WO2025242845A1 - Colorectal cancer treatment - Google Patents

Abstract

The present invention provides methods, compounds, compositions and kits for the treatment of colorectal cancer using anti-CEACAM5 immunoconjugates according to preferred dosing regimens.

Description

COLORECTAL CANCER TREATMENT

TECHNICAL FIELD

The present invention provides methods, compounds, compositions and kits for the treatment of colorectal cancer, in particular metastatic colorectal cancer, using anti-CEACAM5 immunoconjugates according to preferred dosing regimens.

BACKGROUND

Colorectal cancer (CRC) is the third most common cancer type in the world in terms of incidence and the second one in terms of mortality, with an estimated 1 ,800,000 new cases and 881 ,000 deaths in 2018. Approximately 25% of patients present with metastases at initial diagnosis and approximately 50% of patients with early stage disease will develop metastases, which contribute to the high mortality rates reported for CRC.

Therapy for patients with metastatic CRC (mCRC) has mostly palliative intention, except for patients with limited metastatic disease in the liver for whom a surgical approach with curative intent may be used. Systemic therapy for mCRC typically pairs a chemotherapy backbone regimen with a biologic agent. Oxaliplatin, irinotecan and 5-fluorouracil commonly form the chemotherapy backbone in various regimens of two-drug or three-drug regimens. A biologic agent such as anti-vascular endothelial cell growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR) antibody is added to the chemotherapy regimen depending on tumourspecific and patient-specific factors. Molecular testing of the tumour is required before considering treatment with anti-EGFR antibodies such as cetuximab and panitumumab. Mutations in hot spot regions of exons 2, 3 and 4 of KRAS or of NRAS genes (occurring in approximately 55% of mCRC patients) and the BRAF-V600E mutation (occurring in approximately 5-15% of mCRC patients) have been associated with lack of benefit from anti- EGFR treatment (Ducreux 2019; Martinelli 2020; Pietrantonio 2015). Additionally, “sidedness” of the tumour has a key role in the metastatic setting and is increasingly recognised as a predictive marker of response to anti-EGFR drugs, with left sided tumours demonstrating better outcome (Dekker 2019).

Participants with mCRC typically receive several lines of therapy. In clinical practice, of all mCRC patients receiving first-line chemotherapy, approximately 50% go on to receive second line chemotherapy, and of these patients, approximately 25% go on to receive third-line chemotherapy (Walter 2020). This “continuum of treatment” with several subsequent lines of therapy has led to an improvement of the clinical outcome for patients with mCRC, in the last decade. Today, the median overall survival (OS) for patients with mCRC is approximately 30 months; more than double that of 20 years ago (Cervantes 2023).

Most patients with mCRC will eventually become insensitive or unresponsive to first- and second-line chemotherapy (chemo-refractory) or will not tolerate multiple cycles of chemotherapy (chemo-intolerant). The treatment options available in chemo-refractory mCRC in the third-line (3L) setting are limited.

Therapies such as regorafenib and trifluridine/tipiracil are recommended as 3L+ treatments for mCRC. The reported objective response rate (ORR) is less than 5%, with a median OS benefit of only 1 to 2 months compared with placebo (Weinberg 2016). Trifluridine/tipiracil (FTD/TPI, TAS-102) is recommended in patients pre-treated with fluoropyrimidines, oxaliplatin, irinotecan, and biologies if available or in earlier lines of therapy following oxaliplatin and irinotecan regimen failure (Xu 2018).

Additionally, a recently published phase 3 study randomly assigned, in a 1 :1 ratio, mCRC patients who had received no more than two previous chemotherapy regimens to receive trifluridine/tipiracil plus bevacizumab or trifluridine/tipiracil alone and demonstrated a significant overall survival prolongations for patients receiving the combination regimen (median overall survival was 10.8 months in the combination group and 7.5 months in the trifluridine/tipiracil group; HR: 0.61 ; 95% Cl, 0.49 to 0.77; P<0.001) (Prager 2023). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% Cl, 0.36 to 0.54; P<0.001) (Prager 2023).

A randomized phase 3 study assigned, in a 2:1 ratio, patients with metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both to receive fruquintinib (5 mg capsule) or matched placebo. In this population fruquintinib treatment resulted in a significant and clinically meaningful overall survival prolongation compared with placebo (7.4 months (95% Cl 6.7-8.2) in the fruquintinib group versus 4.8 months (4.0-5.8) in the placebo group (HR 0 66, 95% Cl 0-55-0 80; p<0 0001) (Dasari 2023). Median progression-free survival was 3.7 months (95% Cl 3.5-3.8) in the fruquintinib group versus 1.8 months (1.8-1 .9) in the placebo group (absolute difference 1.9 months; HR 0.32, 95% Cl 0.27-0.39; p<0.0001). Fruquitinib is now approved in the USA, while EMA evaluation is ongoing.

Encorafenib in combination with cetuximab is also approved for the treatment of adult patients with metastatic CRC with a BRAFV600E mutation, who have received prior systemic therapy, based on the results of the BEACON study (Tabernero 2021). A further 3L alternative is to rechallenge with chemotherapy or biologicals previously discontinued owing to toxicity or PD (Masuishi 2020). High-quality evidence for this strategy is limited.

For patients in 3L+ disease setting the main recommendation is to include patients in clinical trials (Arnold 2018) and also as per NCCN Clinical Practice Guidelines recommendation for CRC (NCCN CRC 2023).

Thus, at present there are very limited options for the treatment of patients with colorectal cancer, especially metastatic colorectal cancer, who have undergone previous rounds of treatment, such as patients in 3L+ disease settings. Novel treatment options are required that provide improved treatment outcomes (e.g. longer progression-free survival), and/or allow to achieve therapeutic effects with less side effects for such patients.

The present disclosure addresses the above-described problems and needs by the different aspects and embodiments described below.

SUMMARY OF THE INVENTION

The present invention is, in part, based on the surprising observation that anti-CEACAM5 immunoconjugates as described herein (such as the immunoconjugate M9140, which is composed of a CEACAM5-specific antibody conjugated to a B-glucuronide-exatecan linkerpayload), if administered at a specific dosing regimen, address the above-described problems and needs of the prior art by providing excellent therapeutic effects on patients with colorectal cancer, in particular metastatic colorectal cancer, while having a rather favourable spectrum of side effects. In particular, the present inventors made the unexpected observation that these anti-CEACAM5 immunoconjugates, if administered with a dosing regimen of about 2.4-2.8 mg/kg Q3W, provide a surprising combination of superior therapeutic effects (as determined e.g. by progression-free survival) with acceptable side effects in patients with colorectal cancer, such as patients with 3+L metastatic colorectal cancer.

The present invention relates to embodiments described in the claims as well as in the further description herein below.

Thus, in an aspect, the present disclosure relates to a method of treating colorectal cancer, said method comprising administering to a patient in need thereof an anti-CEACAM5 immunoconjugate according to a dosing regimen as defined below.

In another aspect, the present disclosure relates to an anti-CEACAM5 immunoconjugate according to the present disclosure for use in the treatment of colorectal cancer according to a dosing regimen as defined below. In another aspect, the present disclosure relates to an anti-CEACAM5 immunoconjugate according to the present disclosure for use in the treatment of colorectal cancer according to a method which comprises administering said immunoconjugate according to a dosing regimen as defined below.

In another aspect, the present disclosure relates to the use of an anti-CEACAM5 immunoconjugate according to the present disclosure for the preparation of a medicament for the treatment of colorectal cancer wherein the immunoconjugate is to be administered according to a dosing regimen as defined below.

In another aspect, the present disclosure relates to the use of an anti-CEACAM5 immunoconjugate according to the present disclosure for the treatment of colorectal cancer according to a dosing regimen as defined below.

In another aspect, the present disclosure relates to a method of treating colorectal cancer, said method comprising administering to a patient in need thereof a pharmaceutical composition as disclosed herein according to a dosing regimen as defined herein.

In another aspect, the present disclosure relates to a pharmaceutical composition for the treatment of colorectal cancer according to a dosing regimen as defined herein.

In another aspect, the present disclosure relates to a pharmaceutical composition for use in the treatment of colorectal cancer according to a method which comprises administering said pharmaceutical composition according to a dosing regimen as defined herein.

In another aspect, the present disclosure relates to the use of a pharmaceutical composition for the preparation of a medicament for the treatment of colorectal cancer wherein the pharmaceutical composition is to be administered according to a dosing regimen as defined herein.

In another aspect, the present disclosure relates to the use of a pharmaceutical composition for the treatment of colorectal cancer according to a dosing regimen as defined herein.

In another aspect, the present disclosure relates to a kit for the treatment of colorectal cancer, said kit comprising a pharmaceutical composition comprising an anti-CEACAM5 immunoconjugate; and instructions for using the pharmaceutical composition for said treatment of colorectal cancer according to a dosing regimen as defined herein. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 : First line therapy of metastatic CRC (Cervantes et al; Ann Oncol. 2023;34(1):10-32.)

Figure 2: Second line therapy of metastatic CRC (Cervantes et al; Ann Oncol. 2023;34(1):10-32.)

Figure 3: Management of stage IV unresectable mCRC in third-line therapy and beyond (Cervantes et al; Ann Oncol. 2023;34(1): 10-32.)

Figure 4: Summary of key eligibility criteria, dose escalation scheme and key endpoints of clinical trial NCT05464030. The study is a Phase 1 , open-label, multicenter trial of M9140 in patients with metastatic colorectal cancer (mCRC).

Figure 5: Baseline and demographic characteristics.

Figure 6: Dose-limiting toxicities (DLTs).

Figure ?: Safety profile.

Figure 8: Change in tumor burden from baseline (best overall response).

Figure 9: Treatment duration and response over time.

Figure 10: Kaplan-Meier estimates of progression-free survival.

Figure 11 : Treatment duration.

Figure 12: Objective Response (waterfall plot).

Figure 13: Objective Response.

Figure 14: Safety overview.

Figure 15: Progression-free survival (Kaplan-Meier Estimates).

Figure 16: Most common treatment-emergent adverse events (TEAEs) by grade.

Figure 17: Most common treatment-emergent adverse events (TEAEs) and treatment- related adverse events (TRAEs). SUMMARY OF SEQUENCES

DETAILED DESCRIPTION OF THE INVENTION

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.

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.

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. Definitions

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:

MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQHL FGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYTLHVIK SDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSLPV SPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPLNTSY RSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQAHNSDTGLNR TTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRLQLS NDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDDPTISPSYTYYRPGVNLSL SCHAASNPPAQYSWLIDGNIQQHTQELFISNITEKNSGLYTCQANNSASGHSRTTVKTITVSA ELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLTLF NVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTPIISPPDSSYLSGANLNLSCHSASNP SPQYSWRINGIPQQHTQVLFIAKITPNNNGTYACFVSNLATGRNNSIVKSITVSASGTSPGLS AGATVGIMIGVLVGVALI (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).

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".

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

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

A reference sequence of Macaca fascicularis CEACAM5 protein is available (NCBI Reference Sequence XP_005589491.1), and this amino acid sequence reads as follows: mgspsap//7n4zc/pwqf///fas//ffwnppftaqltiesrpfnvaegkevlllahnvsqnlfgyiwykgervdasrrigscvirtqqitpg pahsgretidfnasllihnvtqsdtgsytiqvikedlvneeatgqfrvypelpkpyissnnsnpvedkdavaltcepetqdttylwwv nnqslpvsprlelssdnrtltvfniprndttsykcetqnpvsvrrsdpvtlnvlygpdaptisplntpyragenlnlschaasnptaqyf wfvngtfqqstqelfipnitvnnsgsymcqahnsatglnrttvtaitvyaelpkpyitsnnsnpiedkdavtltcepetqdttylw wvnnqslsvssrlelsndnrtltvfniprndttfyecetqnpvsvrrsdpvtlnvlygpdaptisplntpyragenlnlsch aasnpaaqyswfvngtfqqstqelfipnitvnnsgsymcqahnsatglnrttvtaitvyvelpkpyissnnsnpiedkdav tltcepvaenttylwwvnnqslsvsprlqlsngnriltllsvtrndtgpyecgiqnsesakrsdpvtlnvtygpdtpiisppdlsyrsgan Inlschsdsnpspqvswlinatlrqhtqvlfiskitsnnnaavacfvsnlatamnsivknisvssadsapgssalsaratvqiiiqmlv qvalm (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).

A "coding sequence" or a sequence "encoding" an expression product, such as a polypeptide, protein, or enzyme, is a nucleotide sequence that, when expressed, results in the production of that polypeptide, protein, or enzyme, i.e. , the nucleotide sequence encodes an amino acid sequence for that polypeptide, protein or enzyme. A coding sequence for a protein may include a start codon (usually ATG) and a stop codon.

As used herein, references to specific proteins (e.g. antibodies) can include a polypeptide having a native amino acid sequence, as well as variants and modified forms regardless of their origin or mode of preparation. A protein which has a native amino acid sequence is a protein having the same amino acid sequence as obtained from nature. Such native sequence proteins can be isolated from nature or can be prepared using standard recombinant and/or synthetic methods. Native sequence proteins specifically encompass naturally occurring truncated or soluble forms, naturally occurring variant forms (e.g. alternatively spliced forms), naturally occurring allelic variants and forms including post-translational modifications. Native sequence proteins include proteins carrying post-translational modifications such as glycosylation, or phosphorylation, or other modifications of some amino acid residues.

The term "gene" means a DNA sequence that codes for, or corresponds to, a particular sequence of amino acids which comprises all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine for example the conditions under which the gene is expressed. Some genes, which are not structural genes, may be transcribed from DNA to RNA, but are not translated into an amino acid sequence. Other genes may function as regulators of structural genes or as regulators of DNA transcription. In particular, the term gene may be intended for the genomic sequence encoding a protein, i.e. a sequence comprising regulator, promoter, intron and exon sequences.

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).

A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain with similar chemical properties (e.g., charge, size or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. Examples of groups of amino acids that have side chains with similar chemical properties include 1 ) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine and methionine. Conservative amino acid substitution groups can also be defined on the basis of amino acid size.

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 (I) and kappa (k). 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.

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.

"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.

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; www.imgt.org).

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. 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. A monoclonal antibody may be produced 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.

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. A chimeric antibody may also denote a multispecific antibody having specificity for at least two different antigens.

The term "humanized antibody" refers to an antibody which is wholly or partially of non-human 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.

"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.

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.

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.

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. 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 of 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 stabilised by a disulphide bond. "(dsFv)2" denotes two dsFv coupled by a peptide linker.

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 2 050 764 A1 .

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

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.

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.

By "purified" or "isolated" it is meant, when referring to a polypeptide (e.g. an antibody) or a nucleotide sequence, that the indicated molecule is present in the substantial absence of other biological macromolecules of the same type. The term "purified" as used herein means at least 75%, 85%, 95%, 96%, 97%, or 98% by weight, of biological macromolecules of the same type are present. An "isolated" nucleic acid molecule which encodes a particular polypeptide refers to a nucleic acid molecule which is substantially free of other nucleic acid molecules that do not encode the subject polypeptide; however, the molecule may include some additional bases or moieties which do not deleteriously affect the basic characteristics of the composition.

"Administration" and "treatment," as it applies to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. "Administration" and "treatment" also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human. “Treatment”, as used in a clinical setting, is intended for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cells, inhibiting metastasis of neoplastic cells, shrinking or decreasing the size of tumor, remission of a disease (e.g., cancer), decreasing symptoms resulting from a disease (e.g., cancer), increasing the quality of life of those suffering from a disease (e.g., cancer), decreasing the dose of other medications required to treat a disease (e.g., cancer), delaying the progression of a disease (e.g., cancer), curing a disease (e.g., cancer), and/or prolong survival of patients having a disease (e.g., cancer).

As used herein, the term "subject" denotes a mammal, such as a rodent, a feline, a canine, a primate or a human. In embodiments of the present disclosure, the subject (or patient) is a human.

As used herein the term “single pharmaceutical agent” means any composition that comprising a single substance as the only active pharmaceutical ingredient in the composition.

Treatment of colorectal cancer

The present disclosure relates inter alia to the treatment of colorectal cancer by administration of an immunoconjugate according to a specific dosing regimen, and related aspects of such a treatment as described in more detail below.

