Pharmaceutical compositions containing stabilized antibody-drug conjugates

Abstract

The invention relates to stabilized pharmaceutical compositions comprising antibody-drug conjugates and related products and methods, such as to said pharmaceutical compositions for use in therapy, e.g. as cancer therapy. Moreover, the invention relates to the use of specific substances to stabilize antibody conjugate containing pharmaceutical composition.

Description

[0001] Pharmaceutical Compositions

[0002] Containing Stabilized Antibody-Drug Conjugates

[0003] TECHNICAL FIELD

[0004] The invention relates to stabilized pharmaceutical compositions comprising antibody-drug conjugates and related products and methods, such as to said pharmaceutical compositions for use in therapy, e.g. as cancer therapy. Moreover, the invention relates to the use of specific substances to stabilize antibody conjugate containing pharmaceutical composition.

[0005] TECHNOLOGICAL BACKGROUND

[0006] Antibody-drug conjugates (ADCs) are effective therapeutic immunoconjugates, comprising a target specific antibody linked to a potent, often cytotoxic, small-molecule drug. ADCs face a significant challenge regarding e.g. stability, which requires several FDA approved ADCs, such as Trodelvy®, Enhertu®, Kadcyla®, Adcetris®, Padcev®, Polivy®, Besponsa®, Mylotarg®, BLENREP®, Zynlonta®, and Tivdak®, to be generally packaged in lyophilized form. In contrast, therapeutic monoclonal antibodies can be conveniently packaged as a solution.

[0007] The small-molecule drugs employed in ADCs (also referred to as payloads) can contain photosensitive functional groups. As it is difficult to exclude exposure to light during the synthesis, purification, storage, and administration of ADCs, these photosensitive functional groups contribute to the potential of ADCs for photodegradation.

[0008] The significance of photodegradation as a key factor impacting the stability of ADCs is further underscored by the FDA-approved Prescribing Information (PI) which mandates light protection for the majority of the approved ADCs, including the two marketed ADCs with a camptothecin derivative (sometimes referred to by the general terms “a camptothecin” or "camptothecins” herein, which are used to refer to both camptothecin and camptothecin derivatives in general) as a payload (e.g. Trodelvy® and Enhertu®), wherein amber glass is apparently necessary as the primary packaging material and the FDA prescribing information indicates the necessity of protecting the molecule from light during various stages, including storage, reconstitution, dilution, and administration. Amber glass vials are typically not preferred as primary packaging containers due to complicating the mandatory quality control processes, such as visual inspection, and the potential for unfavorable leaching profiles, including metal ions that can trigger decomposition of the active pharmaceutical ingredient (API) (Sumitra A et al. Pharmaceutical Glass Interactions: A Review of Possibilities. Sumitra A. Pillai et al / J. Pharm. Sci. & Res. Vol. 8(2), 2016, 103-111).

[0009] In addition to camptothecins, which are topoisomerase I inhibitors, typical ADC payloads include microtubule / tubulin polymerisation inhibitors (auristatins), DNA minor groove binders (duocarmycins) and topoisomerase II inhibitors (anthracyclines such as doxorubicin), all of which exhibit hydrophobic properties. The hydrophobic nature of these payloads contributes to the aggregation of ADCs through the mechanism of self-association (Cockrell GM et al. Photoinduced aggregation of a model antibody-drug conjugate. Mol Pharm. 2015 Jun 1; 12(6): 1784-97. Doi: 10.1021 / mp5006799. Epub 2015 May 1. PMID: 25880156). Aggregation not only serves as a direct indicator of reduced solubility but also increases the risk of adverse clinical effects, including immunogenicity or decreased potency. Furthermore, aggregation of ADCs can be exacerbated by light-induced unfolding of the antibody component within the ADC or by light-induced cross-reactions involving the photosensitive functional groups present in the payloads.

[0010] In recent years stabilizing agents were evaluated. However, in the field of ADCs, no particular progress seems available since most of the ADC-containing compositions need to be lyophilized and partly even packed in amber glass. Further, the addition of substances such as buffer components intended to mitigate light-induced degradation of the payload or to counteract its hydrophobicity may inadvertently result in the destabilization or insolubility of the ADC.

[0011] Against this background there is an ongoing need for stable ADC containing compositions e.g. comprising light sensitive ADCs, for instance stable aqueous ADC containing compositions or lyophilizates thereof.

[0012] SUMMARY OF THE INVENTION

[0013] While most therapeutic monoclonal antibodies typically exhibit stability and solubility, allowing convenient primary packaging as a solution, ADCs face a fundamental challenge with solubility and stability, particularly when exposed to light. Exposure of an antibody-drug conjugate (ADC) to light during manufacture, storage and administration of the ADC or ADC containing composition is difficult to avoid. Typically, pharmaceutical compositions, including ADC containing pharmaceutical compositions, are exposed to ambient light (visible light) ranging from about 380 to 740 nanometers during storage and application. The poor stability and solubility of ADCs in a solution give rise to several problems, including such related to drug safety, drug quality, and challenges associated with the storage and administration of ADCs. Therefore, most currently approved ADCs, including Trodelvy®, Enhertu®, Kadcyla®, Adcetris®, Padcev®, Polivy®, Besponsa®, Mylotarg®, BLENREP®, Zynlonta®, and Tivdak®, require lyophilization for primary packaging, and many demand protection from light.

[0014] To overcome such problems, a robust formulation is required that allows a stable pharmaceutical composition of ADCs, especially of ADCs with photosensitive functional groups in their payloads, such as camptothecins.

[0015] Against the above background, it is an object of the present invention to provide a stable (e.g. avoiding aggregation, stabilizing the payload) ADC containing pharmaceutical composition. In particular, it is an object of the present invention to provide an ADC containing pharmaceutical composition that has good stability even after light exposure. It is a further object of the present invention to provide a storage stable ADC containing pharmaceutical composition that is a lyophilizate and is reconstitutable to an aqueous solution. Further, it is an object of the present invention to provide means for a convenient treatment of such diseases that need to be treated with ADC-containing pharmaceutical compositions.

[0016] The inventors surprisingly found that at least one of the above objects can be achieved by a pharmaceutical composition according to the present invention.

[0017] In an aspect, the invention relates to pharmaceutical composition comprising

[0018] an antibody-drug conjugate, such as an antibody-drug conjugate of the general formula [antibody]-[linker-payload]n, wherein n is between 1 and 10;

[0019] a stabilizer selected from the group consisting of methionine, ascorbic acid, hydroxypropyl-β-cyclodextrin, and a mixture thereof;

[0020] a nonionic surfactant, such a polysorbate, a poloxamer, or a mixture thereof; a sugar and / or a sugar alcohol, such as a sugar or sugar alcohol selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and a buffer, such as a histidine buffer or an acetate buffer.

[0021] Preferably, said antibody-drug conjugate is ADC1 as described below.

[0022] Further features are described below. The ADC in a pharmaceutical composition according to the present invention is less susceptible to be oxidized, less susceptible for aggregation, less susceptible for changes in the charge profile, less susceptible for fragmentation and the payload remains more resistant towards degradation. The inventive pharmaceutical composition thus exhibits increased resistance to the variable stresses that a drug product may be exposed to during manufacture, transport, and storage (e.g. shaking, shearing, freeze-thawing, heat, light exposure), resulting in less turbidity or coloration. A pharmaceutical composition according to the present disclosure can surprisingly well (i) be dissolved in or mixed with water and (iia) be stored in the form of an aqueous solution or (iib) be stored as lyophilisate and reconstituted to an aqueous solution, wherein even after light exposure the solution is less susceptible to form aggregates.

[0023] The antibody-drug conjugate in the pharmaceutical composition is prepared using techniques available in the art for generating antibody-drug conjugates, exemplary methods of which are described in more detail in the following sections. The ADC and ADC containing composition is typically manufactured in clear glass vials without insoluble visible particles, increase of aggregate levels, change in charge profile, or changes in physical parameters such as turbidity and a reduced sensitivity towards oxidation when using the below mentioned pharmaceutical composition.

[0024] In another aspect, the present invention relates to a lyophilisate that can be reconstituted to a pharmaceutical composition according to the present disclosure.

[0025] In another aspect, the present invention relates to the pharmaceutical composition according to the present disclosure for use in therapy, preferably the treatment of cancer.

[0026] In another aspect, the present invention relates to the use of a combination of (i) a stabilizer selected from the group consisting of methionine, ascorbic acid, hydroxypropyl-β-cyclodextrin, and a mixture thereof and (ii) a buffer to stabilize a pharmaceutical composition comprising an antibody-drug conjugate of the general formula [antibody]-[linker-payload]n, wherein n is between 1 and 10, wherein, preferably, said antibody-drug conjugate is ADC1 as described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The present disclosure will be more readily appreciated by reference to the following detailed description when being considered in connection with the accompanying drawings:

[0028] Fig. 1: Structural representation of ADC1 comprising a linker cleavable by the human enzyme glucuronidase bound to the payload exatecan (this specific “[linker-payload] moiety” is referred to as “drug linker 1” or “DL1”), wherein DL1 is conjugated to mAb1.

[0029] Fig. 2a: Plot showing increased high molecular weight species (aggregates) of ADC1 and ADC2 as compared to the recombinant human IgG monoclonal antibody mAb1 without payload / linker under unstressed and ambient light stress conditions, respectively, measured by size exclusion chromatography.

[0030] Fig. 2b: Plot showing increased turbidity, an indicator for the formation of particles and aggregation, of ADC1 and ADC2 as compared to mAb1 under unstressed or light stress according to ICH Q1B conditions, measured by UV-light absorption.

[0031] Fig. 2c: Samples showing coloration and therefore strong photo-instability for ADC1 and ADC2 as compared to mAb1 under light stress according to ICH Q1B conditions, no coloration was observed for the controls covered by aluminum foil. “(C)” denotes control sample (i.e. protected by aluminum foil) and “(LS)” denotes ICH light stress sample.

[0032] Fig. 3: Isoelectric profile of ADC1.

[0033] Fig. 4a: Plots showing the effect of various buffer conditions on the reaction of ADC1 and ADC2 to light-stress, as measured by size exclusion chromatography.

[0034] Fig. 4b: Plot showing the effect of extended buffer conditions on the reaction of ADC1 to light-stress, as measured by size exclusion chromatography.

[0035] Fig. 5a: Plot showing aggregation of ADC1 unstressed and after photo-stress in neat histidine buffer (pH 5.5), neat acetate buffer (pH 4.0) and benchmark formulation, measured with size exclusion chromatography. Further, the figure discloses comparing columns of acetate (left) and histidine (right) buffer formulations with various tested substances (ascorbic acid, methionine, tryptophane, arginine, EDTA, HPßCD, SBßCD, riboflavin), measured with size exclusion chromatography. In this connection, it is noted that the first column denotes the acetate buffer formulation, the second column denotes the histidine buffer formulation and the third column, if present, denotes the benchmark formulation.

[0036] Fig. 5b: Plot showing fragmentation of ADC1 unstressed and after photo-stress in neat histidine buffer (pH 5.5), neat acetate buffer (pH 4.0) and benchmark formulation, measured with size exclusion chromatography. Further, the figure discloses comparing columns of acetate (left) and histidine (right) buffer formulations with various tested substances (ascorbic acid, methionine, tryptophane, arginine, EDTA, HPBCD, SBBCD, riboflavin), measured with size exclusion chromatography. In this connection, it is noted that the first column denotes the acetate buffer formulation, the second column denotes the histidine buffer formulation and the third column, if present, denotes the benchmark formulation.

[0037] Fig. 6: Photograph of Formulation A and Formulation B samples after exposure to shearstress conditions (left) and photostress conditions (right), with unstressed Formulation A and Formulation B samples as controls. 1: Formulation A stressed; 2: Formulation A unstressed; 3: Formulation B stressed; 4: Formulation B unstressed; 5: Placebo.

[0038] Fig. 7a: Plot showing that the addition of methionine decreases the increase in high molecular weight species (aggregates) of ADC1 after ambient light stress, measured by size exclusion chromatography. This effect was observed for all methionine concentrations tested (5 mM, 10 mM, 20 mM methionine).

[0039] Fig. 7b: Plot showing that the addition of methionine stabilizes the ADC1 main species after ambient light stress, as measured by ion exchange chromatography.

[0040] Fig. 7c: Plot showing that the addition of methionine decreases the percentage of acidic species of ADC1 after ambient light stress, as measured by ion exchange chromatography, thereby showing increased stability of ADC1.

[0041] Fig. 7d: Plot showing that the addition of methionine decreases the percentage of oxidized species of ADC1 after ambient light stress in a concentration-dependent manner, as measured by affinity chromatography.

[0042] Fig. 8: Plot showing that the addition of methionine decreases the percentage of acidic species of ADC2 after ambient light stress in a concentration-dependent manner, thereby showing increased stability of ADC2, as measured by ion exchange chromatography. BRIEF DESCRIPTION OF THE SEQUENCES

[0043]

[0044]

[0045]

[0046]

[0047] DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0048] In this section, the invention will be explained in more detail.

[0049] Although the present disclosure is described in detail above and below, it is to be understood that this disclosure is not limited to the particular methodologies, protocols and reagents described by the present disclosure, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0050] In the following, certain elements of the present disclosure will be described in more detail, including the description of specific embodiments. However, the variously described examples and preferred embodiments should not be construed to limit the present disclosure to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements and in any manner. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application except for where this leads to logical contradictions or the context indicates otherwise.

[0051] Unless defined otherwise herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclatures and techniques referred to in the present disclosure, e.g. nomenclatures and techniques of organic chemistry, chemical synthesis, biology, medicinal and pharmaceutical chemistry, medicine, pharmacology or toxicology, are those well-known and commonly used in the art. The methods and techniques of the present disclosure are generally performed according to conventional methods well-known in the art and as described in the references cited and discussed throughout the present disclosure unless otherwise indicated.

[0052] The terms “about” in the context of the present disclosure denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±5%, preferably ±3%, more preferably ±2%, and most preferably ±1%. As used herein, the articles “a” and “an” preceding an element or component are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore, “a” or “an” is to be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

[0053] It needs to be understood that the term “comprising” (and equally the term “containing”) is not limiting. For the purposes of the present disclosure, the term “consisting of” is considered to be a preferred embodiment of the term “comprising”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only.

[0054] The term “essentially free of’, as used herein, denotes that the respective substance (e.g. sodium chloride) is contained in the pharmaceutical composition in a concentration of less than 0.5 mM, preferably less than 0.3 mM such as less than 0.1 mM or less than 0.001 mM.

[0055] Pharmaceutical Composition

[0056] The present disclosure provides a pharmaceutical composition for antibody-drug conjugates (ADCs) with good solubility and stability, allowing for convenient packaging and use of pharmaceutical compositions with ADCs in solution.

[0057] A “pharmaceutical composition” (may also be designated as formulation or dosage form), as commonly understood in the art and used herein, refers to a mixture of substances that has been thoroughly prepared, and that can be stored or administered to a patient in a therapeutic context. A pharmaceutical composition typically comprises an active pharmaceutical ingredient (API), such as an antibody-drug conjugates, with a biological activity that targets a medical condition, and further pharmaceutically acceptable excipients, which will be selected depending on which functionality is to be achieved for the dosage form and whose purpose it is to render the API therapeutically effective and stable within the context of treatment or storage.

[0058] Such further substances are e.g. pharmaceutically acceptable carriers, diluents and / or excipients. The API and the further substances are typically combined in a manner that patient safety and treatment efficacy is ensured. Examples of suitable carriers, diluents and / or excipients include, but are not limited to, one or more of water, amino acids, saline, phosphate buffered saline, buffer phosphate, acetate, citrate, succinate; amino acids and derivates such as histidine, arginine, glycine, proline, glycylglycine; inorganic salts such as NaCI or calcium chloride; sugars or polyalcohols such as dextrose, glycerol, ethanol, sucrose, trehalose, mannitol; surfactants such as a polysorbate or poloxamer, e.g. poloxamer 188; and the like, as well as combination thereof. In many cases, it will be useful to include isotonic agents, such as sugars, polyalcohols, or sodium chloride in a pharmaceutical composition, and the pharmaceutical composition may also contain an antioxidant such as tryptamine.

[0059] Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, or mandelic acid, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, glycine, histidine, procaine and the like.

[0060] The skilled person knows that developing a pharmaceutical composition for a new API is not straightforward. It involves finding the right blend of API and specific further substances to ensure the API's efficacy, patient safety, API quality, solubility, stability, and suitability for patient administration. This is particularly true if the API is an ADC.

[0061] Upon formulation, solutions can be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and gender of the patient, etc.

[0062] The pharmaceutical compositions of the present disclosure can be formulated for a parenteral administration such as for intravenous, intramuscular, subcutaneous, intraperitoneal, or intraocular administration and the like.

[0063] A pharmaceutical composition for injectables can be an aqueous solution, a suspension, a frozen aqueous solution or a lyophilizate (a lyophilized powder), wherein the lyophlizate is reconstitutable to an aqueous solution. A pharmaceutical composition that is a lyophilizate has gone through the process of lyophilization (freeze-drying), wherein a solution with the pharmaceutical composition is first frozen, then water and other volatile substances are removed under vacuum through the process of sublimation. In an embodiment, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a pharmaceutical composition for injection. These may be isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline or other physiological compatible carriers (such as 5% glucose, Hanks' solution, Ringer solution, and the like), permit the constitution of injectable solutions.

[0064] Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent with any of the other ingredients enumerated above, as required, followed by sterile filtration.

[0065] For parenteral administration in an aqueous solution, for example, the solution can be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure (see for example, "Remington's Pharmaceutical Sciences" 15th Edition). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

[0066] The pharmaceutical composition according to the present disclosure comprises an antibodydrug conjugate (as API), a stabilizer, a nonionic surfactant, a sugar and / or sugar alcohol and a buffer.

[0067] The inventors found that the specific pharmaceutical composition disclosed herein surprisingly provides a stable ADC containing composition, in particular for ADC1. The pharmaceutical composition of the present disclosure can surprisingly well be dissolved and administered as liquid. A lyophilizate of the pharmaceutical composition of the present disclosure is highly storage stable, even after light-exposure, and it can readily be reconstituted into a pharmaceutical composition according to the present disclosure.

[0068] In the following, further details about the pharmaceutical composition of the present disclosure and particular embodiments are described in further detail. It is to be understood that each embodiment is relevant on its own as well as in combination with other embodiments. According to an aspect, the present disclosure relates to a pharmaceutical composition comprising

[0069] an antibody-drug conjugate,

[0070] a stabilizer selected from the group consisting of methionine, ascorbic acid, hydroxypropyl-β-cyclodextrin, and a mixture thereof;

[0071] a nonionic surfactant;

[0072] a sugar and / or a sugar alcohol; and

[0073] a buffer.

[0074] Antibody-Drug Conjugate

[0075] The pharmaceutical composition according to the present disclosure comprises an antibodydrug conjugate.

[0076] “Antibody-drug conjugates” (ADCs), as commonly understood in the art and used in this context, represent therapeutic immunoconjugates. They comprise a target-specific antibody linked (via a linker) to a drug, often cytotoxic and frequently a small-molecule drug. In the following, the drug is referred to as "payload". Payloads are often e.g. microtubule / tubulin polymerisation inhibitors (auristatins), DNA minor groove binders (duocarmycins) or topoisomerase II inhibitors (anthracyclines such as doxorubicin), but can be a drug of any effect. The target of the specific antibody is not restricted and can be any target. In most cases, the target will be a target that is known to be involved in a disease, in particular cancer.

[0077] By binding to its antigen, the antibody of the ADC serves as targeting component that can direct the ADC to its target site. For example, if the antigen of the antibody component is a tumor antigen, the ADC will be directed to tumor cells expressing this tumor antigen at their cell surface. Upon recruitment of the ADC to the target site, the payload can mediate a therapeutic action (e.g. killing of a cancer cell, local reduction of an inflammation, local stimulation or suppression of the immune system) or, if the payload is a detectable label, the target site can be identified by detection of the detectable label.

[0078] Non-targeted drugs typically reach their site of action by whole-body distribution and passive diffusion. In contrast, ADCs are targeted compounds that are not distributed evenly across the whole body. Due to the interaction of the antibody component with its target antigen, an ADC is concentrated preferentially at its site target site. Therefore, ADCs with a therapeutic agent as payload require lower dosages to be therapeutically effective, thus improving the therapeutic window.

[0079] Antibody-drug conjugates, their structure, preparation and use are described in detail e.g. in Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer, 1st edition (2016), editors Olivier and Hurvitz, publisher John Wiley & Sons, Inc. (U. S.); Toader, Topics in Medicinal Chemistry (2018), vol. 28 (Cancer II), p. 289-332; Chau, Lancet (2019), vol. 394 (10200), p. 793-804; Nimoy, Pharmaceuticals (2018), vol. 11 (2), p. 32 / 1-32 / 22; Fei et al., Journal of Biomedical Nanotechnology (2018), vol. 14(3), p. 405-429; Gorka et al., Accounts of Chemical Research (2018), vol. 51(12), p. 3226-3235; Tiberghien et al., Journal of Organic Chemistry (2019), vol. 84(8), p. 4830-4836; Rohrer, in: Process Scale Purification of Antibodies, 2nd edition (2017), editor: Gottschalk, John Wiley & Sons, Inc., p. 595-614; Vaklavas and Forero, Methods in Molecular Biology (2012), vol.

[0080] 899, p. 489-497.

[0081] Antibody of the ADC

[0082] As antibody of the ADC, any suitable antibody may be used.

[0083] An "antibody" (also referred to as an “immunoglobulin”) may e.g. be a natural or conventional type of antibody in which two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (λ) and kappa (κ). There are five main heavy chain classes (or isotypes) which determine aspects of the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each antibody chain contains distinct sequence domains (or regions). The light chain of a typical IgG antibody includes two regions, a variable region (VL) and a constant region (CL). The heavy chain of a typical IgG antibody includes four regions, namely a variable region (VH) and a constant region (CH), the latter being made up of three constant domains (CH1, CH2 and CH3). The variable regions of both light and heavy chains determine binding and specificity to the antigen. The constant regions of the light and heavy chains can confer important biological properties, such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The Fv fragment is the N-terminal part of the Fab fragment of an antibody and consists of the variable portions of one light chain and one heavy chain.

[0084] The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the so-called hypervariable or complementarity determining regions (CDRs). Complementarity determining regions (CDRs) therefore refer to amino acid sequences which together define the binding affinity and specificity of the Fv region of an antibody. The light (L) and heavy (H) chains of an antibody each have three CDRs, designated CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H, respectively. A conventional antibody’s antigen-binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain variable region.

[0085] "Framework regions" (FRs) refer to amino acid sequences interposed between CDRs, i.e. to those portions of immunoglobulin light and heavy chain variable regions that are relatively conserved among different immunoglobulins in a single species. The light and heavy chains of an immunoglobulin each have four FRs, designated FR1-L, FR2-L, FR3-L, FR4-L, and FR1-H, FR2-H, FR3-H, FR4-H, respectively. As used herein, a "human framework region" is a framework region that is substantially identical (about 85%, or more, for instance 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to the framework region of a naturally occurring human antibody.

[0086] In the context of the present disclosure, CDR / FR definition in an immunoglobulin light or heavy chain is determined based on the IMGT definition (Lefranc et al. Dev. Comp. Immunol., 2003, 27(1):55-77).

[0087] As used herein, the term "antibody" includes conventional antibodies and fragments thereof, as well as single domain antibodies and fragments thereof, such as variable heavy chain of single domain antibodies; the term “antibody” as used herein also includes chimeric, humanized, bispecific or multispecific antibodies, as well as other types of engineered antibodies. The term “antibody” includes monoclonal antibodies.

[0088] The term "monoclonal antibody" or "mAb" as used herein refers to an antibody molecule of a single amino acid sequence, which is directed against a specific antigen, and is not to be construed as requiring production of the antibody by any particular method. Monoclonal antibodies may be obtained using a variety of techniques known to those skilled in the art, including standard hybridoma technology, e.g. by a single clone of B cells or hybridoma, but may also be recombinant, e g. produced by methods involving genetic or protein engineering (see e.g. Kohler and Milstein, Eur. J. Immunol. (1976), vol. 5, p. 511-519; Antibodies: A Laboratory Manual, 2nd edition (2014), editor Greenfield, Cold Spring Harbor Laboratory Press (USA); Immunobiology, 5th ed. (2001), editors Janeway et al., Garland Publishing (USA)). Human antibodies can be produced using various techniques known in the art, including phage-display libraries (Hoogenboom and Winter, J. Mol. Biol. (1991), vol. 227, p. 381; Marks et al., J. Mol. Biol. (1991), vol. 222, p. 581). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., in: Monoclonal Antibodies and Cancer Therapy (1985), editors Reisfeld and Sell, publisher Alan R. Liss Inc. (New York), p.

[0089] 77-96; Boerner et al., J. Immunol. (1991), vol. 147(1), p. 86-95; van Dijk and van de Winkel, Curr. Opin. Pharmacol. (2001), vol. 5, p. 368-374. Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see e.g. U. S. Patent 6,075,181 and U. S. Patent 6,150,584 regarding XENOMOUSE™ technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA (2006), vol. 103, p. 3557-3562 regarding human antibodies generated via a human B-cell hybridoma technology.

[0090] Antibodies of the invention may be produced by any technique known in the art, such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination.

[0091] Knowing the amino acid sequence of a desired antibody, one skilled in the art can readily produce said antibodies or immunoglobulin chains using standard techniques for production of polypeptides. For instance, they can be synthesized using well-known solid phase methods using a commercially available peptide synthesis apparatus (such as that made by Applied Biosystems, Foster City, California) and following the manufacturer's instructions. Alternatively, antibodies and immunoglobulin chains of the invention can be produced by recombinant DNA techniques, as is well-known in the art. For example, these polypeptides (e.g. antibodies) can be obtained as DNA expression products after incorporation of DNA sequences encoding the desired polypeptide into expression vectors and introduction of such vectors into suitable eukaryotic or prokaryotic hosts that will express the desired polypeptide, from which they can be later isolated using well-known techniques.

[0092] The term "chimeric antibody" refers to an engineered antibody which, in its broadest sense, contains one or more regions from one antibody and one or more regions from one or more other antibodies. In an embodiment, a chimeric antibody comprises a VH and a VL of an antibody derived from a non-human animal, in association with a CH and a CL of another antibody which is, in some embodiments, a human antibody. As the non-human animal, any animal such as mouse, rat, hamster, rabbit or the like can be used. See e.g. U. S. Patent 4,816,567; Morrison et al., Proc. Natl. Acad. Sci USA (1984), vol. 81, p. 6851-6855. A chimeric antibody may also denote a multi-specific antibody having specificity for at least two different antigens.

[0093] The term "humanized antibody" refers to an antibody which is wholly or partially of nonhuman origin and which has been modified to replace certain amino acids, for instance in the framework regions of the VH and VL, in order to avoid or minimize an immune response in humans. The constant regions of a humanized antibody are typically human CH and CL regions. For further details, see e.g. Jones et al., Nature (1986), vol. 321, p. 522-525; Riechmann et al., Nature (1988), vol. 332, p. 323-329; and Presta, Curr. Op. Struct. Biol. (1992), vol. 2, p. 593-596. See also, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. (1998), vol. 1, p. 105-115; Harris, Biochem. Soc. Transactions (1995), vol. 23, p. 1035-1038; Hurle and Gross, Curr. Op. Biotech. (1994), vol. 5, p. 428-433; U. S. Patent 6,982,321; U. S. Patent 7,087,409.

[0094] "Fragments" of antibodies (e.g. of conventional antibodies) comprise a portion of an intact antibody such as an IgG, in particular an antigen binding region or variable region of the intact antibody. Examples of antibody fragments include Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, diabodies, as well as bispecific and multispecific antibodies formed from antibody fragments. A fragment of a conventional antibody may also be a single domain antibody, such as a heavy chain antibody or VHH.

[0095] The term "Fab" denotes an antibody fragment having a molecular weight of about 50,000 Da and antigen binding activity, in which about a half of the N-terminal side of the heavy chain and the entire light chain are bound together through a disulfide bond. It is usually obtained among fragments by treating IgG with a protease, papaine.

[0096] The term "F(ab')2" refers to an antibody fragment having a molecular weight of about 100,000 Da and antigen binding activity, which is slightly larger than 2 identical Fab fragments bound via a disulfide bond of the hinge region. It is usually obtained among fragments by treating IgG with a protease, pepsin.

[0097] The term "Fab1 " refers to an antibody fragment having a molecular weight of about 50,000 Da and antigen binding activity, which is obtained by cutting a disulfide bond of the hinge region of the F(ab')2.

