Bispecific antibody-drug conjugates targeting her2 for the treatment of tumors

Abstract

The present disclosure relates to the use of a bispecific antibody-drug conjugate targeting HER2 in the treatment of tumors, which has excellent clinical therapeutic effect in various tumors.

Description

Technical Field

[0001] This disclosure relates to the biopharmaceutical field, specifically to the use of bispecific antibody-drug conjugates targeting HER2. Background Technology

[0002] Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor belonging to the epidermal growth factor receptor (ERBB) family. It plays a crucial role in regulating cell proliferation, differentiation, and survival. Unlike other family members (such as HER1, HER3, and HER4), HER2 lacks a known natural ligand but can activate downstream signaling pathways by forming heterodimers with other ERBB receptors. HER2 regulates cell proliferation, survival, differentiation, and migration. HER2 gene amplification or protein overexpression is commonly found in various solid tumors, including breast cancer and gastric cancer, and is closely associated with high tumor invasiveness and poor prognosis. Representative HER2-targeted therapies include trastuzumab (Herceptin) and pertuzumab (Perjeta), which bind to different domains of HER2, inhibiting signal transduction and inducing antibody-dependent cytotoxicity (ADCC).

[0003] Antibody drugs are widely used in cancer treatment. Because antibodies can selectively bind to antigens or antigen-positive cells, they exhibit low off-target toxicity. However, antibody drugs alone are often insufficient to effectively combat tumors. Antibody-drug conjugates (ADCs) combine the advantages of antibodies and cytotoxins, enhancing the effectiveness and selectivity of tumor cell killing. Since the approval of the first ADC drug, Mylotarg, in 2000, 15 ADC drugs have been approved for marketing, and many more ADC drugs targeting different targets and employing different conjugation technologies are currently in clinical trials.

[0004] Patent application WO2023280092 discloses a bispecific antibody-drug conjugate targeting HER2, and it is necessary to explore its clinical application prospects in different types of tumors. Summary of the Invention

[0005] In a first aspect, this disclosure relates to a method for treating and / or preventing advanced or metastatic solid malignancies, comprising the step of administering an antibody-drug conjugate to a subject in need.

[0006] Secondly, this disclosure also relates to antibody-drug conjugates for the treatment and / or prevention of advanced or metastatic solid malignancies.

[0007] Thirdly, this disclosure also relates to the use of antibody-drug conjugates in the preparation of medicaments for the treatment and / or prevention of advanced or metastatic solid malignancies.

[0008] Fourthly, this disclosure also relates to antibody-drug conjugates for the treatment and / or prevention of advanced or metastatic solid malignancies. Attached Figure Description

[0009] Figure 1 shows: (a) the reaction formula of antibody A with UDP-GalNAz and the structure of UDP-GalNAz; (b) the mass spectrometry information of antibody A-(N3)4; (c) the reaction formula of antibody A-ADC prepared by antibody A-(N3)4 with LP1; and (d) the mass spectrometry information of antibody A-ADC.

[0010] Figure 2 shows: (a) safety data for interim result 1; (b) efficacy data for interim result 1; (c) efficacy data for interim result 2; (d) safety data for interim result 2; (e) safety data for interim result 3; and (f) efficacy data for interim result 3. Detailed Implementation

[0011] Terminology Definition

[0012] Unless otherwise indicated or defined, all terms used herein have their ordinary meaning as will be understood by those skilled in the art. References include, for example, standard manuals such as Sambrook et al., “Molecular Cloning: A Laboratory Manual” (2nd edition), Volumes 1–3, Cold Spring Harbor Laboratory Press (1989); Lewin, “Genes IV”, Oxford University Press, New York, (1990); and Roitt et al., “Immunology” (2nd edition), Gower Medical Publishing, London, New York (1989), and general prior art cited herein; furthermore, unless otherwise stated, all methods, steps, techniques, and operations not specifically detailed herein can and have been performed in a manner known per se as will be understood by those skilled in the art. Also refer to, for example, standard manuals, the aforementioned general prior art, and other references cited therein.

[0013] The terms "complete antibody," "full-length antibody," or "all antibody" are used interchangeably herein and generally refer to an immunoglobulin molecule composed of two identical pairs of polypeptide chains (each pair having one "light" (L) chain and one "heavy" (H) chain). Antibody light chains can be classified as κ and λ light chains. Heavy chains can be classified as μ, δ, γ, α, or ε, and antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within both light and heavy chains, variable and constant regions can be linked by a "J" region of approximately 12 or more amino acids, and the heavy chain may also contain a "D" region of approximately 3 or more amino acids. The heavy chain can consist of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region can consist of three domains (CH1, CH2, and CH3). The light chain can consist of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region can consist of a single domain, CL. The constant regions of an antibody mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The VH and VL regions can be further subdivided into highly degenerated regions (called complementarity-determining regions (CDRs)) interspersed with more conserved regions called framework regions (FRs). For example, VH and VL may each contain or consist of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus, in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions (VH and VL) of each heavy / light chain pair form the antibody binding sites.

[0014] The complementarity-determining region (CDR) or CDR is a region within the antibody variable domain that is highly variable in sequence and forms a structurally defined loop ("hypervariant loop") and / or contains antigen contact residues ("antigen contact sites"). The CDR is primarily responsible for binding to antigen epitopes. The CDRs of the heavy and light chains are typically referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus. CDRs located within the antibody heavy chain variable domain are called HCDR1, HCDR2, and HCDR3, while those located within the antibody light chain variable domain are called LCDR1, LCDR2, and LCDR3. In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any of a number of known antibody CDR assignment systems or combinations thereof, including, for example: Chothia (Chothia et al. (1989) Nature 342: 877-883, Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)) based on antibody sequence variability; Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), and the international ImMunoGeneTics database. (IMGT) (on the World Wide Web imgt.cines.fr / ), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures (North et al., “A New Clustering of AntibodyCDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)).

[0015] In this disclosure, unless otherwise specified, the Kabat assignment system is used to determine the CDR region:

[0016] The term "antibody" is not limited to any particular method of producing antibodies. For example, it includes, in particular, recombinant antibodies, monoclonal antibodies, and polyclonal antibodies. Antibodies can be different isotypes of antibodies, such as IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtypes), IgA1, IgA2, IgD, IgE, or IgM antibodies.

[0017] In this application, the term "bispecific antibody" generally refers to an antibody capable of binding to two antigens or antigenic epitopes, respectively. In some embodiments of the invention, the bispecific antibody may include a light chain and a heavy chain of an antibody capable of specifically binding to a first antigen or antigenic epitope, and a light chain and a heavy chain of an antibody capable of specifically binding to a second antigen or antigenic epitope. In one embodiment of this application, the light chain of the antibody capable of specifically binding to the first antigen or antigenic epitope and the light chain of the antibody capable of specifically binding to the second antigen or antigenic epitope in the bispecific antibody have the same sequence; the two or more light chains having the same sequence are referred to in this application as a "common light chain." In one embodiment of this application, the heavy chain of the antibody capable of specifically binding to the first antigen or antigenic epitope and the heavy chain of the antibody capable of specifically binding to the second antigen or antigenic epitope in the bispecific antibody have different sequences.

[0018] The term "epitope" or "antigenic epitope" generally refers to a site on an antigen that is specifically bound by an immunoglobulin or antibody. "Epitope" is also known in the art as an "antigenic determinant." An epitope or antigenic determinant typically consists of chemically active surface groups of a molecule, such as amino acids or carbohydrate or sugar side chains, and usually has specific three-dimensional structural features and specific charge characteristics. For example, an epitope typically comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive or discontinuous amino acids in a unique spatial conformation, which can be "linear" or "conformal." See, for example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, GE Morris, Ed. (1996). In a linear epitope, all points of interaction between the protein and interacting molecules (e.g., antibodies) are linear along the primary amino acid sequence of the protein. In a conformational epitope, points of interaction are separated by protein amino acid residues.

[0019] The term "specificity" refers to the number of different types of antigens or epitopes that a particular antigen-binding molecule or antigen-binding protein can bind. Specificity can be determined based on the affinity and / or cohesion of the antigen-binding protein. Affinity, expressed as the dissociation equilibrium constant (KD) between the antigen and the antigen-binding protein, is a measure of the strength of binding between the epitope and the antigen-binding site on the antigen-binding protein: the smaller the KD value, the stronger the binding between the epitope and the antigen-binding protein (or, affinity can also be expressed as the association constant (KA), which is 1 / KD). As those skilled in the art will understand, affinity can be determined in known ways depending on the specific antigen of interest. Affinity is a measure of the strength of binding between an antigen-binding protein (e.g., an immunoglobulin, antibody, a single variable domain of an immunoglobulin, or a polypeptide containing such a domain) and the associated antigen. Affinity relates to both the affinity between the antigen and the antigen-binding site on the antigen-binding protein and the number of associated binding sites present on the antigen-binding protein.

[0020] As used in this application, the term "domain" (of a polypeptide or protein) refers to a folded protein structure that is able to maintain its tertiary structure independently of the rest of the protein. Generally, a domain is responsible for a single functional property of a protein and in many cases can be added to, removed from, or transferred to other proteins without loss of the function of the rest of the protein and / or the domain itself.

[0021] As used herein, the term "immunoglobulin domain" refers to a globular region of an antibody chain (e.g., a chain of a conventional four-chain antibody or a chain of a heavy-chain antibody), or to a polypeptide that is substantially composed of such globular regions. An immunoglobulin domain is characterized by its ability to maintain the immunoglobulin folding characteristics of the antibody molecule.

[0022] As used herein, the term "immunoglobulin variable domain" refers to an immunoglobulin domain substantially composed of four "frame regions" referred to in the art and hereinafter as "frame region 1" or "FR1", "frame region 2" or "FR2", "frame region 3" or "FR3", and "frame region 4" or "FR4", respectively, and three "complementarity-determining regions" or "CDRs" spaced apart from the frame regions, referred to in the art and hereinafter as "complementarity-determining region 1" or "CDR1", "complementarity-determining region 2" or "CDR2", and "complementarity-determining region 3" or "CDR3", respectively. Therefore, the general structure or sequence of an immunoglobulin variable domain can be represented as: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The immunoglobulin variable domain confers antibody specificity for antigens by possessing antigen-binding sites.

[0023] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of its constant region. This term includes native sequence Fc regions and variant Fc regions. A native immunoglobulin "Fc domain" contains two or three constant domains: a CH2 domain, a CH3 domain, and optionally a CH4 domain. For example, in native antibodies, the immunoglobulin Fc domain contains the second and third constant domains (CH2 and CH3 domains) of two heavy chains derived from IgG, IgA, and IgD antibodies; or it contains the second, third, and fourth constant domains (CH2, CH3, and CH4 domains) of two heavy chains derived from IgM and IgE antibodies. Unless otherwise stated herein, amino acid residues in the Fc region or heavy chain constant region are numbered according to the EU numbering system (also known as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interes, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991. In this document, the term "Fc region" excludes the heavy chain variable region VH and light chain variable region VL of immunoglobulins, as well as the heavy chain constant region CH1 and light chain constant region CL, but in some cases may include the hinge region at the N-terminus of the heavy chain constant region.

[0024] The term "protein-drug conjugate" generally refers to a binding protein (e.g., an antibody or its antigen-binding fragment) linked to one or more chemical drugs, such as antibody-drug conjugates (ADCs). The chemical drug can be any therapeutic agent and / or cytotoxic agent. The antibody-drug conjugate can have any number of drugs conjugated to the antibody from 1 to 16, for example, it can include 2, 4, 6, or 8 drug-loaded species. In this invention, the drug can include mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemotherapeutic agents, hormones, anti-hormonal agents, corticosteroids, photosensitizing agents, oligonucleotides, radioactive isotopes, topoisomerase inhibitors, tyrosine kinase inhibitors, and / or radiosensitizers, etc.

[0025] The term "drug:antibody ratio" or "DAR" refers to the ratio of a bioactive molecule coupled to the protein described herein to the protein itself. In some embodiments described herein, the DAR may be determined by n in Formula I, for example, the DAR may be 1 to 16, such as 2-16, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6, 6-10, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. The DAR may also be calculated as the average DAR of the molecular population in the product, i.e., the overall ratio of the drug portion coupled to the ligand portion in the product to the ligand portion as determined by detection methods (e.g., by conventional methods such as mass spectrometry, ELISA, electrophoresis, and / or HPLC), this DAR is referred to herein as the average DAR or the measured DAR. In some embodiments, the average DAR value of the conjugates of the present invention is 1 to 16, for example 2-16, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 3-6, 6-10, for example 1.0-8.0, 2.0-6.0, for example 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 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, 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, 7.7, 7.8, 0, 7.9, 8, 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, 9.6, 9.7, 9.8, 9.9, or 10.0, a range with two of these values ​​as endpoints. It should be understood that when referring to the average DAR value, the couplings of the present invention refer to a group of coupling molecules or a mixture of coupling molecules that contain coupling molecules having the same and / or different DAR values.

[0026] The term "linker" refers to a structural segment that connects a drug (e.g., a small molecule drug) to an antibody. It should be understood that a linker has functional groups that can form bonds with functional groups of the antibody or its antigen-binding fragment before it is linked to the antibody or its antigen-binding fragment.

[0027] The term "N-glycan" refers to a glycan chain attached to asparagine (Asn) of a protein's Asn-X-Ser / Thr sequence (Ser is serine, Thr is threonine, and X is any amino acid except proline). The term "O-glycan" refers to a glycan chain covalently linked to the -OH group of a serine or threonine residue in a protein via a terminal monosaccharide residue. O-glycosylation sites do not have conserved sequences, and glycans do not have a fixed core structure; they can be composed of a monosaccharide or a polysaccharide.

[0028] The term "G0 glycoform" refers to a glycosemycology in which the N-glycan molecule does not contain terminal galactose residues or a core fucose residue, such as... ,in It is N-acetylglucosamine. It is mannitol.