Colorectal cancer, Patient

The cancer to be treated by the methods of the present disclosure is colorectal cancer, preferably locally advanced or metastatic colorectal cancer.

The colorectal cancer to be treated by the methods of the present disclosure may be of different stage and there is no specific limitation with respect to the time since initial cancer diagnosis.

Typically, the colorectal cancer to be treated by the methods of the present disclosure is locally advanced or metastatic colorectal cancer. There is no limitation to the site of the primary tumor of the metastatic colorectal cancer, it may e.g. be the colon or rectum. The patient to be treated is not particularly limited, provided that he/she is a cancer with colorectal cancer as described above.

Usually, the patient is a human, preferably an adult human.

The patient may have undergone treatment for colorectal cancer by other treatment options before. The treatment may be 1 L treatment or later. Typically, it is 2L treatment or later, preferably 3L treatment or later. The previous treatment(s) may have been by any generally approved colorectal cancer treatment of clinical practice, such as e.g. treatment with of Cetuximab, Panitumumab, Bevacizumab, Fluorouracil, Oxaliplatin and/or Irinotecan.

Treatment, Dosing Regimen

The patient is treated by administration of an immunoconjugate according to a specific dosing regimen.

The immunoconjugate (or pharmaceutical composition comprising such an immunoconjugate) is typically administered by intravenous (i.v., IV) administration according to standard clinical practice known to the skilled person.

As described in more detail in the Examples section and the different aspects and embodiments below, administration according to the present disclosure occurs by a specific dosing regimen defining a specific amount of immunoconjugate being administered at certain time intervals (e.g. "2.4 mg/kg Q3W"). Specific dosing regimens for use in the present disclosure are defined in particular in embodiments 58 to 126 and 236 to 199 below.

A skilled person is aware how to understand thus dosing regimens.

By way of example, a dosing regimen of "2.4 mg/kg Q3W" means that 2.4 mg of the compound to be administered are administered to the patient under treatment per kg of body weight of the patient, and this amount is administered in a single dose every three weeks (i.e. at the first day of the treatment and then again in regular intervals every time 21 days (3 weeks x 7 days/week = 21 days) have expired (counting including the day when the administration occurred that started the counting of the 21 days). For example, 2.4 mg of the compound per kg of patient body weight are administered on day 1 (the day when treatment starts); then 2.4 mg of the compound per kg of patient body weight are administered again on day 22 (counted from the beginning of treatment); then 2.4 mg of the compound per kg of patient body weight are administered again on day 43 (counted from the beginning of treatment) etc.

Unless explicitly stated otherwise, all dosing amounts and dosing intervals mentioned in the numbered embodiments of the present disclosure refer to the amount and dosing intervals of the immunoconjugate. Thus, for example, a statement that a "dosing regimen is 2.4 mg/kg Q3W" means that 2.4 mg/kg of the immunoconjugate are administered Q3W, i.e. this statement is to be understood as "dosing regimen is 2.4 mg of said immunoconjugate per kg of patient body weight administered Q3W".

Immunoconjugate

Colorectal cancer typically overexpresses the molecule CEACAM5. CEACAM5 (GenBank accession number AAA51967.1 ; human CEACAM5 protein sequence provided as SEQ ID NO: 1) is a cell surface glycoprotein that modulates cell adhesion, differentiation, and proliferation. The molecule has limited expression in adult healthy tissues, but is overexpressed in various adenocarcinomas, particularly in CRC (>90% of patients).

According to the present disclosure, the colorectal cancer is treated by administration of an anti-CEACAM5 immunoconjugate. Different immunoconjugates that may be used in the treatment of the present disclosure are defined in embodiments 29 to 57 below.

The terms "immunoconjugate" and "antibody-drug conjugate" (ADC) are used interchangeably herein. As used herein, an immunoconjugate is a molecule that comprises an antibody covalently linked via a linker to at least one growth inhibitory agent (the term antibody is used broadly herein and also includes e.g. antibody fragments, such as Fabs, or ScFvs). An anti- CECAM5 immunoconjugate is an immunoconjugate with an antibody having specificity for CEACAM5.

An anti-CEACAM5 immunoconjugate to be used in methods according to the present disclosure may comprise an anti-CEACAM5 antibody, such as those described in international patent application PCT/EP2021/072595 (published as WO 2022/048883 A1 , title "Anti- CEACAM5 Antibodies and Conjugates and Uses Thereof"), which is herewith incorporated by reference in its entirety into this specification.

The anti-CEACAM5 antibodies described in international patent application PCT/EP2021/072595 display a combination of several characteristics that make them ideally suited for use in cancer therapy, in particular as part of an immunoconjugate (antibody-drug conjugate). For instance, these antibodies display high affinity for human CEACAM5 protein, and they do not significantly cross-react with human CEACAM1 , CEACAM6, CEACAM7 and CEACAM8 proteins. These antibodies and preferred embodiments thereof are further described in the following.

A preferred antibody for use in the immunoconjugate to be used according to the present disclosure binds to human CEACAM5 protein and comprises a CDR1-H (Complementaritydetermining region 1 of the heavy chain) 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 (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 (NCBI Reference Sequence XP_005589491.1 ; Macaca fascicularis CEACAM5 protein sequence provided as SEQ ID NO: 2).

In 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

EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYF NPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSS (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 EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARF SGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIK (SEQ ID NO: 10) (CDRs shown in bold characters).

In 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.

In 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

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPPVAGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPG (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 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12).

In 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. In more specific embodiments, the antibody of the immunoconjugate according to the present disclosure is an isolated 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

EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYF NPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPPVAGPSVFLFP PKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPG (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 EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARF SGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (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.

In some embodiments, one or more individual amino acids of an antibody of the immunoconjugate according to 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.

In some embodiments, the antibody of the immunoconjugate according to the present disclosure is an isolated 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.

In some embodiments, the antibody of the immunoconjugate according to the present disclosure binds to the A2-B2 domains of human and Macaca fascicularis CEACAM5. Also considered may be an antibody which competes 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).

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.

In some embodiments, the antibody of the immunoconjugate according to the present disclosure 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 crossreact with the extracellular domain of the aforementioned human and Macaca fascicularis CEACAM proteins other than CEACAM5.

"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). 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.

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 ECso 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.

In some embodiments, an antibody of the immunoconjugate according to the present disclosure 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.

In some embodiments, the antibody of the immunoconjugate according to the present disclosure has an affinity for human CEACAM5 or Macaca fascicularis CEACAM5, or both, which is < 10nM; for instance, the antibody of the immunoconjugate according to the present disclosure 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.

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.

Alternatively, for the antibody of the immunoconjugate according to the present disclosure, an apparent dissociation constant (apparent KD) may be determined by FACS analysis e.g. on tumor cell line MKN45 (DSMZ, ACC 409).

Additionally, antibodies for use in the immunoconjugate of the present disclosure 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.

Any combination of the embodiments described herein above and below forms part of the present disclosure. In some embodiments, the antibody of the immunoconjugate is a conventional antibody, such as a conventional monoclonal antibody, or an antibody fragment, a bispecific or multispecific antibody.

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

In some embodiments, the antibody of the immunoconjugate according to the present disclosure may be e.g. 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 charateristics of the parental antibody.

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

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 disclosure.

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 of the immunoconjugate according to the present disclosure 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.

The antibodies of the immunoconjugate of the present disclosure can 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.

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 present disclosure 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.

The antibody can e.g. be expressed from a nucleic acid sequence encoding the antibody in a suitable expression system.

The term "expression system" means a host cell and compatible vector under suitable conditions, e.g. for the expression of a protein coded for by foreign DNA carried by the vector and introduced to the host cell.

Common expression systems include E. coli host cells and plasmid vectors, insect host cells and Baculovirus vectors, and mammalian host cells and vectors. Other examples of host cells include, without limitation, prokaryotic cells (such as bacteria) and eukaryotic cells (such as yeast cells, mammalian cells, insect cells, plant cells, etc.). Specific examples include E. coli, Kluyveromyces or Saccharomyces yeasts, mammalian cell lines (e.g., Vero cells, CHO cells, 3T3 cells, COS cells, etc.) as well as primary or established mammalian cell cultures (e.g., produced from lymphoblasts, fibroblasts, embryonic cells, epithelial cells, nervous cells, adipocytes, etc.). Examples also include mouse SP2/0-Ag14 cell (ATCC CRL1581 ), mouse P3X63-Ag8.653 cell (ATCC CRL1580), CHO cell in which a dihydrofolate reductase gene (hereinafter referred to as "DHFR gene") is defective (llrlaub G et al; 1980), rat YB2/3HL.P2.G11.16Ag.2O cell (ATCC CRL1662, hereinafter referred to as “YB2/0 cell"), and the like. In some embodiments, the YB2/0 cell is used, since ADCC activity of chimeric or humanized antibodies is enhanced when expressed in this cell.

For expression of a humanized antibody, the expression vector may be either of a type in which a gene encoding an antibody heavy chain and a gene encoding an antibody light chain exists on separate vectors or of a type in which both genes exist on the same vector (tandem type). In respect of easiness of construction of a humanized antibody expression vector, easiness of introduction into animal cells, and balance between the expression levels of antibody H and L chains in animal cells, a humanized antibody expression vector is of the tandem type Shitara K et al. J Immunol Methods. 1994 Jan. 3;167(1-2):271-8). Examples of tandem type humanized antibody expression vector include pKANTEX93 (WO 97/10354), pEE18 and the like.

Antibodies of the present disclosure can be suitably separated from the culture medium by conventional immunoglobulin purification procedures such as, for example, protein A- Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

A humanized chimeric antibody can be produced by obtaining nucleic acid sequences encoding humanized VL and VH regions as previously described, constructing a human chimeric antibody expression vector by inserting them into an expression vector for animal cell having genes encoding human antibody CH and human antibody CL, and expressing the coding sequence by introducing the expression vector into an animal cell.

As the CH domain of a human chimeric antibody, any region which belongs to human immunoglobulin heavy chains may be used, for instance those of IgG class are suitable and any one of subclasses belonging to IgG class, such as lgG1 , lgG2, lgG3 and lgG4, can be used. Also, as the CL of a human chimeric antibody, any region which belongs to human immunoglobulin light chains may be used, and those of kappa class or lambda class can be used. Methods for producing humanized or chimeric antibodies may involve conventional recombinant DNA and gene transfection techniques are well known in the art (see e.g. Morrison SL. et al. (1984) and patent documents US5,202,238; and US5,204, 244).

Methods for producing humanized antibodies based on conventional recombinant DNA and gene transfection techniques are well known in the art (see, e. g., Riechmann L. et al. 1988; Neuberger MS. et al. 1985). Antibodies can be humanized using a variety of techniques known in the art including, for example, the technique disclosed in the application W02009/032661 , CDR-grafting (EP 239,400; PCT publication WO91/09967; U.S. Pat. Nos. 5,225,539; 5,530,101 ; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan EA (1991 ); Studnicka GM et al. (1994); Roguska MA. et al. (1994)), and chain shuffling (U.S. Pat. No.5, 565, 332). The general recombinant DNA technology for preparation of such antibodies is also known (see European Patent Application EP 125023 and International Patent Application WO 96/02576).

A Fab can be obtained by treating an antibody of the immunoconjugate according to the present disclosure (e.g. an IgG) with a protease, such as papaine. Also, the Fab can be produced by inserting DNA sequences encoding both chains of the Fab of the antibody into a vector for prokaryotic expression, or for eukaryotic expression, and introducing the vector into prokaryotic or eukaryotic cells (as appropriate) to express the Fab.

A F(ab')2 can be obtained treating an antibody of the immunoconjugate according to the present disclosure (e.g. an IgG) with a protease, pepsin. Also, the F(ab')2 can be produced by binding a Fab' described below via a thioether bond or a disulfide bond.

A Fab' can be obtained by treating F(ab')2 of the present disclosure with a reducing agent, such as dithiothreitol. Also, the Fab' can be produced by inserting DNA sequences encoding Fab' chains of the antibody into a vector for prokaryotic expression, or a vector for eukaryotic expression, and introducing the vector into prokaryotic or eukaryotic cells (as appropriate) to perform its expression.

A scFv can be produced by taking sequences of the CDRs or VH and VL domains as previously described for the antibody of the immunoconjugate according to the present disclosure, then constructing a DNA encoding a scFv fragment, inserting the DNA into a prokaryotic or eukaryotic expression vector, and then introducing the expression vector into prokaryotic or eukaryotic cells (as appropriate) to express the scFv. To generate a humanized scFv fragment, a well-known technology called CDR grafting may be used, which involves selecting the complementary determining regions (CDRs) according to the disclosure, and grafting them onto a human scFv fragment framework of known three dimensional structure (see, e. g., W098/45322; WO 87/02671 ; US5, 859,205; US5,585,089; US4,816,567; EP0173494). Amino acid sequence modification(s) of the antibodies described herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody.

Modifications and changes may be made in the structure of the antibodies of the immunoconjugate according to the present disclosure, and in the DNA sequences encoding them, and still result in a functional antibody or polypeptide with desirable characteristics.

In making the changes in the amino sequences of polypeptide, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index for the interactive biologic function of a protein is generally understood in the art. It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like. Each amino acid has been assigned a hydropathic index on the basis of their hydrophobicity and charge characteristics these are: isoleucine (+4.5); valine (+4.2); leucine (+3.8) ; phenylalanine (+2.8); cysteine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

Moreover, function-conservative variants are considered.

For example, certain amino acids may be substituted by other amino acids in a protein structure without appreciable loss of activity. Since the interactive capacity and nature of a protein define its biological functional activity, certain amino acid substitutions can be made in a protein sequence, and of course in its encoding DNA sequence, while nevertheless obtaining a protein with like properties. It is thus contemplated that various changes may be made in the antibody sequences of the present disclosure, or corresponding DNA sequences which encode said polypeptides, without appreciable loss of their biological activity.

It is known in the art that certain amino acids may be substituted by other amino acids having a similar hydropathic index or score and still result in a protein with similar biological activity, i.e. still obtain a biological functionally equivalent protein. It is also possible to use well- established technologies, such as alanine-scanning approaches, to identify, in an antibody or polypeptide of the present disclosure, all the amino acids that can be substituted without significant loss of binding to the antigen. Such residues can be qualified as neutral, since they are not involved in antigen binding or in maintaining the structure of the antibody. One or more of these neutral positions can be substituted by alanine or by another amino acid can without changing the main characteristics of the antibody or polypeptide of the present disclosure. Neutral positions can be seen as positions where any amino acid substitution could be incorporated. Indeed, in the principle of alanine-scanning, alanine is chosen since it this residue does not carry specific structural or chemical features. It is generally admitted that if an anlanine can be substituted for a specific amino acid without changing the properties of a protein, many other, if not all amino acid substitutions are likely to be also neutral. In the opposite case where alanine is the wild-type amino acid, if a specific substitution can be shown as neutral, it is likely that other substitutions would also be neutral.

As outlined above, amino acid substitutions are generally based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions which take any of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.

It may be also desirable to modify the antibody of the immunoconjugate according to the present disclosure with respect to effector function, e.g. so as to enhance antigen-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) of the antibody, or e.g. to alter the binding to Fc receptors. This may be achieved by introducing one or more amino acid substitutions in an Fc region of the antibody. Alternatively or additionally, cysteine residue(s) may be introduced in the Fc region, thereby allowing inter-chain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and/or antibodydependent cellular cytotoxicity (ADCC) (Caron PC. et al. 1992; and Shopes B. 1992). In some embodiments, an antibody of the immunoconjugate according to the present disclosure may be an antibody with a modified amino acid sequence that results in reduced or eliminated binding to most Fey receptors, which can reduce uptake and toxicity in normal cells and tissues expressing such receptors, e.g. macrophages, liver sinusoidal cells etc. An example for such an antibody is one including substitutions of two leucine (L) residues to alanine (A) at position 234 and 235 (i.e. LALA); this double substitution has been demonstrated to reduce Fc binding to FcyRs and consequently to decrease ADCC as well to reduce complement binding/activation. Another example for such an antibody is one including the substitution P329G in addition to the LALA double substitution (i.e. PG-LALA; see e.g. Schlothauer et al., Novel human lgG1 and lgG4 Fc-engineered antibodies with completely abolished immune effector functions, Protein Engineering, Design and Selection, Volume 29, Issue 10, October 2016, Pages 457-466). In some embodiments, an antibody of the immunoconjugate according to the present disclosure may thus be an antibody having an amino acid sequence that (i) contains e.g. the LALA or the PG-LALA set of substitutions and (ii) is otherwise identical to the amino acid sequence of one of the antibodies of the present disclosure described herein above with reference to the respective SEQ ID NOs.

