antibody composition

Abstract

The present invention relates to (bio)pharmaceutical compositions, in particular liquid (e.g. aqueous) biopharmaceutical compositions, more in particular liquid biopharmaceutical compositions, comprising an anti-EGFR / anti-LGR5 bispecific antibody. The present invention also relates to, inter alia, methods of producing the compositions, kits comprising the compositions, packages comprising the compositions, methods of producing the packages, and methods of treatment, in particular methods of cancer treatment, using the compositions and / or packages, e.g. for the treatment of colorectal cancer.

Description

[Technical Field]

[0001] [introduction] The present invention relates to (bio)pharmaceutical compositions comprising anti-EGFR / anti-LGR5 bispecific antibodies, more particularly to liquid (e.g., aqueous) biopharmaceutical compositions, and more particularly to liquid biopharmaceutical compositions. The present invention also relates, among other things, to methods for producing the compositions, kits containing the compositions, packages containing the compositions, methods for producing the packages, and methods of treatment using the compositions and / or packages, particularly methods of cancer treatment, for example, for the treatment of colorectal cancer. [Background technology]

[0002] Recently, the applicants have developed Biclonics®, characterized by enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) for treating solid tumors, including the potential treatment of colorectal cancer, and which bind to cancer stem cells expressing leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) and epidermal growth factor receptor (EGFR). Antibodies that bind to both EGFR and LGR5 are described in detail in International Publication No. 2017069628A2 (MERUS et al), and their relevant sequences are shown in Figures 1-4. Such antibodies have two distinct mechanisms of action: firstly, by blocking the proliferation and survival pathways of cancer stem cells; and secondly, by recruiting and enhancing immune effector cells to directly kill cancer stem cells that remain present in solid tumors and cause recurrence and metastasis.

[0003] The object of the present invention is to provide viable pharmaceutical compositions of bispecific antibodies that bind to both EGFR and LGR5, and optionally similar variants thereof. The inherent unpredictability in the formulation techniques of biopharmaceuticals, particularly antibodies, has hindered the discovery of such viable pharmaceutical compositions. This is because most formulations of a given biopharmaceutical (if such formulation is arbitrarily selected) are unstable over long periods and / or under stress conditions due to various physical or chemical factors that may affect the biopharmaceutical, particularly aqueous formulations. For example, preventing protein aggregation can be difficult. Furthermore, the pharmaceutical composition should be formulated with the intention of being safe for administration to human subjects, meaning that adverse effects from its administration, e.g., intravenous injection, should be minimized.

[0004] Physical or chemical influences, particularly due to fluctuating stresses (e.g., agitation, heat, frost, light) that different batches of drug products may be exposed to during manufacturing, transport, and storage, can result in either drug products that are unsustainable (potentially unsafe for use in medical procedures) or drug products whose sustainability is volatile and unpredictable.

[0005] U.S. Patent No. 6,171,586 (Lam et al.) describes a stable aqueous antibody formulation. The F(ab')2rhuMAb CD18 antibody was formulated with sodium acetate and histidine-HCl buffer. A preferred formulation of rhuMAb CD18 was formulated with 10 mM sodium acetate, 8% trehalose, 0.01% Tween® 20, and pH 5.0.

[0006] Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody and is available in different formulations depending on whether it is lyophilized or liquid. In its dry form, omalizumab is packaged as a sterile, white, preservative-free lyophilized powder in a single-use vial and is administered subcutaneously after reconstitution with sterile water for injection. Each 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 is designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL of sterile water. In its aqueous form, it is available in pre-filled syringes. The injection solution in the syringe contains L-arginine hydrochloride, L-histidine hydrochloride, L-histidine, polysorbate 20, and water. The label accompanying the pre-filled syringe includes instructions for use, including storing the sealed syringe in a refrigerator at 2°C to 8°C (36°F to 46°F) and mentioning not to freeze the product. It also mentions that the shelf life is 15 months, including potential temperature deviations. The product can be maintained at 25°C for a total of 4 hours, and if necessary, the product can be returned to the refrigerator for later use, but this should not be done more than once.

[0007] International Publication No. 2015 / 130173A1 discloses a bispecific antibody formulated as a pharmaceutical composition having 25 mM histidine, 220 mM trehalose, 0.2 g / L polysorbate 20, or a combination thereof, most preferably set to pH 6.

[0008] The present invention suitably addresses one or more of the aforementioned stability problems and thereby provides a pharmaceutical formulation that can maintain activity for administration to humans. Another object of the present invention is to provide a formulation with improved stability and / or shelf life. [Overview of the project]

[0009] According to one aspect of the present invention, a (bio)pharmaceutical composition is provided comprising a multispecific antibody, a functional moiety thereof, or a derivative thereof, comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5. The pharmaceutical composition of the present invention preferably comprises or consists of some or all of any relevant amounts of any of the components specified herein (e.g., buffers, surfactants, sugar components, amino acid components, isotonic agents, antioxidants, or chelating agents) and / or preferably can be characterized by any, some or all of the parameters specified herein (e.g., pH, pI, osmolality by weight). The pharmaceutical composition is preferably a liquid (e.g., aqueous) pharmaceutical composition.

[0010] According to one aspect of the present invention, a package containing or comprising a pharmaceutical composition as defined herein (e.g., a vial, ampoule, syringe, pre-filled syringe, injection pen (e.g., one that essentially incorporates a syringe), auto-injector, or infusion bag, or any of the above-mentioned packages / containers) is provided.

[0011] According to one aspect of the present invention, a drug delivery device (e.g., a vial, ampoule, syringe, pre-filled syringe, injection pen (e.g., one that essentially incorporates a syringe), autoinjector, or infusion bag, or a package / container containing any of the above) is provided which comprises or contains a pharmaceutical composition as defined herein.

[0012] According to one aspect of the present invention, a kit of parts is provided which includes a drug delivery device, a pharmaceutical composition as defined herein (optionally contained in a package or container), and a set of instructions for use which optionally contains instructions relating to the administration of the pharmaceutical composition.

[0013] According to one aspect of the present invention, a method for producing a pharmaceutical composition is provided, comprising mixing a polyspecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional moiety thereof, a derivative, or a variant thereof, with one or more pharmaceutically acceptable excipients and / or carriers.

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

[0015] According to one aspect of the present invention, a pharmaceutical composition, preferably as defined herein, is provided for use in treating a disease or medical disorder in a patient requiring such treatment.

[0016] According to one aspect of the present invention, the use of a pharmaceutical composition, preferably as defined herein, in the manufacture of a pharmaceutical for treating a disease or disorder is provided.

[0017] Further aspects of the present invention provide a method for treating a disease or medical disorder, a pharmaceutical composition for use in treating a disease or medical disorder, and the use of a pharmaceutical composition in the manufacture of a medicament for treating a disease or medical disorder as defined herein, where the disease or medical disorder is EGFR-related and LGR5-related disease. A polyspecific antibody, functional moiety, derivative, or variant thereof comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5 preferably binds to cancer stem cells expressing leucine-rich repeat-containing G-coupled receptor 5 (LGR5) and epidermal growth factor receptor (EGFR).

[0018] Further aspects of the present invention provide methods for treating a disease or medical disorder, pharmaceutical compositions for use in treating a disease or medical disorder, and the use of pharmaceutical compositions in the manufacture of a medicament for treating a disease or medical disorder as defined herein, wherein the disease or medical 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. The cancer is preferably an EGFR ligand-responsive cancer, preferably one expressing a membrane-bound member of the WNT pathway. The cancer is preferably an adenocarcinoma. In particular, the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer, breast cancer, liver cancer, prostate cancer, ovarian cancer, cervical cancer, endometrial cancer; head and neck cancer, melanoma, testicular cancer, urothelial cancer, kidney cancer, gastric cancer, carcinoid cancer, and any combination thereof. Most preferably, the cancer is colorectal cancer, pancreatic cancer, lung cancer, breast cancer, liver cancer, prostate cancer, ovarian cancer, cervical cancer, endometrial cancer, head and neck cancer, or melanoma. In particularly preferred embodiments, the cancer is gastrointestinal cancer, stomach cancer, or head and neck cancer. The disease or medical disorder in question can preferably be selected from any of those disclosed in International Publication No. 2017069628A2, which thus forms part of this specification by reference. The applicability of the treatment of the present invention is further justified in light of this disclosure by International Publication No. 2017069628A2.

[0019] According to a further aspect of the present invention, there is provided a method for treating a disease or medical disorder, a pharmaceutical composition for use in treating a disease or medical disorder, and the use of a pharmaceutical composition in the manufacture of a medicament for treating a disease or disorder as defined herein, wherein the disease or medical disorder is preferably as defined herein, and the treatment or treatment agent comprises a combination therapy in which the pharmaceutical composition is administered in combination with one or more other pharmaceutical active substances or biopharmaceutical active substances, said combination therapy comprising simultaneous, sequential, or separate dosing of the individual components of the treatment agent. In some embodiments, the additional pharmaceutical active substance or biopharmaceutical active substance may be present within any of the pharmaceutical compositions defined herein.

[0020] All of the foregoing methods of treatment, compositions for use, and use of compositions in the manufacture of a medicament are equally applicable to the relevant packages, drug delivery devices, and kits incorporating said compositions.

[0021] In a preferred embodiment, a pharmaceutical formulation with improved stability characteristics is provided. Also, any feature including a suitable preferred feature as required for any particular aspect of the present invention may be a feature including a suitable preferred feature as required for any other aspect of the present invention.

Brief Description of the Drawings

[0022] [Figure 1] It is a diagram showing the amino acid sequences of SEQ ID NOs: 1 to 16. [Figure 2] It is a diagram showing the amino acid sequences of SEQ ID NOs: 17 to 52. [Figure 3] It is a diagram showing the amino acid sequences of SEQ ID NOs: 53 to 57. [Figure 4] It is a diagram showing the amino acid sequences of SEQ ID NOs: 58 to 62. [Figure 5] It is a diagram showing the amino acid sequences of SEQ ID NOs: 63 to 68.

Mode for Carrying Out the Invention

[0023] [Definition] Unless otherwise stated, the following terms used in this specification and in the claims have the meanings set forth below.

[0024] Throughout this specification and the claims, the words “comprise” and “contain,” and their variations, mean “comprise but not limited to,” and are not intended to exclude (are not excluded) other parts, additives, ingredients, integers, or steps. Throughout this specification and the claims, unless the circumstances require otherwise, the singular includes the plural. In particular, where the indefinite article is used, unless the circumstances require otherwise, this specification should be understood to intend both the singular and the plural.

[0025] Features, integers, properties, compounds, chemical parts, or groups described in connection with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, unless incompatible therewith. All features disclosed herein (including any appended claims, abstracts, and drawings) and / or all steps of any method or process disclosed herein may be combined in any combination except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any aforementioned embodiments. The present invention extends to any novel or novel combination of features disclosed herein (including any appended claims, abstracts, and drawings), or any novel or novel combination of any steps of any method or process disclosed herein.

[0026] The reader's attention is directed to all papers and documents filed concurrently with or prior to this Specified Application and made available to the public together with this Specified, the contents of all such papers and documents by reference to form part of this Specified.

[0027] To avoid any ambiguity, it is hereby stated that the information disclosed at the beginning of this specification under the heading "Background Art" relates to the present invention and should be read as part of the disclosure of the present invention.

[0028] The terms “antibody” and related nomenclature such as “monoclonal,” “polyclonal,” “IgG,” “IgG1,” and “IgG4” are well-known technical terms. For the purposes of this specification, to avoid any doubt, the term “antibody” means a proteinaceous molecule belonging to the immunoglobulin class of proteins that contains one or more domains that bind to an antigen epitope, such domains being variable domains of the antibody, derived from them, or sharing sequence homology with them. Antibodies typically consist of a basic structural unit, each containing two heavy chains and two light chains. Antibodies for therapeutic use are preferably as close as possible to the natural antibody of the subject being treated (e.g., a human antibody in the case of a human subject).

[0029] As used herein, the term “binding domain” refers to a portion of an antibody that contains a variable domain and functions in antigen binding or shares sequence homology with a variable domain. Non-exclusive examples of binding domains containing a variable domain are the Fv domain and the Fab domain. Typical variability is found in the three surface loop-forming regions of the VH and VL domains, which are complementarity-determining regions or CDRs.

[0030] The term “heavy chain” or “immunoglobulin heavy chain” includes an immunoglobulin heavy chain constant region sequence derived from any organism and, unless otherwise specified, includes the heavy chain variable domain. The term “heavy chain variable domain” includes three heavy chain CDRs and four FR regions, unless otherwise specified. Fragments of a heavy chain include CDRs, CDRs, and FRs, as well as combinations thereof. A typical heavy chain has a variable domain followed (from N-terminus to C-terminus) by a CH1 domain, a hinge, a CH2 domain, and a CH3 domain. Functional fragments of a heavy chain include fragments capable of specifically recognizing an antigen and containing at least one CDR. In this specification, the CDR domains of a heavy chain preferably follow a Kabat numbering scheme.

[0031] The term "light chain" includes immunoglobulin light chain variable domains or VLs (or functional fragments thereof) and immunoglobulin constant domains or CLs (or functional fragments thereof) sequences derived from any organism. Unless otherwise specified, the term "light chain" may include light chains selected from human kappa, lambda, and combinations thereof. Unless otherwise specified, the light chain variable (VL) domain typically includes three light chain CDRs and four framework (FR) regions. Generally, a full-length light chain includes a VL domain consisting of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and a light chain constant domain, from the N-terminus to the C-terminus. Examples of light chains that can be used in the present invention include those that do not selectively bind to epitopes to which the heavy chain selectively binds. An example of such a light chain is the light chain shown in Figure 3. In this specification, the CDR domains of the light chain preferably follow the IMGT numbering scheme.

[0032] Suitable light chains for use with the antibodies of the present invention include common light chains that can be identified by screening the most widely used light chains in existing antibody libraries (wet libraries or in silico), which do not substantially impede the affinity and / or selectivity of the epitope-binding domain of the heavy chain, but are also suitable for pairing with a series of heavy chains. For example, suitable light chains include those derived from transgenic animals such as transgenic rodents, which include common light chains integrated into the genome and can be used to generate a large panel of common light chain antibodies that exhibit diversity in the heavy chain upon exposure to an antigen (International Publication No. 2009 / 157771). The relevant sequences of the light chains of the present invention, particularly CL, VL, VL-CDR1, VL-CDR2, and VL-CDR3, are shown in Figure 3.

[0033] The term "common light chain" in this invention refers to a light chain that may be identical or may have differences in some amino acid sequences, but which does not affect the binding specificity of the antibody of this invention; in other words, the differences do not substantially affect the formation of the functional binding domain.

[0034] For example, by introducing and testing amino acid changes in regions that do not contribute to or only partially contribute to binding specificity when paired with a conservative amino acid change, a homogeneous chain, etc., it is possible to prepare or find, for example, a variable chain that is not identical but still functionally equivalent, within the definition of a common chain as used herein. Thus, such variants can also bind to different homogeneous chains and form a functional antigen-binding domain. Therefore, the term “common light chain,” as used herein, refers to a light chain that may be identical or may have some differences in amino acid sequence, but which retains the binding specificity of the antibody obtained after pairing with a heavy chain. Certain combinations of common light chains and such functionally equivalent variants are encompassed within the term “common light chain.”

[0035] Those skilled in the art will recognize that "common" also refers to functional equivalents of light chains that do not have identical amino acid sequences. These light chains have numerous variants containing mutations (deletions, substitutions, additions) that do not substantially affect the formation of the functional binding domain.

[0036] The term "full-length IgG" or "full-length antibody" according to the present invention is defined as containing essentially complete IgG, but not necessarily possessing all the functions of intact IgG. To avoid any doubt, full-length IgG contains two heavy chains and two light chains. Each chain contains a constant (C) region and a variable (V) region, and can be divided into domains designated as CH1, CH2, CH3, VH, and CL, VL. IgG antibodies bind to antigens via the variable region domain contained in the Fab portion, and after binding, can interact with molecules and cells of the immune system via the constant domain, primarily the Fc portion. Full-length antibodies according to the present invention include IgG molecules that may have mutations that provide desired characteristics. Full-length IgG should not have substantial deletions in any of such regions. However, IgG molecules with one or more amino acid residues deleted without essentially altering the binding characteristics of the resulting IgG molecule are included in the term "full-length IgG." For example, such an IgG molecule may preferably have a deletion of 1 to 10 amino acid residues in the non-CDR region, in which case the deleted amino acids are not essential for the antigen-binding specificity of IgG.

[0037] As used herein, a “bispecific antibody” is an antibody in which one variable domain of the antibody binds to a first antigen and a second variable domain of the antibody binds to a second antigen, wherein the first and second antigens are not identical. This term includes antibodies in which at least one VH is specifically recognizable to the first antigen and at least one VH of the immunoglobulin variable domain is paired with a VL that is specifically recognizable to the second antigen. The resulting VH / VL pair binds to either antigen 1 or antigen 2 and is called a “two-in-one antibody,” as described, for example, in International Publication No. 2008 / 027236, International Publication No. 2010 / 108127, and Schaefer et al (Cancer Cell 20, 472-486, October 2011). The bispecific antibody according to the present invention is preferably human IgG, more preferably human IgG1. Preferably, the bispecific antibodies intended herein have binding specificity to LGR5 and EGFR and do not contain further variable domains.

[0038] As used herein, "polyspecific antibody" refers to an antibody in which one variable domain binds to a first antigen, a second variable domain binds to a second antigen, and in the case of a trispecific antibody, a third variable domain binds to a third antigen, such as a bispecific or trispecific antibody, wherein the first, second, and third antigens are not the same, or the epitopes to which the variable domains bind are not the same.

[0039] The “antibody comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5” as intended herein is a polyspecific antibody, preferably a bispecific antibody (BsAb). This antibody is also referred herein as “anti-EGFR / anti-LGR5 bispecific antibody” or simply “EGFR / LGR5 BsAb.” This antibody and its production are described in detail in International Publication No. 2017069628A2 (MERUS et al). The antibody is preferably a full-length human IgG1 heterodimer having an anti-EGFR moiety and an anti-LGR5 moiety, the associated DNA and / or amino acid sequence of which is disclosed in Figures 1-4 of International Publication No. 2017069628A2 and referred herein. The molecular weight is approximately 146 kDa, which is used for all molar calculations. Therefore, a 10 mg / mL antibody aqueous solution corresponds to a 0.068 mM solution, a 20 mg / mL aqueous solution corresponds to a 0.137 mM antibody solution, and a 50 mg / mL antibody aqueous solution corresponds to a 0.342 mM solution.

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

[0041] An antibody "derivative" is a protein in which, excluding the CDR region, at most 20 amino acids deviate from the amino acid sequence of the natural antibody. The antibody derivatives disclosed herein are antibodies in which at most 20 amino acids deviate from the aforementioned amino acid sequence.

[0042] The term "EGFR" herein refers to the epidermal growth factor receptor, a member of the family of four receptor tyrosine kinases (RTKs). EGFR is also known by various synonyms, including HER1 (human epidermal growth factor (EGF) receptor 1) and ErbB1 (erythroblastoma-1). EGFR has an extracellular domain (ECD) consisting of four subdomains, two of which are involved in ligand binding, and two of which are involved in homodimerization and heterodimerization. EGFR integrates extracellular signals from various ligands to trigger diverse intracellular responses. The major signaling pathway activated by EGFR is the Ras mitogen-activated protein kinase (MAPK) mitotic signaling cascade. Activation of this pathway is initiated by the recruitment of Grb2 to tyrosine-phosphorylated EGFR. This leads to Ras activation via the Grb2-binding Ras guanine nucleotide exchange factor Son of Sevenless (SOS). In addition, the PI3 kinase Akt signaling pathway is also activated by EGFR, and this activation is even more potent in the presence of ErbB-3 (HER3) co-expression. EGFR is thought to be involved in several human epithelial malignancies, particularly breast cancer, bladder cancer, non-small cell lung cancer, lung cancer, colon cancer, ovarian cancer, head and neck cancer, and brain cancer. Activating mutations in this gene, as well as overexpression of its receptor and ligand, have been found, creating an autocrine activation loop. Therefore, this RTK is widely used as a target in cancer therapy. Both small molecule inhibitors targeting RTKs and monoclonal antibodies (mAbs) against the extracellular ligand-binding domain have been developed and have shown some clinical success, mainly in certain patient groups.

[0043] The database accession number for the human EGFR protein and the gene encoding it is (GenBank NM_005228.3). This accession number was primarily assigned to provide further methods for identifying the EGFR protein as a target, and the actual sequence of the EGFR protein to which the antibody binds may differ due to mutations in the encoding gene, such as those occurring in the gene in some cancers. In this specification, the terms cancer and tumor are used, and unless otherwise specified, both typically refer to cancer. Where EGFR is mentioned in this specification, unless otherwise specified, it refers to human EGFR. The antigen-binding site that binds to EGFR binds to EGFR and its various variants, including those expressed in some EGFR-positive tumors.

[0044] The term "LGR" refers to a family of proteins known as leucine-rich repeat-containing G protein-coupled receptors. Among the members of this family is LGR5, which is leucine-rich repeat-containing G protein-coupled receptor 5. Other names for this gene or protein include leucine-rich repeat-containing G protein-coupled receptor 5, leucine-rich repeat-containing G protein-coupled receptor 5G protein-coupled receptor HG38, G protein-coupled receptor 49, G protein-coupled receptor 67, GPR67, GPR49, orphan G protein-coupled receptor HG38G, protein-coupled receptor 49, GPR49, HG38, and FEX. The LGR5-binding protein or antibody of the present invention binds to human LGR5. Due to sequence and tertiary structure similarities between human and other mammalian orthologues, the LGR5-binding protein or antibody of the present invention may also bind to such orthologues, but is not necessarily required.