[0098] A single chain Fv ("scFv") is a covalently linked VH:: VL heterodimer which is usually expressed from a gene fusion including VH and VL encoding genes linked by a peptide- encoding linker. The human scFv fragments according to the present disclosure include CDRs that are held in appropriate conformation, for instance by using gene recombination techniques. Divalent and multivalent antibody fragments can form either spontaneously by association of monovalent scFvs, or can be generated by coupling monovalent scFvs by a peptide linker, such as divalent sc(Fv)2. "dsFv" is a VH:: VL heterodimer stabilized by a disulphide bond. "(dsFv)2" denotes two dsFv coupled by a peptide linker. For a review of the scFv, see Pluckthun, in: The Pharmacology of Monoclonal Antibodies, vol. 113 (1994), editors Rosenburg and Moore, Springer-Verlag (New York), p. 269-315.

[0099] The term "bispecific antibody" or "BsAb" denotes an antibody which comprises two different antigen binding sites. Thus, BsAbs are able to e.g. bind two different antigens simultaneously. Genetic engineering has been used with increasing frequency to design, modify, and produce antibodies or antibody derivatives with a desired set of binding properties and effector functions as described for instance in EP 2 050764 A1.

[0100] The term "multispecific antibody" denotes an antibody which comprises two or more different antigen binding sites.

[0101] The term "diabodies" refers to small antibody fragments with two antigen binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains of the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described in greater detail in, for example, EP 0404097; WO 93 / 11161; Hollinger et al., Proc. Natl. Acad. Sci. USA (1993), vol. 90, p. 6444-6448.

[0102] The term "hybridoma" denotes a cell, which is obtained by subjecting a B cell prepared by immunizing a non-human mammal with an antigen to cell fusion with a myeloma cell derived from a mouse or the like which produces a desired monoclonal antibody having an antigen specificity.

[0103] The antibodies described or referred to herein can be produced by any technique known in the art.

[0104] In some embodiments, the antibody-drug conjugate of the pharmaceutical composition according to the present disclosure contains an antibody which is directed against an antigen of interest. Preferably, the antigen is a biologically important target, possibly a polypeptide. Administrating the antibody-drug conjugate to a mammal suffering from a disorder can result in a therapeutic benefit for the mammal.

[0105] In some embodiments, the antibody of the ADC is directed against human CEACAM5 protein. An antibody that is "directed against" a certain antigen is an antibody with an antigenbinding site that binds to said antigen.

[0106] In some embodiments, the antibody of the ADC binds to human CEACAM5 protein. An antibody that "binds to" an antigen of interest is an antibody that is capable of binding that antigen with sufficient affinity such that the antibody is useful in targeting an ADC to a cell expressing the antigen. If an antibody binds to an antigen can e.g. be determined by testing in an immunofluorescence experiment with cultured cells whether the antibody binds to cells that express the target antigen of the antibody at their cell surface.

[0107] As used herein "CEACAM5" designates the "carcino-embryonic antigen-related cell adhesion molecule 5", also known as "CD66e" (Cluster of Differentiation 66e) or CEA. CEACAM5 is a glycoprotein involved in cell adhesion. CEACAM5 is highly expressed especially on the surface of e.g. colorectal cancer, gastric cancer, non-small cell lung cancer, pancreatic cancer, esophageal cancer, prostate cancer and other solid tumors. A reference sequence of full length human CEACAM5, including signal peptide (positions 1 -34) and propeptide (positions 686-702), is available from the GenBank database under accession number AAA51967.1; this amino acid sequence reads as follows:

[0108] MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQH LFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYTLHV IKSDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQS LPVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPL NTSYRSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQAHNSD TGLNRTTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVS PRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDDPTISPSYTYY RPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEKNSGLYTCQANNSASGHSR TTVKTITVSAELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQL SNGNRTLTLFNVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTPIISPPDSSYLSGAN LNLSCHSASNPSPQYSWRINGIPQQHTQVLFIAKITPNNNGTYACFVSNLATGRNNSIVKSI TVSASGTSPGLSAGATVGIMIGVLVGVALI (SEQ ID NO: 1). Five non-synonymous SNPs have been identified with a frequency higher than 2% in Caucasian population, four of them being localized in the N domain (at positions 80, 83, 112, 113), the last one in the A2 domain (at position 398) of human CEACAM5. GenBank AAA51967.1 contains the major haplotype (I80, V83, 1112, 1113 and E398).

[0109] A "domain" or “region” may be any region of a protein, generally defined on the basis of sequence homologies and often related to a specific structural or functional entity. CEACAM family members are known to be composed of Ig-like domains. The term domain is used in this document to designate either individual Ig-like domains, such as "N-domain" or for groups of consecutive domains, such as "A2-B2 domain".

[0110] Domain organization of human CEACAM5 is as follows (based on GenBank AAA51967.1 sequence; SEQ ID NO: 1):

[0111]

[0112] Accordingly, the A2-B2 domain of human CEACAM5 consists of amino acids 321-498 of SEQ ID NO: 1.

[0113] A reference sequence of Macaca fascicularis CEACAM5 protein is available (NCBI Reference Sequence XP_005589491.1), and this amino acid sequence reads as follows: MGSPSAPLHRH / C / PH / QTLLLTASLLTFH / / VPPTTAQLTIESRPFNVAEGKEVLLLAHNVSQN LFGYIWYKGERVDASRRIGSCVIRTQQITPGPAHSGRETIDFNASLLIHNVTQSDTGSYTIQ VIKEDLVNEEATGQFRVYPELPKPYISSNNSNPVEDKDAVALTCEPETQDTTYLWWVNNQ SLPVSPRLELSSDNRTLTVFNIPRNDTTSYKCETQNPVSVRRSDPVTLNVLYGPDAPTISPL NTPYRAGENLNLSCHAASNPTAQYFWFVNGTFQQSTQELFIPNITVNNSGSYMCQAHNS ATGLNRTTVTAITVYAELPKPYITSNNSNPIEDKDAVTLTCEPETQDTTYLWWVNNQSLSV SSRLELSN DN RTLTVFN I PRN DTTFYECETQN PVSVRRSDPVTLN VLYGPDAPTISPLNTP YRAGENLNLSCHAASNPAAQYSWFVNGTFQQSTQELFIPNITVNNSGSYMCQAHNSAT GLNRTTVTAITVYVELPKPYISSNNSNPIEDKDAVTLTCEPVAENTTYLWWVNNQSLSVSP RLQLSNGNRILTLLSVTRNDTGPYECGIQNSESAKRSDPVTLNVTYGPDTPIISPPDLSYRS GANLNLSCHSDSNPSPQYSWLINGTLRQHTQVLFISKITSNNNGAYACFVSNLATGRNNSI VKNISVSSGDSAPGSSGLSARATVGIIIGMLV GVALM (SEQ ID NO: 2) (signal peptide in italics’, A2-B2 domain in bold letters; GPI anchor underlined; N-A1-B1 domain in regular font between signal peptide and A2-B2 domain; A3-B3 domain in regular font between A2-B2 domain and GPI anchor).

[0114] In some embodiments, the antibody of the ADC comprises a CDR1-H consisting of the amino acid sequence DGSVSRGGYY (SEQ ID NO: 3), a CDR2-H consisting of the amino acid sequence IYYSGST (SEQ ID NO: 4), a CDR3-H consisting of the amino acid sequence ARGIAVAPFDY (SEQ ID NO: 5), a CDR1-L consisting of the amino acid sequence QSVRSN (SEQ ID NO: 6), a CDR2-L consisting of the amino acid sequence AAS (which may also be expressed as “Ala-Ala-Ser”; SEQ ID NO: 7), and a CDR3-L consisting of the amino acid sequence QQYTNWPFT (SEQ ID NO: 8). This antibody can also bind to Macaca fascicularis CEACAM5 protein.

[0115] In some embodiments of the present disclosure, the antibody having the above-mentioned six CDR sequences comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTY FNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSS

[0116] (SEQ ID NO: 9) (CDRs shown in bold characters) and a light chain variable region (VL) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIK (SEQ ID NO: 10) (CDRs shown in bold characters).

[0117] Herein, a sequence "at least 85% identical” to a reference sequence is a sequence having, over its entire length, 85% or more, for instance 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the entire length of the reference sequence. The percentage of "sequence identity" may thus be determined by comparing two such sequences over their entire length by global pairwise alignment using the algorithm of Needleman and Wunsch (J. Mol. Biol. 48:443 (1970)), e.g. using the program Needle (EMBOSS) with the BLOSUM62 matrix and the following parameters: gap open=10, gap extend=0.5, end gap penalty=false, end gap open=10, end gap extend=0.5 (which are standard settings). In some embodiments, said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 95 % identical to the amino acid sequence of SEQ ID NO: 10.

[0118] In some embodiments of the present disclosure, the antibody having the above-mentioned six CDR sequences comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10.

[0119] In some embodiments, said antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10.

[0120] In some embodiments of the present disclosure, the antibody further comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPPVAGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 11) and a light chain constant region (CL) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12). In some embodiments of the present disclosure, the antibody comprises a heavy chain constant region (CH) comprising the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising the amino acid sequence of SEQ ID NO: 12.

[0121] In some embodiments, said antibody comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, said antibody comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, said antibody comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 95 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 95 % identical to the amino acid sequence of SEQ ID NO: 12.

[0122] In some embodiments, said antibody comprises a heavy chain constant region (CH) comprising the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising the amino acid sequence of SEQ ID NO: 12.

[0123] In some embodiments, the antibody is an antibody which binds to human CEACAM5 protein and which comprises a heavy chain (HC) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTY FNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPPVAGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 13) and a light chain (LC) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 14). In even more specific embodiments of the present disclosure, the antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 14. In yet more specific embodiments of the present disclosure, the antibody consists of two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0124] In some embodiments, one or more individual amino acids of an antibody in the ADC comprised in the pharmaceutical composition of the present disclosure may be altered by substitution, in particular by conservative substitution, in one or more of the above-mentioned sequences, including the CDR sequences. Such an alteration may be intended for example to remove a glycosylation site or a deamidation site, e.g. in connection with humanization of the antibody.

[0125] In some embodiments, said antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0126] In some embodiments, said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0127] In some embodiments, the antibody of the antibody-drug conjugate in the pharmaceutical composition according to the present disclosure is an antibody which binds to human CEACAM5 protein and which consists of two identical heavy chains (HC) consisting of the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) consisting of the amino acid sequence of SEQ ID NO: 14; this particular antibody is also referred to as “mAb1” herein.

[0128] In some embodiments, said antibody is mAb1. The preparation of the CEACAM5 antibody mAb1 is described in published international patent application WO 2022 / 048883 A1. The preparation of ADC1 is further described in the Examples section of the present disclosure (see subsection "Preparation of Antibody-Drug Conjugate ADC1"). The antibody mAb1 is part of the preferred ADC of the present disclosure, ADC1.

[0129] Exemplary nucleotide sequences that allow for the expression of mAb1 as described in WO 2022 / 048883 A1 are shown below: mAb1 heavy chain nucleotide sequence

[0130] wherein mVk signal peptide is underlined,

[0131] start and stop codons are in italics,

[0132] VH region sequence in boldface, and

[0133] CDRs are indicated with double underlining:

[0134] ATGGAGACCGACACCCTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCCGGGTCGAC CGGTGAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACC CTGTCCCTCACCTGCACTGTCTCTGATGGCTCCGTCAGCAGGGGTGGTTACTACTTG ACCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTA CAGTGGGAGCACCTACTTCAACCCGTCCCTCAGGAGTCGGGTTACCATGTCAGTAG ACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACG GCCGTGTATTACTGTGCGAGAGGGATAGCAGTGGCTCCCTTTGACTACTGGGGCCA GGGAACCCTGGTCACCGTCTCTTCAGCTAGCACCAAGGGCCCCAGCGTGTTCCCCCT GGCCCCCAGCAGCAAGTCCACAAGCGGAGGAACAGCCGCCCTGGGCTGCCTGGTGA AGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCC GGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAG CGTGGTGACAGTGCCAAGCAGCAGCCTGGGAACCCAGACCTACATCTGCAACGTGAA CCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACA AGACCCATACCTGTCCACCCTGCCCAGCCCCCCCAGTGGCCGGACCCTCCGTGTTCC TGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCT GCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAATTGGTATGTG GACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTACAACAG CACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCA AGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCCTCCAGCATCGAGAAAACCA TCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACACTGCCCCCATCT CGGGAAGAAATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTTTAC CCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAA GACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGAC CGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACG AGGCCCTGCACAACCACTACACACAGAAGAGCCTGAGCCTGTCCCCCGGCTGA

[0135] (SEQ ID NO: 15)

[0136] mAb1 light chain nucleotide sequence

[0137] wherein uPA signal peptide is underlined,

[0138] start and stop codons are in italics,

[0139] VL region sequence in boldface, and CDRs are indicated with double underlining:

[0140] ATGAGGGCCCTGCTGGCTAGACTGCTGCTGTGCGTGCTGGTCGTGTCCGACAGCAAG GGCGAAATCGTACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAG AGCCACCCTCTCCTGCAGGACCAGTCAGAGTGTTCGCAGCAACTTAGCCTGGTACC AGCAGAAGCCTGGCCAGGCTCCCAGGCTCCTCATCTATGCTGCATCCACCAGGGCC ACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCAC CATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATACTAA CTGGCCATTCACTTTCGGCCCTGGGACCAAAGTGGACATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTC TGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTG GATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAG GACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAA CACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAG AGCTTCAACAGGGGAGAGTGTTGATAG

[0141] (SEQ ID NO: 16)

[0142] In some embodiments, said antibody is the antibody Precemtabart.

[0143] "Precemtabart" is the international nonproprietary name (INN) of the antibody defined in WHO Drug Information, Volume 37, Number 4 (2023), p. 1135-1136.

[0144] In some embodiments, the antibody binds to the A2-B2 domains of human and Macaca fascicularis CEACAM5. The antibody may also compete for binding to A2-B2 domain of human and / or Macaca fascicularis CEACAM5 proteins with an antibody comprising the heavy and light chain variable regions of mAb1 (i.e. the VH and VL corresponding to SEQ ID NO: 9 and 10, respectively).

[0145] The ability of a candidate antibody to compete for binding to A2-B2 domain of human and / or Macaca fascicularis CEACAM5 proteins with an antibody comprising the VH and VL of mAb1 (hereafter, in the context of competition with a candidate antibody, referred to as a "reference" antibody) may be readily assayed, for instance, by competitive ELISA wherein the antigen (i.e. the A2-B2 domain of human or Macaca fascicularis CEACAM5, or a polypeptide comprising or consisting of a fragment of human or Macaca fascicularis CEACAM5 including the A2-B2 domain, in particular the extracellular domain of human or Macaca fascicularis CEACAM5) is bound to a solid support and two solutions containing the candidate antibody and the reference antibody, respectively, are added and the antibodies are allowed to compete for binding to the antigen. The amount of reference antibody bound to the antigen may then be measured, and compared to the amount of reference antibody bound to the antigen when measured against a negative control (e.g. solution containing no antibody). An amount of bound reference antibody in the presence of the candidate antibody decreased as compared to the amount of bound reference antibody in presence of the negative control indicates that the candidate antibody has competed with the reference antibody. Conveniently, the reference antibody may be labeled (e.g. fluorescently) to facilitate detection of bound reference antibody. Repeated measurements may be performed with serial dilutions of the candidate and / or reference antibody.

[0146] In some embodiments, the antibody does not bind to, or does not significantly cross-react with human CEACAM1, human CEACAM6, human CEACAM7, human CEACAM8 and Macaca fascicularis CEACAM6 proteins. In some embodiments, the antibody does not bind to, or does not significantly cross-react with the extracellular domain of the aforementioned human and Macaca fascicularis CEACAM proteins other than CEACAM5.

[0147] "Affinity" is defined, in theory, by the equilibrium association between the whole antibody and the antigen. It can be experimentally assessed by a variety of known methods, such as measuring association and dissociation rates with surface plasmon resonance or measuring the EC50 (or apparent KD) in an immunochemical assay (ELISA, FACS). In these assays, the EC50 is the concentration of the antibody which induces a response halfway between the baseline and maximum after some specified exposure time on a defined concentration of antigen by ELISA (enzyme-linked immuno-sorbent assay) or cell expressing the antigen by FACS (Fluorescence Activated Cell Sorting).

[0148] A monoclonal antibody binding to an antigen 1 (Ag1) is "cross-reactive" to an antigen 2 (Ag2) when the EC50s are in a similar range for both antigens. In the present application, a monoclonal antibody binding to Ag1 is cross-reactive to Ag2 when its affinity for Ag2 is within 10-fold or less (for instance within 5-fold) from its affinity of Ag1, affinities being measured with the same method for both antigens.

[0149] A monoclonal antibody binding to Ag1 is "not significantly cross-reactive" to Ag2 when the affinities are very different for the two antigens. Affinity for Ag2 may not be measurable if the binding response is too low. In the present application, a monoclonal antibody binding to Ag1 is not significantly cross- reactive to Ag2, when the binding response of the monoclonal antibody to Ag2 is less than 5% of the binding response of the same monoclonal antibody to Ag1 in the same experimental setting and at the same antibody concentration. In practice, the antibody concentration used can be the EC50 or the concentration required to reach the saturation plateau obtained with Ag1. A monoclonal antibody "binds specifically" to (or "is specific for") Ag1 when it is not significantly cross-reactive to Ag2.

[0150] In some embodiments, an antibody has an affinity for Macaca fascicularis CEACAM5 which is within 10-fold or less (for instance within 5-fold) from its affinity for human CEACAM5. Thus, the antibody may be used in toxicological studies performed in monkeys because the toxicity profile observed in monkeys would be relevant to anticipate potential adverse effects in humans.

[0151] In some embodiments, the antibody has an affinity for human CEACAM5 or Macaca fascicularis CEACAM5, or both, which is < 10nM; for instance, the antibody may have an affinity for human CEACAM5 which is between 1 and 10 nM, such as an affinity for human CEACAM5 of about 6 nM.

[0152] Affinity for human CEACAM5 or for Macaca fascicularis CEACAM5 may be determined e.g. as the EC50 value in an ELISA using soluble recombinant CEACAM5 as capture antigen.

[0153] Alternatively, for the antibody, an apparent dissociation constant (apparent KD) may be determined by FACS analysis e.g. on tumor cell line MKN45 (DSMZ, ACC 409).

[0154] Additionally, antibodies have been shown to be able to detect CEACAM5 expression by immunohistochemistry, e.g. in frozen and formalin-fixed and paraffin embedded (FFPE) tissue sections.

[0155] In some embodiments, the antibody is a conventional antibody, such as a conventional monoclonal antibody, or an antibody fragment, a bispecific or multispecific antibody, preferably a monoclonal antibody.

[0156] In some embodiments, the antibody comprises or consists of an IgG, or a fragment thereof.

[0157] In some embodiments, the antibody may be e.g. a murine antibody, a chimeric antibody, a humanized antibody, or a human antibody. Numerous methods for humanization of an antibody sequence are known in the art; see e.g. the review by Almagro & Fransson (2008) Front Biosci. 13: 1619-1633. One commonly used method is CDR grafting, or antibody reshaping, which involves grafting of the CDR sequences of a donor antibody, generally a mouse antibody, into the framework scaffold of a human antibody of different specificity. Since CDR grafting may reduce the binding specificity and affinity, and thus the biological activity, of a CDR grafted non-human antibody, back mutations may be introduced at selected positions of the CDR grafted antibody in order to retain the binding specificity and affinity of the parent antibody. Identification of positions for possible back mutations can be performed using information available in the literature and in antibody databases. Amino acid residues that are candidates for back mutations are typically those that are located at the surface of an antibody molecule, while residues that are buried or that have a low degree of surface exposure will not normally be altered. An alternative humanization technique to CDR grafting and back mutation is resurfacing, in which non-surface exposed residues of non-human origin are retained, while surface residues are altered to human residues. Another alternative technique is known as "guided selection" (Jespers et al. (1994) Biotechnology 12, 899) and can be used to derive from a murine antibody a fully human antibody conserving the epitope and binding characteristics of the parental antibody.

[0158] For chimeric antibodies, humanization typically involves modification of the framework regions of the variable region sequences.

[0159] Amino acid residues that are part of a CDR will typically not be altered in connection with humanization, although in certain cases it may be desirable to alter individual CDR amino acid residues, for example to remove a glycosylation site, a deamidation site or an undesired cysteine residue. N-linked glycosylation occurs by attachment of an oligosaccharide chain to an asparagine residue in the tripeptide sequence Asn-X-Ser or Asn-X-Thr, where X may be any amino acid except Pro. Removal of an N-glycosylation site may be achieved by mutating either the Asn or the Ser / Thr residue to a different residue, for instance by way of conservative substitution. Deamidation of asparagine and glutamine residues can occur depending on factors such as pH and surface exposure. Asparagine residues are particularly susceptible to deamidation, primarily when present in the sequence Asn-Gly, and to a lesser extent in other dipeptide sequences such as Asn-Ala. When such a deamidation site, for instance Asn-Gly, is present in a CDR sequence, it may therefore be desirable to remove the site, typically by conservative substitution to remove one of the implicated residues. Substitution in a CDR sequence to remove one of the implicated residues is also intended to be encompassed by the present present disclosure.

[0160] In a humanized antibody or fragment thereof, the variable domains of heavy and light chains may comprise human acceptor framework regions. A humanized antibody may further comprise human constant heavy and light chain domains, where present. In some embodiments, the antibody may be an antibody fragment (for instance a humanized antibody fragment) selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, and diabodies.

[0161] In some embodiments, the antibody may be a bispecific or multispecific antibody formed from antibody fragments, at least one antibody fragment being a fragment of an antibody as above disclosed. Multispecific antibodies are polyvalent protein complexes as described for instance in EP 2050764 A1 or US 2005 / 0003403 A1.

[0162] Bispecific or multispecific antibodies can have specificity for (a) the human and Macaca fascicularis CEACAM5 proteins and (b) at least one other antigen. In some embodiments, the at least one other antigen is not a human or Macaca fascicularis CEACAM family member. In other embodiments, the at least one other antigen may be an epitope on human or Macaca fascicularis CEACAM5 other than the epitope targeted by mAb1.

[0163] Payload of the ADC

[0164] The ADC in the pharmaceutical composition according to the present disclosure comprises an antibody and a drug, which is preferably a small molecule drug, also referred to as payload herein. The antibody and said payload are linked via a linker to provide an ADC.

[0165] The term "payload", as used herein, refers to a chemical moiety that is conjugated to an antibody component as part of an antibody-drug conjugate. In the antibody-drug conjugate according to the present disclosure, the payload is linked to the antibody component by covalent binding through a linker. The payload in the ADC of the present disclosure can e.g. be a therapeutic agent. Upon recruitment of the ADC to its target site by binding of the antibody of the ADC to its target antigen, the payload can fulfill its function at the target site. For example, if the antibody is specific for the tumor antigen, the payload may be a cytotoxic agent that kills tumor cells, e.g. a maytansinoid or duocarmycin.

[0166] The payload can be introduced into the ADC at different stages of preparation. In one approach, a linker-payload construct (i.e. a construct in which the payload is covalently linked to the linker) is synthesized by standard methods of organic chemistry (as shown in the examples) and subsequently this linker-payload payload construct is conjugated to the antibody component. However, the antibody component, linker and payload can also be prepared and conjugated in different order (e.g. the linker is conjugated to the antibody component and subsequently the payload attached to the linker). Different payloads, their preparation, conjugation and use in antibody-drug conjugates are described e.g. in Nicolaou et al., Accounts of Chemical Research (2019), vol. 52(1), p. 127-139; Maderna et al., Molecular Pharmaceutics (2015), vol. 12(6), p. 1798-1812; Gromek et al., Current Topics in Medicinal Chemistry (2014), vol. 14(24), p. 2822-2834.

[0167] Any suitable payload can be applied.. In some embodiments, the payload is a growth inhibitory agent (also referred to as an “anti-proliferative agent"). The term “growth inhibitory agent” refers to a molecule or compound or composition which inhibits growth of a cell, such as a tumor cell, in vitro and / or in vivo. In some embodiments, the payload (e.g. the growth inhibitory agent) is a cytotoxic drug (also referred to as a cytotoxic agent).

[0168] In some embodiments, the payload is selected from the group consisting of chemotherapeutic agents, enzymes, antibiotics, toxins such as small molecule toxins or enzymatically active toxins, toxoids, vincas, taxanes, maytansinoids or maytansinoid analogs, tomaymycin or pyrrolobenzodiazepine derivatives, cryptophycin derivatives, leptomycin derivatives, auristatin or dolastatin analogs, prodrugs, topoisomerase I inhibitors, topoisomerase II inhibitors, DNA alkylating agents, anti-tubulin agents, CC-1065 and CC-1065 analogs, preferably is a camptothecin, such as Topotecan, Irinotecan, Lurtotecan, or exatecan, more preferably is exatecan which is a topoisomerase I inhibitor.

[0169] Topoisomerase I inhibitors are molecules or compounds that inhibit the human enzyme topoisomerase I which is involved in altering the topology of DNA by catalyzing the transient breaking and rejoining of a single strand of DNA. Topoisomerase I inhibitors are highly toxic to dividing cells e.g. of a mammal. Examples of suitable topoisomerase I inhibitors include camptothecin (CPT) and analogs or derivatives thereof such as topotecan, irinotecan, silatecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan and rubitecan.

[0170] CPTs (i.e. camptothecin and analogs or derivatives thereof) are highly photosensitive, as can be seen on the Prescribing Informaiton of Camptosar®, an Irinotecan containing drug (stable for 24 h in ambient fluorescent lighting).

[0171] In some embodiments, the payload is a camptothecin (i.e. selected from the group consisting of camptothecin and analogs or derivatives thereof). In some embodiments, the payload is selected from the group consisting of topotecan, irinotecan, lurtotecan and exatecan. In some embodiments, the payload of the antibody-drug conjugate is exatecan or a derivate thereof. In some embodiments, the payload is exatecan. Exatecan is a cytotoxic drug and has the chemical name (1S,9S)-1-Amino-9-ethyl-5-fluoro-1,2,3,9, 12, 15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo(de)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-10, 13-dione. Exatecan is represented by the following structural formula (I):

[0172]

[0173] In some embodiments, other CPT analogs and other cytotoxic drugs may be used, e.g. as listed above. Examples of some cytotoxic drugs and of methods of conjugation are further given in the application W02008 / 010101.

[0174] In some embodiments, an average of 2 to 16 payloads are conjugated to the reduced interchain cysteine residues of the antibody. In some embodiments, an average of about eight payloads are conjugated to the reduced interchain cysteine residues of the antibody.

[0175] Linker of the ADC

[0176] As pointed out above, the antibody-drug conjugate according to the present disclosure comprises a linker.

[0177] "Linker", as used herein, means a chemical moiety comprising a covalent bond and / or any chain of atoms that covalently attaches the payload to the antibody. Thus, the linker is a molecular group that covalently links the payload and the antibody component of the ADC.

[0178] When referring to a structural formula representing an ADC, the following nomenclature is also used herein: a payload and a linker, taken together, are also referred to as a [linkerpayload] moiety or [(linker)-(payload)] moiety; for instance, an exatecan molecule and a linker, taken together, are also referred to as a [linker-exatecan] moiety or [(linker)— (exatecan)] moiety.

[0179] Linkers are well known in the art and include e.g. disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups and esterase labile groups. Further linkers that may be used for the ADC of the present disclosure, as well as related methods, are described in WO 2004 / 010957 entitled "Drug Conjugates and Their Use for Treating Cancer, An Autoimmune Disease or an Infectious Disease".

[0180] Covalent linking of the antibody component and the payload via a linker can for example be achieved by a linker having two reactive functional groups (i.e. a linker that is bivalent in a reactive sense). Bivalent linker reagents which are useful to attach two or more functional or biologically active components are known to the skilled person (see e.g. Hermanson, Bioconjugate Techniques (1996), Academic Press (New York), p 234-242). Bifunctional protein coupling agents that can be used for conjugation of an antibody with a payload such as a cytotoxic drug include for example N-succinimidyl pyridyldithiobutyrate (SPDB), butanoic acid 4-[(5-nitro-2-pyridinyl)dithio]-2,5-dioxo-1-pyrrolidinyl ester (nitro-SPDB), 4-(Pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), N-succinimidyl (2-pyridyldithio) propionate (SPDP), succinimidyl (N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl)-hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al (1987).

[0181] Alternatively, a linker-payload construct comprising payload(s) covalently attached to a linker may be prepared by methods of organic synthesis. Subsequently, one or more copies of this linker-payload construct can then be conjugated to the antibody component by methods known to the skilled person (see e.g. Behrens et al., Molecular Pharmaceutics (2015), vol.

[0182] 12(11), p. 3986-3998; Stefano, Methods in Molecular Biology (2013), vol. 1045, p. 145-171; Dickgiesser et al., in: Methods in Molecular Biology: Enzyme-Mediated Ligation Methods (2019), editors Nuijens and Schmidt, vol. 2012, p. 135-149; Dickgiesser et al., Bioconjugate Chem. (2020), vol. 31(4), p. 1070-1076) or described in published international patent application WO 2022 / 048883 A1.

