Use of Anti-her3 antibody-drug conjugates in cancer treatment

Abstract

The invention provides an antibody-drug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, for use in treating a cancer selected from the group consisting of brain tumour, lung cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the ranges as defined herein. Specific antibody-drug conjugates for use in treating breast cancer are also provided.

Description

[0001] USE OF ANTI-HER3 ANTIBODY-DRUG CONJUGATES IN CANCER TREATMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to an antibody-drug conjugate that comprises an anti- HER3 antibody, and compositions containing such antibody-drug conjugates, for use in a method of treating various cancers as defined herein. The present invention also relates to the antibody-drug conjugate, and compositions containing such antibodydrug conjugates, for use in a method of treating various cancers, wherein the method comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose range as defined herein.

[0004] BACKGROUND TO THE INVENTION

[0005] HER3 overexpression has been associated with disease progression and worse survival in various solid tumours, and elevated HER3 signalling has been implicated in resistance to EGFR TKI and endocrine therapies, highlighting HER3’s potential as a therapeutic target (Q. Chen et al., Front Immunol. 2023, 14, 1332057; L. Duan et al., Cancer Biol. Ther. 2022, 23, 1-10).

[0006] WO2022 / 170971 and published national applications derived therefrom describes antibody-drug conjugates, in particular the compounds of formula (I) as defined herein. In particular, it discloses compounds of formula (II), such as Compound 1 as defined herein, which is an antibody-drug conjugate composed of an anti-HER3 IgGl monoclonal antibody attached to an average of 8 moieties of a novel topoisomerase I inhibitor payload, defined herein as the compound of formula (II”), via a cleavable tripeptide-based linker as defined herein. In pre-clinical studies (X. Jian et al., Cancer Res. 2023; 83 (7_Suppl): Abstract nr 563), Compound 1 demonstrated potent, dosedependent anti -tumour activity in HER3 -positive cell line- and patient-derived xenograft (CDX and PDX) mouse models.

[0007] However, WO2022 / 170971 specifically discloses the use of Compound 1 in treating only certain cancers, and at different doses from those described herein. In particular, WO2022 / 170971 does not specifically disclose the use of Compound 1 in treating breast cancer at any dose. There remains a need in the art to develop cancer therapies with better therapeutic efficacy and / or safety.

[0008] SUMMARY OF THE INVENTION

[0009] In a first aspect, the invention provides an antibody-drug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, or a pharmaceutically acceptable salt thereof, for use in treating a cancer selected from the group consisting of brain tumour, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 0.5 mg / kg to about 4 mg / kg.

[0010] In another embodiment of the first aspect, the invention provides use of an antibodydrug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, in the manufacture of a medicament for treating a cancer selected from the group consisting of brain tumour, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 0.5 mg / kg to about 4 mg / kg.

[0011] In another embodiment of the first aspect, the invention provides a method of treating a cancer selected from the group consisting of brain tumour, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer; wherein the method comprises administering to a subject in need of such treatment an antibody-drug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 0.5 mg / kg to about 4 mg / kg

[0012] In a second aspect, the invention provides an antibody-drug conjugate comprising an anti-HER.3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, or a pharmaceutically acceptable salt thereof, for use in treating lung cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 2 mg / kg to about 4 mg / kg.

[0013] In another embodiment of the second aspect, the invention provides use of an antibody-drug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, in the manufacture of a medicament for treating lung cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 2 mg / kg to about 4 mg / kg.

[0014] In another embodiment of the second aspect, the invention provides a method of treating lung cancer; wherein the method comprises administering to a subject in need of such treatment an antibody-drug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 2 mg / kg to about 4 mg / kg

[0015] In a third aspect, the invention provides an antibody-drug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, for use in treating a cancer selected from the group consisting of brain tumour, lung cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 0.5 mg / kg to about 4 mg / kg. In another embodiment of the third aspect, the invention provides use of an antibodydrug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, in the manufacture of a medicament for treating a cancer selected from the group consisting of brain tumour, lung cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 0.5 mg / kg to about 4 mg / kg.

[0016] In another embodiment of the third aspect, the invention provides, a method of treating a cancer selected from the group consisting of brain tumour, lung cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer; wherein the method comprises administering to a subject in need of such treatment an antibody-drug conjugate comprising an anti-HER.3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 0.5 mg / kg to about 4 mg / kg.

[0017] In a fourth aspect, the invention provides an antibody-drug conjugate of formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0018] Ab is an HER3 antibody comprising a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15 as defined herein; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 16 as defined herein; and q is the connection number, and is an integer from 1 to 16; for use in treating breast cancer.

[0019] In one embodiment of the fourth aspect, the invention provides use of an antibodydrug conjugate of formula (II), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating breast cancer.

[0020] In one embodiment of the fourth aspect, the invention provides a method of treating breast cancer, wherein the method comprises administering to a subject in need of such treatment an antibody-drug conjugate of formula (II), as defined above, or a pharmaceutically acceptable salt thereof.

[0021] ADVANTAGES

[0022] The present inventors have found that antibody-drug conjugates as defined herein, in particular Compound 1 as defined herein, demonstrated efficacy and safety in treating non-small-cell lung cancer (NSCLC) and breast cancer (BC), in particular heavily pretreated locally advanced / metastatic NSCLC and BC, when dosed in humans at dosages from 0.5 mg / kg to 4.0 mg / kg. In particular, when Compound 1 was used in the treatment of NSCLC and BC in humans when dosed at 2.0 mg / kg and 3.0 mg / kg, the overall response rates (ORRs) and disease control rates (DCRs) at the 2.0 mg / kg and 3.0 mg / kg dose levels were comparable to those seen at higher dose levels, and the safety profile of Compound 1 was considered manageable below the 4.0 mg / kg dose level. This confers an improvement compared with the higher dose levels disclosed for Compound 1 in NSCLC as described in WO2022 / 170971.

[0023] BRIEF DESCRIPTION OF THE FIGURE

[0024] Figure 1 shows the best percent change from baseline in target lesion size (N=51*) in patients with non-small-cell lung cancer (NSCLC) or breast cancer (BC) treated with Compound 1 at doses ranging from 0.5 mg / kg to 5.5 mg / kg, with the following abbreviations and notes: CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. * One patient had non-measurable target lesions at PD due to obstructive atelectasis induced by PD in non-target lesions, and is therefore not presented in plot. ** CR occurred in patient with target lesion as lymph node that shrank to less than 10 mm.

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] GENERAL TERMS AND DEFINITIONS

[0027] This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation, respectively.

[0028] In the context of the present disclosure, the term "about" denotes an interval of accuracy that the person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±10%, such as ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and for example ±0.01%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect. The term “about” allows to account for technical measurement uncertainty and variations when referring for example to a particular quantity or concentration.

[0029] The term “polypeptide” is used in the conventional sense to mean a series of amino acids, typically L-amino acids, connected one to the other, typically by peptide bonds between the a-amino and carboxyl groups of adjacent amino acids. The term “polypeptide” is used interchangeably with the terms “amino acid sequence”, “peptide” and / or “protein”. The term “residues” is used to refer to amino acids in an amino acid sequence.

[0030] The term "variant" refers to a polypeptide that has an equivalent function to the amino acid sequences described herein, but which includes one or more amino acid substitutions, insertions or deletions.

[0031] The sequence may have one or more deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent molecule. These sequences are encompassed by the present invention. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or the amphipathic nature of the residues as long as the activity is retained.

[0032] For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine, valine, glycine, alanine, asparagine, glutamine, serine, threonine, phenylalanine, and tyrosine.

[0033] As used herein, “variant” is synonymous with “mutant” and refers to a polynucleotide or amino acid sequence which differs in comparison to the corresponding wild-type sequence. The term “wild-type” is used to mean a gene or protein having a polynucleotide or amino acid sequence respectively, which is identical with the native gene or protein respectively.

[0034] The nucleic acid sequence may be an RNA or DNA sequence or a variant thereof. The term "polynucleotide" includes an RNA or DNA sequence. It may be single or double stranded. It may, for example, be genomic, recombinant, mRNA or cDNA.

[0035] The terms “selectively binds / selectively binding” and “specifically binds / specifically binding” may be used interchangeably herein. This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, any nucleic acid sequences are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively.

[0036] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure.

[0037] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0038] The terms "comprising", "comprises" and "comprised of as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms "comprising", "comprises" and "comprised of also include the term "consisting of.

[0039] The terms “identity” and “% sequence identity” as used herein, may refer to the proportion of nucleotides or amino acids (expressed in percent) of a contiguous nucleotide sequence or contiguous amino acid sequence respectively which across the sequence, are identical to a reference sequence. The identity is calculated by counting the number of aligned nucleobases or amino acids that are identical (a Match) between the sequence of interest and a reference sequence, and dividing that number by the total number of nucleotides amino acids respectively and multiplying by 100. Therefore, Percentage of Identity = (Matches x 100) / Length of aligned region. Insertions and deletions are not allowed in the calculation the percentage of identity. Chemical modifications of nucleotides may be disregarded provided that the functional capacity to form Watson-Crick base pairing is retained.

[0040] Identity comparisons can be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs can calculate % identity between two or more sequences. A suitable computer program for carrying out such an alignment is the GCG Wisconsin Bestfit package (University of Wisconsin, U.S.A.; Devereux et al., 1984, Nucleotide sequences Research 12:387). Examples of other software than can perform sequence comparisons include, but are not limited to, the BLAST package (see Ausubel et al., 1999 ibid - Chapter 18), FASTA (Atschul et al., 1990, J. Mol. Biol., 403-410) and the GENEWORKS suite of comparison tools. Both BLAST and FASTA are available for offline and online searching. For example, the percentage identity between two polypeptide sequences may be readily determined by BLAST which is freely available at http: / / blast.ncbi.nlm.nih.gov.

[0041] Once the software has produced an optimal alignment, it is possible to calculate % identity. The software typically does this as part of the sequence comparison and generates a numerical result.

[0042] The term "alkyl" refers to a monoradical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group comprises from 1 to 40, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, carbon atoms, such as 1 to 30, such as 1 to 20 carbon atoms, such as 1 to 12 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, iso-propyl (also called 2-propyl or 1 methylethyl), butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2- dimethylpropyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-undecyl, n-dodecyl, n- tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n- nonadecyl, n-icosyl, n-triacontyl, n-tetracontyl, and the like.

[0043] “Amido” means a group of formula -C(=O)-N(R)-, wherein R is independently H or alkyl (as defined above, either in its broadest aspect or any of the above preferred aspects).

[0044] The term "halogen" generally refers to fluorine, chlorine, bromine or iodine, and it may be, for example, fluorine or chlorine.

[0045] The term "heterocyclic ring" means a saturates or partially unsaturated non-aromatic ring structure having 1, 2, or 3, preferably 1 or 2 rings, and containing from 3 to 14, preferably 3 to 10, such as 3, 4, 5, 6, or 7, ring atoms of which 1, 2, 3, or 4 ring atoms are heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur, and are preferably selected from O, S, and N.