[0029] The term "GOF sugar type" refers to sugar molecules, such as N-glycan molecules, that do not contain terminal galactose residues but contain fucose linked to the core N-acetylglucosamine.

[0030] In this application, the term "HER2" generally refers to human epidermal growth factor receptor 2 (SwissProt P04626). In this application, HER2 may also be referred to as rbB-2, NEU, HER-2, or CD340. HER2 may include any variant, isoform, and species homolog of HER2, which is naturally expressed by cells—including tumor cells—or by cells transfected with the HER2 gene or cDNA.

[0031] The term "optional" or "optionally" means that the event or condition described below either occurs or does not occur, and the description includes instances where the event or condition occurs as well as instances where the event or condition does not occur. For example, when a group or structure is "optionally substituted," the group or structure may or may not be substituted.

[0032] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of the conjugates of the present invention, and that such salt is not biologically or otherwise undesirable. The conjugates of the present invention can exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts. In the present invention, a pharmaceutically acceptable non-toxic acid addition salt refers to a salt formed by the conjugates of the present invention with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. A pharmaceutically acceptable non-toxic base addition salt refers to a salt formed by the conjugates of the present invention with an organic or inorganic base, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts formed by reacting with an organic base containing an N-group.

[0033] Where there is no contradiction in the context, "pharmaceutical acceptable" and "medicinal" are used interchangeably in this article.

[0034] As used herein, the term “and / or” refers to any one of the options or two or more of the options.

[0035] As used herein, the terms “comprising” or “including” mean to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover combinations of the stated elements, integers, or steps.

[0036] The term "administration" generally refers to a method of giving a dose of a compound or pharmaceutical composition to a subject (e.g., a patient). Administerment can be made by any suitable means, including parenteral, intrapulmonary, and intranasal administration, as well as intralesional administration (if required for local treatment). Parenteral infusion includes, for example, intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0037] In this application, the term "about" generally refers to a variation within a range of 0.5% to 10% above or below a specified value, such as a variation within a range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below a specified value. Unless otherwise specified, all values ​​mentioned in this application are considered to be modified by "about". In case of doubt, or if the error range for a particular value or parameter is not generally understood in the art, "about" means ±5% of that value or parameter.

[0038] The term "effective amount" refers to such an amount or dose of the antibody, fragment, composition, or combination of the present invention, which, when administered to a patient in a single or multiple doses, produces the intended effect in a patient requiring treatment or prevention. Depending on the intended effect, it may include "therapeutic effective amount" and "preventive effective amount".

[0039] "Therapeutic effective dose" refers to the amount that, at the required dose and for the required duration, effectively achieves the desired therapeutic outcome. A therapeutic effective dose is also a dose in which any toxic or harmful effects of the antibody, antibody fragment, composition, or combination are less than the beneficial therapeutic effect. "Prophylactic effective dose" refers to the amount that, at the required dose and for the required duration, effectively achieves the desired preventative outcome. Typically, because prophylactic doses are administered in subjects before or at an earlier stage of the disease, the prophylactic effective dose will be less than the therapeutic effective dose.

[0040] "Individual" or "subject" includes mammals. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human.

[0041] The terms "cancer" and "cancerous" refer to or describe a physiological disorder in mammals that is typically characterized by unregulated cell growth. Cancer can be in its early, middle, or late stages, or it can be metastatic.

[0042] The term “tumor” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. “Tumor” encompasses solid tumors and hematologic malignancies as well as metastatic lesions. The terms “cancer,” “cancerous,” and “tumor” are not mutually exclusive when used in this article.

[0043] The term "pharmaceutical excipients" refers to diluents, adjuvants (e.g., Freund's adjuvants (complete and incomplete)), excipients, carriers, or stabilizers that are applied together with the active substance.

[0044] The term "pharmaceutical composition" refers to a composition which is present in a form that allows the biological activity of the active ingredient contained therein to be effective, and which does not contain any additional ingredients that would have unacceptable toxicity to a subject administering the composition.

[0045] When used in this article, "treatment" means to slow down, interrupt, block, alleviate, stop, reduce, or reverse the progression or severity of existing symptoms, conditions, illnesses, or diseases.

[0046] The term "HER2 positive" means that the subject's tumor sample, after immunohistochemical testing, has an IHC score of 3+, or an IHC score of 2+ and a positive ISH (in situ hybridization) (e.g., FISH) result. The term "HER2 low expression" means that the subject's tumor sample has an IHC score of 2+ and a negative ISH (e.g., FISH) result, or an IHC score of 1+. The term "HER2 negative" means that the subject's tumor sample has an IHC score of 0.

[0047] The term "standard treatment" refers to a treatment regimen based on high-level clinical evidence (such as the results of randomized controlled phase III clinical trials), recommended by authoritative international or regional clinical practice guidelines (such as NCCN, ESMO, CSCO, etc.), and widely adopted and accepted in clinical practice. Specifically, first-line treatment refers to the first systemic drug therapy received by a patient diagnosed with advanced (unresectable, locally advanced, or metastatic) cancer; second-line treatment refers to the second systemic treatment regimen administered after disease progression is confirmed by imaging during first-line treatment (or shortly after stopping first-line treatment); third-line treatment refers to the third systemic treatment regimen administered after disease progression occurs again during second-line treatment, following a change in treatment regimen; ≥3-line treatment refers to patients who have received at least three different systemic treatment regimens, all of which have resulted in disease progression, including third-line, fourth-line, and higher-level treatments. Invention Details

[0049] Treatment

[0050] In a first aspect, this disclosure relates to a method for treating and / or preventing advanced or metastatic solid malignancies, comprising the step of administering an antibody-drug conjugate to a subject in need, said antibody-drug conjugate having the structure shown in Formula I: P-(LD)n (I), Where P is a bispecific antibody targeting HER2, D is a bioactive molecule, L is a linker unit, and n is an integer from 1 to 20.

[0051] In some embodiments, the bispecific antibody can bind to different epitopes of human HER2, such as extracellular domain II and extracellular domain IV of human HER2.

[0052] In some embodiments, the bispecific antibody is a bispecific antibody that targets different epitopes of HER2; for example, the bispecific antibody is a bispecific antibody that targets both extracellular domain II and extracellular domain IV of human HER2.

[0053] In some embodiments, the bispecific antibody has the structure of a full-length antibody, but the two heavy chains are different, i.e., it comprises a first heavy chain, a second heavy chain, and two common light chains. In some embodiments, the first heavy chain includes a first heavy chain variable region, the second heavy chain includes a second heavy chain variable region, and / or the common light chain includes a common light chain variable region.

[0054] In some embodiments, the first heavy chain variable region comprises: HC1 CDR1, which comprises the amino acid sequence shown in SEQ ID NO: 4; HC1 CDR2, which comprises the amino acid sequence shown in SEQ ID NO: 5; and HC1 CDR3, which comprises the amino acid sequence shown in SEQ ID NO: 6. The second heavy chain variable region comprises: HC2 CDR1, which contains the amino acid sequence shown in SEQ ID NO: 7; HC2 CDR2, which contains the amino acid sequence shown in SEQ ID NO: 8; and HC2 CDR3, which contains the amino acid sequence shown in SEQ ID NO: 9. The common light chain variable region comprises: LC CDR1, which contains the amino acid sequence shown in SEQ ID NO: 10; LC CDR2, which contains the amino acid sequence shown in SEQ ID NO: 11; and LC CDR3, which contains the amino acid sequence shown in SEQ ID NO: 12.

[0055] In some embodiments, the bispecific antibody comprises a first heavy chain, a second heavy chain, and a common light chain, wherein the first heavy chain includes a first heavy chain variable region, the second heavy chain includes a second heavy chain variable region, and the common light chain includes a common light chain variable region. The first heavy chain variable region includes HC1 CDR1 shown in SEQ ID NO: 4, HC1 CDR2 shown in SEQ ID NO: 5 and HC1 CDR3 shown in SEQ ID NO: 6; The second heavy chain variable region includes HC2 CDR1 shown in SEQ ID NO: 7, HC2 CDR2 shown in SEQ ID NO: 8 and HC2 CDR3 shown in SEQ ID NO: 9; The common light chain variable region includes LC CDR1 shown in SEQ ID NO: 10, LC CDR2 shown in SEQ ID NO: 11, and LC CDR3 shown in SEQ ID NO: 12.

[0056] In some embodiments, the first heavy chain variable region comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 1.

[0057] In some embodiments, the second heavy chain variable region comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 2.

[0058] In some embodiments, the common light chain variable region comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 3.

[0059] In some embodiments, the bispecific antibody comprises a first heavy chain, a second heavy chain, and a common light chain, wherein the first heavy chain includes a first heavy chain variable region, the second heavy chain includes a second heavy chain variable region, and the common light chain includes a common light chain variable region, wherein the first heavy chain variable region includes the amino acid sequence shown in SEQ ID NO: 1, the second heavy chain variable region includes the amino acid sequence shown in SEQ ID NO: 2, and the common light chain variable region includes the amino acid sequence shown in SEQ ID NO: 3.

[0060] In other embodiments, the bispecific antibody comprises a first heavy chain, a second heavy chain, and a common light chain, wherein the first heavy chain includes a first heavy chain variable region, the second heavy chain includes a second heavy chain variable region, and the common light chain includes a common light chain variable region, wherein the first heavy chain variable region is composed of the amino acid sequence shown in SEQ ID NO: 1, the second heavy chain variable region is composed of the amino acid sequence shown in SEQ ID NO: 2, and the common light chain variable region is composed of the amino acid sequence shown in SEQ ID NO: 3.

[0061] In some embodiments, the first heavy chain of the bispecific antibody described in this disclosure further includes a first heavy chain constant region, the second heavy chain further includes a second heavy chain constant region, and the common light chain further includes a common light chain constant region, wherein... The first heavy chain constant region contains, or is composed of, the amino acid sequence shown in SEQ ID NO: 13; the second heavy chain constant region contains, or is composed of, the amino acid sequence shown in SEQ ID NO: 14; the common light chain constant region contains, or is composed of, the amino acid sequence shown in SEQ ID NO: 15; or, The first heavy chain constant region contains, or is composed of, the amino acid sequence shown in SEQ ID NO: 14; the second heavy chain constant region contains, or is composed of, the amino acid sequence shown in SEQ ID NO: 13; and the common light chain constant region contains, or is composed of, the amino acid sequence shown in SEQ ID NO: 15.

[0062] In some embodiments, the first heavy chain of the bispecific antibody comprises the amino acid sequence shown in SEQ ID NO: 16, or an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence.

[0063] In some embodiments, the second heavy chain of the bispecific antibody comprises the amino acid sequence shown in SEQ ID NO: 17, or an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence.

[0064] In some embodiments, the common light chain of the bispecific antibody comprises the amino acid sequence shown in SEQ ID NO: 18, or an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence.

[0065] In some embodiments, the antibody comprises a first heavy chain, a second heavy chain, and a common light chain, wherein the first heavy chain comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 16; the second heavy chain comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 17; and the common light chain comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 18.

[0066] In some embodiments, the bioactive molecule D is a cytotoxin, for example, selected from: DNA alkylating agents, DNA destructive agents, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule inhibitors, ribosome inhibitors, and any combination thereof.

[0067] In some specific implementation schemes, D is selected from: auristatin derivatives, maidansine derivatives, eribulin derivatives, tubulysin derivatives, pyrrolobenzodiazepine (PDB) derivatives, ducarmycin derivatives, calicacin derivatives, PNU-159682 and its derivatives, camptothecin derivatives, amatoxin derivatives, and any combination thereof.

[0068] In some embodiments, D is a topoisomerase I inhibitor, such as a camptothecin derivative, which refers to a compound having the same 5-membered fused core structure as naturally derived camptothecin and having substitution modifications at positions 7, 9, 10, and 11, and having the same or stronger topoisomerase I inhibitory activity as natural camptothecin.

[0069]

[0070] In some implementations, D has the structure shown in Formula II: (II), Wherein, X is selected from CH2, NH, O, S or SO2; Y does not exist, or Y has the structure shown in Equation III: (III); W1 is selected from O, S, and NH. R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyl, amino, cyano, and nitro; or, R a and R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl, a 3-6 membered heterocycloalkyl, or a carbonyl group; or, R a The N atom of the amide moiety is attached to form a 3-6 membered heterocyclic alkyl group and R b It is hydrogen; Each of the alkyl, alkoxy, cycloalkyl and heterocycloalkyl groups is optionally further substituted by a group selected from deuterium, halogen, hydroxyl, amino, cyano, carbonyl and nitro groups. d is an integer selected from 0 to 5.

[0071] In some implementations, D has the structure shown in Formula IV: (IV), Where W1 is O or NH; R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyl, amino, cyano, and nitro; or, R a and R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl, a 3-6 membered heterocycloalkyl, or a carbonyl group; or, R a The N atom of the amide moiety is attached to form a 3-6 membered heterocyclic alkyl group and R b It is hydrogen; Each of the alkyl, alkoxy, cycloalkyl and heterocycloalkyl groups is independently and optionally further substituted with a group selected from deuterium, halogen, hydroxyl, amino, cyano and nitro groups; d is an integer from 0 to 5.

[0072] In some implementations, W1 is 0.

[0073] In some implementations, d is 0, 1, or 2.

[0074] In some implementations, R a Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyl and amino, R b The alkyl, alkoxy, cycloalkyl, and heterocycloalkyl groups are each optionally further substituted with groups selected from deuterium, halogen, hydroxyl, amino, cyano, and nitro groups.

[0075] In some implementations, R a and R b Together with the carbon atom attached thereto, they form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl. Each of the cycloalkyl and heterocycloalkyl groups may be further substituted independently and optionally with a group selected from deuterium, halogen, hydroxyl, amino, cyano, and nitro groups.