[0045] The database accession numbers for the human LGR5 protein and the gene encoding it are (NC_000012.12, NT_029419.13, NC_018923.2, NP_001264155.1, NP_001264156.1, NP_003658.1). These accession numbers are primarily provided to offer further methods for identifying target LGR5 proteins, and the actual sequence of the LGR5 protein to bind may differ due to mutations in the encoding gene, such as those occurring in genes in some cancers. The LGR5 antigen-binding site binds to LGR5 and its various variants, including those expressed by some LGR5-positive tumor cells.

[0046] Any reference herein to any particular bispecific antibody, including those disclosed in International Publication No. 2017069628A2, includes the relevant source active pharmaceutical ingredient, whether commercially available, described in the patent documents, or otherwise described elsewhere in the art.

[0047] The term sequence identity is well known in the art. In this specification, “identity percentage (%)” for nucleic acid sequences or amino acid sequences is defined as the percentage of residues in a candidate sequence that are identical to residues in a selected sequence after the sequences have been aligned for optimal comparison. The sequence identity percentage for comparing nucleic acid sequences is determined using the AlignX application of Vector NTI 30 Advance® 11.5.2 software with default settings that utilize the improved ClustalW algorithm (Thompson, JD, Higgins, DG, and Gibson TJ, (1994) Nuc. Acid Res. 22(22):4673-4680), the swgapdnamt score matrix, a gap-open penalty of 15, and a gap-extension penalty of 6.66. The amino acid sequences are aligned using the AlignX application of Vector NTI Advance® 11.5.2 software, which employs 35 default settings and utilizes the improved ClustalW algorithm (Thompson, JD, Higgins, DG, and Gibson TJ, (1994) Nuc. Acid Res. 22(22):4673-4680), a bloom62mt2 score matrix, a gap-open penalty of 10, and a gap-extension penalty of 0.1.

[0048] In this specification, the terms “buffer solution,” “buffer system,” or “buffer solution” refer to a generally aqueous solution containing a mixture of an acid (usually a weak acid, e.g., acetic acid, citric acid, or the imidazolium form of histidine) and its conjugate base (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 its conjugate acid (e.g., a protonated histidine salt). The pH of a “buffer solution” will change only slightly with the addition of a small amount of strong acid or strong base due to the “buffering effect” imparted by the buffer system.

[0049] In this specification, “buffer system” comprises one or more buffers and / or their conjugate acids / bases, more preferably one or more buffers and their conjugate acids / bases, and most preferably one buffer and / or its conjugate acid / base. Unless otherwise stated, the concentration specified herein with respect to a “buffer system” (i.e., buffer concentration) preferably refers to the total concentration of the buffers and / or their conjugate acids / bases. In other words, the concentration specified herein with respect to a “buffer system” preferably refers to the total concentration of all relevant buffer species (i.e., species in dynamic equilibrium with each other, e.g., acetate / acetic acid). Thus, a given concentration of an acetate buffer system generally relates to the total concentration of acetate (or acetate, e.g., sodium acetate) and acetic acid. The overall pH of a composition containing a relevant buffer system generally reflects the equilibrium concentration of each of the relevant buffer species (i.e., the balance between the buffer and its conjugate acid / base). Any given "buffer system" may consist of a single buffer (or buffer system) or multiple buffers (or buffer systems).

[0050] In this specification, the term “buffer” refers to the acidic or basic component (usually a weak acid or weak base) of a buffer or buffer solution. A buffer helps maintain the pH of a given solution at or near a predetermined value, and buffers are generally selected to complement a predetermined value. The buffer is preferably a single compound that provides the desired buffering effect when mixed with (and preferably proton-exchangeable with) an appropriate amount (depending on the desired predetermined pH) of its corresponding “conjugate acid / base,” or when the required amount of its corresponding “conjugate acid / base” is formed in situ, which can be achieved by adding a strong acid or strong base until the desired pH is reached. Examples are as follows:

[0051] "Acetate buffer" is preferably an acetate, such as sodium acetate, preferably mixed with its conjugate acid / base, acetic acid. Such a buffer system can be formed simply by mixing a given amount of sodium acetate with a given amount of acetic acid. However, instead, such a buffer can be formed by adding a given amount of base, preferably a strong base (e.g., sodium hydroxide), to acetic acid until a desired pH (and therefore a desired balance of sodium acetate / acetic acid) is achieved. In this specification, unless otherwise stated, any concentration given with respect to acetate buffer or acetate buffer preferably refers to the total concentration of the buffer (e.g., sodium acetate) and / or its conjugate acid / base (e.g., acetic acid). Those skilled in the art can easily calculate such concentrations. Such concentrations can be calculated by referring to the total concentration of the buffer and conjugate acid / base, and the buffer system is formed simply by mixing the buffer and conjugate acid / base together. Alternatively, if a buffer system is formed by mixing either a buffering agent or a conjugate acid / base with a pH adjuster (e.g., a strong acid or a strong base) to produce each mixture, preferably such concentrations can be calculated by referring to the initial amount / concentration of the buffering agent or conjugate acid / base, respectively. For example, if a buffer system is formed using a known amount / concentration of acetic acid mixed with a pH adjuster (e.g., sodium hydroxide) until a desired pH is reached, 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 (whichever is related to a specific pH, typically the conjugate acid in the context of the present invention) of a particular “buffer.” The conjugate acid / base of an acetate buffer (e.g., sodium acetate) is preferably acetic acid.

[0053] In this specification, the term “buffer species” refers to a specific species of a given buffer system that is in dynamic equilibrium with (and exchanges protons with) each other (with the exception of any associated counteranions or countercations, and ignoring the sodium ion in the sodium acetate / acetic acid system). For example, the acetate anion and acetic acid together constitute the “acetate buffer species” of the “acetate buffer system.”

[0054] Since it is impractical to determine the amount of a buffer system (whether absolute or relative) by referring to its weight (because the total weight depends on the desired pH, which will affect the amount of counterions present), this specification instead determines the weight-based amount by referring to the theoretical weight of the relevant “buffer species”. Any given set of “buffer species” contains at least two species (in relative amounts that can be determined simply by referring to pH), each having a different molecular weight (usually differing by only 1). Therefore, to enable viable weight calculations and references, for the purposes of this specification, the weight of any given set of “buffer species” is given as the theoretical weight based on only one of the buffer species, i.e., the most acidic of the buffer species (i.e., the most protonated form at any given pH). Thus, the weight of a given set of “buffer species” is cited as the weight of the acid species equivalent. As an example, in an acetate buffer system, the acetate buffer species may consist of acetate anions (ignoring the countercation) and acetic acid. Therefore, the weight of the "buffer species" is calculated as if acetic acid were the only species present in the buffer system (even if acetates are obviously present alongside acetic acid). Thus, references to the weight or weight ratio of the "acetate buffer species" preferably refer to the theoretical weight of the acetic acid equivalent in the buffer system. Therefore, if a composition is formed by adding a pH adjuster (such as sodium hydroxide) to a fixed amount of acetic acid, the original weight of the acetic acid can be considered the weight of the "buffer species," regardless of the final pH. Alternatively, if the concentration (i.e., molar concentration) of the buffer system is known, this can be converted to the weight of the "buffer species" by referring to the molecular weight of the most acidic form of the buffer species in question (e.g., acetic acid), ignoring the fact that acetate anions are also present.

[0055] In this specification, any reference to “buffer system” can preferably be interpreted as a reference to “buffer solution,” and the term “buffer solution” can replace all examples of the term “buffer system.” For example, “acetate buffer system” can preferably be interpreted as “acetate buffer solution.” As described with respect to the term “buffer system,” a particular “buffer solution” generally contains an equilibrium mixture of conjugate acids and conjugate bases. For example, “acetate buffer solution” contains acetate anions (such as acetate) and acetic acid, and “histidine buffer solution” generally contains free histidine (i.e., unprotonated neutral histidine) and the imidazolium (protonated) form of histidine. As described with respect to the term “buffer system,” the concentration of a particular “buffer solution” preferably means the total concentration of all relevant conjugate acids and conjugate bases. For example, the concentration of the “acetate buffer” preferably refers to the total concentration of acetate anion and acetate, and the concentration of the “histidine buffer” preferably refers to the total concentration of free histidine and histidine in its imidazolium form (e.g., the concentration of histidine + the concentration of histidine.HCl). As described with respect to “buffer systems”, a “buffer” may consist of a single “buffer” or multiple “buffers”. In this regard, references to “buffer systems” in this specification may preferably be interpreted as references to “buffers”, and the term “buffer” may replace all examples of the term “buffer system”. If a buffer contains multiple buffers, the concentration of the multiple buffers preferably refers to the total concentration of the multiple buffers (i.e., the total concentration of all relevant conjugate acids and conjugate bases). For example, a buffer (or "buffer system") containing both (or consisting of) an acetate buffer and a histidine buffer preferably includes a combination of an acetate anion and acetic acid (forming an acetate buffer), and further a combination of free histidine and the imidazolium (protonated) form of histidine (forming a histidine buffer), the total concentration of the buffer may be the sum of the acetate anion, acetic acid, free histidine, and the imidazolium form of histidine.

[0056] Preferably, the "buffer system" or "buffer solution" is a component of the composition, rather than the composition itself. Therefore, preferably, the "buffer composition" or "buffer solution" will include the "buffer system" or "buffer solution".

[0057] Here, in the context of this specification, "strong acid" preferably means pK a Some have a pK of -1.0 or lower, and "weak acid" is preferably a pK a The pK is 2.0 or higher. Here, in the context of this specification, “strong base” preferably has a conjugate acid of 12 or higher (preferably 14 or higher) pK. a It has the following characteristics, while a "weak base" preferably has a conjugate acid with a pK of 10 or lower. a It possesses the following characteristics.

[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 (including the pH of the entire composition), the relative concentrations of the relevant conjugate acid and conjugate base, and the pK of the conjugate acid are all relevant factors. a You are probably familiar with the well-known "Henderson-Hasselbalch formula" that relates these two things. The formula is as follows:

[0059]

number

[0060] Unless otherwise stated, "pK" in this specification aReferences to "pK" are to be interpreted as the pK of the conjugate acid of the relevant species, preferably in water, at standard ambient temperature and pressure (SATP). a should be interpreted as the value.

[0061] An "amino acid component" is preferably one or more constituent components containing one or more amino acids, although the amino acid component preferably consists of a single amino acid. For clarity, it is emphasized that the amino acid components intended herein are added to pharmaceutical formulations for the purpose of providing a buffering function. Thus, the amino acid component does not include proteins, antibodies, or active pharmaceutical ingredients.

[0062] As used herein, a "sugar component" is preferably one or more constituent components containing one or more sugars and / or sugar alcohols, although the sugar component may consist of a single sugar or sugar alcohol, and glycosylation of antibodies or active pharmaceutical ingredients is excluded.

[0063] 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).

[0064] As used herein, a "tonicity modifier" or "tonicifier" refers to a reagent that, when included in a composition, preferably contributes to (or increases) the total weight osmolality and volume osmolality of the composition. Preferably, tonicifiers used herein include agents that function to make the osmotic properties of the solution similar to those of physiological fluids.

[0065] As used herein, an "antioxidant" or "antioxidant component" is preferably one or more constituent components containing one or more antioxidant compounds, although the antioxidant component may consist of a single antioxidant compound. Antioxidants in the context of the compositions of the present invention preferably reduce the oxidation of groups within fusion proteins that might otherwise be susceptible to oxidation.

[0066] "Chelating agent" is a technical term referring to a compound that can form complexes with various groups, molecules, atoms, or ions, preferably in a polydentate coordination manner, and can exert antioxidant effects on its own.

[0067] In this specification, whenever a composition is said to be “characterized by the absence of [a particular component],” it preferably means that the composition in question is either substantially or completely free of the component.

[0068] The term “substantially absent” when used in reference to a given component of a composition (e.g., “a liquid pharmaceutical composition substantially absent from amino acid components”) refers to a composition in which such component is essentially not added. As explained above, such reference is independent of the presence of amino acid residues in the protein structure. When a composition “substantially absent” a given component, the composition preferably contains 0.1% by weight or less of the component, preferably 0.01% by weight or less of the component, preferably 0.001% by weight or less of the component, preferably 0.0001% by weight or less of the component, preferably 0.00001% by weight or less of the component, preferably 0.000001% by weight or less, preferably 0.0000001% by weight or less, and most preferably 0.0001 parts per billion (by weight) or less of the component.

[0069] The term "completely free" when used in reference to a given component of a composition (e.g., "a liquid pharmaceutical composition substantially free of amino acid components") refers to a composition in which no such component has been added at all. As explained above, such references are unrelated to the presence of amino acid residues in the protein structure.

[0070] Preferably, unless otherwise stated, when referring to parameters that may depend on pressure and / or temperature (e.g., pH, pKa, etc.) or the state of a material (e.g., liquid, gas, etc.), preferably, unless further clarified, such references refer to said parameters under standard laboratory temperature and pressure conditions.

[0071] In this specification, references to specific amounts of a given component of a composition, particularly buffers or buffering systems, surfactants, sugar components, amino acid components, isotonic agents, antioxidants, and / or chelating agents, preferably relate to the amount of the component in its pure anhydrous form (or the composition formed by using the aforementioned amount of the pure anhydrous form), even if such component may be used in a non-anhydrous form when forming the composition. The amount of any corresponding non-anhydrous form (e.g., monohydrate, dihydrate, etc.) can be easily calculated by simply using the appropriate multiplier. For example, unless otherwise stated (in the example, the amount relating to trehalose dihydrate), the amount specified with respect to trehalose refers to trehalose in its anhydrous form (or the composition formed by using the specified amount / concentration of anhydrous trehalose). Since the molecular weight of anhydrous trehalose is 342.296 g / mol, to calculate the corresponding amount of trehalose dihydrate needed to form the same composition (which will likely involve adding less water), one must multiply the specified amount by 378.33 / 342.296, since the molecular weight of trehalose dihydrate is 378.33. Those skilled in the art will readily understand how to carefully adjust the amount of diluent / water depending on the form of the component used to derive the target concentration. This issue does not apply when the molar amount is specified.

[0072] In this specification, the terms “pharmaceutical composition” or “biopharmaceutical composition” refer to a formulation of a (bio)pharmaceutical active substance that makes the biological activity of the active component therapeutically effective, but does not contain other components that are obviously toxic to the target to which the formulation is intended to be administered. In this specification, references to “composition” generally refer to the (bio)pharmaceutical composition as defined herein.

[0073] In this specification, the term “stable” generally refers to the physical and / or chemical and / or biological stability of an ingredient, typically an active substance or a composition thereof, during storage. For aqueous compositions of biologics, storage stability may preferably mean that the biologic remains sufficiently stable (i.e., within predetermined limits for patient safety) even when stored at 2–8°C for at least 6 months, preferably at least 12 months, preferably up to 24 months or longer. However, accelerated stability studies can be used to provide relevant stability information.

[0074] It should be understood that references to “treating” or “treating” a condition include not only the alleviation of established symptoms of a condition but also prevention. Therefore, “treating” or “treating” a condition, disorder, or state includes (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or state in a person who may have or is predisposed to having a condition, disorder, or state but has not yet experienced or presented any clinical or subclinical symptoms of that condition, disorder, or state; (2) inhibiting a condition, disorder, or state, i.e., blocking, reducing, or delaying the onset or recurrence of the disease (in the case of maintenance treatment) or at least one clinical or subclinical symptom of the disease; or (3) alleviating or reducing the disease, i.e., causing the regression of at least one clinical or subclinical symptom of the condition, disorder, or state.

[0075] The terms “effective dose” or “therapeutic effective dose” refer to the amount of an agonist or combination of agonists that produces a desired biological, therapeutic, and / or prophylactic outcome. The outcome may be the reduction, improvement, remission, mitigation, delay, and / or relief of one or more signs, symptoms, or causes of a disease, or any other desired alteration of the biological system. In some embodiments, the effective dose is sufficient to delay tumor development. In some embodiments, the effective dose is sufficient to prevent or delay tumor recurrence. The effective dose may be administered in one or more doses. An effective dose of a drug or composition may (i) reduce the number of cancer cells, (ii) reduce tumor size, (iii) inhibit, delay, slow, or halt cancer cell infiltration into peripheral organs to some extent, (iv) inhibit tumor metastasis, (v) inhibit tumor growth, (vi) prevent or delay tumor onset and / or recurrence, and / or (vii) alleviate to some extent one or more of the symptoms associated with cancer. In one example, the “effective dose” is the amount of a combination of an EGFR / LGR5 antibody and a topoisomerase I inhibitor used 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 cancer regrowth or recurrence, where the cancer is gastrointestinal cancer, preferably colorectal cancer.

[0076] In this specification, the quantities of ingredients and constituents specified, whether specified in parts, ppm (parts per million), percentage (%, e.g., weight %), or ratio, are intended to be by weight unless otherwise stated.

[0077] When the amount or concentration of a particular component of a given composition is specified as a weight percentage (whether weight %) or weight / weight %), the weight percentage refers to the weight percentage of the component relative to the total weight of the composition as a whole. A person skilled in the art will understand that the sum of the weight percentages of all components of a composition (whether specified or not) will total 100% by weight. However, if not all components are listed (for example, if the composition is said to "contain" one or more specific components), the remainder of the weight percentage may be made up to 100% by weight with unspecified components (e.g., diluents such as water, or other optional but preferred additives) as needed.

[0078] Where a composition is said to contain several specified components (in concentrations in amounts as specified, as applicable), the composition may also contain additional components other than those specified, as applicable. However, in certain embodiments, a composition said to contain several specified components may actually consist of or be composed of all specified components in amounts as specified, as applicable, and if the composition is an aqueous composition, water is an implicit component, even if not specified. In any situation, individual components may themselves contain, consist of, or be composed of subcomponents or one or more subcomponents. Wherever the term “comprise” is used herein, it may be replaced with “consists essentially of” or “consists of,” as is appropriate to the context.

[0079] In this specification, when a composition is said to be "essentially" made up of a particular component, the composition preferably contains at least 70% by weight of the component, preferably at least 90% by weight of the component, preferably at least 95% by weight of the component, and most preferably at least 99% by weight of the component. Preferably, a composition said to be "essentially" made up of a particular component consists of the component with one or more trace impurities.

[0080] In this specification, wherever a component is described as being ionizable (e.g., protonated or deprotonated), unless otherwise incompatible in a given context, the definition of the component preferably includes any suitable salt thereof, preferably a pharmaceutically acceptable salt thereof. For example, this applies to all references herein to buffering agents (e.g., citrate or citrate) and amino acids, etc. Similarly, wherever a component is described as being neutralizable, unless otherwise incompatible in a given context, the definition of the component preferably includes its neutralized form, for example, citrate instead of citrate.

[0081] <Pharmaceutical composition> The present invention provides a pharmaceutical composition, in particular a multispecific antibody comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional moiety or derivative thereof, a buffer system comprising histidine buffer and / or citrate buffer, a sugar component, and a nonionic surfactant.

[0082] The composition is most preferably a liquid pharmaceutical composition, preferably an aqueous pharmaceutical composition. Generally, the amounts and concentrations herein relate to liquid pharmaceutical compositions, but such amounts can be readily converted for calculation purposes to corresponding amounts in the corresponding solid compositions. Thus, amounts can be expressed as (weight or mole) ratios between the respective components, or as absolute concentrations (taking into account the removal of diluents).

[0083] The composition preferably comprises a polyspecific or bispecific antibody (i.e., EGFR / LGR5 BsAb) having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, which may also be simply referred to herein as “antibody”. The composition preferably comprises a diluent. The composition preferably comprises a buffer system, preferably a histidine or citrate buffer system, more preferably a histidine buffer system. The composition preferably comprises a salt isotonic agent. The composition preferably comprises a sugar component, the sugar component preferably being or comprising sucrose. The composition preferably comprises a surfactant, more preferably a nonionic surfactant being polysorbate 80 or comprising the same. The composition preferably comprises an amino acid component.

[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, and most preferably 5.9 or 6.3.

[0085] The antibodies present in the pharmaceutical composition of the present invention are present at concentrations of 0.5 to 150 mg / mL, preferably 1 to 100 mg / mL, more preferably 1 to 50 mg / mL, more preferably 1 to 30 mg / mL, more preferably 5 to 25 mg / mL, more preferably 15 to 25 mg / mL, and most preferably 20 mg / mL.

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

[0087] The nonionic surfactant is present at a concentration of preferably 0.01 to 2 mg / mL, preferably 0.1 to 1.5 mg / mL, more preferably 0.1 to 0.6 mg / mL or 0.6 to 1.2 mg / mL, and most preferably 0.2 mg / mL, 0.5 mg / mL, or 1 mg / mL.

[0088] The buffer system or combination of buffer systems is preferably present at a concentration of 2 to 50 mM, preferably 3 to 20 mM, more preferably 4 to 12 mM, more preferably 3 to 7 mM or 8 to 12 mM, and most preferably 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 1825:1 to 2555:1, more preferably 1970:1 to 2190:1, and most preferably about 2040:1 or 2117:1.

[0090] The molar concentration ratio of nonionic surfactant to antibody is preferably 1:90 to 224:1, preferably 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 1.11:1, about 2.79:1, or about 5.55:1.