[0046] Preferably, in each ring of the heterocyclyl group the maximum number of O atoms is 2, more preferably 1, the maximum number of S atoms is 2, more preferably 1, and the maximum total number of O and S atoms is 2. Exemplary heterocyclic rings include morpholine, pyrrolidine, imidazolidinyl, pyrazolidine, piperidine, piperazine, di- and tetrahydrofuran, di- and tetrahydrothiophene, di- and tetrahydropyran, lactones, lactams, cyclic imides, and cyclic anhydrides.

[0047] The term “treatment cycle” takes its normal meaning in the field of oncology to mean a period of time over which an anti-cancer drug is administered, followed by a rest period during which the drug is not administered.

[0048] ANTIBODY-DRUG CONJUGATE

[0049] The present invention generally relates to antibody-drug conjugates (ADCs) for uses as defined herein. ADCs are a class of targeted therapeutics that improves both the selectivity and the cytotoxic activity of drugs, such as cancer drugs, by targeting the drugs to specific targets such as cancer cells. In general, ADCs comprise three main components: (i) an antibody (such as a monoclonal antibody) conjugated to (ii) a linker, which in turn is also conjugated to (iii) a cargo or payload (such as a cytotoxic or chemotherapeutic drug). The term “cytotoxic” or “chemotherapeutic drug” refers to a drug that reduces or eliminates the viability of a cell. Suitable cytotoxic or chemotherapeutic drugs will be known in the art. Components (ii) and (iii) are together referred to herein as the “payload-linker” or “linker-payload” moiety, and are described in more detail below.

[0050] It will be understood by the person skilled in the art that all references in this specification to the term “antibody-drug conjugate” will also include compositions comprising mixtures of antibody-drug conjugates, each which may have different drug-antibody ratios (DARs). These are described in more detail below with reference to compositions. The drug-antibody ratio (DAR) of the antibody-drug conjugates as described herein may vary. Consequently, the composition may comprise a mixture of antibody-drug conjugates having a number of different DARs, and may therefore have an average DAR which is non-integral. In this specification, the terms “DAR” and “connection number” are synonymous, and the terms “average DAR” and “average connection number” are synonymous.

[0051] It will be understood that the term “DAR” or “connection number” when referring to a specific antibody-drug conjugate refers to the number of drug molecules connected (e.g. conjugated) to the antibody, optionally via linkers, in any single antibody-drug conjugate. Thus, the connection number (referred to herein as “q”) can be considered as the specific number of linker-payload structures conjugated to the antibody in a given antibody-drug conjugate. It will also be understood that the connection number q can affect the safety and therapeutic effectiveness of the antibody-drug conjugate. The number of drug molecules per antibody molecule, also referred to herein as the drug-antibody ratio (DAR), can be characterized by conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays and HPLC.

[0052] The present inventors have surprisingly found that the antibody-drug conjugates according to the invention are particularly effective at treating cancers. The antibody-drug conjugate for use in the first to third aspects of the present invention comprises an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit. In one embodiment, the TOPO1 inhibitor is a camptothecin or a derivative thereof. In one embodiment, the TOPO1 inhibitor is an exatecan or a derivative thereof.

[0053] Any suitable anti-HER3 antibody or fragment thereof may be used. Example anti- HER3 antibody CDRs, variable region sequences, and heavy and light chain sequences are provided below.

[0054] Table 1 - Example anti-HER3 antibody sequences 1 (Antibody A) In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme.

[0055] In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme.

[0056] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme.

[0057] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0058] In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0059] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0060] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0061] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13.

[0062] In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14.

[0063] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0064] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and a light chain variable region of the anti- HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6.

[0065] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and a light chain variable region of the anti- HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12.

[0066] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14. In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 13; and a light chain variable region of the anti-HER3 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 14.

[0067] In some embodiments, a heavy chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15.

[0068] In some embodiments, a light chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 16. In some embodiments, a heavy chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 15, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0069] In some embodiments, a heavy chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and a light chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6.

[0070] In some embodiments, a heavy chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and a light chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12.

[0071] In some embodiments, a heavy chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15; and a light chain of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16. In some embodiments, a heavy chain of the anti- HER3 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 15; and a light chain of the anti-HER3 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 16.

[0072] In some embodiments, the anti-HER3 antibody or fragment thereof comprises two heavy chains and / or two light chains as described above. In some embodiments, the anti-HER3 antibody or fragment thereof comprises or consists of two heavy chains and two light chains as described above. For example, in some embodiments, the anti- HER3 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-HER3 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 15; and two light chains consisting of the amino acid sequence of SEQ ID NO: 16. Table 2 - Example anti-HER3 antibody sequences 2 (Antibody B)

[0073] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 18, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme.

[0074] In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme. In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 18, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme.

[0075] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0076] In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0077] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0078] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0079] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 29, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 29. In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 30 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 30.

[0080] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 29, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 30 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0081] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 29, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 18; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 30 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22.

[0082] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 29, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 24; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 30 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28.

[0083] In some embodiments, the anti-HER3 antibody or fragment thereof comprises two heavy chains and / or two light chains as described above. In some embodiments, the anti-HER3 antibody or fragment thereof comprises or consists of two heavy chains and two light chains as described above. For example, in some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 29; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 30. In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 29; and a light chain variable region of the anti-HER3 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 30. Table 3 - Example anti-HER3 antibody sequences 3 (Antibody C)

[0084] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme.

[0085] In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 34, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 35, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 36, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme. In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 34, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 35, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 36, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat definition scheme.

[0086] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 37, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 38, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0087] In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 40, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 41; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 42, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0088] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 37, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 38, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 40, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 41, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 42, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT definition scheme.

[0089] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0090] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43. In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44.

[0091] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0092] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 34; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 35; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 36.

[0093] In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 37; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 38; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 39; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 40; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 41; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 42.

[0094] In some embodiments, the anti-HER3 antibody or fragment thereof comprises two heavy chains and / or two light chains as described above. In some embodiments, the anti-HER3 antibody or fragment thereof comprises or consists of two heavy chains and two light chains as described above. For example, in some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43; and a light chain variable region of the anti-HER3 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44. In some embodiments, a heavy chain variable region of the anti-HER3 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 43; and a light chain variable region of the anti-HER3 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 44. In one embodiment, the antibody-drug conjugate for use according to the invention has the structure represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0095] Ab is the anti-HER3 antibody or fragment thereof as defined herein; each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, and amido (preferably selected from a direct bond, a carbon-carbon triple bond, and a carbon-carbon double bond);

[0096] Rx and Ry are each independently selected from H and Cl -4 alkyl; each m is independently selected from 0, 1, 2, 3, 4, 5 and 6; yl is selected from any integer between 1 and 6 (such as 4, 5, and 6); each y2 is independently selected from any integer between 0 and 15 (such as between 6 and 15); each y3 is independently selected from 1, 2, and 3; each y4 is independently selected from 0 and 1; position 1 is attached to Ab via an S atom, and position 2 is attached to L2 or L3;

[0097] L2 is absent or present, and when L2 is present, L2 is selected from: selected from any integer between 1 and 6 (such as 4, 5, and 6); each y2 is independently selected from any integer between 0 and 10 (such as between 6 and 10); each y3 is independently selected from 1 or 2; each y4 is independently selected from 0 and 1, position 1 is attached to LI, and position 2 is attached to L3;

[0098] L3 is selected from an amino acid residue or a short peptide consisting of 2-10 amino acid residues; the amino acid residue is selected from natural amino acid residues, non-natural amino acid residues, or selected from amino acid residue represented by AA1 or stereoisomer thereof; ; in the amino acid residue represented by AA1, any one of Ra and

[0099] Rb is H, and the other or, Ra and Rb, together with the carbon atom to which they are both attached, form a 5-6 membered heterocyclic ring, and said 5-6 membered heterocyclic ring is piperidine ring or piperazine ring. r, rl, ria and rib are each independently 0, 1, 2, 3, 4 or 5;

[0100] Rml, Rnl, Rm la, Rnla, Rm lb and Rnlb are each independently H, Cl -6 alkyl or - COORxl, wherein, Rxl is Cl -6 alkyl; or, Rml and Rnl, Rm la and Rnla, and Rm lb and Rnlb, together with the nitrogen atom to which they are both attached, form a 5-6 membered heterocyclic ring, and of said 5-6 membered heterocyclic ring, the heteroatom is selected from 1 or 2 N atoms; the said 5-6 membered heterocyclic ring is optionally substituted with one or more RO’;

[0101] Rz is selected from Cl -6 alkyl;

[0102] RO and RO’ are each independently selected from Cl -6 alkyl, -NRm2Rn2 or 5-6 membered heterocyclyl optionally substituted with Cl -6 alkyl; of said 5-6 membered heterocyclyl, the heteroatom is selected from 1 or 2 N atoms;

[0103] Rm2 and Rn2 are each independently selected from H and Cl -6 alkyl; position 2 is attached to W or X;

[0104] R1 and R2 are each independently selected from H, halogens and Cl -4 alkyl; or, R1 and R2, together with the carbon atom to which they are both attached form a 5-6 membered heterocyclic ring, the heterocyclic ring contains 1, 2, or 3 of O, S, or N or any combination thereof;

[0105] R3 is selected from H and Cl -4 alkyl; or R3 and X, together with the carbon atom to which they are both attached, form a 5-6 membered carbon ring;

[0106] W is absent or present, when W is present, W is selected from -O-, -S-, -NR4-, position 1 is attached to X, and position 2 is attached to L4 or L3;

[0107] X is selected from optionally substituted -(CH2)nl-,v R7 ,R7 , position 1 is attached to the parent ring and position 2 is attached to W or

[0108] L4; the substituent is selected from one or two Cl -4 alkyls;

[0109] R4, R5, and R7 are each independently selected from H and Cl -4 alkyl; and n, nl, n2, n3 are each independently selected from any integer between 0 and 6.

[0110] In one embodiment, Z is selected from a direct bond, a carbon-carbon triple bond, and a carbon-carbon double bond. In one embodiment, Z is a carbon-carbon triple bond.

[0111] In one embodiment, Rx is H or methyl. In one embodiment, Rx is H.

[0112] In one embodiment, Ry is H or methyl. In one embodiment, Ry is H.

[0113] In one embodiment, m is 2, 3 or 4. In one embodiment, m is 3. In one embodiment, L2 is absent.

[0114] In one embodiment, L3 is selected from AA1, AAl-Gly, Val-Cit, Vai-Ala, Val-AAl, Val-AAl-Gly, AAl-Ala-Asn, Ala- Ala- Ala, Ala-Ala-Asn and Gly-Gly-Phe-Gly.

[0115] In one embodiment, L3 is selected from AA1, AAl-Gly, Val-Cit, Val-AAl-Gly, AAl-Ala-Asn and Gly-Gly-Phe-Gly.

[0116] In one embodiment, L3 is Val-AAl-Gly.

[0117] In one embodiment, the amino acid residue represented

[0118] In one embodiment, the amino acid residue represented

[0119] In one embodiment,

[0120] In one embodiment, W is O. In one embodiment, X is -(CH2)nl-. In one embodiment, nl is 2, 3 or 4. In one embodiment, nl is 3.

[0121] In one embodiment, the structure is: wherein position 1 is attached to the connecting atom on the antibody and position 2 is attached to W.