[0076] In some implementations, D may be selected from the following group: , , , , , , , , , , , , , , , , , , and .

[0077] In some implementations, D is selected from: .

[0078] In some implementations, the connecting unit L in Equation I has the structure shown in Equation V: -L1-sp1-L2-sp2- (V), Wherein, L1 is a connector for connecting with P, sp1 is the first spacer unit, L2 is a cuttable connector, and sp2 is the second spacer unit connected to D.

[0079] In some implementations, L1 in formula V is selected from: , , , , , , , , , , , , , and (The side connected to the antibody is marked as P, and the side connected to the first spacer unit is marked as sp1). Where Ar represents C 6-10 aryl groups, which are optionally converted by halogens, C 1-6 Alkyl substitution; R1 is selected from hydrogen, halogen, and C. 1-6 Alkyl group; Z is selected from straight bond, C 2-6 Ethyne group, C 2-6 imidene group, C 6-10 Aryl, 5-10 heteroaryl, amide, sulfonamide, imino and CF2.

[0080] In some implementations, L1 is or .

[0081] In some implementations, the structure of the first spacing unit sp1 in equation V is as follows: (The side connected to L1 is labeled L1, and the side connected to L2 is labeled L2), where a1 = 0 or 1, a2 = an integer from 0 to 6, b1 = 0 or 1, b2 = an integer from 0 to 16, b3 = an integer from 0 to 16, c = an integer from 0 to 6, and at least one of b2 and b3 is 0.

[0082] In some implementations, a1=1 in the structure of sp1; in other implementations, a1=0.

[0083] In some implementations, a2 = 0, 1, 2, 3, 4, 5, or 6.

[0084] In some implementations, b1 = 0 or 1.

[0085] In some implementations, b2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0086] In some implementations, b3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0087] In some implementations, c = 0, 1, 2, 3, 4, 5, or 6.

[0088] The above options a1, a2, b1, b2, b3 and c can be combined in any way, provided that at least one of b2 and b3 is 0.

[0089] In some specific implementations, the structure of sp1 is selected from the following group: (1) a1=0, a2=2, 3, 4, 5 or 6, b1=0, b2=0, b3=0, c=0; (2) a1=0, a2=0, b1=0, b2=0, b3=0, c=2, 3, 4, 5 or 6; (3) a1=1, a2=2, 3, 4, 5 or 6, b1=1, b2=2, 3, 4, 5, 6, 7 or 8, b3=0, c=0; (4) a1=0, a2=2, 3, 4, 5 or 6, b1=1, b2=2, 3, 4, 5, 6, 7 or 8, b3=0, c=0; and (5) a1=1, a2=0, b1=0, b2=0, b3=2, 3, 4, 5, 6, 7 or 8, c=2, 3, 4, 5 or 6.

[0090] In some embodiments, the cleavable linker L2 described in Formula V can be cleaved by cathepsin; for example, the cleavable linker L2 can be cleaved by cathepsin B.

[0091] In some embodiments, L2 is selected from the following dipeptide residues: -Phe-Lys-, -Val-Ala-, -Val-Lys-, -Val-Cit-, -Ala-Lys-, -Phe-Cit-, -Leu-Cit-, -Ile-Cit-, -Phe-Arg-, -Trp-Cit-, -Gly-Gly-, -Ala-Ala-, -Gly-Val-, and -Gly-Glu-; the left side of the dipeptide residue is linked to sp1, and the right side is linked to sp2. Preferably, L2 is selected from -Val-Ala-, -Val-Lys-, and -Val-Cit-.

[0092] In some embodiments, L2 is selected from the following tripeptide residues: -Glu-Val-Ala-, -Glu-Val-Cit-, -αGlu-Val-Ala-, -αGlu-Val-Cit-, -Val-Lys-Gly, and -Val-Cit-Gly-; the left side of the tripeptide residue is linked to sp1 and the right side is linked to sp2.

[0093] In some embodiments, L2 is selected from the following tetrapeptide residues: -Gly-Gly-Phe-Gly- and -Gly-Phe-Gly-Gly-; the left side of the tetrapeptide residue is linked to sp1 and the right side is linked to sp2.

[0094] In some implementations, sp2 in formula II is absent, or sp2 is selected from: , and (The side connected to L2 is labeled L2, and the side connected to the biologically active substance D is labeled D), where, R2 is independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, amino, halogen, nitro, cyano and R3 and R4 are each independently selected from hydrogen and C. 1-6 alkyl; The alkyl group may optionally be substituted with hydroxyl, amino, halogen, nitro, and cyano groups.

[0095] In some implementations, sp2 is .

[0096] In some implementations, sp2 is .

[0097] In some implementations, sp2 is selected from: , and .

[0098] In some implementations, the connecting unit L can be selected from the following structures: , , , , , , ,as well as , Where k is an integer from 1 to 20, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 (marked as P on the side connected to the antibody and as D on the side connected to the bioactive molecule).

[0099] In some implementations, k=2, 4, or 8.

[0100] In some embodiments, in Formula I, the linking unit L is linked to the antibody via a thiol group; preferably, the thiol group is derived from the antibody; more preferably, the thiol group is obtained by reducing the disulfide bonds between heavy chains and / or between heavy chains and light chains.

[0101] In other embodiments, the linker unit L is linked to the antibody via an oligosaccharide; preferably, the oligosaccharide is derived from the antibody's natural sugar chain.

[0102] In some embodiments, the oligosaccharide is derived from the N-glycan chain of the antibody.

[0103] In some embodiments, the oligosaccharide is composed of 2 to 15 monosaccharides; preferably, the oligosaccharide is composed of 2 to 10 monosaccharides.

[0104] In some embodiments, the oligosaccharide has the structure shown in Formula VI: (VI); Among them, P For example, the bispecific antibody targeting HER2 described above in this disclosure; GlcNAc is N-acetylglucosamine, Fuc is fuc, Man is mannose, f is 0 or 1, and m is an integer from 1 to 20 (e.g., m is an integer selected from 1-10, 1-9, 2-8, 4-10, 3-7, 4-6 or 2-6, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, such as m is 1 or 2). Gal The modified galactose is selected from the following structures: or .

[0105] In some embodiments, the oligosaccharide is linked to the antibody via a core GlcNAc. The core GlcNAc typically refers to the leftmost GlcNAc in the sugar chain shown in Formula VI.

[0106] In some implementations, the modified galactose is linked to GlcNAc via a β-1,4-glycosidic bond.

[0107] In some embodiments, the oligosaccharide is linked to the Fc region of the antibody; preferably linked to the CH2 domain of the Fc region; more preferably linked to Asn297 of the Fc region (according to Kabat's EU index number).

[0108] In some specific embodiments, the antibody-drug conjugates described in this application have the structure shown in Formula VII: (VII) Among them, P For example, the bispecific antibody targeting HER2 described above in this disclosure; GlcNAc is N-acetylglucosamine, Fuc is fuc, Man is mannose, f is 0 or 1, and m is an integer from 1 to 10 (e.g., m is an integer selected from 1-9, 2-8, 4-10, 3-7, 4-6 or 2-6, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, such as m is 1 or 2); Gal The modified galactose is selected from the following structures: or LP is as defined in the aforementioned LD.

[0109] In some implementations, the core GlcNAc is directly linked to the antibody. The core GlcNAc refers to the leftmost GlcNAc in formula VII.

[0110] In some implementations, the LP is selected from the following structures: and / or ; Where k is an integer from 1 to 20, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0111] In some implementations, m is an integer from 1 to 4; in some implementations, the DAR value of the entire coupling is from 1 to 8.

[0112] In some implementations, the modified galactose is linked to GlcNAc via a β-1,4-glycosidic bond.

[0113] In some embodiments, the oligosaccharide is linked to the Fc region of the antibody; preferably linked to the CH2 domain of the Fc region; more preferably linked to Asn297 of the Fc region (according to Kabat's EU index number).

[0114] In some embodiments, the antibody comprises a first heavy chain with an amino acid sequence as shown in SEQ ID NO: 16, a second heavy chain with an amino acid sequence as shown in SEQ ID NO: 17, and a common light chain with an amino acid sequence as shown in SEQ ID NO: 18.

[0115] As mentioned above, the oligosaccharide can be derived from the natural N-glycan chain of the antibody. Specifically, the preparation method of the oligosaccharide precursor includes the following steps: reacting an antibody with an N-glycan glycoform mainly of G0 / G0F with UDP-GalNAz or its salt, or with other UDP-GalNAc azide derivatives, in the presence of a catalyst to obtain the aforementioned oligosaccharide precursor.

[0116] The UDP-GalNAz has the following structure: .

[0117] Methods for obtaining G0 / G0F glycoform antibodies (in this article, G0 / G0F bispecific antibodies targeting HER2) are well known in the art. For example, antibodies expressed in eukaryotic cells can be post-translational modified to convert the glycan into the G0 / G0F form by galactosidase treatment, which removes any terminal galactose residues and leaves terminal N-acetylglucosamine residues.

[0118] In other embodiments, the G0F / G0 glycoform antibody described in this disclosure can also be obtained by expression and purification using a B4GALT1 gene knockout cell line. One example of knocking out the B4GALT1 gene in an expression cell line is through homologous recombination technology. Other examples of knocking out the B4GALT1 gene include the use of zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs), as described in Nature Biotechnology, volume 33, pages 842-844 (2015). Int. J. Mol. Sci. 2015, 16(10), 23849-23866, etc.

[0119] In some embodiments, the aforementioned catalyst is a galactosyltransferase or a functional variant or fragment thereof.

[0120] In some embodiments, the catalyst is β-1,4-galactosyltransferase or a functional variant or fragment thereof.

[0121] In some embodiments, the catalyst is bovine β-1,4-galactosyltransferase, human β-1,4-galactosyltransferase, or a functional variant or fragment thereof.

[0122] In some embodiments, the catalyst is human β-(1,4)-GalT1 with the Y285L mutation, for example, containing or consisting of the amino acid sequence shown in SEQ ID NO:19 or 20.

[0123] In some embodiments, the catalyst is bovine β-(1,4)-GalT1 with the Y289L mutation, for example, containing or consisting of the amino acid sequence shown in SEQ ID NO:21.

[0124] In some embodiments, the catalyst is β-1,4-acetylgalactosyltransferase disclosed in patent application WO2016170186.

[0125] In some embodiments, the catalyst comprises or consists of any of the sequences shown in SEQ ID NO: 19-20.

[0126] In some embodiments, the antibody-drug conjugate is the antibody A-ADC described in this disclosure; for example, it has the structure shown in Formula VIII: (VIII) Wherein, A is a bispecific antibody targeting HER2, which consists of a first heavy chain of the amino acid sequence shown in SEQ ID NO: 16, a second heavy chain of the amino acid sequence shown in SEQ ID NO: 17, and a common light chain of the amino acid sequence shown in SEQ ID NO: 18. GlcNAc is N-acetylglucosamine, Fuc is fuc, Man is mannose, and f is 0 or 1; the core GlcNAc (i.e. the leftmost GlcNAc in Formula VIII) is linked to Asn297 of the Fc region of antibody A (according to the EU index number of Kabat). Gal It is a modified galactose with the following structure: ; LP is selected from the following structures: and / or ; m is selected from 1 or 2.

[0127] In some implementations, the tumor is HER2-related or abnormally expressed (e.g., high expression, overexpression, low expression, ultra-low expression, no expression, etc.).

[0128] In some embodiments, the tumor expresses HER2, for example by detecting the expression level of HER2 protein by immunohistochemistry, with IHC ≥ 1+.

[0129] In some embodiments, the tumor is HER2 IHC 3+, or IHC 2+ and FISH (fluorescence in situ hybridization)+.

[0130] In some implementations, the tumor is HER2 IHC 1+, or IHC 2+ and FISH-.

[0131] In some embodiments, the tumor is an advanced, unresectable (or metastatic) solid tumor, or a solid tumor that is resistant to or intolerant of standard treatment, or for which no standard treatment is available. In some embodiments, the tumor is breast cancer. For example, the breast cancer is HER2-low expressing breast cancer (HER2 IHC 1+, or IHC 2+ and FISH-). Another example is HER2-positive breast cancer (IHC 3+, or IHC 2+ and ISH+).

[0132] In some implementations, the tumor is HER2-low expression (HER2 IHC 1+, or IHC 2+ and FISH-), (unresectable, locally recurrent or metastatic) breast cancer.

[0133] In some implementations, the subjects are patients with HER2-low expression (HER2 IHC 1+, or IHC 2+ and FISH-), and (unresectable, locally recurrent or metastatic) breast cancer.

[0134] In some implementations, the subject has received at least one to two lines of chemotherapy for breast cancer during the recurrence / metastasis phase.

[0135] In some implementations, the tumor is HER2-positive (IHC3+, or IHC2+ and ISH-positive) (unresectable locally advanced or metastatic) breast cancer.

[0136] In some implementations, the subject is a patient with unresectable locally advanced or metastatic breast cancer who is HER2-positive (IHC3+, or IHC2+ and ISH-positive).

[0137] In some implementations, the subject has previously received treatment with a regimen containing trastuzumab (trastuzumab or a marketed trastuzumab biosimilar) or inetuzumab at an advanced stage of disease and has radiographic or pathological evidence of disease progression, or radiographic or pathological evidence of disease progression or relapse during or within 12 months after (neo)adjuvant therapy.

[0138] In some implementations, the subject has previously received taxane treatment.

[0139] In some implementations, the tumor is ovarian cancer; for example, the tumor is platinum-resistant ovarian cancer.

[0140] In some embodiments, the tumor is ovarian cancer (such as epithelial ovarian cancer), peritoneal cancer (such as primary peritoneal cancer), or fallopian tube cancer; preferably, the tumor is platinum-resistant recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

[0141] In some implementations, the subjects are patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0142] In some implementations, the subject is a platinum-resistant relapsed individual.