Another type of amino acid modification of the antibody of the immunoconjugate according to the present disclosure may be useful for altering the original glycosylation pattern of the antibody, i.e. by deleting one or more carbohydrate moieties found in the antibody, and/or adding one or more glycosylation sites that are not present in the antibody. The presence of either of the tripeptide sequences asparagine-X-serine, and asparagine-X-threonine, where X is any amino acid except proline, creates a potential glycosylation site. Addition or deletion of glycosylation sites to the antibody can conveniently be accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites).

Another type of modification involves the removal of sequences identified, either in silico or experimentally, as potentially resulting in degradation products or heterogeneity of antibody preparations. As examples, 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, in particular Asn-Gly, is present in an antibody or polypeptide, it may therefore be considered to remove the site, typically by conservative substitution to remove one of the implicated residues. Such substitutions in a sequence to remove one or more of the implicated residues are also intended to be encompassed by the present disclosure.

Another type of covalent modification involves chemically or enzymatically coupling glycosides to the antibody. These procedures are advantageous in that they do not require production of the antibody in a host cell that has glycosylation capabilities for N-or O-linked glycosylation. Depending on the coupling mode used, the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, orhydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine. For example, such methods are described in W087/05330.

Removal of carbohydrate moieties present on the antibody may be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the antibody to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N- acetylgalactosamine), while leaving the antibody intact. Chemical deglycosylation is described by Sojahr H. et al. (1987) and by Edge, AS. et al. (1981). Enzymatic cleavage of carbohydrate moieties on antibodies can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura, NR. et al. (1987).

Another type of covalent modification of the antibody comprises linking the antibody to one of a variety of non-proteinaceous polymers, e.g. polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, e.g. in the manner set forth in US Patent Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791 ,192 or 4,179,337.

Other amino acid sequence modifications known in the art may also be applied to an antibody of the immunoconjugate according to the present disclosure.

A particularly preferred anti-CEACAM5 antibody in the immunoconjugate for the methods of the present disclosure is monoclonal antibody mAb1 (heavy chain CDR1-3 provided as SEQ ID NO: 3-5; light chain CDR1-3 provided as SEQ ID NO: 6-8; sequence of variable domains VH and VL provided as SEQ ID NO: 9 and 10, respectively; sequence of constant domains CH and CL provided as SEQ ID NO: 11 and 12, respectively; heavy chain and light chain amino acid sequence provided as SEQ ID NO: 13 and 14).

The structure and preparation of mAb1 is described in detail in international patent application PCT/EP2021/072595 (published as WO 2022/048883 A1), see in particular Example 1 of PCT/EP2021/072595.

The present disclosure provides the following DNA sequences encoding the antibody mAb1: mAb1 heavy chain nucleotide sequence wherein mVk signal peptide is underlined, start and stop codons are in italics,

VH region sequence in boldface, and

CDRs are indicated with double underlining:

ATGGAGACCGACACCCTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCCGGGTCGACC GGTGAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCT GTCCCTCACCTGCACTGTCTCTGATGGCTCCGTCAGCAGGGGTGGTTACTACTTGACC TGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGT GGGAGCACCTACTTCAACCCGTCCCTCAGGAGTCGGGTTACCATGTCAGTAGACACG TCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTG TATTACTGTGCGAGAGGGATAGCAGTGGCTCCCTTTGACTACTGGGGCCAGGGAACC CTGGTCACCGTCTCTTCAGCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCA GCAGCAAGTCCACAAGCGGAGGAACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACT TCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGCGTGCACA CCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAG TGCCAAGCAGCAGCCTGGGAACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAG CAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCATACCTGT

CCACCCTGCCCAGCCCCCCCAGTGGCCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGC

CCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACG

TGAGCCACGAGGACCCAGAGGTGAAGTTCAATTGGTATGTGGACGGCGTGGAGGTGCA

CAACGCCAAGACCAAGCCCAGAGAGGAACAGTACAACAGCACCTACAGGGTGGTGTCC

GTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCT

CCAACAAGGCCCTGCCCTCCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCC

ACGGGAGCCCCAGGTGTACACACTGCCCCCATCTCGGGAAGAAATGACCAAGAACCAG

GTGTCCCTGACCTGTCTGGTGAAGGGCTTTTACCCCAGCGACATCGCCGTGGAGTGGG

AGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGA CGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGC

AACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACACAGAAGA

GCCTGAGCCTGTCCCCCGGC TGA

(SEQ ID NO: 15) mAb1 light chain nucleotide sequence wherein uPA signal peptide is underlined, start and stop codons are in italics,

VL region sequence in boldface, and

CDRs are indicated with double underlining:

ATGAGGGCCCTGCTGGCTAGACTGCTGCTGTGCGTGCTGGTCGTGTCCGACAGCAAGG

GCGAAATCGTACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAG

CCACCCTCTCCTGCAGGACCAGTCAGAGTGTTCGCAGCAACTTAGCCTGGTACCAGC

AGAAGCCTGGCCAGGCTCCCAGGCTCCTCATCTATGCTGCATCCACCAGGGCCACTG

GTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCA

GCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATACTAACTGGCC

ATTCACTTTCGGCCCTGGGACCAAAGTGGACATCAAACGTACGGTGGCTGCACCATCT

GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTG CCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC

TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC

GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGG

GAGAGTGT TGA TAG

(SEQ ID NO: 16) Also preferred as antibody in the immunoconjugate of the present disclosure is for example an antibody with the same six CDRs as mAb1 , but otherwise divergent amino acid sequence.

Examples of variant antibodies related to mAb1 that may be considered as antibodies in the immunoconjugate for use in the methods of the present disclosure are for example Variant 1 to 10, rb8G4 and hu8G4. The heavy chain (HC) and light chain (HC) amino acid sequences of such antibodies (insofar as they deviate from the HC and LC sequences of mAb1 ) are provided in the Summary of Sequences above. For more details about these variant antibodies, including their full sequences, reference is made to international patent application PCT/EP2021/072595 (for Variants 1 to 10, see e.g. Example 1.5 on pages 55-57 of WO 2022/048883 A1).

In the immunoconjugate to be used in the methods of the present disclosure, an anti-CECAM5 antibody as described above (such as mAb1 , or an antibody with the same six CDRs as mAb1 ) is covalently linked via a linker to at least one growth inhibitory agent.

Suitable methods for preparing immunoconjugates are known in the art. The immunoconjugates of the present disclosure may be prepared by in vitro methods, e.g. as described in the Examples section of international patent application PCT/EP2021/072595 (published as WO 2022/048883 A1).

The term "growth inhibitory agent" (also referred to as an "anti-proliferative 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.

Typically, the growth inhibitory agent is a cytotoxic drug (also referred to as a cytotoxic agent).

The most preferred cytotoxic drug in the immunoconjugate for the present disclosure is exatecan. However, other cytotoxic drugs as described below may also be considered.

The term "cytotoxic drug" as used herein refers to a substance that directly or indirectly inhibits or prevents the function of cells and/or causes destruction of the cells. The term "cytotoxic drug" includes e.g. 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.

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 thereof such as topotecan, irinotecan, silatecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan and rubitecan.

In some embodiments, the immunoconjugates of the present disclosure comprise the cytotoxic drug exatecan as the growth inhibitory agent. Exatecan has the chemical name (1 S,9S)-1- Amino-9-ethyl-5-fluoro-1 ,2,3,9, 12, 15-hexahydro-9-hydroxy-4-methyl-10/7, 13/7- benzo(de)pyrano(3',4':6,7)indolizino(1 ,2-b)quinoline-10,13-dione. Exatecan is represented by the following structural formula (I):

Formula (I)

In further embodiments of the present disclosure, 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 which is incorporated by reference.

The term "radioactive moiety" refers to a chemical entity (such as a molecule, compound or composition) that comprises or consists of a radioactive isotope suitable for treating cancer, such as At²¹¹, Bi²¹², Er¹⁶⁹, I¹³¹, I¹²⁵, Y⁹⁰, In¹¹¹, P³², Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Sr⁸⁹, or radioactive isotopes of Lu. Such radioisotopes generally emit mainly beta-radiation. In some embodiments, the radioactive isotope is an alpha-emitter isotope, for example Thorium 227 which emits alpha-radiation. Immunoconjugates can be prepared e.g. as described in the application WO2004/091668.

In the immunoconjugate to be used in the methods of the present disclosure, an anti- CEACAM5 antibody as described above is covalently linked via a linker to the at least one growth inhibitory agent. "Linker", as used herein, means a chemical moiety comprising a covalent bond and/or any chain of atoms that covalently attaches the growth inhibitory agent to the antibody. 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. Conjugation of an antibody of the immunoconjugate according to the present disclosure with cytotoxic drugs or other growth inhibitory agents may be performed e.g. using a variety of bifunctional protein coupling agents including but not limited to 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). Carbon labeled 1-isothiocyanatobenzyl methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to an antibody (WO 94/11026).

In embodiments of the present disclosure, the linker may be a "cleavable linker", which may facilitate release of the cytotoxic drug or other growth inhibitory agent inside of or in the vicinity of a cell, e.g. a tumor cell. In some embodiments, the linker is a linker cleavable in an endosome of a mammalian cell. For example, 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.

When referring to a structural formula representing an immunoconjugate, the following nomenclature is also used herein: a growth inhibitory agent and a linker, taken together, are also referred to as a [(linker)-(growth inhibitory agent)] moiety; for instance, an exatecan molecule and a linker, taken together, are also referred to as a [(linker)-(exatecan)] moiety.

In some specific embodiments of the present disclosure, the linker is a linker cleavable by the human enzyme glucuronidase. For example, an immunoconjugate of the present disclosure may thus have the following formula (II) which includes a linker cleavable by glucuronidase:

Formula (II), wherein the antibody is the antibody of the immunoconjugate according to the present disclosure, wherein S is a sulfur atom of the antibody, and wherein n is a number of [(linker)— (growth inhibitory agent)] moieties covalently linked to the antibody. The number n 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 the antibody. In some embodiments, the antibody is mAb1 .

The number n is also referred to as "drug-to-antibody ratio" (or "DAR"); this number n is always to be understood as an average number for any given (preparation of an) immunoconjugate.

In other specific embodiments of the present disclosure, the linker is a linker cleavable by the human enzyme legumain. For example, an immunoconjugate of the present disclosure may thus have the following formula (III) which includes a linker cleavable by legumain:

Formula (III), wherein the is the of the immunoconjugate according to the present disclosure, wherein S is a sulfur atom of the antibody, and wherein n is a number of [(linker)— (growth inhibitory agent)] 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, S is a sulfur atom of a cysteine of the antibody. In some embodiments, the antibody is mAb1.

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

In any one of the embodiments with linkers cleavable by glucuronidase or legumain, as described above, the growth inhibitory agent may be exatecan, for example.

Accordingly, in some embodiments, the immunoconjugate to be used in the methods of the present disclosure comprises an antibody of the immunoconjugate according to the present disclosure covalently linked via a linker to exatecan, wherein the conjugate has the following formula (IV):

Formula (IV), 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. In particularly preferred embodiments, the antibody in Formula (IV) is mAb1 , S is a sulfur atom of a cysteine of the antibody mAb1 , and 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.

In other embodiments, the immunoconjugate comprises an antibody of the immunoconjugate according to the present disclosure covalently linked via a linker to exatecan, wherein the conjugate has the following formula (V):

Formula (V), 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.

In some embodiments, in an immunoconjugate 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 lgG1 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 I gG 1 or has the same number of interchain disulfide bonds as an IgG 1 .

Accordingly, in some embodiments, the immunoconjugate to be used in the methods of the present disclosure comprises an antibody of the immunoconjugate according to the present disclosure covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VI):

Formula (VI), 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).

In other embodiments, the immunoconjugate comprises an antibody of the immunoconjugate according to the present disclosure covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VII):

Formula (VII), 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). In any of the immunoconjugates described above, any antibody of the immunoconjugate according to the present disclosure (as described herein above and below) may be used. In some embodiments, the immunoconjugate of the present disclosure comprises mAb1 as the antibody.

Accordingly, in some embodiments, the immunoconjugate to be used in the methods of the present disclosure comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (VIII):

Formula (VIII), 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 immunoconjugate (namely “ADC1”) is further described in the Examples of international patent application PCT/EP2021/072595 (published as WO 2022/048883 A1).

In other embodiments, the immunoconjugate to be according to the present disclosure comprises mAb1 covalently linked via a linker to exatecan, wherein the conjugate has the following formula (IX): 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 immunoconjugate (namely “ADC2”) is further described in the Examples of international patent application PCT/EP2021/072595 (published as WO 2022/048883 A1).

In other embodiments of the immunoconjugate to be used according to the present disclosure, the linker may be a "non-cleavable linker" (for example an SMCC linker). Release of the growth inhibitory agent from the antibody can occur upon lysosomal degradation of the antibody.

In other embodiments of the present disclosure, the immunoconjugate may be a fusion protein comprising an antibody of the immunoconjugate according to the present disclosure and a cytotoxic or growth inhibitory polypeptide (as the growth inhibitory agent); 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.

Suitable methods for preparing an immunoconjugate 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.

In general, an immunoconjugate of the present disclosure can be obtained e.g. by a process comprising the steps of:

(i) preparing a compound comprising the linker and the growth inhibitory agent (e.g. cytotoxic drug), also referred to herein as a “drug-linker compound”;

(ii) bringing into contact an optionally buffered aqueous solution of an antibody of the immunoconjugate according to the present disclosure with a solution of the drug-linker compound;

(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).

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.

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.

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.

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.

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 druglinker compound used along with the experimental 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 drug-linker 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.

Performing conjugation at the cysteine residues of interchain disulfide bridges using an antibody that has four interchain disulfide bridges (e.g. mAb1 or any lgG1 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).

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 AD and 280 nm. 280 nm is a wavelength generally used for measuring protein concentration, such as antibody concentration. The wavelength D is selected so as to allow discriminating the drug from the antibody, i.e. as readily known to the skilled person, AD is a wavelength at which the drug has a high absorbance and AD is sufficiently remote from 280 nm to avoid substantial overlap in the absorbance peaks of the drug and antibody. For instance, AD may be selected as being 370 nm for exatecan (or for camptothecin or other camptothecin analogs), or 252 nm for maytansinoid molecules.

A method of DAR calculation may be derived e.g. from Antony S. Dimitrov (ed), LLC, 2009, Therapeutic Antibodies and Protocols, vol 525, 445, Springer Science: The absorbances for the conjugate at AD (AAD) and at 280 nm (A280) are measured either on the monomeric peak of the size exclusion chromatography (SEC) analysis (allowing to calculate the "DAR(SEC)" parameter) or using a classic spectrophotometer apparatus (allowing to calculate the "DAR(UV)" parameter). The absorbances can be expressed as follows:

AAD = (CD X £D D) + (CA X EA D)

A280 = (CD X £D28O) + (CA X £A28O) wherein:

• CD and CA are respectively the concentrations in the solution of the drug and of the antibody • £DAD and ED28O are respectively the molar extinction coefficients of the drug at AD and 280 nm

• EAAD and £A28O are respectively the molar extinction coefficients of the antibody at D and

280 nm.

Resolution of these two equations with two unknowns leads to the following equations:

CD = [( EA280 X AAD) - (£AAD X A280)] I [(£DAD X EA28O) - ( SAAD X ED28O)]

CA ” [A28O - (CD X ED28O)] I EA280

The average DAR is then calculated from the ratio of the drug concentration to that of the antibody: DAR = CD / CA.