[0122] In one embodiment, the structural fragment represented

[0123] In one embodiment, the structural fragment In one embodiment, the antibody-drug conjugate has the structure wherein:

[0124] Ab is the anti-HER3 antibody or fragment thereof as defined herein; and q is the connection number, and is an integer from 1 to 16.

[0125] In one embodiment, the antibody-drug conjugate is of the formula (II): wherein:

[0126] Ab is an HER3 antibody comprising a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 16; and q is the connection number, and is an integer from 1 to 16.

[0127] The compounds of formula (I) and general and specific methods for their synthesis are disclosed as compounds of formula (I) in WO2022 / 170971 and published national applications derived therefrom. In particular, the compounds of formula (II), such as Compound 1, is disclosed as compound HER3-ADC-07 in WO2022 / 170971 and published national applications derived therefrom.

[0128] In one embodiment of the antibody-drug conjugate for use according to the present invention, the antibody component and the payload-linker component may take the structures shown herein. In another embodiment, the antibody component and the payload-linker component of the antibody-drug conjugate for use in the present invention may take the form of a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer of any of the structures shown.

[0129] As used herein, the connection number q is an integer from 1 to 16. In some embodiments, the connection number q may be selected from the group of integers of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0130] In some embodiments, the connection number q may be an integer selected from the list of ranges selected from: 1 to 16, 2 to 14, 4 to 12, 6 to 10, or 7 to 9.

[0131] In some embodiments, the connection number q may be 2 to 14. In some embodiments, the connection number q may be 4 to 12. In some embodiments, the connection number q may be 6 to 10. In some embodiments, the connection number q may be 7 to 9. In some embodiments, the connection number q may be 7. In some embodiments, the connection number q may be 8. In some embodiments, the connection number q may be 9.

[0132] The antibody component and the linker-payload drug component of the antibody-drug conjugate of the invention are linked (i.e. conjugated) to each other via the linker as defined in the claims. Such linkers typically have chemically reactive groups at each end. These linkers can form a covalent attachment between two molecules, e.g. the antibody and the drug. Thus, the antibody and the drug are typically be covalently linked via a linker. Suitably, one region of the linker may bind to the antibody and another region of the linker may bind to the drug.

[0133] In one embodiment, the antibody-drug conjugate is Compound 1, which is a compound of formula (II), as defined above, wherein Ab is an HER3 antibody comprising a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 16; and q is 8.

[0134] COMPOSITION

[0135] The present invention also generally relates to compositions containing antibody-drug conjugates (ADCs) as defined herein, and mixtures thereof, for uses as defined herein.

[0136] In contrast to the term “connection number” when used alone, it will be understood that the term “ average connection number” in the context of a composition containing antibody-drug conjugates refers to the average number of drug molecules connected (e.g. conjugated) to the antibody in all of the ADCs present in the composition. As the skilled person will readily understand, the average connection number (defined as q’ when referred to in the context of a composition containing multiple ADCs) may therefore be an integer or be non-integral.

[0137] Thus, the average connection number q’ can be considered as the number of linkerpayload moieties (e.g. cytotoxic drugs attached via a linker) per antibody when expressed as an average across the whole of the composition. It will also be understood that the average connection number q’ can affect the safety and therapeutic effectiveness of the antibody-drug conjugate. The number of drug molecules per antibody molecule can be characterized by conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays and HPLC.

[0138] In one embodiment, the term “average” may refer to the arithmetic mean, which is calculated as the sum of the connection numbers in all ADCs present in the composition divided by the number of ADCs present. In one embodiment, the term “average” may refer to the median, which is calculated as the middle value separating the greater and lesser halves of the connection numbers in all ADCs present in the composition. In one embodiment, the term “average” may refer to the mode, which is calculated as most frequent value of the connection number in all ADCs present in the composition. In one embodiment, the term “average” may refer to the mid-range, which is calculated as the arithmetic mean of the highest and lowest values of the connection number in all ADCs present in the composition. Preferably, the term “average” refers to the arithmetic mean.

[0139] As used herein, the average connection number q’ is an integer or a decimal from 1 to 16. In some embodiments, the average connection number q may be selected from the group of integers or decimals of about: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,

[0140] 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,

[0141] 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,

[0142] 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5,

[0143] 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1,

[0144] 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6,

[0145] 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1,

[0146] 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6,

[0147] 15.7, 15.8, 15.9, or 16.0.

[0148] In some embodiments, the average connection number q’ may be an integer or a decimal selected from the list of ranges selected from: 1 to 16, 2 to 14, 4 to 12, 6 to 10, or 7 to 9.

[0149] In some embodiments, the average connection number q’ may be an integer or a decimal from 2 to 14. In some embodiments, the average connection number q’ may be an integer or a decimal from 4 to 12. In some embodiments, the average connection number q’ may be an integer or a decimal from 6 to 10. In some embodiments, average connection number q’ may be an integer or a decimal from 7 to 9. In some embodiments, the average connection number q’ is an integer or a decimal from 7 to 8. In some embodiments, the average connection number q’ is an integer or a decimal from 8 to 9. In some embodiments, the average connection number q’ is about 7.5. In some embodiments, the average connection number q’ is about 7.6. In some embodiments, the average connection number q’ is about 7.7. In some embodiments, the average connection number q’ is about 7.8. In some embodiments, the average connection number q’ is about 7.9. In some embodiments, the average connection number q’ is about 8.0. In some embodiments, the average connection number q’ is about 8.1. In some embodiments, the average connection number q’ is about 8.2. In some embodiments, the average connection number q’ is about 8.3. In some embodiments, the average connection number q’ is about 8.4. In some embodiments, the average connection number q’ is about 8.5.

[0150] ANTIBODY

[0151] The antibody-drug conjugate for use according to the invention comprises an antibody, or a fragment thereof, which binds to HER3.

[0152] It will be understood that the terms “binding to”, “binds”, “targeting” and “targets” are interchangeable. An antibody that “specifically binds to” a specified target protein may refer to an antibody that exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives. Antibodies, or binding fragments thereof, useful in the present invention will bind to the target protein with an affinity that is at least twofold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with nontarget proteins. As used herein, an antibody is said to bind specifically to a polypeptide comprising a given amino acid sequence if it binds to polypeptides comprising that sequence but does not bind to proteins lacking that sequence.

[0153] Antibodies are glycoproteins belonging to the immunoglobulin superfamily. The term "full-length antibody" may refer to an immunoglobulin molecule that binds to a target molecule and contains four peptide chains: two heavy chains and two light chains which are connected to each other through disulfide bonds. An antibody may recognise an antigen via the fragment antigen-binding (Fab) variable region. The fragment crystallizable region (Fc region) may refer to the tail region of an antibody that may allow antibodies to activate the immune system. The hinge region may refer to a stretch of heavy chains linking the Fab and Fc regions. The heavy chain and light chain may each comprise a variable domain and one or more constant domains. For example, in IgG antibodies, a heavy chain comprises a variable domain (VH) and three constant domains (CHI, CH2, and CH3) and a light chain comprises a variable domain (VL) and one constant domain (CL). Examples of suitable antibodies include a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, and a polyclonal antibody.

[0154] The term “antibody fragment” may refer to a fragment of an antibody, or a genetically engineered product of one of more fragments of an antibody, which fragment is involved in binding with the target molecule. Examples of antibody fragments include an antigen-binding fragment (Fab), a Fab', a Fab'-SH, a fragment antibody (F(ab’)2), a variable region (Fv), a single chain antibody (scFv), a single-domain antibody (sdAb), and a camelid antibody (VHH). The term “Antigen-binding fragment” or “Fab” may refer to a region of an antibody that binds to antigens and is composed of one constant and one variable region of each of the heavy and the light chain. The term “fragment antibody” or “F(ab’)2” may refer to a region of an antibody that remains following digestion of the Fc region while leaving intact some of the hinge region. The term “Fab”’ may refer to a fragment formed by the reduction of a F(ab')2 fragment. The term “Fab’-SH” may refer to a Fab’ fragment with a free sulfhydryl group. The term “Single chain antibody” or “scFv” may refer to an engineered antibody consisting of a light chain variable region and a heavy chain variable region which are connected to each other. Examples of single-domain antibodies include, but are not limited to, VHH fragments, and VNAR fragments.

[0155] The term “complementarity determining region” or "CDR" generally refers to one of the 6 hypervariable regions within the variable domain of an antibody.

[0156] “Complementarity determining region” or “CDR” with regard to antigen-binding domain or antibody refers to a hypervariable region or a highly variable loop in the variable region of the heavy chain of the light chain of an antibody, which contribute primarily to antigen binding. CDRs can interact with the antigen conformation and largely determine binding to the antigen (although some framework regions are known to be involved in binding). The heavy chain variable region and the light chain variable region typically each contain 3 CDRs (heavy chain CDRs 1, 2 and 3 and light chain CDRs 1, 2 and 3, numbered from the amino to the carboxy terminus). It may be possible to introduce one or more mutations (substitutions, additions or deletions) into each CDR without negatively affecting binding activity. Each CDR may, for example, have one, two or three amino acid mutations.

[0157] The CDRs of the variable regions of a heavy and light chain of an antigen-binding domain or antibody can be predicted from the heavy and light chain variable region sequences of the antibody, using prediction software available in the art, e.g. using the Abysis algorithm, or using the IMGT / V-QUEST software, e.g. the IMGT algorithm (ImMunoGeneTics) which can be found at www.IMGT.org, (see for example Lefranc et al, 2009 NAR 37:D1006-D1012 and Lefranc 2003, Leukemia 17: 260-266). CDR regions identified by either algorithm are considered to be equally suitable for use in the invention. CDRs may vary in length, depending on the antigen-binding domain or antibody from which they are predicted and between the heavy and light chains. Thus, the three heavy chain CDRs of an intact antigen-binding domain or antibody may be of different lengths (or may be of the same length) and the three light chain CDRs of an intact antigen-binding domain or antibody may be of different lengths (or may be of the same length). A CDR for example, may range from 2 or 3 amino acids in length to 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids in length. Particularly, a CDR may be from 3-14 amino acids in length, e.g. at least 3 amino acids and less than 15 amino acids.

[0158] The CDRs of the variable regions of a heavy and light chain of an antigen-binding domain or antibody can be defined according to various definition schemes known in the art (see e.g. Dondelinger, M., et al., 2018. Frontiers in immunology, 9, p.2278), such as the Kabat definition scheme (see e.g. Kabat et al., 1992, Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719), the Chothia definition scheme (see e.g. Chothia et al. (1989) Nature 342:878-883) or the IMGT definition scheme (see e.g. Lefranc et al., Dev. Comparat. Immunol.27:55-77, 2003). For a given antibody, those skilled in the art will readily identify the CDRs defined by each definition scheme. The correspondence between different definition schemes is well known to those skilled in the art. In some embodiments, the sequence of the antibody may be defined using Kabat numbering (Kabat E.A. et al., Sequences of proteins of immunological interest. NIH Publication 91-3242 (1991)). Techniques for preparing and using various antibody -based constructs and fragments are well known in the art.