[0183] As linker of the ADC according to the present disclosure, any suitable linker may be used.

[0184] The linker can be a "cleavable linker", which may facilitate release of the cytotoxic drug or other payload inside of or in the vicinity of a cell, e.g. a tumor cell. For example, the linker may be cleavable in an endosome of a mammalian cell. For this purpose, e.g. an acid-labile linker, a peptidase-sensitive linker, an esterase labile linker, a photolabile linker or a disulfide- containing linker (see e.g. U. S. Patent No. 5,208,020) may be used. Further examples of suitable cleavable linkers, including such linkers that are cleavable by the human enzyme glucuronidase or legumain, are described below.

[0185] In some embodiments, the payload of the antibody-drug conjugate is linked to the antibody by a cleavable linker. In some embodiments, the cleavable linker is cleavable in an endosome of a mammalian cell. In some embodiments, the cleavable linker is cleavable by a human enzyme selected from glucuronidase and legumain. In some embodiments, the linker is a linker cleavable by the human enzyme glucuronidase. In some embodiments, one or more payloads are linked to the antibody by a maleimide-glucuronic acid-based linker.

[0186] In other embodiments of the present present disclosure, the linker may be a "non-cleavable linker" (for example an SMCC linker). Release of the payload from the antibody can occur upon lysosomal degradation of the antibody.

[0187] In some embodiments, the linker of said antibody-drug conjugate is covalently linked to a reduced interchain cysteine residue of the antibody.

[0188] In some embodiments, the ADC of the present disclosure has the following formula (II):

[0189]

[0190] wherein S is a sulfur atom of the antibody, and wherein n is between 1 and 10. The number n is also referred to as "drug-to-antibody ratio" (or "DAR"), as further discussed below. The linker included in the ADC according to formula (II) is cleavable by glucuronidase. In some embodiments, the ADC of the present disclosure has the following formula (III):

[0191]

[0192] wherein S is a sulfur atom of the antibody, and wherein n is between 1 and 10

[0193] The linker included in the ADC according to formula (III) is cleavable by the human enzyme legumain.

[0194] In each of the above formulae (II) and (III), the chemical structure between the sulfur atom of the antibody and the payload is a linker. One of these linkers is also contained in each of the formulae (IV) to (IX) depicted further below.

[0195] In any one of the embodiments with linkers cleavable by glucuronidase or legumain, as described above, the payload may be exatecan, for example.

[0196] Drug-Antibody-Ratio (DAR)

[0197] As used herein, the "drug-antibody ratio" of an ADC (abbreviated as "DAR") is the (average) number of payloads per ADC molecule divided by the number of antibody components per ADC molecule.

[0198] The DAR is designated in structural representations and feature descriptions throughout the present disclosure by the letter "n". Thus, n is the number of [linker-payload] moieties (or in embodiments where the payload is exatecan, [linker-exatecan] moieties) covalently linked to the antibody of the ADC (wherein this linkage is via the linker).

[0199] For example, if an ADC is represented by the formula

[0200] [antibody]-[linker-payload]n

[0201] n reflects the DAR, i.e. the number of [linker-payload] components linked to the antibody of said ADC. The number n is always to be understood as an average number for any given (preparation of an) ADC. Thus, if in this example n is indicated to be 8, this means that in this ADC, an average 8 [linker-payload] components are attached per antibody.

[0202] An exemplary method which can be used to determine the DAR consists of measuring spectrophotometrically the ratio of the absorbance at of a solution of purified conjugate at λD and 280 nm. 280 nm is a wavelength generally used for measuring protein concentration, such as antibody concentration. The wavelength λD is selected so as to allow discriminating the drug from the antibody, i.e. as readily known to the skilled person, λD is a wavelength at which the drug has a high absorbance and λD is sufficiently remote from 280 nm to avoid substantial overlap in the absorbance peaks of the drug and antibody. For instance, λD may be selected as being 370 nm for exatecan (or for camptothecin or other camptothecin analogs), or 252 nm for maytansinoid molecules.

[0203] In some embodiments, n / the DAR is determined by a method based on photometric measurements (as described above).

[0204] In some embodiments, n / the DAR is determined by a method based on RP-HPLC (reversed-phase high performance liquid chromatography) (as described in the Examples section).

[0205] In some embodiments, the DAR is determined by the method described above. In some embodiments, the DAR is determined by RP-HPLC (Reversed-phase high performance liquid chromatography) as described in the Example 1 below.

[0206] As the skilled person understands, n is the number of [linker-payload] moieties covalently linked to the antibody of the ADC. In embodiments where the payload is exatecan, n is the number of [linker-exatecan] moieties covalently linked to the antibody of the ADC.

[0207] In some embodiments, n is between 1 and 10. In some embodiments, n is between 4 and 8. In some embodiments, n is between 6 and 8. In some embodiments, n is between 7 and 8. In some embodiments, n is between 7.5 and 8.0. In some embodiments, n is about 8. In some embodiments, wherein n is 8.

[0208] In some embodiments, said antibody-drug conjugate has a DAR (drug-to-antibody ratio) of about 8. In some embodiments, said antibody-drug conjugate has a DAR (drug-to-antibody ratio) of 8. In some embodiments, the cysteine of the antibody is one of the cysteines capable of forming an interchain disulfide bond.

[0209] Further features of the ADC

[0210] In some embodiments, in an ADC of the present disclosure such as the exatecan conjugates with glucuronidase- or legumain-cleavable linkers as described above, the linker is covalently attached to the antibody at a sulfur atom of a cysteine residue of the antibody. For example, this cysteine residue of the antibody may be one of the cysteine residues capable of forming an interchain disulfide bond (also referred to herein as an interchain disulfide bridge). As there are four interchain disulfide bonds in an I gG 1 antibody, involving a total of eight cysteine residues, attachment of the linker to the antibody at a sulfur atom of such cysteine residues provides that the DAR may be up to 8 and, in such cases, the DAR is typically between 7 and 8, such as between 7.5 and 8.0 (i.e. about 8), provided that the antibody is an IgG 1 or has the same number of interchain disulfide bonds as an lgG1.

[0211] In some embodiments, the linker-payloads comprised in said antibody-drug conjugate are conjugated to reduced interchain cysteine residues of the antibody.

[0212] In some embodiments, in formula (II) to (IX) as disclosed herein, S is a sulfur atom of the antibody. In some embodiments, in formula (II) to (IX) as disclosed herein, S is a sulfur atom of a cysteine of the antibody. In some embodiments, the cysteine of the antibody is one of the cysteines capable of forming an interchain disulfide bond.

[0213] In some embodiments, said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 1 to 50 mg / mL. In some embodiments, said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 3 to 30 mg / mL. In some embodiments, said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 5 to 25 mg / mL. In some embodiments, said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 8 to 18 mg / mL. In some embodiments, said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 5 to 15 mg / mL. In some embodiments, said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 8 to 12 mg / mL. In some embodiments, said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of about 10 mg / mL. In some embodiments, said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 10 mg / mL. In some embodiments, the antibody-drug conjugate has the general formula

[0214] [antibody]-[linker-payload]n

[0215] wherein n is between 1 and 10.

[0216] In some embodiments, the linker-payload is tocentecan. "Tocentecan" is the linker-payload component of precemtabart tocentecan. "Precemtabart tocentecan" is the international nonproprietary name (INN) of the antibody-drug-conjugate defined in WHO Drug Information, Volume 37, Number 4 (2023), p. 1137-1139.

[0217] In some embodiments, said antibody-drug conjugate has the formula (IV)

[0218]

[0219] wherein S is a sulfur atom of the antibody, and wherein n is between 1 and 10.

[0220] In some embodiments, the antibody-drug conjugate has the formula selected from the group consisting of (II), (III), (IV) and (V):

[0221]

[0222] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker-payload] moieties covalently linked to the antibody, wherein n is between 1 and 10, preferably wherein n is between 7 and 8, more preferably between 7.5 and 8.0;

[0223]

[0224] Payload

[0225]

[0226] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker-payload] moieties covalently linked to the antibody, wherein n is between 1 and 10, preferably wherein n is between 7 and 8, more preferably between 7.5 and 8.0;

[0227]

[0228] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker–exatecan] moieties covalently linked to the antibody, wherein n is between 1 and 10, preferably wherein n is between 7 and 8, more preferably between 7.5 and 8.0;

[0229]

[0230] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker–exatecan] moieties covalently linked to the antibody, wherein n is between 1 and 10, preferably wherein n is between 7 and 8, more preferably between 7.5 and 8.0.

[0231] In some embodiments, said antibody-drug conjugate binds to human CEACAM5 protein. In some embodiments, said antibody-drug conjugate is ADC1 as described herein.

[0232] In some embodiments, said antibody-drug conjugate is Precemtabart Tocentecan.

[0233] "Precemtabart tocentecan" is the international nonproprietary name (INN) of the antibody-drug-conjugate defined in WHO Drug Information, Volume 37, Number 4 (2023), p. 1137-1139.

[0234] In some embodiments, the antibody-drug-conjugate comprises an antibody covalently linked via a linker to exatecan, wherein the conjugate has the following formula (IV):

[0235]

[0236] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker–exatecan] moieties covalently linked to the antibody. The number n (also referred to as the DAR) may be e.g. between 1 and 10; in more specific embodiments, n is between 7 and 8; in even more specific embodiments, n is between 7.5 and 8.0 (i.e. about 8). In some embodiments, the antibody is mAb1.

[0237] In some embodiments, the antibody-drug-conjugate comprises an antibody covalently linked via a linker to exatecan, wherein the conjugate has the following formula (V):

[0238]

[0239] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker–exatecan] moieties covalently linked to the antibody. The number n (also referred to as the DAR) may be e.g. between 1 and 10; in more specific embodiments, n is between 7 and 8; in even more specific embodiments, n is between 7.5 and 8.0 (i.e. about 8). In some embodiments, the antibody is mAb1.

[0240] In some embodiments, the antibody-drug-conjugate comprises an antibody covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VI):

[0241]

[0242] wherein the antibody is any suitable antibody, wherein S is a sulfur atom of a cysteine of the antibody, and wherein n is a number of [linker–exatecan] moieties covalently linked to the antibody. The number n (also referred to as the DAR) may be e.g. between 1 and 10; in more specific embodiments, n is between 7 and 8; in even more specific embodiments, n is between 7.5 and 8.0 (i.e. about 8).

[0243] In some embodiments, the antibody-drug-conjugate comprises an antibody covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VII):

[0244]

[0245] wherein S is a sulfur atom of a cysteine of the antibody, and wherein n is a number of [linker–exatecan] moieties covalently linked to the antibody. The number n (also referred to as the DAR) may be e.g. between 1 and 10; in more specific embodiments, n is between 7 and 8; in even more specific embodiments, n is between 7.5 and 8.0 (i.e. about 8).

[0246] In any of the ADCs described above, any suitable antibody (as described herein above and below) may be used. In some embodiments, the ADC of the present disclosure comprises mAb1 as the antibody.

[0247] Accordingly, in some embodiments, the antibody-drug-conjugate comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VIII):

[0248]

[0249] wherein S is a sulfur atom of a cysteine of the antibody mAb1, and wherein n is a number of [linker-exatecan] moieties covalently linked to mAb1. The number n (also referred to as the DAR) may be e.g. between 1 and 10; in more specific embodiments, n is between 7 and 8; in even more specific embodiments, n is between 7.5 and 8.0 (i.e. about 8). In some embodiments, S is a sulfur atom of a cysteine of mAb1 capable of forming an interchain disulfide bridge and the DAR is about 8. An example of such an ADC (namely “ADC1”) is further described in the Examples. In some embodiments, the antibody-drug-conjugate comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (IX):

[0250]

[0251] wherein S is a sulfur atom of a cysteine of the antibody mAb1, and wherein n is a number of [linker-exatecan] moieties covalently linked to mAb1. The number n (also referred to as the DAR) may be e.g. between 1 and 10; in more specific embodiments, n is between 7 and 8; in even more specific embodiments, n is between 7.5 and 8.0 (i.e. about 8). In some embodiments, S is a sulfur atom of a cysteine of mAb1 capable of forming an interchain disulfide bridge and the DAR is about 8. An example of such an ADC (namely “ADC2”) is further described in the Examples.

[0252] In some embodiment, the ADC comprises an average of 2 to 16, preferably of 4 to 14, more preferably of 6 to 12, still more preferably of 6 to 10, and most preferably about eight payloads conjugated via a by a maleimide-glucuronic acid-based linker to the reduced interchain cysteine residues of the antibody.

[0253] In some embodiments, the payload of antibody-drug conjugate is exatecan or a derivate thereof, preferably wherein one or more such payloads are linked to the antibody by a maleimide-glucuronic acid-based linker, more preferably wherein an average of 2 to 16, preferably of 4 to 14, more preferably of 6 to 12, still more preferably of 6 to 10, and most preferably about eight payloads are conjugated to the reduced interchain cysteine residues of the antibody.

[0254] In other embodiments of the present disclosure, the ADC may be a fusion protein comprising an antibody and a cytotoxic or growth inhibitory polypeptide (as the payload); such fusion proteins may be made by recombinant techniques or by peptide synthesis, i.e. methods well known in the art. A molecule of encoding DNA may comprise respective regions encoding the two portions of the conjugate (antibody and cytotoxic or growth inhibitory polypeptide, respectively) either adjacent to one another or separated by a region encoding a linker peptide.

[0255] In some embodiments, the present disclosure provides a stable pharmaceutical composition for ADC1 and ADC2 as further specified herein.

[0256] ADC1 is an antibody-drug conjugate known from e.g. WO 2022 / 048883 and manufactured from a recombinant human IgG monoclonal antibody (referred to herein as mAb1), which has been reduced and conjugated via maleimide-conjugation to DL1, an exatecan containing drug-linker. A total of 8 exatecan molecules is attached to one antibody. The antibody mAb1 used for ADC1 binds towards the cell surface protein CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5). Exatecan is a topoisomerase- 1 inhibitor. The structure of ADC1 is shown in Fig. 1. The preparation of ADC1 is described in detail in WO 2022 / 048883 and further in the Examples section of the present disclosure (see subsection "Preparation of Antibody-Drug Conjugate ADC1").

[0257] Similarly, ADC2 is an antibody-drug conjugate composed of the same antibody (mAb1) as ADC1, with the same payload (exatecan), the same conjugation chemistry (maleimide conjugation) and the same drug-to-antibody ratio (DAR = 8). However, ADC2 uses a different payload-linker with the identifier DL2 and has the formula (IX) described above. The preparation of ADC2 is described in detail in WO 2022 / 048883 and further in the Examples section of the present disclosure (see subsection "Preparation of Antibody-Drug Conjugate ADC2").

[0258] In some embodiments, the drug-linker compound is a compound of formula (X):

[0259]

[0260] or a pharmaceutically acceptable salt thereof; this compound is also referred to herein as “drug-linker compound 1” or “DL1”.

[0261] In some embodiments, the drug linker is a compound of formula (XI):

[0262]

[0263] or a pharmaceutically acceptable salt thereof; this compound is also referred to herein as “drug-linker compound 2” or “DL2”.

[0264]

[0265] Suitable methods for preparing an ADC suitable for pharmaceutical compositions of the present disclosure are well known in the art (see e.g. Hermanson G. T., Bioconjugate Techniques, Third Edition, 2013, Academic Press). For instance, methods of conjugating a cytotoxic drug to an antibody via a linker that attaches covalently to cysteine residues of interchain disulfide bridges of the antibody are well known.

[0266] In general, an ADC can be obtained e.g. by a process comprising the steps of:

[0267] (i) preparing a compound comprising the linker and the payload (e.g. cytotoxic drug), also referred to herein as a “drug-linker compound”;

[0268] (ii) bringing into contact an optionally buffered aqueous solution of an antibody with a solution of the drug-linker compound;

[0269] (iii) then optionally separating the conjugate which was formed in (ii) from the unreacted antibody and / or drug-linker compound. The aqueous solution of antibody can be buffered with buffers such as e.g. histidine, potassium phosphate, acetate, citrate or N-2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid (Hepes buffer). The buffer may be chosen depending upon the nature of the antibody. The drug-linker compound can be dissolved e.g. in an organic polar solvent such as dimethyl sulfoxide (DMSO) or dimethylacetamide (DMA).

[0270] For conjugation to the cysteine residues of an antibody, the antibody is subjected to reduction (e.g. using TCEP) before step (ii). Suitable reduction conditions to reduce only the interchain disulfide bonds are known in the art.

[0271] The reaction temperature for conjugation is usually between 20 and 40°C. The reaction time can vary and is typically from 1 to 24 hours. The reaction between the antibody and the druglinker compound can be monitored by size exclusion chromatography (SEC) with a refractometric and / or UV detector. If the conjugate yield is too low, the reaction time can be extended.

[0272] A number of different chromatography methods can be used by the person skilled in the art in order to perform the separation of step (iii): the conjugate can be purified e.g. by SEC, adsorption chromatography (such as ion exchange chromatography, I EC), hydrophobic interaction chromatography (HIC), affinity chromatography, mixed-support chromatography such as hydroxyapatite chromatography, or high performance liquid chromatography (HPLC) such as reverse-phase HPLC. Purification by dialysis or filtration or diafiltration can also be used.

[0273] After step (ii) and / or (iii), the conjugate-containing solution can be subjected to an additional step (iv) of purification e.g. by chromatography, ultrafiltration and / or diafiltration. Such an additional step of purification e.g. by chromatography, ultrafiltration and / or diafiltration can also be performed with the antibody-containing solution after the reduction reaction, in cases where reduction is performed prior to conjugation.

[0274] The conjugate is recovered at the end of such a process in an aqueous solution. The drug-to-antibody ratio (DAR) is a number that can vary with the nature of the antibody and of the drug-linker compound used along with the manufacturing conditions used for the conjugation (such as the ratio (drug-linker compound) / (antibody), the reaction time, the nature of the solvent and of the cosolvent if any). Thus, the contact between the antibody and the druglinker compound can lead to a mixture comprising several conjugates differing from one another by different drug-to-antibody ratios. The DAR that is determined is thus an average value.

[0275] After chromatography or diafiltration, usually a ADC solution in buffer is yielded (e.g. 2x concentrated), that is subsequently diluted with the remaining excipients. Said formulated ADC is typically filtered, e.g. aseptically filtered.

[0276] Performing conjugation at the cysteine residues of interchain disulfide bridges using an antibody that has four interchain disulfide bridges (e.g. mAb1 or any IgG1 antibody) - which is a method well known in the art - offers the advantage that a relatively homogeneous DAR of about 8 can be achieved by choosing reaction conditions that allow conjugation to proceed to completion (or at least close to completion).

[0277] An exemplary method which can be used to determine the DAR consists of measuring spectrophotometrically the ratio of the absorbance at of a solution of purified conjugate at λDand 280 nm. 280 nm is a wavelength generally used for measuring protein concentration, such as antibody concentration. The wavelength λDis selected so as to allow discriminating the drug from the antibody, i.e. as readily known to the skilled person, λDis a wavelength at which the drug has a high absorbance and λDis sufficiently remote from 280 nm to avoid substantial overlap in the absorbance peaks of the drug and antibody. For instance, λDmay be selected as being 370 nm for exatecan (or for camptothecin or other camptothecin analogs), or 252 nm for maytansinoid molecules.

[0278] Stabilizer

[0279] The pharmaceutical composition of the present disclosure further comprises a stabilizer.

[0280] The term “stabilizer”, as used herein, refers to an agent in a pharmaceutical composition that stabilizes the API (in the present pharmaceutical composition the ADC).

[0281] Unexpectedly, the inventors found that methionine, hydroxypropyl-β-cyclodextrin (HPpCD), and / or ascorbic acid were effective in providing both stability and solubility of ADCs.

[0282] In some embodiments, the stabilizer is methionine. In this connection, it was surprisingly found that methionine not only prevents oxidizing of the pharmaceutical composition, but also the ADC’s vulnerability from aggregation, cleavage and fragmentation is reduced and the payload’s degradation in the ADC is reduced, even after light-exposure. In some embodiments, the stabilizer is selected from the group consisting of ascorbic acid, hydroxypropyl-β-cyclodextrin, and a mixture thereof.

[0283] Amounts and concentrations in relation to the stabilizer relate to total amounts and concentrations of all stabilizers, unless only a single antioxidant is stipulated.

[0284] In some embodiments, said stabilizer is methionine. In some embodiments, said stabilizer is hydroxypropyl-β-cyclodextrin (HPpCD). In some embodiments, said stabilizer is ascorbic acid.

[0285] In some embodiments, said pharmaceutical composition comprises methionine, ascorbic acid, hydroxypropyl-β-cyclodextrin (HPpCD), or a mixture thereof. In some embodiments, said pharmaceutical composition comprises methionine, ascorbic acid or hydroxypropyl-β-cyclodextrin (HPpCD). In some embodiments, said pharmaceutical composition comprises methionine, hydroxypropyl-β-cyclodextrin (HPpCD), or a mixture thereof. In some embodiments, the pharmaceutical composition comprises methionine and hydroxypropyl-β-cyclodextrin. In some embodiments, the pharmaceutical composition comprises methionine. In some embodiments, the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD). In some embodiments, the pharmaceutical composition comprises ascorbic acid.

[0286] In some embodiments, the concentration of the stabilizer in the pharmaceutical composition is from 1 to 250 mM. In some embodiments, the concentration of the stabilizer in the pharmaceutical composition is from 2 to 150 mM. In some embodiments, the concentration of the stabilizer in the pharmaceutical composition is from 3 to 120 mM. In some embodiments, the concentration of the stabilizer in the pharmaceutical composition is from 4 to 100 mM. In some embodiments, said pharmaceutical composition comprises said stabilizer in a concentration of 2.5 to 20 mM. In some embodiments, said pharmaceutical composition comprises said stabilizer in a concentration of 2.5 to 10 mM. In some embodiments, said pharmaceutical composition comprises said stabilizer in a concentration of 4 to 6 mM. In some embodiments, said pharmaceutical composition comprises said stabilizer in a concentration of about 5 mM. In some embodiments, said pharmaceutical composition comprises said stabilizer in a concentration of 5 mM. In some embodiments, the concentration of the stabilizer in the pharmaceutical composition is from 50 to 100 mM.

[0287] In some embodiments, the concentration of said methionine in the pharmaceutical composition is from 1 to 50 mM. In some embodiments, the concentration of said methionine in the pharmaceutical composition is from 2 to 30 mM. In some embodiments, the concentration of said methionine in the pharmaceutical composition is from 3 to 10 mM. In some embodiments, the concentration of said methionine in the pharmaceutical composition is from 4 to 6 mM. In some embodiments, the concentration of said methionine in the pharmaceutical composition is about 5 mM. In some embodiments, the concentration of said methionine in the pharmaceutical composition is 5 mM.

[0288] In some embodiments, the pharmaceutical composition comprises methionine in a concentration of from about 1 to about 50 mM, preferably from about 2 to about 30 mM, more preferably from about 3 to about 10 mM, still more preferably from about 4 to about 6 mM, and most preferably about 5 mM and hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of from about 5 to about 250 g / L, preferably form about 70 to about 200 g / L, more preferably from about 80 to about 150 g / L, and most preferably about 100 g / L.

[0289] In some embodiments, the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of 1 to 500 g / L. In some embodiments, the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of 5 to 250 g / L. In some embodiments, the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of 50 to 150 g / L. In some embodiments, the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of 80 to 120 g / L. In some embodiments, the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of about 100 g / L.

[0290] In some embodiments, the pharmaceutical composition comprises ascorbic acid in a concentration of 0.1 to 20 g / L. In some embodiments, the pharmaceutical composition comprises ascorbic acid in a concentration of 0.4 to 10 g / L. In some embodiments, the pharmaceutical composition comprises ascorbic acid in a concentration of 0.6 to 4 g / L. In some embodiments, the pharmaceutical composition comprises ascorbic acid in a concentration of about 1 g / L.

[0291] In some embodiments, said pharmaceutical composition does not comprise hydroxypropyl-P- cyclodextrin (HPpCD). In some embodiments, said pharmaceutical composition does not comprise ascorbic acid. Nonionic Surfactant

[0292] The pharmaceutical composition of the present disclosure further comprises a nonionic surfactant.

[0293] The term "surfactant", as used herein, denotes a pharmaceutically acceptable excipient which is used to protect protein formulations against mechanical stresses like agitation and shearing. Examples of pharmaceutically acceptable nonionic surfactants include polysorbates, poloxamers, polyoxy ethylene alkyl ethers (Brij) or alkylphenylpolyoxyethylene ethers (Triton-X). Any suitable nonionic surfactant may be applied. Preferred nonionic surfactants according to the present disclosure are polysorbates and poloxamers.

[0294] In some embodiments, said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.1 to 1.0 g / L. In some embodiments, said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.3 to 0.8 g / L. In some embodiments, said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.4 to 0.6 g / L. In some embodiments, said pharmaceutical composition comprises the nonionic surfactant in a concentration of about 0.5 g / L. In some embodiments, said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.5 g / L.

[0295] Typically, the nonionic surfactant in the pharmaceutical composition of the present disclosure is a polysorbate or a poloxamer.

[0296] In some embodiments, the nonionic surfactant is selected from the group consisting of a polysorbate, a poloxamer, and a mixture thereof. Such a mixture thereof may comprise one or more polysorbates and / or one or more poloxamers, preferably one polysorbate and one poloxamer.

[0297] As used herein, the term "polysorbate" refers to mixtures of partial esters of fatty acids of sorbitol and its anhydrides, typically copolymerized with ethylene oxide. Examples of polysorbates are polysorbate 20 (see European Pharmacopoeia 11.6; mixture of partial esters of fatty acids, mainly lauric (dodecanoic) acid, with sorbitol and its anhydrides ethoxylated with approximately 20 moles of ethylene oxide for each molecule of sorbitol and sorbitol anhydrides, Tween 20) or polysorbate 80 (see European Pharmacopoeia 11.6; mixture of partial esters of fatty acids, mainly oleic acid, with sorbitol and its anhydrides ethoxylated with approximately 20 moles of ethylene). In some embodiments, the nonionic surfactant is a polysorbate. In some embodiments, said nonionic surfactant is polysorbate 20 or polysorbate 80. In some embodiments, said nonionic surfactant is polysorbate 20.

[0298] In some embodiments, the polysorbate is present in the pharmaceutical composition in a concentration of 0.1 to 1 g / L. In some embodiments, the polysorbate is present in the pharmaceutical composition in a concentration of 0.3 to 0.8 g / L. In some embodiments, the polysorbate is present in the pharmaceutical composition in a concentration of 0.4 to 0.6 g / L. In some embodiments, the polysorbate is present in the pharmaceutical composition in a concentration of about 0.5 g / L. In some embodiments, the polysorbate is present in the pharmaceutical composition in a concentration of 0.5 g / L.

[0299] In some embodiments, the nonionic surfactant is a polysorbate and is present in the pharmaceutical composition in a concentration of about 0.1 to about 1 g / L, preferably of about 0.3 to about 0.8 g / L, more preferably of about 0.4 to about 0.6 g / L, and most preferably of about 0.5 g / L. In this connection, the stabilizing effect of the ADC is particularly effective when about 0.3 to about 0.8 g / L (such as about 0.5 g / L) polysorbate 20 is combined with histidine buffer at pH of about 5.3 to about 5.7 (such as about 5.5).

[0300] In some embodiments, said polysorbate is polysorbate 20 or polysorbate 80. In some embodiments, said polysorbate is polysorbate 20.

[0301] In some embodiments, the nonionic surfactant is polysorbate 20 and / or polysorbate 80, preferably polysorbate 20, and is present in the pharmaceutical composition in a concentration of about 0.1 to about 1 g / L, preferably of about 0.3 to about 0.8 g / L, and more preferably of about 0.3 to about 0.5 g / L. In this connection, the stabilizing effect of the ADC is particularly effective when about 0.3 to about 0.8 g / L (such as about 0.3 to about 0.5 g / L) polysorbate 20 is combined with histidine buffer at pH of about 5.3 to about 5.7 (such as about 5.5).

[0302] In some embodiment, the nonionic surfactant is a poloxamer, preferably poloxamer 188, and is present in the pharmaceutical composition in a concentration of about 1 to about 15 g / L, preferably of about 3 to about 10 g / L, and most preferably of about 6 g / L.

[0303] In some embodiments, said nonionic surfactant is poloxamer 188. The term "poloxamer", as used herein, refers to a polyoxyethylene-polyoxypropylene block copolymer as described in the following. A “polyoxyethylene-polyoxypropylene block copolymer” is a block copolymer having at least one polyoxyethylene block and at least one polyoxypropylene block. Such polyoxyethylene-polyoxypropylene block copolymers are for example represented by the formula HO-(CH2-CH2O-)a-(CH2-CH(CH3)-O)b-(CH2-CH2-O)a-H, wherein a is an integer of from 10 to 200 and b is an integer of 10 to 100. Suitable polyoxyethylene-polyoxypropylene block copolymers include a variety of commercially available products sold under various trade names, including Synperonic PE Series (ICI); Pluronic™ Series (BASF), Lutrol (BASF). These polyoxyethylene-polyoxypropylene block copolymers are generically referred to as poloxamers.