Exemplary methods for preparing an immunoconjugate of the present disclosure are also described in the Examples section of international patent application PCT/EP2021/072595 (published as WO 2022/048883 A1).

Also useful for the preparation of immunoconjugates for use in the methods of the present disclosure are compounds comprising a linker and a growth inhibitory agent (e.g. a cytotoxic drug). Such compounds are referred to herein also as “drug-linker compounds”. For instance, the immunoconjugate may be prepared using a compound with the following formula (X):

Formula (X) or a physiologically acceptable salt thereof; this compound is also referred to herein as “druglinker compound 1”, “compound DL1” or“DL1”.

Similarly, a compound may be used with the following formula (XI):

Formula (XI) or a physiologically acceptable salt thereof; this compound is also referred to herein as “druglinker compound 2”, “compound DL2” or “DL2”.

These drug-linker compounds may be used to prepare immunoconjugates for use in the methods of the present disclosure.

The drug-linker compounds of the present disclosure (e.g. those of formula (X) or (XI) depicted above) may be prepared by chemical synthesis, for instance as described in the Examples section of international patent application PCT/EP2021/072595.

ADC1 (also referred to herein as M9140) is the preferred immunoconjugate to be used in the treatment of colorectal cancer according to the present disclosure. The preparation of ADC1 is described in detail in international patent application PCT/EP2021/072595 (published as WO 2022/048883 A1). Specifically, the preparation of the antibody of ADC1 (the monoclonal anti- CEACAM5 antibody mAb1) is for example described in Example 1 of international patent application PCT/EP2021/072595. The synthesis of the drug-linker compound with glucuronide- based linker of ADC1 (Drug-Linker Compound 1 , DL1) is described in Example 2 of international patent application PCT/EP2021/072595. Preparation of the immunoconjugate ADC1 by conjugation of the antibody mAb1 and the drug-linker compound DL1 , formulation of the immunoconjugate for administration and characterization is described in Example 4 of international patent application PCT/EP2021/072595. Upon preparation, the anti-CEACAM5 immunoconjugates of the present disclosure will be formulated for administration. This can be performed according to well-known pharmaceutical methods.

To this end, for example the formulation described in Example 4 of international patent application PCT/EP2021/072595 can be used.

In brief, in this formulation procedure 361.5 mL of concentrated filtrate of immunoconjugate, obtained by Ultrafiltration/Diafiltration to > 25 mg/mL in Diafiltration buffer (10 mM Histidine, pH 5.5), was diluted to 20.0 mg/mL with 112.1 mL of Diafiltration Buffer. The resulting solution was diluted to 15.0 mg/mL with 157.6 mL of 4X Formulation Buffer (10 mM Histidine, 12% (w/v) Trehalose Dihydrate, 400 mM NaCI, pH 5.5) for a final target bulk drug substance (BDS) concentration of 15.0 mg/mL.

The final formulated ADC was then filtered using a 0.2 pm Millipak Gamma Gold 40 (MPGL04GH2) filter to yield 619.6 mL (Filter Load: 464.6 g/m2 [protein], 31.0 L/m2 [solution]) ADC1 BDS. The material was packaged into HDPE bottles and stored at < -65°C.

Further details on techniques for formulation and administration may be found e.g. in Remington: The Science and Practice of Pharmacy, 22nd ed. (2012), Pharmaceutical Press.

Various Aspects and Embodiments of the Treatment according to the Present Disclosure

First aspect of the present disclosure (also referred to as "Embodiment 1"): According to an aspect, the present disclosure relates to a method of treating colorectal cancer, said method comprising administering to a patient in need thereof an anti-CEACAM5 immunoconjugate according to a dosing regimen.

Second aspect of the present disclosure (also referred to as "Embodiment 2"): According to another aspect, the present disclosure relates to an anti-CEACAM5 immunoconjugate for use in the treatment of colorectal cancer (i.e. for the treatment of colorectal cancer) according to a dosing regimen.

Embodiment 3: The immunoconjugate according to embodiment 2, wherein said treatment comprises administering said immunoconjugate according to said dosing regimen.

Embodiment 4: The immunoconjugate according to any one of embodiments 2 or 3, wherein said treatment comprises administering said immunoconjugate to a patient in need thereof according to said dosing regimen.

Third aspect of the present disclosure (also referred to as "Embodiment 5"): According to another aspect, the present disclosure relates to an anti-CEACAM5 immunoconjugate for use in the treatment of colorectal cancer according to a method which comprises administering said immunoconjugate according to a dosing regimen.

Embodiment 6: The immunoconjugate for use according to embodiment 5, wherein said method comprises administering said immunoconjugate to a patient in need thereof according to said dosing regimen.

Fourth aspect of the present disclosure (also referred to as "Embodiment 7"): According to another aspect, the present disclosure relates to the use of an anti-CEACAM5 immunoconjugate for the preparation of a medicament for the treatment of colorectal cancer wherein the immunoconjugate is to be administered according to a dosing regimen.

Embodiment 8: The use according to embodiment 7, wherein said immunoconjugate is be administered to a patient in need thereof.

Fifth aspect of the present disclosure (also referred to as "Embodiment 9"): According to another aspect, the present disclosure relates to the use of an anti-CEACAM5 immunoconjugate for the treatment of colorectal cancer according to a dosing regimen.

Embodiment 10: The use according to embodiment 9, wherein said treatment comprises administering said immunoconjugate.

Embodiment 11 : The use according to any one of embodiments 9 or 10, wherein said treatment comprises administering said immunoconjugate to a patient in need thereof.

Sixth aspect of the present disclosure (also referred to as "Embodiment 12"): According to another aspect, the present disclosure relates to a method of treating colorectal cancer, said method comprising administering to a patient in need thereof a pharmaceutical composition according to a dosing regimen.

Seventh aspect of the present disclosure (also referred to as "Embodiment 13"): According to another aspect, the present disclosure relates to a pharmaceutical composition for the treatment of colorectal cancer according to a dosing regimen.

Embodiment 14: The pharmaceutical composition according to embodiment 12, wherein said treatment comprises administering said pharmaceutical composition according to said dosing regimen.

Embodiment 15: The pharmaceutical composition according to any one of embodiments 12 or 13, wherein said treatment comprises administering said pharmaceutical composition to a patient in need thereof according to said dosing regimen. Eighth aspect of the present disclosure (also referred to as "Embodiment 16"): According to another aspect, the present disclosure relates to a pharmaceutical composition for use in the treatment of colorectal cancer according to a method which comprises administering said pharmaceutical composition according to a dosing regimen.

Embodiment 17: The pharmaceutical composition for use according to embodiment 15, wherein said method comprises administering said pharmaceutical composition to a patient in need thereof according to said dosing regimen.

Nineth aspect of the present disclosure (also referred to as "Embodiment 18"): According to another aspect, the present disclosure relates to the use of a pharmaceutical composition for the preparation of a medicament for the treatment of colorectal cancer wherein the pharmaceutical composition is to be administered according to a dosing regimen.

Embodiment 19: The use according to embodiment 18, wherein said pharmaceutical composition is be administered to a patient in need thereof.

Tenth aspect of the present disclosure (also referred to as "Embodiment 20"): According to another aspect, the present disclosure relates to the use of a pharmaceutical composition for the treatment of colorectal cancer according to a dosing regimen.

Embodiment 21 : The use according to embodiment 20, wherein said treatment comprises administering said pharmaceutical composition.

Embodiment 22: The use according to any one of embodiments 20 or 21 , wherein said treatment comprises administering said pharmaceutical composition to a patient in need thereof.

Eleventh aspect of the present disclosure (also referred to as "Embodiment 23"): According to another aspect, the present disclosure relates to a kit for the treatment of colorectal cancer, said kit comprising a pharmaceutical composition comprising an anti-CEACAM5 immunoconjugate; and instructions for using the pharmaceutical composition for said treatment of colorectal cancer according to a dosing regimen.

Embodiment 24: The kit according to embodiment 23, wherein said treatment comprises administering said pharmaceutical composition.

Embodiment 25: The kit according to any one of embodiments 24 or 25, wherein said treatment comprises administering said pharmaceutical composition to a patient in need thereof. Embodiment 26: The method according to embodiment 12 or the pharmaceutical composition according to any one of embodiments 13 to 15 or the pharmaceutical composition for use according to any one of embodiments 16 or 17 or the use according to any one of embodiments 18 to 22 or the kit according to any one of embodiments 23 to 25, wherein said pharmaceutical composition comprises an anti-CEACAM5 immunoconjugate.

Embodiment 27: The method according to any one of embodiments 12 or 26 or the pharmaceutical composition according to any one of embodiments 13 to 15 or 26 or the pharmaceutical composition for use according to any one of embodiments 16 or 17 or 26 or the use according to any one of embodiments 18 to 22 or 26 or the kit according to any one of embodiments 23 to 26, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent and/or excipient.

Methods for preparing pharmaceutical compositions are known to a skilled person in the art (Remington: The Science and Practice of Pharmacy, 22nd ed. (2012), Pharmaceutical Press).

The term "pharmaceutically acceptable" designates that said carrier, diluent or excipient is a non-toxic, inert material that is compatible with the other ingredients of the pharmaceutical composition and not harmful to the patient that the pharmaceutical composition is administered to, such that it can be used in a pharmaceutical product. Substances suitable as carriers, diluents or excipients in pharmaceutical compositions are known to a skilled person in the art (Remington: The Science and Practice of Pharmacy, 22nd ed. (2012), Pharmaceutical Press). The pharmaceutical composition may further include e.g. additional adjuvants, antioxidants, buffering agents, bulking agents, colorants, emulsifiers, fillers, flavoring agents, preservatives, stabilizers, suspending agents and/or other customary pharmaceutical auxiliaries.

Embodiment 28: The method according to any one of embodiments 12 or 26 or 27 or the pharmaceutical composition according to any one of embodiments 13 to 15 or 26 or 27 or the pharmaceutical composition for use according to any one of embodiments 16 or 17 or 26 or 27 or the use according to any one of embodiments 18 to 22 or 26 or 27 or the kit according to any one of embodiments 23 to 27, wherein said pharmaceutical composition further comprises at least one additional component selected from the group consisting of an adjuvant, an antioxidant, a buffering agent, a bulking agent, a colorant, an emulsifier, a filler, a flavoring agent, a preservative, a stabilizer and a suspending agent.

Embodiment 29: The method according to any one of embodiments 1 or 26 to 28 or the immunoconjugate according to any one of embodiments 2 to 6 or the use according to any one of embodiments 7 to 11 or 26 to 28 or the pharmaceutical composition according to any one of embodiments 26 to 28 or the kit according to any one of embodiments 26 to 28, wherein said immunoconjugate comprises an antibody covalently linked via a linker to at least one growth inhibitory agent.

Embodiment 30: The method according to embodiment 29 or the immunoconjugate according to embodiment 29 or the use according to embodiment 29 or the pharmaceutical composition according to embodiment 29 or the kit according to embodiment 29, wherein said antibody is an antibody which binds to human CEACAM5 protein and which 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.

Embodiment 31 : The method according to any one of embodiments 29 or 30 or the immunoconjugate according to any one of embodiments 29 or 30 or the use according to any one of embodiments 29 or 30 or the pharmaceutical composition according to any one of embodiments 29 or 30 or the kit according to any one of embodiments 29 or 30, wherein 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.

Embodiment 32: The method according to any one of embodiments 29 to 31 or the immunoconjugate according to any one of embodiments 29 to 31 or the use according to any one of embodiments 29 to 31 or the pharmaceutical composition according to any one of embodiments 29 to 31 or the kit according to any one of embodiments 29 to 31 , wherein 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.

Embodiment 33: The method according to any one of embodiments 29 to 32 or the immunoconjugate according to any one of embodiments 29 to 32 or the use according to any one of embodiments 29 to 32 or the pharmaceutical composition according to any one of embodiments 29 to 32 or the kit according to any one of embodiments 29 to 32, wherein 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. Embodiment 34: The method according to any one of embodiments 29 to 33 or the immunoconjugate according to any one of embodiments 29 to 33 or the use according to any one of embodiments 29 to 33 or the pharmaceutical composition according to any one of embodiments 29 to 33 or the kit according to any one of embodiments 29 to 33, wherein 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.

Embodiment 35: The method according to any one of embodiments 29 to 34 or the immunoconjugate according to any one of embodiments 29 to 34 or the use according to any one of embodiments 29 to 34 or the pharmaceutical composition according to any one of embodiments 29 to 34 or the kit according to any one of embodiments 29 to 34, wherein 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.

Embodiment 36: The method according to any one of embodiments 29 to 35 or the immunoconjugate according to any one of embodiments 29 to 35 or the use according to any one of embodiments 29 to 35 or the pharmaceutical composition according to any one of embodiments 29 to 35 or the kit according to any one of embodiments 29 to 35, wherein said antibody is an antibody which competes for binding to A2-B2 domain of human CEACAM5 protein with an antibody comprising a heavy chain variable region (VH) of the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) of the amino acid sequence of SEQ ID NO: 10.

Embodiment 37: The method according to any one of embodiments 29 to 35 or the immunoconjugate according to any one of embodiments 29 to 35 or the use according to any one of embodiments 29 to 35 or the pharmaceutical composition according to any one of embodiments 29 to 35 or the kit according to any one of embodiments 29 to 35, wherein the antibody competes for binding to A2-B2 domain of Macaca fascicularis CEACAM5 protein with an antibody comprising a heavy chain variable region (VH) of the amino acid sequence of SEQ ID NO: 9 and a light chain variable region (VL) of the amino acid sequence of SEQ ID NO: 10.

Embodiment 38: The method according to any one of embodiments 29 to 37 or the immunoconjugate according to any one of embodiments 29 to 37 or the use according to any one of embodiments 29 to 37 or the pharmaceutical composition according to any one of embodiments 29 to 37 or the kit according to any one of embodiments 29 to 37, wherein the antibody does not significantly cross-react with human CEACAM1 , human CEACAM6, human CEACAM7, human CEACAM8 and Macaca fascicularis CEACAM6. Embodiment 39: The method according to any one of embodiments 29 to 38 or the immunoconjugate according to any one of embodiments 29 to 38 or the use according to any one of embodiments 29 to 38 or the pharmaceutical composition according to any one of embodiments 29 to 38 or the kit according to any one of embodiments 29 to 38, wherein the antibody is an antibody fragment.

Embodiment 40: The method according to any one of embodiments 29 to 39 or the immunoconjugate according to any one of embodiments 29 to 39 or the use according to any one of embodiments 29 to 39 or the pharmaceutical composition according to any one of embodiments 29 to 39 or the kit according to any one of embodiments 29 to 39, wherein the antibody is an antibody fragment selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, and diabodies.

Embodiment 41 : The method according to any one of embodiments 29 to 40 or the immunoconjugate according to any one of embodiments 29 to 40 or the use according to any one of embodiments 29 to 40 or the pharmaceutical composition according to any one of embodiments 29 to 40 or the kit according to any one of embodiments 29 to 40, wherein the antibody is a bispecific or a multispecific antibody.

Embodiment 42: The method according to any one of embodiments 29 to 41 or the immunoconjugate according to any one of embodiments 29 to 41 or the use according to any one of embodiments 29 to 41 or the pharmaceutical composition according to any one of embodiments 29 to 41 or the kit according to any one of embodiments 29 to 41 , wherein said antibody is an antibody which binds to human CEACAM5 protein and which 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.

Embodiment 43: The method according to any one of embodiments 29 to 42 or the immunoconjugate according to any one of embodiments 29 to 42 or the use according to any one of embodiments 29 to 42 or the pharmaceutical composition according to any one of embodiments 29 to 42 or the kit according to any one of embodiments 29 to 42, wherein the antibody is the antibody mAb1 as described in international patent application PCT/EP2021/072595, published as WO 2022/048883 A1.

Embodiment 44: The method according to any one of embodiments 29 to 43 or the immunoconjugate according to any one of embodiments 29 to 43 or the use according to any one of embodiments 29 to 43 or the pharmaceutical composition according to any one of embodiments 29 to 43 or the kit according to any one of embodiments 29 to 43, wherein the growth inhibitory agent is a cytotoxic drug or a radioactive moiety. Embodiment 45: The method according to any one of embodiments 29 to 44 or the immunoconjugate according to any one of embodiments 29 to 44 or the use according to any one of embodiments 29 to 44 or the pharmaceutical composition according to any one of embodiments 29 to 44 or the kit according to any one of embodiments 29 to 44, wherein the growth inhibitory agent is selected from a 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.