[0159] In some embodiments, the antibody may comprise a heavy chain variable (VH) region and a light chain variable (VL) region. In some embodiments, the antibody may comprise a heavy chain variable (VH) region. In some embodiments, the antibody may comprise a light chain variable (VL) region.

[0160] It will be understood that a VH region may be termed as a VH domain. It will also be understood that a VL region may be termed as a VL domain.

[0161] “Heavy chain variable region” or “VH” refers to the fragment of the heavy chain of an antigen-binding domain or antibody that contains three CDRs interposed between flanking stretches known as framework regions, which are more highly conserved than the CDRs and form a scaffold to support the CDRs. “Light chain variable region” or “VL” refers to the fragment of the light chain of an antigen-binding domain or antibody that contains three CDRs interposed between framework regions.

[0162] The term "monoclonal antibody" may refer to an antibody obtained from a substantially homogeneous population of antibodies. The individual antibodies composing the population may be identical except for possible naturally occurring mutations, which may be present in minor amounts. Monoclonal antibodies are highly specific and target a single antigenic epitope. In contrast, polyclonal antibody preparations typically include a large number of antibodies which are specific for different epitopes.

[0163] The term "chimeric antibody" generally refers to an antibody obtained by fusing a variable region of a murine antibody and a constant region of a human antibody, which can reduce an immune response induced by the murine antibody. For establishment of a chimeric antibody, a hybridoma secreting murine specific monoclonal antibody can be established, and a variable region gene is cloned from the mouse hybridoma cells; then a constant region gene of human antibody can be cloned as required, and the mouse variable region gene and the human constant region gene are connected to form a chimeric gene; then the chimeric gene is inserted into an expression vector, wherein chimeric antibody molecules can be expressed in a eukaryotic system or a prokaryotic system.

[0164] The term "humanized antibody", also referred to as CDR-grafted antibody, generally refers to an antibody produced by grafting mouse CDR sequences into a human antibody variable region framework, i.e., an antibody produced in a different type of human germline antibody framework sequence. Therefore, the heterogeneous reaction induced by the presence of a large number of mouse protein components in the chimeric antibody can be overcome. Such framework sequences can be obtained from public DNA databases or disclosed references that include germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes can be obtained from the "VBase" human germline sequence database.

[0165] The term “human antibody”, "fully humanized antibody", "fully human antibody" or "completely human antibody", which may also be known as "fully humanized monoclonal antibody", may have both humanized variable region and constant region so as to eliminate immunogenicity and toxic side effects. The development of monoclonal antibodies has four stages, namely murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully humanized monoclonal antibodies. The antibodies or ligands described herein can be fully humanized monoclonal antibodies. Relevant technologies for the preparation of fully human antibodies may be: human hybridoma technology, EBV-transformed B- lymphocyte technology, phage display technology, transgenic mouse antibody preparation technology, single B-cell antibody preparation technology, and the like.

[0166] Antibodies may be obtained by techniques comprising immunizing an animal with a target antigen and isolating the antibody from serum. Monoclonal antibodies may be made by the hybridoma method first described by Kohler et al., Nature 256:495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature 352:624-628 (1991) and Marks et al., J. Mol. Biol. 222:581-597 (1991), for example. The antibody may be a chimeric or humanized antibody. The antibody according to the invention may have any binding affinity value. Binding affinity is typically described as the strength of the binding interaction between two molecules, (e.g. between a receptor and its ligand or an antibody and its cognate antigen). Binding affinity may be defined by determining the equilibrium dissociation constant (KD), which is used to measure the strengths of molecular interactions. A lower KD value indicates a higher binding affinity, and vice versa a higher KD value indicates a lower binding affinity.

[0167] Binding affinity (e.g. a KD value) may be quantitatively determined or measured using methods know in the art, such as by surface plasmon resonance (SPR), for example by using the Biacore® system (e.g. Biacore T200). In addition to the equilibrium dissociation constant (KD), the association rate constant (Ka (1 / Ms)), and the dissociation rate constant (Kd (1 / s)) may also be determined.

[0168] Methods for determining binding specificity of an antibody to a particular antigen are known in the art include, but are not limited to, ELISA, western blot, immunohistochemistry, flow cytometry, Forster resonance energy transfer (FRET), phage display libraries, yeast two-hybrid screens, co-immunoprecipitation, bimolecular fluorescence complementation and tandem affinity purification. Binding affinity can also be determined using methods such as fluorescence quenching, isothermal titration calorimetry.

[0169] ANTI-HER3 ANTIBODY

[0170] According to the invention, the antibody of the antibody-drug conjugate is an anti- HER3 antibody or fragment thereof.

[0171] The anti-HER3 antibody or fragment thereof may specifically bind HER3. In some embodiments, the anti-HER3 antibody or fragment thereof has an EC50 value for binding to human Her3 protein of 100 pM or less, 80 pM or less, 60 pM or less, 40 pM or less, or 20 pM or less. In some embodiments, the human Her3 protein does not bind to human EGFR, human Her2, or human Her4 proteins. The binding affinity may be determined by an ELISA method. The anti-HER3 antibody may be a monoclonal antibody. In some embodiments, the anti-HER3 antibody or fragment thereof is a humanized antibody. In some embodiments, the anti-HER3 antibody or fragment thereof is a monoclonal humanized antibody. In some embodiments, the anti-HER3 antibody or fragment thereof is a human antibody. In some embodiments, the anti-HER3 antibody or fragment thereof is a monoclonal human antibody. The fragment thereof may be any antigen-binding fragment thereof, for example a Fab, a Fab', a F(ab')2, a Fv, an ScFv, a Fab'-SH, an sdAb, or a VHH. In some embodiments, the anti-HER3 antibody or fragment thereof is a full-length anti-HER3 antibody.

[0172] The anti-HER3 antibody or fragment thereof may comprise a variable region that specifically binds HER3. In some embodiments, the anti-HER3 antibody or fragment thereof comprises a heavy chain variable region and / or a light chain variable domain. In some embodiments, the anti-HER3 antibody or fragment thereof comprises a heavy chain variable region and a light chain variable domain. In some embodiments, the anti-HER3 antibody or fragment thereof comprises a constant region, preferably derived from a human antibody, preferably the constant region is selected from the constant region of human IgGl, IgG2, IgG3 or IgG4. In some embodiments, the anti- HER3 antibody or fragment thereof comprises a heavy chain and / or a light chain. In some embodiments, the anti-HER3 antibody or fragment thereof comprises a heavy chain and a light chain. In some embodiments, the anti-HER3 antibody or fragment thereof comprises or consists of two heavy chains and two light chains.

[0173] The anti-HER3 antibody or fragment thereof may comprise any CDRs, variable region sequences, and / or heavy and light chain sequences described herein. For example, in some embodiments, the anti-HER3 antibody or fragment thereof comprises a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 16. LINKER-PAYLOAD, LINKER AND PAYLOAD MOIETIES

[0174] The linker-payload moiety of the antibody-drug conjugate as referred to herein comprises a linker, which is a chemical structural fragment, which is linked to the anti-HER3 antibody at one end and linked to a payload (such as a cytotoxic drug) at the other end, or linked to other linkers and then linked to the payload. The direct or indirect linking of an antibody may mean that the group is directly linked to the antibody via a covalent bond, and may also be linked to the antibody via a linker structure. The payload compound and, where present, the linker structure are together referred to herein as the “payload-linker” or “linker-payload” moiety.

[0175] The antibody-drug conjugate as referred to herein is cleaved in vivo, typically at the target site, to release the linker-payload moiety in situ. Typically, the linker-payload moiety is then itself cleaved to release the payload moiety in situ.

[0176] Typically, the linker is a cleavable linker. In some embodiments, the linker is a linker cleavable by a lysosomal peptidase.

[0177] In some embodiments, the linker comprises a peptide linker. In some embodiments, the linker consists essentially of a peptide linker. In some embodiments, the linker consists of a peptide linker. Typically, the peptide linker comprises, essentially of or consist of 1 to 10 amino acid residues. The peptide linker may comprise, consist essentially of or consist of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues. In some embodiments, the peptide linker comprises, consists essentially of or consists of 1 to 6 amino acid residues. In some embodiments, the peptide linker comprises, consists essentially of or consists of 1 to 5 amino acid residues. In some embodiments, the peptide linker comprises, consists essentially of or consists of 2 to 4 amino acid residues. In some embodiments, the peptide linker comprises, consists essentially of or consists of 3 amino acid residues.

[0178] The payload of the antibody-drug conjugate for use in the present invention is typically a TOPO1 inhibitor drug. In one embodiment, the TOPO1 inhibitor is a camptothecin or a derivative thereof. In one embodiment, the TOPO1 inhibitor is an exatecan or a derivative thereof. It will be understood by the person skilled in the art that the linker-payload, linker and payload moieties may optionally, or alternatively, comprise isomers (such as structural isomers, geometric isomers, enantiomers, diastereomers or mesomers), racemic and non-racemic mixtures of such isomers, of the compounds having the structures shown herein. Reference to a specific stereochemical form as shown herein is not therefore to be considered limiting to that specific isomer but also includes all other stereoisomers in all proportions.

[0179] The linker-payload moiety of the antibody-drug conjugate of formula (I) above is a payload-linker of formula (I’): wherein Li, L2, L3, L4, W, X, Ri, R2 and R3 are as defined above for the antibody-drug conjugate of formula (I), either in its broadest aspect or a preferred aspect, and the squiggly line marks the point of attachment to the antibody.

[0180] Typically, the linker-payload moiety is attached to the antibody via reaction of a reactive group, typically a sulfhydryl (-SH) group, on the antibody, displacing a leaving group (LG) on an intermediate of formula LG-I’, where I’ is the linkerpayload moiety of formula (T) above, to form a covalent bond (typically a thioether bond) between the antibody and the linker-payload moiety.

[0181] The linker portion of the linker-payload moiety of the antibody-drug conjugate used in the present invention is a group having the structure I-1 I-2 L3 I-4 where Li, L2, L3 and L4 are as defined herein, e ther in their broadest aspect or i preferred aspect, position 1 is attached to the antibody in the antibody-drug conjugate, and position 2 is attached to the payload moiety in the antibody-drug conjugate.

[0182] In one preferred embodiment, wherein the antibody-drug conjugate is of formula (II),

[0183] The payload moiety of the antibody-drug conjugate used in the present invention is a moiety having the structure wherein W, X, Ri, R2 and R3 are as defined above for the antibody-drug conjugate of formula (I), either in its broadest aspect or a preferred aspect, and position 1 is attached to the linker moiety, typically the group L4. This is cleaved in vivo to leave a payload compound having the formula (I”) below:

[0184] wherein W, X, Ri, R2 and R3 are as defined above for the antibody-drug conjugate of formula (I), either in its broadest aspect or a preferred aspect.