[0091] The molar concentration ratio of buffer system (or combination of buffer systems) versus antibody is preferably 2.9:1 to 7300:1, preferably 6:1 to 700:1, preferably 14:1 to 365:1, preferably 21:1 to 146:1, preferably 29:1 to 88:1, more preferably 21:1 to 51:1 or 58:1 to 88:1, and 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 comprises only a single buffer system, such as a histidine buffer or a citrate buffer.

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

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

[0096] The composition can preferably be characterized by the absence of water or by having less than 5% by weight of water. The composition can preferably be characterized by the absence of (unbuffered) salt isotonic agents. The composition can preferably be characterized by the absence of antioxidants (or one or more of the antioxidants specifically mentioned herein). The composition can preferably be characterized by the absence of chelating agents (or one or more of the chelating agents specifically mentioned herein).

[0097] A) Embodiments of combinations of constituent components to be included The pharmaceutical composition comprises an antibody, a functional portion thereof, a derivative or variant thereof, and optionally 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, comprises, optionally together with water for injection) the following and is characterized by the following: A1. EGFR / LGR5 BsAb, and buffer system. A2. EGFR / LGR5 BsAb and salt isotonic agents. A3. EGFR / LGR5 BsAb and glucose components. A4. EGFR / LGR5 BsAb, and surfactants. A5. EGFR / LGR5 BsAb and amino acid components. A6. EGFR / LGR5 BsAb and antioxidants. A7. EGFR / LGR5 BsAb and chelating agents. A8. EGFR / LGR5 BsAb, buffer system, and salt isotonic agent. A9. EGFR / LGR5 BsAb, buffer system, and glucose components. A10. EGFR / LGR5 BsAb, buffering systems, and surfactants. A11. EGFR / LGR5 BsAb, buffer system, and amino acid components. A12. EGFR / LGR5 BsAb, buffering system, and antioxidant. A13. EGFR / LGR5 BsAb, buffering system, and chelating agent. A14. EGFR / LGR5 BsAb, salt isotonic agent, and sugar component. A15. EGFR / LGR5 BsAb, salt isotonic agents, and surfactants. A16. EGFR / LGR5 BsAb, salt isotonic agent, and amino acid components. A17. EGFR / LGR5 BsAb, salt isotonic agent, and antioxidant. 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, buffer system, sugar components, and surfactants. A35. EGFR / LGR5 BsAb, buffer system, glucose components, and amino acid components. A36. EGFR / LGR5 BsAb, buffer 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 systems, surfactants, and antioxidants. 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, buffering 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 agent, surfactant, and amino acid component. A49. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, and antioxidant. A50. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, and chelating agent. A51. EGFR / LGR5 BsAb, salt isotonic agent, amino acid component, and antioxidant. A52. EGFR / LGR5 BsAb, salt isotonic agent, amino acid component, and chelating agent. 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 components, surfactants, and antioxidants. A56. EGFR / LGR5 BsAb, sugar components, surfactants, and chelating agents. A57. EGFR / LGR5 BsAb, sugar components, amino acid components, and antioxidants. A58. EGFR / LGR5 BsAb, sugar components, amino acid components, and chelating agents. A59. EGFR / LGR5 BsAb, sugar component, antioxidant, and chelating agent. A60. EGFR / LGR5 BsAb, surfactant, amino acid component, and antioxidant. 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 components, antioxidants, and chelating agents. A64. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, and surfactant. A65. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, and amino acid component. A66. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, and antioxidant. A67. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, and chelating agent. A68. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, surfactant, and amino acid component. A69. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, surfactant, and antioxidant. A70. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, surfactant, and chelating agent. A71. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, amino acid component, and antioxidant. A72. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, amino acid component, and chelating agent. A73. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, antioxidant, and chelating agent. A74. EGFR / LGR5 BsAb, buffering system, sugar components, surfactants, and amino acid components. A75. EGFR / LGR5 BsAb, buffering system, sugar component, surfactant, and antioxidant. A76. EGFR / LGR5 BsAb, buffering system, sugar component, surfactant, and chelating agent. A77. EGFR / LGR5 BsAb, buffer system, sugar components, amino acid components, and antioxidants. A78. EGFR / LGR5 BsAb, buffering system, sugar components, amino acid components, and chelating agents. A79. EGFR / LGR5 BsAb, buffering system, sugar component, antioxidant, and chelating agent. A80. EGFR / LGR5 BsAb, buffering system, surfactant, amino acid component, and antioxidant. A81. EGFR / LGR5 BsAb, buffering system, surfactant, amino acid component, and chelating agent. A82. EGFR / LGR5 BsAb, buffering system, surfactant, antioxidant, and chelating agent. A83. EGFR / LGR5 BsAb, buffering system, amino acid component, antioxidant, and chelating agent. A84. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, and amino acid component. 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 antioxidant. 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 chelating agent. A90. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, amino acid component, and antioxidant. A91. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, amino acid component, and chelating agent. A92. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, antioxidant, and chelating agent. A93. EGFR / LGR5 BsAb, salt isotonic agent, amino acid component, antioxidant, and 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 agents. A96. EGFR / LGR5 BsAb, sugar component, surfactant, antioxidant, and chelating agent. A97. EGFR / LGR5 BsAb, sugar components, amino acid components, antioxidants, and chelating agents. A98. EGFR / LGR5 BsAb, surfactant, amino acid component, antioxidant, and chelating agent. A99. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, surfactant, and amino acid component. A100. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, surfactant, and antioxidant. A101. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, surfactant, and chelating agent. A102. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, amino acid component, and antioxidant. A103. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, amino acid component, and chelating agent. A104. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, antioxidant, and chelating agent. A105. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, surfactant, amino acid component, and antioxidant. A106. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, surfactant, amino acid component, and chelating agent. A107. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, surfactant, antioxidant, and chelating agent. A108. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, amino acid component, antioxidant, and chelating agent. A109. EGFR / LGR5 BsAb, buffering system, sugar components, surfactants, amino acid components, and antioxidants. A110. EGFR / LGR5 BsAb, buffering system, sugar components, surfactants, amino acid components, and chelating agents. A111. EGFR / LGR5 BsAb, buffering system, sugar component, surfactant, antioxidant, and chelating agent. A112. EGFR / LGR5 BsAb, buffering system, sugar component, amino acid component, antioxidant, and chelating agent. A113. EGFR / LGR5 BsAb, buffering system, surfactant, amino acid component, antioxidant, and chelating agent. A114. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, amino acid component, and antioxidant. A115. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, amino acid component, and chelating agent. A116. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, antioxidant, and chelating agent. A117. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, amino acid component, antioxidant, and chelating agent. A118. EGFR / LGR5 BsAb, salt isotonic agent, surfactant, amino acid component, antioxidant, and chelating agent. A119. EGFR / LGR5 BsAb, sugar components, surfactants, amino acid components, antioxidants, and chelating agents. A120. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, surfactant, amino acid component, and antioxidant. A121. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, surfactant, amino acid component, and chelating agent. A122. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, sugar component, surfactant, antioxidant, and chelating agent. A123. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, amino acid component, antioxidant, and chelating agent. A124. EGFR / LGR5 BsAb, buffering system, salt isotonic agent, surfactant, amino acid component, antioxidant, and chelating agent. A125. EGFR / LGR5 BsAb, buffering system, sugar component, surfactant, amino acid component, antioxidant, and chelating agent. A126. EGFR / LGR5 BsAb, salt isotonic agent, sugar component, surfactant, amino acid component, antioxidant, and chelating agent. A127. EGFR / LGR5 BsAb, buffer system, salt isotonic agent, sugar component, surfactant, amino acid component, antioxidant, and chelating agent.

[0099] In A1 to A127, the bispecific antibody, referred to as EGFR / LGR5 BsAb, which includes a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, its functional moiety, derivative, or variant preferably includes a full-length IgG antibody.

[0100] B) Embodiments of combinations of constituent components to be included and solution concentration The following numbered paragraphs B1 to B128 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, optionally together with water for injection) the following and is characterized by the following: 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 salt isotonic agent. B4. EGFR / LGR5 BsAb, pH 4-8.5, and 20-400 mM sugar components. 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 amino acid 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, and 3-200 mM salt isotonic agent. B10. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, and 20-400 mM sugar component. B11. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, and 0.01-2 mg / mL surfactant. B12. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, and 5-150 mM amino acid components. B13. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, and 0.1-100 mM antioxidant. B14. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, and 0.001-0.5 mM chelating agent. B15. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, and 20-400 mM sugar component. B16. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, and 0.01-2 mg / mL surfactant. B17. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, and 5-150 mM amino acid component. B18. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, and 0.1-100 mM antioxidant. B19. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, and 0.001-0.5 mM chelating agent. B20. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar component, and 0.01-2 mg / mL surfactant. B21. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar components, and 5-150 mM amino acid components. B22. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar component, and 0.1-100 mM antioxidant. B23. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar component, and 0.001-0.5 mM chelating agent. B24. EGFR / LGR5 BsAb, pH 4-8.5, 0.01-2 mg / mL surfactant, and 5-150 mM amino acid components. B25. EGFR / LGR5 BsAb, pH 4-8.5, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B26. EGFR / LGR5 BsAb, pH 4-8.5, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. B27. EGFR / LGR5 BsAb, pH 4-8.5, 5-150 mM amino acid components, and 0.1-100 mM antioxidants. B28. EGFR / LGR5 BsAb, pH 4-8.5, 5-150 mM amino acid components, and 0.001-0.5 mM chelating agent. B29. EGFR / LGR5 BsAb, pH 4-8.5, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B30. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, and 20-400 mM sugar component. B31. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, and 0.01-2 mg / mL surfactant. B32. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, and 5-150 mM amino acid component. B33. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, and 0.1-100 mM antioxidant. B34. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, and 0.001-0.5 mM chelating agent. B35. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, and 0.01-2 mg / mL surfactant. B36. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar components, and 5-150 mM amino acid components. B37. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, and 0.1-100 mM antioxidant. B38. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, and 0.001-0.5 mM chelating agent. B39. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 0.01-2 mg / mL surfactant, and 5-150 mM amino acid component. B40. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B41. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. B42. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 5-150 mM amino acid components, and 0.1-100 mM antioxidant. B43. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B44. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 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 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 agent, 20-400 mM sugar component, and 5-150 mM amino acid component. B47. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 0.1-100 mM antioxidant. B48. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 0.001-0.5 mM chelating agent. B49. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic 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 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 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 agent, 5-150 mM amino acid component, and 0.1-100 mM antioxidant. B53. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic 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 agent, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B55. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar components, 0.01-2 mg / mL surfactant, and 5-150 mM amino acid components. B56. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar components, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B57. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. B58. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar components, 5-150 mM amino acid components, and 0.1-100 mM antioxidants. B59. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar component, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B60. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B61. EGFR / LGR5 BsAb, pH 4-8.5, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.1-100 mM antioxidant. B62. EGFR / LGR5 BsAb, pH 4-8.5, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B63. EGFR / LGR5 BsAb, pH 4-8.5, 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B64. EGFR / LGR5 BsAb, pH 4-8.5, 5-150 mM amino acid components, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agents. B65. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 0.01-2 mg / mL surfactant. B66. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 5-150 mM amino acid component. B67. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 0.1-100 mM antioxidant. B68. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, and 0.001-0.5 mM chelating agent. B69. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, and 5-150 mM amino acid component. B70. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B71. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. B72. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 5-150 mM amino acid component, and 0.1-100 mM antioxidant. B73. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B74. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B75. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 5-150 mM amino acid component. B76. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B77. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. B78. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar components, 5-150 mM amino acid components, and 0.1-100 mM antioxidants. B79. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B80. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B81. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.1-100 mM antioxidant. B82. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B83. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B84. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 5-150 mM amino acid components, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B85. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 5-150 mM amino acid component. B86. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B87. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic 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 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 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 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 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 agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B93. EGFR / LGR5 BsAb, pH 4-8.5, 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. B94. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B95. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar components, 0.01-2 mg / mL surfactant, 5-150 mM amino acid components, and 0.1-100 mM antioxidant. B96. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B97. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B98. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar components, 5-150 mM amino acid components, 0.1-100 mM antioxidants, and 0.001-0.5 mM chelating agents. B99. EGFR / LGR5 BsAb, pH 4-8.5, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B100. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 5-150 mM amino acid component. B101. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 0.1-100 mM antioxidant. B102. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. B103. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 5-150 mM amino acid component, and 0.1-100 mM antioxidant. B104. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B105. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B106. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.1-100 mM antioxidant. B107. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B108. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 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; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B110. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar components, 0.01-2 mg / mL surfactant, 5-150 mM amino acid components, and 0.1-100 mM antioxidant. B111. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B112. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B113. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar components, 5-150 mM amino acid components, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B114. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B115. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.1-100 mM antioxidant. B116. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B117. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B118. EGFR / LGR5 BsAb, pH 4-8.5, 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. B119. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B120. EGFR / LGR5 BsAb, pH 4-8.5, 20-400 mM sugar components, 0.01-2 mg / mL surfactant, 5-150 mM amino acid components, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B121. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.1-100 mM antioxidant. B122. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, and 0.001-0.5 mM chelating agent. B123. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B124. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 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; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B126. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B127. EGFR / LGR5 BsAb, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent. B128. EGFR / LGR5 BsAb; 1-100 mM buffer system, pH 4-8.5, 3-200 mM salt isotonic agent, 20-400 mM sugar component, 0.01-2 mg / mL surfactant, 5-150 mM amino acid component, 0.1-100 mM antioxidant, and 0.001-0.5 mM chelating agent.

[0101] In B1 to B128, the bispecific antibody, which includes a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, its functional moiety, derivative, or variant preferably includes a full-length IgG antibody.

[0102] C) Embodiments of combinations and molar ratios of constituent components to be included The following numbered paragraphs C1 to C128 disclose specific embodiments of the present invention, wherein the pharmaceutical composition comprises (or, in the case of an aqueous composition, optionally together with water for injection) the following and is characterized by the following: C1. EGFR / LGR5 BsAb, and pH 4-8.5. C2. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, and pH 4 to 8.5. C3. Salt isotonic agent with EGFR / LGR5 BsAb, pH 4-8.5, and a molar ratio of salt isotonic agent to antibody of 7:1-3000:1. C4. EGFR / LGR5 BsAb, pH 4-8.5, and sugar components with a molar ratio of sugar component to antibody of 100:1-5500:1. C5. A surfactant with EGFR / LGR5 BsAb, pH 4-8.5, and a surfactant-to-antibody molar ratio of 1:11-17:1. C6. EGFR / LGR5 BsAb, pH 4-8.5, and amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1. C7. Antioxidants with EGFR / LGR5 BsAb, pH 4-8.5, and an antioxidant-to-antibody molar ratio of 2:1-750:1. C8. A chelating agent with EGFR / LGR5 BsAb, pH 4-8.5, and a molar ratio of chelating agent to antibody of 1:420-8:1. C9. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, and salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1. C10. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, and sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1. C11. EGFR / LGR5 BsAb, a buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, and a surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1. C12. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, and amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C13. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C14. EGFR / LGR5 BsAb, a buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, and a chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C15. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, and sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1. C16. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, and surfactant with a molar ratio of surfactant to antibody of 1:11-17:1. C17. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1. C18. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C19. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C20. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, and surfactant with a molar ratio of surfactant to antibody of 1:11-17:1. C21. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1. C22. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C23. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C24. EGFR / LGR5 BsAb, pH 4-8.5, surfactant with a surfactant-to-antibody molar ratio of 1:11-17:1, and amino acid component with an amino acid component-to-antibody molar ratio of 10:1-2500:1. C25. EGFR / LGR5 BsAb, pH 4-8.5, surfactant with a surfactant-to-antibody molar ratio of 1:11-17:1, and antioxidant with an antioxidant-to-antibody molar ratio of 2:1-750:1. C26. EGFR / LGR5 BsAb, pH 4-8.5, surfactant with a surfactant-to-antibody molar ratio of 1:11-17:1, and chelating agent with a chelating agent-to-antibody molar ratio of 1:420-8:1. C27. EGFR / LGR5 BsAb, pH 4-8.5, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C28. EGFR / LGR5 BsAb, pH 4-8.5, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C29. EGFR / LGR5 BsAb, pH 4-8.5, antioxidant with an antioxidant-to-antibody molar ratio of 2:1-750:1, and chelating agent with a chelating agent-to-antibody molar ratio of 1:420-8:1. C30. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, and sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1. C31. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, and surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1. C32. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C33. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C34. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C35. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, and surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1. C36. EGFR / LGR5 BsAb, buffer system with a buffer system-to-antibody molar ratio of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a sugar component-to-antibody molar ratio of 100:1 to 5500:1, and amino acid component with an amino acid component-to-antibody molar ratio of 10:1 to 2500:1. C37. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C38. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C39. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C40. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C41. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C42. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C43. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C44. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C45. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, and surfactant with a molar ratio of surfactant to antibody of 1:11-17:1. C46. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1. C47. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C48. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C49. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, and amino acid component with a molar ratio of 10:1-2500:1 to antibody. C50. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, and antioxidant with a molar ratio of 2:1-750:1 to antibody. C51. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C52. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C53. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C54. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C55. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11-17:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1. C56. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11-17:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C57. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11-17:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C58. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C59. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C60. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C61. EGFR / LGR5 BsAb, pH 4-8.5, surfactant with a surfactant-to-antibody molar ratio of 1:11-17:1, amino acid component with an amino acid component-to-antibody molar ratio of 10:1-2500:1, and antioxidant with an antioxidant-to-antibody molar ratio of 2:1-750:1. C62. EGFR / LGR5 BsAb, pH 4-8.5, surfactant with a surfactant-to-antibody molar ratio of 1:11-17:1, amino acid component with an amino acid component-to-antibody molar ratio of 10:1-2500:1, and chelating agent with a chelating agent-to-antibody molar ratio of 1:420-8:1. C63. EGFR / LGR5 BsAb, pH 4-8.5, surfactant with a surfactant-to-antibody molar ratio of 1:11-17:1, antioxidant with an antioxidant-to-antibody molar ratio of 2:1-750:1, and chelating agent with a chelating agent-to-antibody molar ratio of 1:420-8:1. C64. EGFR / LGR5 BsAb, pH 4-8.5, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C65. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, and surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1. C66. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C67. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C68. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C69. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C70. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, and antioxidant with a molar ratio of 2:1 to 750:1 against antibody. C71. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C72. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C73. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C74. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C75. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C76. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C77. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C78. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C79. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C80. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C81. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, and antioxidant with a molar ratio of 2:1 to 750:1 against antibody. C82. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C83. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, surfactant with a molar ratio of 1:11 to 17:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C84. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C85. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, and amino acid component with a molar ratio of 10:1-2500:1 to antibody. C86. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, and antioxidant with a molar ratio of 2:1-750:1 to antibody. C87. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C88. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C89. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1-3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C90. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, antioxidant with a molar ratio of 2:1-750:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C91. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, amino acid component with a molar ratio of 10:1-2500:1 to antibody, and antioxidant with a molar ratio of 2:1-750:1 to antibody. C92. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, amino acid component with a molar ratio of 10:1-2500:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C93. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, antioxidant with a molar ratio of 2:1-750:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C94. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, amino acid component with a molar ratio of 10:1-2500:1 to antibody, antioxidant with a molar ratio of 2:1-750:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C95. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11-17:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1. C96. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11-17:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C97. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11-17:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C98. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C99. EGFR / LGR5 BsAb, pH 4-8.5, surfactant with a surfactant-to-antibody molar ratio of 1:11-17:1, amino acid component with an amino acid component-to-antibody molar ratio of 10:1-2500:1, antioxidant with an antioxidant-to-antibody molar ratio of 2:1-750:1, and chelating agent with a chelating agent-to-antibody molar ratio of 1:420-8:1. C100. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1. C101. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C102. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C103. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C104. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C105. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C106. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, and antioxidant with a molar ratio of 2:1 to 750:1 against antibody. C107. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C108. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C109. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C110. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11 to 17:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, and antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1. C111. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C112. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C113. EGFR / LGR5 BsAb, buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1, pH 4 to 8.5, sugar component with a molar ratio of sugar component to antibody of 100:1 to 5500:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1 to 2500:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1 to 750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420 to 8:1. C114. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C115. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, amino acid component with a molar ratio of 10:1-2500:1 to antibody, and antioxidant with a molar ratio of 2:1-750:1 to antibody. C116. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, amino acid component with a molar ratio of 10:1-2500:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C117. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, antioxidant with a molar ratio of 2:1-750:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C118. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, amino acid component with a molar ratio of 10:1-2500:1 to antibody, antioxidant with a molar ratio of 2:1-750:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C119. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, amino acid component with a molar ratio of 10:1-2500:1 to antibody, antioxidant with a molar ratio of 2:1-750:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C120. EGFR / LGR5 BsAb, pH 4-8.5, sugar component with a molar ratio of sugar component to antibody of 100:1-5500:1, surfactant with a molar ratio of surfactant to antibody of 1:11-17:1, amino acid component with a molar ratio of amino acid component to antibody of 10:1-2500:1, antioxidant with a molar ratio of antioxidant to antibody of 2:1-750:1, and chelating agent with a molar ratio of chelating agent to antibody of 1:420-8:1. C121. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, and antioxidant with a molar ratio of 2:1 to 750:1 against antibody. C122. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C123. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C124. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C125. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C126. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody. C127. EGFR / LGR5 BsAb, pH 4-8.5, salt isotonic agent with a molar ratio of 7:1-3000:1 to antibody, sugar component with a molar ratio of 100:1-5500:1 to antibody, surfactant with a molar ratio of 1:11-17:1 to antibody, amino acid component with a molar ratio of 10:1-2500:1 to antibody, antioxidant with a molar ratio of 2:1-750:1 to antibody, and chelating agent with a molar ratio of 1:420-8:1 to antibody. C128. EGFR / LGR5 BsAb, buffer system with a molar ratio of 4:1 to 1050:1 against antibody, pH 4 to 8.5, salt isotonic agent with a molar ratio of 7:1 to 3000:1 against antibody, sugar component with a molar ratio of 100:1 to 5500:1 against antibody, surfactant with a molar ratio of 1:11 to 17:1 against antibody, amino acid component with a molar ratio of 10:1 to 2500:1 against antibody, antioxidant with a molar ratio of 2:1 to 750:1 against antibody, and chelating agent with a molar ratio of 1:420 to 8:1 against antibody.