Embodiment 46: The method according to any one of embodiments 29 to 45 or the immunoconjugate according to any one of embodiments 29 to 45 or the use according to any one of embodiments 29 to 45 or the pharmaceutical composition according to any one of embodiments 29 to 45 or the kit according to any one of embodiments 29 to 45, wherein the growth inhibitory agent is exatecan.

Embodiment 47: The method according to any one of embodiments 29 to 47 or the immunoconjugate according to any one of embodiments 29 to 47 or the use according to any one of embodiments 29 to 47 or the pharmaceutical composition according to any one of embodiments 29 to 47 or the kit according to any one of embodiments 29 to 47, wherein linker is a cleavable linker.

Embodiment 48: The method according to any one of embodiments 29 to 47 or the immunoconjugate according to any one of embodiments 29 to 47 or the use according to any one of embodiments 29 to 47 or the pharmaceutical composition according to any one of embodiments 29 to 47 or the kit according to any one of embodiments 29 to 47, wherein the linker is a linker cleavable in an endosome of a mammalian cell.

Embodiment 49: The method according to any one of embodiments 29 to 48 or the immunoconjugate according to any one of embodiments 29 to 48 or the use according to any one of embodiments 29 to 48 or the pharmaceutical composition according to any one of embodiments 29 to 48 or the kit according to any one of embodiments 29 to 48, wherein the linker is a linker cleavable by a human enzyme selected from glucuronidase and legumain.

Embodiment 50: The method according to any one of embodiments 29 to 48 or the immunoconjugate according to any one of embodiments 29 to 48 or the use according to any one of embodiments 29 to 48 or the pharmaceutical composition according to any one of embodiments 29 to 48 or the kit according to any one of embodiments 29 to 48, wherein the immunoconjugate has the following formula (II):

Formula (II), wherein S is a sulfur atom of the antibody, and wherein n is a number of [(linker)-(growth inhibitory agent)] moieties covalently linked to the antibody.

Embodiment 51 : The method according to any one of embodiments 29 to 49 or the immunoconjugate according to any one of embodiments 29 to 49 or the use according to any one of embodiments 29 to 49 or the pharmaceutical composition according to any one of embodiments 29 to 49 or the kit according to any one of embodiments 29 to 49, wherein the immunoconjugate has the following formula (III):

Formula (III), wherein S is a sulfur atom of the antibody, and wherein n is a number of [(linker)-(growth inhibitory agent)] moieties covalently linked to the antibody.

Embodiment 52: The method according to any one of embodiments 29 to 50 or the immunoconjugate according to any one of embodiments 29 to 50 or the use according to any one of embodiments 29 to 50 or the pharmaceutical composition according to any one of embodiments 29 to 50 or the kit according to any one of embodiments 29 to 50, wherein the immunoconjugate has the following formula (IV):

Formula (IV), wherein S is a sulfur atom of the antibody, and wherein n is a number of [(linker)-(exatecan)] moieties covalently linked to the antibody. Embodiment 53: The method according to any one of embodiments 29 to 50 or 52 or the immunoconjugate according to any one of embodiments 29 to 50 or 52 or the use according to any one of embodiments 29 to 50 or 52 or the pharmaceutical composition according to any one of embodiments 29 to 50 or 52 or the kit according to any one of embodiments 29 to 50 or 52, wherein the immunoconjugate has the following formula (V):

Formula (V), wherein S is a sulfur atom of the antibody, and wherein n is a number of [(linker)-(exatecan)] moieties covalently linked to the antibody. Embodiment 54: The method according to any one of embodiments 50 to 53 or the immunoconjugate according to any one of embodiments 50 to 53 or the use according to any one of embodiments 50 to 53 or the pharmaceutical composition according to any one of embodiments 50 to 53 or the kit according to any one of embodiments 50 to 53, wherein the S is a sulfur atom of a cysteine of the antibody.

Embodiment 55: The method according to embodiment 54 or the immunoconjugate according to embodiment 54 or the use according to embodiment 54 or the pharmaceutical composition according to embodiment 54 or the kit according to embodiment 54, wherein the cysteine of the antibody is one of the cysteines capable of forming an interchain disulfide bond.

Embodiment 56: The method according to any one of embodiments 50 to 55 or the immunoconjugate according to any one of embodiments 50 to 55 or the use according to any one of embodiments 50 to 55 or the pharmaceutical composition according to any one of embodiments 50 to 55 or the kit according to any one of embodiments 50 to 55, wherein n is between 7 and 8.

Embodiment 57: The method according to any one of embodiments 50 to 56 or the immunoconjugate according to any one of embodiments 50 to 56 or the use according to any one of embodiments 50 to 56 or the pharmaceutical composition according to any one of embodiments 50 to 56 or the kit according to any one of embodiments 50 to 56, wherein n is between 7.5 and 8.0.

Embodiment 58: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 2.0 mg/kg Q3W.

Embodiment 59: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 2.2 mg/kg Q3W.

Embodiment 60: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 2.3 mg/kg Q3W. Embodiment 61 : The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 2.4 mg/kg Q3W.

Embodiment 62: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 2.5 mg/kg Q3W.

Embodiment 63: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 2.6 mg/kg Q3W.

Embodiment 64: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 2.7 mg/kg Q3W.

Embodiment 65: The method according to any one of embodiments 1 or 12 or 26 to 64 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 64 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 64 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 64 or the kit according to any one of embodiments 23 to 64, wherein said dosing regimen is < 3.2 mg/kg Q3W.

Embodiment 66: The method according to any one of embodiments 1 or 12 or 26 to 64 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 64 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 64 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 64 or the kit according to any one of embodiments 23 to 64, wherein said dosing regimen is < 3.0 mg/kg Q3W.

Embodiment 67: The method according to any one of embodiments 1 or 12 or 26 to 64 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 64 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 64 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 64 or the kit according to any one of embodiments 23 to 64, wherein said dosing regimen is < 2.9 mg/kg Q3W.

Embodiment 68: The method according to any one of embodiments 1 or 12 or 26 to 64 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 64 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 64 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 64 or the kit according to any one of embodiments 23 to 64, wherein said dosing regimen is < 2.8 mg/kg Q3W.

Embodiment 69: The method according to any one of embodiments 1 or 12 or 26 to 63 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 63 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 63 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 63 or the kit according to any one of embodiments 23 to 63, wherein said dosing regimen is < 2.7 mg/kg Q3W.

Embodiment 70: The method according to any one of embodiments 1 or 12 or 26 to 62 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 62 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 62 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 62 or the kit according to any one of embodiments 23 to 62, wherein said dosing regimen is < 2.6 mg/kg Q3W.

Embodiment 71 : The method according to any one of embodiments 1 or 12 or 26 to 61 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 61 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 61 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 61 or the kit according to any one of embodiments 23 to 61 , wherein said dosing regimen is < 2.5 mg/kg Q3W.

Embodiment 72: The method according to any one of embodiments 1 or 12 or 26 to 57 or 65 to 71 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 65 to 71 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 65 to 71 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 65 to 71 or the kit according to any one of embodiments 23 to 57 or 65 to 71 , wherein said dosing regimen is > 2.0 mg/kg Q3W.

Embodiment 73: The method according to any one of embodiments 1 or 12 or 26 to 57 or 65 to 71 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 65 to 71 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 65 to 71 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 65 to 71 or the kit according to any one of embodiments 23 to 57 or 65 to 71 , wherein said dosing regimen is > 2.2 mg/kg Q3W. Embodiment 74: The method according to any one of embodiments 1 or 12 or 26 to 57 or 65 to 71 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 65 to 71 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 65 to 71 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 65 to 71 or the kit according to any one of embodiments 23 to 57 or 65 to 71 , wherein said dosing regimen is > 2.3 mg/kg Q3W.

Embodiment 75: The method according to any one of embodiments 1 or 12 or 26 to 57 or 65 to 71 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 65 to 71 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 65 to 71 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 65 to 71 or the kit according to any one of embodiments 23 to 57 or 65 to 71 , wherein said dosing regimen is > 2.4 mg/kg Q3W.

Embodiment 76: The method according to any one of embodiments 1 or 12 or 26 to 57 or 65 to 70 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 65 to 70 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 65 to 70 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 65 to 70 or the kit according to any one of embodiments 23 to 57 or 65 to 70, wherein said dosing regimen is > 2.5 mg/kg Q3W.

Embodiment 77: The method according to any one of embodiments 1 or 12 or 26 to 57 or 65 to 69 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 65 to 69 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 65 to 69 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 65 to 69 or the kit according to any one of embodiments 23 to 57 or 65 to 69, wherein said dosing regimen is > 2.6 mg/kg Q3W.

Embodiment 78: The method according to any one of embodiments 1 or 12 or 26 to 57 or 65 to 68 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 65 to 68 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 65 to 68 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 65 to 68 or the kit according to any one of embodiments 23 to 57 or 65 to 68, wherein said dosing regimen is > 2.7 mg/kg Q3W.

Embodiment 79: The method according to any one of embodiments 1 or 12 or 26 to 57 or 65 to 67 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 65 to 67 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 65 to 67 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 65 to 67 or the kit according to any one of embodiments 23 to 57 or 65 to 67, wherein said dosing regimen is > 2.8 mg/kg Q3W.

Embodiment 80: The method according to any one of embodiments 1 or 12 or 26 to 64 or 72 to 79 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 64 or 72 to 79 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 64 or 72 to 79 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 64 or 72 to 79 or the kit according to any one of embodiments 23 to 64 or 72 to 79, wherein said dosing regimen is < 3.2 mg/kg Q3W.

Embodiment 81 : The method according to any one of embodiments 1 or 12 or 26 to 64 or 72 to 79 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 64 or 72 to 79 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 64 or 72 to 79 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 64 or 72 to 79 or the kit according to any one of embodiments 23 to 64 or 72 to 79, wherein said dosing regimen is < 3.0 mg/kg Q3W.

Embodiment 82: The method according to any one of embodiments 1 or 12 or 26 to 64 or 72 to 79 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 64 or 72 to 79 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 64 or 72 to 79 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 64 or 72 to 79 or the kit according to any one of embodiments 23 to 64 or 72 to 79, wherein said dosing regimen is < 2.9 mg/kg Q3W.

Embodiment 83: The method according to any one of embodiments 1 or 12 or 26 to 64 or 72 to 79 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 64 or 72 to 79 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 64 or 72 to 79 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 64 or 72 to 79 or the kit according to any one of embodiments 23 to 64 or 72 to 79, wherein said dosing regimen is < 2.8 mg/kg Q3W.

Embodiment 84: The method according to any one of embodiments 1 or 12 or 26 to 63 or 72 to 78 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 63 or 72 to 78 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 63 or 72 to 78 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 63 or 72 to 78 or the kit according to any one of embodiments 23 to 63 or 72 to 78, wherein said dosing regimen is < 2.7 mg/kg Q3W.

Embodiment 85: The method according to any one of embodiments 1 or 12 or 26 to 62 or 72 to 77 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 62 or 72 to 77 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 62 or 72 to 77 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 62 or 72 to 77 or the kit according to any one of embodiments 23 to 62 or 72 to 77, wherein said dosing regimen is < 2.6 mg/kg Q3W.

Embodiment 86: The method according to any one of embodiments 1 or 12 or 26 to 61 or 72 to 76 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 61 or 72 to 76 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 61 or 72 to 76 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 61 or 72 to 76 or the kit according to any one of embodiments 23 to 61 or 72 to 76, wherein said dosing regimen is < 2.5 mg/kg Q3W.

Embodiment 87: The method according to any one of embodiments 1 or 12 or 26 to 60 or 72 to 75 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 60 or 72 to 75 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 60 or 72 to 75 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 60 or 72 to 75 or the kit according to any one of embodiments 23 to 60 or 72 to 75, wherein said dosing regimen is < 2.4 mg/kg Q3W.

Embodiment 88: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.0-3.2 mg/kg Q3W.

Embodiment 89: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.2-3.0 mg/kg Q3W.

Embodiment 90: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.3-2.9 mg/kg Q3W.

Embodiment 91 : The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.4-2.8 mg/kg Q3W.

Embodiment 92: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.3 mg/kg Q3W.

Embodiment 93: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.4 mg/kg Q3W.

Embodiment 94: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.5 mg/kg Q3W.

Embodiment 95: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.6 mg/kg Q3W.

Embodiment 96: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.7 mg/kg Q3W.

Embodiment 97: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.8 mg/kg Q3W. Embodiment 98: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 2.9 mg/kg Q3W.

Embodiment 99: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 150 mg flat dose Q3W.

Embodiment 100: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 160 mg flat dose Q3W.

Embodiment 101 : The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 170 mg flat dose Q3W.

Embodiment 102: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 180 mg flat dose Q3W.

Embodiment 103: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 190 mg flat dose Q3W.

Embodiment 104: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 200 mg flat dose Q3W.

Embodiment 105: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 210 mg flat dose Q3W.

Embodiment 106: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is > 220 mg flat dose Q3W.

Embodiment 107: The method according to any one of embodiments 1 or 12 or 26 to 57 or 99 to 106 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 99 to 106 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 99 to 106 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 99 to 106 or the kit according to any one of embodiments 23 to 57 or 99 to 106, wherein said dosing regimen is < 250 mg flat dose Q3W.

Embodiment 108: The method according to any one of embodiments 1 or 12 or 26 to 57 or 99 to 106 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 99 to 106 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 99 to 106 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 99 to 106 or the kit according to any one of embodiments 23 to 57 or 99 to 106, wherein said dosing regimen is < 240 mg flat dose Q3W.

Embodiment 109: The method according to any one of embodiments 1 or 12 or 26 to 57 or 99 to 106 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 99 to 106 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 99 to 106 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 99 to 106 or the kit according to any one of embodiments 23 to 57 or 99 to 106, wherein said dosing regimen is < 230 mg flat dose Q3W.

Embodiment 110: The method according to any one of embodiments 1 or 12 or 26 to 57 or 99 to 106 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 99 to 106 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 99 to 106 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 99 to 106 or the kit according to any one of embodiments 23 to 57 or 99 to 106, wherein said dosing regimen is < 220 mg flat dose Q3W.

Embodiment 111 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 99 to 105 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 99 to 105 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 99 to 105 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 99 to 105 or the kit according to any one of embodiments 23 to 57 or 99 to 105, wherein said dosing regimen is < 210 mg flat dose Q3W.

Embodiment 112: The method according to any one of embodiments 1 or 12 or 26 to 57 or 99 to 104 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 99 to 104 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 99 to 104 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 99 to 104 or the kit according to any one of embodiments 23 to 57 or 99 to 104, wherein said dosing regimen is < 200 mg flat dose Q3W.

Embodiment 113: The method according to any one of embodiments 1 or 12 or 26 to 57 or 99 to 103 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 99 to 103 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 99 to 103 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 99 to 103 or the kit according to any one of embodiments 23 to 57 or 99 to 103, wherein said dosing regimen is < 190 mg flat dose Q3W.

Embodiment 114: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 150-250 mg flat dose Q3W.

Embodiment 115: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 180-240 mg flat dose Q3W.

Embodiment 116: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 190-230 mg flat dose Q3W.

Embodiment 117: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 190-225 mg flat dose Q3W.

Embodiment 118: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 192-224 mg flat dose Q3W.

Embodiment 119: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 190 mg flat dose Q3W.

Embodiment 120: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 200 mg flat dose Q3W.

Embodiment 121 : The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 210 mg flat dose Q3W.

Embodiment 122: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 220 mg flat dose Q3W. Embodiment 123: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 230 mg flat dose Q3W.

Embodiment 124: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 192 mg flat dose Q3W.

Embodiment 125: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 208 mg flat dose Q3W.

Embodiment 126: The method according to any one of embodiments 1 or 12 or 26 to 57 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or the kit according to any one of embodiments 23 to 57, wherein said dosing regimen is 224 mg flat dose Q3W.