[0185] In a preferred embodiment, the payload portion of the linker-payload moiety of the antibody-drug conjugate used in the present invention is a compound having the formula (II”):

[0186] DOSE

[0187] In the fourth aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at any dose. In these embodiments, the antibody-drug conjugate is the compound of formula (II), such as Compound 1, or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 0.5 mg / kg to 4 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 0.5 mg / kg to 3.5 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 0.5 mg / kg to 3.0 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 0.5 mg / kg to 0.7 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 0.5 mg / kg to 0.6 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 0.8 mg / kg to 1.2 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 0.9 mg / kg to 1.1 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 1.3 mg / kg to 1.7 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 1.4 mg / kg to 1.6 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 1.8 mg / kg to 2.2 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 1.9 mg / kg to 2.1 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.3 mg / kg to 2.7 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.4 mg / kg to 2.6 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.8 mg / kg to 3.2 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.9 mg / kg to 3.1 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 3.3 mg / kg to 3.7 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 3.4 mg / kg to 3.6 mg / kg. In these embodiments, the antibody-drug conjugate is preferably the compound of formula (II), such as Compound 1, or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 0.5 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 1.0 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 2.0 mg / kg. In some embodiments of the first, third or fourth aspects of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 3.0 mg / kg. In these embodiments, the antibody-drug conjugate is preferably the compound of formula (II), such as Compound 1, or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2 mg / kg to 4 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2 mg / kg to 3.5 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2 mg / kg to 3.0 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2 mg / kg to 2.2 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2 mg / kg to 2.1 mg / kg. In some embodiments of the second aspect of the invention, the antibodydrug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.3 mg / kg to 2.7 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.4 mg / kg to 2.6 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.8 mg / kg to 3.2 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.9 mg / kg to 3.1 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 3.3 mg / kg to 3.7 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 3.4 mg / kg to 3.6 mg / kg. In these embodiments, the antibody-drug conjugate is preferably the compound of formula (II), such as Compound 1, or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 2.0 mg / kg. In some embodiments of the second aspect of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 3.0 mg / kg. In these embodiments, the antibody-drug conjugate is preferably the compound of formula (II), such as Compound 1, or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every three weeks.

[0193] It will be understood that the dose should be selected based on considerations of age, body weight, disease symptoms, disease progression and / or severity, sex, and / or any other factors which may interfere with the therapeutic effects the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention. ADMINISTRATION AND TREATMENT CYCLES

[0194] In some embodiments, the form of administration of the antibody-drug conjugate or pharmaceutically acceptable salt thereof, or the composition containing it, may be, for example, in a form suitable for oral, parenteral, intraperitoneal, systemic, intravenous (such as intravenous infusion or intravenous drip), intramuscular, subcutaneous, topical, inhalative, rectal, sublingual, transdermal, or vaginal administration.

[0195] In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof, or the composition containing it, may be administered intravenously (e.g. by being injected into a subject).

[0196] In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof, or the composition containing it, may be administered to a subject once (i.e. as a one-off treatment). For example, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a subject once over a continuous period of hours or days.

[0197] In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof, or the composition containing it, may be administered to a subject on multiple, separate occasions (e.g. as part of an on-going treatment). For example, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a subject on multiple, separate occasions over a total period of hours, days, weeks, months or years (generally described herein as “treatment cycles” or “exposure cycles”).

[0198] In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered over a number of treatment cycles (as defined above). In each treatment cycle, the period over which the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered is preferably 30 minutes to 3 hours, more preferably 40 minutes to 2 hours, more preferably 60 to 90 minutes, and the rest period is preferably 7 to 35 days, more preferably 14 to 28 days, even more preferably 18 to 23 days, most preferably 21 days. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 1 treatment cycle. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 2 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 3 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 4 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 5 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 6 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 7 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 8 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 9 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 10 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 11 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 12 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 13 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 14 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 15 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 16 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 17 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 18 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 19 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 20 treatment cycles. In these embodiments, the antibody-drug conjugate is preferably administered once every 3 weeks. In these embodiments, the antibody-drug conjugate is preferably the compound of formula (II), such as Compound 1, or a pharmaceutically acceptable salt thereof.

[0199] As is known to the skilled person, there is no upper limit on the number of treatment cycles - treatment is continued until disease progression or unacceptable toxicity occurs, or the patient or oncologist decides to discontinue administration of the antibody-drug conjugate. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 1 to 20 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 2 to 20 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 3 to 18 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 4 to 14 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 1 to 15 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 2 to 12 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 3 to 11 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in 1 to 6 treatment cycles. In these embodiments, the antibody-drug conjugate is preferably administered once every 3 weeks. In these embodiments, the antibody-drug conjugate is preferably the compound of formula (II), such as Compound 1, or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is dosed at 0.5 mg / kg and is administered in from 2 to 20 treatment cycles. In some embodiments of the invention, the antibodydrug conjugate or pharmaceutically acceptable salt thereof is dosed at 0.5 mg / kg and is administered in from 1 to 11 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is dosed at 2.0 mg / kg and is may be administered in from 4 to 14 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is dosed at 3.0 mg / kg and is administered in from 3 to 11 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is dosed at 4.0 mg / kg and is administered in 1 to 6 treatment cycles. In these embodiments, the antibody-drug conjugate is preferably administered once every 3 weeks. In these embodiments, the antibodydrug conjugate is preferably the compound of formula (II), such as Compound 1, or a pharmaceutically acceptable salt thereof.

[0201] PHARMACEUTICAL COMPOSITION

[0202] The present invention also provides a composition comprising the antibody-drug conjugate or pharmaceutically acceptable salt thereof as defined herein, for use according to the invention. In some embodiments, the composition is a pharmaceutical composition.

[0203] As used herein, the term “pharmaceutically acceptable salt” is an acid or base addition salt of the antibody-drug conjugate formed with one or more suitable acids or bases that provides pharmaceutically acceptable anions or cations. Suitable acid addition salts include, but are not limited to formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, a-ketoglutarate, a-glycerophosphate, alkyl sulfonate (where the alkyl part is as defined above, either in its broadest aspect or a preferred aspect, preferably methyl or ethyl), or arylsulfonate (wherein the aryl part is phenyl, optionally substituted by one or more C1-3 alkyl groups or halogen atoms); preferably, the alkyl sulfonate is methyl sulfonate or ethyl sulfonate; the arylsulfonate is a benzenesulfonate or p-toluenesulfonate. Suitable inorganic acid addition salts include but are not limited to hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate, carbonate, sulfate and phosphate. Suitable base addition salts include sodium, potassium, calcium, iron, ammonium, isopropylamine, triethylamine, 2- ethylaminoethanol, histidine, and procaine.

[0204] In some embodiments, the pharmaceutical composition according to the invention may comprise one or more carriers and / or excipients, in addition to the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention.

[0205] Depending on the method of administration, in some embodiments the composition may contain 0.1 wt.% to 99 wt.% of the active compound (i.e. the antibody-drug conjugate or pharmaceutically acceptable salt thereof for use according to the invention). In some embodiments, the composition may contain 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,

[0206] 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,

[0207] 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,

[0208] 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt.% of the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention.

[0209] Pharmaceutical compositions typically should be sterile and stable under the conditions of manufacture and storage. The pharmaceutical composition according to the invention may be produced using current good manufacturing practices (CGMP).

[0210] The term “pharmaceutical composition” as used herein refers to a substance and / or a combination of substances that can be used for the identification, prevention or treatment of a tissue status or disease. The pharmaceutical composition may be formulated to be suitable for administration to a patient in order to prevent and / or treat disease. Further a pharmaceutical composition may refer to the combination of an active agent with a carrier, inert, making the composition suitable for therapeutic use. Pharmaceutical compositions can be formulated for oral, parenteral, topical, inhalative, rectal, sublingual, transdermal, subcutaneous or vaginal application routes according to their chemical and physical properties.

[0211] Pharmaceutical compositions may comprise solid, semisolid, liquid, transdermal therapeutic systems (TTS). Solid compositions are selected from the group consisting of tablets, coated tablets, powder, granulate, pellets, capsules, effervescent tablets or transdermal therapeutic systems. Also comprised are liquid compositions, selected from the group consisting of solutions, syrups, infusions, extracts, solutions for intravenous application, solutions for infusion or solutions of the carrier systems of the present invention. Semisolid compositions that can be used in the context of the invention comprise emulsion, suspension, creams, lotions, gels, globules, buccal tablets and suppositories.

[0212] The term “carrier”, as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.

[0213] A sterile saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously.

[0214] Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0215] The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. The compounds of the invention can be formulated as neutral or salt forms.

[0216] Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0217] In some embodiments, the pharmaceutical composition may comprise an aqueous diluent or solvent. In some embodiments, the aqueous diluent or solvent may be a phosphate buffered saline solution, such as a sterile phosphate buffered saline solution.

[0218] In some embodiments, the pharmaceutical composition may be in a form suitable for intravenous infusion. In some embodiments, the pharmaceutical composition may be administered intravenously.

[0219] MEDICAL USE / METHOD OF TREATMENT

[0220] According to the present invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof, or composition containing it, as defined herein, are for use in treating cancer.

[0221] Cancer is a well-known term that refer to a disease or group of diseases involving abnormal cell growth. The term “cancer” may be used interchangeably with “tumour” or “cancerous disease”.

[0222] The term "disease" and "disorder" may be used interchangeably herein, referring to an abnormal condition especially an abnormal medical condition such as an illness or injury, wherein a cell, a tissue, an organ, or an individual is not able to efficiently fulfil its function anymore. Typically, but not necessarily, a disease is associated with specific symptoms or signs indicating the presence of such disease. The presence of such symptoms or signs may thus, be indicative for a cell, a tissue, an organ, or an individual suffering from a disease. An alteration of these symptoms or signs may be indicative for the progression of such a disease. A progression of a disease is typically characterised by an increase or decrease of such symptoms or signs which may indicate a "worsening" or "bettering" of the disease. The "worsening" of a disease is characterised by a decreasing ability of a cell, tissue, organ or individual / patient to fulfil its function efficiently, whereas the "bettering" of a disease is typically characterised by an increase in the ability of a cell, tissue, an organ or an individual / patient to fulfil its function efficiently.

[0223] The terms “treat”, “treatment” and “treating” refers to lessening, reducing or improving at least one symptom associated with an existing disease or condition and / or to slow down, reduce or block the progression of the disease or condition and / or to delay or prevent the onset of symptoms (such as further symptoms) of the disease or condition.

[0224] The terms “prevent”, “prevention” and “preventing” refers to preventing the onset of symptoms of a disease or condition, and as such encompasses prophylactic treatment.

[0225] In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may result in a lowered incidence of disease or symptoms, delayed onset of disease or symptoms, and / or reduced severity of disease or symptoms, compared to other therapies that are known in the art.

[0226] In the first aspect of the present invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof, or a composition containing it, is for use as a medicament in the treatment of a cancer selected from brain tumour, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer.

[0227] In the second aspect of the present invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof, or a composition containing it, is for use as a medicament in the treatment of lung cancer. In the third aspect of the present invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof, or a composition containing it, is for use as a medicament in the treatment of a cancer selected from brain tumour, lung cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer.

[0228] The present invention also provides a use of an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the first aspect of the invention, or a composition containing it, in the manufacture of a medicament for the treatment and / or prevention of a cancer selected from brain tumour, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer.

[0229] The present invention also provides a use of an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the second aspect of the invention, or a composition containing it, in the manufacture of a medicament for the treatment and / or prevention of lung cancer.