[0143] In some implementations, the subject has previously received bevacizumab treatment.

[0144] In some implementations, the subject has previously received PARP inhibitor treatment.

[0145] In some implementations, the tumor is a digestive system tumor.

[0146] In some implementations, the tumor is gastric cancer.

[0147] In some implementations, the tumor is colorectal cancer.

[0148] In some implementations, the tumor is lung cancer.

[0149] In some implementations, the tumor is cholangiocarcinoma.

[0150] In some implementations, the tumor is esophageal cancer.

[0151] In some implementations, the tumor is head and neck cancer.

[0152] In some implementations, the subject is resistant to or cannot tolerate standard treatment, or there is no standard treatment available.

[0153] In some implementations, the subject's tumor tissue has HER2 expression, for example, IHC ≥ 1+.

[0154] In some implementations, the subject's tumor tissue is HER2 IHC 3+, or IHC 2+ and FISH (fluorescence in situ hybridization)+.

[0155] In some implementations, the subject's tumor tissue is HER2 IHC 1+, or IHC 2+ and FISH-.

[0156] In some implementations, the subject has previously received ≥3 lines of treatment.

[0157] In some implementations, the subject has previously received anti-HER2 therapy and / or anti-HER2 antibody-drug conjugate therapy.

[0158] Therapeutic and pharmaceutical uses

[0159] In a second aspect, this disclosure also relates to antibody-drug conjugates for the treatment and / or prevention of advanced or metastatic solid malignancies; said antibody-drug conjugates are as defined in the first aspect.

[0160] Thirdly, this disclosure also relates to the use of antibody-drug conjugates in the preparation of medicaments for the treatment and / or prevention of advanced or metastatic solid malignancies; said antibody-drug conjugates are as defined in the first aspect.

[0161] Fourthly, this disclosure also relates to antibody-drug conjugates for the treatment and / or prevention of advanced or metastatic solid malignancies.

[0162] Regarding the second, third, and fourth aspects: In some implementations, the tumor is HER2-related or abnormally expressed (e.g., high expression, overexpression, low expression, ultra-low expression, no expression, etc.).

[0163] In some embodiments, the tumor expresses HER2, for example by immunohistochemistry to detect the expression level of HER2 protein, with IHC ≥ 1+ or ultra-low expression of IHC 0 (with cell membrane staining).

[0164] In some embodiments, the tumor is HER2 IHC 3+, or IHC 2+ and FISH (fluorescence in situ hybridization)+.

[0165] In some implementations, the tumor is HER2 IHC 1+, or IHC 2+ and FISH-.

[0166] In some implementations, the tumor is an advanced, unresectable (or resectable) or metastatic solid tumor, or a solid tumor that is resistant to or intolerant of standard treatment, or for which there is no standard treatment.

[0167] In some embodiments, the tumor is breast cancer. For example, the breast cancer is HER2-low expression (HER2 IHC 1+, or IHC 2+ and FISH-). As another example, the breast cancer is HER2-positive (IHC 3+, or IHC 2+ and ISH+).

[0168] In some implementations, the tumor is HER2-low expression (HER2 IHC 1+, or IHC 2+ and FISH-), (unresectable, locally recurrent or metastatic) breast cancer.

[0169] In some implementations, the subjects are patients with HER2-low expression (HER2 IHC 1+, or IHC 2+ and FISH-), and (unresectable, locally recurrent or metastatic) breast cancer.

[0170] In some implementations, the subject has received at least one to two lines of chemotherapy for breast cancer during the recurrence / metastasis phase.

[0171] In some implementations, the tumor is HER2-positive (IHC3+, or IHC2+ and ISH (e.g. FISH) positive) (unresectable locally advanced or metastatic breast cancer).

[0172] In some implementations, the subject is a HER2-positive (IHC3+, or IHC2+ and ISH (e.g. FISH)-positive) patient with (unresectable locally advanced) or metastatic breast cancer.

[0173] In some implementations, the subject has previously received treatment with a regimen containing trastuzumab (trastuzumab or a marketed trastuzumab biosimilar) or inetuzumab at an advanced stage of disease and has radiographic or pathological evidence of disease progression, or radiographic or pathological evidence of disease progression or relapse during or within 12 months after (neo)adjuvant therapy.

[0174] In some implementations, the subject has previously received taxane treatment.

[0175] In some implementations, the tumor is ovarian cancer; for example, the tumor is platinum-resistant ovarian cancer.

[0176] In some embodiments, the tumor is ovarian cancer (such as epithelial ovarian cancer), peritoneal cancer (such as primary peritoneal cancer), or fallopian tube cancer; preferably, the tumor is platinum-resistant recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

[0177] In some implementations, the subjects are patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0178] In some implementations, the subject is a platinum-resistant relapsed individual.

[0179] In some implementations, the subject has previously received bevacizumab treatment.

[0180] In some implementations, the subject has previously received PARP inhibitor treatment.

[0181] In some implementations, the tumor is a digestive system tumor.

[0182] In some implementations, the tumor is gastric cancer.

[0183] In some implementations, the tumor is colorectal cancer.

[0184] In some implementations, the tumor is lung cancer.

[0185] In some implementations, the tumor is cholangiocarcinoma.

[0186] In some implementations, the tumor is esophageal cancer.

[0187] In some implementations, the tumor is head and neck cancer.

[0188] In some implementations, the subject is resistant to or cannot tolerate standard treatment, or there is no standard treatment available.

[0189] In some implementations, the subject's tumor tissue has HER2 expression, for example, IHC ≥ 1+.

[0190] In some implementations, the subject's tumor tissue is HER2 IHC 3+, or IHC 2+ and FISH (fluorescence in situ hybridization)+.

[0191] In some implementations, the subject's tumor tissue is HER2 IHC 1+, or IHC 2+ and FISH-.

[0192] In some implementations, the subject has previously received ≥3 lines of treatment.

[0193] In some implementations, the subject has previously received anti-HER2 therapy and / or anti-HER2 antibody-drug conjugate therapy.

[0194] In the aforementioned treatment methods, therapeutic and pharmaceutical uses, The antibody-drug conjugate shown in Formula I is administered to a subject or patient requiring treatment at a therapeutically effective dose to treat a tumor. The therapeutically effective dose refers to a dose that alleviates, inhibits, or eliminates tumor growth, benefiting the subject or patient without causing intolerable toxic side effects.

[0195] In some embodiments, the therapeutically effective dose (calculated as the antibody-drug conjugate shown in Formula I) per administration is 1 mg / dose to 1000 mg / dose, preferably 5 mg / dose to 500 mg / dose, or 10 to 300 mg / dose, or 20 to 200 mg / dose, or 50 to 150 mg / dose, or 50 to 300 mg / dose, or 50 to 400 mg / dose, or 100 to 200 mg / dose, or 100 to 300 mg / dose, or 100 to 500 mg / dose, more preferably 5 mg / dose. Dosage: 6mg / dose, 8mg / dose, 10mg / dose, 15mg / dose, 20mg / dose, 25mg / dose, 30mg / dose, 40mg / dose, 50mg / dose, 60mg / dose, 70mg / dose, 80mg / dose, 90mg / dose, 100mg / dose, 150mg / dose, 200mg / dose, 250mg / dose, 300mg / dose, 500mg / dose, 600mg / dose, 700mg / dose, 800mg / dose, 900mg / dose, etc.

[0196] In some embodiments, the therapeutically effective dose (calculated as the antibody-drug conjugate shown in Formula I) is 1 mg / day to 1000 mg / day, preferably 5 mg / day to 500 mg / day, or 10 to 300 mg / day, or 20 to 200 mg / day, or 50 to 150 mg / day, or 50 to 300 mg / day, or 50 to 400 mg / day, or 100 to 200 mg / day, or 100 to 300 mg / day, or 100 to 500 mg / day. 00mg / day, preferably 10mg / day, 20mg / day, 30mg / day, 40mg / day, 50mg / day, 60mg / day, 70mg / day, 80mg / day, 90mg / day, 100mg / day, 150mg / day, 200mg / day, 250mg / day, 300mg / day, 500mg / day, 600mg / day, 700mg / day, 800mg / day, 900mg / day, etc.

[0197] In some embodiments, the therapeutically effective dose (based on the antibody-drug conjugate of Formula I and the subject's body weight, where mg is the dosage of the antibody-drug conjugate of Formula I and kg is the patient's body weight) is 0.05 mg / kg to 50 mg / kg, preferably 0.1 mg / kg to 20 mg / kg, or 0.2 mg / kg to 20 mg / kg, or 0.5 mg / kg to 20 mg / kg, or 0.5 mg / kg to 15 mg / kg, or 0.5 mg / kg to 10 mg / kg, or 0.5 mg / kg to 8 mg / kg, or 0.5 mg / kg to 6 mg / kg. mg / kg, or 0.5 mg / kg-4 mg / kg, or 0.5 mg / kg-2 mg / kg, or 1 mg / kg-20 mg / kg, or 1 mg / kg-10 mg / kg, or 1 mg / kg-8 mg / kg, or 2 mg / kg-20 mg / kg, or 2 mg / kg-10 mg / kg, or 2 mg / kg-8 mg / kg, or 3 mg / kg-20 mg / kg, or 3 mg / kg-10 mg / kg, or 3 mg / kg-8 mg / kg, or 5 mg / kg-20 mg / kg, or 5 mg / kg 10 mg / kg, or 0.3 mg / kg, or 0.4 mg / kg, or 0.6 mg / kg, or 0.8 mg / kg, or 1.0 mg / kg, or 1.5 mg / kg, or 1.8 mg / kg, or 2.0 mg / kg, or 2.1 mg / kg, or 2.2 mg / kg, or 2.4 mg / kg, or 2.5 mg / kg, or 2.8 mg / kg, or 3 mg / kg, or 3.2 mg / kg, or 3.5 mg / kg, or 3.6 mg / kg, or 3.8 mg / kg, or 4.0 mg / kg, or 4 0.2 mg / kg, or 4.3 mg / kg, or 4.4 mg / kg, or 4.5 mg / kg, or 4.6 mg / kg, or 4.8 mg / kg, or 5.0 mg / kg, or 5.2 mg / kg, or 5.3 mg / kg, or 5.4 mg / kg, or 5.5 mg / kg, or 5.6 mg / kg, or 5.8 mg / kg, or 6.0 mg / kg, or 6.2 mg / kg, or 6.3 mg / kg, or 6.4 mg / kg, or 6.8 mg / kg, or 7.0 mg / kg, or 7.2 mg / kg, or 7.3 mg / kg. mg / kg, or 7.5 mg / kg, or 7.8 mg / kg, or 8.0 mg / kg, or 8.3 mg / kg, or 8.4 mg / kg, or 8.5 mg / kg, or 9.0 mg / kg, or 9.3 mg / kg, or 9.4 mg / kg, or 9.5 mg / kg, or 10.5 mg / kg, or 11 mg / kg, or 11.5 mg / kg, or 12.0 mg / kg, or 16.8 mg / kg, or 18.0 mg / kg.

[0198] In some embodiments, the dosage of the antibody-drug conjugate, based on the subject's body weight, is selected from 1.0 mg / kg to 10.5 mg / kg; preferably, based on the subject's body weight, it is selected from 4.2 mg / kg to 8.4 mg / kg; more preferably, based on the subject's body weight, it is selected from 6.3 mg / kg to 7.3 mg / kg.

[0199] In some implementations, the dosage of the antibody-drug conjugate, based on the subject's weight, may be selected from 1.0, 2.1, 4.2, 5.2, 5.3, 6.3, 7.3, 8.4, 9.4, and 10.5 mg / kg.

[0200] In some implementations, the antibody-drug conjugate is administered via intravenous infusion.

[0201] In some implementations, the therapeutic dose can be administered once daily (QD), or the therapeutic dose can be divided into multiple administrations throughout the day as a total daily dose, such as twice daily (BID) or three times daily (TID). The therapeutic dose can be administered once weekly (QW), or the therapeutic dose can be divided into multiple administrations throughout the week as a total weekly dose, such as twice weekly (BIW) or three times weekly (TIW). The therapeutic dose can be administered once every two weeks (Q2W), or the therapeutic dose can be divided into multiple administrations throughout the two weeks as a total weekly dose, such as twice every two weeks (BI2W) or three times every two weeks (TI2W). The therapeutic dose can be administered once every three weeks (Q3W), or the therapeutic dose can be divided into multiple administrations throughout the three weeks as a total dose, such as twice every three weeks (BI3W, e.g., D1, D8 every three weeks) or three times every three weeks (TI3W). The above-mentioned effective dose can be administered once a month (QM), or it can be administered as a total dose divided into multiple doses over several days within a month, such as twice a month (BI2M) or three times a month (TIM). The above-mentioned effective dose can also be administered at intervals, such as once every 2-7 days, or once every 3 days, 4 days, 5 days, or 6 days, or once every 2-4 weeks, such as once every 2 weeks (once every 3 weeks, every 3-week cycle), once every 1 week (once every 2 weeks, every 2-week cycle or every 4-week cycle), and once every 3 weeks (once every 4 weeks, every 4-week cycle), or once every 1-3 months, such as once every 1 month (every 2 months); or continuously for 3 weeks, stop for 1 week, every 4-week cycle, or continuously for 2 weeks, stop for 1 week, every 3-week cycle, or continuously for 2 weeks, stop for 2 weeks, every 4-week cycle, or once every 1 week (once every 2 weeks), every 4-week cycle. Exemplary administration methods include administering the antibody-drug conjugate once on the first day of each 3-week cycle. In some embodiments, the antibody-drug conjugate is administered once every three weeks (Q3W).

[0202] In some implementations, the antibody-drug conjugate is administered via intravenous infusion every three weeks at a dose of 6.3 mg / kg based on the subject's weight.