Embodiment 127: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said dosing regimen is applied for N weeks.

Embodiment 128: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 2.

Embodiment 129: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 3. Embodiment 130: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 4.

Embodiment 131 : The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 6.

Embodiment 132: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 8.

Embodiment 133: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 9.

Embodiment 134: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 10.

Embodiment 135: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 12.

Embodiment 136: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 14.

Embodiment 137: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 15. Embodiment 138: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 16.

Embodiment 139: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 18.

Embodiment 140: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 20.

Embodiment 141 : The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 22.

Embodiment 142: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is > 24.

Embodiment 143: The method according to any one of embodiments 127 to 142 or the immunoconjugate according to any one of embodiments 127 to 142 or the use according to any one of embodiments 127 to 142 or the pharmaceutical composition according to any one of embodiments 127 to 142 or the kit according to any one of embodiments 127 to 142, wherein N is < 24.

Embodiment 144: The method according to any one of embodiments 127 to 141 or the immunoconjugate according to any one of embodiments 127 to 141 or the use according to any one of embodiments 127 to 141 or the pharmaceutical composition according to any one of embodiments 127 to 141 or the kit according to any one of embodiments 127 to 141 , wherein N is < 22.

Embodiment 145: The method according to any one of embodiments 127 to 140 or the immunoconjugate according to any one of embodiments 127 to 140 or the use according to any one of embodiments 127 to 140 or the pharmaceutical composition according to any one of embodiments 127 to 140 or the kit according to any one of embodiments 127 to 140, wherein N is < 20.

Embodiment 146: The method according to any one of embodiments 127 to 139 or the immunoconjugate according to any one of embodiments 127 to 139 or the use according to any one of embodiments 127 to 139 or the pharmaceutical composition according to any one of embodiments 127 to 139 or the kit according to any one of embodiments 127 to 139, wherein N is < 18.

Embodiment 147: The method according to any one of embodiments 127 to 138 or the immunoconjugate according to any one of embodiments 127 to 138 or the use according to any one of embodiments 127 to 138 or the pharmaceutical composition according to any one of embodiments 127 to 138 or the kit according to any one of embodiments 127 to 138, wherein N is < 16.

Embodiment 148: The method according to any one of embodiments 127 to 137 or the immunoconjugate according to any one of embodiments 127 to 137 or the use according to any one of embodiments 127 to 137 or the pharmaceutical composition according to any one of embodiments 127 to 137 or the kit according to any one of embodiments 127 to 137, wherein N is < 15.

Embodiment 149: The method according to any one of embodiments 127 to 136 or the immunoconjugate according to any one of embodiments 127 to 136 or the use according to any one of embodiments 127 to 136 or the pharmaceutical composition according to any one of embodiments 127 to 136 or the kit according to any one of embodiments 127 to 136, wherein N is < 14.

Embodiment 150: The method according to any one of embodiments 127 to 135 or the immunoconjugate according to any one of embodiments 127 to 135 or the use according to any one of embodiments 127 to 135 or the pharmaceutical composition according to any one of embodiments 127 to 135 or the kit according to any one of embodiments 127 to 135, wherein N is < 12.

Embodiment 151 : The method according to any one of embodiments 127 to 134 or the immunoconjugate according to any one of embodiments 127 to 134 or the use according to any one of embodiments 127 to 134 or the pharmaceutical composition according to any one of embodiments 127 to 134 or the kit according to any one of embodiments 127 to 134, wherein N is < 10. Embodiment 152: The method according to any one of embodiments 127 to 133 or the immunoconjugate according to any one of embodiments 127 to 133 or the use according to any one of embodiments 127 to 133 or the pharmaceutical composition according to any one of embodiments 127 to 133 or the kit according to any one of embodiments 127 to 133, wherein N is < 9.

Embodiment 153: The method according to any one of embodiments 127 to 132 or the immunoconjugate according to any one of embodiments 127 to 132 or the use according to any one of embodiments 127 to 132 or the pharmaceutical composition according to any one of embodiments 127 to 132 or the kit according to any one of embodiments 127 to 132, wherein N is < 8.

Embodiment 154: The method according to any one of embodiments 127 to 131 or the immunoconjugate according to any one of embodiments 127 to 131 or the use according to any one of embodiments 127 to 131 or the pharmaceutical composition according to any one of embodiments 127 to 131 or the kit according to any one of embodiments 127 to 131 , wherein N is < 6.

Embodiment 155: The method according to any one of embodiments 127 to 130 or the immunoconjugate according to any one of embodiments 127 to 130 or the use according to any one of embodiments 127 to 130 or the pharmaceutical composition according to any one of embodiments 127 to 130 or the kit according to any one of embodiments 127 to 130, wherein N is < 4.

Embodiment 156: The method according to any one of embodiments 127 to 129 or the immunoconjugate according to any one of embodiments 127 to 129 or the use according to any one of embodiments 127 to 129 or the pharmaceutical composition according to any one of embodiments 127 to 129 or the kit according to any one of embodiments 127 to 129, wherein N is < 3.

Embodiment 157: The method according to any one of embodiments 127 to 128 or the immunoconjugate according to any one of embodiments 127 to 128 or the use according to any one of embodiments 127 to 128 or the pharmaceutical composition according to any one of embodiments 127 to 128 or the kit according to any one of embodiments 127 to 128, wherein N is < 2.

Embodiment 158: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 2. Embodiment 159: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 3.

Embodiment 160: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 4.

Embodiment 161 : The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 6.

Embodiment 162: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 8.

Embodiment 163: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 9.

Embodiment 164: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 10.

Embodiment 165: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 12.

Embodiment 166: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 14. Embodiment 167: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 15.

Embodiment 168: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 16.

Embodiment 169: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 18.

Embodiment 170: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 20.

Embodiment 171: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 22.

Embodiment 172: The method according to embodiment 127 or the immunoconjugate according to embodiment 127 or the use according to embodiment 127 or the pharmaceutical composition according to embodiment 127 or the kit according to embodiment 127, wherein N is 24.

Embodiment 173: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for at least 1 month.

Embodiment 174: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for at least 2 months.

Embodiment 175: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for at least 3 months.

Embodiment 176: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for at least 6 months.

Embodiment 177: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for at least 9 months.

Embodiment 178: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for at least 12 months.

Embodiment 179: The method according to any one of embodiments 1 or 12 or 26 to 126 or 173 to 178 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or 173 to 178 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or 173 to 178 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or 173 to 178 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for up to 12 months.

Embodiment 180: The method according to any one of embodiments 1 or 12 or 26 to 126 or 173 to 177 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or 173 to 177 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or 173 to 177 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or 173 to 177 or the kit according to any one of embodiments 23 to 126 or 173 to 177, wherein said treatment is applied for up to 9 months. Embodiment 181 : The method according to any one of embodiments 1 or 12 or 26 to 126 or 173 to 176 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or 173 to 176 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or 173 to 176 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or 173 to 176 or the kit according to any one of embodiments 23 to 126 or 173 to 176, wherein said treatment is applied for up to 6 months.

Embodiment 182: The method according to any one of embodiments 1 or 12 or 26 to 126 or 173 to 175 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or 173 to 175 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or 173 to 175 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or 173 to 175 or the kit according to any one of embodiments 23 to 126 or 173 to 175, wherein said treatment is applied for up to 3 months.

Embodiment 183: The method according to any one of embodiments 1 or 12 or 26 to 126 or 173 to 174 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or 173 to 174 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or 173 to 174 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or 173 to 174 or the kit according to any one of embodiments 23 to 126 or 173 to 174, wherein said treatment is applied for up to 2 months.

Embodiment 184: The method according to any one of embodiments 1 or 12 or 26 to 126 or 173 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or 173 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or 173 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or 173 or the kit according to any one of embodiments 23 to 126 or 173, wherein said treatment is applied for up to 1 month.

Embodiment 185: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for 1 month.

Embodiment 186: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for 2 months. Embodiment 187: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for 3 months.

Embodiment 188: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for 6 months.

Embodiment 189: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for 9 months.

Embodiment 190: The method according to any one of embodiments 1 or 12 or 26 to 126 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 126 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 126 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 126 or the kit according to any one of embodiments 23 to 126, wherein said treatment is applied for 12 months.

Embodiment 191 : The method according to any one of embodiments 1 or 12 or 26 to 190 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 190 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 190 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 190 or the kit according to any one of embodiments 23 to 190, wherein said colorectal cancer is locally advanced or metastatic colorectal cancer.

Embodiment 192: The method according to any one of embodiments 1 or 12 or 26 to 190 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 190 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 190 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 190 or the kit according to any one of embodiments 23 to 190, wherein said colorectal cancer is locally advanced colorectal cancer.

Embodiment 193: The method according to any one of embodiments 1 or 12 or 26 to 190 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 190 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 190 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 190 or the kit according to any one of embodiments 23 to 190, wherein said colorectal cancer is metastatic colorectal cancer.

Embodiment 194: The method according to any one of embodiments 1 or 12 or 26 to 193 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 193 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 193 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 193 or the kit according to any one of embodiments 23 to 193, wherein the colorectal cancer is a CEACAM5 expressing colorectal cancer.

Embodiment 195: The method according to any one of embodiments 1 or 12 or 26 to 194 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 194 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 194 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 194 or the kit according to any one of embodiments 23 to 194, wherein at least 60% of the tumor cells of said colorectal cancer are CEACAM5-positive.

Embodiment 196: The method according to any one of embodiments 1 or 12 or 26 to 194 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 194 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 194 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 194 or the kit according to any one of embodiments 23 to 194, wherein at least 70% of the tumor cells of said colorectal cancer are CEACAM5-positive.

Embodiment 197: The method according to any one of embodiments 1 or 12 or 26 to 194 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 194 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 194 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 194 or the kit according to any one of embodiments 23 to 194, wherein at least 80% of the tumor cells of said colorectal cancer are CEACAM5-positive.

Embodiment 198: The method according to any one of embodiments 1 or 12 or 26 to 194 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 194 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 194 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 194 or the kit according to any one of embodiments 23 to 194, wherein at least 90% of the tumor cells of said colorectal cancer are CEACAM5-positive. Preferably, a tumor cell that is CEACAM5-positive is a cell that results in 2+ staining in CEACAM5 expression analysis by immunohistochemistry.

Embodiment 199: The method according to any one of embodiments 1 or 12 or 26 to 198 or the immunoconjugate according to any one of embodiments 4 or 6 or 29 to 198 or the use according to any one of embodiments 8 or 11 or 19 or 22 or 26 to 198 or the pharmaceutical composition according to any one of embodiments 15 or 17 or 26 to 198 or the kit according to any one of embodiments 25 to 198, wherein the patient is a human.

Embodiment 200: The method according to any one of embodiments 1 or 12 or 26 to 198 or the immunoconjugate according to any one of embodiments 4 or 6 or 29 to 198 or the use according to any one of embodiments 8 or 11 or 19 or 22 or 26 to 198 or the pharmaceutical composition according to any one of embodiments 15 or 17 or 26 to 198 or the kit according to any one of embodiments 25 to 198, wherein the patient is an adult human.

Embodiment 201 : The method according to any one of embodiments 1 or 12 or 26 to 200 or the immunoconjugate according to any one of embodiments 4 or 6 or 29 to 200 or the use according to any one of embodiments 8 or 11 or 19 or 22 or 26 to 200 or the pharmaceutical composition according to any one of embodiments 15 or 17 or 26 to 200 or the kit according to any one of embodiments 25 to 200, wherein said patient is of white or Asian race.

Embodiment 202: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201, wherein said treatment is first-line treatment.

Embodiment 203: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201, wherein said treatment is second-line treatment.

Embodiment 204: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201, wherein said treatment is third-line treatment. Embodiment 205: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said treatment is fourth-line treatment.

Embodiment 206: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said treatment is 1 L+ treatment (i.e. first-line or later).

Embodiment 207: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said treatment is 2L+ treatment (i.e. second- line or later).

Embodiment 208: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said treatment is 3L+ treatment (i.e. third-line or later).

Embodiment 209: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said treatment is 4L+ treatment (i.e. fourth-line or later).

Embodiment 210: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said patient has undergone at least 1 systemic anticancer therapies before said treatment.

Embodiment 211 : The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said patient has undergone at least 2 systemic anticancer therapies before said treatment.

Embodiment 212: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said patient has undergone at least 3 systemic anticancer therapies before said treatment.

Embodiment 213: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said patient has undergone at least 4 systemic anticancer therapies before said treatment.

Embodiment 214: The method according to any one of embodiments 1 or 12 or 26 to 201 or 210 to 213 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or 210 to 213 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or 210 to 213 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or 210 to 213 or the kit according to any one of embodiments 23 to 201 or 210 to 212, wherein said patient has undergone not more than 4 systemic anticancer therapies before said treatment.

Embodiment 215: The method according to any one of embodiments 1 or 12 or 26 to 201 or 210 to 212 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or 210 to 212 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or 210 to 212 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or 210 to 212 or the kit according to any one of embodiments 23 to 201 or 210 to 212, wherein said patient has undergone not more than 3 systemic anticancer therapies before said treatment. Embodiment 216: The method according to any one of embodiments 1 or 12 or 26 to 201 or 210 or 211 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or 210 or 211 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or 210 or 211 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or 210 or or the kit according to any one of embodiments 23 to 201 or 210 or 211 , wherein said patient has undergone not more than 2 systemic anticancer therapies before said treatment.

Embodiment 217: The method according to any one of embodiments 1 or 12 or 26 to 201 or 209 or 210 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or 209 or 210 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or 209 or 210 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or 209 or 210 or the kit according to any one of embodiments 23 to 201 or 209 or 210, wherein said patient has undergone not more than 1 systemic anticancer therapies before said treatment.

Embodiment 218: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said patient has undergone 1 systemic anticancer therapies before said treatment.

Embodiment 219: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said patient has undergone 2 systemic anticancer therapies before said treatment.

Embodiment 220: The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said patient has undergone 3 systemic anticancer therapies before said treatment.

Embodiment 221 : The method according to any one of embodiments 1 or 12 or 26 to 201 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or the kit according to any one of embodiments 23 to 201 , wherein said patient has undergone 4 systemic anticancer therapies before said treatment.

Embodiment 222: The method according to any one of embodiments 210 to 221 or the immunoconjugate according to any one of embodiments 210 to 221 or the use according to any one of embodiments 210 to 221 or the pharmaceutical composition according to any one of embodiments 210 to 221 or the kit according to any one of embodiments 210 to 221 , wherein said systemic anticancer therapies are selected from the group consisting of Cetuximab treatment, Panitumumab treatment, Bevacizumab treatment, Fluorouracil treatment, Oxaliplatin treatment and Irinotecan treatment.

Embodiment 223: The method according to any one of embodiments 210 to 221 or the immunoconjugate according to any one of embodiments 210 to 221 or the use according to any one of embodiments 210 to 221 or the pharmaceutical composition according to any one of embodiments 210 to 221 or the kit according to any one of embodiments 210 to 221 , wherein said systemic anticancer therapies are selected from the group consisting of Bevacizumab treatment, Fluorouracil treatment, Oxaliplatin treatment and Irinotecan treatment.

Embodiment 224: The method according to any one of embodiments 1 or 12 or 26 to 201 or 203 to 223 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 201 or 203 to 223 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 201 or 203 to 223 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 201 or 203 to 223 or the kit according to any one of embodiments 23 to 201 or 203 to 223, wherein before said treatment said patient has undergone Irinotecan treatment.

Embodiment 225: The method according to any one of embodiments 1 or 12 or 26 to 224 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 224 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 224 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 224 or the kit according to any one of embodiments 23 to 224, wherein said treatment results in a Disease Control Rate (DCR) of at least 40%.

As the skilled person understands, in order to assess the DCR, the effects of said treatment must be assessed over a group of patients that are similar to the patient undergoing said treatment (same type of disease, disease stage, line of treatment etc.).

Embodiment 226: The method according to any one of embodiments 1 or 12 or 26 to 224 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 224 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 224 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 224 or the kit according to any one of embodiments 23 to 224, wherein said treatment results in a Disease Control Rate (DCR) of at least 50%.

