sucrose to antibody of 300:1 to 2600:1. Contains sucrose. In certain embodiments, the pharmaceutical composition has a molar ratio of sucrose to antibody of 600:1 It contains sucrose in a ratio of ~4500:1. In certain embodiments, the pharmaceutical composition contains sucrose. Contains sucrose with a molar ratio of sucrose to antibody of 1800:1 to 2200:1.

[0266] In certain embodiments, the pharmaceutical composition contains 150 to 350 mM trehalose. In the embodiment, the pharmaceutical composition contains 250-300 mM trehalose. Specific implementation In this state, the pharmaceutical composition has a molar ratio of trehalose to antibody of 100:1 to 5500:1. Contains trehalose. In certain embodiments, the pharmaceutical composition is trehalose versus antibody molar ratio It contains trehalose in a ratio of 300:1 to 2600:1. In certain embodiments, the pharmaceutical composition The product contains trehalose with a trehalose-to-antibody molar ratio of 600:1 to 4500:1. In certain embodiments, the pharmaceutical composition has a molar ratio of trehalose versus antibody of 1800:1. It contains trehalose in a ratio of 2200:1. In many preferred embodiments, the sugar component is trehalose. In many preferred embodiments that do not use halos, the sugar component does not contain trehalose. In some preferred embodiments, the sugar component is concentrated to 99 mM or lower, as needed. Otherwise, it is neither trehalose nor does it contain trehalose.

[0267] In certain embodiments, the pharmaceutical composition contains 150-350 mM mannitol. In this embodiment, the pharmaceutical composition contains 250-300 mM mannitol. In terms of form, the pharmaceutical composition has a molar ratio of mannitol to antibody of 100:1 to 5500:1. It contains mannitol. In certain embodiments, the pharmaceutical composition contains mannitol versus antibody in moles. It contains mannitol in a ratio of 300:1 to 2600:1. In certain embodiments, the pharmaceutical compound The product is mannitol with a molar ratio of mannitol to antibody of 600:1 to 4500:1. Includes. In certain embodiments, the pharmaceutical composition has a molar ratio of mannitol to antibody of 1800:1 It contains mannitol at a ratio of approximately 2200:1.

[0268] In certain embodiments, the pharmaceutical composition contains 150 to 350 mM sorbitol. In this embodiment, the pharmaceutical composition contains 250-300 mM sorbitol. Specific implementation In terms of form, the pharmaceutical composition has a molar ratio of sorbitol to antibody of 100:1 to 5500:1. It contains sorbitol. In certain embodiments, the pharmaceutical composition contains sorbitol versus antibody in molar form. It contains sorbitol in a ratio of 300:1 to 2600:1. In certain embodiments, the pharmaceutical compound The product is sorbitol with a sorbitol-to-antibody molar ratio of 600:1 to 4500:1. Includes. In certain embodiments, the pharmaceutical composition has a sorbitol-to-antibody molar ratio of 1800:1 Contains sorbitol in a ratio of approximately 2200:1.

[0269] In certain embodiments, the pharmaceutical composition contains 150-350 mM glucose. In this embodiment, the pharmaceutical composition contains 250-300 mM glucose.

[0270] In certain embodiments, the pharmaceutical composition contains 150 to 350 mM maltose. In this embodiment, the pharmaceutical composition contains 250 to 300 mM maltose.

[0271] In certain embodiments, the pharmaceutical composition contains 150 to 350 mM lactose. In this embodiment, the pharmaceutical composition contains 250 to 300 mM lactose.

[0272] The amount and concentration of sugar components are all, unless only a single sugar component is specified. This relates to the total amount and concentration of sugar components. The concentration of the sugar component or any specific sugar component is This can be replaced with a molar ratio.

[0273] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. , B1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1 ~G16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, It can be combined with any of the M1-M1080 and N1-N2686.

[0274] <Surfactants> The pharmaceutical composition preferably contains a surfactant. The surfactant contains antibodies within the pharmaceutical composition. It can promote the dissolution of and / or other components. In the context of the present invention, the surfactant is This prevents aggregation of components present in the pharmaceutical composition.

[0275] However, in some embodiments, the pharmaceutical composition is a surfactant (or a surfactant). The absence of any one or more of the items specifically mentioned herein. It is characterized by the following.

[0276] Preferably, the surfactant is at most one surfactant, or consists of one surfactant, It includes that.

[0277] Preferably, the surfactant is a nonionic surfactant, or consists of one such nonionic surfactant, or It includes that. Preferably, the surfactant is an aliphatic alcohol, an aliphatic alcohol ether fatty acid esters, fatty acid amides, polyoxyalkylene alkyl ethers, polyoxy Ethylene alkyl ether, nonionic block copolymer, alpha-tocopherol A nonionic surfactant selected from the group consisting of , and any combination thereof. Or, consisting of or containing the same. Preferably, the surfactant is sorbitan ester. Span, ethoxylated sorbitan ester (polysorbate, Tween (registered) Selected from the group consisting of (also known as trademarks) and block alkoxylates It is a nonionic surfactant, consists of, or contains. Preferably, The surfactant is an ethoxylated fatty acid ester surfactant, or consists of one such surfactant, It includes that.

[0278] Preferably, the surfactant is polysorbate 20, polysorbate 80, or poloxamer. A surfactant selected from the group consisting of 188 and all combinations thereof, It consists of or contains the same. Preferably, the surfactant is polysorbate 20. A surfactant selected from the group consisting of polysorbate 80 and poloxamer 188. It is present, consists of, or contains. Preferably, the surfactant is polysorbate A surfactant selected from or consisting of T20 or polysorbate 80, or including it.