[0103] The bispecific antibody, which is denoted as EGFR / LGR5 BsAb in C1-C128 and includes a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, its functional moiety, derivative, or variant preferably includes a full-length IgG antibody.

[0104] <Bispecific antibody> The pharmaceutical composition comprises a polyspecific antibody or preferably a bispecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional moiety or derivative thereof, preferably a bispecific antibody (BsAb) (EGFR / LGR5 BsAb) having both anti-EGFR binding properties and anti-LGR5 binding properties.

[0105] EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific monoclonal antibody (EGFR / LGR5 BsAb). EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 heterodimer bispecific antibody. EGFR / LGR5 BsAb is preferably a human monoclonal antibody. EGFR / LGR5 BsAb is preferably an IgG antibody. EGFR / LGR5 BsAb is preferably an IgG1 antibody. EGFR / LGR5 BsAb is preferably a full-length antibody. EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific heterodimer IgG1 monoclonal antibody. EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific heterodimer full-length human IgG1 monoclonal antibody.

[0106] A bispecific antibody preferably comprises a first binding (or variable) domain that binds to the extracellular portion of EGFR and a second binding or variable domain that binds to the extracellular portion of LGR5. The EGFR / LGR5 antibodies described herein are preferably bispecific antibodies having two variable domains, i.e., one that binds to EGFR and another that binds to LGR5, as described herein.

[0107] The binding (or variable) domain that binds to human EGFR is preferably a domain having a heavy chain variable region that includes at least the CDR3 sequence of the VH of MF3755 shown in Figure 1, or a CDR3 sequence that differs from the CDR3 sequence of the VH of MF3755 shown in Figure 1 by at most three, preferably at most two, and preferably one or fewer amino acids.

[0108] The binding (or variable) domain that binds to human EGFR is preferably a domain having a heavy chain variable region that includes the CDR1, CDR2, and CDR3 sequences of the VH of MF3755 shown in Figure 1, or at most three, preferably at most two, and preferably at most one amino acid substitution.

[0109] The binding (or variable) domain that binds to human EGFR is preferably a domain having a heavy chain variable region containing the amino acid sequence of the VH chain of MF3755 shown in Figure 1, or a heavy chain variable region containing 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 combinations thereof, relative to the VH chain of MF3755.

[0110] The binding (or variable) domain that binds to human EGFR is preferably a domain having a heavy chain variable region that includes at least the CDR3 sequence of the VH of MF4280 shown in Figure 1, or a CDR3 sequence that differs from the CDR3 sequence of the VH of MF4280 shown in Figure 1 by at most three, preferably at most two, and preferably one or fewer amino acids.

[0111] The binding (or variable) domain that binds to human EGFR is preferably a domain having a heavy chain variable region that includes the CDR1, CDR2, and CDR3 sequences of the VH of MF4280 shown in Figure 1, or at most three, preferably at most two, and preferably at most one amino acid substitution.

[0112] The antibody preferably contains an EGFR-binding domain that includes a heavy chain variable region (VH) containing the VH chain sequence of MF3370, MF3755, MF4280, or MF4289 as shown in Figure 1, or an EGFR-binding domain that includes a heavy chain variable region (VH) containing the VH chain sequence of MF3370, MF3755, MF4280, or MF4289 as shown in Figure 1, having 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 combinations thereof.

[0113] The binding (or variable) domain that binds to human EGFR is preferably a domain having a heavy chain variable region containing the amino acid sequence of the VH chain of MF4280 shown in Figure 1, 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, substitutions, or combinations thereof, relative to the VH chain of MF4280.

[0114] In one embodiment, the present invention provides a pharmaceutical composition comprising an antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the heavy chain variable region of the domain includes at least a CDR3 sequence of an EGFR-specific heavy chain variable region selected from the group consisting of MF3370, MF3755, MF4280, or MF4289 shown in Figure 1, or the heavy chain variable region of the domain includes a VH CDR3 sequence selected from the group consisting of MF3370, MF3755, MF4280, or MF4289 shown in Figure 1, and a heavy chain CDR3 sequence that differs by at most three, preferably at most two, and preferably one or less amino acids. The variable domain preferably includes a heavy chain variable region containing at least a CDR3 sequence of MF3370, MF3755, MF4280, or MF4289 shown in Figure 1.

[0115] The binding (or variable) domain preferably includes a heavy chain variable region containing at least the CDR1, CDR2, and CDR3 sequences of an EGFR-specific heavy chain variable region selected from the group consisting of MF3370, MF3755, MF4280, or MF4289 shown in Figure 1, or a heavy chain variable region containing at least the CDR1, CDR2, and CDR3 sequences of an EGFR-specific heavy chain variable region selected from the group consisting of MF3370, MF3755, MF4280, or MF4289 shown in Figure 1, and at least the CDR1, CDR2, and CDR3 sequences that differ by at most three, preferably at most two, and preferably at most one amino acid. The domain preferably includes a heavy chain variable region containing at least the CDR1, CDR2, and CDR3 sequences of MF3370, MF3755, MF4280, or MF4289 shown in Figure 1. The preferred heavy chain variable region is MF3755. Another preferred heavy chain variable region is MF4280.

[0116] Preferably, the pharmaceutical composition comprises an antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the EGFR binding domain has CDR3, CDR1, CDR2, and CDR3, and / or the VH sequence shown above in this specification is preferably MF5790, MF5803, MF5805, MF5808, MF5809, MF5814, MF5816, MF5817, or MF5818 as shown in Figure 2. The LGR5-binding variable domain includes at least one CDR3 sequence of an LGR5-specific heavy chain variable region selected from the group, or a VH CDR3 sequence selected from the group consisting of MF5790, MF5803, MF5805, MF5808, MF5809, MF5814, MF5816, MF5817, or MF5818 shown in Figure 2, and a heavy chain CDR3 sequence that differs by at most three, preferably at most two, and preferably one or less amino acids. The binding or variable domain preferably includes a heavy chain variable region containing at least one CDR3 sequence of MF5790, MF5803, MF5805, MF5808, MF5809, MF5814, MF5816, MF5817, or MF5818 shown in Figure 2.

[0117] The LGR5-binding (or variable) domain preferably includes at least CDR1, CDR2, and CDR3 sequences of an LGR5-specific heavy chain variable region selected from the group consisting of MF5790, MF5803, MF5805, MF5808, MF5809, MF5814, MF5816, MF5817, or MF5818 shown in Figure 2, or a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences of an LGR5-specific heavy chain variable region selected from the group consisting of MF5790, MF5803, MF5805, MF5808, MF5809, MF5814, MF5816, MF5817, or MF5818 shown in Figure 2, and heavy chain variable regions comprising heavy chain CDR1, CDR2, and CDR3 sequences that differ by at most three, preferably at most two, and preferably at most one amino acid. The domain preferably includes a heavy chain variable region containing at least the CDR1, CDR2, and CDR3 sequences of MF5790, MF5803, MF5805, MF5808, MF5809, MF5814, MF5816, MF5817, or MF5818 as shown in Figure 2. Preferred heavy chain variable regions are MF5790, MF5803, MF5814, MF5816, MF5817, or MF5818. Particularly preferred heavy chain variable regions are MF5790, MF5814, MF5816, and MF5818, preferably MF5814, MF5818, and MF5816, with heavy chain variable region MF5816 being particularly preferred. Another preferred heavy chain variable region is MF5818.

[0118] Preferably, the antibody includes an LGR5 binding domain containing a heavy chain variable region that includes the VH chain sequence of MF5790, MF5803, MF5805, MF5808, MF5809, MF5814, MF5816, MF5817, or MF5818 shown in Figure 2, 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, substitutions, or combinations thereof.

[0119] The VH chain of the variable domain that binds to EGFR or LGR5 may have one or more amino acid substitutions relative to the sequence shown in Figure 1 or Figure 2. Preferably, the VH chain has the amino acid sequence of EGFR VH or LGR5 VH shown in Figure 1 or Figure 2, having 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 combinations thereof relative to the VH chain sequence in Figure 1 or Figure 2.

[0120] Preferably, any 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 1, 2, 3, 4, or 5, amino acid substitutions mentioned in the VH or VL specified herein are preferably conservative amino acid substitutions. Amino acid insertions, deletions, and substitutions in the VH or VL specified herein are preferably not present in the CDR3 region. Furthermore, the mentioned amino acid insertions, deletions, and substitutions are preferably not present in the CDR1 and CDR2 regions. Also, the mentioned amino acid insertions, deletions, and substitutions are preferably not present in the FR4 region.

[0121] The most numerous amino acid substitutions mentioned, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 1, 2, 3, 4, or 5, are preferably conservative amino acid substitutions, and insertions, deletions, substitutions, or combinations thereof are preferably not present in the CDR3 region of the VH chain, preferably not in the CDR1, CDR2, or CDR3 region of the VH chain, and preferably not in the FR4 region.

[0122] Preferably, the pharmaceutical composition is an antibody having a variable domain that binds to the extracellular portion of EGFR and a variable domain that binds to the extracellular portion of LGR5, and preferably, - The amino acid sequence of VH chain MF3755 shown in Figure 1, or - The VH chain of the variable domain that binds to LGR5 contains the amino acid sequence of the VH chain MF3755 shown in Figure 1, which has 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 combinations thereof relative to the VH, - The amino acid sequence of VH chain MF5790 shown in Figure 2, or - The antibody comprises the amino acid sequence of the VH chain MF5790 shown in Figure 2, having 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 combinations thereof relative to the VH.

[0123] Preferably, the pharmaceutical composition is an antibody having a variable domain that binds to the extracellular portion of EGFR and a variable domain that binds to the extracellular portion of LGR5, and preferably, - The amino acid sequence of VH chain MF3755 shown in Figure 1, or - The VH chain of the variable domain that binds to LGR5 contains the amino acid sequence of the VH chain MF3755 shown in Figure 1, which has 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 combinations thereof relative to the VH, - The amino acid sequence of VH chain MF5816 shown in Figure 2, or - The antibody comprises the amino acid sequence of the VH chain MF5816 shown in Figure 2, having 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 combinations thereof, relative to the VH.

[0124] Preferably, the pharmaceutical composition is an antibody having a variable domain that binds to the extracellular portion of EGFR and a variable domain that binds to the extracellular portion of LGR5, and preferably, - The amino acid sequence of VH chain MF3755 shown in Figure 1, or - The VH chain of the variable domain that binds to LGR5 contains the amino acid sequence of the VH chain MF3755 shown in Figure 1, which has 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 combinations thereof relative to the VH, - The amino acid sequence of VH chain MF5818 shown in Figure 2, or - The antibody comprises the amino acid sequence of the VH chain MF5818 shown in Figure 2, having 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 combinations thereof, relative to the VH.

[0125] Preferably, the pharmaceutical composition is an antibody having a variable domain that binds to the extracellular portion of EGFR and a variable domain that binds to the extracellular portion of LGR5, and preferably, - The amino acid sequence of VH chain MF4280 shown in Figure 1, or - The VH chain of the variable domain that binds to LGR5 contains the amino acid sequence of the VH chain MF4280 shown in Figure 1, which has 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 combinations thereof relative to the VH, - The amino acid sequence of VH chain MF5790 shown in Figure 2, or - The antibody comprises the amino acid sequence of the VH chain MF5790 shown in Figure 2, having 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 combinations thereof relative to the VH.

[0126] Preferably, the pharmaceutical composition is an antibody having a variable domain that binds to the extracellular portion of EGFR and a variable domain that binds to the extracellular portion of LGR5, and preferably, - The amino acid sequence of VH chain MF4280 shown in Figure 1, or - The VH chain of the variable domain that binds to LGR5 contains the amino acid sequence of the VH chain MF4280 shown in Figure 1, which has 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 combinations thereof relative to the VH, - The amino acid sequence of VH chain MF5816 shown in Figure 2, or - The antibody comprises the amino acid sequence of the VH chain MF5816 shown in Figure 2, having 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 combinations thereof, relative to the VH.

[0127] Preferably, the pharmaceutical composition is an antibody having a variable domain that binds to the extracellular portion of EGFR and a variable domain that binds to the extracellular portion of LGR5, and preferably, - The amino acid sequence of VH chain MF4280 shown in Figure 1, or - The VH chain of the variable domain that binds to LGR5 contains the amino acid sequence of the VH chain MF4280 shown in Figure 1, which has 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 combinations thereof relative to the VH, - The amino acid sequence of VH chain MF5818 shown in Figure 2, or - The antibody comprises the amino acid sequence of the VH chain MF5818 shown in Figure 2, having 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 combinations thereof, relative to the VH.

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

[0129] The antibody preferably includes a binding domain containing a light chain variable region (VL) containing the VL chain sequence shown in Figure 3, or a binding domain containing a light chain variable region (VL) containing the VL chain sequence shown in Figure 3, having 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 combinations thereof.

[0130] The antibody preferably contains a binding domain comprising the CDR1, CDR2, and / or CDR3 amino acid sequences of the VL chain shown in Figure 3, or a binding domain comprising the CDR1, CDR2, and / or CDR3 amino acid sequences of the VL chain shown in Figure 3, having 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 combinations thereof.

[0131] The antibody preferably contains a light chain constant region (CL) containing the CL chain sequence shown in Figure 3, or a light chain constant region (CL) containing the CL chain sequence shown in Figure 3 having 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 combinations thereof.

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

[0133] In certain embodiments, the light chain variable region of one or both VH / VL variable domains of the EGFR / LGR5 antibody includes a common light chain variable region. In some embodiments, the common light chain variable region of one or both VH / VL variable domains includes the germline IgVκ1-39 variable region V segment. In certain embodiments, the light chain variable region of one or both VH / VL variable domains includes the kappa light chain V segment IgVκ1-39*01. IgVκ1-39 is an abbreviation for the immunoglobulin variable kappa 1-39 gene. This gene is also known as immunoglobulin kappa variable 1-39, IGKV139, or IGKV1-39. The external ID of this gene is HGNC:5740, Entrez Gene:28930, Ensembl:ENSG00000242371. A preferred amino acid sequence of the V region is provided in Figure 2. The V region can be combined with one of five J regions. The preferred J regions are jk1 and jk5, and the joined sequences are denoted as IGKV1~39 / jk1 and IGKV1~39 / jk5, with alternative names being IgVκ1~39*01 / IGJκ1*01 or IgVκ1~39*01 / IGJκ5*01 (nomenclature conforms to the IMGT database World Wide Web at imgt.org). In certain embodiments, the light chain variable regions of one or both VH / VL variable domains include the kappa light chain IgVκ1~39*01 / IGJκ1*01 or IgVκ1~39*01 / IGJκ1*05 (as shown in Figure 3).

[0134] In some embodiments, the light chain variable region of one or both VH / VL variable domains of the EGFR / LGR5 bispecific antibody includes LCDR1 containing the amino acid sequence QSISSY (shown in Figure 3), LCDR2 containing the amino acid sequence AAS (shown in Figure 3), and LCDR3 containing the amino acid sequence QQSYSTP (shown in Figure 3) (i.e., CDRs of IGKV1-39 according to IMGT). In some embodiments, the light chain variable region of one or both VH / VL variable domains of the EGFR / LGR5 antibody includes LCDR1 containing the amino acid sequence QSISSY (shown in Figure 3), LCDR2 containing the amino acid sequence AASLQS (shown in Figure 3), and LCDR3 containing the amino acid sequence QQSYSTP (shown in Figure 3).

[0135] In some embodiments, the EGFR / LGR5 antibody includes a light chain variable region containing an amino acid sequence that is at least 90%, preferably at least 95%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, or 100% identical to the amino acid sequence shown in Figure 3.

[0136] For example, in some embodiments, the EGFR / LGR5 antibody may have 0 to 10, preferably 0 to 5, amino acid insertions, deletions, substitutions, additions, or combinations thereof with respect to the sequence in Figure 2. In some embodiments, the light chain variable region of one or both VH / VL variable domains of the EGFR / LGR5 antibody may contain 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, preferably 0 to 3, preferably 0 to 2, preferably 0 to 1, or preferably 0 amino acid insertions, deletions, substitutions, additions, or combinations thereof with respect to the indicated amino acid sequence.

[0137] In other embodiments, the light chain variable region of the EGFR / LGR5 antibody contains the amino acid sequence shown in Figure 3. In a particular embodiment, the EGFR / LGR5 antibody contains the same VL region. In one embodiment, the EGFR / LGR5 bispecific antibody contains the amino acid sequence shown in Figure 3.

[0138] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 or MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5790, MF5816 or MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM histidine buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 5.8-6.0, preferably about 5.9.

[0139] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM histidine buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 5.8-6.0, preferably about 5.9.

[0140] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 15 mM sodium citrate buffer; about 270 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.7-6.9, preferably about 6.8.

[0141] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM histidine buffer; about 290 mM maltose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.2-6.4, preferably about 6.3.

[0142] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM citrate-phosphate buffer; about 290 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0143] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium succinate buffer; about 280 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 5.5-5.7, preferably about 5.6.

[0144] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM histidine buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 5.8-6.0, preferably about 5.9.

[0145] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM histidine buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 5.8-6.0, preferably about 5.9.

[0146] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This specific anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of the appended claims, any aspect of the invention defined herein, and / or any embodiment of the invention defined herein. This specific anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1 to A127, B1 to B128, C1 to C128, D1 to D36, E1 to E16, F1 to F16, G1 to G16, H1 to H12, I1 to I16, J1 to J24, K1 to K32, L1 to L64, M1 to M1080, and N1 to N2686. More preferably, the pharmaceutical composition of the present disclosure comprises or consists essentially of about 20 mg / ml of this specific anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM histidine buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; and the composition has a pH of 5.8 to 6.0, preferably about 5.9.

[0147] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 15 mM sodium citrate buffer; about 270 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.7-6.9, preferably about 6.8.

[0148] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1 to A127, B1 to B128, C1 to C128, D1 to D36, E1 to E16, F1 to F16, G1 to G16, H1 to H12, I1 to I16, J1 to J24, K1 to K32, L1 to L64, M1 to M1080 and N1 to N2686. More preferably, the pharmaceutical composition of the present disclosure comprises or consists essentially of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM histidine buffer; about 290 mM maltose; about 0.2 mg / mL polysorbate 80; and water; and the composition has a pH of 6.2 to 6.4, preferably about 6.3.

[0149] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM citrate-phosphate buffer; about 290 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0150] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium succinate buffer; about 280 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 5.5-5.7, preferably about 5.6.

[0151] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium citrate buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0152] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium citrate buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0153] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 15 mM sodium citrate buffer; about 270 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.7-6.9, preferably about 6.8.

[0154] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM histidine buffer; about 290 mM maltose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.2-6.4, preferably about 6.3.

[0155] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM citrate-phosphate buffer; about 290 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0156] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium succinate buffer; about 280 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 5.5-5.7, preferably about 5.6.

[0157] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM histidine buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 5.8-6.0, preferably about 5.9.

[0158] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium citrate buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0159] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 15 mM sodium citrate buffer; about 270 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.7-6.9, preferably about 6.8.

[0160] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM histidine buffer; about 290 mM maltose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.2-6.4, preferably about 6.3.

[0161] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM citrate-phosphate buffer; about 290 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0162] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5816 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium succinate buffer; about 280 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 5.5-5.7, preferably about 5.6.

[0163] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF4280 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium citrate buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0164] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 15 mM sodium citrate buffer; about 270 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.7-6.9, preferably about 6.8.

[0165] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium citrate buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0166] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM histidine buffer; about 290 mM maltose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.2-6.4, preferably about 6.3.

[0167] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM citrate-phosphate buffer; about 290 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0168] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium succinate buffer; about 280 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 5.5-5.7, preferably about 5.6.

[0169] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5818 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1 to A127, B1 to B128, C1 to C128, D1 to D36, E1 to E16, F1 to F16, G1 to GQ16, H1 to H12, I1 to I16, J1 to J24, K1 to K32, L1 to L64, M1 to M1080, and N1 to N2686. More preferably, the pharmaceutical composition of the present disclosure comprises or consists essentially of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM histidine buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; and the composition has a pH of 5.8 to 6.0, preferably about 5.9.

[0170] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 15 mM sodium citrate buffer; about 270 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.7-6.9, preferably about 6.8.

[0171] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium citrate buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0172] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM histidine buffer; about 290 mM maltose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.2-6.4, preferably about 6.3.

[0173] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 5 mM citrate-phosphate buffer; about 290 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 6.9-7.1, preferably about 7.0.

[0174] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM sodium succinate buffer; about 280 mM sucrose; about 0.2 mg / mL polysorbate 80; and water; the composition has a pH of 5.5-5.7, preferably about 5.6.

