Treatment method and use of pharmaceutical combination containing conjugate

Abstract

The present invention relates to a treatment method and the use of a pharmaceutical combination containing a conjugate. Specifically, the present invention relates to a pharmaceutical composition, a kit and a treatment combination for treating cell proliferative disorders (e.g., cancers), the use of the treatment combination, and a method for treating cell proliferative disorders (e.g., cancers).

Description

Methods of treatment and uses of drug combinations comprising conjugates

[0001] This application is based on PCT application number PCT / CN2023 / 105235, with an application date of June 30, 2023; and CN application number 202410821898.2, with an application date of June 24, 2024, and claims priority. The contents of the PCT application are hereby introduced as a whole into this application. Technical Field

[0002] The present disclosure relates to methods of treating and using pharmaceutical compositions comprising immunoconjugates. Specifically, the present disclosure relates to pharmaceutical compositions, kits, and pharmaceutical compositions comprising immunoconjugates. The present disclosure also relates to methods of treating cell proliferative disorders in patients, particularly non-small cell lung cancer (NSCLC). Background Art

[0003] PD-1 is considered an important player in immune regulation and maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T cells, B cells, and NKT cells and is upregulated by T / B cell receptor signaling on lymphocytes, monocytes, and myeloid cells.

[0004] Two known ligands of PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in various human tissues that develop cancer. In large cohorts of cancers such as ovarian cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, and melanoma, PD-L1 expression has been shown to be associated with poor prognosis and decreased overall survival, regardless of subsequent treatment.

[0005] Similarly, in breast cancer and melanoma, PD-1 expression on tumor-infiltrating lymphocytes marks dysfunctional T cells and is associated with a poor prognosis in renal cancer.19 Therefore, it has been proposed that tumor cells expressing PD-L1 interact with PD-1-expressing T cells to attenuate T cell activation and evade immune surveillance, resulting in an impaired immune response against the tumor.

[0006] Immune checkpoint therapy targeting the PD-1 axis has achieved breakthrough clinical responses in a variety of human cancers. Immunotherapy targeting the PD-1 axis includes monoclonal antibodies targeting the PD-1 receptor (KEYTRUDA TM (pembrolizumab), Merck and Co., Inc., Kenilworth, NJ, USA, and OPDIVO TM(Nivolumab), Bristol-Meyers Squibb Company, Princeton, NJ, USA), and a monoclonal antibody that binds to the PD-L1 ligand (MPDL3280A; TECENTRIQ TM (atezolizumab, Genentech, San Francisco, CA, USA) Both treatments have been shown to have anti-tumor effects in many cancer types.

[0007] It has been suggested that the efficacy of such antibodies may be enhanced if used in combination with other approved or experimental cancer treatments (e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, drugs that inhibit other signaling pathways that are dysregulated in tumors, and other immune-enhancing agents).

[0008] Trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein involved in calcium signaling and expressed in various tumor types. Trop-2 is expressed in normal trophoblasts, enabling their growth, migration, and proliferation. Trop-2 is involved in multiple cell signaling pathways, including intracellular calcium transduction, MAPK signaling, RAF, NF-κB, and cyclin D / E.

[0009] It has been shown that Trop-2 is upregulated in cancer cells compared to normal cells. This increased expression has been observed in many different tumor types, including breast cancer, colon cancer, non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma, thyroid cancer, and hepatobiliary cancer, raising the possibility that Trop-2 could serve as a pan-cancer biomarker. The reason why Trop-2 is upregulated in cancer cells is unclear; however, it is hypothesized that Trop-2 has a key regulatory role in cell proliferation and invasion, meaning that overexpression would lead to selective tumor progression. Indeed, preclinical data suggest that Trop-2 overexpression stimulates tumor growth, while Trop-2 knockdown inhibits tumor growth.

[0010] Specifically in breast cancer, elevated Trop-2 expression is associated with decreased survival. Trop-2 gene expression has been detected in all breast cancer subtypes, with higher expression levels in HR+ / HER2- and triple-negative cancers (TNBC) compared to HER2+ disease. Genomic profiling of TNBC has also identified Trop-2 as an attractive candidate for targeted therapy and has led to further investigation of Trop-2 as a novel therapeutic target.