[0279] More preferably, the surfactant is polysorbate 20 or consists of the same, It includes that.

[0280] Preferably, the surfactant is poloxamer 188, or consists of the same, or This includes

[0281] Preferably, the surfactant is polysorbate 80, or consists of it, or It contains [this]. Preferably, the surfactant is polysorbate 80.

[0282] In one embodiment, the pharmaceutical composition contains 0.01 to 2 mg / mL of surfactant. In form, the pharmaceutical composition contains 0.05 to 1.5 mg / mL of surfactant. One embodiment The pharmaceutical composition contains 0.1 to 1.3 mg / mL of surfactant. In one embodiment, The pharmaceutical composition contains 0.1 to 0.6 mg / mL of surfactant. In one embodiment, the pharmaceutical composition The product contains 0.1 to 0.3 mg / mL of surfactant. In one embodiment, the pharmaceutical composition It contains 0.2 mg / mL of surfactant. In one embodiment, the pharmaceutical composition is 0.2 to 0. It contains 8 mg / mL of surfactant. In one embodiment, the pharmaceutical composition contains 0.4 to 0.6 mg It contains a surfactant at a concentration of / mL. In one embodiment, the pharmaceutical composition contains 0.5 mg / mL of surfactant. Contains a surfactant. In one embodiment, the pharmaceutical composition contains 0.4 to 1.2 mg / mL of surfactant. Includes. In one embodiment, the pharmaceutical composition contains 0.9 to 1.1 mg / mL of surfactant. In one embodiment, the pharmaceutical composition contains 1 mg / mL of surfactant.

[0283] In one embodiment, the pharmaceutical composition has a surfactant-to-antibody molar ratio of 1:11 to 17:1. It contains a surfactant. In one embodiment, the pharmaceutical composition has a surfactant to antibody molar ratio of 1: It contains a surfactant in a ratio of 4 to 9.1. In one embodiment, the pharmaceutical composition is a surfactant counter antibody. The compound contains a surfactant having a molar ratio of 1:1.5 to 7:1. In one embodiment, the pharmaceutical composition The product contains surfactants in which the molar ratio of surfactant to antibody is 2:1 to 4:1.

[0284] In one embodiment, the pharmaceutical composition is polysorbate 20, polysorbate 80, poloxa Selected from the group consisting of Mar 188 and all combinations thereof, 0.01 to 1.5 Contains a surfactant in mg / mL.

[0285] In one embodiment, the pharmaceutical composition contains 0.05 to 1.5 mg / mL of polysorbate 80. Includes. In one embodiment, the pharmaceutical composition contains 0.1 to 0.6 mg / mL of polysorbate 80. Includes. In one embodiment, the pharmaceutical composition contains 0.1 to 0.3 mg / mL of polysorbate 80. Includes. In one embodiment, the pharmaceutical composition contains 0.4 to 1.2 mg / mL of polysorbate 80. Includes. In one embodiment, the pharmaceutical composition contains 0.4 to 0.6 mg / mL of polysorbate 80. Includes. In one embodiment, the pharmaceutical composition contains 0.5 mg / mL of polysorbate 80. In this embodiment, the pharmaceutical composition contains 0.9 to 1.1 mg / mL of polysorbate 80. In one embodiment, the pharmaceutical composition contains 1 mg / mL of polysorbate 80. The pharmaceutical composition is a polysorbate 80 to antibody molar ratio of 1:11 to 17:1. Contains Polysorbate 80. In one embodiment, the pharmaceutical composition is molar of Polysorbate 80 versus antibody. It contains polysorbate 80 in a ratio of 1:4 to 9:1. In one embodiment, the pharmaceutical composition is Contains polysorbate 80 with a polysorbate 80 vs. antibody molar ratio of 1:1.5 to 7:1. In one embodiment, the pharmaceutical composition has a molar ratio of polysorbate 80 to antibody of 2:1 to 4: It contains polysorbate 80, which is 1 in concentration.

[0286] In one embodiment, the pharmaceutical composition contains 0.05 to 1.5 mg / mL of polysorbate 20. In one embodiment, the pharmaceutical composition contains 0.1 to 0.6 mg / mL of polysorbate 20. In one embodiment, the pharmaceutical composition contains 0.1 to 0.3 mg / mL of polysorbate 20. In one embodiment, the pharmaceutical composition contains 0.4 to 1.2 mg / mL of polysorbate 20. In one embodiment, the pharmaceutical composition contains 0.4 to 0.6 mg / mL of polysorbate 20. In one embodiment, the pharmaceutical composition contains 0.5 mg / mL of polysorbate 20. In the application form, the pharmaceutical composition contains 0.9 to 1.1 mg / mL of polysorbate 20. In the application form, the pharmaceutical composition contains 1 mg / mL of polysorbate 20. In one embodiment, The pharmaceutical composition is polysorbate with a molar ratio of 20 to antibody of 1:11 to 17:1. Contains β-20. In one embodiment, the pharmaceutical composition is polysorbate 20 versus antibody in molar ratio It contains polysorbate 20 in a ratio of 1:4 to 9:1. In one embodiment, the pharmaceutical composition is poly Includes polysorbate 20 with a polysorbate 20 vs. antibody molar ratio of 1:1.5 to 7:1. In one embodiment, the pharmaceutical composition has a molar ratio of polysorbate 20 to antibody of 2:1 to 4:1. It contains polysorbate 20, which is a surfactant. In many preferred embodiments, the surfactant is not necessary. Polysorbate 20 It is neither a polysorbate nor does it contain polysorbate 20.