[0203] In some implementations, the antibody-drug conjugate is administered via intravenous infusion every three weeks at a dose of 7.3 mg / kg based on the subject's weight.

[0204] In some implementations, the antibody-drug conjugate is administered via intravenous infusion every three weeks at a dose of 8.4 mg / kg based on the subject's weight.

[0205] To provide a more concise description, the term "about" is not used for some quantitative data in this document. It should be understood that, whether the term "about" is explicitly used or not, every numerical value given herein includes not only the actual given value (the given value), but also approximations of such a given value that would be reasonably inferred by one of ordinary skill in the art, including equivalents and approximations of such a given value due to experimental and / or measurement conditions. These approximations are preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, or ±1% of the given value.

[0206] Beneficial effects

[0207] Clinical studies have shown that the antibody-drug conjugate shown in formula (I) can effectively treat advanced, unresectable, recurrent or metastatic malignant tumors, especially HER2-related advanced solid tumors. It can overcome HER2 monoclonal antibody or platinum resistance and bring clinical benefits superior to existing treatments to patients with advanced solid tumors, including breast cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, digestive system tumors (such as gastric cancer, colorectal cancer, bile duct cancer, esophageal cancer), lung cancer, and head and neck cancer, and can control or alleviate the disease.

[0208] Example

[0209] Example 1: Preparation of Antibody A-ADC

[0210] Antibody A-ADC is an antibody-drug conjugate consisting of a bispecific antibody targeting HER2 (hereinafter referred to as antibody A) and a linker-toxin (LP1).

[0211] 1.1 Preparation of Antibody A

[0212] Antibody A comprises a first heavy chain, a second heavy chain, and a common light chain, wherein the amino acid sequence of the first heavy chain is shown in SEQ ID NO: 16, the amino acid sequence of the second heavy chain is shown in SEQ ID NO: 17, and the amino acid sequence of the common light chain is shown in SEQ ID NO: 18.

[0213] A vector containing a nucleic acid sequence encoding the aforementioned first heavy chain, second heavy chain, and common light chain is transduced into cells, and antibody A is obtained through expression and purification. For specific preparation procedures, please refer to patent application document WO2016110267.

[0214] 1.2 Preparation of linker-toxin

[0215] The following linker-toxin (LP1) was prepared according to the process described in patent application CN113264983A:

[0216] The measured LP1 MS m / z (ESI) was 1375.77.

[0217] 1.3 Conjugation of antibody A to linker-toxin

[0218] Step 1: Synthesis of Antibody A-(N3)4: Antibody A stock solution (mainly G0F) was desalted and placed in HEPES buffer for later use. Ultrapure water, MnCl2 (10 mM), UDP-GalNAz (50 mM), Tris-HCl (10 mM), antibody A (10 mg / mL), and GalT1 (0.125 mg / mL) were added to a centrifuge tube and reacted at 400 rpm for 12 h at room temperature. After the reaction was complete, Protein A was purified, concentrated by ultrafiltration, and desalted into DPBS to obtain antibody A-(N3)4 (148796 Da). The reaction formula and the structure of UDP-GalNAz are shown in [reference needed]. Figure 1a The mass spectra of the products are shown in the figure. Figure 1b .

[0219] Step 2: Synthesis of the antibody-drug conjugate: LP1 (950 μM), DMSO, antibody A-(N3)4 (63 μM), and ultrapure water were added to a centrifuge tube, and the reaction was carried out at room temperature and 400 rpm for 12 h. After the reaction was complete, the antibody was desalted into DPBS to obtain antibody A-ADC (DAR=4, 154301 Da). The reaction formula is shown below. Figure 1c The mass spectra of the products are shown in the figure. Figure 1d .

[0220] Example 2: Clinical study of antibody A-ADC

[0221] 2.1 Research Plan

[0222] 2.1.1 First-ever human study in patients with advanced or metastatic solid malignancies Brief summary This study is an open-label, multicenter, first-in-human, phase I dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of antibody A-ADC in subjects with advanced, unresectable or metastatic solid malignancies (expected to be HER2-expressing).

[0223] Detailed description

[0224] The dose escalation study will utilize accelerated dose titration in individual patients, with the first two dose levels at 1.0 and 2.1 mg / kg, followed by dose groups of 4.2, 5.2, 6.3, 7.3, and 8.4 mg / kg. All dose groups will be recruited and monitored using a Bayesian optimal interval design to determine the MTD (maximum tolerated dose), RDE (recommended extension dose), and RP2D (recommended phase II dose) for the antibody A-ADC. Dose escalations at 9.4 mg / kg and 10.5 mg / kg will be decided upon through discussion between the Safety Monitoring Committee (SMC) and the sponsor. The SMC has the authority to decide on dose escalations at other dose levels if necessary. Furthermore, the SMC is responsible for determining the MTD and recommended dose levels for the dose extension study.

[0225] Enrolled patients will be sequentially assigned to the planned dose level as required by the protocol and will receive antibody A-ADC IV Q3W to monitor for treatment-related adverse events (AEs) and dose-limiting toxicities (DLTs). The DLT observation period is 21 days from the start of the first dose of antibody A-ADC.

[0226] This study will use an improved ADT design and a BOIN design for dosing cohort management to determine MTD and RDE / RP2D. The antibody A-ADC will be administered at an initial dose of 1.0 mg / kg, followed by 2.1, 4.2, 5.3, 6.3, 7.3, 8.4, 9.4, and 10.5 mg / kg, via intravenous infusion on day 1 of every 3 weeks. The first cycle of antibody A-ADC treatment will be used for DLT assessment.

[0227] Inclusion criteria

[0228] (1) Willing and able to provide a signed informed consent form (ICF) for the trial.

[0229] (2) Male or female, 18 years of age or older; willing and able to comply with the research requirements.

[0230] (3) The Eastern Cooperative Oncology Group has an ECOG PS of 0 or 1 and has not deteriorated within 2 weeks of the planned study treatment, with a life expectancy of ≥12 weeks.

[0231] (4) Advanced / unresectable or metastatic solid malignant tumors with pathological records, HER-2 expression (IHC≥1+), resistant to or intolerant of standard treatment, or without standard treatment.

[0232] (5) Baseline measurable disease according to RECIST 1.1. If such disease progression has been confirmed, the target lesion located in the previously irradiated area is considered measurable.

[0233] (6) Organ function was adequate as assessed within 7 days prior to the first trial treatment [no blood transfusion, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) or other related medical support was received within 14 days prior to administration of the study product].

[0234] (7) Sufficient treatment washout period before the first trial treatment.

[0235] (8) Within 28 days prior to the first trial treatment, LVEF ≥ 50% was measured by echocardiography (ECHO) or multiple gating acquisition (MUGA).

[0236] (9) Female or male subjects of reproductive age should be willing to use highly effective contraceptive methods (with an annual failure rate of less than 1.0%) from the first study treatment to 180 days after completion of the trial treatment. Women of fertility should have a negative pregnancy test result within 7 days prior to the first trial treatment (fertility is defined as premenopausal women without a recorded tubal ligation or hysterectomy, or women within 1 year of postmenopause).

[0237] Key outcome metrics: Maximum tolerated dose, recommended extended dose / recommended phase II dose, dose-limiting toxicities, treatment-related adverse events (TEAEs), treatment-related adverse events (TRAEs), and incidence and severity of serious adverse events (SAEs).

[0238] Secondary outcome metrics: (1) Cmax: The maximum (peak) plasma concentration of antibody A-ADC after the first dose (Cmax); (2) Tmax: The time to the maximum plasma concentration of antibody A-ADC after the first dose (Tmax); (3) AUC: Blood PK parameters of antibody A-ADC and its analytes were estimated using standard non-compartmental methods, including the area under the concentration-time curve (AUClast) from time 0 to the last quantifiable concentration calculated by the linear ascending log descending trapezoidal method and the elimination rate constant (AUCinf) from time 0 to infinity associated with the terminal phase. (4) T 1 / 2 Blood pharmacokinetic parameters of the terminal elimination half-life of antibody A-ADC; (5) ORR: Objective response rate (ORR) was reviewed by an independent center and defined as the proportion of subjects who achieved complete response (CR) or partial response (PR) according to the RECIST version 1.1 criteria for evaluating efficacy of treatment in solid tumors. (6) TTR: TTR is defined as the time between the date of first dosing and the date of first achievement of a qualified response; (7) DoR: For responders (complete remission [CR] or partial remission [PR]), the duration of response is defined as the time interval from the date of first achieving a qualified response to the date of disease progression (PD) or death from any cause, whichever occurs earlier; (8) PFS: Progression-free survival (PFS) is defined as the time from the date of first administration to disease progression or death, whichever occurs earlier. Subjects who do not experience an event (no disease progression or still alive at the last visit) will be truncated on the date of the "last tumor assessment". (9) Anti-drug antibodies: the status (positive or negative) of anti-antibody A-ADC antibody and serum titer.

[0239] 2.1.2 Evaluation of the safety and tolerability of antibody A-ADC in Chinese patients with advanced solid tumors. Brief summary This is an open-label, multicenter phase I / II study conducted in Chinese subjects with unresectable locally advanced / metastatic solid tumors. The study was divided into a dose-escalation phase and a cohort expansion phase. In the dose-escalation phase, eight dose groups were designed (administered intravenously every 3 weeks on day 1). The initial dose was 1.0 mg / kg, administered every 3 weeks (Q3W), with a dose-limiting toxicity (DLT) observation period of 21 days. In the dose expansion phase, seven cohorts were established.

[0240] Detailed description

[0241] During the dose escalation phase, eight dose groups were designed (administered intravenously every 3 weeks, day 1 of each cycle). The dose groups were 1.0, 2.1, 4.2, 5.2, 6.3, 7.3, 8.4, and 10.5 mg / kg. A BOIN (Bayesian optimal interval) design was used, combined with accelerated titration, and the dose-limiting toxicity (DLT) observation period was set at 21 days.

[0242] The specific implementation steps of BOIN design in clinical trials are as follows: 1. Accelerated Titration Procedure: The first subject receives a Grade 1 dose. If no dose-limiting toxicity (DLT) occurs in this subject, the second subject receives the next higher dose level. Only one subject is treated at a time, and the dose escalation process continues until the first DLT is observed, or a second Grade 2 toxicity occurs, or the maximum dose is reached. Subsequently, two more subjects are treated at the current dose level. Afterward, steps 2 and 3 are followed, with the number of cases in each group set to 3 for subsequent subjects.

[0243] 2. Dosage Allocation: The dose is allocated to the next group of subjects according to the dose increase / decrease rules in the Bayesian Optimal Interval (BOIN) decision table.

[0244] 3. Repeat step 2 until the maximum sample size of 45 is reached, or 12 evaluable subjects are treated at the current dose level, and decide to maintain the current dose according to the dose increase / decrease decision table rules.

[0245] After the dose escalation phase, the mean time to dose (MTD) was determined using sequential regression. This calculation can be performed using the "Select MTD" function in the BOIN online software (Zhou et al., 2020). Specifically, the dose whose toxicity rate, estimated through sequential regression, is closest to the target toxicity rate was determined as the MTD. During the dose escalation phase, the sponsor may, with the approval of the Sponsor Medical Monitoring Committee (SMC), expand to an appropriate dose group based on the safety, efficacy, and pharmacokinetic (PK) data obtained during the dose escalation phase, provided that the number of subjects in the expanded dose group is consistent with the total sample size during the dose expansion phase. Safety monitoring can still be performed during the dose expansion phase based on the exclusion boundaries in the decision table. Subject data from the expanded dose group were not involved in the dose increase / decrease decisions and sequential regression calculations during the dose escalation phase.

[0246] During the dose escalation phase, the Safety Monitoring Committee (SMC) will conduct ongoing safety assessments. Safety data for each dose group must be reviewed and approved by the SMC before dosing for the next dose group can begin. If the SMC decides to require additional safety, efficacy, and pharmacokinetic (PK) data for a dose group, subjects may continue to be enrolled in that dose group after completing the BOIN dose escalation; if the SMC has determined that a dose group is eligible for the cohort expansion phase, then direct entry into the cohort expansion phase for that dose group is permitted. The composition and responsibilities of the SMC will be further detailed in the SMC bylaws.

[0247] SMC will determine the recommended dose (RDE) for cohort expansion based on safety / tolerability, pharmacokinetic (PK) data, and other available data such as preliminary antitumor activity. The RDE may be equal to or lower than the MTD; the RDE may also vary for different indications.

[0248] SMC and the sponsor will evaluate the effectiveness of the maximum tolerated dose (MTD) determined through the BOIN design based on data from dose escalation and dose expansion clinical studies, and determine whether it is necessary to explore a higher dose group of 12.6 mg / kg.

[0249] Inclusion criteria

[0250] (1) The participants must be at least 18 years old, of any gender (male or female), and willing to follow the research procedures when signing the informed consent form; (2) Performance status score (ECOG) of 0 or 1, with expected survival time ≥ 12 weeks; (3) Unresectable locally advanced or metastatic solid tumors confirmed by pathology; (4) According to RECIST 1.1 criteria, there is a measurable lesion at baseline; if the subject has only one measurable lesion at baseline, the lesion area has not been previously treated with radiotherapy, or there is evidence of significant progression after the completion of radiotherapy. (5) Agree to provide a sufficient number of paraffin sections or fresh tissue samples of the tumor for testing; (6) Laboratory test results within 7 days or echocardiogram results within 28 days prior to the first dose meet the protocol standards; (7) The drug has been adequately washed off from previous treatments before the first administration; (8) Female subjects of reproductive age or male subjects of reproductive age with a partner of reproductive age agree to use highly effective contraception (annual failure rate of less than 1%) from the first dose to the end of 180 days. Female subjects of reproductive age must have a negative pregnancy test result within 7 days prior to the first dose (females of reproductive age are defined as women who are not yet menopausal and have no history of tubal ligation or hysterectomy, or women who have been menopausal for less than 1 year).