[0230] The present invention also provides a use of an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the third aspect of the invention, or a composition containing it, in the manufacture of a medicament for the treatment and / or prevention of a cancer selected from brain tumour, lung cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer.

[0231] The present invention also provides a method for treating and / or preventing a cancer selected from brain tumour, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer, comprising administering an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the first aspect of the invention, or a composition containing it, to a subject in need thereof.

[0232] The present invention also provides a method for treating and / or preventing lung cancer, comprising administering an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the second aspect of the invention, or a composition containing it, to a subject in need thereof.

[0233] The present invention also provides a method for treating and / or preventing a cancer selected from brain tumour, lung cancer, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer, comprising administering an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the third aspect of the invention, or a composition containing it, to a subject in need thereof.

[0234] In one embodiment of the third aspect, the cancer is selected from the group consisting of breast cancer and lung cancer (such as but not limited to non-small-cell lung cancer, NSCLC). In one embodiment of the first or third aspect, the cancer is breast cancer. In one embodiment of the second or third aspect, the cancer is lung cancer. In one embodiment of the second or third aspect, the cancer is non-small-cell lung cancer (NSCLC).

[0235] In the fourth aspect, the cancer is breast cancer.

[0236] In one embodiment, the cancer is an unresectable cancer. In one embodiment, the cancer is an advanced cancer. In one embodiment, the cancer is a locally advanced cancer. In one embodiment, the cancer is a metastatic cancer. In one embodiment of the first, third or fourth aspects, the cancer is HER-2 negative breast cancer. In one embodiment of the first, third or fourth aspects, the cancer is HER-2 positive breast cancer.

[0237] In some embodiments, the patient may have been determined to have a cancer which is a HER2 positive cancer. In some embodiments, the patient may have been determined to have a cancer which is a HER2 overexpressive cancer. It will be understood that a “HER2 positive cancer” or “HER2 overexpressive cancer” is a cancer that is associated with increased expression of HER2, wherein the levels of expression of HER2 are considered to be increased compared to the expression of HER2 in, for example, a non-cancerous cell or tissue, which may not express HER2, or may express HER2 at baseline levels.

[0238] In some embodiments, the patient may have been determined to have a cancer which is a HER2 low cancer. In some embodiments of the fourth aspect of the present invention, the patient may have been determined to have a cancer which is a HER2 negative cancer. It will be understood that a “HER2 low cancer” or “HER2 negative cancer” is a cancer that is not associated with expression of HER2 or is associated with low levels of expression of HER2, wherein the low levels of expression of HER2 are considered to be reduced compared to the expression of HER2 in, for example, a non-cancerous cell or tissue.

[0239] In some embodiments, the cancer is HER2-overexpressing cancer (also described herein as HER2 positive cancer).

[0240] In some embodiments, the HER2-overexpressing cancer is cancer given a score of 3+ for the expression of HER2 in an immunohistochemical method.

[0241] In some embodiments, the HER2-overexpressing cancer is cancer given a score of 2+ for the expression of HER2 in an immunohistochemical method and determined as positive for the expression of HER2 in an in situ hybridization method. The in situ hybridization method of the present invention includes a fluorescence in situ hybridization method (FISH) and a dual color in situ hybridization method (DISH). In some embodiments, the cancer is HER2 low-expressing cancer (also described herein as HER2 low cancer).

[0242] In some embodiments, the HER2 low-expressing cancer is cancer given a score of 2+ for the expression of HER2 in an immunohistochemical method and determined as negative for the expression of HER2 in an in situ hybridization method.

[0243] In some embodiments, the HER2 low-expressing cancer is cancer given a score of Infor the expression of HER2 in an immunohistochemical method.

[0244] In some embodiments, the HER2 low-expressing cancer is cancer given a score of >0 and <1+ for the expression of HER2 in an immunohistochemical method.

[0245] The method for scoring the degree of HER2 expression by the immunohistochemical method, or the method for determining positivity or negativity to HER2 expression by the in situ hybridization method is not particularly limited as long as it is recognized by those skilled in the art. Examples of the method can include a method described in ASCO 2018 for Breast and Endometrial Cancer. In particular, algorithms for evaluation of HER2 protein expression by immunohistochemistry (IHC) assay of the invasive component of a breast cancer specimen, by in situ hybridization (ISH) assay of the invasive component of a breast cancer specimen using a single-signal (HER2 gene) assay (single-probe ISH), and by in situ hybridization (ISH) assay of the invasive component of a breast cancer specimen using a dual-signal (HER2 gene) assay (dual-probe ISH), were published by ASCO in 2018. These algorithms were derived from recommendations in Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology / College of American Pathologists Clinical Practice Guideline Focused Update.

[0246] In each of these embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably the compound of formula (II) (also referred to below as Compound 1) or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may be used for the purpose of diagnostics. SUBJECT

[0248] In this specification, the terms “subject” and “patient” are synonymous.

[0249] In some embodiments, the subject of the medical uses and methods of treatment according to the present invention may be a mammal.

[0250] In some embodiments, the subject may be a human.

[0251] In some embodiments, the subject may alternatively be a non-human mammal, including for example, a primate, a monkey, a dog, a cat, a horse, a cow, a sheep, a pig, a rabbit, a rat, or a mouse.

[0252] In some embodiments, the subject has not previously been treated with a HER3- targeting agent or an ADC including a HER3 -targeting agent.

[0253] In some embodiments, the subject has an EGFR-active mutation.

[0254] In some embodiments, the subject is intolerant to a TOPO1 inhibitor or an ADC including a TOPO1 inhibitor.

[0255] EXAMPLES

[0256] Example 1 - Synthesis of Compound 1

[0257] Expression of anti-Her3 Antibody A

[0258] The heavy chain and light chain sequences of clone 202-2-1 (SEQ ID NOs: 15 and 16) were constructed into a PTT5 vector by codon optimization and gene synthesis (General Biosystems (Anhui) Co., Ltd.), respectively. Expression plasmids of the heavy chain and the light chain were co-transfected into HEK293F cells by PEI max reagent and expressed in a 5% CO2 shaker at 37°C for 7 days. Supernatants were collected and purified by Protein A magnetic beads to obtain anti-Her3 Antibody A. The affinity and specificity of the anti-Her3 Antibody A to Her3 proteins was confirmed by ELISA methods.

[0259] Synthesis of Intermediates

[0260] Preparation 1 : Synthesis of (S)-7-ethyl-7-hydroxy-14-(3-hydoxypropyl)-10,13- dihydro-1 lH-[l,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-8,l 1(7H)- dione (Al)

[0261] Step 1 : Synthesis of (S)-14-(3-chloropropyl)-7-ethyl-7-hydroxyl-10,13-dihydro-l lH- [l,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-8,l l(7H)-dione (A1B)

[0262] In ice bath, to a solution of compound (5) 7-ethyl-7-hydroxy-10,13-dihydro-l 1H- [l,3]dioxolo[4,5-g]pyrano[3',4':6,7]indeno[l,2-b]quinolin-8,l l(7H)-dione (Al A, 500 mg) in 75% sulfuric acid solution (5 mL), was added ferrous sulfate heptahydrate (570 mg of ferrous sulfate heptahydrate was dissolved in 1 mL of water) and 4- dimethoxy chlorobutane (3.89 g), and after the reaction solution was stirred for 3 minutes, hydrogen peroxide (29%, 2.5 mL) was added dropwise. The reaction solution was stirred at 0 °C for 5 minutes, warmed to room temperature, and then reacted for 3 h under stirring. The reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (80 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was further purified by C18 column (acetonitrile / 0.05% formic acid in water: 5%-60%), to obtain the target compound A1B (yellow solid, 400 mg, yield: 67%). LCMS (ESI) [M+H]+: 468.9; *HNMR (400 MHz, DMSO-d6) 6 7.65 (s, 1H), 7.51 (s, 1H), 7.24 (s, 1H), 6.50 (s, 1H), 6.30 (s, 2H), 5.42 (s, 2H), 5.26 (s, 2H), 3.81 (d, J = 5.9 Hz, 2H), 3.22 (s, 2H), 1.98 (d, J = 6.7 Hz, 4H), 0.88 (t, J = 7.2 Hz, 3H).

[0263] Step 2: Synthesis of (S)-7-ethyl-7-hydroxyl-14-(3-hydroxylpropyl)-10,13-dihydro- 1 lH-[l,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-8,l l(7H)-dione (Al)

[0264] Compound (S)-7-ethyl-7-hydroxyl-14-(3-chloropropyl)-10,13-dihydro-l lH- [l,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-8,l l(7H)-dione (A1B) (100 mg, 0.213 mmol) was dissolved in 10% sulfuric acid (5 mL) solution and reacted at 110 °C for 48 h. To the reaction solution was added saturated sodium bicarbonate (30 mL) solution, and then the resultant solution was extracted with di chloromethane (10 mL x 5), dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure to obtain crude products, which was purified by preparative HPLC (acetonitrile / water containing 0.05% formic acid), to obtain (S)-7- ethyl-7-hydroxyl-14-(3-hydroxylpropyl)-10,13-dihydro-HH-[l,3]dioxolo[4,5- g]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-8,l l(7H)-dione (Al, 1.78 mg).

[0265] LCMS (ESI) [M+H]+: 451.0; *HNMR (400 MHz, DMSO-t / 6) 8 7.63 (s, 1H), 7.50 (s, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 6.28 (s, 2H), 5.47 - 5.37 (m, 2H), 5.32 - 5.19 (m, 2H), 3.51 - 3.46 (m, 2H), 3.17 - 3.13 (m, 2H), 1.92 - 1.76 (m, 4H), 0.90 - 0.84 (m, 3H). Preparation 2: Synthesis of (S)-2-amino-N-((3-(7-ethyl-7-hydroxyl-8,l l-dioxo- 7,8,1 l,13-tetrahydro-10H-[l,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino [1,2- b]quinolin-14-yl)propoxy)methyl)acetamide (B2)

[0266] Step 1 : Compound BIA (368 mg), compound Al (440 mg) and pyridinium p- toluenesulfonic acid (PPTS) (25 mg) were refluxed in dichloromethane (20 ml) for 20 h, and then the reaction solution was washed with aqueous sodium bicarbonate solution and aqueous hydrochloric acid solution, respectively. The organic solvent was removed under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (dichloromethane:methanol = 10 / 1) to obtain the target compound B2A (240 mg).

[0267] LCMS (ESI) [M+H]+: 759.

[0268] Step 2: Compound B2A (240 mg) was dissolved in DMF (5 ml), to which was added piperidine (1ml), and then the compound was stirred for 20 min. The low boiling point components were removed under reduced pressure, and the residue was directly used in the next synthesis step. A small amount of the crude product was purified by reversed phase chromatography (acetonitrile / 0.05% FA in water: 5% to 50%) to obtain the target compound B2.