[0287] In one embodiment, the pharmaceutical composition contains 0.05 to 1.5 mg / mL of poloxamer 188. Includes. In one embodiment, the pharmaceutical composition contains 0.7 to 1.3 mg / mL of poloxamer 188. Includes. In one embodiment, the pharmaceutical composition contains 0.9 to 1.1 mg / mL of poloxamer 18 It includes 8. In one embodiment, the pharmaceutical composition contains 1 mg / mL of poloxamer 188.

[0288] The amount and concentration of surfactants should be specified unless only a single surfactant is specified. This relates to the total amount and concentration of all surfactants. The surfactant or any specific The concentration of a surfactant can be expressed as a molar ratio.

[0289] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. This can be combined with any of B1-B128 and C1-C128. The embodiments and features disclosed in this section are preferably embodiments D1 to D36, E1 to E16, F1~F16, G1~G16, H1~H12, I1~I16, J1~J24, K Paired with any of the following: 1-K32, L1-L64, M1-M1080, and N1-N2686 They can be combined.

[0290] <Antioxidants> The pharmaceutical composition may preferably contain an antioxidant. However, the most preferred is In one embodiment, the pharmaceutical composition is an antioxidant (or an antioxidant as specifically referred to herein). It is characterized by the absence of one or more of the things that are present. Antioxidants inhibit oxidative degradation pathways that antibodies and / or other components in pharmaceutical compositions are susceptible to. It can be harmful. For example, antioxidants can harm certain easily oxidized amino acids in antibodies. Antibody oxidation can be inhibited by inhibiting the oxidation of acid residues, and / or acid It can inhibit the chemical deamination pathway.

[0291] Preferably, the antioxidant is an amino acid or peptide antioxidant, a mineral antioxidant, or a vitamin. Antioxidants, carotenoid antioxidants, polyphenol antioxidants, aromatic or phenol antioxidants From oxidizing agents, chelating agents, antioxidants, thiol antioxidants, and any combination thereof. It is an antioxidant selected from the group, consists of, or contains an antioxidant. Preferably The antioxidant is an amino acid antioxidant, consists of, or contains an amino acid antioxidant. Antioxidants include cysteine, methionine, N-acetylcysteine, and glutathione. , and antioxidants selected from the group consisting of any combination thereof, or It may be or contain the same. Preferably, the antioxidants are cysteine, methionine, and It is an antioxidant selected from the group consisting of all combinations thereof, or it consists of such antioxidants. or includes it. Preferably, the antioxidant is cysteine ​​or consists of it, It contains it. Preferably, the antioxidant is methionine, or consists of it, That includes it.

[0292] In certain embodiments, the pharmaceutical composition contains 0.1 to 100 mM of an antioxidant. In the application form, the pharmaceutical composition contains 1 to 50 mM of antioxidant. In a particular embodiment, the pharmaceutical The composition contains 2 to 25 mM of antioxidant. In certain embodiments, the pharmaceutical composition contains 3 to 1 Contains 2 mM antioxidant. In certain embodiments, the pharmaceutical composition contains 4-6 mM antioxidant. include.

[0293] In certain embodiments, the pharmaceutical composition has an antioxidant to antibody molar ratio of 2:1 to 750:1. It contains an antioxidant. In certain embodiments, the pharmaceutical composition has a molar ratio of antioxidant to antibody of 2 It contains antioxidants in a ratio of 71 to 400:1. In certain embodiments, the pharmaceutical composition contains antioxidants The antioxidant has a molar ratio of 7:1 to 180:1 with respect to the antibody. In certain embodiments, the pharmaceutical The composition contains an antioxidant having a molar ratio of antioxidant to antibody of 20:1 to 90:1.

[0294] In certain embodiments, the pharmaceutical composition contains cysteine, methionine, and any of the following It contains 1 to 50 mM of an antioxidant selected from the group consisting of such combinations. In a particular embodiment, it contains 1 to 50 mM of an antioxidant selected from the group consisting of such combinations. The pharmaceutical composition contains 2 to 25 mM cysteine. In certain embodiments, the pharmaceutical composition , containing 3-12 mM cysteine. In certain embodiments, the pharmaceutical composition contains 4-6 mM Contains cysteine. In certain embodiments, the pharmaceutical composition has a molar ratio of cysteine ​​to antibody of 2 It contains cysteine ​​in a ratio of 1 to 750. In certain embodiments, the pharmaceutical composition contains cysteine It contains cysteine ​​with an in-antibody molar ratio of 271 to 400:1. In certain embodiments, it contains cysteine. The pharmaceutical composition contains cysteine ​​in which the molar ratio of cysteine ​​to antibody is 7:1 to 180:1. In certain embodiments, the pharmaceutical composition has a molar ratio of cysteine ​​versus antibody of 20:1 to 90: It contains cysteine, which is 1.