[0304] A preferred poloxamer is poloxamer 188, having a polyoxypropylene molecular mass of 1800 g / mol and 80% polyoxyethylene content. Therefore, one embodiment of the present disclosure is directed to the pharmaceutical composition, wherein the poloxamer is poloxamer 188.

[0305] In some embodiments, the pharmaceutical composition comprises the poloxamer at 0.1 mM to 2 mM. In some embodiments, the pharmaceutical composition comprises the poloxamer at 0.2 mM to 1.5 mM. In some embodiments, the pharmaceutical composition comprises the poloxamer at 0.5 mM to 1 mM.

[0306] In some embodiments, the poloxamer is present in the pharmaceutical composition in a concentration of 1 to 15 g / L. In some embodiments, the poloxamer is present in the pharmaceutical composition in a concentration of 3 to 10 g / L. In some embodiments, the poloxamer is present in the pharmaceutical composition in a concentration of 5 to 8 g / L. In some embodiments, the poloxamer is present in the pharmaceutical composition in a concentration of about 6 g / L. In some embodiments, the poloxamer is present in the pharmaceutical composition in a concentration of 6 g / L.

[0307] Amounts and concentrations in relation to the polysorbate or poloxamer relate to total amounts and concentrations of all included species.

[0308] In some embodiments, the nonionic surfactant is selected from the group consisting of a polysorbate selected from the group consisting of polysorbate 20 and polysorbate 80 or a poloxamer that is poloxamer 188 or a mixture thereof. Such a mixture thereof may comprise three components (two polysorbates and one poloxamer) or two components (two polysorbates or one polysorbate and one poloxamer). In some embodiments, the pharmaceutical composition comprises two polysorbates.

[0309] Sugar / Sugar Alcohol

[0310] The pharmaceutical composition of the present disclosure further comprises a sugar and / or sugar alcohol.

[0311] In some embodiments, the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 20 to 400 mM. In some embodiments, the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 100 to 350 mM. In some embodiments, the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 150 to 300 mM. In some embodiments, the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 200 to 260 mM. In some embodiments, the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 230 to 240 mM. In some embodiments, the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of about 235 mM. In some embodiments, the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of about 234 mM. In some embodiments, the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 234 mM.

[0312] In some embodiments, said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of 210 to 260 mM. In some embodiments, said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of 220 to 250 mM. In some embodiments, said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of 230 to 240 mM. In some embodiments, said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of about 235 mM. In some embodiments, said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of about 234 mM. In some embodiments, said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of 234 mM.

[0313] Amounts and concentrations in relation to the sugar / sugar alcohol relate to total amounts and concentrations of all sugar components, unless only a single sugar component is stipulated.

[0314] Any suitable sugar such as monosaccharides and / or disaccharides may be applied. In some embodiments, said pharmaceutical composition comprises a disaccharide. In some embodiments, the sugar and / or sugar alcohol is a disaccharide. In some embodiments, the disaccharide is selected from the group consisting of trehalose, maltose, sucrose, and a mixture thereof. In some embodiments, the disaccharide is trehalose. In some embodiments, the disaccharide is trehalose-dihydrate.

[0315] Any suitable sugar alcohol may be applied. Suitably, the sugar alcohol is mannitol.

[0316] In some embodiments, the pharmaceutical composition comprises the sugar and the sugar alcohol. In some embodiments, said pharmaceutical composition comprises a sugar. In some embodiments, said pharmaceutical composition comprises no sugar alcohol.

[0317] In some embodiments, the sugar and / or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof. In some embodiments, the sugar and / or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, and a mixture thereof. In some embodiments, the sugar and / or sugar alcohol is trehalose. In some embodiments, the sugar and / or sugar alcohol is trehalose-dihydrate.

[0318] In some embodiments, the sugar / sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof. In some embodiments, the sugar / sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, and a mixture thereof. In some embodiments, the sugar / sugar alcohol is selected from the groups consisting of trehalose, mannitol and a mixture thereof. In some embodiments, the sugar / sugar alcohol is trehalose. In some embodiments, the sugar / sugar alcohol is trehalose-dihydrate.

[0319] In some embodiments, the sugar and / or sugar alcohol is mannitol. In some embodiments, the sugar alcohol is mannitol.

[0320] In a preferred embodiment, the sugar is trehalose dihydrate, which is preferably present in the pharmaceutical composition in a concentration of about 234 mM (88.42 g / L). The inventors surprisingly found that respective excipient provide particularly ADC stability. Buffer

[0321] The pharmaceutical composition according to the present disclosure further comprises a buffer.

[0322] As used herein, the term “buffer” refers to a mixture of an acid (usually a weak acid, e.g. citric acid, acetic acid) and its conjugate base (e.g. an citrate or acetate salt, for example, sodium acetate, sodium citrate, or histidine) or alternatively a mixture of a base (usually a weak base, e.g. histidine) and its conjugate acid (e.g. protonated histidine salt), which in aqueous solution have a “buffering effect” meaning that upon addition of a small quantity of strong acid or base the pH of the aqueous solution to only slightly changed.

[0323] Any suitable buffer may be applied.

[0324] In some embodiments, said pharmaceutical composition comprises 1 to 50 mM of said buffer. In some embodiments, said pharmaceutical composition comprises 5 to 50 mM of said buffer. In some embodiments, said pharmaceutical composition comprises 5 to 30 mM of said buffer. In some embodiments, said pharmaceutical composition comprises 5 to 20 mM of said buffer. In some embodiments, said pharmaceutical composition comprises 8 to 12 mM of said buffer. In some embodiments, said pharmaceutical composition comprises about 10 mM of said buffer. In some embodiments, said pharmaceutical composition comprises 10 mM of said buffer.

[0325] In some embodiments, the buffer is selected from the group consisting of acetate buffer, succinate buffer, lactate buffer, 2-(N-morpholino)ethanesulfonic acid (MES) buffer, histidine buffer, and a mixture thereof, preferably at a pH of about 3.0 to about 5.5, more preferably of about 3.5 to about 5.0, and most preferably of about 4.0 to about 4.5. In some embodiments, the buffer is selected from the group consisting of acetate buffer, succinate buffer, 2-(N-morpholino)ethanesulfonic acid (MES) buffer, histidine buffer, and a mixture thereof. In some embodiment, the buffer is selected from the group consisting of acetate buffer, lactate buffer, histidine buffer, and a mixture thereof at a pH of about 3.0 to about 7.0, preferably of about 4.0 to about 6.5, and most preferably of about 5.0 to about 6.0.

[0326] In some embodiments, the buffer is selected from the group consisting of acetate buffer, histidine buffer, and a mixture thereof. In some embodiment, the buffer is selected from the group consisting of acetate buffer at a pH of about 3.5 to about 5.5 and histidine buffer at a pH of about 4.0 to about 7.0, preferably of about 5.0 to about 6.5, more preferably of about 5.3 to about 5.7, and most preferably of about 5.5. In some embodiments, the buffer comprises of acetate salt(s) and / or histidine salt(s) and / or the respective free acid or base thereof or a mixture of one or more of the various salts and / or the acid(s) or base(s) thereof. In some embodiments, the buffer comprises acetate salt(s) and / or the free acid thereof or L-histidine and / or an acid-addition salt thereof, preferably L-histidine and / or an acid-addition salt thereof, which is preferably L-histidine hydrochloric acid.

[0327] In the pharmaceutical composition according to the present disclosure, the buffer is preferably a histidine buffer. Surprisingly, when the pharmaceutical composition uses histidine buffer at a suitable pH, not only is oxidation of the pharmaceutical composition reduced, but also the aggregation, cleavage and fragmentation of the ADC and the payload’s degradation in the ADC, even after light-exposure. Without being bound by any theory, it is believed that histidine-buffered solution are particularly advantageous, since the respective compositions can be used in pH ranges suitable for biopharmaceutical intravenous formulations (such as pH 4 to 7). In this connection, the inventors found that surprisingly histidine buffer composed of L-histidine and L-histidine-HCl-H2O at a ratio that leads to a pH of about 5.5 and a total concentration of about 10 mM is particularly well stabilizing ADCs, e.g. camptothecin-based antibody-drug conjugate, preferably exatecan-based antibody-drug conjugate such as ADC1 and ADC2.

[0328] In some embodiments, said buffer is a histidine buffer.

[0329] In some embodiments, the histidine buffer is a histidine buffer at a pH of 5.0 to 6.5. In some embodiments, the histidine buffer is a histidine buffer at a pH of 5.3 to 5.7. In some embodiments, the histidine buffer is a histidine buffer at a pH of about 5.5. In some embodiments, the histidine buffer is a histidine buffer at a pH of 5.5.

[0330] In some embodiments, the concentration of said histidine buffer in the pharmaceutical composition is from about 1 to 50 mM. In some embodiments, the concentration of said histidine buffer in the pharmaceutical composition is from about 5 to 30 mM. In some embodiments, the concentration of said histidine buffer in the pharmaceutical composition is from about 5 to 20 mM. In some embodiments, the concentration of said histidine buffer in the pharmaceutical composition is about 10 mM.

[0331] In some embodiments, said buffer is an acetate buffer. In some embodiments, the acetate buffer is an acetate buffer at a pH of 3.5 to 5.0. In some embodiments, the acetate buffer is an acetate buffer at a pH of 4.0 to 5.0. In some embodiments, the acetate buffer is an acetate buffer at a pH of 4.2 to 4.8. In some embodiments, the acetate buffer is an acetate buffer at a pH of about 4.5. In some embodiments, the acetate buffer is an acetate buffer at a pH of 4.5.

[0332] Further embodiments of the pharmaceutical composition

[0333] In some embodiments, said pharmaceutical composition has a pH of 5.0 to 6.5. In some embodiments, said pharmaceutical composition has a pH of 5-6. In some embodiments, said pharmaceutical composition has a pH of 5.2-5.8. In some embodiments, said pharmaceutical composition has a pH of 5.3 to 5.7. In some embodiments, said pharmaceutical composition has a pH of 5.4-5.6. In some embodiments, said pharmaceutical composition has a pH of about 5.5. In some embodiments, said pharmaceutical composition has a pH of 5.5.

[0334] In some embodiments, the pharmaceutical composition is an aqueous solution with a pH of 4.5 to 7.0. In some embodiments, the pharmaceutical composition is an aqueous solution with a pH of 5.0 to 6.0. In some embodiments, the pharmaceutical composition is an aqueous solution with a pH of 5.3 to 5.7. In some embodiments, the pharmaceutical composition is an aqueous solution with a pH of 5.4 to 5.6. In some embodiments, the pharmaceutical composition is an aqueous solution with a pH of about 5.5.

[0335] In some embodiments, said pharmaceutical composition comprises

[0336] 3 to 30 mg / mL of said antibody-drug conjugate;

[0337] a stabilizer, wherein said stabilizer is

[0338] 2.5 to 20 mM of methionine,

[0339] 0.6 to 4 g / L of ascorbic acid,

[0340] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[0341] or a mixture thereof;

[0342] a nonionic surfactant, wherein said nonionic surfactant is

[0343] 0.1 to 1.0 g / L of a polysorbate,

[0344] 3 to 10 g / L of a poloxamer,

[0345] or a mixture thereof;

[0346] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[0347] 5 to 50 mM of a buffer, wherein the buffer is

[0348] a histidine buffer at a pH of 5.0 to 6.5 or an acetate buffer at a pH of 4.0 to 5.0.

[0349] In some embodiments, said pharmaceutical composition comprises

[0350] 3 to 30 mg / mL of said antibody-drug conjugate;

[0351] a stabilizer, wherein said stabilizer is

[0352] 5 to 15 mM of methionine or

[0353] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0354] a nonionic surfactant, wherein said nonionic surfactant is

[0355] 0.3 to 0.8 g / L of polysorbate 20 or

[0356] 5 to 8 g / L of poloxamer 188;

[0357] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0358] 5 to 20 mM of a buffer, wherein the buffer is

[0359] a histidine buffer at a pH of 5.2 to 5.8 or

[0360] an acetate buffer at a pH of 4.0 to 5.0.

[0361] In some embodiments, said pharmaceutical composition comprises

[0362] 8 to 12 mg / mL of said antibody-drug conjugate;

[0363] a stabilizer, wherein said stabilizer is

[0364] 4 to 6 mM of methionine or

[0365] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0366] a nonionic surfactant, wherein said nonionic surfactant is

[0367] 0.4 to 0.6 g / L of polysorbate 20 or

[0368] 5 to 8 g / L of poloxamer 188;

[0369] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0370] 8 to 12 mM of a buffer, wherein the buffer is

[0371] a histidine buffer at a pH of 5.4 to 5.6 or

[0372] an acetate buffer at a pH of 4.2 to 4.8.

[0373] In some embodiments, said pharmaceutical composition comprises

[0374] 3 to 30 mg / mL of said antibody-drug conjugate,

[0375] 2.5 to 20 mM of said stabilizer;

[0376] 0.1 to 1.0 g / L of said nonionic surfactant; 210 to 260 mM of said sugar / sugar alcohol, and 5 to 50 mM of said buffer,

[0377] wherein said pharmaceutical composition has a pH of 5-6.

[0378] In some embodiments, said pharmaceutical composition comprises 5 to 15 mg / mL of said antibody-drug conjugate,

[0379] 2.5 to 10 mM of said stabilizer;

[0380] 0.3 to 0.8 g / L of said nonionic surfactant;

[0381] 220 to 250 mM of said sugar / sugar alcohol, and

[0382] 5 to 20 mM of said buffer,

[0383] wherein said pharmaceutical composition has a pH of 5.2-5.8.

[0384] In some embodiments, said pharmaceutical composition comprises 8 to 12 mg / mL of said antibody-drug conjugate,

[0385] 4 to 6 mM of said stabilizer;

[0386] 0.4 to 0.6 g / L of said nonionic surfactant;

[0387] 230 to 240 mM of said sugar / sugar alcohol, and

[0388] 8 to 12 mM of said buffer,

[0389] wherein said pharmaceutical composition has a pH of 5.4-5.6.

[0390] In some embodiments, said pharmaceutical composition comprises about 10 mg / mL of said antibody-drug conjugate,

[0391] about 5 mM of said stabilizer;

[0392] about 0.5 g / L of said nonionic surfactant;

[0393] about 234 mM of said sugar / sugar alcohol, and

[0394] about 10 mM of said buffer,

[0395] wherein said pharmaceutical composition has a pH of about 5.5.

[0396] In some embodiments, said pharmaceutical composition comprises 10 mg / mL of said antibody-drug conjugate,

[0397] 5 mM of said stabilizer;

[0398] 0.5 g / L of said nonionic surfactant;

[0399] 234 mM of said sugar / sugar alcohol, and 10 mM of said buffer,

[0400] wherein said pharmaceutical composition has a pH of 5.5.

[0401] In some embodiments,

[0402] said stabilizer is methionine;

[0403] said nonionic surfactant is polysorbate 20;

[0404] said sugar and / or sugar alcohol is trehalose; and

[0405] said buffer is histidine buffer.

[0406] In some embodiments, said pharmaceutical composition comprises

[0407] 10 mg / mL of said antibody-drug conjugate,

[0408] 5 mM of a stabilizer, wherein said stabilizer is methionine;

[0409] 0.5 g / L of a nonionic surfactant, wherein said nonionic surfactant is polysorbate 20; 234 mM of a sugar, wherein said sugar is trehalose; and

[0410] 10 mM of a buffer, wherein said buffer is a histidine buffer at a pH of 5.5.

[0411] In some embodiments, said pharmaceutical composition comprises

[0412] 3 to 30 mg / mL of said antibody-drug conjugate,

[0413] 2.5 to 20 mM methionine;

[0414] 0.1 to 1.0 g / L polysorbate 20;

[0415] 210 to 260 mM trehalose, and

[0416] 5 to 50 mM histidine buffer at a pH of 5-6.

[0417] In some embodiments, said pharmaceutical composition comprises

[0418] 5 to 15 mg / mL of said antibody-drug conjugate,

[0419] 2.5 to 10 mM methionine;

[0420] 0.3 to 0.8 g / L polysorbate 20;

[0421] 220 to 250 mM trehalose, and

[0422] 5 to 20 mM histidine buffer at a pH of 5.2-5.8.

[0423] In some embodiments, said pharmaceutical composition comprises

[0424] 8 to 12 mg / mL of said antibody-drug conjugate,

[0425] 4 to 6 mM methionine;

[0426] 0.4 to 0.6 g / L polysorbate 20; 230 to 240 mM trehalose, and

[0427] 8 to 12 mM histidine buffer at a pH of 5.4-5.6.

[0428] In some embodiments, said pharmaceutical composition comprises

[0429] about 10 mg / mL of said antibody-drug conjugate,

[0430] about 5 mM methionine;

[0431] about 0.5 g / L polysorbate 20;

[0432] about 234 mM trehalose, and

[0433] about 10 mM histidine buffer at a pH of about 5.5.

[0434] In some embodiments, said pharmaceutical composition comprises

[0435] 10 mg / mL of said antibody-drug conjugate,

[0436] 5 mM methionine;

[0437] 0.5 g / L polysorbate 20;

[0438] 234 mM trehalose, and

[0439] 10 mM histidine buffer at a pH 5.5.

[0440] wherein said pharmaceutical composition has a pH of 5.5.

[0441] In some embodiments, the pharmaceutical composition comprises methionine, polysorbate 20, trehalose-dihydrate, and a histidine buffer, preferably wherein the antibody-drug conjugate comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VIII):

[0442]

[0443] wherein S is a sulfur atom of a cysteine of the antibody mAb1, and wherein n is a number of [linker–exatecan] moieties covalently linked to mAb1 and is between 1 and 10, preferably between 7 and 8. In some embodiments, the pharmaceutical composition comprises methionine, polysorbate 20, trehalose-dihydrate, and a histidine buffer, wherein the antibody-drug conjugate comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (IX):

[0444]

[0445] wherein S is a sulfur atom of a cysteine of the antibody mAb1, and wherein n is a number of [linker–exatecan] moieties covalently linked to mAb1 and is between 1 and 10, preferably between 7 and 8.

[0446] In some embodiments, the pharmaceutical composition comprises the ADC in a concentration of about 1 to about 50 mg / mL, preferably of about 5 to about 25 mg / mL, more preferably of about 7 to about 20 mg / mL, and most preferably of about 10 mg / mL.

[0447] In some embodiments, the pharmaceutical composition comprises

[0448] the ADC in a concentration of about 1 to about 50 mg / mL, preferably of about 5 to about 25 mg / mL, more preferably of about 7 to about 20 mg / mL, and most preferably of about 10 mg / mL;

[0449] the stabilizer in a concentration of about 1 to about 250 mM, preferably of about 2 to about 150 mM, more preferably of about 3 to about 100 mM, still more preferably of 4 to 50 mM, and most preferably about 5 mM;

[0450] the nonionic surfactant in a concentration of about 0.1 to about 1 g / L, preferably of about 0.3 to about 0.8 g / L, and most preferably of about 0.5 g / L;

[0451] the sugar or the sugar alcohol, preferably the sugar, in a concentration of about 20 to about 400 mM, preferably of about 100 to about 350 mM, more preferably of about 150 to about 300 mM, still more preferably of about 200 to about 260 mM, and most preferably about 234 mM; and

[0452] the buffer in a concentration of about 1 to about 50 mM, preferably of about 5 to about 30 mM, more preferably of about 5 to 20 mM, and most preferably of about 10 mM. In some embodiment, the pharmaceutical composition comprises

[0453] the antibody-drug conjugate in a concentration of about 1 to about 50 mg / mL, preferably in a concentration of about 5 to about 25 mg / mL, and most preferably in a concentration of about 10 mg / mL;

[0454] the buffer, which is preferably a histidine buffer, in a concentration of about 5 to about 50 mM, preferably in a concentration of about 5 to about 15 mM, and most preferably in a concentration of about 10 mM;

[0455] the nonionic surfactant, which is preferably polysorbate 20 or polysorbate 80, more preferably polysorbate 20, in a concentration of about 0.1 to about 1 g / L, preferably in a concentration of about 0.3 to about 0.8 g / L, and most preferably in a concentration of about 0.5 g / L, or poloxamer 188, in a concentration of about 1 to 15 g / L, preferably in a concentration of about 3 to about 10 g / L, and most preferably in a concentration of about 6 g / L;

[0456] a disaccharide selected from the group consisting of sucrose, trehalose, maltose, and a mixture thereof, preferably trehalose-dihydrate, or the sugar alcohol, preferably mannitol, in a concentration of about 50 to about 500 mM, preferably in a concentration of about 100 to about 300 mM, and most preferably in a concentration of about 234 mM;

[0457] the methionine in a concentration of about 1 to about 100 mM, preferably in a concentration of about 5 to about 30 mM, and most preferably in a concentration of about 5 mM; and optionally hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of about 1 to about 500 g / L, preferably in a concentration of about 5 to about 250 g / L, and most preferably in a concentration of about 100 g / L; and

[0458] has a pH of about 5.0 to about 6.5, preferably about 5.3 to about 5.7 and most preferably about 5.5; and

[0459] wherein the antibody-drug conjugate comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VIII):

[0460]

[0461] wherein S is a sulfur atom of a cysteine of the antibody mAb1, and wherein n is a number of [linker–exatecan] moieties covalently linked to mAb1 and is between 1 and 10, preferably between 7 and 8.

[0462] In this connection, it is noted that mAb1 according to the present disclosure is an antibody, which binds to human CEACAM5 protein and which consists of two identical heavy chains (HC) consisting of the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) consisting of the amino acid sequence of SEQ ID NO: 14.

[0463] In a preferred embodiment, the pharmaceutical composition comprises

[0464] the ADC being an mAb1 / camptothecin-based antibody-drug conjugate, preferably an mAb1 / exatecan- based antibody-drug conjugate, wherein the DAR is preferably between 7 and 8 such as about 8, in a concentration of about 1 to about 50 mg / mL, preferably of about 5 to about 25 mg / mL, more preferably of about 7 to about 20 mg / mL, and most preferably of about 10 mg / mL;

[0465] methionine in a concentration of about 1 to about 250 mM, preferably of about 2 to about 150 mM, more preferably of about 3 to about 100 mM, still more preferably of 4 to 50 mM, and most preferably about 5 mM;

[0466] the nonionic surfactant selected from the group consisting of polysorbate and poloxamer, wherein

[0467] the polysorbate is selected from the group consisting of polysorbate 20 or, preferably polysorbate 20, which is present in a concentration of about 0.1 to about 1 g / L, preferably of about 0.3 to about 0.8 g / L, and most preferably of about 0.5 g / L, and

[0468] the poloxamer is poloxamer 188, which is present in a concentration of about 1 to about 15 g / L, preferably of about 3 to about 10 g / L, and most preferably of about 6 g / L; the sugar being a disaccharide selected from the group consisting of sucrose, trehalose and maltose, preferably trehalose-dihydrate, which is present in a concentration of about 20 to about 400 mM, preferably of about 100 to about 350 mM, more preferably of about 150 to about 300 mM, and still more preferably of about 200 to about 260 mM, and most preferably about 234 mM;

[0469] the buffer being a histidine buffer, which is present in a concentration of about 1 to about 50 mM, preferably from about 5 to about 30 mM, more preferably from about 5 to about 20 mM, and most preferably of about 10 mM; and

[0470] optionally hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of about 1 to about 500 g / L, preferably of about 5 to about 250 g / L, and most preferably about 100 g / L. When a pharmaceutical composition comprises the above mentioned concentrations, the pharmaceutical composition can surprisingly be provided in the form of an aqueous solution, wherein even after light exposure, the solution shows no turbidity or coloration.

[0471] A particularly stable and soluble pharmaceutical composition comprises about 10 mg / mL of the antibody-drug conjugate, about 10 mM histidine buffer (about 7.6 mM L-histidine-HCl-H₂O + about 2.4 mM L-histidine), about 80 g / L trehalose (about 88.42 g / L or about 234 mM trehalose-dihydrate), about 0.5 g / L polysorbate 20, about 5 mM methionine, and has a pH of about 5.5. In this connection, the antibody in the antibody-drug conjugate is preferably directed against human CEACAM5 protein, comprising a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence AAS (which may also be expressed as “Ala-Ala-Ser”; SEQ ID NO: 7), and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8, wherein the drug (payload) in the antibody-drug conjugate is preferably exatecan, wherein exatecan is preferably linked to the antibody via maleimide-conjugation, and wherein in up to total 8 molecules exatecan are linked to each antibody.

[0472] In a preferred embodiment, the pharmaceutical composition is characterized by a pH of about 5.5 and comprises about 10 mg / mL of the antibody-drug conjugate, about 10 mM histidine buffer (e.g. about 7.6 mM L-histidine-HCl-H2O + about 2.4 mM L-histidine), about 234 mM trehalose-dihydrate, about 0.5 g / L polysorbate 20, about 5 mM methionine, and optionally about 100 g / L hydroxypropyl-β-cyclodextrin (HPpCD);

[0473] preferably wherein the antibody-drug conjugate comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VIII):

[0474]

[0475] wherein S is a sulfur atom of a cysteine of the antibody mAb1, and wherein n is a number of [linker-exatecan] moieties covalently linked to mAb1 and is between 1 and 10, preferably between 7 and 8 such as about 8.

[0476] In a preferred embodiment, the pharmaceutical composition is characterizes by a pH of about 5.5 and comprises about 10 mg / mL of the antibody-drug conjugate, about 10 mM histidine buffer (e.g. about 7.6 mM L-histidine-HCl-H2O + about 2.4 mM L-histidine), about 234 mM trehalose-dihydrate, about 0.3 to about 0.5 g / L polysorbate 20, about 5 mM methionine, and optionally about 100 g / L hydroxypropyl-β-cyclodextrin (HPpCD);

[0477] preferably wherein the antibody-drug conjugate comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VIII):

[0478]

[0479] wherein S is a sulfur atom of a cysteine of the antibody mAb1, and wherein n is a number of [linker-exatecan] moieties covalently linked to mAb1 and is between 1 and 10, preferably between 7 and 8 such as about 8.

[0480] Such pharmaceutical compositions indicated a particularly robust storage and stress stability during various stability studies (research stage short term stability studies, and human formulation feasibility study, supporting (IND enabling) stability study, GMP stability studies).