[0175] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising the EGFR variable heavy chain MF3755 shown in Figure 1, the LGR5 variable heavy chain MF5790 shown in Figure 2, the variable light chain (VL) shown in Figure 3, the constant light chain (CL) shown in Figure 3, the CH1 domain sequence shown in Figure 4, 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. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with the appended claims, any aspect of the invention as defined herein, and / or any embodiment of the invention as defined herein. This particular anti-EGFR / anti-LGR5 bispecific antibody is preferably combined with any of embodiments A1-A127, B1-B128, C1-C128, D1-D36, E1-E16, F1-F16, G1-G16, H1-H12, I1-I16, J1-J24, K1-K32, L1-L64, M1-M1080, and N1-N2686. More preferably, the pharmaceutical composition of this disclosure comprises or is essentially composed of about 20 mg / ml of this particular anti-EGFR / anti-LGR5 bispecific antibody, about 10 mM histidine buffer; about 280 mM sucrose; about 0.5 mg / mL polysorbate 80; and water; the composition has a pH of 5.8-6.0, preferably about 5.9.

[0176] The EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising a heavy chain sequence corresponding to Figure 5a, 5b, 5c, 5d, 5e, or 5f, or a variant thereof having at least 85% sequence identity with any of the sequences of Figure 5a, 5b, 5c, 5d, 5e, or 5f. Antibodies having at least 88% sequence identity with any of the sequences of Figure 5a, 5b, 5c, 5d, 5e, or 5f are also included herein. Preferably, the sequence identity is at least 92%, more preferably at least 93%, and even more preferably at least 94% or 95%.

[0177] Instead, the EGFR / LGR5 BsAb is preferably an anti-EGFR / anti-LGR5 bispecific antibody comprising a heavy chain sequence corresponding to Figure 5a, 5b, 5c, 5d, 5e, or 5f, and a light chain sequence corresponding to Figure 3, or a variant thereof that, in combination with the sequence of Figure 3, has at least 85% sequence identity with any of the sequences of Figure 5a, 5b, 5c, 5d, 5e, or 5f. Antibodies that, in combination with the sequence of Figure 3, have at least 88% sequence identity with any of the sequences of Figure 5a, 5b, 5c, 5d, 5e, or 5f are also included herein. Preferably, the sequence identity, in combination with the sequence of Figure 3, is at least 92%, more preferably at least 93%, and even more preferably at least 94 or 95% sequence identity with any of the sequences of Figure 5a, 5b, 5c, 5d, 5e, or 5f. When calculating the sequence identity of combinations of sequences from Figure 3 and Figure 5, these sequences are arranged to generate a full-length anti-EGFR / anti-LGR5 bispecific antibody sequence. Next, sequence identity can be determined using the Vector NTI program mentioned herein.

[0178] In one embodiment, the pharmaceutical composition contains 1 to 150 mg / mL of EGFR / LGR5 BsAb. In one embodiment, the pharmaceutical composition contains 1 to 60 mg / mL of EGFR / LGR5 BsAb. In one embodiment, the pharmaceutical composition contains 1 to 25 mg / mL of EGFR / LGR5 BsAb. In one embodiment, the pharmaceutical composition contains 10 to 60 mg / mL of EGFR / LGR5 BsAb. In one embodiment, the pharmaceutical composition contains 10 to 30 mg / mL of EGFR / LGR5 BsAb. In one embodiment, the pharmaceutical composition contains 15 to 25 mg / mL of EGFR / LGR5 BsAb. In one embodiment, the pharmaceutical composition contains 20 mg / mL of EGFR / LGR5 BsAb.

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

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

[0181] The pharmaceutical composition is preferably an aqueous composition comprising 1 to 30 mg / mL of a bispecific antibody containing a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional moiety or derivative thereof, a buffer system of 3 to 20 mM containing histidine buffer and / or citrate buffer, 200 to 400 mM of sugar and / or sugar alcohol component, and 0.01 to 2 mg / mL of a nonionic surfactant, wherein the composition has a pH of 5.4 to 6.4.

[0182] The pharmaceutical composition is preferably an aqueous composition comprising 15-25 mg / mL of a bispecific antibody containing a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional moiety or derivative thereof, a buffer system of 4-12 mM containing histidine buffer and / or citrate buffer, 250-350 mM sucrose, and 0.1-1.5 mg / mL of polysorbate 80, wherein the composition has a pH of 5.4-6.4.

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

[0184] The pharmaceutical composition preferably comprises a bispecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional moiety or derivative thereof, a buffer system (or combination of buffer systems) having a molar concentration ratio of 21:1 to 146:1 between the buffer system and the antibody, a histidine buffer and / or citrate buffer, a sugar and / or sugar alcohol component having a molar concentration ratio of 1460:1 to 2920:1 between the sugar and / or sugar alcohol component and the antibody, and a nonionic surfactant having a molar concentration ratio of 1:18 to 11:1 between the nonionic surfactant and the antibody, and the composition has a pH of 5.4 to 6.4.

[0185] The pharmaceutical composition preferably comprises a bispecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional moiety or derivative thereof, a buffer system (or combination of buffer systems) having a molar concentration ratio of buffer system versus antibody of 29:1 to 88:1, sucrose having a molar concentration ratio of sucrose versus antibody of 1825:1 to 2555:1, and polysorbate 80 having a molar concentration ratio of polysorbate 80 versus antibody of 1:2 to 8.5:1, wherein the composition has a pH of 5.4 to 6.4.

[0186] The pharmaceutical composition preferably comprises or consists of a bispecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, a functional molar or derivative thereof, 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 polysorbate 80 versus antibody of 2.79:1, and water as needed, and the composition has a pH of 5.8 to 6.0.

[0187] Preferably, the pharmaceutical composition of the present invention comprises a bispecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody comprises the VH amino acid sequence of MF3370 shown in Figure 1 and / or the VH amino acid sequence of MF5790 shown in Figure 2 and the VL amino acid sequence shown in Figure 3. Preferably, the antibody further comprises the CH1, hinge, CH2, and CH3-DE and CH3-KK amino acid sequences shown in Figure 4.

[0188] Preferably, the pharmaceutical composition of the present invention comprises a bispecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody comprises the VH amino acid sequence of MF3755 shown in Figure 1 and / or the VH amino acid sequence of MF5816 shown in Figure 2 and the VL amino acid sequence shown in Figure 3. Preferably, the antibody further comprises the CH1, hinge, CH2, and CH3-DE and CH3-KK amino acid sequences shown in Figure 4.

[0189] Preferably, the pharmaceutical composition of the present invention comprises a bispecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody comprises the VH amino acid sequence of MF4280 shown in Figure 1 and / or the VH amino acid sequence of MF5809 shown in Figure 2 and the VL amino acid sequence shown in Figure 3. Preferably, the antibody further comprises the CH1, hinge, CH2, and CH3-DE and CH3-KK amino acid sequences shown in Figure 4.

[0190] Preferably, the pharmaceutical composition of the present invention comprises a bispecific antibody having a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody comprises the VH amino acid sequence of MF4289 shown in Figure 1 and / or the VH amino acid sequence of MF5818 shown in Figure 2 and the VL amino acid sequence shown in Figure 3. Preferably, the antibody further comprises the CH1, hinge, CH2, and CH3-DE and CH3-KK amino acid sequences shown in Figure 4.

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

[0192] Preferably, the diluent can constitute the remainder of the components in any composition, for example, such that the total weight percentage of all components is 100%. Preferably, any concentration given herein with respect to any component of the composition represents the concentration of said component (preferably dissolved) in the diluent mixed with any other components.

[0193] The compositions of the present invention are preferably solutions and preferably (substantially or completely) free of particles or precipitates.

[0194] However, in one embodiment, the pharmaceutical composition is water-free or contains at most 10% by weight of water, preferably at most 5% by weight of water, preferably at most 2% by weight of water, or preferably at most 1% by weight of water. Such embodiments may be solid pharmaceutical compositions or lyophilized pharmaceutical compositions that can be reconstituted (preferably by adding water and / or other relevant diluents, e.g., intravenous fluids, e.g., physiological saline solution) before use, administration, or (preferably short-term) storage. Such lyophilized formulations can be reconstituted to obtain aqueous pharmaceutical compositions disclosed herein (e.g., with or without the components present at the concentrations specified herein).

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

[0196] <Buffer system> The pharmaceutical composition preferably includes a buffer system. The buffer system preferably acts as a pH buffer that creates inertia to pH changes even when small amounts of (strong) acid or (strong) base are added to the pharmaceutical composition (or potentially generated internally as a result of the degradation of one or more components of the pharmaceutical composition, possibly its antibody). Thus, the buffer system preferably maintains the pH of the composition substantially constant over time, thereby preferably mitigating pH-induced degradation pathways. Preferably, the pharmaceutical composition is well buffered to resist pH changes of 1 pH unit or more, preferably 0.5 pH units or more, and most preferably 0.2 pH units or more, during storage at 2-8°C for 6 months under the same storage conditions.

[0197] Preferably, the composition is a buffer solution whose pH is stabilized by a buffer (or buffer system), preferably in combination with the buffer's conjugate acid / base. Therefore, the biopharmaceutical composition preferably contains a buffer as defined herein. Preferably, the composition further contains a conjugate acid / base, the conjugate acid / base corresponding to the buffer's conjugate acid or conjugate base, depending on whether the buffer itself is a base or an acid. The buffer and its conjugate acid / base can be collectively considered a “buffer system.” Therefore, the composition preferably contains a “buffer system” (preferably including the buffer and its conjugate acid / base), and any concentration specified with respect to the buffer system generally relates to the total concentration of the buffer and all of its conjugate acid / bases. Any “buffer system” preferably includes a weak acid and a weak base (see definition above).

[0198] Preferably, the composition contains a buffering agent and its conjugate acid / base. The buffer system consists of a combination of the buffering agent and its conjugate acid / base. Preferably, the composition contains the buffering agent and its corresponding conjugate acid / base such that the buffering agent and its conjugate acid / base are both present at levels (i.e., absolute or concentrated) and relative amounts (or concentrations) sufficient to provide the composition with a desired pH. The buffer system may be formed by simply mixing the buffering agent and its conjugate acid / base, or alternatively, by mixing an acid or base with the buffering agent or either of its conjugate acid / base to form a desired mixture of buffering agent and conjugate acid / base in situ. For example, the buffer system may be formed by simply mixing an acetate buffering agent (e.g., sodium acetate) and its conjugate acid / base (i.e., acetic acid) in a ratio suitable to preferably yield a desired pH. Alternatively, a buffer system may be formed by adding a base (e.g., sodium hydroxide) to the conjugate acid / base (e.g., acetic acid) of an acetate buffer, preferably in an appropriate amount to bring about a desired pH and a mixture of the buffer (e.g., sodium acetate) and the corresponding conjugate acid / base (i.e., acetic acid). More preferably, to obtain a histidine buffer system, a histidine buffer system is formed by adding an appropriate amount of acid (particularly HCl or histidine HCl) to histidine, preferably to bring about a desired pH and a mixture of the buffer. Alternatively, any method for forming a buffer system may be used, and the pH may be carefully adjusted by adding either a further acid (preferably a strong acid such as HCl) or a further base (preferably a strong base such as sodium hydroxide). Preferably, the formulation of the present invention does not contain a histidine-acetate buffer.

[0199] The buffer system is preferably a buffer system comprising one or more buffers. The buffer system is preferably a buffer system comprising at most one buffer. The buffer system is preferably a double buffer system (e.g., a phosphate-citrate buffer). However, in some embodiments, the pharmaceutical composition may be characterized by the absence of a buffer system (or any one or more of the buffer systems specifically mentioned herein). The pharmaceutical composition may be sufficiently stable without a buffer if, for example, the antibody provides sufficient self-buffering. This preferably occurs at higher concentrations of antibody.

[0200] The buffer system is preferably selected from inorganic buffers (e.g., ammonium buffers, bicarbonate buffers, carbonate buffers, borate buffers, phosphate buffers), organic buffers (e.g., carboxylate buffers, organic ammonium buffers, alkanol ammonium buffers, zwitterionic buffers, amino acid buffers, aromatic nitrogen buffers, sugar buffers), and any combination thereof.

[0201] The buffer system is preferably an amphoteric buffer system (e.g., an amino acid buffer system, e.g., histidine), consists of, or includes such a system.

[0202] The buffer system is preferably a monocarboxylate buffer system (e.g., acetate buffer, formate buffer, lactate buffer, salicylate buffer, benzoate buffer), consisting of, or containing thereof.

[0203] The buffer system is preferably a dicarboxylate buffer system (e.g., succinate buffer, maleate buffer, malate buffer, fumarate buffer, tartrate buffer, adipine buffer, hexanediate buffer), consisting of, or including thereof.

[0204] The buffer system is preferably a tricarboxylate buffer system (e.g., a citrate buffer system), consists of, or includes a tricarboxylate buffer system.

[0205] The buffer system is preferably a zwitterionic buffer system (e.g., amino acid buffer, zwitterionic sulfonate buffer, e.g., N-(2-acetamide)-2-aminoethanesulfonic acid (ACES) buffer, 2-aminoethanesulfonic acid (AES) buffer, N-(1,1-dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid (AMPSO) buffer, N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) buffer, 3-(cyclohexylamino)-propanesulfonic acid (CAPS)), consisting of, or containing thereof.

[0206] The buffer system is preferably an amino acid buffer system (e.g., histidine buffer, glycine buffer, lysine buffer, glycylglycine buffer, N-[Tris(hydroxymethyl)-methyl]-glycine (tricine) buffer, glutamate buffer, asparate buffer, N,N-bis(2-hydroxy-ethyl)-glycine (bicine) buffer, N-(2-acetamide)-iminodiacetic acid (ADA) buffer), consisting of, or containing thereof.

[0207] The buffer system is preferably an alkanol ammonium buffer system (e.g., aminomethylpropanol (AMP) buffer, aminomethylpropanediol (AMPD) buffer, tris(hydroxymethyl)aminomethane (Tris) buffer, [bis-(2-hydroxyethyl)-imino]-tris-(hydroxymethylmethane) (BIS-Tris) buffer, 1,3-bis[tris(hydroxymethyl)-methylamino]propane (bis-trispropane) buffer), consists of, or includes thereof.

[0208] The buffering system is preferably a buffering system selected from the group consisting of histidine buffering systems, acetate buffering systems, citrate buffering systems, succinate buffering systems, phosphate buffering systems, citrate-phosphate buffering systems, tris buffering systems, and any combination thereof, or consists of such a buffering system or includes such a buffering system.

[0209] The buffer system is preferably a buffer system selected from the group consisting of histidine buffer systems (preferably excluding histidine-acetate buffers), citrate buffer systems, and any combination thereof, or consists of such a buffer system or includes such a buffer system.

[0210] The buffering system is preferably a histidine buffering system, consisting of, or containing a histidine buffering system.

[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, consisting of, or containing a citrate buffering system.

[0213] The buffering system is preferably a succinate buffering system, consisting of, or containing a succinate buffering system.

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

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

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

[0217] In one embodiment, the pharmaceutical composition includes 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. In one embodiment, the pharmaceutical composition includes a buffer system of 3 to 50 mM. In one embodiment, the pharmaceutical composition includes a buffer system of 4 to 30 mM. In one embodiment, the pharmaceutical composition includes a buffer system of 5 to 20 mM. In one embodiment, the pharmaceutical composition includes a buffer system of 5 to 14 mM. In one embodiment, the pharmaceutical composition includes a buffer system of 10 mM. In one embodiment, the pharmaceutical composition includes a buffer system of 3 to 12 mM. In one embodiment, the pharmaceutical composition includes a buffer system of 5 mM.

[0218] In one embodiment, the pharmaceutical composition includes a buffer system with a molar ratio of buffer system to antibody of 4:1 to 1050:1. In one embodiment, the pharmaceutical composition includes a buffer system with a molar ratio of buffer system to antibody of 14:1 to 520:1. In one embodiment, the pharmaceutical composition includes a buffer system with a molar ratio of buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition includes a buffer system with a molar ratio of buffer system to antibody of 20:1 to 90:1.

[0219] In one embodiment, the pharmaceutical composition includes a buffer system of 3 to 25 mM selected from the group consisting of histidine buffer systems, acetate buffer systems, citrate buffer systems, succinate buffer systems, phosphate buffer systems, citrate-phosphate buffer systems, tris buffer systems, and any combination thereof. In another embodiment, the pharmaceutical composition includes a buffer system of 3 to 12 mM selected from the group consisting of histidine buffer systems, acetate buffer systems, citrate buffer systems, succinate buffer systems, phosphate buffer systems, citrate-phosphate buffer systems, tris buffer systems, and any combination thereof.

[0220] In one embodiment, the pharmaceutical composition includes a buffer system of 3 to 25 mM selected from a histidine buffer system or a citrate buffer system. In another embodiment, the pharmaceutical composition includes a buffer system of 3 to 12 mM selected from a histidine buffer system or a citrate buffer system.

[0221] In one embodiment, the pharmaceutical composition contains 3 to 25 mM histidine buffer. In another embodiment, the pharmaceutical composition contains 3 to 12 mM histidine buffer. In yet another embodiment, the pharmaceutical composition contains 5 mM histidine buffer. In yet another embodiment, the pharmaceutical composition contains 10 mM histidine buffer.

[0222] In one embodiment, the pharmaceutical composition includes a histidine buffer system having a molar ratio of histidine buffer system to antibody of 4:1 to 1050:1. In one embodiment, the pharmaceutical composition includes a histidine buffer system having a molar ratio of histidine buffer system to antibody of 14:1 to 520:1. In one embodiment, the pharmaceutical composition includes a histidine buffer system having a molar ratio of histidine buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition includes a histidine buffer system having a molar ratio of histidine buffer system to antibody of 20:1 to 90:1.

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

[0224] In one embodiment, the pharmaceutical composition includes an acetate buffer system having a molar ratio of acetate buffer system to antibody of 4:1 to 1050:1. In one embodiment, the pharmaceutical composition includes an acetate buffer system having a molar ratio of acetate buffer system to antibody of 14:1 to 520:1. In one embodiment, the pharmaceutical composition includes an acetate buffer system having a molar ratio of acetate buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition includes an acetate buffer system having a molar ratio of acetate buffer system to antibody of 20:1 to 90:1.

[0225] In one embodiment, the pharmaceutical composition contains 3 to 25 mM citrate buffering system. In one embodiment, the pharmaceutical composition contains 3 to 12 mM citrate buffering system. In one embodiment, the pharmaceutical composition contains 5 mM citrate buffering system. In one embodiment, the pharmaceutical composition contains 10 mM citrate buffering system.

[0226] In one embodiment, the pharmaceutical composition includes a citrate buffer system having a molar ratio of citrate buffer system to antibody of 4:1 to 1050:1. In one embodiment, the pharmaceutical composition includes a citrate buffer system having a molar ratio of citrate buffer system to antibody of 14:1 to 520:1. In one embodiment, the pharmaceutical composition includes a citrate buffer system having a molar ratio of citrate buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition includes a citrate buffer system having a molar ratio of citrate buffer system to antibody of 20:1 to 90:1.

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

[0228] In one embodiment, the pharmaceutical composition includes a succinate buffer system having a molar ratio of succinate buffer system to antibody of 4:1 to 1050:1. In one embodiment, the pharmaceutical composition includes a succinate buffer system having a molar ratio of succinate buffer system to antibody of 14:1 to 520:1. In one embodiment, the pharmaceutical composition includes a succinate buffer system having a molar ratio of succinate buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition includes a succinate buffer system having a molar ratio of succinate buffer system to antibody of 20:1 to 90:1.

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

[0230] In one embodiment, the pharmaceutical composition includes a phosphate buffer system having a molar ratio of phosphate buffer system to antibody of 4:1 to 1050:1. In one embodiment, the pharmaceutical composition includes a phosphate buffer system having a molar ratio of phosphate buffer system to antibody of 14:1 to 520:1. In one embodiment, the pharmaceutical composition includes a phosphate buffer system having a molar ratio of phosphate buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition includes a phosphate buffer system having a molar ratio of phosphate buffer system to antibody of 20:1 to 90:1.

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

[0232] In one embodiment, the pharmaceutical composition includes a citrate-phosphate buffer system with a molar ratio of citrate-phosphate buffer system versus antibody of 4:1 to 1050:1. In one embodiment, the pharmaceutical composition includes a citrate-phosphate buffer system with a molar ratio of citrate-phosphate buffer system versus antibody of 14:1 to 520:1. In one embodiment, the pharmaceutical composition includes a citrate-phosphate buffer system with a molar ratio of citrate-phosphate buffer system versus antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition includes a citrate-phosphate buffer system with a molar ratio of citrate-phosphate buffer system versus antibody of 20:1 to 90:1.

[0233] In one embodiment, the pharmaceutical composition contains 3 to 25 mM Tris buffering system. In another embodiment, the pharmaceutical composition contains 3 to 12 mM Tris buffering system.

[0234] In one embodiment, the pharmaceutical composition includes a Tris buffer system having a molar ratio of Tris buffer system to antibody of 4:1 to 1050:1. In one embodiment, the pharmaceutical composition includes a Tris buffer system having a molar ratio of Tris buffer system to antibody of 14:1 to 520:1. In one embodiment, the pharmaceutical composition includes a Tris buffer system having a molar ratio of Tris buffer system to antibody of 7:1 to 180:1. In one embodiment, the pharmaceutical composition includes a Tris buffer system having a molar ratio of Tris buffer system to antibody of 20:1 to 90:1.

[0235] In one embodiment, the pharmaceutical composition includes a 3-25 mM histidine buffer system that yields a pH of composition 5.4-7.1. In another embodiment, the pharmaceutical composition includes a 3-25 mM histidine buffer system that yields a pH of composition 5.7-6.5.