[0269] ESI-MS (m / z): 537 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 8 9.13 (t, 1H), 8.04 (br, 2H), 7.58 (s, 1H), 7.51 (s, 1H), 7.25 (s, 1H), 6.29 (s, 2H), 5.43 (S, 2H), 5.21 (s, 2H), 4.65 (d, 2H), 3.63 (m, 2H), 3.53 (m, 2H), 3.11 (m, 2H), 1.87 (m, 4H), 0.88 (t, 3H). Preparation 3 : N6,N6-dipropyl-N2-((6-(2-(methanesulfonyl)pyrimidin-5-yl)hexan-5- ynoyl)-L-valinyl)-L-lysine (C4)

[0270] Step 1 :

[0271] Compound C3A (5.0 g, 12 mmol) was dissolved in dichloromethane (100 mL), to which was added n-propionaldehyde (4.2 g, 72.3 mmol), and then the reaction was stirred at room temperature for 10 min, followed by addition of sodium triacetoxyborohydride (12.8 g, 60.25 mmol). The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was complete. To the reaction solution, was added saturated aqueous solution of ammonium chloride, and then the solution was stirred for 1 h and evaporated under rotation to dryness. After filtration, the filtrate was separated and purified over reversed phase Cl 8 column (acetonitrile to 0.05% formic acid aqueous solution: 5% to 55%), to obtain the target compound C4A (4.57 g, yield 82.0%) as a white solid.

[0272] LCMS (ESI) [M+H]+= 464.0; 'H NMR (400 MHz, DMSO-d6) 8 7.81 (d, J= 7.3 Hz, 1H), 7.38 - 7.28 (m, 5H), 5.04 (d, J= 1.7 Hz, 2H), 4.12 - 4.02 (m, 1H), 3.94 - 3.82 (m, 1H), 2.65 - 2.52 (m, 6H), 2.06 - 1.94 (m, 1H), 1.76 - 1.64 (m, 1H), 1.64 - 1.53 (m, 1H), 1.52 - 1.40 (m, 6H), 1.34 - 1.18 (m, 2H), 0.92 - 0.80 (m, 12H).

[0273] Step 2:

[0274] At room temperature, compound C4A (2.0 g, 4.32 mmol) was dissolved in methanol (80 mL), to which was then added Pd / C (0.16 g), and the reaction was stirred at room temperature under hydrogen atmosphere for 12 h. LCMS indicated completion of the reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound C4B (1.2 g, yield 85.5%) as a white solid.

[0275] Step 3 :

[0276] Compound 6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-ynoic acid (100 mg, 0.373 mmol) was dissolved in N,N-dimethylformamide (1 mL), to which were then added HATU (142 mg, 0.373 mmol) and N,N-diisopropylethylamine (120 mg, 0.93 mmol), and the reaction was stirred for 30 min. Then, compound C4B (122 mg, 0.371 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. After LCMS indicated that the reaction was complete, the reaction solution was directly purified over a reversed-phase C18 column (acetonitrile and 0.05% formic acid aqueous solution system), to obtain the target compound N6,N6-dipropyl-N2-((6-(2- (methanesulfonyl)pyrimidin-5-yl)hexan-5-ynoyl)-L-valinyl)-L-lysine (C4, 50 mg, yield 28%) as a pale yellow solid.

[0277] LCMS (ESI) [M+H]+= 580.0; 'H NMR (400 MHz, DMSO-d6) 8 8.24 (s, 2H), 7.98 - 7.93 (m, 2H), 4.24 - 4.16 (m, 1H), 4.10 (d, J= 5.2 Hz, 1H), 3.41 (s, 3H), 2.79 - 2.64 (m, 6H), 2.55 (t, J= 7.1 Hz, 2H), 2.45 - 2.26 (m, 2H), 2.06 - 1.91 (m, 1H), 1.89 - 1.78 (m, 2H), 1.76 - 1.66 (m, 1H), 1.64 - 1.57 (m, 1H), 1.57 - 1.42 (m, 6H), 1.37 - 1.24 (m, 2H), 0.93 - 0.78 (m, 12H).

[0278] Preparation 4: N-((l lS,14S)-l l-(4-(di-n-propylamino)butyl)-l-((S)-7-ethyl-7- hydroxyl-8,1 l-dioxo-7,8,1 l,13-tetrahydro-10H-[l,3]dioxolo[4,5-g]pyrano[3',4':6,7]- indolizinof 1 ,2-b]quinolin- 14-yl)- 15-methyl-7, 10,13 -trioxo-4-oxa-6,9, 12- triazahexadecan-14-yl)-6-(2-(methanesulfonyl)pyrimidin-5-yl)hexan-5-ynamide (DL- 04)

[0279] Compound C4 (43 mg, 0.074 mmol) and compound B2 (40 mg, 0.075 mmol) were dissolved in N,N-dimethylformamide (1 mL), to which were then added HBTU (28 mg, 0.075 mmol) and N,N-diisopropylethylamine (24 mg, 0.187 mmol). The reaction solution was stirred for 1 h at room temperature. LCMS detection indicated completion of the reaction. The reaction solution was directly purified by preparative chromatography (0.01% trifluoroacetic acid in water, acetonitrile), to provide the target compound (DL-04, 8.5 mg, yield 10%) as a yellow solid.

[0280] LCMS (ESI) [M+H]+= 1098.6; *H NMR (400 MHz, DMSO-d6) 8 9.10 (s, 2H), 9.03 (s, 1H), 8.64 (t, .7= 6.4 Hz, 1H), 8.19 (t, J= 5.9 Hz, 1H), 8.08 (d, J= 7.4 Hz, 1H), 7.92 (d, J= 8.5 Hz, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.24 (s, 1H), 6.49 (s, 1H), 6.29 (s, 2H), 5.42 (s, 2H), 5.24 (s, 2H), 4.66 - 4.52 (m, 2H), 4.31 - 4.21 (m, 1H), 4.19 - 4.10 (m, 1H), 3.74 (d, J= 5.5 Hz, 2H), 3.49 - 3.48 (m, 2H), 3.40 (s, 3H), 3.15 - 3.06 (m, 2H), 3.02 - 2.95 (m, 6H), 2.59 - 2.52 (m, 3H), 2.41 - 2.29 (m, 2H), 2.05 - 1.90 (m, 2H), 1.91 - 1.77 (m, 6H), 1.63 - 1.57 (m, 6H), 1.31 - 1.29 (m, 2H), 0.92 - 0.80 (m, 15H).

[0281] Synthesis of Compound 1 q can be inferred from the data provided in the determination of DAR.

[0282] 30 mg of anti-Her3 Antibody A was diluted with diluent (20 mM PB + 105 mM NaCl, pH 7.7), to which was added sodium edetate solution at a final concentration of 5 mM, and then the solution was mixed homogeneously; 20 mmol / L of TCEP solution was added at 4.5-fold molar equivalent of the antibody, and then the solution was mixed homogeneously and allowed to stand at room temperature for 30 min. To the above solution, was added 10 mmol / L of DL-04 dissolved in dimethyl sulfoxide at 10-fold molar equivalent (relative to the antibody), and then the solution was mixed homogeneously, and allowed to stand at room temperature for 2h to obtain a conjugated sample. After completion of the reaction, a 30 KDa ultrafiltration tube was used to transfer the sample into a 10 mM histidine buffer with a pH of 5.5 and remove low molecular weight substances, and finally the sample was concentrated to obtain a solution containing Compound 1. The average DAR value was measured to be 8.0 by mass spectrometry.

[0283] According to the mass spectrometry results of Compound 1, the antibody light chain was conjugated with 0-1 toxin molecule (the percentages of LC, DARI are 0%, 100%, respectively), and the heavy chain was conjugated with 0-3 toxin molecules (the percentages of mAb, DARI, DAR2, DAR3 were 0%, 0%, 0%, 100%, respectively). It can be inferred that the value of q is 8.

[0284] Example 2 - A First-In Human Phase I Trial of Compound 1 in patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) and Breast Cancer (BC)

[0285] Trial objectives and endpoints:

[0286] Primary: Assess the safety and tolerability, and determine the maximum tolerated dose (MTD), of Compound 1 in patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) and breast cancer (BC).

[0287] Secondary: Characterize the pharmacokinetics of the ADC, antibody, and unconjugated payload; evaluate immunogenicity as measured by the presence of antidrug antibodies (AD As); evaluate antitumor activity; find the recommended phase 2 dose (RP2D).

[0288] Exploratory: Evaluate the expression level of HER3 in tumour tissues and its relationship with anti-tumour activity.

[0289] Methods

[0290] Trial design: This is a phase 1, multicentre, open-label, first-in-human study of Compound 1, which was administered at 7 dose levels (DLs) as described in more detail below, by intravenous infusion once every 3 weeks (Q3W). A Bayesian optimal interval (BOIN) dose escalation scheme was used for escalation / de-escalation decisions, followed by cohort backfill at selected doses. Table 4, Key inclusion and exclusion criteria

[0291] Enrolment and Patient characteristics: All patients had metastases and previous exposure to systemic cancer therapy.

[0292] Table 5, Demographics and Baseline Characteristics Safety

[0293] 55 patients who received at least one dose of Compound 1 were analyzed for safety. The most common treatment-related adverse events were due to hematologic toxicity (see Table 3) and gastrointestinal and nutritional disorders, including nausea (60%), decreased appetite (41.8%), vomiting (40%), and stomatitis (30.9%).

[0294] During dose escalation, one dose-limiting toxicity (DLT, grade 3 febrile neutropenia) occurred at 5.5 mg / kg; during backfill, 2 patients died at 4.0 mg / kg due to sepsis after febrile neutropenia and pancytopenia; 1 patient died at 5.5 mg / kg after interstitial pneumonia following COVID-19 infection.

[0295] Table 6. Summary of treatment-related adverse events (TRAEs)

[0296]

[0297] Clinical activity:

[0298] 52 / 55 patients who received at least 1 dose of Compound 1 and have baseline and at least 1 post-baseline assessment were evaluated for response-related efficacy. Of the non-evaluable patients, 2 died and 1 discontinued treatment prior to the first assessment.

[0299] Median duration of response (DOR, N=52) was 5.8 months (95% CI; 2.9, not reached). Median progression-free survival (PFS, N=55) was 6.0 months (95% CI, 4.2-9.7); the PFS rate at 9 months was 35.6% (95% CI, 19.5-52.1)

[0300] Conclusions:

[0301] Compound 1 demonstrated encouraging efficacy in heavily pre-treated locally advanced / metastatic NSCLC and BC. Of 52 evaluable patients, ORR was 42.3% (n=22) and DCR was 94.2% (n=49), with responses seen beginning at 0.5 mg / kg. ORRs and DCRs at the 2.0 mg / kg and 3.0 mg / kg dose levels were comparable to those seen at higher dose levels, and the safety profile of Compound 1 was considered manageable below the 4.0 mg / kg dose level. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto.

Claims

1. CLAIMS1. An antibody-drug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, or a pharmaceutically acceptable salt thereof, for use in treating a cancer selected from the group consisting of brain tumour, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, liver cancer, kidney cancer, urothelial cancer, epidermal cancer, non-Hodgkin lymphoma, central nervous system tumour, or thyroid cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 0.5 mg / kg to about 4 mg / kg.

2. The antibody-drug conjugate for use of claim 1, wherein the cancer is breast cancer.

3. An antibody-drug conjugate comprising an anti-HER3 antibody or fragment thereof linked to a TOPO1 inhibitor drug via a linker unit, or a pharmaceutically acceptable salt thereof, for use in treating lung cancer; wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 2 mg / kg to about 4 mg / kg.