[0295] In certain embodiments, the pharmaceutical composition contains 2 to 25 mM methionine. In this state, the pharmaceutical composition contains 3 to 12 mM methionine. In a specific embodiment, the pharmaceutical composition The product contains 4-6 mM methionine. In a particular embodiment, the pharmaceutical composition contains methionine It contains methionine with a molar ratio of methionine to antibody of 2:1 to 750:1. In certain embodiments, The pharmaceutical composition contains methionine in which the molar ratio of methionine to antibody is 271 to 400:1. In certain embodiments, the pharmaceutical composition has a molar ratio of methionine versus antibody of 7:1 to 180:1. It contains methionine. In certain embodiments, the pharmaceutical composition contains methionine versus antibody molars It contains methionine in a ratio of 20:1 to 90:1.

[0296] The amount and concentration of antioxidants should be specified for all antioxidants unless only a single antioxidant is specified. The total amount and concentration of the antioxidants. The antioxidants or any specific antioxidants The concentration can be replaced with a molar ratio.

[0297] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. , B1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1 ~G16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, It can be combined with any of the M1-M1080 and N1-N2686.

[0298] <Chelating agent> The pharmaceutical composition may preferably contain a chelating agent. However, the most preferred practical In terms of application, the pharmaceutical composition contains a chelating agent (or, with respect to a chelating agent, as specifically referred to herein). It is characterized by the absence of one or more of the things that are present. In the context of the present invention, chelating agents such as EDTA (other chelating agents are well known in the art) (and can perform similar or identical functions) increases the stability of the pharmaceutical composition. In particular, it can inhibit the degradation of antibodies. For example, chelating agents reduce the likelihood of aggregation. It can do that and can also act as an antioxidant. Chelating agents, on the other hand, This may promote the degradation of antibodies and / or other components present in the pharmaceutical composition. It can also isolate residual metals.

[0299] Preferably, the chelating agent is EDTA, consists of EDTA, or contains EDTA.

[0300] In one embodiment, the pharmaceutical composition contains 0.001 to 0.5 mM of a chelating agent. In form, the pharmaceutical composition contains 0.01 to 0.2 mM of a chelating agent. In one embodiment, The pharmaceutical composition contains 0.025 to 0.075 mM of a chelating agent.

[0301] In one embodiment, the pharmaceutical composition has a molar ratio of chelating agent to antibody of 1:420 to 8:1. It contains a chelating agent. In one embodiment, the pharmaceutical composition has a molar ratio of chelating agent to antibody of 1: It contains a chelating agent in a ratio of 140 to 4:1. In one embodiment, the pharmaceutical composition contains a chelating agent in a ratio of 140 to 4:1. The drug contains a chelating agent in which the molar ratio of the antibody is 1:16 to 1.1:1. In one embodiment, the drug combination The product contains a chelating agent with a molar ratio of chelating agent to antibody of 1:6 to 1:1.5.

[0302] In one embodiment, the pharmaceutical composition contains 0.001 to 0.5 mM EDTA. In this state, the pharmaceutical composition contains 0.01 to 0.2 mM EDTA. In one embodiment, the pharmaceutical The composition contains 0.025 to 0.075 mM EDTA. In one embodiment, the pharmaceutical composition This includes EDTA in which the molar ratio of EDTA to antibody is 1:420 to 8:1. In one embodiment, The pharmaceutical composition contains EDTA with a molar ratio of EDTA to antibody of 1:140 to 4:1. In one embodiment, the pharmaceutical composition has a molar ratio of EDTA to antibody of 1:16 to 1.1:1. It contains EDTA. In one embodiment, the pharmaceutical composition has a molar ratio of EDTA to antibody of 1:6. It contains EDTA in a 1:1.5 ratio.

[0303] The amount and concentration of chelating agents should be specified unless only a single chelating agent is specified. The total amount and concentration of all chelating agents. The chelating agent or any specific The concentration of the chelating agent can be expressed as a molar ratio.

[0304] The embodiments and features disclosed in this section are preferably embodiments A1 to A127. , B1~B128, C1~C128, D1~D36, E1~E16, F1~F16, G1 ~G16, H1~H12, I1~I16, J1~J24, K1~K32, L1~L64, It can be combined with any of the M1-M1080 and N1-N2686.