[0236] In one embodiment, the pharmaceutical composition includes a 3-25 mM acetate buffer system that yields a pH of 4-5.6 for the composition.

[0237] In one embodiment, the pharmaceutical composition includes a 3-25 mM citrate buffer system that yields a pH of 4.5-7.5 for the composition. In one embodiment, the pharmaceutical composition includes a 3-25 mM citrate buffer system that yields a pH of 6-7.5 for the composition. In one embodiment, the pharmaceutical composition includes a 3-25 mM citrate buffer system that yields a pH of 6.5-7.5 for the composition.

[0238] In one embodiment, the pharmaceutical composition includes a 3-25 mM succinate buffer system that yields a pH of 4-6.6 for the composition.

[0239] In one embodiment, the pharmaceutical composition includes a 3-25 mM phosphate buffer system that yields a pH of 5.8-8.1 for the composition.

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

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

[0242] The quantities and concentrations of buffer systems refer to the total quantities and concentrations of all buffer systems unless only a single buffer system is specified. The concentrations of the buffer systems or any specific buffer system may be replaced with molar ratios.

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

[0244] <ph> The pharmaceutical composition preferably has a pH of 4 to 8.5. While antibodies in the pharmaceutical composition can be resistant and reasonably stable across a range of pH values, certain pH levels are particularly advantageous, especially in the context of the present invention, in the presence of specific excipients or combinations thereof.

[0245] In one embodiment, the pharmaceutical composition has a pH of 4.5 to 7.5. In one embodiment, the pharmaceutical 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. In one embodiment, the pharmaceutical composition has a pH of 5.4 to 5.6. In one embodiment, the pharmaceutical composition has a pH of 5.8 to 6.0. In one embodiment, the pharmaceutical composition has a pH of 5.9 to 6.1. In one embodiment, the pharmaceutical composition has a pH of 6.2 to 6.4. In one embodiment, the pharmaceutical composition has a pH of 6 to 7.5. In one embodiment, 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 7.2.

[0246] In a preferred embodiment, the pharmaceutical composition has a pH of 5.4 to 6.5 and includes a histidine buffer system. In another preferred embodiment, the pharmaceutical composition has a pH of 5.8 to 6.4 and includes a histidine buffer system. In a more preferred embodiment, the pharmaceutical composition has a pH of 5.8 to 6.0 and includes a histidine buffer system. In yet another preferred embodiment, the pharmaceutical composition has a pH of 6.2 to 6.4 and includes a histidine buffer system.

[0247] In a preferred embodiment, the pharmaceutical composition has a pH of 6 to 7.5 and includes a citrate buffer system. In another preferred embodiment, the pharmaceutical composition has a pH of 6.5 to 7.5 and includes a citrate buffer system. In yet another preferred embodiment, the pharmaceutical composition has a pH of 6.8 to 7.2 and includes a citrate buffer system. In yet another preferred embodiment, the pharmaceutical composition has a pH of 6.9 to 7.1 and includes a citrate buffer system.

[0248] In one embodiment, the buffer system has a pH of 4 to 8.5. In one embodiment, the buffer system has a pH of 4 to 8.5. In one embodiment, the buffer system has a pH of 4.5 to 7.5. In one embodiment, the buffer system has a pH of 5.0 to 6.7. In one embodiment, the buffer system has a pH of 5.4 to 6.5. In one embodiment, the buffer system has a pH of 5.4 to 6.0. In one embodiment, the buffer system has a pH of 5.4 to 5.6. In one embodiment, the buffer system has a pH of 5.8 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 6.2 to 6.4.

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

[0250] <Salt isotonic agent> The pharmaceutical composition may preferably contain a salt isotonic agent (e.g., NaCl or other such salts), preferably a non-buffered isotonic agent (i.e., an isotonic agent that does not impart a pH buffering effect, unlike buffered salts which can themselves contribute to some extent to the overall tonicity). In the context of the present invention, the salt isotonic agent can be used to adjust the gravimetric osmolality of the pharmaceutical composition, for example, to bring the gravimetric osmolality to a preferred range (e.g., for isotonic compositions, for example, 200-400 mOsmol / L, preferably 250-350 mOsmol / L, most preferably 270-310 mOsmol / L), although the gravimetric osmolality may not be as important for intravenous compositions as it is for subcutaneous compositions. Additionally, the salt isotonic agent can promote the solubility of antibodies and / or other excipients in the pharmaceutical composition. Furthermore, salt isotonic agents can impart stabilizing effects to antibodies in pharmaceutical compositions, such as improved three-dimensional stability (e.g., reduction of protein unfolding events that may increase the likelihood of final aggregation), reduced aggregation, and / or reduced fragmentation.

[0251] However, a pharmaceutical composition can be characterized by the absence of (unbuffered) salt isotonic agents (or any one or more of the salt isotonic agents specifically referred to herein). In particular, a pharmaceutical composition can be characterized by the absence of sodium chloride, most preferably. In the absence of sodium chloride or salt isotonic agents, other components in the pharmaceutical composition, such as sugar components, buffers, or other tonicity-imparting components, may contribute to the tonicity of the composition.

[0252] The salt isotonic agent is preferably a salt isotonic agent selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, zinc chloride, or any combination thereof, consisting of, or containing thereof. The salt isotonic agent is preferably sodium chloride, consisting of, or containing thereof. The salt isotonic agent is preferably potassium chloride, consisting of, or containing thereof. The salt isotonic agent is preferably magnesium chloride, consisting of, or containing thereof. The salt isotonic agent is preferably calcium chloride, consisting of, or containing thereof. The salt isotonic agent is preferably zinc chloride, consisting of, or containing thereof.

[0253] In one embodiment, the pharmaceutical composition contains 3 to 200 mM of a salt isotonic agent. In one embodiment, the pharmaceutical composition contains 3 to 7 mM of a salt isotonic agent. In one embodiment, the pharmaceutical composition contains 5 to 100 mM of a salt isotonic agent. In one embodiment, the pharmaceutical composition contains 5 to 50 mM of a salt isotonic 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 to 170 mM of a salt isotonic agent. In one embodiment, the pharmaceutical composition contains 140 to 160 mM of a salt isotonic agent. In one embodiment, the pharmaceutical composition contains a salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 7:1 to 3000:1. In one embodiment, the pharmaceutical composition contains a salt isotonic agent with a molar ratio of salt isotonic agent to antibody of 21:1 to 1500:1. In one embodiment, the pharmaceutical composition contains a salt isotonic agent having a molar ratio of salt isotonic agent to antibody of 340:1 to 2500:1. In another embodiment, the pharmaceutical composition contains a salt isotonic agent having a molar ratio of salt isotonic agent to antibody of 900:1 to 1300:1.

[0254] In one embodiment, the pharmaceutical composition contains 4 to 160 mM of a salt isotonic agent selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, zinc chloride, or any combination thereof. In another embodiment, the pharmaceutical composition contains 10 to 180 mM of sodium chloride.

[0255] In one embodiment, the pharmaceutical composition contains 50 to 170 mM sodium chloride. In one embodiment, the pharmaceutical composition contains 140 to 160 mM sodium chloride. In one embodiment, the pharmaceutical composition contains sodium chloride with a sodium chloride to antibody molar ratio of 7:1 to 3000:1. In one embodiment, the pharmaceutical composition contains sodium chloride with a sodium chloride to antibody molar ratio of 21:1 to 1500:1. In one embodiment, the pharmaceutical composition contains sodium chloride with a sodium chloride to antibody molar ratio of 340:1 to 2500:1. In one embodiment, the pharmaceutical composition contains sodium chloride with a sodium chloride to antibody molar ratio of 900:1 to 1300:1. In one embodiment, the pharmaceutical composition contains sodium chloride at a concentration sufficient to produce a composition of 200 to 400 mOsmol / L. In one embodiment, the pharmaceutical composition contains sodium chloride at a concentration sufficient to produce a composition of 250 to 350 mOsmol / L. In one embodiment, the pharmaceutical composition contains sodium chloride at a concentration sufficient to produce a composition of 270-310 mOsmol / L.

[0256] The amounts and concentrations of salt isotonic agents refer to the total amounts and concentrations of all salt isotonic agents unless only a single salt isotonic agent is specified. The concentrations of the salt isotonic agents or any specific salt isotonic agents can be replaced with molar ratios.

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

[0258] <Sugar component> The pharmaceutical composition preferably contains a sugar component, preferably a non-reducing sugar component. In the context of the present invention, the sugar components can play one or more roles within the pharmaceutical composition. For example, they can act as cryoprotectants during lyophilization. Sugar components can impart tonicity to bring the osmolality to a desired range (e.g., in the case of isotonicity, e.g., 200-400 mOsmol / L, more preferably 250-350 mOsmol / L, most preferably 270-310 mOsmol / L osmolality). Contributing tonicity using sugar components can be particularly useful when high ionic strength is undesirable. Sugar components can promote the solubility of antibodies and / or other excipients within the pharmaceutical composition. Sugar components can also provide stabilizing effects to antibodies in the pharmaceutical composition, e.g., improved stereostructural stability (e.g., reduction of protein unfolding events that may increase the likelihood of final aggregation), reduced aggregation, and / or reduced fragmentation.

[0259] Preferably, the sugar component is a single compound. Preferably, the sugar component is one or more sugars and / or sugar alcohols, 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 one), consisting of, or containing such sugar. Preferably, the sugar component is a sugar, consisting of, or containing such sugar. Preferably, the sugar component is a sugar selected from the group consisting of monosaccharides, disaccharides, polysaccharides, and complex carbohydrates, consisting of, or containing such sugar. Preferably, the sugar component is a monosaccharide, consisting of, or containing such monosaccharide. More preferably, the sugar component is a disaccharide, consisting of, or containing such disaccharide. Preferably, the sugar component is a disaccharide selected from the group consisting of sucrose, trehalose, maltose, and lactose, consisting of, or containing such disaccharide. Preferably, the sugar component is a disaccharide selected from maltose, trehalose, and / or sucrose, consisting of, or containing such disaccharide. Most preferably, the sugar component is sucrose, consisting of, or containing such sucrose.

[0261] Preferably, the sugar component is one or more sugar alcohols, consists of or contains them. Preferably, the sugar component is a sugar alcohol, consists of or contains it. Preferably, the sugar component is a (3-12C) sugar alcohol, consists of or contains it. Preferably, the sugar component is a (3-6C) sugar alcohol, consists of or contains it. Preferably, the sugar component is a (5-6C) sugar alcohol, consists of or contains it. Preferably, the sugar component is a sugar alcohol selected from mannitol or sorbitol, consists of or contains it.

[0262] Most preferably, the sugar component is sucrose, consists of it, or contains it. Preferably, the sugar component is sucrose, or sucrose alone. In certain embodiments, the pharmaceutical composition contains sucrose in amounts of 20-400 mM, 50-350 mM, 100-320 mM, 170-310 mM, or 220-320 mM, more preferably 250-300 mM of sucrose. In certain embodiments, the pharmaceutical composition contains 275-295 mM of sucrose. Most preferably, the pharmaceutical composition contains 280 mM of sucrose.

[0263] In certain embodiments, the pharmaceutical composition contains a sugar component, particularly a sugar component with a sucrose-to-antibody molar ratio of 100:1 to 5500:1. In certain embodiments, the pharmaceutical composition contains a sugar component with a sugar component-to-antibody molar ratio of 300:1 to 2600:1. In certain embodiments, the pharmaceutical composition contains a sugar component with a sugar component-to-antibody molar ratio of 600:1 to 4500:1. In certain embodiments, the pharmaceutical composition contains a sugar component with a sugar component-to-antibody molar ratio of 1800:1 to 2200:1.

[0264] In certain embodiments, the pharmaceutical composition contains 100-400 mM of a sugar component selected from the group consisting of sucrose, trehalose, mannitol, sorbitol, glucose, maltose, lactose, and any combination thereof. In certain embodiments, the pharmaceutical composition contains 100-400 mM of a sugar component selected from the group consisting of sucrose, trehalose, mannitol, and sorbitol. In certain embodiments, the pharmaceutical composition contains 100-400 mM of a sugar component selected from the group consisting of sucrose, mannitol, sorbitol, and maltose, most preferably sucrose.

[0265] In certain embodiments, the pharmaceutical composition contains 150 to 350 mM sucrose. In certain embodiments, the pharmaceutical composition contains 250 to 300 mM sucrose. In certain embodiments, the pharmaceutical composition contains 280 mM sucrose. In certain embodiments, the pharmaceutical composition contains 290 mM sucrose. In certain embodiments, the pharmaceutical composition contains sucrose with a sucrose-to-antibody molar ratio of 100:1 to 5500:1. In certain embodiments, the pharmaceutical composition contains sucrose with a sucrose-to-antibody molar ratio of 300:1 to 2600:1. In certain embodiments, the pharmaceutical composition contains sucrose with a sucrose-to-antibody molar ratio of 600:1 to 4500:1. In certain embodiments, the pharmaceutical composition contains sucrose with a sucrose-to-antibody molar ratio of 1800:1 to 2200:1.

[0266] In certain embodiments, the pharmaceutical composition contains 150-350 mM trehalose. In certain embodiments, the pharmaceutical composition contains 250-300 mM trehalose. In certain embodiments, the pharmaceutical composition contains trehalose with a trehalose-to-antibody molar ratio of 100:1-5500:1. In certain embodiments, the pharmaceutical composition contains trehalose with a trehalose-to-antibody molar ratio of 300:1-2600:1. In certain embodiments, the pharmaceutical composition contains trehalose with a trehalose-to-antibody molar ratio of 600:1-4500:1. In certain embodiments, the pharmaceutical composition contains trehalose with a trehalose-to-antibody molar ratio of 1800:1-2200:1. In many preferred embodiments, the sugar component is not trehalose. In many preferred embodiments, the sugar component is neither trehalose nor trehalose-containing, unless it is in a concentration of 99 mM or lower as needed.

[0267] In certain embodiments, the pharmaceutical composition contains 150-350 mM mannitol. In certain embodiments, the pharmaceutical composition contains 250-300 mM mannitol. In certain embodiments, the pharmaceutical composition contains mannitol with a mannitol-to-antibody molar ratio of 100:1-5500:1. In certain embodiments, the pharmaceutical composition contains mannitol with a mannitol-to-antibody molar ratio of 300:1-2600:1. In certain embodiments, the pharmaceutical composition contains mannitol with a mannitol-to-antibody molar ratio of 600:1-4500:1. In certain embodiments, the pharmaceutical composition contains mannitol with a mannitol-to-antibody molar ratio of 1800:1-2200:1.

[0268] In certain embodiments, the pharmaceutical composition contains 150 to 350 mM sorbitol. In certain embodiments, the pharmaceutical composition contains 250 to 300 mM sorbitol. In certain embodiments, the pharmaceutical composition contains sorbitol with a sorbitol-to-antibody molar ratio of 100:1 to 5500:1. In certain embodiments, the pharmaceutical composition contains sorbitol with a sorbitol-to-antibody molar ratio of 300:1 to 2600:1. In certain embodiments, the pharmaceutical composition contains sorbitol with a sorbitol-to-antibody molar ratio of 600:1 to 4500:1. In certain embodiments, the pharmaceutical composition contains sorbitol with a sorbitol-to-antibody molar ratio of 1800:1 to 2200:1.

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

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

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

[0272] The amounts and concentrations of sugar components refer to the total amounts and concentrations of all sugar components unless only a single sugar component is specified. The concentrations of the sugar components or any specific sugar components can be replaced with molar ratios.

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

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

[0275] However, in some embodiments, the pharmaceutical composition is characterized by the absence of a surfactant (or any one or more surfactants as specifically referred to herein).

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

[0277] Preferably, the surfactant is a nonionic surfactant, consists of, or includes a nonionic surfactant. Preferably, the surfactant is a nonionic surfactant selected from the group consisting of aliphatic alcohols, aliphatic alcohol ethers, fatty acid esters, fatty acid amides, polyoxyalkylene alkyl ethers, polyoxyethylene alkyl ethers, nonionic block copolymers, alpha-tocopherol, and any combination thereof, consists of, or includes a nonionic surfactant selected from the group consisting of sorbitan esters (Span), ethoxylated sorbitan esters (also known as polysorbate, Tween®), and block alkoxylates, consists of, or includes a nonionic surfactant. Preferably, the surfactant is an ethoxylated fatty acid ester surfactant, consists of, or includes a nonionic surfactant.

[0278] Preferably, the surfactant is, consists of, or includes a surfactant selected from the group consisting of polysorbate 20, polysorbate 80, poloxamer 188, and any combination thereof. Preferably, the surfactant is, consists of, or includes a surfactant selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. Preferably, the surfactant is, consists of, or includes a surfactant selected from polysorbate 20 or polysorbate 80.

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

[0280] Preferably, the surfactant is poloxamer 188, consists of, or contains poloxamer 188.

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

[0282] In one embodiment, the pharmaceutical composition contains 0.01 to 2 mg / mL of surfactant. In one embodiment, the pharmaceutical composition contains 0.05 to 1.5 mg / mL of surfactant. In 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 contains 0.1 to 0.3 mg / mL of surfactant. In one embodiment, the pharmaceutical composition contains 0.2 mg / mL of surfactant. In one embodiment, the pharmaceutical composition contains 0.2 to 0.8 mg / mL of surfactant. In one embodiment, the pharmaceutical composition contains 0.4 to 0.6 mg / mL of surfactant. In one embodiment, the pharmaceutical composition contains 0.5 mg / mL of surfactant. In one embodiment, the pharmaceutical composition contains 0.4 to 1.2 mg / mL of surfactant. 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 contains a surfactant having a surfactant-to-antibody molar ratio of 1:11 to 17:1. In one embodiment, the pharmaceutical composition contains a surfactant having a surfactant-to-antibody molar ratio of 1:4 to 9:1. In one embodiment, the pharmaceutical composition contains a surfactant having a surfactant-to-antibody molar ratio of 1:1.5 to 7:1. In one embodiment, the pharmaceutical composition contains a surfactant having a surfactant-to-antibody molar ratio of 2:1 to 4:1.

[0284] In one embodiment, the pharmaceutical composition contains 0.01 to 1.5 mg / mL of a surfactant selected from the group consisting of polysorbate 20, polysorbate 80, poloxamer 188, and any combination thereof.

[0285] In one embodiment, the pharmaceutical composition contains 0.05 to 1.5 mg / mL of polysorbate 80. In one embodiment, the pharmaceutical composition contains 0.1 to 0.6 mg / mL of polysorbate 80. In one embodiment, the pharmaceutical composition contains 0.1 to 0.3 mg / mL of polysorbate 80. In one embodiment, the pharmaceutical composition contains 0.4 to 1.2 mg / mL of polysorbate 80. In one embodiment, the pharmaceutical composition contains 0.4 to 0.6 mg / mL of polysorbate 80. In one embodiment, the pharmaceutical composition contains 0.5 mg / mL of polysorbate 80. In one 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. In one embodiment, the pharmaceutical composition contains polysorbate 80 with a polysorbate 80 to antibody molar ratio of 1:11 to 17:1. In one embodiment, the pharmaceutical composition contains polysorbate 80 with a polysorbate 80 to antibody molar ratio of 1:4 to 9:1. In another embodiment, the pharmaceutical composition contains polysorbate 80 with a polysorbate 80 to antibody molar ratio of 1:1.5 to 7:1. In yet another embodiment, the pharmaceutical composition contains polysorbate 80 with a polysorbate 80 to antibody molar ratio of 2:1 to 4:1.

[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 one embodiment, the pharmaceutical composition contains 0.9 to 1.1 mg / mL of polysorbate 20. In one embodiment, the pharmaceutical composition contains 1 mg / mL of polysorbate 20. In one embodiment, the pharmaceutical composition contains polysorbate 20 with a polysorbate 20 to antibody molar ratio of 1:11 to 17:1. In one embodiment, the pharmaceutical composition contains polysorbate 20 with a polysorbate 20-to-antibody molar ratio of 1:4 to 9:1. In one embodiment, the pharmaceutical composition contains polysorbate 20 with a polysorbate 20-to-antibody molar ratio of 1:1.5 to 7:1. In one embodiment, the pharmaceutical composition contains polysorbate 20 with a polysorbate 20-to-antibody molar ratio of 2:1 to 4:1. In many preferred embodiments, the surfactant is neither polysorbate 20 nor contains polysorbate 20, unless it is in a concentration of 0.4 mg / mL or higher as needed.

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

[0288] The amounts and concentrations of surfactants refer to the total amounts and concentrations of all surfactants unless only a single surfactant is specified. The concentrations of the surfactants or any specific surfactants can be replaced with molar ratios.

[0289] The embodiments and features disclosed in this section can preferably be combined with any of embodiments A1 to A127, B1 to B128, and C1 to C128. The embodiments and features disclosed in this section can preferably be combined with any of embodiments D1 to D36, E1 to E16, F1 to F16, G1 to G16, H1 to H12, I1 to I16, J1 to J24, K1 to K32, L1 to L64, M1 to M1080, and N1 to N2686.

[0290] <Antioxidants> The pharmaceutical composition may preferably contain an antioxidant. However, in the most preferred embodiment, the pharmaceutical composition is characterized by the absence of an antioxidant (or any one or more of the antioxidants specifically mentioned herein). Antioxidants can inhibit oxidative degradation pathways to which antibodies and / or other components in the pharmaceutical composition are susceptible. For example, antioxidants can inhibit the oxidation of antibodies by, for example, inhibiting the oxidation of certain easily oxidizable amino acid residues in the antibody, and / or inhibit oxidative deamination pathways.