[0251] Key outcome metrics: (1) Dose-limiting toxicity (DLT) (Phase I dose escalation phase): Incidence of dose-limiting toxicity (DLT) during the dose escalation phase; (2) Maximum tolerated dose (MTD) in Phase I or recommended dose (RP2D) in Phase II: The maximum tolerated dose (MTD) is the dose that, according to the BOIN design, the sequential estimate of the toxicity rate is closest to the target toxicity rate. (3) Percentage of subjects who experienced any treatment-related adverse events (TEAEs) and serious treatment-related adverse events (SAEs) during Phase I: TEAEs and SAEs were graded according to CTCAE 5.0; (4) Objective response rate (ORR) in Phase II: The objective response rate (ORR) is defined as the proportion of subjects who achieve complete response (CR) or partial response (PR) according to the evaluation criteria for efficacy of solid tumors (RECIST v1.1).

[0252] Secondary outcome metrics: (1) Clinical benefit rate (CBR): Clinical benefit rate (CR + PR + [stable disease (SD) ≥ 6 months]) is defined as the best response being a complete response (CR) or partial response (PR), or stable disease (SD) lasting at least 6 months. The 6-month duration of SD is defined as the time from the first dose to the first recorded tumor progression (PD), or the time to the last adequate response assessment prior to the data cutoff date, whichever is earlier.

[0253] (2) Progression-free survival (PFS): PFS is defined as the time from the start of treatment to tumor progression or death from any cause.

[0254] (3) Cmax: The highest (peak) plasma concentration of antibody A-ADC after the first dose (Cmax).

[0255] (4) Tmax: The time (Tmax) for antibody A-ADC to reach its highest blood concentration after the first administration.

[0256] (5) AUC: Pharmacokinetic parameters of the area under the plasma concentration-time curve (AUC) of antibody A-ADC and its metabolites, including the AUC from time 0 to the last quantifiable concentration (AUClast) and the AUC from time 0 to infinity (AUCinf). The elimination rate constant of the terminal phase is estimated by the standard non-compartmental model method.

[0257] (6) Terminal elimination half-life (t1 / 2): pharmacokinetic parameter of the terminal elimination half-life of antibody A-ADC.

[0258] (7) Anti-drug antibodies: the status (positive or negative) of anti-antibody A-ADC antibody and serum titer.

[0259] (8) Duration of response (DOR): defined as the time between the first assessment of objective response and the first assessment of tumor progression (PD) or death from any cause prior to PD.

[0260] 2.2 Results and Analysis

[0261] 2.2.1 Interim Results 1

[0262] As of April 5, 2024, a total of 46 patients (25 with breast cancer, 11 with gastric cancer, 8 with colorectal cancer, 1 with lung cancer, and 1 with ovarian cancer) were enrolled in the Phase I study and received antibody A-ADC therapy, covering six dose levels: 2.1 mg / kg (n=1), 4.2 mg / kg (n=10), 5.2 mg / kg (n=14), 6.3 mg / kg (n=15), 7.3 mg / kg (n=3), and 8.4 mg / kg (n=3), administered every 3 weeks (Q3W). 34 patients (73.9%) had previously received ≥3 lines of therapy, with 60.9% and 45.7% having previously received anti-HER2 therapy and anti-HER2 antibody-drug conjugate (ADC) therapy, respectively.

[0263] The median duration of treatment was 19.2 weeks (range: 3.0–52.0 weeks), and 26 patients (56.5%) were still receiving treatment. Treatment-related adverse events (TRAEs) occurred in all 46 patients (100%), with only 9 patients (19.6%) experiencing grade 3 TRAEs; no TRAEs were grade >3. Three patients (6.5%) experienced treatment-related serious adverse events (SAEs): one grade 3 nausea and two grade 2 interstitial lung disease. No dose-limiting toxicities (DLT) occurred, and no TRAEs led to treatment discontinuation. Safety data are as follows: Figure 2a As shown.

[0264] Following a single dose, the exposure (Cmax and AUC) of antibody A-ADC increased with increasing dose, with a mean half-life of approximately 5 days at a dose of 6.3 mg / kg. No significant accumulation was observed after completing four cycles of treatment. The systemic exposure of the free payload was significantly lower than that of antibody A-ADC, indicating the stability of antibody A-ADC in circulation.

[0265] In 45 evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 51.1% (95% CI: 35.8, 66.3) and 93.3% (95% CI: 81.7, 98.6), respectively. The ORRs for IHC 1+, 2+, and 3+ patients were 14.3% (95% CI: 0.4, 57.9), 35.0% (95% CI: 15.4, 59.2), and 83.3% (95% CI: 58.6, 96.4), respectively. In 28 patients who had previously received anti-HER2 therapy, the ORR was 57.1% (95% CI: 37.2, 75.5); and in 21 patients who had previously received anti-HER2 ADC therapy, the ORR was 57.1% (95% CI: 34.0, 78.2). For patients with HER2-positive (HER2 IHC 3+, or IHC 2+ and FISH+) breast and gastric cancer, the objective response rate (ORR) was 73.3% (95% CI: 44.9, 92.2) in 15 patients and 80% (95% CI: 28.4, 99.5) in 5 patients. For patients with HER2-low expression (HER2 IHC 1+, or IHC 2+ and FISH-) breast and gastric cancer, the ORR was 33.3% (95% CI: 7.5, 70.1) in 9 patients and 20% (95% CI: 0.5, 71.6) in 5 patients. Efficacy data are as follows: Figure 2b As shown.

[0266] Summary: Antibody A-ADCs were well tolerated at intravenous doses ranging from 2.1 to 8.4 mg / kg every 21 days: no dose-limiting toxicities (DLTs) were observed, and the maximum tolerated dose (MTD) was not reached; the safety profile was manageable, with a low incidence of hematologic toxicity and interstitial lung disease (ILD) (only 2 of 46 patients experienced grade 2). Encouraging antitumor activity was observed in heavily treated, previously treated patients during the dose escalation phase, even before the MTD was reached: the objective response rate (ORR) was 51.1% in all evaluable patients (including those with low HER2 expression and those who were HER2 positive); the ORR was 57.1% in patients who had previously received anti-HER2 therapy; and in breast cancer patients, the ORR was 73.3% in 15 HER2-positive patients (HER2 IHC 3+, or IHC 2+ and FISH+) and 33.3% in 9 HER2-low expression patients (HER2 IHC 1+, or IHC 2+ and FISH-).

[0267] 2.2.2 Interim Results 2

[0268] As of July 15, 2024, a total of 29 patients (9 with colorectal cancer, 6 with gastric cancer, 4 with biliary tract cancer, 3 with esophageal cancer, 2 with ovarian cancer, 1 with head and neck cancer, and 4 with other types) were enrolled in the study and received antibody A-ADC therapy, covering seven dose levels: 2.1 mg / kg (n=1), 4.2 mg / kg (n=1), 5.2 mg / kg (n=1), 6.3 mg / kg (n=17), 7.3 mg / kg (n=5), 8.4 mg / kg (n=3), and 10.5 mg / kg (n=1), administered every 3 weeks (Q3W). Twelve patients (41.4%) had previously received ≥3 lines of therapy, with 48.3% and 24.1% having previously received anti-HER2 therapy and anti-HER2 antibody-drug conjugate (ADC) therapy, respectively.

[0269] In 28 evaluable patients, the objective response rate (ORR) was 75.0%, and the disease control rate (DCR) was 89.3%. In 7 patients who had previously received anti-HER2 ADC therapy, the ORR was 71.4%. The ORRs for gastric cancer and colorectal cancer were 83.3% (6 / 7) and 66.7% (6 / 9), respectively. Efficacy data can be found in [link to relevant data]. Figure 2c .

[0270] The median duration of treatment was 23.6 weeks (range: 4.7–52.0 weeks), and 14 patients were still receiving treatment. Treatment-related adverse events (TRAEs) occurred in all patients. The most common Grade 1 and 2 TRAEs were diarrhea (60.9%), nausea (65.5%), infusion-related reactions (24.1%), fatigue (24.1%), decreased appetite (24.1%), and rash (20.7%) (see Table 3). Six patients (20.7%) experienced ≥ Grade 3 TRAEs, namely neutropenia (6.9%), vomiting (3.4%), fatigue (3.4%), leukopenia (3.4%), and decreased appetite (3.4%). Three patients developed interstitial lung disease (2 in the 6.3 mg / kg dose group and 1 in the 8.4 mg / kg dose group), all of whom subsequently recovered. No TRAEs resulted in death, and only one patient discontinued treatment due to a TRAE. Security data can be found Figure 2d .

[0271] In summary, antibody A-ADCs were well tolerated at intravenous doses ranging from 2.1 to 10.5 mg / kg every 21 days. Encouraging antitumor activity was observed in patients with previously heavily treated advanced HER2-positive solid tumors. Antibody A-ADCs demonstrated a favorable tolerability and safety profile, with a lower incidence of hematologic toxicity compared to other DXd ADCs (Guo Z, et al.). J Clin Pharm Ther. 2022;47:1837-1844; Jänne PA, et al. Cancer Discov. 2022;12:74-89).

[0272] 2.2.3 Interim Results 3

[0273] As of July 15, 2024, a total of 50 patients with platinum-resistant ovarian cancer received antibody A-ADC therapy at dose levels of 4.2 mg / kg (n=2), 5.2 mg / kg (n=2), 6.3 mg / kg (n=44), 7.3 mg / kg (n=1), and 8.4 mg / kg (n=1). All 50 patients were enrolled based on their local HER2 testing results, of which 10 (20.0%) had HER2 IHC 0, 20 (40.0%) had IHC 1+, 18 (36.0%) had IHC 2+, and 2 (4.0%) had IHC 3+. Based on the results of central laboratory testing, 17 patients (34.0%) had IHC 0, 10 patients (20.0%) had IHC 1+, 5 patients (10.0%) had IHC 2+, 2 patients (4.0%) had IHC 3+, and another 16 patients (32.0%) had no HER2 results because they were not tested before July 15, 2024. 28 patients (56.0%) had previously received ≥3 lines of therapy, 37 patients (74.0%) had previously received bevacizumab therapy, and 28 patients (56.0%) had previously received PARP inhibitor therapy.

[0274] The median duration of treatment was 12.4 weeks (range: 0.7–51.0 weeks), and 32 patients (64.0%) were still receiving treatment. Treatment-related adverse events (TRAEs) occurred in 47 patients (94.0%), with the most common TRAEs being nausea (32.0%), elevated AST (26.0%), diarrhea (24.0%), anemia (24.0%), fatigue (20.0%), and vomiting (18.0%), mostly grade 1–2. Grade 3 or higher drug-related adverse events occurred in 5 patients (10.0%), with the most common being diarrhea (2.0%) and anemia (2.0%). Serious drug-related adverse events occurred in 2 patients (4.0%). Drug-related adverse events led to dose reduction in 2 patients (4.0%) and discontinuation in 1 patient (2.0%). Drug-related interstitial lung disease / pneumonia occurred in 3 patients, with only 1 of them being a grade ≥3 event. No fatal TRAEs occurred. See safety data. Figure 2e .

[0275] In 44 evaluable patients, the objective response rate (ORR) was 56.8% (95% CI: 41.0, 71.7), with tumor shrinkage in 39 / 44 patients. The ORRs for locally confirmed HER2 IHC 0 and HER2 expression (IHC 1+, 2+, and 3+) patients were 75.0% (95% CI: 34.9, 96.8) and 52.8% (95% CI: 35.5, 69.6), respectively. The ORRs for centrally confirmed HER2 IHC 0 and HER2 expression patients were 52.9% (95% CI: 27.8, 77.0) and 68.8% (95% CI: 41.3, 89.0), respectively. For 33 patients who had previously received bevacizumab treatment, the objective response rate (ORR) was 54.5% (95% CI: 36.4, 71.9); for 26 patients who had previously received PARP inhibitor treatment, the ORR was 46.2% (95% CI: 26.6, 66.6). Efficacy data can be found in [link to relevant data]. Figure 2f .

[0276] The median follow-up time was 2.8 months, therefore the median progression-free survival (PFS) was not yet mature, and the 6-month PFS rate was 44.7%.

[0277] In summary, antibody A-ADCs demonstrated encouraging efficacy in previously heavily treated PROC patients, regardless of their HER2 expression status. Antibody A-ADCs exhibited favorable tolerability and safety profiles, with lower incidences of gastrointestinal and hematologic toxicities compared to other DXd ADCs. These data support further clinical evaluation of antibody A-ADCs in PROC patients.

[0278] 2.2.4 Interim Results 4

[0279] As of the data collection date, in Phase I / II clinical trials conducted in China and Australia on the safety, tolerability, pharmacokinetics / pharmacodynamics, and antitumor activity of antibody A-ADC in subjects with advanced malignant solid tumors, the dosage has been increased to 10.5 mg / kg, and no DLT events occurred in any dosage group. A total of 414 subjects were exposed, with 392 (94.7%) experiencing TRAEs. Most CTCAEs were grade 1-2, and most recovered / improved after symptomatic treatment. According to PT classification, common TRAEs included nausea (44.0%), anemia (34.3%), diarrhea (33.1%), elevated aspartate aminotransferase (31.2%), decreased appetite (30.9%), vomiting (26.3%), elevated alanine aminotransferase (24.9%), weakness (23.2%), decreased white blood cell count (22.5%), and decreased platelet count (20.5%). A total of 77 subjects (18.6%) experienced grade 3 or higher TRAEs. 35 subjects (8.5%) experienced TRSAEs, including 12 cases (2.9%) of interstitial lung disease, 4 cases (1.0%) of anemia, 3 cases (0.7%) of infectious pneumonia, 2 cases each of pulmonary inflammation, nausea, and gastrointestinal disorders (0.5%), and 1 case each of herpes zoster, aspergillosis, Pneumocystis jirovecii pneumonia, Pneumocystis jirovecii infection, diarrhea, vomiting, febrile neutropenia, allergic dermatitis, fatigue, and angle-closure glaucoma (0.2%). A total of 35 subjects (8.5%) experienced infusion-related reactions, all of which were grade 1-2. A total of 100 subjects (24.2%) experienced TRAEs leading to discontinuation of medication. 10 subjects (2.4%) experienced TRAEs leading to permanent discontinuation of medication; no TRAEs resulted in death.