[0305] <Specific Embodiments> Sucrose, along with the bispecific antibody of the present invention that binds to both EGFR and LGR5, It was found to be a particularly advantageous component for use, but trehalose and mal Toss is a promising alternative. Therefore, D) The following numbered paragraphs D1 to D36 state that the pharmaceutical composition contains (or is aqueous) the following: In the case of a composition, it consists of the following (and, if necessary, water for injection), and the following Specific embodiments of the present invention, characterized by their features, are disclosed. D1. EGFR / LGR5 BsAb, and the molar ratio of glucose component to antibody is 300:1~ The sugar component ratio is 2600:1. D2. EGFR / LGR5 BsAb at 1-150 mg / mL, and glucose component counter antibodies. Sugar components with a molar ratio of 300:1 to 2600:1. D3. EGFR / LGR5 BsAb, and disaccharide. D4. EGFR / LGR5 BsAb and disaccharides at 1-150 mg / mL. D5. EGFR / LGR5 BsAb, as well as sucrose, trehalose, and A disaccharide selected from the group consisting of maltose. D6. EGFR / LGR5 BsAb at 1-150 mg / mL, and sucrose A disaccharide selected from the group consisting of trehalose and maltose. D7. EGFR / LGR5 BsAb, and sucrose. Day 8. EGFR / LGR5 BsAb at 1-150 mg / mL, and sucrose. D9. EGFR / LGR5 BsAb, and 150-350 mM sucrose. D10. EGFR / LGR5 BsAb at 1-150 mg / mL, and 150-3 50 mM sucrose. D11. EGFR / LGR5 BsAb, and trehalose. D12. EGFR / LGR5 BsAb at 1-150 mg / mL, and trehalose vinegar. D13. EGFR / LGR5 BsAb and 150-350 mM trehalose . D14. EGFR / LGR5 BsAb at 1-150 mg / mL, and 150-3 50 mM trehalose. D15. EGFR / LGR5 BsAb, and maltose. D16. EGFR / LGR5 BsAb at 1-150 mg / mL, and maltose . D17. EGFR / LGR5 BsAb, and maltose at 150-350 mM. D18. EGFR / LGR5 BsAb at 1-150 mg / mL, and 150-3 50 mM maltose. D19. EGFR / LGR5 BsAb, 4-30 mM buffer system, and glucose component countermeasures Sugar components with a molar ratio of 300:1 to 2600:1. D20. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild serocongestive therapy. A sugar component in which the molar ratio of the sugar component to the antibody is 300:1 to 2600:1. D21. EGFR / LGR5 BsAb, 4-30 mM buffer system, and disaccharide. D22. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild serocongestive therapy. Combocytopenia and disaccharides. D23. EGFR / LGR5 BsAb, 4-30 mM buffer system, and sucrose. A disaccharide selected from the group consisting of s, trehalose, and maltose. D24. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild serocongestive therapy. Selected from the group consisting of the opposition system, as well as sucrose, trehalose, and maltose. Disaccharide. D25. EGFR / LGR5 BsAb, 4-30 mM buffer system, and sucrose . D26. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild serocongestive therapy. The opposition system, and sucrose. D27. EGFR / LGR5 BsAb, buffer system of 4-30 mM, and 150-3 50 mM sucrose. D28. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild EGFR / LGR The impingement system, and sucrose in the range of 150-350 mM. D29. EGFR / LGR5 BsAb, 4-30 mM buffer system, and trehalose vinegar. D30. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild serocongestive therapy. Impact system, and trehalose. D31. EGFR / LGR5 BsAb, buffer system of 4-30 mM, and 150-3 50 mM trehalose. D32. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild serocongestive therapy. Aqueous system, and trehalose at 150-350 mM. D33. EGFR / LGR5 BsAb, buffer system of 4-30 mM, and maltose . D34. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild EGFR / LGR5 BsAb The opposition system, and maltose. D35. EGFR / LGR5 BsAb, buffer system of 4-30 mM, and 150-3 50 mM maltose. D36. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild EGFR / LGR Opposition system, and maltose at 150-350 mM.

[0306] Similarly, sodium chloride is also used in conjunction with bispecific antibodies that bind to both EGFR and LGR5. It was found to be a potentially advantageous ingredient for use in [a certain application], but compared to sucrose, It is probably more advantageous than sucrose at relatively higher pH levels. Therefore, E) The following numbered paragraphs E1 to E16 state that the pharmaceutical composition contains (or is aqueous) the following: In the case of a composition, it consists of the following (and, if necessary, water for injection), and the following Specific embodiments of the present invention, characterized by their features, are disclosed. E1. EGFR / LGR5 BsAb, and sodium chloride. E2. EGFR / LGR5 BsAb at 1-150 mg / mL, and sodium chloride Hmm. E3. EGFR / LGR5 BsAb, and 10-180 mM sodium chloride. E4. EGFR / LGR5 BsAb at 1-150 mg / mL, and 10-180 mM sodium chloride. E5. EGFR / LGR5 BsAb, 4-30 mM buffer system, and sodium chloride Hmm. E6. EGFR / LGR5 BsAb at 1-150 mg / mL, buffered at 4-30 mM. System, and sodium chloride. E7. EGFR / LGR5 BsAb, buffer system of 4-30 mM, and 10-180 mM sodium chloride. E8. EGFR / LGR5 BsAb at 1-150 mg / mL, buffered at 4-30 mM. A system, and 10-180 mM sodium chloride. E9. EGFR / LGR5 BsAb, pH 5.9-7.0, and sodium chloride. . E10. EGFR / LGR5 BsAb 1-150 mg / mL, pH 5.9-7. 0, and sodium chloride. E11. EGFR / LGR5 BsAb, pH 5.9~7.0, and 10~180 mM sodium chloride. E12. EGFR / LGR5 BsAb at 1~150mg / mL, pH5.9~7. Sodium chloride at concentrations of 0 and 10-180 mM. E13. EGFR / LGR5 BsAb, 4~30mM buffer system, pH5.9~7.0 , and sodium chloride. E14. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild EGFR / LGR Aqueous system, pH 5.9-7.0, and sodium chloride. E15. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 5.9-7. Sodium chloride at concentrations of 0 and 10-180 mM. E16. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild EGFR / LGR5 BsAb Sodium chloride with a neutral pH of 5.9-7.0 and a concentration of 10-180 mM.