4. The antibody-drug conjugate for use of claim 3, wherein the cancer is non-smallcell lung cancer (NSCLC).

5. The antibody-drug conjugate for use of any one of claims 1 to 4, wherein the cancer is an unresectable, advanced and / or metastatic cancer.

6. The antibody-drug conjugate for use of any one of claims 1 to 5, wherein the anti- HER3 antibody or fragment thereof is selected from a full-length antibody, a Fab, a Fab', a F(ab')2, a Fv, an ScFv, a Fab'-SH, an sdAb, or a VHH.

7. The antibody-drug conjugate for use of any one of claims 1 to 6, wherein the anti- HER3 antibody or fragment thereof is a monoclonal humanized anti-HER3 antibody or a monoclonal human anti-HER3 antibody.

8. The antibody-drug conjugate for use of any one of claims 1 to 7, wherein the anti- HER3 antibody or fragment thereof comprises: a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and / or a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, wherein the CDRs are defined according to the Kabat definition scheme.

9. The antibody-drug conjugate for use of any one of claims 1 to 8, wherein the anti- HER3 antibody or fragment thereof comprises: a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and / or a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, wherein the CDRs are defined according to the IMGT definition scheme.

10. The antibody-drug conjugate for use according to any one of claims 1 to 9, wherein the anti-HER3 antibody or fragment thereof comprises: a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

11. The antibody-drug conjugate for use according to any one of claims 1 to 10, wherein the anti-HER3 antibody or fragment thereof comprises: a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

12. The antibody-drug conjugate for use according to any one of claims 1 to 11, wherein the antibody-drug conjugate has the structure represented by formula (I):or a pharmaceutically acceptable salt thereof, wherein:Ab is the anti-HER3 antibody or fragment thereof;each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, and amido;Rx and Ry are each independently selected from H and Cl -4 alkyl; each m is independently selected from 0, 1, 2, 3, 4, 5 and 6; yl is selected from any integer between 1 and 6 (such as 4, 5, and 6); each y2 is independently selected from any integer between 0 and 15 (such as between 6 to 15); each y3 is independently selected from 1, 2, and 3; each y4 is independently selected from 0 and 1; position 1 is attached to Ab (preferably via an S atom), and position 2 is attached to L2 or L3;L2 is absent or present, and when L2 is present, L2 is selected from:yl is selected from any integer between 1 and 6 (such as 4, 5, and 6); each y2 is independently selected from any integer between 0 and 10 (such as between 6 and 10); each y3 is independently selected from 1 or 2; each y4 is independently selected from 0 and 1; position 1 is attached to LI, and position 2 is attached to L3;L3 is selected from an amino acid residue or a short peptide consisting of 2-10 amino acid residues; the amino acid residue is selected from natural amino acid residues, non-natural amino acid residues, or selected from amino acid residues represented by AA1 or stereoisomer thereof;; in the amino acid residue represented by AA1, any one of Ra andRb is H, and the otheror, Ra and Rb, together with the carbon atom to which they are both attached, form a 5-6 membered heterocyclic ring, and said 5-6 membered heterocyclic ring is piperidine ring or piperazine ring. r, rl, ria and rib are each independently 0, 1, 2, 3, 4 or 5;Rml, Rnl, Rm la, Rnla, Rm lb and Rnlb are each independently H, Cl -6 alkyl or - COORxl, wherein, Rxl is Cl -6 alkyl; or, Rml and Rnl, Rm la and Rnla, and Rm lb and Rnlb, together with the nitrogen atom to which they are both attached, form a 5-6 membered heterocyclic ring, and of said 5-6 membered heterocyclic ring, the heteroatom is selected from 1 or 2 N atoms; the said 5-6 membered heterocyclic ring is optionally substituted with one or more RO’;Rz is selected from Cl -6 alkyl;RO and RO’ are each independently selected from Cl -6 alkyl, -NRm2Rn2 or 5-6 membered heterocyclyl optionally substituted with Cl -6 alkyl; of said 5-6 membered heterocyclyl, the heteroatom is selected from 1 or 2 N atoms;Rm2 and Rn2 are each independently selected from H and Cl -6 alkyl;position 1 is attached to L3, and position 2 is attached to W or X;Rl and R2 are each independently selected from H, halogens and Cl -4 alkyl; or, Rl and R2, together with the carbon atom to which they are both attached form a 5-6 membered heterocyclic ring, the heterocyclic ring contains 1, 2, or 3 of O, S, or N or any combination thereof;R3 is selected from H and Cl -4 alkyl; or R3 and X, together with the carbon atom to which they are both attached, form a 5-6 membered carbon ring;W is absent or present, when W is present, W is selected from -O-, -S-, -NR4-,position 1 is attached to X, and position 2 is attached toL4 or L3;X is selected from optionally substituted -(CJfcjni-,position 1 is attached to the parent ring and position 2 is attached to W orL4; the substituent is selected from one or two Cl -4 alkyls;R4, R5, and R7 are each independently selected from H and Cl -4 alkyl; and n, nl, n2, n3 are each independently selected from any integer between 0 and 6.

14. The antibody-drug conjugate for use according to claim 13, wherein LI is15. The antibody-drug conjugate for use according to any one of claims 12 to 14, wherein Z is selected from a direct bond, a carbon-carbon triple bond, and a carboncarbon double bond.

16. The antibody-drug conjugate for use according to claim 15, wherein Z is a carbon-carbon triple bond.

17. The antibody-drug conjugate for use according to any one of claims 12 to 16, wherein Rx is H or methyl.

18. The antibody-drug conjugate for use according to claim 17, wherein Rx is H.

19. The antibody-drug conjugate for use according to any one of claims 12 to 18, wherein Ry is H or methyl.

20. The antibody-drug conjugate for use according to claim 19, wherein Ry is H.

21. The antibody-drug conjugate for use according to any one of claims 12 to 20, wherein m is 2, 3 or 4.

22. The antibody-drug conjugate for use according to claim 21, wherein m is 3.

23. The antibody-drug conjugate for use according to any one of claims 12 to 22, wherein L2 is absent.

24. The antibody-drug conjugate for use according to any one of claims 12 to 23, wherein L3 is selected from AA1, AAl-Gly, Val-Cit, Vai-Ala, Val-AAl, Val-AAl - Gly, AAl-Ala-Asn, Ala- Ala- Ala, Ala-Ala-Asn and Gly-Gly-Phe-Gly.

25. The antibody-drug conjugate for use according to claim 24, wherein L3 is selected from AA1, AAl-Gly, Val-Cit, Val-AAl -Gly, AAl-Ala-Asn and Gly-Gly-Phe-Gly.

26. The antibody-drug conjugate for use according to claim 25, wherein L3 is Val- AAl -Gly.

27. The antibody-drug conjugate for use according to any one of claims 24 to 26, wherein, the amino acid residue represented by AA1 is selected from,28. The antibody-drug conjugate for use according to claim 27, wherein the amino acid residue represented29. The antibody-drug conjugate for use according to any one of claims 12 to 28, wherein L4 is selected from30. The antibody-drug conjugate for use according to claim 29, wherein L4 is31. The antibody-drug conjugate for use according to any one of claims 12 to 30, wherein W is O.

32. The antibody-drug conjugate for use according to any one of claims 12 to 31, wherein X is -(C fcjni-.

33. The antibody-drug conjugate for use according to claim 32, wherein nl is 2, 3 or 4.

34. The antibody-drug conjugate for use according to claim 33, wherein nl is 3.

35. The antibody-drug conjugate for use according to any one of claims 12 to 34,wherein position 1 is attached to the connecting atom on the anti-HER3 antibody and position 2 is attached to W.

36. The antibody-drug conjugate for use according to any one of claims 12 to 35, wherein the structural fragment represented37. The antibody-drug conjugate for use according to any one of claims 12 to 36, wherein the structural fragmentwherein X is -(CH2)3-.

38. The antibody-drug conjugate for use according to any one of claims 12 to 37, wherein the antibody-drug conjugate has the structureor a pharmaceutically acceptable salt thereof, wherein:Ab is the anti-HER3 antibody or fragment thereof as defined in claims 6 to 11; and q is the connection number, and is an integer from 1 to 16.

39. An antibody-drug conjugate of formula (II):or a pharmaceutically acceptable salt thereof, wherein:Ab is an HER3 antibody comprising a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 16; and q is the connection number, and is an integer from 1 to 16; for use in treating breast cancer.

40. The antibody-drug conjugate for use according to any one of claims 12 to 39, wherein q is from 4 to 12.

41. The antibody-drug conjugate for use according to claim 40, wherein q is from 6 to 10.

42. The antibody-drug conjugate for use according to claim 41, wherein q is 7 to 9.

43. The antibody-drug conjugate for use according to claim 42, wherein q is 8.

44. The antibody-drug conjugate for use of any one of claims 39 to 43, wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of about 0.5 mg / kg to about 4 mg / kg.

45. The antibody-drug conjugate for use of any one of claims 1-2, 5-38 or 40, wherein the use comprises administering the antibody-drug conjugate or composition to a patient at a dose in the range of about 0.5 mg / kg to about 3.5 mg / kg.

46. The antibody-drug conjugate for use of claim 45, wherein the use comprises administering the antibody-drug conjugate to a patient at a dose of about 0.5 mg / kg.

47. The antibody-drug conjugate for use of claim 45, wherein the use comprises administering the antibody-drug conjugate to a patient at a dose of about 1.0 mg / kg.

48. The antibody-drug conjugate for use of claim 45, wherein the use comprises administering the antibody-drug conjugate to a patient at a dose of about 2.0 mg / kg.

49. The antibody-drug conjugate for use of claim 45, wherein the use comprises administering the antibody-drug conjugate to a patient at a dose of about 3.0 mg / kg.

50. The antibody-drug conjugate for use of any one of claims 3 to 38 or 40, wherein the use comprises administering the antibody-drug conjugate or composition to a patient at a dose in the range of about 2.0 mg / kg to about 3.5 mg / kg.

51. The antibody-drug conjugate for use of claim 50, wherein the use comprises administering the antibody-drug conjugate to a patient at a dose of about 2.0 mg / kg.

52. The antibody-drug conjugate for use of claim 50, wherein the use comprises administering the antibody-drug conjugate to a patient at a dose of about 3.0 mg / kg.

53. The antibody-drug conjugate for use of any preceding claim, wherein the use comprises administering the antibody-drug conjugate to a patient once every 3 weeks.

54. The antibody-drug conjugate for use of any preceding claim, wherein the use comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient intravenously.

55. The antibody-drug conjugate for use of any preceding claim, wherein the cancer is a HER3 -expressing cancer.

56. The antibody-drug conjugate for use of any preceding claim, wherein the use comprises administering to a patient which has not previously been treated with a HER3 -targeting agent or an ADC including a HER3 -targeting agent.

57. The antibody-drug conjugate for use of any preceding claim, wherein the use comprises administering to a patient having an EGFR-active mutation.

58. The antibody-drug conjugate for use of any preceding claim, wherein the use comprises administering to a patient which is intolerant to a TOPO1 inhibitor or an ADC including a TOPO1 inhibitor.

Images