[0481] In some embodiments, the pharmaceutical composition comprises

[0482] 3 to 30 mg / mL of said antibody-drug conjugate;

[0483] a stabilizer, wherein said stabilizer is

[0484] 2.5 to 20 mM of methionine,

[0485] 0.6 to 4 g / L of ascorbic acid,

[0486] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[0487] or a mixture thereof;

[0488] a nonionic surfactant, wherein said nonionic surfactant is

[0489] 0.1 to 1.0 g / L of a polysorbate, 3 to 10 g / L of a poloxamer,

[0490] or a mixture thereof;

[0491] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[0492] 5 to 50 mM of a buffer, wherein the buffer is

[0493] a histidine buffer at a pH of 5.0 to 6.5 or

[0494] an acetate buffer at a pH of 4.0 to 5.0;

[0495] wherein said antibody-drug conjugate has the formula (IV)

[0496]

[0497] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,

[0498] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[0499] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[0500] In some embodiments, the pharmaceutical composition comprises

[0501] 3 to 30 mg / mL of said antibody-drug conjugate;

[0502] a stabilizer, wherein said stabilizer is 5 to 15 mM of methionine or

[0503] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0504] a nonionic surfactant, wherein said nonionic surfactant is

[0505] 0.3 to 0.8 g / L of polysorbate 20 or

[0506] 5 to 8 g / L of poloxamer 188;

[0507] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0508] 5 to 20 mM of a buffer, wherein the buffer is

[0509] a histidine buffer at a pH of 5.2 to 5.8 or

[0510] an acetate buffer at a pH of 4.0 to 5.0;

[0511] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0512] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,

[0513] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[0514] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[0515] In some embodiments, the pharmaceutical composition comprises

[0516] 8 to 12 mg / mL of said antibody-drug conjugate;

[0517] a stabilizer, wherein said stabilizer is

[0518] 4 to 6 mM of methionine or

[0519] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0520] a nonionic surfactant, wherein said nonionic surfactant is

[0521] 0.4 to 0.6 g / L of polysorbate 20 or

[0522] 5 to 8 g / L of poloxamer 188;

[0523] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0524] 8 to 12 mM of a buffer, wherein the buffer is a histidine buffer at a pH of 5.4 to 5.6 or

[0525] an acetate buffer at a pH of 4.2 to 4.8;

[0526] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0527] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody binds to human CEACAM5 protein,

[0528] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[0529] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[0530] In some embodiments, the pharmaceutical composition comprises

[0531] 3 to 30 mg / mL of said antibody-drug conjugate,

[0532] 2.5 to 20 mM methionine;

[0533] 0.1 to 1.0 g / L polysorbate 20;

[0534] 210 to 260 mM trehalose, and

[0535] 5 to 50 mM histidine buffer,

[0536] wherein said pharmaceutical composition has a pH of 5-6,

[0537] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0538] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,

[0539] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8, and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[0540] In some embodiments, the pharmaceutical composition comprises

[0541] 5 to 15 mg / mL of said antibody-drug conjugate,

[0542] 2.5 to 10 mM methionine;

[0543] 0.3 to 0.8 g / L polysorbate 20;

[0544] 220 to 250 mM trehalose, and

[0545] 5 to 20 mM histidine buffer,

[0546] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[0547] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0548] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,

[0549] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[0550] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[0551] In some embodiments, the pharmaceutical composition comprises

[0552] 8 to 12 mg / mL of said antibody-drug conjugate,

[0553] 4 to 6 mM methionine;

[0554] 0.4 to 0.6 g / L polysorbate 20;

[0555] 230 to 240 mM trehalose, and

[0556] 8 to 12 mM histidine buffer, wherein said pharmaceutical composition has a pH of 5.4-5.6,

[0557] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0558] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody binds to human CEACAM5 protein,

[0559] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[0560] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[0561] In some embodiments, the pharmaceutical composition comprises

[0562] 10 mg / mL of an antibody-drug conjugate,

[0563] 5 mM methionine;

[0564] 0.5 g / L polysorbate 20;

[0565] 234 mM trehalose, and

[0566] 10 mM histidine buffer,

[0567] wherein said pharmaceutical composition has a pH of 5.5,

[0568] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0569] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody binds to human CEACAM5 protein,

[0570] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[0571] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[0572] In some embodiments, the pharmaceutical composition comprises

[0573] 3 to 30 mg / mL of said antibody-drug conjugate;

[0574] a stabilizer, wherein said stabilizer is

[0575] 2.5 to 20 mM of methionine,

[0576] 0.6 to 4 g / L of ascorbic acid,

[0577] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[0578] or a mixture thereof;

[0579] a nonionic surfactant, wherein said nonionic surfactant is

[0580] 0.1 to 1.0 g / L of a polysorbate,

[0581] 3 to 10 g / L of a poloxamer,

[0582] or a mixture thereof;

[0583] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[0584] 5 to 50 mM of a buffer, wherein the buffer is

[0585] a histidine buffer at a pH of 5.0 to 6.5 or

[0586] an acetate buffer at a pH of 4.0 to 5.0;

[0587] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0588] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[0589] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[0590] In some embodiments, the pharmaceutical composition comprises

[0591] 3 to 30 mg / mL of said antibody-drug conjugate;

[0592] a stabilizer, wherein said stabilizer is 5 to 15 mM of methionine or

[0593] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0594] a nonionic surfactant, wherein said nonionic surfactant is

[0595] 0.3 to 0.8 g / L of polysorbate 20 or

[0596] 5 to 8 g / L of poloxamer 188;

[0597] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0598] 5 to 20 mM of a buffer, wherein the buffer is

[0599] a histidine buffer at a pH of 5.2 to 5.8 or

[0600] an acetate buffer at a pH of 4.0 to 5.0;

[0601] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0602] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[0603] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[0604] In some embodiments, the pharmaceutical composition comprises

[0605] 8 to 12 mg / mL of said antibody-drug conjugate;

[0606] a stabilizer, wherein said stabilizer is

[0607] 4 to 6 mM of methionine or

[0608] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0609] a nonionic surfactant, wherein said nonionic surfactant is

[0610] 0.4 to 0.6 g / L of polysorbate 20 or

[0611] 5 to 8 g / L of poloxamer 188;

[0612] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0613] 8 to 12 mM of a buffer, wherein the buffer is

[0614] a histidine buffer at a pH of 5.4 to 5.6 or

[0615] an acetate buffer at a pH of 4.2 to 4.8; wherein said antibody-drug conjugate has the formula (IV) as shown above, wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[0616] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[0617] In some embodiments, the pharmaceutical composition comprises

[0618] 3 to 30 mg / mL of said antibody-drug conjugate,

[0619] 2.5 to 20 mM methionine;

[0620] 0.1 to 1.0 g / L polysorbate 20;

[0621] 210 to 260 mM trehalose, and

[0622] 5 to 50 mM histidine buffer,

[0623] wherein said pharmaceutical composition has a pH of 5-6,

[0624] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0625] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[0626] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[0627] In some embodiments, the pharmaceutical composition comprises

[0628] 5 to 15 mg / mL of said antibody-drug conjugate,

[0629] 2.5 to 10 mM methionine; 0.3 to 0.8 g / L polysorbate 20;

[0630] 220 to 250 mM trehalose, and

[0631] 5 to 20 mM histidine buffer,

[0632] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[0633] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0634] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[0635] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[0636] In some embodiments, the pharmaceutical composition comprises

[0637] 8 to 12 mg / mL of said antibody-drug conjugate,

[0638] 4 to 6 mM methionine;

[0639] 0.4 to 0.6 g / L polysorbate 20;

[0640] 230 to 240 mM trehalose, and

[0641] 8 to 12 mM histidine buffer,

[0642] wherein said pharmaceutical composition has a pH of 5.4-5.6,

[0643] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0644] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[0645] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the pharmaceutical composition comprises

[0646] 10 mg / mL of an antibody-drug conjugate,

[0647] 5 mM methionine;

[0648] 0.5 g / L polysorbate 20;

[0649] 234 mM trehalose, and

[0650] 10 mM histidine buffer,

[0651] wherein said pharmaceutical composition has a pH of 5.5,

[0652] and wherein said antibody-drug conjugate has the formula (IV) as shown above, wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0;

[0653] wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[0654] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[0655] In some embodiments, the pharmaceutical composition comprises

[0656] 3 to 30 mg / mL of said antibody-drug conjugate;

[0657] a stabilizer, wherein said stabilizer is

[0658] 2.5 to 20 mM of methionine,

[0659] 0.6 to 4 g / L of ascorbic acid,

[0660] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[0661] or a mixture thereof;

[0662] a nonionic surfactant, wherein said nonionic surfactant is

[0663] 0.1 to 1.0 g / L of a polysorbate,

[0664] 3 to 10 g / L of a poloxamer,

[0665] or a mixture thereof;

[0666] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[0667] 5 to 50 mM of a buffer, wherein the buffer is a histidine buffer at a pH of 5.0 to 6.5 or

[0668] an acetate buffer at a pH of 4.0 to 5.0;

[0669] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0670] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0671] In some embodiments, the pharmaceutical composition comprises

[0672] 3 to 30 mg / mL of said antibody-drug conjugate;

[0673] a stabilizer, wherein said stabilizer is

[0674] 5 to 15 mM of methionine or

[0675] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0676] a nonionic surfactant, wherein said nonionic surfactant is

[0677] 0.3 to 0.8 g / L of polysorbate 20 or

[0678] 5 to 8 g / L of poloxamer 188;

[0679] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0680] 5 to 20 mM of a buffer, wherein the buffer is

[0681] a histidine buffer at a pH of 5.2 to 5.8 or

[0682] an acetate buffer at a pH of 4.0 to 5.0;

[0683] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0684] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0685] In some embodiments, the pharmaceutical composition comprises

[0686] 8 to 12 mg / mL of said antibody-drug conjugate;

[0687] a stabilizer, wherein said stabilizer is

[0688] 4 to 6 mM of methionine or

[0689] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0690] a nonionic surfactant, wherein said nonionic surfactant is

[0691] 0.4 to 0.6 g / L of polysorbate 20 or 5 to 8 g / L of poloxamer 188;

[0692] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0693] 8 to 12 mM of a buffer, wherein the buffer is

[0694] a histidine buffer at a pH of 5.4 to 5.6 or

[0695] an acetate buffer at a pH of 4.2 to 4.8;

[0696] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0697] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8;

[0698] wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0699] In some embodiments, the pharmaceutical composition comprises

[0700] 3 to 30 mg / mL of said antibody-drug conjugate,

[0701] 2.5 to 20 mM methionine;

[0702] 0.1 to 1.0 g / L polysorbate 20;

[0703] 210 to 260 mM trehalose, and

[0704] 5 to 50 mM histidine buffer,

[0705] wherein said pharmaceutical composition has a pH of 5-6,

[0706] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0707] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0708] In some embodiments, the pharmaceutical composition comprises

[0709] 5 to 15 mg / mL of said antibody-drug conjugate,

[0710] 2.5 to 10 mM methionine;

[0711] 0.3 to 0.8 g / L polysorbate 20;

[0712] 220 to 250 mM trehalose, and

[0713] 5 to 20 mM histidine buffer,

[0714] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[0715] and wherein said antibody-drug conjugate has the formula (IV) as shown above, wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0716] In some embodiments, the pharmaceutical composition comprises

[0717] 8 to 12 mg / mL of said antibody-drug conjugate,

[0718] 4 to 6 mM methionine;

[0719] 0.4 to 0.6 g / L polysorbate 20;

[0720] 230 to 240 mM trehalose, and

[0721] 8 to 12 mM histidine buffer,

[0722] wherein said pharmaceutical composition has a pH of 5.4-5.6,

[0723] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0724] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0725] In some embodiments, the pharmaceutical composition comprises

[0726] 10 mg / mL of an antibody-drug conjugate,

[0727] 5 mM methionine;

[0728] 0.5 g / L polysorbate 20;

[0729] 234 mM trehalose, and

[0730] 10 mM histidine buffer,

[0731] wherein said pharmaceutical composition has a pH of 5.5,

[0732] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0733] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[0734] In some embodiments, the pharmaceutical composition comprises

[0735] 3 to 30 mg / mL of said antibody-drug conjugate; a stabilizer, wherein said stabilizer is

[0736] 2.5 to 20 mM of methionine,

[0737] 0.6 to 4 g / L of ascorbic acid,

[0738] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[0739] or a mixture thereof;

[0740] a nonionic surfactant, wherein said nonionic surfactant is

[0741] 0.1 to 1.0 g / L of a polysorbate,

[0742] 3 to 10 g / L of a poloxamer,

[0743] or a mixture thereof;

[0744] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[0745] 5 to 50 mM of a buffer, wherein the buffer is

[0746] a histidine buffer at a pH of 5.0 to 6.5 or

[0747] an acetate buffer at a pH of 4.0 to 5.0;

[0748] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0749] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[0750] In some embodiments, the pharmaceutical composition comprises

[0751] 3 to 30 mg / mL of said antibody-drug conjugate;

[0752] a stabilizer, wherein said stabilizer is

[0753] 5 to 15 mM of methionine or

[0754] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0755] a nonionic surfactant, wherein said nonionic surfactant is

[0756] 0.3 to 0.8 g / L of polysorbate 20 or

[0757] 5 to 8 g / L of poloxamer 188;

[0758] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0759] 5 to 20 mM of a buffer, wherein the buffer is

[0760] a histidine buffer at a pH of 5.2 to 5.8 or

[0761] an acetate buffer at a pH of 4.0 to 5.0;

[0762] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0763] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody mAb1 as disclosed herein. In some embodiments, the pharmaceutical composition comprises

[0764] 8 to 12 mg / mL of said antibody-drug conjugate;

[0765] a stabilizer, wherein said stabilizer is

[0766] 4 to 6 mM of methionine or

[0767] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0768] a nonionic surfactant, wherein said nonionic surfactant is

[0769] 0.4 to 0.6 g / L of polysorbate 20 or

[0770] 5 to 8 g / L of poloxamer 188;

[0771] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0772] 8 to 12 mM of a buffer, wherein the buffer is

[0773] a histidine buffer at a pH of 5.4 to 5.6 or

[0774] an acetate buffer at a pH of 4.2 to 4.8;

[0775] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0776] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[0777] In some embodiments, the pharmaceutical composition comprises

[0778] 3 to 30 mg / mL of said antibody-drug conjugate,

[0779] 2.5 to 20 mM methionine;

[0780] 0.1 to 1.0 g / L polysorbate 20;

[0781] 210 to 260 mM trehalose, and

[0782] 5 to 50 mM histidine buffer,

[0783] wherein said pharmaceutical composition has a pH of 5-6,

[0784] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0785] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[0786] In some embodiments, the pharmaceutical composition comprises

[0787] 5 to 15 mg / mL of said antibody-drug conjugate,

[0788] 2.5 to 10 mM methionine;

[0789] 0.3 to 0.8 g / L polysorbate 20; 220 to 250 mM trehalose, and

[0790] 5 to 20 mM histidine buffer,

[0791] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[0792] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0793] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[0794] In some embodiments, the pharmaceutical composition comprises

[0795] 8 to 12 mg / mL of said antibody-drug conjugate,

[0796] 4 to 6 mM methionine;

[0797] 0.4 to 0.6 g / L polysorbate 20;

[0798] 230 to 240 mM trehalose, and

[0799] 8 to 12 mM histidine buffer,

[0800] wherein said pharmaceutical composition has a pH of 5.4-5.6,

[0801] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0802] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8;

[0803] wherein said antibody is the antibody mAb1 as disclosed herein.

[0804] In some embodiments, the pharmaceutical composition comprises

[0805] 10 mg / mL of an antibody-drug conjugate,

[0806] 5 mM methionine;

[0807] 0.5 g / L polysorbate 20;

[0808] 234 mM trehalose, and

[0809] 10 mM histidine buffer,

[0810] wherein said pharmaceutical composition has a pH of 5.5,

[0811] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0812] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody is the antibody mAb1 as disclosed herein.

[0813] In some embodiments, the pharmaceutical composition comprises

[0814] 3 to 30 mg / mL of said antibody-drug conjugate;

[0815] a stabilizer, wherein said stabilizer is 2.5 to 20 mM of methionine,

[0816] 0.6 to 4 g / L of ascorbic acid,

[0817] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[0818] or a mixture thereof;

[0819] a nonionic surfactant, wherein said nonionic surfactant is

[0820] 0.1 to 1.0 g / L of a polysorbate,

[0821] 3 to 10 g / L of a poloxamer,

[0822] or a mixture thereof;

[0823] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[0824] 5 to 50 mM of a buffer, wherein the buffer is

[0825] a histidine buffer at a pH of 5.0 to 6.5 or

[0826] an acetate buffer at a pH of 4.0 to 5.0;

[0827] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0828] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody Precemtabart.

[0829] In some embodiments, the pharmaceutical composition comprises

[0830] 3 to 30 mg / mL of said antibody-drug conjugate;

[0831] a stabilizer, wherein said stabilizer is

[0832] 5 to 15 mM of methionine or

[0833] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0834] a nonionic surfactant, wherein said nonionic surfactant is

[0835] 0.3 to 0.8 g / L of polysorbate 20 or

[0836] 5 to 8 g / L of poloxamer 188;

[0837] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0838] 5 to 20 mM of a buffer, wherein the buffer is

[0839] a histidine buffer at a pH of 5.2 to 5.8 or

[0840] an acetate buffer at a pH of 4.0 to 5.0;

[0841] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0842] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody Precemtabart. In some embodiments, the pharmaceutical composition comprises

[0843] 8 to 12 mg / mL of said antibody-drug conjugate;

[0844] a stabilizer, wherein said stabilizer is

[0845] 4 to 6 mM of methionine or

[0846] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0847] a nonionic surfactant, wherein said nonionic surfactant is

[0848] 0.4 to 0.6 g / L of polysorbate 20 or

[0849] 5 to 8 g / L of poloxamer 188;

[0850] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0851] 8 to 12 mM of a buffer, wherein the buffer is

[0852] a histidine buffer at a pH of 5.4 to 5.6 or

[0853] an acetate buffer at a pH of 4.2 to 4.8;

[0854] wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0855] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody is the antibody Precemtabart.

[0856] In some embodiments, the pharmaceutical composition comprises

[0857] 3 to 30 mg / mL of said antibody-drug conjugate,

[0858] 2.5 to 20 mM methionine;

[0859] 0.1 to 1.0 g / L polysorbate 20;

[0860] 210 to 260 mM trehalose, and

[0861] 5 to 50 mM histidine buffer,

[0862] wherein said pharmaceutical composition has a pH of 5-6,

[0863] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0864] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody Precemtabart.

[0865] In some embodiments, the pharmaceutical composition comprises

[0866] 5 to 15 mg / mL of said antibody-drug conjugate,

[0867] 2.5 to 10 mM methionine;

[0868] 0.3 to 0.8 g / L polysorbate 20;

[0869] 220 to 250 mM trehalose, and 5 to 20 mM histidine buffer,

[0870] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[0871] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0872] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody Precemtabart.

[0873] In some embodiments, the pharmaceutical composition comprises

[0874] 8 to 12 mg / mL of said antibody-drug conjugate,

[0875] 4 to 6 mM methionine;

[0876] 0.4 to 0.6 g / L polysorbate 20;

[0877] 230 to 240 mM trehalose, and

[0878] 8 to 12 mM histidine buffer,

[0879] wherein said pharmaceutical composition has a pH of 5.4-5.6,

[0880] and wherein said antibody-drug conjugate has the formula (IV) as shown above, wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8;

[0881] wherein said antibody is the antibody Precemtabart.

[0882] In some embodiments, the pharmaceutical composition comprises

[0883] 10 mg / mL of an antibody-drug conjugate,

[0884] 5 mM methionine;

[0885] 0.5 g / L polysorbate 20;

[0886] 234 mM trehalose, and

[0887] 10 mM histidine buffer,

[0888] wherein said pharmaceutical composition has a pH of 5.5,

[0889] and wherein said antibody-drug conjugate has the formula (IV) as shown above,

[0890] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody is the antibody Precemtabart.

[0891] In some embodiments, the pharmaceutical composition comprises

[0892] 3 to 30 mg / mL of said antibody-drug conjugate;

[0893] a stabilizer, wherein said stabilizer is

[0894] 2.5 to 20 mM of methionine, 0.6 to 4 g / L of ascorbic acid,

[0895] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[0896] or a mixture thereof;

[0897] a nonionic surfactant, wherein said nonionic surfactant is

[0898] 0.1 to 1.0 g / L of a polysorbate,

[0899] 3 to 10 g / L of a poloxamer,

[0900] or a mixture thereof;

[0901] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[0902] 5 to 50 mM of a buffer, wherein the buffer is

[0903] a histidine buffer at a pH of 5.0 to 6.5 or

[0904] an acetate buffer at a pH of 4.0 to 5.0;

[0905] wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[0906] In some embodiments, the pharmaceutical composition comprises

[0907] 3 to 30 mg / mL of said antibody-drug conjugate;

[0908] a stabilizer, wherein said stabilizer is

[0909] 5 to 15 mM of methionine or

[0910] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0911] a nonionic surfactant, wherein said nonionic surfactant is

[0912] 0.3 to 0.8 g / L of polysorbate 20 or

[0913] 5 to 8 g / L of poloxamer 188;

[0914] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0915] 5 to 20 mM of a buffer, wherein the buffer is

[0916] a histidine buffer at a pH of 5.2 to 5.8 or

[0917] an acetate buffer at a pH of 4.0 to 5.0;

[0918] wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[0919] In some embodiments, the pharmaceutical composition comprises

[0920] 8 to 12 mg / mL of said antibody-drug conjugate;

[0921] a stabilizer, wherein said stabilizer is

[0922] 4 to 6 mM of methionine or

[0923] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0924] a nonionic surfactant, wherein said nonionic surfactant is

[0925] 0.4 to 0.6 g / L of polysorbate 20 or 5 to 8 g / L of poloxamer 188;

[0926] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0927] 8 to 12 mM of a buffer, wherein the buffer is

[0928] a histidine buffer at a pH of 5.4 to 5.6 or

[0929] an acetate buffer at a pH of 4.2 to 4.8;

[0930] wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[0931] In some embodiments, the pharmaceutical composition comprises

[0932] 3 to 30 mg / mL of said antibody-drug conjugate,

[0933] 2.5 to 20 mM methionine;

[0934] 0.1 to 1.0 g / L polysorbate 20;

[0935] 210 to 260 mM trehalose, and

[0936] 5 to 50 mM histidine buffer,

[0937] wherein said pharmaceutical composition has a pH of 5-6,

[0938] and wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[0939] In some embodiments, the pharmaceutical composition comprises

[0940] 5 to 15 mg / mL of said antibody-drug conjugate,

[0941] 2.5 to 10 mM methionine;

[0942] 0.3 to 0.8 g / L polysorbate 20;

[0943] 220 to 250 mM trehalose, and

[0944] 5 to 20 mM histidine buffer,

[0945] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[0946] and wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[0947] In some embodiments, the pharmaceutical composition comprises

[0948] 8 to 12 mg / mL of said antibody-drug conjugate,

[0949] 4 to 6 mM methionine;

[0950] 0.4 to 0.6 g / L polysorbate 20;

[0951] 230 to 240 mM trehalose, and

[0952] 8 to 12 mM histidine buffer,

[0953] wherein said pharmaceutical composition has a pH of 5.4-5.6, and wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[0954] In some embodiments, the pharmaceutical composition comprises

[0955] 10 mg / mL of an antibody-drug conjugate,

[0956] 5 mM methionine;

[0957] 0.5 g / L polysorbate 20;

[0958] 234 mM trehalose, and

[0959] 10 mM histidine buffer,

[0960] wherein said pharmaceutical composition has a pH of 5.5,

[0961] and wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[0962] In some embodiments, the pharmaceutical composition comprises

[0963] 3 to 30 mg / mL of said antibody-drug conjugate;

[0964] a stabilizer, wherein said stabilizer is

[0965] 2.5 to 20 mM of methionine,

[0966] 0.6 to 4 g / L of ascorbic acid,

[0967] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[0968] or a mixture thereof;

[0969] a nonionic surfactant, wherein said nonionic surfactant is

[0970] 0.1 to 1.0 g / L of a polysorbate,

[0971] 3 to 10 g / L of a poloxamer,

[0972] or a mixture thereof;

[0973] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[0974] 5 to 50 mM of a buffer, wherein the buffer is

[0975] a histidine buffer at a pH of 5.0 to 6.5 or

[0976] an acetate buffer at a pH of 4.0 to 5.0;

[0977] wherein said antibody-drug conjugate is Precemtabart tocentecan.

[0978] In some embodiments, the pharmaceutical composition comprises

[0979] 3 to 30 mg / mL of said antibody-drug conjugate;

[0980] a stabilizer, wherein said stabilizer is

[0981] 5 to 15 mM of methionine or

[0982] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD); a nonionic surfactant, wherein said nonionic surfactant is

[0983] 0.3 to 0.8 g / L of polysorbate 20 or

[0984] 5 to 8 g / L of poloxamer 188;

[0985] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0986] 5 to 20 mM of a buffer, wherein the buffer is

[0987] a histidine buffer at a pH of 5.2 to 5.8 or

[0988] an acetate buffer at a pH of 4.0 to 5.0;

[0989] wherein said antibody-drug conjugate is Precemtabart tocentecan.

[0990] In some embodiments, the pharmaceutical composition comprises

[0991] 8 to 12 mg / mL of said antibody-drug conjugate;

[0992] a stabilizer, wherein said stabilizer is

[0993] 4 to 6 mM of methionine or

[0994] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[0995] a nonionic surfactant, wherein said nonionic surfactant is

[0996] 0.4 to 0.6 g / L of polysorbate 20 or

[0997] 5 to 8 g / L of poloxamer 188;

[0998] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[0999] 8 to 12 mM of a buffer, wherein the buffer is

[1000] a histidine buffer at a pH of 5.4 to 5.6 or

[1001] an acetate buffer at a pH of 4.2 to 4.8;

[1002] wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1003] In some embodiments, the pharmaceutical composition comprises

[1004] 3 to 30 mg / mL of said antibody-drug conjugate,

[1005] 2.5 to 20 mM methionine;

[1006] 0.1 to 1.0 g / L polysorbate 20;

[1007] 210 to 260 mM trehalose, and

[1008] 5 to 50 mM histidine buffer,

[1009] wherein said pharmaceutical composition has a pH of 5-6,

[1010] and wherein said antibody-drug conjugate is Precemtabart tocentecan. In some embodiments, the pharmaceutical composition comprises

[1011] 5 to 15 mg / mL of said antibody-drug conjugate,

[1012] 2.5 to 10 mM methionine;

[1013] 0.3 to 0.8 g / L polysorbate 20;

[1014] 220 to 250 mM trehalose, and

[1015] 5 to 20 mM histidine buffer,

[1016] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[1017] and wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1018] In some embodiments, the pharmaceutical composition comprises

[1019] 8 to 12 mg / mL of said antibody-drug conjugate,

[1020] 4 to 6 mM methionine;

[1021] 0.4 to 0.6 g / L polysorbate 20;

[1022] 230 to 240 mM trehalose, and

[1023] 8 to 12 mM histidine buffer,

[1024] wherein said pharmaceutical composition has a pH of 5.4-5.6,

[1025] and wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1026] In some embodiments, the pharmaceutical composition comprises

[1027] 10 mg / mL of an antibody-drug conjugate,

[1028] 5 mM methionine;

[1029] 0.5 g / L polysorbate 20;

[1030] 234 mM trehalose, and

[1031] 10 mM histidine buffer,

[1032] wherein said pharmaceutical composition has a pH of 5.5,

[1033] and wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1034] In some embodiments, the pharmaceutical composition does not comprise sodium chloride (NaCl) at a concentration of more than 50 mM. In some embodiments, the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 20 mM. In some embodiments, the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 10 mM. In some embodiments, the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 5 mM. In some embodiments, the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 2 mM. In some embodiments, the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 1 mM. In some embodiments, the pharmaceutical composition is essentially free of sodium chloride.

[1035] In some embodiments, the pharmaceutical composition does not contain sodium chloride.

[1036] In some embodiments, the pharmaceutical composition is essentially free of any substances other than those explicitly listed.

[1037] In some embodiments, the pharmaceutical composition further com prises complexing agents such as EDTA. Complexing agents may be present in the pharmaceutical composition in concentrations of from about 0.01 to about 10 g / L.

[1038] In some embodiments, the pharmaceutical composition comprises at least one additional active agent (different to the ADC). Any suitable active agent may be applied, e.g. an anticancer drug, an analgesic, and the like.

[1039] In some embodiments, the pharmaceutical composition is an aqueous solution, a frozen aqueous solution or a lyophilizate. When the pharmaceutical composition is a lyophilizate, the lyophlizate is preferably reconstitutable to an aqueous solution.

[1040] "Aqueous" above and below is taken to mean water or mixtures of water with other solvents, in particular organic solvents (preferably, "aqueous" above and below is taken to mean water). If one or more substances are dissolved in water or in the mixtures of water with other solvents, aqueous solutions are present. If the aqueous solution comprises one or more active compounds and if it is suitable for therapeutic or prophylactic use in humans or animals, an aqueous pharmaceutical composition is present. If the aqueous solution / aqueous pharmaceutical composition comprises organic solvents, the latter are preferably those which are suitable for pharmaceutical use, such as dimethyl sulfoxide (DMSO), but in particular alcohols, such as, for example, ethanol, 1,2-propanediol, glycerol, polyethylene glycols and glycofurol. In some embodiments, "aqueous" means at least 90% water (i.e. not more than 10% of other solvents, such as organic solvents). In some embodiments, "aqueous" means at least 95% water. In some embodiments, "aqueous" means at least 98% water. In some embodiments, "aqueous" means at least 99% water. In some embodiments, "aqueous" means water in the absence of other solvents (such as organic solvents). The term “frozen aqueous solution” as used herein, is an aqueous solution which has been converted to a solid state of aggregation by applying temperatures below 0°Celsius.

[1041] It will be appreciated that pharmaceutical compositions of the invention may be provided, and preferably duly stored as in the form of an aqueous solution. However, the pharmaceutical composition of the invention may be provided, and preferably duly stored, as a frozen solution or lyophilizate. A frozen solution may be formed by applying to the liquid a temperature below 0° Celsius and thereby converting it to a solid state of aggregation. Preferably any such frozen solution will be thawed prior to use, administration, or even (potentially short-term) storage to afford a liquid or aqueous solution as defined herein. A lyophilized solution may be formed by freeze-drying a liquid (e.g. aqueous) solution as defined herein. Most preferably any such lyophilized solution will be reconstituted prior to use, administration, or even (potentially short-term) storage to afford a liquid or aqueous pharmaceutical solution as defined herein. Such reconstitution preferably comprises dissolving the lyophilized solution in water (e.g. for injection), preferably to afford a solution of a desired concentration of the ADC.

[1042] Freezing to a frozen solution or removal of the water by freeze-drying enables the stability of the aqueous conjugate solutions, which are already relatively stable per se, to be increased still further.

[1043] Typically, the pharmaceutical composition of the present disclosure is an aqueous solution. When the pharmaceutical composition is an aqueous solution, the pharmaceutical composition is very soluble and stable, even after a long period of time and light exposure, for which it can be stored and directly, or after dilution in a physiological fluid, preferable normal saline, administered to a patient later. In some embodiments, the pharmaceutical composition comprises water. When the pharmaceutical composition is a lyophilizate, the pharmaceutical composition is very stable even after a long period of time and light exposure and can well be reconstituted to an aqueous solution and administered to a patient later.