[0307] Surfactants are thought to enhance formulation stability, but from the perspective of freeze-thaw cycles, polysulfide Rubate 80 and Poloxamer 188 are considered more beneficial, and polysorbate 2 Polysorbate 80 and 0 are particularly resistant to heat stress in the presence of buffers and glucose stabilizers. This greatly improves stability. This is because polysorbate 80 has good versatility. It means that. Therefore, F) The following numbered paragraphs F1-F16 indicate that the pharmaceutical composition contains (or is aqueous) the following: In the case of a composition, it consists of the following (and, if necessary, water for injection), and the following Specific embodiments of the present invention, characterized by their features, are disclosed. F1. EGFR / LGR5 BsAb, buffer system of 4-30mM, 50-350mM Sugar components and surfactants in concentrations of 0.01-2 mg / mL. F2. EGFR / LGR5 BsAb at 1-150 mg / mL, buffered at 4-30 mM. A system containing 50-350 mM sugar components and 0.01-2 mg / mL surfactant. F3. EGFR / LGR5 BsAb, buffer system of 4-30mM, 50-350mM Sugar components, and 0.05-1.5 mg / mL of polysorbate 80. F4. EGFR / LGR5 BsAb at 1-150 mg / mL, buffered at 4-30 mM. The system contains 50-350 mM sugar components and 0.05-1.5 mg / mL of polysorbate 8. 0. F5. EGFR / LGR5 BsAb, buffer system of 4-30 mM, 50-350 mM Sugar components, and 0.05-1.5 mg / mL of polysorbate 20. F6. EGFR / LGR5 BsAb at 1-150 mg / mL, buffered at 4-30 mM. The system contains 50-350 mM sugar components and 0.05-1.5 mg / mL of polysorbate 2. 0. F7. EGFR / LGR5 BsAb, buffer system of 4-30mM, 50-350mM Sugar components and poloxamer 188 at 0.05-1.5 mg / mL. F8. EGFR / LGR5 BsAb at 1-150 mg / mL, buffered at 4-30 mM. The system contains 50-350 mM sugar components and 0.05-1.5 mg / mL of poloxamer 18. 8. F9. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4 50-350 mM sugar components and 0.01-2 mg / mL surfactant. F10. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild EGFR / LGR5 BsAb Aqueous system, pH 4.4-7.4, sugar components at 50-350 mM, and 0.01-2 mg / mL. A surfactant. F11. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7. 4. Sugar components of 50-350 mM, and polysorbate 8 of 0.05-1.5 mg / mL. 0. F12. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild EGFR / LGR5 BsAb Aqueous system, pH 4.4-7.4, sugar components of 50-350 mM, and 0.05-1.5 mg / mL of polysorbate 80. F13. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7. 4. Sugar components of 50-350 mM, and polysorbate 2 of 0.05-1.5 mg / mL. 0. F14. EGFR / LGR5 BsAb 1-150 mg / mL, 4-30 mM mild EGFR / LGR5 BsAb Aqueous system, pH 4.4-7.4, sugar components of 50-350 mM, and 0.05-1.5 mg / 20 mL of polysorbate. F15. EGFR / LGR5 BsA...

Claims

1. A first binding domain that binds to EGFR and a second binding domain that binds to LGR5 A polyspecific antibody containing, its functional moiety or derivative, A buffer system containing histidine buffer and / or citrate buffer, Sugar components, and Nonionic surfactants A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the composition is an aqueous composition.

3. The sugar component is sucrose or contains sucrose, according to claim 1 or 2. Pharmaceutical composition.

4. The nonionic surfactant is polysorbate 80 or polysorbate 80 A pharmaceutical composition according to any one of claims 1 to 3.

5. The buffer system includes a histidine buffer system, and the composition is 5 to 7, preferably 5.4 to 6.

6. More preferably having a pH of 5.6 to 6.4, most preferably 5.7 to 6.

2. A pharmaceutical composition according to any one of claims 1 to 4.

6. The buffer system includes a citrate buffer system, and the composition is 6.2 to 7.8, preferably 6. A pH of 5 to 7.5, more preferably 6.8 to 7.2, and most preferably 6.9 to 7.

1. A pharmaceutical composition having any one of claims 1 to 5.

7. The antibody is present in a concentration of 0.5 to 150 mg / mL, preferably 1 to 100 mg / mL, more preferably More preferably 1 to 50 mg / mL, more preferably 1 to 30 mg / mL, more preferably 5 to 2 5 mg / mL, more preferably 15-25 mg / mL, most preferably 20 mg / mL A pharmaceutical composition according to any one of claims 1 to 6, present in a concentration.

8. The sugar component is 200 to 400 mM, preferably 250 to 350 mM, more preferably 27 mM The present concentration is 0 to 300 mM, most preferably 280 mM or 290 mM, according to the claim. A pharmaceutical composition according to any one of items 1 to 7.

9. The nonionic surfactant is present in a concentration of 0.01 to 2 mg / mL, preferably 0.1 to 1.5 mg / mL. g / mL, more preferably 0.1 to 0.6 mg / mL or 0.6 to 1.2 mg / mL, It is most preferably present at concentrations of 0.2 mg / mL, 0.5 mg / mL, or 1 mg / mL. The pharmaceutical composition according to any one of claims 1 to 8.

10. The buffer system or combination of buffer systems has a concentration of 2 to 50 mM, preferably 3 to 20 mM, more preferably More preferably 4 to 12 mM, more preferably 3 to 7 mM or 8 to 12 mM, most preferably A pharmaceutical composition according to any one of claims 1 to 9, present at a concentration of 5 mM or 10 mM. thing.

11. The molar concentration ratio of sugar component to antibody is 250:1 to 60,000:1, preferably 500:

1. ~5000:1, preferably 1460:1 to 2920:1, preferably 1825:1 to 2 555:1, more preferably 1970:1 to 2190:1, most preferably about 2040: A pharmaceutical composition according to any one of claims 1 to 10, wherein the ratio is 1 or 2117:

1.