[0280] As of the date of data collection, among the 46 subjects with platinum-resistant ovarian cancer, the ORR was 63.0% (95% CI: 47.5, 76.8), the DCR was 93.5% (95% CI: 82.1, 98.6), and the mPFS was 7.7 months (95% CI: 5.7, 9.7).

[0281] As of the data collection date, among the 26 subjects with HER2 3+ gastric cancer, the ORR was 63.0% (95% CI: 42.4, 80.6), the DCR was 92.6% (95% CI: 86.9, 98.5), the mPFS was 9.6 months (95% CI: 4.3, 11.6), and the mDoR was 9.6 months (95% CI: 3.0, NE).

[0282] As of the date of data collection, among the 32 HER2-positive colorectal cancer patients, the ORR was 68.8% (95% CI: 50.0, 83.9), the DCR was 96.9% (95% CI: 83.8, 99.9), the mPFS was 11.0 months (95% CI: 6.9, 14.0), and the mDoR was 9.9 months (95% CI: 5.8, NE).

[0283] Example 3: Further Clinical Studies of Antibody A-ADC

[0284] 3.1 Research Plan

[0285] 3.1.1 Randomized, open-label, parallel-controlled, multicenter phase III clinical trial comparing antibody A-ADC with investigator-selective chemotherapy for HER2-low expression recurrent / metastatic breast cancer Experimental Objective This study aimed to evaluate the progression-free survival (PFS) of antibody A-ADC versus investigator-selected chemotherapy in patients with recurrent / metastatic breast cancer, as assessed by a blinded independent center (BIRC); overall survival (OS) of antibody A-ADC versus investigator-selected chemotherapy in patients with recurrent / metastatic breast cancer; other efficacy endpoints assessed by BIRC and investigator-assessed efficacy endpoints of antibody A-ADC versus investigator-selected chemotherapy in patients with recurrent / metastatic breast cancer; safety of antibody A-ADC versus investigator-selected chemotherapy in patients with recurrent / metastatic breast cancer; patient-reported outcomes of antibody A-ADC versus investigator-selected chemotherapy for recurrent / metastatic breast cancer; pharmacokinetic (PK) characteristics and immunogenicity (ADA) of antibody A-ADC; correlation between antibody A-ADC drug exposure levels and efficacy and safety; and correlation between biomarkers and antibody A-ADC efficacy.

[0286] Experimental Groups

[0287] Investigational drug: Antibody A-ADC; Dosage and administration: 6.3 mg / kg intravenously; Dosage schedule: once every 3 weeks (Q3W), the duration of the first infusion of antibody A-ADC is 90 min ± 10 min, and if the first cycle of infusion is well tolerated, the subsequent infusion time can be shortened to 60 ± 15 min.

[0288] Reference drug 1: Capecitabine tablets; Dosage and administration: The recommended dose is 1250 mg / m². 2 Oral administration; Dosage: twice daily (once in the morning and once in the evening, total daily dose 2500 mg / m²). 2 Take the tablet whole with water within 30 minutes after a meal; administer continuously for days 1-14, with 21 days constituting one cycle.

[0289] Control drug 2: Gemcitabine hydrochloride for injection; Dosage and administration: The recommended dose is 1000 mg / m². 2 Medication schedule: Dosage is administered on days 1 and 8 of each cycle, with each cycle lasting 21 days.

[0290] Control drug 3: Vinorelbine tartrate injection; Dosage and administration: The recommended dose is 25 mg / m². 2 Intravenous infusion; Dosage schedule: Administer on days 1 and 8 of each cycle, with 21 days constituting one cycle.

[0291] Control drug 4: Paclitaxel for injection (albumin-bound); Dosage and administration: Recommended 260 mg / m² 2 Intravenous infusion; Dosage schedule: Administer on day 1 of each cycle, with 21 days constituting one cycle.

[0292] Control drug 5: Docetaxel injection; Dosage and administration: Recommended 75 mg / m2; Duration of treatment: Administer on day 1 of each cycle, with 21 days constituting one cycle.

[0293] Control drug 6: Eribulin mesylate injection; Dosage and administration: Intravenous bolus injection, recommended 1.4 mg / m2, intravenous bolus injection over 2-5 minutes; Dosage schedule: Intravenous bolus injection over 2-5 minutes, administered on days 1 and 8 of each cycle, with 21 days constituting one cycle.

[0294] Inclusion criteria

[0295] (1) The subject was able to understand the informed consent form, voluntarily participated and signed the informed consent form.

[0296] (2) Subjects must be ≥18 years old on the day they sign the informed consent form, regardless of gender.

[0297] (3) HER2-low expression, unresectable locally recurrent or metastatic breast cancer.

[0298] (4) Received at least one or at most two lines of chemotherapy for breast cancer during the recurrence / metastasis stage.

[0299] (5) Willing to provide sufficient archived tumor pathology specimens for the central laboratory to test HER2 status.

[0300] (6) Documented radiographic progression of disease (during or after the most recent treatment).

[0301] (7) According to RECIST 1.1 criteria, there is at least one measurable extracranial lesion at the baseline.

[0302] (8) Expected survival ≥ 3 months.

[0303] (9) ECOG score of 0 or 1 within 14 days prior to administration.

[0304] (10) Female subjects with fertility or male subjects whose partners are fertile agree to use effective contraception from the time they sign the informed consent form.

[0305] (11) Full organ function.

[0306] (12) The previous treatment has been adequately washed off before the drug was administered.

[0307] Primary endpoint indicators

[0308] BICR evaluates PFS according to RECIST v1.1 standards.

[0309] Secondary endpoint indicators

[0310] (1) OS, defined as the time from random grouping to death from any cause; (2) Other efficacy endpoints of BICR as determined by RECIST v1.1 criteria: ORR, DOR, DCR, CBR, TTR; (3) The efficacy endpoints determined by the investigators according to the RECIST v1.1 criteria, including: PFS, ORR, DOR, DCR, CBR, TTR; (4) Safety endpoints: the incidence and severity of adverse events and treatment-related adverse events that occurred during treatment (according to NCI CTCAE 5.0 classification), serious adverse events, laboratory tests, other auxiliary examinations, changes in vital signs and physical examinations, and abnormal results.

[0311] (5) Patient-specific quality of life scales for breast cancer self-assessment, using the European Core Quality of Life Scale (EORTC QLQ-C30) and the European Five-Level Five-Dimensional Health Scale (EQ-5D-5L).

[0312] (6) Blood drug concentrations of A-ADC, total antibody, and free toxin; (7) Anti-A-ADC antibody, neutralizing antibody (if applicable) and titer; The study has been launched and plans to enroll approximately 408 participants. As of the date of data collection, 175 participants have been randomly assigned to the trial.

[0313] 3.1.2 Randomized, open-label, parallel-controlled, multicenter phase III clinical trials comparing antibody A-ADC with investigator-selective chemotherapy for platinum-resistant recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Experimental objective: The primary objective was to compare the progression-free survival of antibody A-ADC investigator-selected chemotherapy in patients with platinum-resistant recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, as evaluated by blinded, independent central imaging.

[0314] Experimental Groups: Investigational drug: Antibody A-ADC; Dosage and administration: 6.3 kg / mg, intravenous infusion, once every 3 weeks; Duration of treatment: until the treatment termination event specified in the protocol occurs.

[0315] Control drug 1: Paclitaxel injection; Dosage and administration: Intravenous infusion, administered on D1, D8, D15, and D22 of each cycle, 80 mg / m2 each time; Duration of treatment: until the treatment termination event specified in the protocol occurs.

[0316] Control drug 2: Doxorubicin hydrochloride liposome injection; Dosage and administration: Intravenous infusion, dose is 40 mg / m². 2 d1, repeated every 4 weeks; duration of medication: until the treatment termination event specified in the protocol occurs.

[0317] Control drug 3: Topotecan hydrochloride for injection; Dosage and administration: Intravenous infusion, dose 4 mg / m² 2 , d1, d8, d15, repeated every 4 weeks (preferred); or 1.25 mg / m 2 , d1~d5, repeated every 3 weeks; duration of medication: until the treatment termination event specified in the protocol occurs.

[0318] Inclusion criteria

[0319] (1) The subject was able to understand the informed consent form, voluntarily participated, and signed the informed consent form; (2) The subject was ≥18 years old on the day he / she signed the informed consent form; (3) Subjects with a histologically confirmed diagnosis of epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer; (4) Those who have been confirmed to have relapsed platinum resistance; (5) Patients who have previously received bevacizumab treatment are permitted; (6) According to RECIST 1.1 criteria, there is at least one measurable lesion at the baseline; (7) Expected survival ≥ 3 months; (8) ECOG score of 0 or 1; (9) Sufficient organ function within the 7 days prior to randomization: (10) Able to provide sufficient fresh or archived tumor tissue specimens; (11) The subjects are capable and willing to comply with the visit, treatment plan, laboratory tests and other research-related procedures stipulated in the study protocol; Primary endpoint indicators Progression-free survival (PFS) was assessed using RECIST 1.1 criteria in blinded independent center review.

[0320] Secondary endpoint indicators

[0321] (1) Total lifespan (OS); (2) ORR, DoR, and DCR assessed by blinded independent center review according to RECIST 1.1 criteria; (3) PFS2 is defined as randomization to the second disease progression or death from any cause, whichever comes first; (4) The efficacy endpoints determined by the investigators according to the RECIST v1.1 criteria, including: PFS, ORR, DOR, and DCR; (5) CA-125 remission rate assessed by researchers based on the GCIG CA-125 criteria; (6) Incidence and severity of adverse events (AEs); (7) Patient self-assessment of quality of life specific scales, using the European Core Quality of Life Scale (EORTC QLQ-C30) and the European Ovarian Cancer Patient Quality of Life Specific Scale (EORTC QLQ-OV28). (8) Population pharmacokinetic characteristics (PopPK) and the correlation between drug exposure levels and efficacy and safety; (9) Frequency and titer of anti-ADC antibodies and neutralizing antibodies (if applicable); (10) Correlation between HER2 expression level and the efficacy of antibody A-ADC.

[0322] The study has been launched and plans to enroll approximately 556 participants. As of the date of data collection, 82 participants have been randomly assigned to the study.

[0323] 3.1.3 A randomized, controlled, open-label, multicenter phase III clinical trial comparing the efficacy and safety of antibody A-ADC versus trastuzumab emtansine (T-DM1) in the treatment of HER2-positive advanced breast cancer. Experimental Objective Primary objective: To compare progression-free survival (PFS) in participants treated with antibody A-ADC versus T-DM1 in HER2-positive advanced breast cancer (BIRC assessment). Secondary objectives: To compare PFS (investigator-assessed), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and disease-free survival rate (DoR) (BIRC and investigator-assessed) in participants treated with antibody A-ADC versus T-DM1 in HER2-positive advanced breast cancer; to evaluate the safety of antibody A-ADC versus T-DM1 in HER2-positive advanced breast cancer; and to evaluate the pharmacokinetic characteristics and immunogenicity of antibody A-ADC.

[0324] Experimental Groups

[0325] Investigational drug: Antibody A-ADC; Dosage and administration: 6.3 mg / kg, Q3W, intravenous infusion (administered on day 1 of each treatment cycle), with each treatment cycle lasting 3 weeks; Duration of treatment: until disease progression, intolerable toxicity, loss to follow-up, death, or termination of the study by the sponsor, whichever occurs first.

[0326] Comparative drug: Trastuzumab emtansine (trade name: Hercelium); Dosage and administration: 3.6 mg / kg, Q3W, intravenous infusion (administered on day 1 of each treatment cycle), with each treatment cycle lasting 3 weeks; Duration of treatment: until disease progression, intolerable toxicity, loss to follow-up, death, or termination of the study by the sponsor, whichever occurs first.

[0327] Inclusion criteria

[0328] (1) Voluntarily join this study and sign an informed consent form; (2) ≥18 years old; (3) Unresectable locally advanced or metastatic breast cancer confirmed by histology or cytology; (4) The tissue sample was confirmed to be HER2 positive (IHC3+, or IHC2+ and ISH positive) by the research center laboratory. (5) Previously received treatment with trastuzumab or inetuzumab in advanced stages of disease and have radiographic or pathological evidence of disease progression, or radiographic or pathological evidence of disease progression or relapse within 12 months during or after (neo)adjuvant therapy (using trastuzumab or marketed trastuzumab biosimilars or inetuzumab). (6) Previous use of taxane therapy; (7) The most recent systemic antitumor therapy showed radiographic and / or pathological progression or intolerance; (8) At least one RECIST 1.1 non-intracranial measurable lesion is present; (9) ECOG PS score: 0-1 point; (10) Adequate organ and bone marrow function (without blood transfusion or hematopoietic stimulating factor drugs for correction within 14 days prior to testing): a) Hemoglobin ≥ 90 g / L; b) Platelet count ≥ 100 × 10⁹ / L; c) Neutrophil count ≥ 1.0 × 10⁹ / L; d) Liver function: Total bilirubin ≤ 1.5 × ULN; Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases); e) Kidney function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL / min (calculated using the Cockcroft-Gault formula); f) Coagulation function: International Normalized Ratio (INR) ≤ 1.5, and Activated Partial Thromboplastin Time (APLT) ≤ 1.5 × ULN (for participants receiving anticoagulation therapy, the investigator judged that both INR and APLT were within a safe and effective therapeutic range); g) LVEF ≥ 50%; (11) Expected survival time ≥ 3 months; (12) For female participants of reproductive age and male participants whose partners are women of reproductive age, consent must be given to use reliable and effective methods of contraception during the study treatment and for at least 7 months after the last study treatment (antibody A-ADC or T-DM1).