Embodiment 227: The method according to any one of embodiments 1 or 12 or 26 to 224 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 224 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 224 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 224 or the kit according to any one of embodiments 23 to 224, wherein said treatment results in a Disease Control Rate (DCR) of at least 60%.

Embodiment 228: The method according to any one of embodiments 1 or 12 or 26 to 224 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 224 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 224 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 224 or the kit according to any one of embodiments 23 to 224, wherein said treatment results in a Disease Control Rate (DCR) of at least 65%.

Embodiment 229: The method according to any one of embodiments 1 or 12 or 26 to 228 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 228 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 228 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 228 or the kit according to any one of embodiments 23 to 228, wherein said treatment results in a median of progression-free survival of at least 4 months.

As the skilled person understands, in order to assess the median of progression-free survival, the effects of said treatment must be assessed over a group of patients that are similar to the patient undergoing said treatment (same type of disease, disease stage, line of treatment etc.).

Embodiment 230: The method according to any one of embodiments 1 or 12 or 26 to 228 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 228 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 228 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 228 or the kit according to any one of embodiments 23 to 228, wherein said treatment results in a median of progression-free survival of at least 5 months.

Embodiment 231 : The method according to any one of embodiments 1 or 12 or 26 to 228 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 228 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 228 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 228 or the kit according to any one of embodiments 23 to 228, wherein said treatment results in a median of progression-free survival of at least 6 months.

Embodiment 232: The method according to any one of embodiments 1 or 12 or 26 to 228 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 228 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 228 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 228 or the kit according to any one of embodiments 23 to 228, wherein said treatment results in a median of progression-free survival of at least 6.5 months.

Embodiment 233: The method according to any one of embodiments 229 to 232 or the immunoconjugate according to any one of embodiments 229 to 232 or the use according to any one of embodiments 229 to 232 or the pharmaceutical composition according to any one of embodiments 229 to 232 or the kit according to any one of embodiments 229 to 232, wherein said median of progression-free survival is determined over a group of patients undergoing the same treatment according to said dosing regimen as said patient.

Embodiment 234: The method according to any one of embodiments 1 or 12 or 26 to 233 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 233 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 233 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 233 or the kit according to any one of embodiments 23 to 233, wherein said treatment results in a reduction of tumor size.

Embodiment 235: The method according to any one of embodiments 1 or 12 or 26 to 234 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 234 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 234 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 234 or the kit according to any one of embodiments 23 to 234, wherein said treatment results in a partial response or stable disease.

Embodiment 236: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 1.2 mg/kg Q2W. Embodiment 237: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 1.4 mg/kg Q2W.

Embodiment 238: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 1.5 mg/kg Q2W.

Embodiment 239: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 1.6 mg/kg Q2W.

Embodiment 240: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 1.7 mg/kg Q2W.

Embodiment 241 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 1.8 mg/kg Q2W.

Embodiment 242: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 1.9 mg/kg Q2W.

Embodiment 243: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or the kit according to any one of embodiments 23 to 57 or 127 to 242, wherein said dosing regimen is < 2.4 mg/kg Q2W.

Embodiment 244: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or the kit according to any one of embodiments 23 to 57 or 127 to 242, wherein said dosing regimen is < 2.2 mg/kg Q2W.

Embodiment 245: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or the kit according to any one of embodiments 23 to 57 or 127 to 242, wherein said dosing regimen is < 2.1 mg/kg Q2W.

Embodiment 246: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or the kit according to any one of embodiments 23 to 57 or 127 to 242, wherein said dosing regimen is < 2.0 mg/kg Q2W.

Embodiment 247: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 241 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 241 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 241 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 241 or the kit according to any one of embodiments 23 to 57 or 127 to 241 , wherein said dosing regimen is < 1.9 mg/kg Q2W.

Embodiment 248: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 240 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 240 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 240 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 240 or the kit according to any one of embodiments 23 to 57 or 127 to 240, wherein said dosing regimen is < 1.8 mg/kg Q2W.

Embodiment 249: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 239 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 239 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 239 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 239 or the kit according to any one of embodiments 23 to 57 or 127 to 239, wherein said dosing regimen is < 1.7 mg/kg Q2W.

Embodiment 250: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 242 to 249 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 242 to 249 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 242 to 249 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 242 to 249 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 242 to 249, wherein said dosing regimen is > 1 .2 mg/kg Q2W.

Embodiment 251 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 242 to 249 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 242 to 249 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 242 to 249 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 242 to 249 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 242 to 249, wherein said dosing regimen is > 1 .4 mg/kg Q2W.

Embodiment 252: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 242 to 249 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 242 to 249 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 242 to 249 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 242 to 249 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 242 to 249, wherein said dosing regimen is > 1.5 mg/kg Q2W.

Embodiment 253: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 242 to 249 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 242 to 249 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 242 to 249 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 242 to 249 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 242 to 249, wherein said dosing regimen is > 1 .6 mg/kg Q2W.

Embodiment 254: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 242 to 248 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 242 to 248 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 242 to 248 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 242 to 248 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 242 to 248, wherein said dosing regimen is > 1.7 mg/kg Q2W.

Embodiment 255: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 242 to 247 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 242 to 247 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 242 to 247 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 242 to 247 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 242 to 247, wherein said dosing regimen is > 1.8 mg/kg Q2W.

Embodiment 256: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 242 to 246 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 242 to 246 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 242 to 246 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 242 to 246 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 242 to 246, wherein said dosing regimen is > 1.9 mg/kg Q2W.

Embodiment 257: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 242 to 245 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 242 to 245 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 242 to 245 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 242 to 245 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 242 to 245, wherein said dosing regimen is > 2.0 mg/kg Q2W.

Embodiment 258: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 257 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 257 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 257 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 257 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 257, wherein said dosing regimen is < 2.4 mg/kg Q2W.

Embodiment 259: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 257 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 257 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 257 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 257 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 257, wherein said dosing regimen is < 2.2 mg/kg Q2W.

Embodiment 260: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 257 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 257 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 257 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 257 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 257, wherein said dosing regimen is < 2.1 mg/kg Q2W.

Embodiment 261 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 257 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 257 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 257 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 257 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 257, wherein said dosing regimen is < 2.0 mg/kg Q2W.

Embodiment 262: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 241 or 250 to 256 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 241 or 250 to 256 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 241 or 250 to 256 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 241 or 250 to 256 or the kit according to any one of embodiments 23 to 57 or 127 to 241 or 250 to 256, wherein said dosing regimen is < 1.9 mg/kg Q2W. Embodiment 263: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 240 or 250 to 255 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 240 or 250 to 255 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 240 or 250 to 255 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 240 or 250 to 255 or the kit according to any one of embodiments 23 to 57 or 127 to 240 or 250 to 255, wherein said dosing regimen is < 1.8 mg/kg Q2W.

Embodiment 264: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 239 or 250 to 254 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 239 or 250 to 254 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 239 or 250 to 254 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 239 or 250 to 254 or the kit according to any one of embodiments 23 to 57 or 127 to 239 or 250 to 254, wherein said dosing regimen is < 1.7 mg/kg Q2W.

Embodiment 265: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 238 or 250 to 253 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 238 or 250 to 253 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 238 or 250 to 253 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 238 or 250 to 253 or the kit according to any one of embodiments 23 to 57 or 127 to 238 or 250 to 253, wherein said dosing regimen is < 1 .6 mg/kg Q2W.

Embodiment 266: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 1.2-2.4 mg/kg Q2W.

Embodiment 267: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 1.4-2.2 mg/kg Q2W. Embodiment 268: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 1.5-2.1 mg/kg Q2W.

Embodiment 269: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 1.4-2.0 mg/kg Q2W.

Embodiment 270: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 1.6 mg/kg Q2W.

Embodiment 271 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 1.8 mg/kg Q2W.

Embodiment 272: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 2.0 mg/kg Q2W.

Embodiment 273: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 90 mg flat dose Q2W.

Embodiment 274: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 100 mg flat dose Q2W.

Embodiment 275: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 110 mg flat dose Q2W.

Embodiment 276: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 120 mg flat dose Q2W.

Embodiment 277: The method according to any one of embodiments 1 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 130 mg flat dose Q2W.

Embodiment 278: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 140 mg flat dose Q2W.

Embodiment 279: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 150 mg flat dose Q2W.

Embodiment 280: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is > 160 mg flat dose Q2W.

Embodiment 281 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 273 to 280 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 273 to 280 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 273 to 280 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 273 to 280 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 273 to 280, wherein said dosing regimen is < 200 mg flat dose Q2W.

Embodiment 282: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 273 to 280 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 273 to 280 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 273 to 280 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 273 to 280 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 273 to 280, wherein said dosing regimen is < 190 mg flat dose Q2W.

Embodiment 283: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 273 to 280 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 273 to 280 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 273 to 280 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 273 to 280 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 273 to 280, wherein said dosing regimen is < 180 mg flat dose Q2W.

Embodiment 284: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 273 to 280 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 273 to 280 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 273 to 280 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 273 to 280 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 273 to 280, wherein said dosing regimen is < 170 mg flat dose Q2W.

Embodiment 285: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 273 to 280 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 273 to 280 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 273 to 280 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 273 to 280 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 273 to 280, wherein said dosing regimen is < 160 mg flat dose Q2W.

Embodiment 286: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 273 to 279 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 273 to 279 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 273 to 279 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 273 to 279 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 273 to 279, wherein said dosing regimen is < 150 mg flat dose Q2W.

Embodiment 287: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or 273 to 278 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or 273 to 278 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or 273 to 278 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or 273 to 278 or the kit according to any one of embodiments 23 to 57 or 127 to 235 or 273 to 278, wherein said dosing regimen is < 140 mg flat dose Q2W.

Embodiment 288: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 90-200 mg flat dose Q2W.

Embodiment 289: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 100-190 mg flat dose Q2W.

Embodiment 290: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 110-180 mg flat dose Q2W.

Embodiment 291 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 190-225 mg flat dose Q2W.

Embodiment 292: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 192-224 mg flat dose Q2W.

Embodiment 293: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 120 mg flat dose Q2W.

Embodiment 294: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 130 mg flat dose Q2W. Embodiment 295: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 140 mg flat dose Q2W.

Embodiment 296: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 150 mg flat dose Q2W.

Embodiment 297: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 128 mg flat dose Q2W.

Embodiment 298: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 144 mg flat dose Q2W.

Embodiment 299: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 235 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 235 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 235 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 235 or the kit according to any one of embodiments 23 to 57 or 127 to 235, wherein said dosing regimen is 160 mg flat dose Q2W.

Embodiment 300: The method according to any one of embodiments 1 or 12 or 26 to 299 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 299 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 299 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 299 or the kit according to any one of embodiments 23 to 299, wherein said treatment with said immunoconjugate is carried out as a monotherapy.

Embodiment 301 : The method according to any one of embodiments 1 or 12 or 26 to 300 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 300 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 300 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 300 or the kit according to any one of embodiments 23 to 300, wherein said immunoconjugate is precemtabart tocentecan.

Embodiment 302: The method according to any one of embodiments 1 or 12 or 26 to 301 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 301 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 301 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 301 or the kit according to any one of embodiments 23 to 301 , wherein said immunoconjugate is the compound disclosed as precemtabart tocentecan in WHO Drug Information, Vol. 37, No. 4, 2023 (page 1135-1139).

Precemtabart tocentecan can be prepared by standard methods of molecular biology, protein preparation and chemical synthesis known to the skilled person and described herein in the context of ADC1.

Embodiment 303: The method according to any one of embodiments 1 or 12 or 26 to 302 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 302 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 302 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 302 or the kit according to any one of embodiments 23 to 302, wherein said immunoconjugate is the compound defined by CAS (Chemical Abstracts Service) number 2873366-83-5.

Embodiment 304: The method according to any one of embodiments 52 to 303 or the immunoconjugate according to any one of embodiments 52 to 303 or the use according to any one of embodiments 52 to 303 or the pharmaceutical composition according to any one of embodiments 52 to 303 or the kit according to any one of embodiments 52 to 303, wherein the antibody in Formula (IV) is mAb1 , S is a sulfur atom of a cysteine of the antibody mAb1 , and n is a number of [(linker)-(exatecan)] moieties covalently linked to mAb1 , wherein S is a sulfur atom of a cysteine of mAb1 capable of forming an interchain disulfide bridge.

Embodiment 305: The method according to any one of embodiments 50 to 304 or the immunoconjugate according to any one of embodiments 50 to 304 or the use according to any one of embodiments 50 to 304 or the pharmaceutical composition according to any one of embodiments 50 to 304 or the kit according to any one of embodiments 50 to 304, wherein n (also referred to as the DAR (drug-to-antibody ratio)) is between 1 and 10.

Embodiment 306: The method according to any one of embodiments 50 to 304 or the immunoconjugate according to any one of embodiments 50 to 304 or the use according to any one of embodiments 50 to 304 or the pharmaceutical composition according to any one of embodiments 50 to 304 or the kit according to any one of embodiments 50 to 304, wherein n is between 7.5 and 8.0.

Embodiment 307: The method according to any one of embodiments 50 to 304 or the immunoconjugate according to any one of embodiments 50 to 304 or the use according to any one of embodiments 50 to 304 or the pharmaceutical composition according to any one of embodiments 50 to 304 or the kit according to any one of embodiments 50 to 304, wherein n is about 8.

Embodiment 308: The method according to any one of embodiments 1 or 12 or 26 to 307 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 307 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 307 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 307 or the kit according to any one of embodiments 23 to 307, wherein all doses of said immunoconjugate administered to said patient contain the same amount of said immunoconjugate.

Embodiment 309: The method according to any one of embodiments 1 or 12 or 26 to 308 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 308 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 308 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 308 or the kit according to any one of embodiments 23 to 308, wherein said cancer/said patient is ECOG PS (Eastern Cooperative Oncology Group Performance Status) <1 .

Embodiment 310: The method according to any one of embodiments 1 or 12 or 26 to 309 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 309 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 309 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 309 or the kit according to any one of embodiments 23 to 309, wherein said administration is by intravenous administration.

Embodiment 311 : The method according to any one of embodiments 1 or 12 or 26 to 310 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 310 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 310 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 310 or the kit according to any one of embodiments 23 to 310, wherein said treatment is performed in combination with primary G-CSF prophylaxis.

Embodiment 312: The method according to any one of embodiments 29 to 311 or the immunoconjugate according to any one of embodiments 29 to 311 or the use according to any one of embodiments 29 to 311 or the pharmaceutical composition according to any one of embodiments 29 to 311 or the kit according to any one of embodiments 29 to 311 , wherein the linker is a linker cleavable by the human enzyme glucuronidase.

Embodiment 313: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said administration is Q2W.

Embodiment 314: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said treatment comprises dosing of said immunoconjugate Q2W.

Embodiment 315: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen involves administration of said immunoconjugate Q2W.

Embodiment 316: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is > 2.0 mg/kg Q2W. Embodiment 317: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is > 2.2 mg/kg Q2W.

Embodiment 318: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is > 2.4 mg/kg Q2W.

Embodiment 319: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 318 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 318 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 318 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 318 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 318, wherein said dosing regimen is < 2.6 mg/kg Q2W.

Embodiment 320: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 318 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 318 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 318 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 318 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 318, wherein said dosing regimen is < 2.8 mg/kg Q2W.

Embodiment 321 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 318 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 318 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 318 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 318 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 318, wherein said dosing regimen is 2.0-2.6 mg/kg Q2W. Embodiment 322: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 318 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 318 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 318 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 318 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 318, wherein said dosing regimen is 2.2-2.6 mg/kg Q2W.

Embodiment 323: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 318 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 318 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 318 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 318 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 318, wherein said dosing regimen is 2.0-2.4 mg/kg Q2W.

Embodiment 324: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.2-2.4 mg/kg Q2W.

Embodiment 325: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.3-2.5 mg/kg Q2W.

Embodiment 326: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.1 mg/kg Q2W. Embodiment 327: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.2 mg/kg Q2W.

Embodiment 328: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.3 mg/kg Q2W.

Embodiment 329: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.4 mg/kg Q2W.

Embodiment 330: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.5 mg/kg Q2W.

Embodiment 331 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.6 mg/kg Q2W. Embodiment 332: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.7 mg/kg Q2W.