12. The molar concentration ratio of nonionic surfactant to antibody is 1:90 to 224:1, preferably 1: 50 to 20:1, preferably 1:18 to 11:1, preferably 1:2 to 8.5:1, more Preferably 1:2 to 3.5:1 or 3.5:1 to 7:1, most preferably about 1.11:

1. The ratio is approximately 2.79:1 or approximately 5.55:1, as described in any one of claims 1 to 11. A listed pharmaceutical composition.

13. The molar concentration ratio of buffer system (or combination of buffer systems) versus antibody is 2.9:1 to 7300:

1. Preferably 6:1 to 700:1, preferably 14:1 to 365:1, preferably 21:1 ~146:1, preferably 29:1 to 88:1, more preferably 21:1 to 51:

1. The ratio is 58:1 to 88:1, most preferably about 36.5:1 or 73:1, claim 1 A pharmaceutical composition according to any one of the following items (12).

14. Claims 1 to 13, wherein the buffer system consists of a citrate buffer system or a histidine buffer system. A pharmaceutical composition as described in any one of the items.

15. The pharmaceutical combination according to any one of claims 1 to 14, wherein the composition comprises only a single buffer system. Finished product.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the composition does not contain trehalose. composition.

17. The composition described in any one of claims 1 to 16, wherein the composition does not contain polysorbate 20. Pharmaceutical composition.

18. The composition does not contain a non-buffered salt isotonic agent, and most preferably does not contain sodium chloride. A pharmaceutical composition according to any one of claims 1 to 17.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the composition does not contain an antioxidant. 。

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the composition does not contain a chelating agent. thing.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the antibody is a bispecific antibody.

22. The aforementioned antibodies are MF3370, MF3755, MF4280, or M shown in Figure 1. The EGFR-binding domain containing the heavy chain variable region (VH) including the VH chain sequence of F4289, There are at most 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Preferably, 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or the same The combinations shown in Figure 1 are MF3370, MF3755, MF4280, and if MF4289 contains a heavy chain variable region (VH) including the VH chain sequence and EGFR-bound domain A pharmaceutical composition according to any one of claims 1 to 21, comprising n.

23. The aforementioned antibodies are MF3370, MF3755, MF4280, or M shown in Figure 1. Contains the CDR1, CDR2, and / or CDR3 amino acid sequences of the VH chain of F4289 EGFR binding domains, or at most 15, preferably 1, 2, 3, 4, 5, 6, Insertion of 7, 8, 9, or 10 amino acids, preferably 1, 2, 3, 4, or 5 amino acids. MF3370, MF3 shown in Figure 1, which have deletions, substitutions, or combinations thereof. CDR1, CDR2, and / of the VH chain of 755, MF4280, or MF4289 Alternatively, the claims 1 to 22 include an EGFR-binding domain containing a CDR3 amino acid sequence. A pharmaceutical composition as described in any one of the items.

24. The aforementioned antibodies are MF5790, MF5803, MF5805, and MF580, as shown in Figure 2.

8. MF5809, MF5814, MF5816, MF5817, or MF5818 The sequence of the VH chain, or at most 15, preferably 1, 2, 3, 4, 5, 6, 7, 8 9 or 10, preferably 1, 2, 3, 4, or 5 amino acid insertions or deletions, MF5790, MF5803, shown in Figure 2, have substitutions or combinations thereof. MF5805, MF5808, MF5809, MF5814, MF5816, MF581 7. LGR5 chain containing the heavy chain variable region including the amino acid sequence of the VH chain of MF5818. A pharmaceutical composition according to any one of claims 1 to 23, comprising a synthetic domain.

25. The antibody corresponds to one of the sequences in Figures 5a, 5b, 5c, 5d, 5e, or 5f. The heavy chain sequence, or any of the sequences in Figures 5a, 5b, 5c, 5d, 5e, or 5f. And, having at least 85% sequence identity, preferably as shown in Figures 5a, 5b, 5c, 5d, 5e , or at least 88%, more preferably at least 92%, of either of the 5f sequences , having at least 93%, at least 94%, or at least 95% sequence identity A pharmaceutical composition according to any one of claims 1 to 24, comprising the variant.

26. The antibody corresponds to one of the sequences in Figures 5a, 5b, 5c, 5d, 5e, or 5f. A heavy chain sequence, or at most 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 Alternatively, insertion, deletion, or placement of 10 amino acids, preferably 1, 2, 3, 4, or 5 amino acids. Figures 5a, 5b, 5c, 5d, 5e, or 5f have substitutions or combinations thereof. A medical device according to any one of claims 1 to 25, comprising a heavy chain sequence corresponding to any of the sequences. A pharmaceutical composition.

27. The antibody contains a light chain variable region (VL) including the VL chain sequence shown in Figure 3. In, or at most 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or This involves 10, preferably 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions. or a light chain variable region (VL) containing the VL chain sequence shown in Figure 3, which has a combination of these. A pharmaceutical composition according to any one of claims 1 to 26, comprising a binding domain including the above.

28. The antibody is CDR1, CDR2, and / or CDR3 of the VL chain shown in Figure 3. A binding domain containing an amino acid sequence, or at most 15, preferably 1, 2, 3, 4. 5, 6, 7, 8, 9, or 10 meshes, preferably 1, 2, 3, 4, or 5 meshes CD of the VL chain shown in Figure 3, which has no acid insertions, deletions, substitutions, or combinations thereof. Includes a binding domain containing the R1, CDR2, and / or CDR3 amino acid sequences. A pharmaceutical composition as described in any one of the requests 1 to 27.