[0291] Preferably, the antioxidant is, consists of, or includes an antioxidant selected from the group consisting of amino acid or peptide antioxidants, mineral antioxidants, vitamin antioxidants, carotenoid antioxidants, polyphenol antioxidants, aromatic or phenol antioxidants, chelating antioxidants, thiol antioxidants, and any combination thereof. Preferably, the antioxidant is, consists of, or includes an amino acid antioxidant. Preferably, the antioxidant is, consists of, or includes an antioxidant selected from the group consisting of cysteine, methionine, N-acetylcysteine, glutathione, and any combination thereof. Preferably, the antioxidant is, consists of, or includes an antioxidant selected from the group consisting of cysteine, methionine, and any combination thereof. Preferably, the antioxidant is cysteine, consists of, or includes cysteine. Preferably, the antioxidant is methionine, consists of, or includes methionine.

[0292] In certain embodiments, the pharmaceutical composition contains 0.1 to 100 mM of antioxidant. In certain embodiments, the pharmaceutical composition contains 1 to 50 mM of antioxidant. In certain embodiments, the pharmaceutical composition contains 2 to 25 mM of antioxidant. In certain embodiments, the pharmaceutical composition contains 3 to 12 mM of antioxidant. In certain embodiments, the pharmaceutical composition contains 4 to 6 mM of antioxidant.

[0293] In certain embodiments, the pharmaceutical composition contains an antioxidant having an antioxidant-to-antibody molar ratio of 2:1 to 750:1. In certain embodiments, the pharmaceutical composition contains an antioxidant having an antioxidant-to-antibody molar ratio of 271 to 400:1. In certain embodiments, the pharmaceutical composition contains an antioxidant having an antioxidant-to-antibody molar ratio of 7:1 to 180:1. In certain embodiments, the pharmaceutical composition contains an antioxidant having an antioxidant-to-antibody molar ratio of 20:1 to 90:1.

[0294] In certain embodiments, the pharmaceutical composition contains 1 to 50 mM of an antioxidant selected from the group consisting of cysteine, methionine, and any combination thereof. In certain embodiments, the pharmaceutical composition contains 2 to 25 mM of cysteine. In certain embodiments, the pharmaceutical composition contains 3 to 12 mM of cysteine. In certain embodiments, the pharmaceutical composition contains 4 to 6 mM of cysteine. In certain embodiments, the pharmaceutical composition contains cysteine ​​with a cysteine-to-antibody molar ratio of 2:1 to 750:1. In certain embodiments, the pharmaceutical composition contains cysteine ​​with a cysteine-to-antibody molar ratio of 271 to 400:1. In certain embodiments, the pharmaceutical composition contains cysteine ​​with a cysteine-to-antibody molar ratio of 7:1 to 180:1. In certain embodiments, the pharmaceutical composition contains cysteine ​​with a cysteine-to-antibody molar ratio of 20:1 to 90:1.

[0295] In certain embodiments, the pharmaceutical composition contains 2 to 25 mM methionine. In certain embodiments, the pharmaceutical composition contains 3 to 12 mM methionine. In certain embodiments, the pharmaceutical composition contains 4 to 6 mM methionine. In certain embodiments, the pharmaceutical composition contains methionine with a methionine-to-antibody molar ratio of 2:1 to 750:1. In certain embodiments, the pharmaceutical composition contains methionine with a methionine-to-antibody molar ratio of 271 to 400:1. In certain embodiments, the pharmaceutical composition contains methionine with a methionine-to-antibody molar ratio of 7:1 to 180:1. In certain embodiments, the pharmaceutical composition contains methionine with a methionine-to-antibody molar ratio of 20:1 to 90:1.

[0296] The amounts and concentrations of antioxidants refer to the total amount and concentration of all antioxidants unless only a single antioxidant is specified. The concentrations of said antioxidants or any specific antioxidants can be replaced with molar ratios.

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

[0298] <Chelating agent> The pharmaceutical composition may preferably contain a chelating agent. However, in the most preferred embodiment, the pharmaceutical composition is characterized by the absence of a chelating agent (or any one or more of the chelating agents specifically mentioned herein). In the context of the present invention, a chelating agent such as EDTA (other chelating agents are well known in the art and may perform similar or identical functions) can increase the stability of the pharmaceutical composition and, in particular, inhibit the degradation of antibodies. For example, a chelating agent can reduce the likelihood of aggregation and may also act as an antioxidant. A chelating agent can also sequester residual metals that may otherwise promote the degradation of antibodies and / or other components present in the pharmaceutical composition.

[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 another embodiment, the pharmaceutical composition contains 0.01 to 0.2 mM of a chelating agent. In yet another embodiment, the pharmaceutical composition contains 0.025 to 0.075 mM of a chelating agent.

[0301] In one embodiment, the pharmaceutical composition contains a chelating agent having a molar ratio of chelating agent to antibody of 1:420 to 8:1. In one embodiment, the pharmaceutical composition contains a chelating agent having a molar ratio of chelating agent to antibody of 1:140 to 4:1. In one embodiment, the pharmaceutical composition contains a chelating agent having a molar ratio of chelating agent to antibody of 1:16 to 1.1:1. In one embodiment, the pharmaceutical composition contains a chelating agent having 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 one embodiment, the pharmaceutical composition contains 0.01 to 0.2 mM EDTA. In one embodiment, the pharmaceutical composition contains 0.025 to 0.075 mM EDTA. In one embodiment, the pharmaceutical composition contains EDTA with a molar ratio of EDTA to antibody of 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 contains EDTA with a molar ratio of EDTA to antibody of 1:16 to 1.1:1. In one embodiment, the pharmaceutical composition contains EDTA with a molar ratio of EDTA to antibody of 1:6 to 1:1.5.

[0303] The amounts and concentrations of chelating agents refer to the total amounts and concentrations of all chelating agents unless only a single chelating agent is specified. The concentrations of the chelating agents or any specific chelating agents can be replaced with molar ratios.

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

[0305] <Specific Embodiments> Sucrose has been found to be a particularly advantageous component for use with the bispecific antibodies of the present invention that bind to both EGFR and LGR5, but trehalose and maltose are promising alternatives. Therefore, D) The following numbered paragraphs D1 to D36 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, as may be, the following together with water for injection) the following and is characterized by the following: D1. EGFR / LGR5 BsAb, and sugar components with a molar ratio of sugar component to antibody of 300:1 to 2600:1. D2. EGFR / LGR5 BsAb at a concentration of 1-150 mg / mL, and a sugar component with a molar ratio of sugar component to antibody of 300:1-2600:1. D3. EGFR / LGR5 BsAb, and disaccharide. D4. EGFR / LGR5 BsAb and disaccharides at 1-150 mg / mL. D5. EGFR / LGR5 BsAb, and disaccharides selected from the group consisting of sucrose, trehalose, and maltose. D6. EGFR / LGR5 BsAb in a dose of 1-150 mg / mL, and a disaccharide selected from the group consisting of sucrose, 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 sucrose at 150-350 mM. D11. EGFR / LGR5 BsAb, and trehalose. D12. EGFR / LGR5 BsAb at 1-150 mg / mL, and trehalose. D13. EGFR / LGR5 BsAb, and 150-350 mM trehalose. D14. EGFR / LGR5 BsAb at 1-150 mg / mL and trehalose at 150-350 mM. 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 maltose at 150-350 mM. D19. EGFR / LGR5 BsAb, a buffer system of 4-30 mM, and a sugar component with a molar ratio of sugar component to antibody of 300:1-2600:1. D20. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and a glucose component with a molar ratio of glucose component to antibody of 300:1-2600:1. D21. EGFR / LGR5 BsAb, 4-30 mM buffer system, and disaccharide. D22. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and disaccharide. D23. EGFR / LGR5 BsAb, a buffer system of 4-30 mM, and a disaccharide selected from the group consisting of sucrose, trehalose, and maltose. D24. EGFR / LGR5 BsAb in a concentration of 1-150 mg / mL, a buffer system of 4-30 mM, and a disaccharide selected from the group consisting of sucrose, trehalose, and maltose. D25. EGFR / LGR5 BsAb, 4-30 mM buffer system, and sucrose. D26. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and sucrose. D27. EGFR / LGR5 BsAb, 4-30 mM buffer system, and 150-350 mM sucrose. D28. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and sucrose at 150-350 mM. D29. EGFR / LGR5 BsAb, 4-30 mM buffer system, and trehalose. D30. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and trehalose. D31. EGFR / LGR5 BsAb, 4-30 mM buffer system, and 150-350 mM trehalose. D32. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and trehalose at 150-350 mM. D33. EGFR / LGR5 BsAb, 4-30 mM buffer system, and maltose. D34. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and maltose. D35. EGFR / LGR5 BsAb, buffer system of 4-30 mM, and maltose of 150-350 mM. D36. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and maltose at 150-350 mM.

[0306] Sodium chloride was also found to be a potentially advantageous component for use with bispecific antibodies that bind to both EGFR and LGR5, but perhaps more advantageous than sucrose at relatively higher pH levels. Therefore, E) The following numbered paragraphs E1 to E16 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, as may be, the following together with water for injection) the following and is characterized by the following: E1. EGFR / LGR5 BsAb, and sodium chloride. E2. EGFR / LGR5 BsAb at 1-150 mg / mL, and sodium chloride. E3. EGFR / LGR5 BsAb, and 10-180 mM sodium chloride. E4. EGFR / LGR5 BsAb at 1-150 mg / mL and sodium chloride at 10-180 mM. E5. EGFR / LGR5 BsAb, 4-30 mM buffer system, and sodium chloride. E6. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and sodium chloride. E7. EGFR / LGR5 BsAb, 4-30 mM buffer system, and 10-180 mM sodium chloride. E8. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, and sodium chloride at 10-180 mM. E9. EGFR / LGR5 BsAb, pH 5.9-7.0, and sodium chloride. E10. EGFR / LGR5 BsAb at 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 1-150 mg / mL, pH 5.9-7.0, and sodium chloride at 10-180 mM. E13. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 5.9-7.0, and sodium chloride. E14. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 5.9-7.0, and sodium chloride. E15. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 5.9-7.0, and 10-180 mM sodium chloride. E16. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 5.9-7.0, and sodium chloride at 10-180 mM.

[0307] While surfactants are thought to enhance formulation stability, polysorbate 80 and poloxamer 188 are considered more beneficial from a freeze-thaw perspective, and polysorbate 20 and polysorbate 80 most significantly improve stability against thermal stress, especially in the presence of buffers and sugar stabilizers. This means that polysorbate 80 has good versatility. Therefore, F) The following numbered paragraphs F1 to F16 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, as may be, the following together with water for injection) the following and is characterized by the following: F1. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. F2. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. F3. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM glucose component, and 0.05-1.5 mg / mL polysorbate 80. F4. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose component at 50-350 mM, and polysorbate 80 at 0.05-1.5 mg / mL. F5. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM glucose component, and 0.05-1.5 mg / mL polysorbate 20. F6. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose component at 50-350 mM, and polysorbate 20 at 0.05-1.5 mg / mL. F7. EGFR / LGR5 BsAb, 4-30 mM buffering system, 50-350 mM glucose component, and 0.05-1.5 mg / mL poloxamer 188. F8. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose component at 50-350 mM, and poloxamer 188 at 0.05-1.5 mg / mL. F9. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. F10. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. F11. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, and 0.05-1.5 mg / mL polysorbate 80. F12. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, sugar component at 50-350 mM, and polysorbate 80 at 0.05-1.5 mg / mL. F13. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, and 0.05-1.5 mg / mL polysorbate 20. F14. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, sugar component at 50-350 mM, and polysorbate 20 at 0.05-1.5 mg / mL. F15. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, and 0.05-1.5 mg / mL poloxamer 188. F16. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, glucose component at 50-350 mM, and poloxamer 188 at 0.05-1.5 mg / mL.

[0308] Amino acid components, such as non-antioxidant amino acid components, can contribute to formulation stability. Proline, lysine, and glycine (and possibly arginine as well) may be particularly advantageous, although proline and lysine tend to improve stability more than glycine in terms of freeze-thaw cycles, while glycine exhibits greater stabilization ability with respect to thermal stress. Therefore, G) The following numbered paragraphs G1 to G16 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, as may be, the following together with water for injection) the following: G1. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM carbohydrate components, and 5-150 mM amino acid components. G2. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose components at 50-350 mM, and amino acid components at 5-150 mM. G3. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM glucose component, and 10-150 mM proline. G4. EGFR / LGR5 BsAb 1-150 mg / mL, buffer system 4-30 mM, glucose component 50-350 mM, and proline 10-150 mM. G5. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM sugar component, and 10-150 mM glycine. G6. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose component at 50-350 mM, and glycine at 10-150 mM. G7. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM glucose component, and 5-150 mM lysine. G8. EGFR / LGR5 BsAb 1-150 mg / mL, buffer system 4-30 mM, glucose component 50-350 mM, and lysine 5-150 mM. G9. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar components, and 5-150 mM amino acid components. G10. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, glucose components at 50-350 mM, and amino acid components at 5-150 mM. G11. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, and 10-150 mM proline. G12. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, glucose component at 50-350 mM, and proline at 10-150 mM. G13. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, and 10-150 mM glycine. G14. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, sugar components at 50-350 mM, and glycine at 10-150 mM. G15. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM glucose component, and 5-150 mM lysine. G16. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, glucose component at 50-350 mM, and lysine at 5-150 mM.

[0309] Antioxidants, such as amino acid antioxidants, can contribute to the stability of pharmaceutical formulations. Methionine and cysteine, in particular, may be advantageous. While cysteine ​​slightly outperforms methionine in freeze-thaw experiments, methionine is considered superior in terms of resistance to heat stress. Therefore, H) The following numbered paragraphs H1 to H12 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, as may be, the following together with water for injection) the following and is characterized by the following: H1. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM sugar component, and 1-50 mM antioxidant. H2. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, sugar component at 50-350 mM, and antioxidant at 1-50 mM. H3. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM sugar component, and 2-25 mM cysteine. H4. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose component at 50-350 mM, and cysteine ​​at 2-25 mM. H5. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM glucose component, and 2-25 mM methionine. H6. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose components at 50-350 mM, and methionine at 2-25 mM. H7. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar components, and 1-50 mM antioxidant. H8. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, sugar components at 50-350 mM, and antioxidants at 1-50 mM. H9. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar components, and 2-25 mM cysteine. H10. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, sugar components at 50-350 mM, and cysteine ​​at 2-25 mM. H11. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar components, and 2-25 mM methionine. H12. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, glucose components at 50-350 mM, and methionine at 2-25 mM.

[0310] Chelating agents such as EDTA can contribute to formulation stability by being resistant to both freeze-thaw cycles and heat stress. Therefore, I) The following numbered paragraphs I1 to I16 disclose specific embodiments of the present invention, wherein the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, as may be, the following together with water for injection) the following and is characterized by the following: I1. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM sugar component, and 0.001-0.5 mM chelating agent. I2. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose component at 50-350 mM, and chelating agent at 0.001-0.5 mM. I3. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM glucose component, and 0.001-0.5 mM EDTA. I4. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, glucose component at 50-350 mM, and EDTA at 0.001-0.5 mM. I5. EGFR / LGR5 BsAb, a buffer system of 4-30 mM, pH 4.4-7.4, a sugar component of 50-350 mM, and a chelating agent of 0.001-0.5 mM. I6. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, sugar component at 50-350 mM, and chelating agent at 0.001-0.5 mM. I7. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, and 0.001-0.5 mM EDTA. I8. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, glucose component at 50-350 mM, and EDTA at 0.001-0.5 mM. I9. EGFR / LGR5 BsAb, 4-30 mM buffering system, 50-350 mM sugar component, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. I10. EGFR / LGR5 BsAb in 1-150 mg / mL, buffer system in 4-30 mM, sugar component in 50-350 mM, surfactant in 0.01-2 mg / mL, and chelating agent in 0.001-0.5 mM. I11. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM sugar component, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM EDTA. I12. EGFR / LGR5 BsAb in 1-150 mg / mL, buffer system in 4-30 mM, sugar component in 50-350 mM, surfactant in 0.01-2 mg / mL, and EDTA in 0.001-0.5 mM. I13. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM chelating agent. I14. EGFR / LGR5 BsAb in 1-150 mg / mL, buffer system in 4-30 mM, pH 4.4-7.4, sugar component in 50-350 mM, surfactant in 0.01-2 mg / mL, and chelating agent in 0.001-0.5 mM. I15. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 50-350 mM sugar component, 0.01-2 mg / mL surfactant, and 0.001-0.5 mM EDTA. I16. EGFR / LGR5 BsAb in 1-150 mg / mL, buffer system in 4-30 mM, pH 4.4-7.4, sugar component in 50-350 mM, surfactant in 0.01-2 mg / mL, and EDTA in 0.001-0.5 mM.

[0311] Certain metal(II) salts, particularly alkaline earth metal salts such as magnesium chloride and calcium chloride, can contribute to formulation stability in terms of resistance to freeze-thaw and / or heat stress. Therefore, J) The following numbered paragraphs J1 to J24 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, as may be, the following together with water for injection) the following and is characterized by the following: J1. EGFR / LGR5 BsAb, 4-30 mM buffer system, 1-30 mM magnesium chloride, and 50-350 mM sugar component. J2. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, magnesium chloride at 1-30 mM, and glucose component at 50-350 mM. J3. EGFR / LGR5 BsAb, 4-30 mM buffer system, 1-30 mM calcium chloride, and 50-350 mM sugar components. J4. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, calcium chloride at 1-30 mM, and glucose component at 50-350 mM. J5. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 1-30 mM magnesium chloride, and 50-350 mM sugar components. J6. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, magnesium chloride at 1-30 mM, and sugar components at 50-350 mM. J7. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 1-30 mM calcium chloride, and 50-350 mM sugar components. J8. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, calcium chloride at 1-30 mM, and sugar components at 50-350 mM. J9. EGFR / LGR5 BsAb, 4-30 mM buffer system, 1-30 mM magnesium chloride, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. J10. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, magnesium chloride at 1-30 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. J11. EGFR / LGR5 BsAb, 4-30 mM buffer system, 1-30 mM calcium chloride, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. J12. EGFR / LGR5 BsAb in 1-150 mg / mL, buffer system in 4-30 mM, calcium chloride in 1-30 mM, sugar component in 50-350 mM, and surfactant in 0.01-2 mg / mL. J13. EGFR / LGR5 BsAb, 4-30 mM buffer system, 1-30 mM magnesium chloride, 50-350 mM sugar component, and 0.05-1.5 mg / mL polysorbate 80. J14. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, magnesium chloride at 1-30 mM, glucose component at 50-350 mM, and polysorbate 80 at 0.05-1.5 mg / mL. J15. EGFR / LGR5 BsAb, 4-30 mM buffer system, 1-30 mM calcium chloride, 50-350 mM sugar component, and 0.05-1.5 mg / mL polysorbate 80. J16. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, calcium chloride at 1-30 mM, glucose component at 50-350 mM, and polysorbate 80 at 0.05-1.5 mg / mL. J17. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 1-30 mM magnesium chloride, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. J18. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, magnesium chloride at 1-30 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. J19. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 1-30 mM calcium chloride, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. J20. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, calcium chloride at 1-30 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. J21. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 1-30 mM magnesium chloride, 50-350 mM sugar component, and 0.05-1.5 mg / mL polysorbate 80. J22. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, magnesium chloride at 1-30 mM, sugar component at 50-350 mM, and polysorbate 80 at 0.05-1.5 mg / mL. J23. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 4.4-7.4, 1-30 mM calcium chloride, 50-350 mM sugar component, and 0.05-1.5 mg / mL polysorbate 80. J24. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 4.4-7.4, calcium chloride at 1-30 mM, sugar component at 50-350 mM, and polysorbate 80 at 0.05-1.5 mg / mL.