Embodiment 333: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen is 2.8 mg/kg Q2W.

Embodiment 334: The method according to any one of embodiments 1 or 12 or 26 to 333 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 333 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 333 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 333 or the kit according to any one of embodiments 23 to 333, wherein said treatment with said immunoconjugate/said pharmaceutical composition is a combination therapy with bevacizumab.

Embodiment 335: The method according to any one of embodiments 1 or 12 or 26 to 334 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 334 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 334 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 334 or the kit according to any one of embodiments 23 to 334, wherein said treatment with said immunoconjugate/said pharmaceutical composition is a combination therapy with capecitabine.

Embodiment 336: The method according to any one of embodiments 1 or 12 or 26 to 335 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 335 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 335 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 335 or the kit according to any one of embodiments 23 to 335, wherein said treatment with said immunoconjugate/said pharmaceutical composition is a combination therapy with 5-fluorouracil. Embodiment 337: The method according to any one of embodiments 1 or 12 or 26 to 336 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 336 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 336 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 336 or the kit according to any one of embodiments 23 to 336, wherein said treatment with said immunoconjugate/said pharmaceutical composition is a combination therapy with bevacizumab and capecitabine.

Embodiment 338: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 336 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 336 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 336 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 336 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 336, wherein said treatment with said immunoconjugate/said pharmaceutical composition is a combination therapy with 5-fluorouracil and bevacizumab.

Embodiment 339: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen involves a combination treatment with bevacizumab.

Embodiment 340: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen involves a combination treatment with capecitabine.

Embodiment 341 : The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen involves a combination treatment with 5-fluorouracil.

Embodiment 342: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen involves a combination treatment with bevacizumab and capecitabine.

Embodiment 343: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said dosing regimen involves a combination treatment with 5-fluorouracil and bevacizumab.

Embodiment 344: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said immunoconjugate/pharmaceutical composition is administered as part of a combination treatment with bevacizumab.

Embodiment 345: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said immunoconjugate/pharmaceutical composition is administered as part of a combination treatment with capecitabine. Embodiment 346: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said immunoconjugate/pharmaceutical composition is administered as part of a combination treatment with 5-fluorouracil.

Embodiment 347: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said immunoconjugate/pharmaceutical composition is administered as part of a combination treatment with bevacizumab and capecitabine.

Embodiment 348: The method according to any one of embodiments 1 or 12 or 26 to 57 or 127 to 242 or 250 to 312 or the immunoconjugate according to any one of embodiments 2 to 6 or 29 to 57 or 127 to 242 or 250 to 312 or the use according to any one of embodiments 7 to 11 or 18 to 22 or 26 to 57 or 127 to 242 or 250 to 312 or the pharmaceutical composition according to any one of embodiments 13 to 17 or 26 to 57 or 127 to 242 or 250 to 312 or the kit according to any one of embodiments 23 to 57 or 127 to 242 or 250 to 312, wherein said immunoconjugate/pharmaceutical composition is administered as part of a combination treatment with 5-fluorouracil and bevacizumab.

EXAMPLES

The following examples describe inter alia treatment of cancer patients with an immunoconjugate. It is understood that various embodiments of the disclosure reflected in the examples may be practiced, given the general description provided above. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the description and examples should not be construed as limiting the scope of the invention.

Example 1

In the clinical study NCT05464030, subjects suffering from colorectal cancer were treated with the anti-CEACAM5 antibody-drug conjugate M9140, as described below.

CEACAM5 is a cell surface protein with limited expression in adult healthy tissues, but high expression in various adenocarcinomas, particularly in colorectal cancer (> 90% of patients). M9140 is a novel anti-CEACAM5 ADC with a topoisomerase 1 inhibitor (Topl i) payload (exatecan). The B-glucuronide linker connecting the M9140 antibody backbone to the payload is highly stable in circulation (drug-to-antibody ratio = 8). In preclinical models, M9140 has demonstrated strong potency, antitumor activity, and a bystander effect.

NCT05464030 is a phase I, two-part, multicenter, open-label study of anti-CEACAM5 antibody drug conjugate M9140 in participants with colorectal cancer.

In Example 1 , the dose escalation part (Part 1A) of the trial was carried out. This part of the study NCT05464030 investigated the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of M9140 as monotherapy (Q3W [Day 1 of 21-day cycles]; /.v.) in adults with CRC (Eastern Cooperative Oncology Group Performance Status (ECOG PS) < 1) who had received >2 prior lines of treatment. The primary objective of Part 1A was to determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE). Key eligibility criteria, the dose escalation scheme and key endpoints are summarized in Fig. 4.

As can be seen from Figure 4, at a data cut-off date of April 23, 2024, 40 patients from the US, EU, and Japan were treated across 7 dose levels (DLs): 0.6 mg/kg, 1.2 mg/kg (n = 3, each), 2.4 mg/kg (n = 7), 2.6 mg/kg (n = 4), 2.8 mg/kg (n = 12), 3.0 mg/kg (n = 4), and 3.2 mg/kg (n = 7, including 3 patients with primary Granulocyte-Colony Stimulating Factor (G-CSF) prophylaxis). Most patients were heavily pre-treated (80% had >3 lines of prior treatment; 100% received irinotecan). Baseline and demographic characteristics are summarized in Figure 5. The observed dose-limiting toxicities (DLTs) are summarized in Figure 6. Overall, 7 patients experienced DLTs; the majority were hematological adverse events at dose levels 3.0 and 3.2 mg/kg; one patient (at 2.8 mg/kg) experienced a grade 5 event of sepsis. Figure 7 summarizes the incidence of severe adverse events. The most frequently reported Grade >3 treatment-emergent adverse events (TEAEs) were neutropenia in 19 (47.5%) patients, and leukopenia in 12 (30%) patients. No events of ocular toxicity or interstitial lung disease (ILD) were reported.

As can be seen from Figure 8, the best objective response per RECIST v1.1 was partial response (PR) in 4 (10.0%) patients (3 confirmed), and all these occurred at dose levels of >2.4 mg/kg. Stable disease (SD) was observed in 22 (55%) patients, including 6 (15.0%) lasting for >100 days and progressive disease (PD) in 7 (17.5%) patients. For a total of 8 (20%) patients, the best overall response was not evaluable.

Figure 9 summarizes the treatment duration and response over time. At dose levels >2.4 mg/kg, 8 of 34 (23.5%) patients stayed on treatment for 6 months, 2 of whom were on treatment for >9 months. Treatment-emergent adverse events led to dose reductions in 8 (20.0%) patients, all at dose level >2.8 mg/kg.

Figure 10 shows that the preliminary median progression-free survival (PFS) was 6.6 months (95% Cl: 4.6, 8.4) for the overall population. As of data cut-off (April 23, 2024), 11 (27.5%) patients are continuing treatment. Median progression free survival was 6.7 [95% Cl: 5.0, 8.8] vs 2.1 [95% Cl: 1.2, ne] months for patients treated with M9140 >2.4 mg/kg vs <2.4 mg/kg, respectively.

M9140 showed systemic stability in this first-in-human trial.

In sum, based on clinical data on safety, tolerability, clinical activity and pharmacokinetics (PK) collected during dose escalation, and PK/pharmacodynamics modelling data it was found that 2.4 mg/kg and 2.8 mg/kg are particularly advantageous. Indeed, encouraging and durable antitumor activity was observed at therapeutic doses >2.4 mg/kg, and all partial responses were observed at doses >2.4 mg/kg, while simulations based on Quantitative systems pharmacology (QSP) model imply that dose levels < 2.0 mg/kg are expected to result in limited tumor growth inhibition in patients. At the same time, all treatment-emergent adverse events that led to dose reductions occurred at dose level >2.8 mg/kg. Thus, 2.4 mg/kg and 2.8 mg/kg were selected as the recommended doses for expansion (RDEs), and 2.8 mg/kg was selected as maximum tolerable dose (MTD). Example 2

A dose expansion study is carried out.

Approximately 60 participants with locally advanced or metastatic colorectal cancer are randomized in a 1 :1 ratio to M9140 at a dosing regimen of 2.8 mg/kg i.v. Q3W (A1) and 2.4 mg/kg i.v. Q3W (A2).

It is expected that the data obtained with respect to safety and efficacy are consistent with the data of Example 1 .

Furthermore, approximately 20-30 additional participants with locally advanced or metastatic colorectal cancer receive M9140 with an administration regime of 1.6 mg/kg i.v. Q2W (DL1) and 2.0 mg/kg i.v. Q2W (DL2).

With respect to the total dose administered, the dosing regimen of 1.6 mg/kg i.v. Q2W (DL1) corresponds to 2.4 mg/kg i.v. Q3W and the dosing regimen of 2.0 mg/kg i.v. Q2W (DL2) corresponds to 2.8 mg/kg i.v. Q3W.

It is expected that also 1.6 mg/kg i.v. Q2Wand 2.0 mg/kg i.v. Q2W result in safe and efficacious treatment.

The data obtained in Example 2 for A1 and A2 at a data cut-off date of 25 March 2025 confirmed the observations made in Example 1 .

As of 25 March 2025, -42% patients remained on treatment (Figure 11), including 3 patients on treatment for >9 months. The mean duration of therapy was 23.3 ± 11 .72 weeks, with nearly 60% of patients having received >6 cycles of M9140 therapy.

Tumor shrinkage was >10% in 35% of patients (n=21), of whom 21.7% (n=13) had >30% shrinkage (n=13) (Figure 12). With a dosing regime of 2.8 mg/kg Q3W DL, the (unconfirmed) ORR was 31.0% (95% Cl: 15.3, 50.8) (Figure 13) with 3 unconfirmed responders still on- treatment. DCR at week 12 was 72.4% (DCR defined as having a overall response assessment of CR, PR, SD, or non-CR/non-PD at week 12 visit (at relative day 84-7) or later, prior to documented PD). Median PFS was 6.9 months (95% Cl: 4.4, NE) after a median follow-up of 8.1 months (Figure 15).

Most common grade >3 TEAEs were anemia and neutropenia (38.3% and 43.3%, respectively) (Figure 16). Hematologic AEs (any grade) were reported in 83.3% patients; grade >3, 53.3% patients, with anemia (38.5%) and neutropenia (43.3%) being most common. Most common TRAEs were anemia, nausea, and neutrophil count decreased (Figure 17); most common serious TRAEs were febrile neutropenia, anemia, and platelet count decreased. Most Gl toxicities were grade 1-2 (76.7%); grade 3 gastrointestinal (Gl) events were reported in 5 patients (none related to M9140); no grade 4/5 Gl events (Figure 16). There were no discontinuations due to M9140-related AEs, and no treatment-related deaths (Figure 14). Moreover, there were no cases of ILD or ocular toxicities (Figure 14).

The PK profiles at 2.4 mg/kg and 2.8 mg/kg were consistent with the dose escalation phase data (Example 1) with large inter-individual variability (%CV of 55%).

With a treatment of 2.8 mg/kg Q3W, an ORR of 31 % (95% Cl: 15.3, 50.8; confirmed: 17.2% [95% Cl: 5.8, 35.8]) was observed. The median PFS at 2.8 mg/kg Q3Wwas 6.9 months (95% Cl: 4.4, NE) after median follow-up of 8.1 months. No ILD or ocular toxicities were observed; gastrointestinal (Gl) toxicities were mild. Grade >3 AEs were mainly hematological.

The ORR with 2.8 mg/kg Q3W treatment was higher than with 2.4 mg/kg Q3W treatment, and overall comparable safety and consistent PK profiles between the dose levels tested were observed. This supports 2.4 mg/kg Q3Wand 2.8 mg/kg Q3W, in particular 2.8 mg/kg Q3W, as highly advantageous dosing regimens.

ORRs and mPFS observed in this Phase 1 study of M9140 compare favorably vs. current monotherapy standard of care treatments (ORRs 1-2%; mPFS 1.9-3.7 months; cf. Dasari A, et al. The Lancet 2023; 402:41-53; Weinberg BA, et al. Clin Adv Hematol Oncol. 2016; 14:630- 638; Mayer RJ, et al. N Engl J Med. 2015; 372:1909-1919; Grothey A, et al. The Lancet 2013; 381 :303-312) in 3L+ mCRC and recent phase 3 data with trifluridine-tipiracil + bevacizumab (ORR 6.1 %; mPFS 5.6 months [95% Cl: 4.5, 5.9]; cf. Prager GW, et al. N Engl J Med 2023; 388:1657-1667).

REFERENCES

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Cervantes A, Adam R, Rosello D, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up; Ann Oncol. 2023;34(1): 10-32.

Dasari et al; Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study Lancet 2023; 402: 41-53

Dekker E, Tanis PJ, Vleugels JLA, et al. Colorectal cancer. Lancet. 2019;394(10207): 1467-80. [PE0155605]

Ducreux M, Chamseddine A, Laurent-Puig P, et al. Molecular targeted therapy of BRAF- mutant colorectal cancer. TherAdv Med Oncol. 2019;11 :1758835919856494. [PE0161036]

Grothey A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. The Lancet 2013; 381 :303-312.

Martinelli E, Ciardiello D, Martini G, et al. Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives. Ann Oncol. 2020;31 (1):30-40. [PE0161034]

Masuishi T, Tsuji A, Kotaka M, et al. Phase 2 study of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type metastatic colorectal cancer: JACCRO CC-08. Br J Cancer. 2020;23:1490-95.

Mayer RJ, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015; 372:1909-1919.

National Comprehensive Cancer Network. Colon Cancer (Version 4.2023). https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed November 30, 2023.

Prager et al ; Trifluridine— Tipiracil and Bevacizumab in Refractory Metastatic Colorectal

Cancer N Engl J Med 2023;388:1657-67 Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51(5):587-94. [PE0161040]

Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021 ;39:273- 84.

Walter T, Hawkins NS, Pollock RF, et al. Systematic review and network meta-analyses of third-line treatments for metastatic colorectal cancer. J Cancer Res Clin Oncol. 2020; 146(10):2575-87. [PE0158720]

Weinberg BA, Marshall JL, Salem ME. Trifluridine/tipiracil and regorafenib: new weapons in the war against metastatic colorectal cancer. Clin Adv Hematol Oncol. 2016;14:630-8.

Xu J, Kim TW, Shen L, et al. Results of a randomized, double-blind, placebo-controlled, Phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA Study. J Clin Oncol. 2018;36:350-358.

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Claims

1. An anti-CEACAM5 immunoconjugate for use in the treatment of colorectal cancer according to a method which comprises administering said immunoconjugate according to a dosing regimen of 2.3-2.9 mg/kg Q3W, wherein said immunoconjugate comprises an antibody covalently linked via a linker to at least one growth inhibitory agent, wherein said antibody is an antibody which binds to human CEACAM5 protein and which 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 wherein the linker is a linker cleavable by a human enzyme selected from glucuronidase and legumain, and wherein the growth inhibitory agent is exatecan.

2. The anti-CEACAM5 immunoconjugate for use according to claim 1 , wherein 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.

3. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 or 2, wherein 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.

4. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 3, wherein said antibody is an antibody which binds to human CEACAM5 protein and which 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.

5. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 4, wherein the immunoconjugate has the following formula (II):

Formula (II), wherein S is a sulfur atom of the antibody, and wherein n is a number of [(linker)-(growth inhibitory agent)] moieties covalently linked to the antibody.

6. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 4, wherein the immunoconjugate has the following formula (IV):

Formula (IV), wherein S is a sulfur atom of the antibody, and wherein n is a number of [(linker)—

(exatecan)] moieties covalently linked to the antibody.

7. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 6, wherein said dosing regimen is 2.4-2.8 mg/kg Q3W.

8. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 7, wherein said dosing regimen is applied for n weeks, wherein n is > 6.

9. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 8, wherein said colorectal cancer is locally advanced or metastatic colorectal cancer.

10. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 9, wherein at least 60% of the tumor cells of said colorectal cancer are CEACAM5-positive.

11. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 10, wherein the patient is a human.

12. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 11 , wherein said treatment is 2L+ treatment (i.e. second-line or later).

13. The anti-CEACAM5 immunoconjugate for use according to any one of claims 1 to 12, wherein before said treatment said patient has undergone Irinotecan treatment.

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