29. The antibody contains a light chain constant region (CL) including the CL chain sequence shown in Figure 3, or more Also 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably This involves the insertion, deletion, substitution, or combination of one, two, three, four, or five amino acids. Claims 1 to A pharmaceutical composition according to any one of item 28.

30. The antibody is the VH amino acid sequence of MF3370 shown in Figure 1 and / or shown in Figure 2. The VH amino acid sequence of MF5790 and the VL amino acid sequence shown in Figure 3 are included. A pharmaceutical composition according to any one of claims 1 to 29.

31. The antibody is the VH amino acid sequence of MF3755 shown in Figure 1 and / or shown in Figure 2. The VH amino acid sequence of MF5816 and the VL amino acid sequence shown in Figure 3 are included. A pharmaceutical composition according to any one of claims 1 to 30.

32. The antibody is the VH amino acid sequence of MF4280 shown in Figure 1 and / or shown in Figure 2. The VH amino acid sequence of MF5809 and the VL amino acid sequence shown in Figure 3 are included. A pharmaceutical composition according to any one of claims 1 to 31.

33. The antibody is the VH amino acid sequence of MF4289 shown in Figure 1 and / or shown in Figure 2. The VH amino acid sequence of MF5818 and the VL amino acid sequence shown in Figure 3 are included. A pharmaceutical composition according to any one of claims 1 to 32.

34. The antibodies mentioned above are EGFR variable heavy chain MF3755, MF3370, and MF42, as shown in Figure 1. 80, or MF4289, LGR5 variable heavy chain MF5790, MF580 shown in Figure 2 9. MF5816 or MF5818, variable light chain (VL) shown in Figure 3, shown in Figure 3 The stationary light chain (CL), the CH1 domain sequence shown in Figure 4, and the hinge sequence shown in Figure 4. The CH2 domain sequence shown in Figure 4, the CH3-DE domain sequence shown in Figure 4, and The CH3-KK domain sequence shown in Figure 4, as described in any one of claims 1 to 33. A listed pharmaceutical composition.

35. The composition is A first binding domain that binds to EGFR and a second binding domain that binds to LGR5 A bispecific antibody containing 1 to 30 mg / mL, its functional moiety or derivative, A buffer system of 3–20 mM containing histidine buffer and / or citrate buffer, A sugar and / or sugar alcohol component in a concentration of 200-400 mM, and 0.01–2 mg / mL of nonionic surfactant an aqueous composition containing The composition has a pH of 5.4 to 7.4, according to any one of claims 1 to 34. A pharmaceutical composition.

36. The aforementioned composition, A first binding domain that binds to EGFR and a second binding domain that binds to LGR5 A bispecific antibody containing 15-25 mg / mL, its functional portion or derivative, A buffer system of 4–12 mM containing histidine buffer and / or citrate buffer, Sucrose in 250-350 mM, and Polysorbate 80 at 0.1–1.5 mg / mL an aqueous composition containing The composition has a pH of 5.4 to 7.4, according to any one of claims 1 to 35. A pharmaceutical composition.

37. A first binding domain that binds to EGFR and a second binding domain that binds to LGR5 A 20 mg / mL bispecific antibody containing the functional portion or derivative thereof, 10 mM histidine buffer system, 280 mM sucrose, 0.5 mg / mL of polysorbate 80, and water It consists of, The composition has a pH of 5.8 to 6.0, according to any one of claims 1 to 36. A pharmaceutical composition.

38. The composition is A first binding domain that binds to EGFR and a second binding domain that binds to LGR5 A bispecific antibody containing, its functional moiety or derivative, The molar concentration ratio of the buffer system (or combination of buffer systems) versus the antibody is between 21:1 and 146:

1. A buffer system containing histidine buffer and / or citrate buffer, The molar concentration ratio of sugar and / or sugar alcohol component to antibody is between 1460:1 and 2920:

1. sugar and / or sugar alcohol components, and Nonionic interface where the molar concentration ratio of nonionic surfactant to antibody is 1:18 to 11:1 Activating agent Includes, The composition has a pH of 5.4 to 7.4, according to any one of claims 1 to 37. A pharmaceutical composition.

39. The composition is A first binding domain that binds to EGFR and a second binding domain that binds to LGR5 A bispecific antibody containing, its functional moiety or derivative, The molar concentration ratio of buffer system (or combination of buffer systems) versus antibody is 29:1 to 88:

1. A buffering system containing stidine buffer and / or citrate buffer, If the molar concentration ratio of sucrose to antibody is between 1825:1 and 2555:1, then Bini Polysorbate 80 with an antibody molar concentration ratio of 1:2 to 8.5:1 ０ Includes, The composition has a pH of 5.4 to 7.4, according to any one of claims 1 to 38. A pharmaceutical composition.

40. The composition is A first binding domain that binds to EGFR and a second binding domain that binds to LGR5 A bispecific antibody containing, its functional moiety or derivative, A histidine buffer system with a molar concentration ratio of histidine buffer system versus antibody of 73:

1. Sucrose with a molar concentration ratio of sucrose versus antibody of 2040:1 Polysorbate 80 with a molar concentration ratio of 2.79:1, Rabini Water It consists of, The composition has a pH of 5.8 to 6.0, according to any one of claims 1 to 39. A pharmaceutical composition.

41. A drug delivery device comprising the pharmaceutical composition according to any one of claims 1 to 40.

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