[0312] Buffers such as histidine, succinates, citrates, phosphates, citrate-phosphates, and acetates function particularly well at intermediate pH, especially in the presence of surfactants and sugar components (particularly maltose as well as sucrose). Therefore, K) The following numbered paragraphs K1 to K32 disclose specific embodiments of the present invention, wherein the pharmaceutical composition comprises (or, in the case of an aqueous composition, optionally together with water for injection) the following and is characterized by the following: K1. EGFR / LGR5 BsAb, 4-30 mM buffer system, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K2. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K3. EGFR / LGR5 BsAb, 3-25 mM histidine buffer system, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K4. EGFR / LGR5 BsAb at 1-150 mg / mL, histidine buffer at 3-25 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K5. EGFR / LGR5 BsAb, 3-25 mM acetate buffer system, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K6. EGFR / LGR5 BsAb at 1-150 mg / mL, acetate buffer system at 3-25 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K7. EGFR / LGR5 BsAb, 3-25 mM citrate buffer system, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K8. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate buffer at 3-25 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K9. EGFR / LGR5 BsAb, 3-25 mM succinate buffer system, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K10. EGFR / LGR5 BsAb at 1-150 mg / mL, succinate buffer at 3-25 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K11. EGFR / LGR5 BsAb, 3-25 mM phosphate buffer system, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K12. EGFR / LGR5 BsAb at 1-150 mg / mL, phosphate buffer at 3-25 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K13. EGFR / LGR5 BsAb, 3-25 mM citrate-phosphate buffer system, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K14. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate-phosphate buffer system at 3-25 mM, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K15. EGFR / LGR5 BsAb, Tris buffer system with a molar ratio of Tris buffer system to antibody of 20:1 to 90:1, 50 to 350 mM sugar component, and 0.01 to 2 mg / mL surfactant. K16. EGFR / LGR5 BsAb at 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K17. EGFR / LGR5 BsAb, 4-30 mM buffer system, pH 5.4-7.5, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K18. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 5.4-7.5, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K19. EGFR / LGR5 BsAb, 3-25 mM histidine buffer system, pH 5.4-7.0, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K20. EGFR / LGR5 BsAb at 1-150 mg / mL, histidine buffer system at 3-25 mM, pH 5.4-7.0, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K21. EGFR / LGR5 BsAb, 3-25 mM acetate buffer system, pH 5.4-7.5, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K22. EGFR / LGR5 BsAb at 1-150 mg / mL, acetate buffer system at 3-25 mM, pH 5.4-7.5, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K23. EGFR / LGR5 BsAb, 3-25 mM citrate buffer system, pH 5.8-7.5, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K24. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate buffer at 3-25 mM, pH 5.8-7.5, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K25. EGFR / LGR5 BsAb, 3-25 mM succinate buffer system, pH 5.4-7.5, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K26. EGFR / LGR5 BsAb at 1-150 mg / mL, succinate buffer system at 3-25 mM, pH 5.4-7.5, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K27. EGFR / LGR5 BsAb, 3-25 mM phosphate buffer system, pH 5.4-7.5, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K28. EGFR / LGR5 BsAb at 1-150 mg / mL, phosphate buffer at 3-25 mM, pH 5.4-7.5, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K29. EGFR / LGR5 BsAb, 3-25 mM citrate-phosphate buffer system, pH 5.4-7.5, 50-350 mM sugar component, and 0.01-2 mg / mL surfactant. K30. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate-phosphate buffer system at 3-25 mM, pH 5.4-7.5, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL. K31. EGFR / LGR5 BsAb, Tris buffer system with a molar ratio of 20:1 to 90:1 for Tris buffer system versus antibody, pH 5.4 to 7.5, 50 to 350 mM sugar component, and 0.01 to 2 mg / mL surfactant. K32. EGFR / LGR5 BsAb at 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, pH 5.4-7.5, sugar component at 50-350 mM, and surfactant at 0.01-2 mg / mL.

[0313] Buffers such as histidine, succinates, citrates, phosphates, citrate-phosphates, and acetates function particularly well at intermediate pH levels, especially in the presence of surfactants and disaccharide components (particularly maltose as well as sucrose), when used with higher concentrations of antibody preparations. Therefore, L) The following numbered paragraphs L1 to L64 disclose specific embodiments of the present invention in which the pharmaceutical composition comprises (or, in the case of an aqueous composition, comprises, as may be, the following together with water for injection) the following and is characterized by the following: L1. EGFR / LGR5 BsAb in 1-150 mg / mL, a buffer system in 4-30 mM, a disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and a surfactant in 0.01-2 mg / mL. L2. EGFR / LGR5 BsAb in 1-150 mg / mL, a disaccharide in 50-350 mM selected from the group consisting of a histidine buffer system in 3-25 mM, sucrose, trehalose, and maltose, and a surfactant in 0.01-2 mg / mL. L3. EGFR / LGR5 BsAb in 1-150 mg / mL, acetate buffer system in 3-25 mM, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L4. EGFR / LGR5 BsAb in 1-150 mg / mL, citrate buffer in 3-25 mM, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and a surfactant in 0.01-2 mg / mL. L5. EGFR / LGR5 BsAb in 1-150 mg / mL, succinate buffer system in 3-25 mM, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L6. EGFR / LGR5 BsAb in 1-150 mg / mL, phosphate buffer in 3-25 mM, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L7. EGFR / LGR5 BsAb in 1-150 mg / mL, citrate-phosphate buffer system in 3-25 mM, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L8. EGFR / LGR5 BsAb in 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, a disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and a surfactant in 0.01-2 mg / mL. L9. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, sucrose at 250-300 mM, and surfactant at 0.01-2 mg / mL. L10. EGFR / LGR5 BsAb at 1-150 mg / mL, histidine buffer at 3-25 mM, sucrose at 250-300 mM, and surfactant at 0.01-2 mg / mL. L11. EGFR / LGR5 BsAb at 1-150 mg / mL, acetate buffer system at 3-25 mM, sucrose at 250-300 mM, and surfactant at 0.01-2 mg / mL. L12. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate buffer at 3-25 mM, sucrose at 250-300 mM, and surfactant at 0.01-2 mg / mL. L13. EGFR / LGR5 BsAb at 1-150 mg / mL, succinate buffer at 3-25 mM, sucrose at 250-300 mM, and surfactant at 0.01-2 mg / mL. L14. EGFR / LGR5 BsAb in 1-150 mg / mL, phosphate buffer system in 3-25 mM, sucrose in 250-300 mM, and surfactant in 0.01-2 mg / mL. L15. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate-phosphate buffer system at 3-25 mM, sucrose at 250-300 mM, and surfactant at 0.01-2 mg / mL. L16. EGFR / LGR5 BsAb at 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, 250-300 mM sucrose, and 0.01-2 mg / mL of surfactant. L17. EGFR / LGR5 BsAb in 1-150 mg / mL, a buffer system in 4-30 mM, a disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L18. EGFR / LGR5 BsAb in 1-150 mg / mL, a disaccharide in 50-350 mM selected from the group consisting of a histidine buffer system in 3-25 mM, sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L19. EGFR / LGR5 BsAb in 1-150 mg / mL, 50-350 mM disaccharide selected from the group consisting of 3-25 mM acetate buffer system, sucrose, trehalose, and maltose, and 0.05-1.5 mg / mL polysorbate 80. L20. EGFR / LGR5 BsAb in 1-150 mg / mL, citrate buffer in 3-25 mM, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L21. EGFR / LGR5 BsAb in 1-150 mg / mL, 50-350 mM disaccharide selected from the group consisting of succinate buffers in 3-25 mM, sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L22. EGFR / LGR5 BsAb in 1-150 mg / mL, phosphate buffer in 3-25 mM, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L23. EGFR / LGR5 BsAb in 1-150 mg / mL, a disaccharide in 50-350 mM selected from the group consisting of a citrate-phosphate buffer system in 3-25 mM, sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L24. EGFR / LGR5 BsAb in 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, a disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L25. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, sucrose at 250-300 mM, and polysorbate 80 at 0.05-1.5 mg / mL. L26. EGFR / LGR5 BsAb at 1-150 mg / mL, histidine buffer at 3-25 mM, sucrose at 250-300 mM, and polysorbate 80 at 0.05-1.5 mg / mL. L27. EGFR / LGR5 BsAb at 1-150 mg / mL, acetate buffer system at 3-25 mM, sucrose at 250-300 mM, and polysorbate 80 at 0.05-1.5 mg / mL. L28. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate buffer at 3-25 mM, sucrose at 250-300 mM, and polysorbate 80 at 0.05-1.5 mg / mL. L29. EGFR / LGR5 BsAb at 1-150 mg / mL, succinate buffer at 3-25 mM, sucrose at 250-300 mM, and polysorbate 80 at 0.05-1.5 mg / mL. L30. EGFR / LGR5 BsAb at 1-150 mg / mL, phosphate buffer at 3-25 mM, sucrose at 250-300 mM, and polysorbate 80 at 0.05-1.5 mg / mL. L31. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate-phosphate buffer system at 3-25 mM, sucrose at 250-300 mM, and polysorbate 80 at 0.05-1.5 mg / mL. L32. EGFR / LGR5 BsAb at 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, 250-300 mM sucrose, and 0.05-1.5 mg / mL polysorbate 80. L33. EGFR / LGR5 BsAb in 1-150 mg / mL, a buffer system in 4-30 mM, pH 5.4-7.2, a disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and a surfactant in 0.01-2 mg / mL. L34. EGFR / LGR5 BsAb in 1-150 mg / mL, a histidine buffer system in 3-25 mM, pH 5.4-7.0, a disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and a surfactant in 0.01-2 mg / mL. L35. EGFR / LGR5 BsAb in 1-150 mg / mL, acetate buffer system in 3-25 mM, pH 5.4-7.2, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L36. EGFR / LGR5 BsAb in 1-150 mg / mL, citrate buffer system in 3-25 mM, pH 5.8-7.6, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L37. EGFR / LGR5 BsAb in 1-150 mg / mL, succinate buffer system in 3-25 mM, pH 5.4-7.2, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L38. EGFR / LGR5 BsAb in 1-150 mg / mL, phosphate buffer system in 3-25 mM, pH 5.4-7.2, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L39. EGFR / LGR5 BsAb in 1-150 mg / mL, citrate-phosphate buffer system in 3-25 mM, pH 5.8-7.6, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and surfactant in 0.01-2 mg / mL. L40. EGFR / LGR5 BsAb in 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, pH 5.4-7.2, 50-350 mM disaccharide selected from the group consisting of sucrose, trehalose, and maltose, and 0.01-2 mg / mL of surfactant. L41. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 5.4-7.2, sucrose at 250-300 mM, and surfactant at 0.01-2 mg / mL. L42. EGFR / LGR5 BsAb at 1-150 mg / mL, histidine buffer at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and surfactant at 0.01-2 mg / mL. L43. EGFR / LGR5 BsAb at 1-150 mg / mL, acetate buffer system at 3-25 mM, pH 5.4-7.2, sucrose at 250-300 mM, and surfactant at 0.01-2 mg / mL. L44. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate buffer at 3-25 mM, pH 5.8-7.6, 250-300 mM sucrose, and surfactant at 0.01-2 mg / mL. L45. EGFR / LGR5 BsAb at 1-150 mg / mL, succinate buffer at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and surfactant at 0.01-2 mg / mL. L46. EGFR / LGR5 BsAb at 1-150 mg / mL, phosphate buffer at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and surfactant at 0.01-2 mg / mL. L47. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate-phosphate buffer system at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and surfactant at 0.01-2 mg / mL. L48. EGFR / LGR5 BsAb at 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, pH 5.4-7.2, 250-300 mM sucrose, and 0.01-2 mg / mL of surfactant. L49. EGFR / LGR5 BsAb in 1-150 mg / mL, a buffer system in 4-30 mM, pH 5.4-7.2, a disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L50. EGFR / LGR5 BsAb in 1-150 mg / mL, histidine buffer system in 3-25 mM, pH 5.4-7.2, a disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L51. EGFR / LGR5 BsAb in 1-150 mg / mL, acetate buffer system in 3-25 mM, pH 5.4-7.2, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L52. EGFR / LGR5 BsAb in 1-150 mg / mL, citrate buffer system in 3-25 mM, pH 5.8-7.8, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L53. EGFR / LGR5 BsAb in 1-150 mg / mL, succinate buffer system in 3-25 mM, pH 5.4-7.2, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L54. EGFR / LGR5 BsAb in 1-150 mg / mL, phosphate buffer system in 3-25 mM, pH 5.4-7.2, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L55. EGFR / LGR5 BsAb in 1-150 mg / mL, citrate-phosphate buffer system in 3-25 mM, pH 5.4-7.2, disaccharide in 50-350 mM selected from the group consisting of sucrose, trehalose, and maltose, and polysorbate 80 in 0.05-1.5 mg / mL. L56. EGFR / LGR5 BsAb in 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, pH 5.4-7.2, 50-350 mM disaccharide selected from the group consisting of sucrose, trehalose, and maltose, and 0.05-1.5 mg / mL of polysorbate 80. L57. EGFR / LGR5 BsAb at 1-150 mg / mL, buffer system at 4-30 mM, pH 5.4-7.2, 250-300 mM sucrose, and polysorbate 80 at 0.05-1.5 mg / mL. L58. EGFR / LGR5 BsAb at 1-150 mg / mL, histidine buffer at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and 0.05-1.5 mg / mL polysorbate 80. L59. EGFR / LGR5 BsAb at 1-150 mg / mL, acetate buffer system at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and polysorbate 80 at 0.05-1.5 mg / mL. L60. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate buffer at 3-25 mM, pH 5.8-7.8, 250-300 mM sucrose, and polysorbate 80 at 0.05-1.5 mg / mL. L61. EGFR / LGR5 BsAb at 1-150 mg / mL, succinate buffer system at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and polysorbate 80 at 0.05-1.5 mg / mL. L62. EGFR / LGR5 BsAb at 1-150 mg / mL, phosphate buffer at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and 0.05-1.5 mg / mL of polysorbate 80. L63. EGFR / LGR5 BsAb at 1-150 mg / mL, citrate-phosphate buffer system at 3-25 mM, pH 5.4-7.2, 250-300 mM sucrose, and polysorbate 80 at 0.05-1.5 mg / mL. L64. EGFR / LGR5 BsAb at 1-150 mg / mL, Tris buffer system with a molar ratio of Tris buffer system versus antibody of 20:1-90:1, pH 5.4-7.2, 250-300 mM sucrose, and 0.05-1.5 mg / mL polysorbate 80.

[0314] During careful investigatio...

Claims

1. A human bispecific IgG antibody comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody comprises the VH amino acid sequence of MF3755 shown in SEQ ID NO: 5, the VH amino acid sequence of MF5816 shown in SEQ ID NO: 41, and the VL amino acid sequence shown in SEQ ID NO:

53. Histidine buffer and / or citrate buffer, Sucrose, and Polysorbate 80 A pharmaceutical composition comprising the above.

2. The pharmaceutical composition according to claim 1, wherein the composition comprises a histidine buffer and the composition has a pH of 5 to 7.

3. The pharmaceutical composition according to claim 1, wherein the composition comprises a citrate buffer and the composition has a pH of 6.2 to 7.

8.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the antibody is present at a concentration of 0.5 to 150 mg / mL.

5. The sucrose is present at a concentration of 200 to 400 mM, or The molar concentration ratio of sucrose versus antibody is 250:1 to 60,000:

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

6. Polysorbate 80 is present at a concentration of 0.01 to 2 mg / mL, or The molar concentration ratio of polysorbate 80 to antibody is 1:90 to 224:

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

7. The aforementioned histidine buffer, citrate buffer, or combination of histidine buffer and citrate buffer is present at a concentration of 2 to 50 mM, A pharmaceutical composition according to any one of claims 1 to 6, wherein the molar concentration ratio of histidine buffer or citrate buffer (or a combination of histidine buffer and citrate buffer) to antibody is 2.9:1 to 7300:

1.

8. The pharmaceutical composition according to any one of claims 1 and 4 to 6, wherein the composition comprises a histidine buffer or a citrate buffer.

9. The pharmaceutical composition according to any one of claims 1 and 4 to 6, wherein the composition comprises only one of either a histidine buffer or a citrate buffer.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition does not contain trehalose.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the composition does not contain polysorbate 20 and / or sodium chloride and / or an antioxidant and / or a chelating agent.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the antibody comprises a light chain constant region (CL) containing the sequence of Sequence ID No.

57.

13. The pharmaceutical composition according to any one of claims 1 to 11, wherein the antibody comprises the light chain constant region (CL) sequence shown in SEQ ID NO: 57, the CH1 domain sequence shown in SEQ ID NO: 58, the hinge sequence shown in SEQ ID NO: 59, the CH2 domain sequence shown in SEQ ID NO: 60, the CH3-DE domain sequence shown in SEQ ID NO: 61, and the CH3-KK domain sequence shown in SEQ ID NO:

62.

14. The composition is Antibodies in concentrations of 1-30 mg / mL, 3–20 mM histidine buffer and / or citrate buffer, Sucrose in 200-400 mM, and Polysorbate 80 at 0.01–2 mg / mL an aqueous composition containing The pharmaceutical composition according to any one of claims 1, 4-7, and 10-13, wherein the composition has a pH of 5.4 to 7.

4.

15. The composition is 15-25 mg / mL antibody, 4–12 mM 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 pharmaceutical composition according to any one of claims 1, 4-7, and 10-13, wherein the composition has a pH of 5.4 to 7.

4.

16. 20 mg / mL antibody, 10 mM histidine buffer, 280 mM sucrose, Polysorbate 80 in a concentration of 0.5 mg / mL or 1.0 mg / mL, and water Includes, The pharmaceutical composition according to any one of claims 1, 2, and 4 to 13, wherein the composition has a pH of 5.8 to 6.

0.

17. i) 20 mg / ml antibody, 5 mM histidine pH 6.3, 290 mM sucrose, 0.1% polysorbate 80, and water, or ii) 20 mg / ml antibody, 10 mM histidine pH 5.9, 280 mM sucrose, 0.05% polysorbate 80, and water, or iii) 20 mg / ml antibody, 10 mM histidine pH 5.9, 280 mM sucrose, 0.1% polysorbate 80, and water, or iv) 20 mg / ml antibody, 10 mM sodium citrate pH 7.0, 280 mM sucrose, 0.05% polysorbate 80, and water A pharmaceutical composition according to any one of claims 1 and 4 to 13, comprising any one of the above.

18. The composition is the antibody, Histidine buffer or citrate buffer (or a combination of histidine buffer and citrate buffer) versus antibody molar concentration ratio is 21:1 to 146:1, histidine buffer and / or citrate buffer, Sucrose with a molar concentration ratio of sucrose versus antibody of 1460:1 to 2920:1, and Polysorbate 80 with a molar concentration ratio of 1:18 to 11:1 Includes, The pharmaceutical composition according to any one of claims 1, 4-7, and 10-13, wherein the composition has a pH of 5.4 to 7.

4.

19. the antibody, Histidine buffer or citrate buffer (or a combination of histidine buffer and citrate buffer) versus antibody molar concentration ratio is 29:1 to 88:1, histidine buffer and / or citrate buffer, Sucrose with a molar concentration ratio of sucrose versus antibody of 1825:1 to 2555:1, and Polysorbate 80 with an antibody molar concentration ratio of 1:2 to 8.5:1 Includes, The pharmaceutical composition according to any one of claims 1 and 4 to 13, wherein the composition has a pH of 5.4 to 7.

4.

20. the antibody, Histidine buffer with a molar concentration ratio of 73:1 to antibody, Sucrose with a molar concentration ratio of sucrose versus antibody of 2040:1 Polysorbate 80 having a molar concentration ratio of 2.79:1 to antibody, and Water Includes, The pharmaceutical composition according to any one of claims 1, 2, and 4 to 13, wherein the composition has a pH of 5.8 to 6.

0.

21. A human bispecific IgG1 antibody comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody is The VH amino acid sequence of MF3755 shown in Sequence ID No. 5, The VH amino acid sequence of MF5816 shown in Sequence ID No. 41, The VL amino acid sequence shown in Sequence ID No. 53, The heavy chain sequence corresponding to sequence number 63, and Light chain constant region (CL) sequence shown in Sequence ID No. 57 Includes, Histidine buffer and / or citrate buffer, Sucrose, and Polysorbate 80 The pharmaceutical composition according to claim 1, comprising the following:

22. A human bispecific IgG1 antibody containing a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody is, The VH amino acid sequence of MF3755 shown in Sequence ID No. 5, The VH amino acid sequence of MF5816 shown in Sequence ID No. 41, The VL amino acid sequence shown in Sequence ID No. 53, The CH1 domain sequence shown in Sequence ID No. 58, the hinge sequence shown in Sequence ID No. 59, the CH2 domain sequence shown in Sequence ID No. 60, the CH3-DE domain sequence shown in Sequence ID No. 61, and the CH3-KK domain sequence shown in Sequence ID No. 62, and Light chain constant region (CL) sequence shown in Sequence ID No. 57 Includes, 4–12 mM histidine buffer and / or citrate buffer, Sucrose in a concentration of 250-350 mM or 290 mM, and Polysorbate 80 at 0.1–1.5 mg / mL The pharmaceutical composition according to claim 1, comprising the following:

23. A 20 mg / mL human bispecific IgG1 antibody comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody is The VH amino acid sequence of MF3755 shown in Sequence ID No. 5, The VH amino acid sequence of MF5816 shown in Sequence ID No. 41, The VL amino acid sequence shown in Sequence ID No. 53, The CH1 domain sequence shown in Sequence ID No. 58, the hinge sequence shown in Sequence ID No. 59, the CH2 domain sequence shown in Sequence ID No. 60, the CH3-DE domain sequence shown in Sequence ID No. 61, and the CH3-KK domain sequence shown in Sequence ID No. 62, and Light chain constant region (CL) sequence shown in Sequence ID No. 57 Includes, 5 mM or 10 mM histidine buffer and / or citrate buffer, Sucrose in a concentration of 280 mM or 290 mM, and 0.5 mg / mL or 1 mg / mL of polysorbate 80 The pharmaceutical composition according to claim 1, comprising the following:

24. A human bispecific IgG1 antibody comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody is The VH amino acid sequence of MF3755 shown in Sequence ID No. 5, The VH amino acid sequence of MF5816 shown in Sequence ID No. 41, The VL amino acid sequence shown in Sequence ID No. 53, The CH1 domain sequence shown in Sequence ID No. 58, the hinge sequence shown in Sequence ID No. 59, the CH2 domain sequence shown in Sequence ID No. 60, the CH3-DE domain sequence shown in Sequence ID No. 61, and the CH3-KK domain sequence shown in Sequence ID No. 62, and Light chain constant region (CL) sequence shown in Sequence ID No. 57 Includes, Histidine buffer or citrate buffer (or a combination of histidine buffer and citrate buffer) versus antibody molar concentration ratio is 29:1 to 88:1, histidine buffer and / or citrate buffer, Sucrose with a molar concentration ratio of sucrose versus antibody of 1460:1 to 2920:1, and Polysorbate 80 with a molar concentration ratio of 1:18 to 11:1 Includes, The pharmaceutical composition according to claim 1, wherein the composition has a pH of 5.4 to 7.4.

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