[0329] Primary endpoint indicators

[0330] PFS (BIRC assessment, RECIST 1.1) Secondary endpoint indicators (1) PFS (Investigator assessment, RECIST 1.1); (2) OS; (3) ORR, DCR, DoR (BIRC and investigator assessment, RECIST 1.1); (4) The incidence and severity of TEAE and SAE; abnormalities in vital signs, physical examination, laboratory tests, and other indicators; (5) Blood drug concentrations of antibody A-ADC, total antibody, and free toxin; (6) The incidence of ADA, antibody titer, and the occurrence of NAb (if applicable); (7) Patient self-assessment of breast cancer quality of life specific scales, using the European Core Quality of Life Scale (EORTC QLQ-C30) and the European Five-Level Five-Dimensional Health Scale (EQ-5D-5L). The study has been initiated and plans to enroll approximately 228 participants. As of the date of data collection, 232 participants have been randomly assigned to the study.

[0331] SEQ ID NO: 1 (HC1 VH, first heavy chain variable region)

[0332] EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS

[0333] SEQ ID NO: 2 (HC2 VH, second heavy chain variable region)

[0334] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS

[0335] SEQ ID NO: 3 (LC VL, common light chain variable region)

[0336] DIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK

[0337] SEQ ID NO: 4 (HC1 CDR1)

[0338] DYTMD

[0339] SEQ ID NO: 5 (HC1 CDR2)

[0340] DVNPNSGGSIYNQRFKG

[0341] SEQ ID NO: 6 (HC1 CDR3)

[0342] NLGPSFYFDY

[0343] SEQ ID NO: 7 (HC2 CDR1)

[0344] DTYIH

[0345] SEQ ID NO: 8 (HC2 CDR2)

[0346] RIYPTNGYTRYADSVKG

[0347] SEQ ID NO: 9 (HC2 CDR3)

[0348] WGGDGFYAMDY

[0349] SEQ ID NO: 10 (LC CDR1)

[0350] RASQDVNTAVA

[0351] SEQ ID NO: 11 (LC CDR2)

[0352] SASFLYS

[0353] SEQ ID NO: 12 (LC CDR3)

[0354] QQHYTTPPT

[0355] SEQ ID NO: 13 (HC1 CH, first heavy chain constant region, comprising CH1, hinge region, CH2, CH3)

[0356] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSALTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0357] SEQ ID NO: 14 (HC2 CH, second heavy chain constant region)

[0358] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFKLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0359] SEQ ID NO: 15 (CL, common light chain constant region)

[0360] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0361] SEQ ID NO: 16 (HC1, full first heavy chain)

[0362] EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSALTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0363] SEQ ID NO: 17 (HC2, full second heavy chain)

[0364] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFKLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0365] SEQ ID NO: 18 (LC, full light chain)

[0366] DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0367] SEQ ID NO: 19 (Human β-1,4-galactosyltransferase, human GalT1 Y285L)

[0368] GSNSAAAIGQSSGELRTGGARPPPPLGASSQPRPGGDSSPVVDSGPGPASNLTSVPVPHTTALSLPACPEESPLLVGPMLIEFNMPVDLELVAKQNPNVKMGGRYAPRDCVSPHKVAIIIPFRNRQEHLKYWLYYLHPVLQRQQLDYGIYVINQAGDTIFNRAKLLNVGFQEALKDYDYTCFVFSDVDLIPMNDHNAYRCFSQPRHISVAMDKFGFSLPYVQLFGGVSALSKQQFLTINGFPNNYWGWGGEDDDIFNRLVFRGMSISRPNAVVGRCRMIRHSRDKKNEPNPQRFDRIAHTKETMLSDGLNSLTYQVLDVQRYPLYTQITVDIGTPS

[0369] SEQ ID NO: 20 (Human β-1,4-galactosyltransferase, human GalT1 Y285L)

[0370] MRLREPLLSGSAAMPGASLQRACRLLVAVCALHLGVTLVYYLAGRDLSRLPQLVGVSTPLQGGSNSAAAIGQSSGELRTGGARPPPPLGASSQPRPGGDSSPVVDSGPGPASNLTSVPVPHTTALSLPACPEESPLLVGPMLIEFNMPVDLELVAKQNPNVKMGGRYAPRDCVSPHKVAIIIPFRNRQEHLKYWLYYLHPVLQRQQLDYGIYVINQAGDTIFNRAKLLNVGFQEALKDYDYTCFVFSDVDLIPMNDHNAYRCFSQPRHISVAMDKFGFSLPYVQLFGGVSALSKQQFLTINGFPNNYWGWGGEDDDIFNRLVFRGMSISRPNAVVGRCRMIRHSRDKKNEPNPQRFDRIAHTKETMLSDGLNSLTYQVLDVQRYPLYTQITVDIGTPS

[0371] SEQ ID NO: 21 (bovine β-1,4-galactosyltransferase, bovine GalT1 Y289L)

[0372] MKFREPLLGGSAAMPGASLQRACRLLVAVCALHLGVTLVYYLAGRDLRRLPQLVGVHPPLQGSSHGAAAIGQPSGELRLRGVAPPPPLQNSSKPRSRAPSNLDAYSHPGPGPGPGSNLTSAPVPSTTTRSLTACPEESPLLVGPMLIEFNIPVDLKLVEQQNPKVKLGGRYTPMDCISPHKVAIIIPFRNRQEHLKYWLYYLHPILQRQQLDYGIYVINQAGESMFNRAKLLNVGFKEALKDYDYNCFVFSDVDLIPMNDHNTYRCFSQPRHISVAMDKFGFSLPYVQLFGGVSALSKQQFLSINGFPNNYWGWGGEDDDIYNRLAFRGMSVSRPNAVIGKCRMIRHSRDKKNEPNPQRFDRIAHTKETMLSDGLNSLTYMVLEVQRYPLYTKITVDIGTPS

Claims

1. Use of the antibody-drug conjugate of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of advanced or metastatic solid malignancies, said antibody-drug conjugate having the structure shown in formula I: P-(LD)n (I), in, P is a bispecific antibody targeting HER2, D is a bioactive molecule, L is a linker unit, and n is an integer from 1 to 20. The bispecific antibody comprises a first heavy chain, a second heavy chain, and a common light chain. The first heavy chain includes a first heavy chain variable region, the second heavy chain includes a second heavy chain variable region, and the common light chain includes a common light chain variable region, wherein: The first heavy chain variable region comprises: HC1 CDR1, which contains the amino acid sequence shown in SEQ ID NO: 4; HC1 CDR2, which contains the amino acid sequence shown in SEQ ID NO: 5; and HC1 CDR3, which contains the amino acid sequence shown in SEQ ID NO:

6. The second heavy chain variable region comprises: HC2 CDR1, which contains the amino acid sequence shown in SEQ ID NO: 7; HC2 CDR2, which contains the amino acid sequence shown in SEQ ID NO: 8; and HC2 CDR3, which contains the amino acid sequence shown in SEQ ID NO:

9. The common light chain variable region comprises: LC CDR1, which contains the amino acid sequence shown in SEQ ID NO: 10; LC CDR2, which contains the amino acid sequence shown in SEQ ID NO: 11; and LC CDR3, which contains the amino acid sequence shown in SEQ ID NO:

12.

2. The method or use according to claim 1, wherein, The first heavy chain variable region includes HC1 CDR1 shown in SEQ ID NO:4, HC1 CDR2 shown in SEQ ID NO:5 and HC1 CDR3 shown in SEQ ID NO:6; The second heavy chain variable region includes HC2 CDR1 shown in SEQ ID NO: 7, HC2 CDR2 shown in SEQ ID NO: 8 and HC2 CDR3 shown in SEQ ID NO: 9; The common light chain variable region includes LC CDR1 shown in SEQ ID NO: 10, LC CDR2 shown in SEQ ID NO: 11, and LC CDR3 shown in SEQ ID NO:

12.

3. The use according to claim 1, wherein the first heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 1, the second heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 2, and the common light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 3; or, The first heavy chain variable region contains an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identity with the amino acid sequence shown in SEQ ID NO: 1; the second heavy chain variable region contains an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identity with the amino acid sequence shown in SEQ ID NO: 2; and the common light chain variable region contains an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identity with the amino acid sequence shown in SEQ ID NO:

3.

4. The use according to any one of claims 1-3, wherein the first heavy chain of the specific antibody comprises the amino acid sequence shown in SEQ ID NO: 16, the second heavy chain of the bispecific antibody comprises the amino acid sequence shown in SEQ ID NO: 17, and the common light chain of the bispecific antibody comprises the amino acid sequence shown in SEQ ID NO: 18; or, The first heavy chain of the specific antibody comprises an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identity with the amino acid sequence shown in SEQ ID NO: 16; the second heavy chain of the specific antibody comprises an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identity with the amino acid sequence shown in SEQ ID NO: 17; and the common light chain comprises an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identity with the amino acid sequence shown in SEQ ID NO:

18.

5. The use according to any one of claims 1-4, wherein the bioactive molecule D is selected from: .

6. The use according to any one of claims 1-5, wherein the antibody-drug conjugate has the structure shown in formula VII: (VII) in, P The bispecific antibody targeting HER2 as described in any one of claims 1-4; GlcNAc is N-acetylglucosamine, Fuc is fuc, Man is mannose, f is 0 or 1, and m is an integer from 1 to 10; Gal The modified galactose is selected from the following structures: or ;LP is selected from the following structures: and / or ; Where k is an integer from 1 to 20.

7. The use according to any one of claims 1-6, wherein the subject's tumor tissue is HER2-related or abnormally expressed, such as high expression, overexpression, low expression, ultra-low expression, or no expression.

8. The use according to any one of claims 1-7, wherein the subject's tumor tissue is HER2 IHC 3+, or IHC 2+ and FISH+.

9. The use according to any one of claims 1-8, wherein the subject's tumor tissue is HER2 IHC 1+, or IHC 2+ and FISH-.

10. The use according to any one of claims 1-9, wherein the subject has previously received ≥3 lines of treatment.

11. The use according to any one of claims 1-10, wherein the tumor is an unresectable locally recurrent or metastatic breast cancer with low HER2 expression.

12. The use according to any one of claims 1-7, wherein the tumor is HER2-positive, unresectable locally advanced or metastatic breast cancer.

13. The use according to any one of claims 1-10, wherein the tumor is ovarian cancer; preferably, the tumor is platinum-resistant ovarian cancer, or the tumor is epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer; preferably, the tumor is platinum-resistant recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

14. The use according to any one of claims 1-10, wherein the tumor is a digestive system tumor (such as gastric cancer, colorectal cancer, bile duct cancer or esophageal cancer), lung cancer or head and neck cancer.

15. The use according to any one of claims 1-14, wherein the therapeutically effective dose of the antibody-drug conjugate is 1-1000 mg / dose, preferably 5-500 mg / dose, more preferably 10-150 mg / dose; or The therapeutically effective dose is 1 mg / day to 1000 mg / day, preferably 5 mg to 500 mg / day, and more preferably 10 to 150 mg / day; or The therapeutically effective dose, based on the subject's body weight, is 0.05 mg / kg to 50 mg / kg, preferably 0.1 mg / kg to 20 mg / kg, more preferably 4.2 mg / kg to 8.4 mg / kg; and even more preferably, selected from 6.3 mg / kg to 7.3 mg / kg.

16. The use according to any one of claims 1-15, wherein the antibody-drug conjugate is administered by intravenous infusion.

17. The method or use according to any one of claims 1-16, wherein the antibody-drug conjugate may be administered once daily (QD) as the therapeutically effective dose, or may be administered multiple times a day as the total daily dose, for example, twice daily (BID) or three times daily (TID); may be administered once weekly (QW), or may be administered as the total weekly dose divided into multiple days within a week, for example, twice weekly (BIW) or three times weekly (TIW); may be administered once every two weeks (Q2W), or may be administered as the total weekly dose divided into multiple days within two weeks, for example, twice weekly (BI2W) or three times weekly (TI2W); may be administered once every three weeks (Q3W), or may be administered as the total dose divided into multiple days within three weeks, for example, twice weekly (BI3W, such as D1, D8 every three weeks) or three times weekly (TI3W); the therapeutically effective dose may be administered once a month (QM). Alternatively, the above-mentioned effective therapeutic dose can be administered as a total dose divided into multiple administrations over a month, such as twice a month (BI2M) or three times a month (TIM). The above-mentioned effective therapeutic dose can also be administered at intervals, such as once every 2-7 days, or once every 3, 4, 5, or 6 days, or once every 2-4 weeks, such as once every 2 weeks (once every 3 weeks, in a 3-week cycle), once every 1 week (once every 2 weeks, in a 2-week cycle or every 4 weeks). The antibody-drug conjugate can be administered once every 3 weeks (once every 4 weeks, every 4 weeks), or once every 1-3 months, such as once every 1 month (every 2 months); or continuously for 3 weeks, stop for 1 week, every 4 weeks; or continuously for 2 weeks, stop for 1 week, every 3 weeks; or continuously for 2 weeks, stop for 2 weeks, every 4 weeks; or once every 2 weeks (once every 2 weeks), every 4 weeks; preferably, the antibody-drug conjugate can be administered once every 3 weeks (Q3W).

18. The method or use according to any one of claims 1-17, wherein the antibody-drug conjugate is administered by intravenous infusion once every three weeks at a dose of 1.0, 2.1, 4.2, 5.2, 5.3, 6.3, 7.3, 8.4, 9.4 or 10.5 mg / kg, preferably 6.3 mg / kg, based on the subject's weight.

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