[1044] In some embodiments, the pharmaceutical composition is an aqueous solution. In some embodiments, the pharmaceutical composition is an aqueous pharmaceutical composition.

[1045] In some embodiments, said pharmaceutical composition is lyophilized. In some embodiments, said pharmaceutical composition is lyophilized and can be reconstituted to an aqueous solution. In some embodiments, said pharmaceutical composition is a lyophilized pharmaceutical composition which can be reconstituted (i.e. turned into to an aqueous pharmaceutical composition according to the present disclosure) by addition of water. In some embodiments, said pharmaceutical composition has been reconstituted from a lyophilisate. In some embodiments, said pharmaceutical composition has been reconstituted from a lyophilisate by the addition of water.

[1046] The explanations and definitions provided above apply accordingly also to the further aspects of the present disclosure described below.

[1047] Lyophilisate

[1048] In another aspect the present disclosure relates to a lyophilisate that can be reconstituted to a pharmaceutical composition according to the present disclosure.

[1049] The term "lyophilisate", as used herein, refers to a composition obtained by a freeze-drying process. The concentration of the ingredients in the lyophilisate is set such that the lyophilisate upon reconstitution with a defined volume of a defined liquid composition (e.g. distilled water) results in a pharmaceutical composition according to the present disclosure. For example, a lyophilisate that can be reconstituted to the pharmaceutical composition of the present disclosure can be obtained by preparing a pharmaceutical composition according to the present disclosure and then freeze-drying it. Such a lyophilisate has the advantage of being extremely stable even after a prolonged periods of time and light exposure. Upon addition of water, a pharmaceutical composition according to the present disclosure can be formed from such a lyophilisate. Thus, the lyophilisate according to the present disclosure combines the advantage of extremely high stability with quick access to the pharmaceutical composition of the present disclosure, with all its advantages like high solubility and stability of the ADC while at the same time allowing for direct use e.g. in treatment.

[1050] In another aspect the present disclosure relates to a lyophilisate that can be reconstituted to an (aqueous) pharmaceutical composition according to the present disclosure by addition of water.

[1051] Medical Use

[1052] As above-mentioned, the present disclosure further relates in a further aspect to the pharmaceutical composition as described above for use in therapy. In a further aspect, the present disclosure relates to the pharmaceutical composition according to the present disclosure for use in the treatment of cancer. In a further aspect, the present disclosure relates to use of a pharmaceutical composition according to the present disclosure for the preparation of a medicament for the treatment of cancer.

[1053] In a further aspect, the present disclosure relates to a method of treating cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition of the present disclosure to a subject in need thereof. In some embodiments, said subject has cancer.

[1054] In a further aspect, the present disclosure relates to the use of a pharmaceutical composition according to the present disclosure or a lyophilisate according to the present disclosure for the preparation of a medicament for the treatment of cancer.

[1055] Particular embodiments (e.g. regarding the pharmaceutical composition) have already been described above and shall hold for the aspects of this section, as well. In the following, particular embodiments are described in further detail. It is to be understood that each embodiment is relevant on its own as well as in combination with other embodiments.

[1056] The inventors found a solution to the problem of decreased stability and decreased solubility of ADCs. In some embodiments, the pharmaceutical composition comprises an ADC, where the target of the antibody in the ADC is human CEACAM5 as further described above (see also WO 2022 / 048883).

[1057] In the context of the present disclosure, the term "treating" or "treatment", as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. By the term "treating cancer" as used herein is meant the inhibition of the growth of malignant cells of a tumor and / or the progression of metastases from said tumor. Such treatment can also lead to the regression of tumor growth, i.e., the decrease in size of a measurable tumor. For instance, such treatment can lead to the complete regression of the tumor or metastasis.

[1058] In the context of the therapeutic applications of the present disclosure, the term “subject” or "patient” or “subject in need thereof” or “patient in need thereof” refers to a subject (e.g. a human or non-human mammal) affected or likely to be affected by a tumor. For instance, said patient may be a patient who has been determined to be susceptible to a therapeutic agent targeting CEACAM5, in particular to an ADC containing pharmaceutical composition according to the present disclosure, for instance according to a method as described herein below.

[1059] By a "therapeutically effective amount" is meant a sufficient amount to treat said (cancer) disease at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the pharmaceutical compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific pharmaceutical composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific pharmaceutical composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific pharmaceutical composition employed; and like factors well known in the medical arts. For example, it is well known within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

[1060] The present disclosure further provides a pharmaceutical composition of ADC1 for use as a medication, e.g. for use in the treatment of cancer. Data supporting the successful treatment of cancer with ADC1 has e.g. been published in international patent application WO 2022 / 048883 A1. The present disclosure further provides a method of treating cancer, comprising administering the pharmaceutical composition of the present disclosure to a subject in need thereof.

[1061] The cancer to be treated with the pharmaceutical compositions of the present disclosure is preferably a cancer expressing CEACAM5, more preferably a cancer overexpressing CEACAM5 as compared to normal (i.e. non-tumoral) cells of the same tissue origin.

[1062] In some embodiments, the cancer is a CEACAM5 expressing cancer.

[1063] In some embodiments, the cancer to be treated with the pharmaceutical compositions of the present disclosure is a colorectal cancer, non-small-cell lung carcinoma, pancreatic cancer, gastric cancer, cervical cancer, esophageal cancer (e.g. esophageal adenocarcinoma), cholangiocarcinoma, breast cancer, prostate cancer, ovarian cancer, urothelial cancer, bladder cancer, or cancer of the stomach, uterus, endometrium, thyroid, or skin. In some specific embodiments, the cancer to be treated with the pharmaceutical compositions of the present disclosure is colorectal cancer, gastric cancer, lung cancer such as non-small cell lung cancer, pancreatic cancer, esophageal cancer or prostate cancer.

[1064] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, gastric cancer, lung cancer, pancreatic cancer, esophageal cancer and prostate cancer.

[1065] When the pharmaceutical composition comprises exatecan as a payload and an antibody against human CEACAM5, and the further substances as described herein, the pharmaceutical composition is very effective in cancer therapy, preferably wherein the cancer is a colorectal cancer, gastric cancer, lung cancer, pancreatic cancer, esophageal cancer or prostate cancer, wherein the preparation is preferably applied via a parenteral administration, preferably via an intravenous infusion or a pharmaceutical preparation, whereby such preparation is applied after dilution in an aqueous medium, preferably in normal saline.

[1066] The pharmaceutical composition of the present disclosure may be used in cancer therapy alone or in combination with any suitable active agents.

[1067] It is also well known that therapeutic monoclonal antibodies can lead to the depletion of cells bearing the antigen specifically recognized by the antibody. This depletion can be mediated through at least three mechanisms: antibody mediated cellular cytotoxicity (ADCC), complement dependent lysis, and direct inhibition of tumor growth through signals mediated by the antigen targeted by the antibody.

[1068] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which antibodies bound to Fc receptors (FcRs) present on certain cytotoxic cells (e.g. Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell. To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in US Patent No. 5,500,362 or 5,821,337 may be performed.

[1069] "Complement dependent cytotoxicity" or "CDC" refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system to antibodies which are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g. as described in Gazzano-Santoro et al. (Journal of Immunological Methods. 1997 Mar;202(2):163-171) may be performed. Efficacy of the treatment with a pharmaceutical composition according to the present disclosure may be readily assayed in vivo, for instance in a mouse model of cancer and by measuring e.g. changes in tumor volume between treated and control groups, % tumor regression, partial regression or complete regression.

[1070] Stabilizing use

[1071] In a further aspect, the present disclosure relates to the use of a combination of (i) a stabilizer selected from the group consisting of methionine, ascorbic acid, hydroxypropyl-β-cyclodextrin, and a mixture thereof and (ii) a buffer to stabilize a pharmaceutical composition comprising an antibody-drug conjugate of the general formula [antibody]-[linker-payload]n, wherein n is between 1 and 10.

[1072] Particular embodiments (e.g. regarding the pharmaceutical composition, antibody-drug-conjugate, stabilizer, methionine, ascorbic acid, or hydroxypropyl-β-cyclodextrin) have already been outlined above and shall hold for the present aspect, as well. In the following, particular embodiments of the third aspect are described in further detail. It is to be understood that each embodiment is relevant on its own as well as in combination with other embodiments.

[1073] In some embodiments, the stabilizer is selected from the group consisting of methionine, hydroxypropyl-β-cyclodextrin, and a mixture thereof such as methionine or a mixture of methionine and hydroxypropyl-β-cyclodextrin. In one embodiment, the stabilizer is methionine.

[1074] In some embodiments, the buffer is a histidine buffer.

[1075] In some embodiments, the buffer comprises of histidine salt(s) and / or the respective free acid or base thereof.

[1076] In some embodiments, the buffer comprises L-histidine and / or an acid-addition salt thereof, preferably L-histidine and / or an acid-addition salt thereof, which is preferably L-histidine hydrochloric acid.

[1077] The concentration of the buffer in the pharmaceutical composition is generally from about 1 to about 50 mM, preferably from about 5 to about 30 mM, more preferably from about 5 to about 20 mM, and in particular of about 10 mM. In a preferred embodiment, the buffer is a histidine buffer and the concentration of said histidine buffer in the pharmaceutical composition is from about 1 to about 50 mM, preferably from about 5 to about 30 mM, more preferably from about 5 to about 20 mM, and most preferably of about 10 mM. Without being bound by any theory, it is believed that histidine-buffered solution are particularly suitable since the respective compositions can be used in pH ranges suitable for biopharmaceutical intravenous formulations (such as pH 4 to 7). In this connection, the inventors found that surprisingly histidine buffer composed of L-histidine and L-histidine-HCl-H2O at a ratio that leads to a pH of about 5.5 and a total concentration of about 10 mM is particularly well stabilizing ADCs.

[1078] In some embodiments, the pharmaceutical composition further comprises a nonionic surfactant such as polysorbate 20 and / or a sugar such as trehalose-dihydrate and / or a sugar alcohol.

[1079] In some embodiment, the used combination provides a stability of the ADC in the pharmaceutical composition towards light. In this connection, aggregation, fragmentation, the formation of oxidized species, and / or the formation of acidic species is reduced.

[1080] It will be obvious for a person skilled in the art that these embodiments and items only depict examples of a plurality of possibilities. Hence, the embodiments shown here should not be understood to form a limitation of these features and configurations. Any possible combination and configuration of the described features can be chosen according to the scope of the invention.

[1081] Also disclosed herein is the following subject matter:

[1082] Embodiment 1: A pharmaceutical composition comprising

[1083] an antibody-drug conjugate,

[1084] a stabilizer selected from the group consisting of methionine, ascorbic acid, hydroxypropyl-β-cyclodextrin, and a mixture thereof;

[1085] a nonionic surfactant;

[1086] a sugar and / or a sugar alcohol; and

[1087] a buffer.

[1088] Embodiment 2: The pharmaceutical composition according to embodiment 1, wherein said antibody-drug conjugate comprises an antibody. Embodiment 3: The pharmaceutical composition according to any one of embodiments 1 or 2, wherein said antibody-drug conjugate comprises an antibody, a linker and a payload.

[1089] Embodiment 4: The pharmaceutical composition according to embodiment 3, wherein said antibody-drug conjugate comprises n copies of said payload, where in is between 1 and 10.

[1090] Embodiment 5: The pharmaceutical composition according to any one of embodiments 1 to 4, wherein said antibody-drug conjugate has the general formula

[1091] [antibody]-[linker-payload]n

[1092] wherein n is between 1 and 10.

[1093] Embodiment 6: The pharmaceutical composition according to any one of embodiments 1 to 5, wherein the payload (i.e. the payload of said antibody-drug conjugate) is a camptothecin.

[1094] Embodiment 7: The pharmaceutical composition according to any one of embodiments 1 to 6, wherein the payload (i.e. the payload of said antibody-drug conjugate) is selected from the group consisting of topotecan, irinotecan, lurtotecan and exatecan.

[1095] Embodiment 8: The pharmaceutical composition according to any one of embodiments 1 to 7, wherein the payload of the antibody-drug conjugate is exatecan or a derivate thereof.

[1096] Embodiment 9: The pharmaceutical composition according to any one of embodiments 1 to 8, wherein the payload (i.e. the payload of said antibody-drug conjugate) is exatecan.

[1097] Embodiment 10: The pharmaceutical composition according to any one of embodiments 1 to 9, wherein one or more payloads are linked to the antibody (i.e. the antibody of said antibody-drug conjugate) by a maleimide-glucuronic acid-based linker.

[1098] Embodiment 11: The pharmaceutical composition according to any one of embodiments 1 to 10, wherein the linker-payloads comprised in said antibody-drug conjugate are conjugated to reduced interchain cysteine residues of the antibody.

[1099] Embodiment 12: The pharmaceutical composition according to any one of embodiments 1 to 11, wherein the linker of said antibody-drug conjugate is covalently linked to a reduced interchain cysteine residue of the antibody. Embodiment 13: The pharmaceutical composition according to any one of embodiments 1 to 12, wherein an average of 2 to 16 payloads are conjugated to the reduced interchain cysteine residues of the antibody.

[1100] Embodiment 14: The pharmaceutical composition according to any one of embodiments 1 to 12, wherein an average of about eight payloads are conjugated to the reduced interchain cysteine residues of the antibody.

[1101] Embodiment 15: The pharmaceutical composition according to any one of embodiments 1 to 14, wherein the payload of the antibody-drug conjugate is linked to the antibody by a cleavable linker.

[1102] Embodiment 16: The pharmaceutical composition according to embodiment 15, wherein the cleavable linker is cleavable in an endosome of a mammalian cell.

[1103] Embodiment 17: The pharmaceutical composition according to any one of embodiments 15 or 16, wherein the cleavable linker is cleavable by a human enzyme selected from glucuronidase and legumain.

[1104] Embodiment 18: The pharmaceutical composition according to any one of embodiments 3 to 17, wherein the linker is a linker cleavable by the human enzyme glucuronidase.

[1105] Embodiment 19: The pharmaceutical composition according to any one of embodiments 1 to 18, wherein the antibody-drug-conjugate has the following formula (II):

[1106]

[1107] wherein S is a sulfur atom of the antibody, and wherein n is between 1 and 10.

[1108] Embodiment 20: The pharmaceutical composition according to any one of embodiments 1 to 19, wherein the ADC of the present disclosure has the following formula (III):

[1109]

[1110] wherein S is a sulfur atom of the antibody, and wherein n is between 1 and 10.

[1111] Embodiment 21: The pharmaceutical composition according to any one of embodiments 1 to 20, wherein said antibody-drug conjugate has the formula (IV)

[1112]

[1113] wherein S is a sulfur atom of the antibody, and wherein n is between 1 and 10.

[1114] Embodiment 22: The pharmaceutical composition according to any one of embodiments 1 to 20, wherein the antibody-drug conjugate has the formula selected from the group consisting of (II), (III), (IV) and (V):

[1115]

[1116] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker-payload] moieties covalently linked to the antibody, wherein n is between 1 and 10, preferably wherein n is between 7 and 8, more preferably between 7.5 and 8.0;

[1117]

[1118] Payload

[1119]

[1120] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker-payload] moieties covalently linked to the antibody, wherein n is between 1 and 10, preferably wherein n is between 7 and 8, more preferably between 7.5 and 8.0;

[1121]

[1122] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker-exatecan] moieties covalently linked to the antibody, wherein n is between 1 and 10, preferably wherein n is between 7 and 8, more preferably between 7.5 and 8.0;

[1123]

[1124] wherein S is a sulfur atom of the antibody, and wherein n is a number of [linker-exatecan] moieties covalently linked to the antibody, wherein n is between 1 and 10, preferably wherein n is between 7 and 8, more preferably between 7.5 and 8.0.

[1125] Embodiment 23: The pharmaceutical composition according to any one of embodiments 1 to 22, wherein said pharmaceutical composition comprises 3 to 30 mg / mL of said antibody-drug conjugate;

[1126] a stabilizer, wherein said stabilizer is

[1127] 2.5 to 20 mM of methionine,

[1128] 0.6 to 4 g / L of ascorbic acid,

[1129] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[1130] or a mixture thereof;

[1131] a nonionic surfactant, wherein said nonionic surfactant is

[1132] 0.1 to 1.0 g / L of a polysorbate,

[1133] 3 to 10 g / L of a poloxamer,

[1134] or a mixture thereof;

[1135] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[1136] 5 to 50 mM of a buffer, wherein the buffer is

[1137] a histidine buffer at a pH of 5.0 to 6.5 or

[1138] an acetate buffer at a pH of 4.0 to 5.0.

[1139] Embodiment 24: The pharmaceutical composition according to any one of embodiments 1 to 23, wherein said pharmaceutical composition comprises

[1140] 3 to 30 mg / mL of said antibody-drug conjugate;

[1141] a stabilizer, wherein said stabilizer is

[1142] 5 to 15 mM of methionine or

[1143] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1144] a nonionic surfactant, wherein said nonionic surfactant is

[1145] 0.3 to 0.8 g / L of polysorbate 20 or

[1146] 5 to 8 g / L of poloxamer 188;

[1147] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1148] 5 to 20 mM of a buffer, wherein the buffer is

[1149] a histidine buffer at a pH of 5.2 to 5.8 or

[1150] an acetate buffer at a pH of 4.0 to 5.0.

[1151] Embodiment 25: The pharmaceutical composition according to any one of embodiments 1 to 24, wherein said pharmaceutical composition comprises

[1152] 8 to 12 mg / mL of said antibody-drug conjugate;

[1153] a stabilizer, wherein said stabilizer is 4 to 6 mM of methionine or

[1154] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1155] a nonionic surfactant, wherein said nonionic surfactant is

[1156] 0.4 to 0.6 g / L of polysorbate 20 or

[1157] 5 to 8 g / L of poloxamer 188;

[1158] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1159] 8 to 12 mM of a buffer, wherein the buffer is

[1160] a histidine buffer at a pH of 5.4 to 5.6 or

[1161] an acetate buffer at a pH of 4.2 to 4.8.

[1162] Embodiment 26: The pharmaceutical composition according to any one of embodiments 1 to 23, wherein said pharmaceutical composition comprises

[1163] 3 to 30 mg / mL of said antibody-drug conjugate,

[1164] 2.5 to 20 mM of said stabilizer;

[1165] 0.1 to 1.0 g / L of said nonionic surfactant;

[1166] 210 to 260 mM of said sugar / sugar alcohol, and

[1167] 5 to 50 mM of said buffer,

[1168] wherein said pharmaceutical composition has a pH of 5-6.

[1169] Embodiment 27: The pharmaceutical composition according to any one of embodiments 1 to 23 or 26, wherein said pharmaceutical composition comprises

[1170] 5 to 15 mg / mL of said antibody-drug conjugate,

[1171] 2.5 to 10 mM of said stabilizer;

[1172] 0.3 to 0.8 g / L of said nonionic surfactant;

[1173] 220 to 250 mM of said sugar / sugar alcohol, and

[1174] 5 to 20 mM of said buffer,

[1175] wherein said pharmaceutical composition has a pH of 5.2-5.8.

[1176] Embodiment 28: The pharmaceutical composition according to any one of embodiments 1 to 23 or 26 to 27, wherein said pharmaceutical composition comprises

[1177] 8 to 12 mg / mL of said antibody-drug conjugate,

[1178] 4 to 6 mM of said stabilizer;

[1179] 0.4 to 0.6 g / L of said nonionic surfactant; 230 to 240 mM of said sugar / sugar alcohol, and

[1180] 8 to 12 mM of said buffer,

[1181] wherein said pharmaceutical composition has a pH of 5.4-5.6.

[1182] Embodiment 29: The pharmaceutical composition according to any one of embodiments 1 to 23 or 26 to 28, wherein said pharmaceutical composition comprises

[1183] about 10 mg / mL of said antibody-drug conjugate,

[1184] about 5 mM of said stabilizer;

[1185] about 0.5 g / L of said nonionic surfactant;

[1186] about 234 mM of said sugar / sugar alcohol, and

[1187] about 10 mM of said buffer,

[1188] wherein said pharmaceutical composition has a pH of about 5.5.

[1189] Embodiment 30: The pharmaceutical composition according to any one of embodiments 1 to 23 or 26 to 29, wherein said pharmaceutical composition comprises

[1190] 10 mg / mL of said antibody-drug conjugate,

[1191] 5 mM of said stabilizer;

[1192] 0.5 g / L of said nonionic surfactant;

[1193] 234 mM of said sugar / sugar alcohol, and

[1194] 10 mM of said buffer,

[1195] wherein said pharmaceutical composition has a pH of 5.5.

[1196] Embodiment 31: The pharmaceutical composition according to any one of embodiments 1 to 30,

[1197] wherein said stabilizer is methionine;

[1198] wherein said nonionic surfactant is polysorbate 20;

[1199] wherein said sugar and / or sugar alcohol is trehalose; and

[1200] wherein said buffer is histidine buffer.

[1201] Embodiment 32: The pharmaceutical composition according to any one of embodiments 1 to 31, wherein said pharmaceutical composition comprises

[1202] 10 mg / mL of said antibody-drug conjugate,

[1203] 5 mM of a stabilizer, wherein said stabilizer is methionine;

[1204] 0.5 g / L of a nonionic surfactant, wherein said nonionic surfactant is polysorbate 20; 234 mM of a sugar, wherein said sugar is trehalose; and

[1205] 10 mM of a buffer, wherein said buffer is a histidine buffer at a pH of 5.5.

[1206] Embodiment 33: The pharmaceutical composition according to any one of embodiments 1 to 23, wherein said pharmaceutical composition comprises

[1207] 3 to 30 mg / mL of said antibody-drug conjugate,

[1208] 2.5 to 20 mM methionine;

[1209] 0.1 to 1.0 g / L polysorbate 20;

[1210] 210 to 260 mM trehalose, and

[1211] 5 to 50 mM histidine buffer at a pH of 5-6.

[1212] Embodiment 34: The pharmaceutical composition according to any one of embodiments 1 to 23 or 33, wherein said pharmaceutical composition comprises

[1213] 5 to 15 mg / mL of said antibody-drug conjugate,

[1214] 2.5 to 10 mM methionine;

[1215] 0.3 to 0.8 g / L polysorbate 20;

[1216] 220 to 250 mM trehalose, and

[1217] 5 to 20 mM histidine buffer at a pH of 5.2-5.8.

[1218] Embodiment 35: The pharmaceutical composition according to any one of embodiments 1 to 23 or 33 to 34, wherein said pharmaceutical composition comprises

[1219] 8 to 12 mg / mL of said antibody-drug conjugate,

[1220] 4 to 6 mM methionine;

[1221] 0.4 to 0.6 g / L polysorbate 20;

[1222] 230 to 240 mM trehalose, and

[1223] 8 to 12 mM histidine buffer at a pH of 5.4-5.6.

[1224] Embodiment 36: The pharmaceutical composition according to any one of embodiments 1 to 23 or 33 to 35, wherein said pharmaceutical composition comprises

[1225] about 10 mg / mL of said antibody-drug conjugate,

[1226] about 5 mM methionine;

[1227] about 0.5 g / L polysorbate 20;

[1228] about 234 mM trehalose, and

[1229] about 10 mM histidine buffer at a pH of about 5.5. Embodiment 37: The pharmaceutical composition according to any one of embodiments 1 to 23 or 33 to 36, wherein said pharmaceutical composition comprises

[1230] 10 mg / mL of said antibody-drug conjugate,

[1231] 5 mM methionine;

[1232] 0.5 g / L polysorbate 20;

[1233] 234 mM trehalose, and

[1234] 10 mM histidine buffer at a pH 5.5.

[1235] wherein said pharmaceutical composition has a pH of 5.5.

[1236] Embodiment 38: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1237] 3 to 30 mg / mL of said antibody-drug conjugate;

[1238] a stabilizer, wherein said stabilizer is

[1239] 2.5 to 20 mM of methionine,

[1240] 0.6 to 4 g / L of ascorbic acid,

[1241] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[1242] or a mixture thereof;

[1243] a nonionic surfactant, wherein said nonionic surfactant is

[1244] 0.1 to 1.0 g / L of a polysorbate,

[1245] 3 to 10 g / L of a poloxamer,

[1246] or a mixture thereof;

[1247] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[1248] 5 to 50 mM of a buffer, wherein the buffer is

[1249] a histidine buffer at a pH of 5.0 to 6.5 or

[1250] an acetate buffer at a pH of 4.0 to 5.0;

[1251] wherein said antibody-drug conjugate has the formula (IV)

[1252]

[1253] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,

[1254] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[1255] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[1256] Embodiment 39: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1257] 3 to 30 mg / mL of said antibody-drug conjugate;

[1258] a stabilizer, wherein said stabilizer is

[1259] 5 to 15 mM of methionine or

[1260] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1261] a nonionic surfactant, wherein said nonionic surfactant is

[1262] 0.3 to 0.8 g / L of polysorbate 20 or

[1263] 5 to 8 g / L of poloxamer 188;

[1264] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1265] 5 to 20 mM of a buffer, wherein the buffer is

[1266] a histidine buffer at a pH of 5.2 to 5.8 or

[1267] an acetate buffer at a pH of 4.0 to 5.0; wherein said antibody-drug conjugate has the formula (IV)

[1268]

[1269] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,

[1270] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[1271] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[1272] Embodiment 40: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1273] 8 to 12 mg / mL of said antibody-drug conjugate;

[1274] a stabilizer, wherein said stabilizer is

[1275] 4 to 6 mM of methionine or

[1276] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1277] a nonionic surfactant, wherein said nonionic surfactant is

[1278] 0.4 to 0.6 g / L of polysorbate 20 or

[1279] 5 to 8 g / L of poloxamer 188;

[1280] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1281] 8 to 12 mM of a buffer, wherein the buffer is a histidine buffer at a pH of 5.4 to 5.6 or

[1282] an acetate buffer at a pH of 4.2 to 4.8;

[1283] wherein said antibody-drug conjugate has the formula (IV)

[1284]

[1285] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody binds to human CEACAM5 protein,

[1286] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[1287] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[1288] Embodiment 41: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1289] 3 to 30 mg / mL of said antibody-drug conjugate,

[1290] 2.5 to 20 mM methionine;

[1291] 0.1 to 1.0 g / L polysorbate 20;

[1292] 210 to 260 mM trehalose, and

[1293] 5 to 50 mM histidine buffer,

[1294] wherein said pharmaceutical composition has a pH of 5-6, and wherein said antibody-drug conjugate has the formula (IV)

[1295]

[1296] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,

[1297] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[1298] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[1299] Embodiment 42: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1300] 5 to 15 mg / mL of said antibody-drug conjugate,

[1301] 2.5 to 10 mM methionine;

[1302] 0.3 to 0.8 g / L polysorbate 20;

[1303] 220 to 250 mM trehalose, and

[1304] 5 to 20 mM histidine buffer,

[1305] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[1306] and wherein said antibody-drug conjugate has the formula (IV)

[1307]

[1308] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,

[1309] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[1310] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[1311] Embodiment 43: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1312] 8 to 12 mg / mL of said antibody-drug conjugate,

[1313] 4 to 6 mM methionine;

[1314] 0.4 to 0.6 g / L polysorbate 20;

[1315] 230 to 240 mM trehalose, and

[1316] 8 to 12 mM histidine buffer,

[1317] wherein said pharmaceutical composition has a pH of 5.4-5.6, and wherein said antibody-drug conjugate has the formula (IV)

[1318]

[1319] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody binds to human CEACAM5 protein,

[1320] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[1321] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[1322] Embodiment 44: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1323] 10 mg / mL of an antibody-drug conjugate,

[1324] 5 mM methionine;

[1325] 0.5 g / L polysorbate 20;

[1326] 234 mM trehalose, and

[1327] 10 mM histidine buffer,

[1328] wherein said pharmaceutical composition has a pH of 5.5, and wherein said antibody-drug conjugate has the formula (IV)

[1329]

[1330] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody binds to human CEACAM5 protein,

[1331] wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[1332] and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[1333] Embodiment 45: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1334] 3 to 30 mg / mL of said antibody-drug conjugate;

[1335] a stabilizer, wherein said stabilizer is

[1336] 2.5 to 20 mM of methionine,

[1337] 0.6 to 4 g / L of ascorbic acid,

[1338] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[1339] or a mixture thereof;

[1340] a nonionic surfactant, wherein said nonionic surfactant is

[1341] 0.1 to 1.0 g / L of a polysorbate,

[1342] 3 to 10 g / L of a poloxamer,

[1343] or a mixture thereof; 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[1344] 5 to 50 mM of a buffer, wherein the buffer is

[1345] a histidine buffer at a pH of 5.0 to 6.5 or

[1346] an acetate buffer at a pH of 4.0 to 5.0;

[1347] wherein said antibody-drug conjugate has the formula (IV)

[1348]

[1349] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[1350] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[1351] Embodiment 46: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1352] 3 to 30 mg / mL of said antibody-drug conjugate;

[1353] a stabilizer, wherein said stabilizer is

[1354] 5 to 15 mM of methionine or

[1355] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1356] a nonionic surfactant, wherein said nonionic surfactant is

[1357] 0.3 to 0.8 g / L of polysorbate 20 or

[1358] 5 to 8 g / L of poloxamer 188; 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1359] 5 to 20 mM of a buffer, wherein the buffer is

[1360] a histidine buffer at a pH of 5.2 to 5.8 or

[1361] an acetate buffer at a pH of 4.0 to 5.0;

[1362] wherein said antibody-drug conjugate has the formula (IV)

[1363]

[1364] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[1365] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[1366] Embodiment 47: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1367] 8 to 12 mg / mL of said antibody-drug conjugate;

[1368] a stabilizer, wherein said stabilizer is

[1369] 4 to 6 mM of methionine or

[1370] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1371] a nonionic surfactant, wherein said nonionic surfactant is

[1372] 0.4 to 0.6 g / L of polysorbate 20 or

[1373] 5 to 8 g / L of poloxamer 188; 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1374] 8 to 12 mM of a buffer, wherein the buffer is

[1375] a histidine buffer at a pH of 5.4 to 5.6 or

[1376] an acetate buffer at a pH of 4.2 to 4.8;

[1377] wherein said antibody-drug conjugate has the formula (IV)

[1378]

[1379] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[1380] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[1381] Embodiment 48: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1382] 3 to 30 mg / mL of said antibody-drug conjugate,

[1383] 2.5 to 20 mM methionine;

[1384] 0.1 to 1.0 g / L polysorbate 20;

[1385] 210 to 260 mM trehalose, and

[1386] 5 to 50 mM histidine buffer,

[1387] wherein said pharmaceutical composition has a pH of 5-6,

[1388] and wherein said antibody-drug conjugate has the formula (IV)

[1389]

[1390] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[1391] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[1392] Embodiment 49: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1393] 5 to 15 mg / mL of said antibody-drug conjugate,

[1394] 2.5 to 10 mM methionine;

[1395] 0.3 to 0.8 g / L polysorbate 20;

[1396] 220 to 250 mM trehalose, and

[1397] 5 to 20 mM histidine buffer,

[1398] wherein said pharmaceutical composition has a pH of 5.2-5.8, and wherein said antibody-drug conjugate has the formula (IV)

[1399]

[1400] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[1401] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[1402] Embodiment 50: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1403] 8 to 12 mg / mL of said antibody-drug conjugate,

[1404] 4 to 6 mM methionine;

[1405] 0.4 to 0.6 g / L polysorbate 20;

[1406] 230 to 240 mM trehalose, and

[1407] 8 to 12 mM histidine buffer,

[1408] wherein said pharmaceutical composition has a pH of 5.4-5.6, and wherein said antibody-drug conjugate has the formula (IV)

[1409]

[1410] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[1411] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[1412] Embodiment 51: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1413] 10 mg / mL of an antibody-drug conjugate,

[1414] 5 mM methionine;

[1415] 0.5 g / L polysorbate 20;

[1416] 234 mM trehalose, and

[1417] 10 mM histidine buffer,

[1418] wherein said pharmaceutical composition has a pH of 5.5, and wherein said antibody-drug conjugate has the formula (IV)

[1419]

[1420] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;

[1421] and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[1422] Embodiment 52: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1423] 3 to 30 mg / mL of said antibody-drug conjugate;

[1424] a stabilizer, wherein said stabilizer is

[1425] 2.5 to 20 mM of methionine,

[1426] 0.6 to 4 g / L of ascorbic acid,

[1427] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[1428] or a mixture thereof;

[1429] a nonionic surfactant, wherein said nonionic surfactant is

[1430] 0.1 to 1.0 g / L of a polysorbate,

[1431] 3 to 10 g / L of a poloxamer,

[1432] or a mixture thereof; 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[1433] 5 to 50 mM of a buffer, wherein the buffer is

[1434] a histidine buffer at a pH of 5.0 to 6.5 or

[1435] an acetate buffer at a pH of 4.0 to 5.0;

[1436] wherein said antibody-drug conjugate has the formula (IV)

[1437]

[1438] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1439] Embodiment 53: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1440] 3 to 30 mg / mL of said antibody-drug conjugate;

[1441] a stabilizer, wherein said stabilizer is

[1442] 5 to 15 mM of methionine or

[1443] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1444] a nonionic surfactant, wherein said nonionic surfactant is

[1445] 0.3 to 0.8 g / L of polysorbate 20 or

[1446] 5 to 8 g / L of poloxamer 188;

[1447] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1448] 5 to 20 mM of a buffer, wherein the buffer is

[1449] a histidine buffer at a pH of 5.2 to 5.8 or

[1450] an acetate buffer at a pH of 4.0 to 5.0; wherein said antibody-drug conjugate has the formula (IV)

[1451]

[1452] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1453] Embodiment 54: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1454] 8 to 12 mg / mL of said antibody-drug conjugate;

[1455] a stabilizer, wherein said stabilizer is

[1456] 4 to 6 mM of methionine or

[1457] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1458] a nonionic surfactant, wherein said nonionic surfactant is

[1459] 0.4 to 0.6 g / L of polysorbate 20 or

[1460] 5 to 8 g / L of poloxamer 188;

[1461] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1462] 8 to 12 mM of a buffer, wherein the buffer is

[1463] a histidine buffer at a pH of 5.4 to 5.6 or

[1464] an acetate buffer at a pH of 4.2 to 4.8; wherein said antibody-drug conjugate has the formula (IV)

[1465]

[1466] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1467] Embodiment 55: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1468] 3 to 30 mg / mL of said antibody-drug conjugate,

[1469] 2.5 to 20 mM methionine;

[1470] 0.1 to 1.0 g / L polysorbate 20;

[1471] 210 to 260 mM trehalose, and

[1472] 5 to 50 mM histidine buffer,

[1473] wherein said pharmaceutical composition has a pH of 5-6,

[1474] and wherein said antibody-drug conjugate has the formula (IV)

[1475]

[1476] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1477] Embodiment 56: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1478] 5 to 15 mg / mL of said antibody-drug conjugate,

[1479] 2.5 to 10 mM methionine;

[1480] 0.3 to 0.8 g / L polysorbate 20;

[1481] 220 to 250 mM trehalose, and

[1482] 5 to 20 mM histidine buffer,

[1483] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[1484] and wherein said antibody-drug conjugate has the formula (IV)

[1485]

[1486] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1487] Embodiment 57: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1488] 8 to 12 mg / mL of said antibody-drug conjugate,

[1489] 4 to 6 mM methionine;

[1490] 0.4 to 0.6 g / L polysorbate 20; 230 to 240 mM trehalose, and

[1491] 8 to 12 mM histidine buffer,

[1492] wherein said pharmaceutical composition has a pH of 5.4-5.6,

[1493] and wherein said antibody-drug conjugate has the formula (IV)

[1494]

[1495] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1496] Embodiment 58: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1497] 10 mg / mL of an antibody-drug conjugate,

[1498] 5 mM methionine;

[1499] 0.5 g / L polysorbate 20;

[1500] 234 mM trehalose, and

[1501] 10 mM histidine buffer,

[1502] wherein said pharmaceutical composition has a pH of 5.5, and wherein said antibody-drug conjugate has the formula (IV)

[1503]

[1504] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1505] Embodiment 59: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1506] 3 to 30 mg / mL of said antibody-drug conjugate;

[1507] a stabilizer, wherein said stabilizer is

[1508] 2.5 to 20 mM of methionine,

[1509] 0.6 to 4 g / L of ascorbic acid,

[1510] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[1511] or a mixture thereof;

[1512] a nonionic surfactant, wherein said nonionic surfactant is

[1513] 0.1 to 1.0 g / L of a polysorbate,

[1514] 3 to 10 g / L of a poloxamer,

[1515] or a mixture thereof;

[1516] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[1517] 5 to 50 mM of a buffer, wherein the buffer is

[1518] a histidine buffer at a pH of 5.0 to 6.5 or

[1519] an acetate buffer at a pH of 4.0 to 5.0; wherein said antibody-drug conjugate has the formula (IV)

[1520]

[1521] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[1522] Embodiment 60: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1523] 3 to 30 mg / mL of said antibody-drug conjugate;

[1524] a stabilizer, wherein said stabilizer is

[1525] 5 to 15 mM of methionine or

[1526] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1527] a nonionic surfactant, wherein said nonionic surfactant is

[1528] 0.3 to 0.8 g / L of polysorbate 20 or

[1529] 5 to 8 g / L of poloxamer 188;

[1530] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1531] 5 to 20 mM of a buffer, wherein the buffer is

[1532] a histidine buffer at a pH of 5.2 to 5.8 or

[1533] an acetate buffer at a pH of 4.0 to 5.0; wherein said antibody-drug conjugate has the formula (IV)

[1534]

[1535] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[1536] Embodiment 61: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1537] 8 to 12 mg / mL of said antibody-drug conjugate;

[1538] a stabilizer, wherein said stabilizer is

[1539] 4 to 6 mM of methionine or

[1540] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1541] a nonionic surfactant, wherein said nonionic surfactant is

[1542] 0.4 to 0.6 g / L of polysorbate 20 or

[1543] 5 to 8 g / L of poloxamer 188;

[1544] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1545] 8 to 12 mM of a buffer, wherein the buffer is

[1546] a histidine buffer at a pH of 5.4 to 5.6 or

[1547] an acetate buffer at a pH of 4.2 to 4.8; wherein said antibody-drug conjugate has the formula (IV)

[1548]

[1549] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[1550] Embodiment 62: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1551] 3 to 30 mg / mL of said antibody-drug conjugate,

[1552] 2.5 to 20 mM methionine;

[1553] 0.1 to 1.0 g / L polysorbate 20;

[1554] 210 to 260 mM trehalose, and

[1555] 5 to 50 mM histidine buffer,

[1556] wherein said pharmaceutical composition has a pH of 5-6,

[1557] and wherein said antibody-drug conjugate has the formula (IV)

[1558]

[1559] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody mAb1 as disclosed herein. Embodiment 63: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1560] 5 to 15 mg / mL of said antibody-drug conjugate,

[1561] 2.5 to 10 mM methionine;

[1562] 0.3 to 0.8 g / L polysorbate 20;

[1563] 220 to 250 mM trehalose, and

[1564] 5 to 20 mM histidine buffer,

[1565] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[1566] and wherein said antibody-drug conjugate has the formula (IV)

[1567]

[1568] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[1569] Embodiment 64: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1570] 8 to 12 mg / mL of said antibody-drug conjugate,

[1571] 4 to 6 mM methionine;

[1572] 0.4 to 0.6 g / L polysorbate 20;

[1573] 230 to 240 mM trehalose, and

[1574] 8 to 12 mM histidine buffer,

[1575] wherein said pharmaceutical composition has a pH of 5.4-5.6, and wherein said antibody-drug conjugate has the formula (IV)

[1576]

[1577] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody is the antibody mAb1 as disclosed herein.

[1578] Embodiment 65: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1579] 10 mg / mL of an antibody-drug conjugate,

[1580] 5 mM methionine;

[1581] 0.5 g / L polysorbate 20;

[1582] 234 mM trehalose, and

[1583] 10 mM histidine buffer,

[1584] wherein said pharmaceutical composition has a pH of 5.5,

[1585] and wherein said antibody-drug conjugate has the formula (IV)

[1586]

[1587] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody is the antibody mAb1 as disclosed herein. Embodiment 66: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1588] 3 to 30 mg / mL of said antibody-drug conjugate;

[1589] a stabilizer, wherein said stabilizer is

[1590] 2.5 to 20 mM of methionine,

[1591] 0.6 to 4 g / L of ascorbic acid,

[1592] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[1593] or a mixture thereof;

[1594] a nonionic surfactant, wherein said nonionic surfactant is

[1595] 0.1 to 1.0 g / L of a polysorbate,

[1596] 3 to 10 g / L of a poloxamer,

[1597] or a mixture thereof;

[1598] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[1599] 5 to 50 mM of a buffer, wherein the buffer is

[1600] a histidine buffer at a pH of 5.0 to 6.5 or

[1601] an acetate buffer at a pH of 4.0 to 5.0;

[1602] wherein said antibody-drug conjugate has the formula (IV)

[1603]

[1604] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody Precemtabart. Embodiment 67: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1605] 3 to 30 mg / mL of said antibody-drug conjugate;

[1606] a stabilizer, wherein said stabilizer is

[1607] 5 to 15 mM of methionine or

[1608] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1609] a nonionic surfactant, wherein said nonionic surfactant is

[1610] 0.3 to 0.8 g / L of polysorbate 20 or

[1611] 5 to 8 g / L of poloxamer 188;

[1612] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1613] 5 to 20 mM of a buffer, wherein the buffer is

[1614] a histidine buffer at a pH of 5.2 to 5.8 or

[1615] an acetate buffer at a pH of 4.0 to 5.0;

[1616] wherein said antibody-drug conjugate has the formula (IV)

[1617]

[1618] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody Precemtabart. Embodiment 68: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1619] 8 to 12 mg / mL of said antibody-drug conjugate;

[1620] a stabilizer, wherein said stabilizer is

[1621] 4 to 6 mM of methionine or

[1622] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1623] a nonionic surfactant, wherein said nonionic surfactant is

[1624] 0.4 to 0.6 g / L of polysorbate 20 or

[1625] 5 to 8 g / L of poloxamer 188;

[1626] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1627] 8 to 12 mM of a buffer, wherein the buffer is

[1628] a histidine buffer at a pH of 5.4 to 5.6 or

[1629] an acetate buffer at a pH of 4.2 to 4.8;

[1630] wherein said antibody-drug conjugate has the formula (IV)

[1631]

[1632] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody is the antibody Precemtabart. Embodiment 69: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1633] 3 to 30 mg / mL of said antibody-drug conjugate,

[1634] 2.5 to 20 mM methionine;

[1635] 0.1 to 1.0 g / L polysorbate 20;

[1636] 210 to 260 mM trehalose, and

[1637] 5 to 50 mM histidine buffer,

[1638] wherein said pharmaceutical composition has a pH of 5-6,

[1639] and wherein said antibody-drug conjugate has the formula (IV)

[1640]

[1641] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody Precemtabart.

[1642] Embodiment 70: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1643] 5 to 15 mg / mL of said antibody-drug conjugate,

[1644] 2.5 to 10 mM methionine;

[1645] 0.3 to 0.8 g / L polysorbate 20;

[1646] 220 to 250 mM trehalose, and

[1647] 5 to 20 mM histidine buffer,

[1648] wherein said pharmaceutical composition has a pH of 5.2-5.8, and wherein said antibody-drug conjugate has the formula (IV)

[1649]

[1650] wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody is the antibody Precemtabart.

[1651] Embodiment 71: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1652] 8 to 12 mg / mL of said antibody-drug conjugate,

[1653] 4 to 6 mM methionine;

[1654] 0.4 to 0.6 g / L polysorbate 20;

[1655] 230 to 240 mM trehalose, and

[1656] 8 to 12 mM histidine buffer,

[1657] wherein said pharmaceutical composition has a pH of 5.4-5.6,

[1658] and wherein said antibody-drug conjugate has the formula (IV)

[1659]

[1660] wherein S is a sulfur atom of the antibody, and wherein n is between 7 and 8; wherein said antibody is the antibody Precemtabart. Embodiment 72: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1661] 10 mg / mL of an antibody-drug conjugate,

[1662] 5 mM methionine;

[1663] 0.5 g / L polysorbate 20;

[1664] 234 mM trehalose, and

[1665] 10 mM histidine buffer,

[1666] wherein said pharmaceutical composition has a pH of 5.5,

[1667] and wherein said antibody-drug conjugate has the formula (IV)

[1668]

[1669] wherein S is a sulfur atom of the antibody, and wherein n is between 7.5 and 8.0; wherein said antibody is the antibody Precemtabart.

[1670] Embodiment 73: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1671] 3 to 30 mg / mL of said antibody-drug conjugate;

[1672] a stabilizer, wherein said stabilizer is

[1673] 2.5 to 20 mM of methionine,

[1674] 0.6 to 4 g / L of ascorbic acid,

[1675] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[1676] or a mixture thereof;

[1677] a nonionic surfactant, wherein said nonionic surfactant is

[1678] 0.1 to 1.0 g / L of a polysorbate,

[1679] 3 to 10 g / L of a poloxamer,

[1680] or a mixture thereof; 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[1681] 5 to 50 mM of a buffer, wherein the buffer is

[1682] a histidine buffer at a pH of 5.0 to 6.5 or

[1683] an acetate buffer at a pH of 4.0 to 5.0;

[1684] wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[1685] Embodiment 74: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1686] 3 to 30 mg / mL of said antibody-drug conjugate;

[1687] a stabilizer, wherein said stabilizer is

[1688] 5 to 15 mM of methionine or

[1689] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1690] a nonionic surfactant, wherein said nonionic surfactant is

[1691] 0.3 to 0.8 g / L of polysorbate 20 or

[1692] 5 to 8 g / L of poloxamer 188;

[1693] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1694] 5 to 20 mM of a buffer, wherein the buffer is

[1695] a histidine buffer at a pH of 5.2 to 5.8 or

[1696] an acetate buffer at a pH of 4.0 to 5.0;

[1697] wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[1698] Embodiment 75: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1699] 8 to 12 mg / mL of said antibody-drug conjugate;

[1700] a stabilizer, wherein said stabilizer is

[1701] 4 to 6 mM of methionine or

[1702] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1703] a nonionic surfactant, wherein said nonionic surfactant is

[1704] 0.4 to 0.6 g / L of polysorbate 20 or

[1705] 5 to 8 g / L of poloxamer 188;

[1706] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and 8 to 12 mM of a buffer, wherein the buffer is

[1707] a histidine buffer at a pH of 5.4 to 5.6 or

[1708] an acetate buffer at a pH of 4.2 to 4.8;

[1709] wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[1710] Embodiment 76: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1711] 3 to 30 mg / mL of said antibody-drug conjugate,

[1712] 2.5 to 20 mM methionine;

[1713] 0.1 to 1.0 g / L polysorbate 20;

[1714] 210 to 260 mM trehalose, and

[1715] 5 to 50 mM histidine buffer,

[1716] wherein said pharmaceutical composition has a pH of 5-6,

[1717] and wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[1718] Embodiment 77: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1719] 5 to 15 mg / mL of said antibody-drug conjugate,

[1720] 2.5 to 10 mM methionine;

[1721] 0.3 to 0.8 g / L polysorbate 20;

[1722] 220 to 250 mM trehalose, and

[1723] 5 to 20 mM histidine buffer,

[1724] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[1725] and wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[1726] Embodiment 78: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1727] 8 to 12 mg / mL of said antibody-drug conjugate,

[1728] 4 to 6 mM methionine;

[1729] 0.4 to 0.6 g / L polysorbate 20;

[1730] 230 to 240 mM trehalose, and

[1731] 8 to 12 mM histidine buffer,

[1732] wherein said pharmaceutical composition has a pH of 5.4-5.6, and wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[1733] Embodiment 79: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1734] 10 mg / mL of an antibody-drug conjugate,

[1735] 5 mM methionine;

[1736] 0.5 g / L polysorbate 20;

[1737] 234 mM trehalose, and

[1738] 10 mM histidine buffer,

[1739] wherein said pharmaceutical composition has a pH of 5.5,

[1740] and wherein said antibody-drug conjugate is ADC1 as disclosed herein.

[1741] Embodiment 80: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1742] 3 to 30 mg / mL of said antibody-drug conjugate;

[1743] a stabilizer, wherein said stabilizer is

[1744] 2.5 to 20 mM of methionine,

[1745] 0.6 to 4 g / L of ascorbic acid,

[1746] 50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD),

[1747] or a mixture thereof;

[1748] a nonionic surfactant, wherein said nonionic surfactant is

[1749] 0.1 to 1.0 g / L of a polysorbate,

[1750] 3 to 10 g / L of a poloxamer,

[1751] or a mixture thereof;

[1752] 210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and

[1753] 5 to 50 mM of a buffer, wherein the buffer is

[1754] a histidine buffer at a pH of 5.0 to 6.5 or

[1755] an acetate buffer at a pH of 4.0 to 5.0;

[1756] wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1757] Embodiment 81: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1758] 3 to 30 mg / mL of said antibody-drug conjugate; a stabilizer, wherein said stabilizer is

[1759] 5 to 15 mM of methionine or

[1760] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1761] a nonionic surfactant, wherein said nonionic surfactant is

[1762] 0.3 to 0.8 g / L of polysorbate 20 or

[1763] 5 to 8 g / L of poloxamer 188;

[1764] 220 to 250 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1765] 5 to 20 mM of a buffer, wherein the buffer is

[1766] a histidine buffer at a pH of 5.2 to 5.8 or

[1767] an acetate buffer at a pH of 4.0 to 5.0;

[1768] wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1769] Embodiment 82: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1770] 8 to 12 mg / mL of said antibody-drug conjugate;

[1771] a stabilizer, wherein said stabilizer is

[1772] 4 to 6 mM of methionine or

[1773] 80 to 120 g / L of hydroxypropyl-β-cyclodextrin (HPpCD);

[1774] a nonionic surfactant, wherein said nonionic surfactant is

[1775] 0.4 to 0.6 g / L of polysorbate 20 or

[1776] 5 to 8 g / L of poloxamer 188;

[1777] 230 to 240 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose and mannitol; and

[1778] 8 to 12 mM of a buffer, wherein the buffer is

[1779] a histidine buffer at a pH of 5.4 to 5.6 or

[1780] an acetate buffer at a pH of 4.2 to 4.8;

[1781] wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1782] Embodiment 83: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1783] 3 to 30 mg / mL of said antibody-drug conjugate,

[1784] 2.5 to 20 mM methionine;

[1785] 0.1 to 1.0 g / L polysorbate 20;

[1786] 210 to 260 mM trehalose, and 5 to 50 mM histidine buffer,

[1787] wherein said pharmaceutical composition has a pH of 5-6,

[1788] and wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1789] Embodiment 84: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1790] 5 to 15 mg / mL of said antibody-drug conjugate,

[1791] 2.5 to 10 mM methionine;

[1792] 0.3 to 0.8 g / L polysorbate 20;

[1793] 220 to 250 mM trehalose, and

[1794] 5 to 20 mM histidine buffer,

[1795] wherein said pharmaceutical composition has a pH of 5.2-5.8,

[1796] and wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1797] Embodiment 85: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1798] 8 to 12 mg / mL of said antibody-drug conjugate,

[1799] 4 to 6 mM methionine;

[1800] 0.4 to 0.6 g / L polysorbate 20;

[1801] 230 to 240 mM trehalose, and

[1802] 8 to 12 mM histidine buffer,

[1803] wherein said pharmaceutical composition has a pH of 5.4-5.6,

[1804] and wherein said antibody-drug conjugate is Precemtabart tocentecan.

[1805] Embodiment 86: The pharmaceutical composition according to any one of embodiments 1 to 22, comprising

[1806] 10 mg / mL of an antibody-drug conjugate,

[1807] 5 mM methionine;

[1808] 0.5 g / L polysorbate 20;

[1809] 234 mM trehalose, and

[1810] 10 mM histidine buffer,

[1811] wherein said pharmaceutical composition has a pH of 5.5,

[1812] and wherein said antibody-drug conjugate is Precemtabart tocentecan. Embodiment 87: The pharmaceutical composition according to any one of embodiments 4 to 86, wherein n is the number of [linker–payload] moieties covalently linked to the antibody.

[1813] Embodiment 88: The pharmaceutical composition according to any one of embodiments 4 to 87, wherein n is a number of [linker–exatecan] moieties covalently linked to the antibody.

[1814] Embodiment 89: The pharmaceutical composition according to any one of embodiments 4 to 37 or 73 to 88, wherein n is between 1 and 10.

[1815] Embodiment 90: The pharmaceutical composition according to any one of embodiments 4 to 37 or 73 to 88, wherein n is between 4 and 8.

[1816] Embodiment 91: The pharmaceutical composition according to any one of embodiments 4 to 39, 41 to 42, 45 to 46, 48 to 49, 52 to 53, 55 to 56, 59 to 60, 62 to 63, 66 to 67, 69 to 70 or 73 to 88, wherein n is between 6 and 8.

[1817] Embodiment 92: The pharmaceutical composition according to any one of embodiments 4 to 43, 45 to 50, 52 to 57, 59 to 64, 66 to 71 or 73 to 88, wherein n is between 7 and 8.

[1818] Embodiment 93: The pharmaceutical composition according to any one of embodiments 4 to 88, wherein n is between 7.5 and 8.0.

[1819] Embodiment 94: The pharmaceutical composition according to any one of embodiments 4 to 88, wherein n is about 8.

[1820] Embodiment 95: The pharmaceutical composition according to any one of embodiments 4 to 88, wherein n is 8.

[1821] Embodiment 96: The pharmaceutical composition according to any one of embodiments 1 to 91, wherein said antibody-drug conjugate has a DAR (drug-to-antibody ratio) in a range of 7 to 8.

[1822] Embodiment 97: The pharmaceutical composition according to any one of embodiments 1 to 92, wherein said antibody-drug conjugate has a DAR (drug-to-antibody ratio) in a range of 7.5 to 8.0.

[1823] Embodiment 98: The pharmaceutical composition according to any one of embodiments 1 to 93, wherein said antibody-drug conjugate has a DAR (drug-to-antibody ratio) of about 8. Embodiment 99: The pharmaceutical composition according to any one of embodiments 1 to 94, wherein said antibody-drug conjugate has a DAR (drug-to-antibody ratio) of 8.

[1824] Embodiment 100: The pharmaceutical composition according to any one of embodiments 1 to 99, wherein n / the DAR is determined by a method based on photometric measurements.

[1825] Embodiment 101: The pharmaceutical composition according to any one of embodiments 1 to 99, wherein n / the DAR is determined by a method based on RP-HPLC (reversed-phase high performance liquid chromatography).

[1826] Embodiment 102: The pharmaceutical composition according to any one of embodiments 1 to 101, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) binds to human CEACAM5 protein.

[1827] Embodiment 103: The pharmaceutical composition according to any one of embodiments 1 to 102, wherein the antibody of the antibody-drug conjugate is directed against human CEACAM5 protein.

[1828] Embodiment 104: The pharmaceutical composition according to any one of embodiments 1 to 103, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,

[1829] Embodiment 105: The pharmaceutical composition according to any one of embodiments 1 to 37 and 87 to 104, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence of SEQ ID NO: 10.

[1830] Embodiment 106: The pharmaceutical composition according to any one of embodiments 1 to 44 and 87 to 105, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

[1831] Embodiment 107: The pharmaceutical composition according to any one of embodiments 1 to 44 and 87 to 106, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 95 % identical to the amino acid sequence of SEQ ID NO: 10.

[1832] Embodiment 108: The pharmaceutical composition according to any one of embodiments 1 to 107, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10.

[1833] Embodiment 109: The pharmaceutical composition according to any one of embodiments 1 to 44 and 87 to 108, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 85 % identical to the amino acid sequence of SEQ ID NO: 12.

[1834] Embodiment 110: The pharmaceutical composition according to any one of embodiments 1 to 44 and 87 to 109, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

[1835] Embodiment 111: The pharmaceutical composition according to any one of embodiments 1 to 51 and 87 to 110, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 95 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 95 % identical to the amino acid sequence of SEQ ID NO: 12.

[1836] Embodiment 112: The pharmaceutical composition according to any one of embodiments 1 to 111, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain constant region (CH) comprising the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising the amino acid sequence of SEQ ID NO: 12.

[1837] Embodiment 113: The pharmaceutical composition according to any one of embodiments 1 to 112, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1838] Embodiment 114: The pharmaceutical composition according to any one of embodiments 1 to 113, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1839] Embodiment 115: The pharmaceutical composition according to any one of embodiments 1 to 114, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) consists of two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

[1840] Embodiment 116: The pharmaceutical composition according to any one of embodiments 1 to 115, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) is mAb1.

[1841] Embodiment 117: The pharmaceutical composition according to any one of embodiments 1 to 116, wherein said antibody (i.e. said antibody of said antibody-drug conjugate) is the antibody Precemtabart.

[1842] Embodiment 118: The pharmaceutical composition according to any one of embodiments 1 to 117, wherein the antibody-drug conjugate comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VIII):

[1843]

[1844] wherein S is a sulfur atom of a cysteine of the antibody mAb1, and wherein n is a number of [linker–exatecan] moieties covalently linked to mAb1 and is between 1 and 10, preferably between 7 and 8.

[1845] Embodiment 119: The pharmaceutical composition according to any one of embodiments 1 to 118, wherein said antibody-drug conjugate binds to human CEACAM5 protein.

[1846] Embodiment 120: The pharmaceutical composition according to any one of embodiments 1 to 119, wherein said antibody-drug conjugate is ADC1.

[1847] Embodiment 121: The pharmaceutical composition according to any one of embodiments 1 to 120, wherein said antibody-drug conjugate is Precemtabart Tocentecan.

[1848] Embodiment 122: The pharmaceutical composition according to any one of embodiments 1 to 22, 31 or 87 to 121, wherein said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 1 to 50 mg / mL.

[1849] Embodiment 123: The pharmaceutical composition according to any one of embodiments 1 to 24, 26, 31, 33, 38 to 39, 41, 45 to 46, 48, 52 to 53, 55, 59 to 60, 62, 66 to 67, 69, 73 to 74, 76, 80 to 81, 83 or 87 to 122, wherein said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 3 to 30 mg / mL.

[1850] Embodiment 124: The pharmaceutical composition according to any one of embodiments 1 to 24, 26, 31, 33, 38 to 39, 41, 45 to 46, 48, 52 to 53, 55, 59 to 60, 62, 66 to 67, 69, 73 to 74, 76, 80 to 81, 83 or 87 to 123, wherein said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 5 to 25 mg / mL.

[1851] Embodiment 125: The pharmaceutical composition according to any one of embodiments 1 to 24, 26, 31, 33, 38 to 39, 41, 45 to 46, 48, 52 to 53, 55, 59 to 60, 62, 66 to 67, 69, 73 to 74, 76, 80 to 81, 83 or 87 to 124, wherein said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 8 to 18 mg / mL.

[1852] Embodiment 126: The pharmaceutical composition according to any one of embodiments 1 to 24, 26 to 27, 31, 33 to 34, 38 to 39, 41 to 42, 45 to 46, 48 to 49, 52 to 53, 55 to 56, 59 to 60, 62 to 63, 66 to 67, 69 to 70, 73 to 74, 76 to 77, 80 to 81, 83 to 84 or 87 to 125, wherein said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 5 to 15 mg / mL. Embodiment 127: The pharmaceutical composition according to any one of embodiments 1 to 28, 31, 33 to 35, 38 to 43, 45 to 50, 52 to 57, 59 to 64, 66 to 71, 73 to 78, 80 to 85 or 87 to 126, wherein said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 8 to 12 mg / mL.

[1853] Embodiment 128: The pharmaceutical composition according to any one of embodiments 1 to 29, 31, 33 to 36, 38 to 43, 45 to 50, 52 to 57, 59 to 64, 66 to 71, 73 to 78, 80 to 85 or 87 to 127, wherein said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of about 10 mg / mL.

[1854] Embodiment 129: The pharmaceutical composition according to any one of embodiments 1 to 128, wherein said pharmaceutical composition comprises said antibody-drug conjugate in a concentration of 10 mg / mL.

[1855] Embodiment 130: The pharmaceutical composition according to any one of embodiments 1 to 129, wherein the concentration of the stabilizer in the pharmaceutical composition is from 1 to 250 mM.

[1856] Embodiment 131: The pharmaceutical composition according to any one of embodiments 1 to 130, wherein the concentration of the stabilizer in the pharmaceutical composition is from 2 to 150 mM.

[1857] Embodiment 132: The pharmaceutical composition according to any one of embodiments 1 to 131, wherein the concentration of the stabilizer in the pharmaceutical composition is from 3 to 120 mM.

[1858] Embodiment 133: The pharmaceutical composition according to any one of embodiments 1 to 132, wherein the concentration of the stabilizer in the pharmaceutical composition is from 4 to 100 mM.

[1859] Embodiment 134: The pharmaceutical composition according to any one of embodiments 1 to 133, wherein said pharmaceutical composition comprises said stabilizer in a concentration of 2.5 to 20 mM.

[1860] Embodiment 135: The pharmaceutical composition according to any one of embodiments 1 to 134, wherein said pharmaceutical composition comprises said stabilizer in a concentration of 2.5 to 10 mM. Embodiment 136: The pharmaceutical composition according to any one of embodiments 1 to 135, wherein said pharmaceutical composition comprises said stabilizer in a concentration of 4 to 6 mM.

[1861] Embodiment 137: The pharmaceutical composition according to any one of embodiments 1 to 136, wherein said pharmaceutical composition comprises said stabilizer in a concentration of about 5 mM.

[1862] Embodiment 138: The pharmaceutical composition according to any one of embodiments 1 to 137, wherein said pharmaceutical composition comprises said stabilizer in a concentration of 5 mM.

[1863] Embodiment 139: The pharmaceutical composition according to any one of embodiments 1 to 138, wherein said pharmaceutical composition comprises said stabilizer in a concentration of 50 to 100 mM.

[1864] Embodiment 140: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 139, wherein said pharmaceutical composition comprises methionine, ascorbic acid, hydroxypropyl-β-cyclodextrin (HPpCD), or a mixture thereof.

[1865] Embodiment 141: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 140, wherein said pharmaceutical composition comprises methionine, ascorbic acid or hydroxypropyl-β-cyclodextrin (HPpCD).

[1866] Embodiment 142: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 141, wherein said pharmaceutical composition comprises methionine, hydroxypropyl-β-cyclodextrin (HPpCD), or a mixture thereof.

[1867] Embodiment 143: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 142, wherein said pharmaceutical composition comprises methionine and hydroxypropyl-β-cyclodextrin (HPpCD).

[1868] Embodiment 144: The pharmaceutical composition according to any one of embodiments 1 to 143, wherein the pharmaceutical composition comprises methionine.

[1869] Embodiment 145: The pharmaceutical composition according to any one of embodiments 1 to 144, wherein the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPPCD). Embodiment 146: The pharmaceutical composition according to any one of embodiments 1 to 145, wherein the pharmaceutical composition comprises ascorbic acid.

[1870] Embodiment 147: The pharmaceutical composition according to any one of embodiments 1 to 146, wherein said stabilizer is methionine.

[1871] Embodiment 148: The pharmaceutical composition according to any one of embodiments 1 to 146, wherein said stabilizer is hydroxypropyl-β-cyclodextrin (HPpCD).

[1872] Embodiment 149: The pharmaceutical composition according to any one of embodiments 1 to 146, wherein said stabilizer is ascorbic acid.

[1873] Embodiment 150: The pharmaceutical composition according to any one of embodiments 1 to 147, wherein the concentration of said methionine in the pharmaceutical composition is from 1 to 50 mM.

[1874] Embodiment 151: The pharmaceutical composition according to any one of embodiments 1 to 147, wherein the concentration of said methionine in the pharmaceutical composition is from 2 to 30 mM.

[1875] Embodiment 152: The pharmaceutical composition according to any one of embodiments 1 to 147, wherein the concentration of said methionine in the pharmaceutical composition is from 3 to 10 mM.

[1876] Embodiment 153: The pharmaceutical composition according to any one of embodiments 1 to 147, wherein the concentration of said methionine in the pharmaceutical composition is from 4 to 6 mM.

[1877] Embodiment 154: The pharmaceutical composition according to any one of embodiments 1 to 147, wherein the concentration of said methionine in the pharmaceutical composition is about 5 mM.

[1878] Embodiment 155: The pharmaceutical composition according to any one of embodiments 1 to 147, wherein the concentration of said methionine in the pharmaceutical composition is 5 mM.

[1879] Embodiment 156: The pharmaceutical composition according to any one of embodiments 1 to 146 or 148, wherein the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of 1 to 500 g / L. Embodiment 157: The pharmaceutical composition according to any one of embodiments 1 to 146 or 148, wherein the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of 5 to 250 g / L.

[1880] Embodiment 158: The pharmaceutical composition according to any one of embodiments 1 to 146 or 148, wherein the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of 50 to 150 g / L.

[1881] Embodiment 159: The pharmaceutical composition according to any one of embodiments 1 to 146 or 148, wherein the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of 80 to 120 g / L.

[1882] Embodiment 160: The pharmaceutical composition according to any one of embodiments 1 to 146 or 148, wherein the pharmaceutical composition comprises hydroxypropyl-β-cyclodextrin (HPpCD) in a concentration of about 100 g / L.

[1883] Embodiment 161: The pharmaceutical composition according to any one of embodiments 1 to 146 or 149, wherein the pharmaceutical composition comprises ascorbic acid in a concentration of 0.1 to 20 g / L.

[1884] Embodiment 162: The pharmaceutical composition according to any one of embodiments 1 to 146 or 149, wherein the pharmaceutical composition comprises ascorbic acid in a concentration of 0.4 to 10 g / L.

[1885] Embodiment 163: The pharmaceutical composition according to any one of embodiments 1 to 146 or 149, wherein the pharmaceutical composition comprises ascorbic acid in a concentration of 0.6 to 4 g / L.

[1886] Embodiment 164: The pharmaceutical composition according to any one of embodiments 1 to 146 or 149, wherein the pharmaceutical composition comprises ascorbic acid in a concentration of about 1 g / L.

[1887] Embodiment 165: The pharmaceutical composition according to any one of embodiments 1 to 147 or 149 to 155 or 161 to 164, wherein said pharmaceutical composition does not comprise hydroxypropyl-β-cyclodextrin (HPpCD). Embodiment 166: The pharmaceutical composition according to any one of embodiments 1 to 148 or 150 to 160 or 165, wherein said pharmaceutical composition does not comprise ascorbic acid.

[1888] Embodiment 167: The pharmaceutical composition according to any one of embodiments 1 to 166, wherein said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.1 to 1.0 g / L.

[1889] Embodiment 168: The pharmaceutical composition according to any one of embodiments 1 to 166, wherein said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.3 to 0.8 g / L.

[1890] Embodiment 169: The pharmaceutical composition according to any one of embodiments 1 to 166, wherein said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.4 to 0.6 g / L.

[1891] Embodiment 170: The pharmaceutical composition according to any one of embodiments 1 to 166, wherein said pharmaceutical composition comprises the nonionic surfactant in a concentration of about 0.5 g / L.

[1892] Embodiment 171: The pharmaceutical composition according to any one of embodiments 1 to 166, wherein said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.5 g / L.

[1893] Embodiment 172: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 166, wherein the nonionic surfactant is selected from the group consisting of a polysorbate, a poloxamer, and a mixture thereof.

[1894] Embodiment 173: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 166, wherein the nonionic surfactant is selected from the group consisting of a polysorbate selected from the group consisting of polysorbate 20 and polysorbate 80 or a poloxamer that is poloxamer 188 or a mixture thereof.

[1895] Embodiment 174: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 166, wherein said nonionic surfactant is a polysorbate.

[1896] Embodiment 175: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 166, wherein said polysorbate is polysorbate 20 or polysorbate 80. Embodiment 176: The pharmaceutical composition according to any one of embodiments 1 to 175, wherein said polysorbate is polysorbate 20.

[1897] Embodiment 177: The pharmaceutical composition according to any one of embodiments 1 to 30 or 33 to 166, wherein said nonionic surfactant is polysorbate 20 or polysorbate 80.

[1898] Embodiment 178: The pharmaceutical composition according to any one of embodiments 1 to 177, wherein said nonionic surfactant is polysorbate 20.

[1899] Embodiment 179: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate is present in the pharmaceutical composition in a concentration of 0.1 to 1 g / L.

[1900] Embodiment 180: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate is present in the pharmaceutical composition in a concentration of 0.3 to 0.8 g / L.

[1901] Embodiment 181: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate is present in the pharmaceutical composition in a concentration of 0.4 to 0.6 g / L.

[1902] Embodiment 182: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate is present in the pharmaceutical composition in a concentration of about 0.5 g / L.

[1903] Embodiment 183: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate is present in the pharmaceutical composition in a concentration of 0.5 g / L.

[1904] Embodiment 184: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate 20 is present in the pharmaceutical composition in a concentration of 0.1 to 1 g / L.

[1905] Embodiment 185: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate 20 is present in the pharmaceutical composition in a concentration of 0.3 to 0.8 g / L. Embodiment 186: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate 20 is present in the pharmaceutical composition in a concentration of 0.4 to 0.6 g / L.

[1906] Embodiment 187: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate 20 is present in the pharmaceutical composition in a concentration of about 0.5 g / L.

[1907] Embodiment 188: The pharmaceutical composition according to any one of embodiments 1 to 178, wherein the polysorbate 20 is present in the pharmaceutical composition in a concentration of 0.5 g / L.

[1908] Embodiment 189: The pharmaceutical composition according to any one of embodiments 1 to 188, wherein the poloxamer is present in the pharmaceutical composition in a concentration of 1 to 15 g / L.

[1909] Embodiment 190: The pharmaceutical composition according to any one of embodiments 1 to 188, wherein the poloxamer is present in the pharmaceutical composition in a concentration of 3 to 10 g / L.

[1910] Embodiment 191: The pharmaceutical composition according to any one of embodiments 1 to 188, wherein the poloxamer is present in the pharmaceutical composition in a concentration of 5 to 8 g / L.

[1911] Embodiment 192: The pharmaceutical composition according to any one of embodiments 1 to 188, wherein the poloxamer is present in the pharmaceutical composition in a concentration of about 6 g / L.

[1912] Embodiment 193: The pharmaceutical composition according to any one of embodiments 1 to 188, wherein the poloxamer is present in the pharmaceutical composition in a concentration of 6 g / L.

[1913] Embodiment 194: The pharmaceutical composition according to any one of embodiments 1 to 188, wherein said nonionic surfactant is poloxamer 188.

[1914] Embodiment 195: The pharmaceutical composition according to any one of embodiments 1 to 194, wherein said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of 210 to 260 mM. Embodiment 196: The pharmaceutical composition according to any one of embodiments 1 to 194, wherein said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of 220 to 250 mM.

[1915] Embodiment 197: The pharmaceutical composition according to any one of embodiments 1 to 194, wherein said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of 230 to 240 mM.

[1916] Embodiment 198: The pharmaceutical composition according to any one of embodiments 1 to 194, wherein said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of about 235 mM.

[1917] Embodiment 199: The pharmaceutical composition according to any one of embodiments 1 to 194, wherein said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of about 234 mM.

[1918] Embodiment 200: The pharmaceutical composition according to any one of embodiments 1 to 194, wherein said pharmaceutical composition comprises said sugar / sugar alcohol in a concentration of 234 mM.

[1919] Embodiment 201: The pharmaceutical composition according to any one of embodiments 1 to 200, wherein said pharmaceutical composition comprises a sugar.

[1920] Embodiment 202: The pharmaceutical composition according to any one of embodiments 1 to 201, wherein said pharmaceutical composition comprises no sugar alcohol.

[1921] Embodiment 203: The pharmaceutical composition according to any one of embodiments 1 to 194 or 201 to 202, wherein the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 20 to 400 mM.

[1922] Embodiment 204: The pharmaceutical composition according to any one of embodiments 1 to 194 or 201 to 202, wherein the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 100 to 350 mM.

[1923] Embodiment 205: The pharmaceutical composition according to any one of embodiments 1 to 194 or 201 to 202, wherein the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 150 to 300 mM. Embodiment 206: The pharmaceutical composition according to any one of embodiments 1 to 194 or 201 to 202, wherein the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 200 to 260 mM.

[1924] Embodiment 207: The pharmaceutical composition according to any one of embodiments 1 to 194 or 201 to 202, wherein the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 230 to 240 mM.

[1925] Embodiment 208: The pharmaceutical composition according to any one of embodiments 1 to 194 or 201 to 202, wherein the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of about 235 mM.

[1926] Embodiment 209: The pharmaceutical composition according to any one of embodiments 1 to 194 or 201 to 202, wherein the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of about 234 mM.

[1927] Embodiment 210: The pharmaceutical composition according to any one of embodiments 1 to 194 or 201 to 202, wherein the sugar and / or sugar alcohol is present in the pharmaceutical composition in a concentration of 234 mM.

[1928] Embodiment 211: The pharmaceutical composition according to any one of embodiments 1 to 210, wherein said pharmaceutical composition comprises a disaccharide.

[1929] Embodiment 212: The pharmaceutical composition according to any one of embodiments 1 to 211, wherein the sugar and / or sugar alcohol is a disaccharide.

[1930] Embodiment 213: The pharmaceutical composition according to any one of embodiments 210 or 211, wherein the disaccharide is selected from the group consisting of trehalose, maltose, sucrose, and a mixture thereof.

[1931] Embodiment 214: The pharmaceutical composition according to any one of embodiments 210 or 211, wherein the disaccharide is trehalose.

[1932] Embodiment 215: The pharmaceutical composition according to any one of embodiments 210 or 211, wherein the disaccharide is trehalose-dihydrate.

[1933] Embodiment 216: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar and / or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof. Embodiment 217: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar and / or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, and a mixture thereof.

[1934] Embodiment 218: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar and / or sugar alcohol is trehalose.

[1935] Embodiment 219: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar and / or sugar alcohol is trehalose-dihydrate.

[1936] Embodiment 220: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar / sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof.

[1937] Embodiment 221: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar / sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, and a mixture thereof.

[1938] Embodiment 222: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar / sugar alcohol is selected from the groups consisting of trehalose, mannitol and a mixture thereof.

[1939] Embodiment 223: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar / sugar alcohol is trehalose.

[1940] Embodiment 224: The pharmaceutical composition according to any one of embodiments 1 to 215, wherein the sugar / sugar alcohol is trehalose-dihydrate.

[1941] Embodiment 225: The pharmaceutical composition according to any one of embodiments 1 to 224, wherein the sugar and / or sugar alcohol is mannitol.

[1942] Embodiment 226: The pharmaceutical composition according to any one of embodiments 1 to 224, wherein the sugar alcohol is mannitol.

[1943] Embodiment 227: The pharmaceutical composition according to any one of embodiments 1 to 226, wherein said pharmaceutical composition comprises the trehalose in a concentration of 210 to 260 mM. Embodiment 228: The pharmaceutical composition according to any one of embodiments 1 to 226, wherein said pharmaceutical composition comprises the trehalose in a concentration of 220 to 250 mM.

[1944] Embodiment 229: The pharmaceutical composition according to any one of embodiments 1 to 226, wherein said pharmaceutical composition comprises the trehalose in a concentration of 230 to 240 mM.

[1945] Embodiment 230: The pharmaceutical composition according to any one of embodiments 1 to 226, wherein said pharmaceutical composition comprises the trehalose in a concentration of about 235 mM.

[1946] Embodiment 231: The pharmaceutical composition according to any one of embodiments 1 to 226, wherein said pharmaceutical composition comprises the trehalose in a concentration of about 234 mM.

[1947] Embodiment 232: The pharmaceutical composition according to any one of embodiments 1 to 226, wherein said pharmaceutical composition comprises the trehalose in a concentration of 234 mM.

[1948] Embodiment 233: The pharmaceutical composition according to any one of embodiments 1 to 232, wherein said pharmaceutical composition comprises 5 to 50 mM of said buffer.

[1949] Embodiment 234: The pharmaceutical composition according to any one of embodiments 1 to 232, wherein said pharmaceutical composition comprises 5 to 20 mM of said buffer.

[1950] Embodiment 235: The pharmaceutical composition according to any one of embodiments 1 to 232, wherein said pharmaceutical composition comprises 8 to 12 mM of said buffer.

[1951] Embodiment 236: The pharmaceutical composition according to any one of embodiments 1 to 232, wherein said pharmaceutical composition comprises about 10 mM of said buffer.

[1952] Embodiment 237: The pharmaceutical composition according to any one of embodiments 1 to 232, wherein said pharmaceutical composition comprises 10 mM of said buffer.

[1953] Embodiment 238: The pharmaceutical composition according to any one of embodiments 1 to 237, wherein the buffer is selected from the group consisting of acetate buffer, succinate buffer, lactate buffer, 2-(N-morpholino)ethanesulfonic acid (MES) buffer, histidine buffer, and a mixture thereof. Embodiment 239: The pharmaceutical composition according to any one of embodiments 1 to 237, wherein the buffer is selected from the group consisting of acetate buffer, histidine buffer, and a mixture thereof.

[1954] Embodiment 240: The pharmaceutical composition according to any one of embodiments 1 to 239, wherein the buffer is selected from the group consisting of acetate buffer at a pH of 3.5 to 5.5 and histidine buffer at a pH of 4.0 to 7.0.

[1955] Embodiment 241: The pharmaceutical composition according to any one of embodiments 1 to 240, wherein said buffer is a histidine buffer.

[1956] Embodiment 242: The pharmaceutical composition according to any one of embodiments 23 to 241, wherein the histidine buffer is a histidine buffer at a pH of 5.0 to 6.5.

[1957] Embodiment 243: The pharmaceutical composition according to any one of embodiments 23 to 241, wherein the histidine buffer is a histidine buffer at a pH of 5.3 to 5.7.

[1958] Embodiment 244: The pharmaceutical composition according to any one of embodiments 23 to 241, wherein the histidine buffer is a histidine buffer at a pH of about 5.5.

[1959] Embodiment 245: The pharmaceutical composition according to any one of embodiments 23 to 241, wherein the histidine buffer is a histidine buffer at a pH of 5.5.

[1960] Embodiment 246: The pharmaceutical composition according to any one of embodiments 23 to 245, wherein the histidine buffer is prepared by mixing histidine base with hydrochloric acid.

[1961] Embodiment 247: The pharmaceutical composition according to any one of embodiments 23 to 245, wherein the histidine buffer is prepared by forming a suitable mixture of L-histidine-HCl-H2O and L-histidine.

[1962] Embodiment 248: The pharmaceutical composition according to any one of embodiments 23 to 245, wherein the histidine buffer is prepared from a suitable mixture of 7.6 mM L-histidine-HCl-H2O and 2.4 mM L-histidine.

[1963] Embodiment 249: The pharmaceutical composition according to any one of embodiments 1 to 248, wherein said buffer is an acetate buffer. Embodiment 250: The pharmaceutical composition according to any one of embodiments 23 to 248, wherein the acetate buffer is an acetate buffer at a pH of 3.5 to 5.0.

[1964] Embodiment 251: The pharmaceutical composition according to any one of embodiments 23 to 248, wherein the acetate buffer is an acetate buffer at a pH of 4.0 to 5.0.

[1965] Embodiment 252: The pharmaceutical composition according to any one of embodiments 23 to 248, wherein the acetate buffer is an acetate buffer at a pH of 4.2 to 4.8.

[1966] Embodiment 253: The pharmaceutical composition according to any one of embodiments 23 to 248, wherein the acetate buffer is an acetate buffer at a pH of about 4.5.

[1967] Embodiment 254: The pharmaceutical composition according to any one of embodiments 23 to 248, wherein the acetate buffer is an acetate buffer at a pH of 4.5.

[1968] Embodiment 255: The pharmaceutical composition according to any one of embodiments 1 to 254, wherein the buffer is a histidine buffer and the concentration of said histidine buffer in the pharmaceutical composition is from about 1 to 50 mM.

[1969] Embodiment 256: The pharmaceutical composition according to any one of embodiments 23 to 255, wherein the concentration of said histidine buffer in the pharmaceutical composition is from about 5 to 30 mM.

[1970] Embodiment 257: The pharmaceutical composition according to any one of embodiments 23 to 255, wherein the concentration of said histidine buffer in the pharmaceutical composition is from about 5 to 20 mM.

[1971] Embodiment 258: The pharmaceutical composition according to any one of embodiments 23 to 255, wherein the concentration of said histidine buffer in the pharmaceutical composition is about 10 mM.

[1972] Embodiment 259: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein said pharmaceutical composition has a pH of 5.0 to 6.5.

[1973] Embodiment 260: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein said pharmaceutical composition has a pH of 5-6.

[1974] Embodiment 261: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein said pharmaceutical composition has a pH of 5.2-5.8. Embodiment 262: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein said pharmaceutical composition has a pH of 5.3 to 5.7.

[1975] Embodiment 263: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein said pharmaceutical composition has a pH of 5.4-5.6.

[1976] Embodiment 264: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein said pharmaceutical composition has a pH of about 5.5.

[1977] Embodiment 265: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein said pharmaceutical composition has a pH of 5.5.

[1978] Embodiment 266: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein the pharmaceutical composition is an aqueous solution with a pH of 4.5 to 7.0.

[1979] Embodiment 267: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein the pharmaceutical composition is an aqueous solution with a pH of 5.0 to 6.0.

[1980] Embodiment 268: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein the pharmaceutical composition is an aqueous solution with a pH of 5.3 to 5.7.

[1981] Embodiment 269: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein the pharmaceutical composition is an aqueous solution with a pH of 5.4 to 5.6.

[1982] Embodiment 270: The pharmaceutical composition according to any one of embodiments 1 to 258, wherein the pharmaceutical composition is an aqueous solution with a pH of about 5.5.

[1983] Embodiment 271: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium chloride (NaCl) at a concentration of more than 50 mM. Embodiment 272: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 20 mM.

[1984] Embodiment 273: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 10 mM.

[1985] Embodiment 274: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 5 mM.

[1986] Embodiment 275: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 2 mM.

[1987] Embodiment 276: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium chloride at a concentration of more than 1 mM.

[1988] Embodiment 277: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition is essentially free of sodium chloride.

[1989] Embodiment 278: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not contain sodium chloride.

[1990] Embodiment 279: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium ions at a concentration of more than 50 mM.

[1991] Embodiment 280: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium ions at a concentration of more than 20 mM.

[1992] Embodiment 281: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium ions at a concentration of more than 10 mM. Embodiment 282: The pharmaceutical composition according to any one of embodiments 1 to 270, wherein the pharmaceutical composition does not comprise sodium ions at a concentration of more than 5 mM.

[1993] Embodiment 283: The pharmaceutical composition according to a...

Claims

CLAIMS1. A pharmaceutical composition comprising3 to 30 mg / mL of a antibody-drug conjugate;a stabilizer, wherein said stabilizer is2.5 to 20 mM of methionine,0.6 to 4 g / L of ascorbic acid,50 to 150 g / L of hydroxypropyl-β-cyclodextrin (HPpCD), or a mixture thereof;a nonionic surfactant, wherein said nonionic surfactant is0.1 to 1.0 g / L of a polysorbate,3 to 10 g / L of a poloxamer,or a mixture thereof;210 to 260 mM of a sugar or sugar alcohol, wherein said sugar or sugar alcohol is selected from the group consisting of trehalose, maltose, sucrose, mannitol, and a mixture thereof; and5 to 50 mM of a buffer, wherein the buffer isa histidine buffer at a pH of 5.0 to 6.5 oran acetate buffer at a pH of 4.0 to 5.0;wherein said antibody-drug conjugate has the formula (IV)wherein S is a sulfur atom of the antibody, and wherein n is between 6 and 8; wherein said antibody binds to human CEACAM5 protein,wherein said antibody comprises a CDR1-H consisting of the amino acid sequence of SEQ ID NO: 3, a CDR2-H consisting of the amino acid sequence of SEQ ID NO: 4, a CDR3-H consisting of the amino acid sequence of SEQ ID NO: 5, a CDR1-L consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2-L consisting ofthe amino acid sequence of SEQ ID NO: 7, and a CDR3-L consisting of the amino acid sequence of SEQ ID NO: 8,and wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 10.

2. The pharmaceutical composition according to claim 1, whereinthe stabilizer is 2.5 to 20 mM methionine;the nonionic surfactant is 0.1 to 1.0 g / L polysorbate 20;the sugar or sugar alcohol is 210 to 260 mM trehalose, andthe buffer is 5 to 50 mM histidine buffer,wherein said pharmaceutical composition has a pH of 5-6.

3. The pharmaceutical composition according to any one of claims 1 or 2, wherein said antibody of said antibody-drug conjugate comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 10;and wherein said antibody of said antibody-drug conjugate comprises a heavy chain constant region (CH) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 11 and a light chain constant region (CL) comprising an amino acid sequence that is at least 90 % identical to the amino acid sequence of SEQ ID NO: 12.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein said antibody comprises two identical heavy chains (HC) comprising the amino acid sequence of SEQ ID NO: 13 and two identical light chains (LC) comprising the amino acid sequence of SEQ ID NO: 14.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein said pharmaceutical composition comprises said methionine in a concentration of 2.5 to6. The pharmaceutical composition according to any one of claims 1 to 5, wherein said pharmaceutical composition comprises said methionine in a concentration of 4 to 6 mM.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein said pharmaceutical composition comprises the nonionic surfactant in a concentration of 0.3 to 0.8 g / L.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein said pharmaceutical composition comprises the polysorbate 20 in a concentration of about 0.5 g / L.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein said pharmaceutical composition comprises said trehalose in a concentration of 220 to 250 mM.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein said pharmaceutical composition comprises said trehalose in a concentration of 230 to 240 mM.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein said pharmaceutical composition comprises 5 to 20 mM of said histidine buffer.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein said pharmaceutical composition comprises 8 to 12 mM of said histidine buffer.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein said pharmaceutical composition has a pH of 5.2-5.8.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein said pharmaceutical composition has a pH of 5.4-5.6.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition is an aqueous solution.

16. The pharmaceutical composition according to any one of embodiments 1 to 15 for use in therapy.

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