[0011] The success of targeting Trop-2 with antibody-drug conjugates (ADCs) in metastatic breast cancer (MBC) and urothelial carcinoma, as well as ongoing trials in NSCLC, has established Trop-2 targeting as a promising strategy, and several targeted Trop-2 therapies, such as anti-Trop-2 antibodies and Trop-2-targeted ADCs, have recently been developed for clinical use. Subsequently, multiple early clinical trials have demonstrated that Trop-2-based ADCs have good safety and clinical benefits in a variety of tumor types. This includes clinical benefits and tolerability in tumor types with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial carcinoma, and small cell carcinoma. Examples of immunoconjugates currently in early clinical trials are immunoconjugates A:

[0012] Wherein Ab is an anti-Trop-2 antibody (sacituzumab), which is described in US Patent Publication 20200347075.

[0013] Given its involvement in several traditional molecular pathways associated with cancer development, Trop-2 may play a role in tumor progression. High Trop-2 expression has been associated with poor prognosis in pancreatic cancer, hilar cholangiocarcinoma, cervical cancer, gastric cancer, and other diseases. In a meta-analysis of 2569 patients, increased Trop-2 expression was associated with poor overall survival and disease-free survival in several solid tumors. Given the expression pattern of Trop-2 and its associated poor prognostic outcomes, Trop-2 is a plausible prognostic marker and therapeutic target.

[0014] Based on the promising results shown by anti-human PD-1 antibodies and immunoconjugates in the treatment of cancer as monotherapy, combinations of these therapeutic agents with distinct mechanisms of action and non-additive toxicities have the potential to provide more pronounced and prolonged responses in many cancer types.

[0015] SUMMARY OF THE INVENTION

[0016] In a first aspect, the present disclosure provides a method of treating a cell proliferative disorder, such as cancer, in a patient, comprising administering to the patient:

[0017] (a) anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs);

[0018] (b) Immunoconjugates of formula (I):

[0019] in,

[0020] Ab is an antibody that binds to Trop-2, and

[0021] n is an integer selected from 1 to 10;

[0022] The amounts of (a) and (b) are effective for treating a cell proliferative disorder.

[0023] In some embodiments, the present disclosure provides methods of treating a cell proliferative disorder, such as cancer, in a patient, comprising administering to the patient:

[0024] (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof; and

[0025] (b) Immunoconjugates of formula (I):

[0026] in,

[0027] Ab is an antibody that binds to Trop-2; and

[0028] n is an integer selected from 1 to 10,

[0029] The amounts of (a) and (b) administered together are effective for treating cancer.

[0030] In one embodiment of the method (embodiment 1), the cell proliferative disorder is cancer, wherein the cancer is colorectal cancer (CRC), prostate cancer, pancreatic cancer, melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, urothelial carcinoma, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular carcinoma, non-Hodgkin's lymphoma, kidney cancer, Hodgkin's lymphoma, mesothelioma, ovarian cancer, small cell lung cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, or salivary cancer. In addition, in some embodiments of the above method, the cancer PD-L1 expression level is increased, such as a cancer with a tumor proportion score (TPS) ≥1%, 1%-49% or ≥50%, or a combined positive score (CPS) ≥1 or ≥10. For example, the level of PD-L1 TPS or CPS is determined by a test method approved by the U.S. Food and Drug Administration.

[0031] In embodiment 2 of the method, the cancer is non-small cell lung cancer. In a specific embodiment, the non-small cell lung cancer is advanced or metastatic non-small cell lung cancer. In another specific embodiment, the patient requires first-line treatment, and the non-small cell lung cancer does not have an EGFR mutation and an ALK fusion gene. In another specific embodiment, the non-small cell lung cancer is a non-small cell lung cancer with an EGFR actionable mutation, and the patient has previously failed EGFR-TKI treatment. In another specific embodiment, the non-small cell lung cancer has a 19del mutation and / or has a 21L858R mutation. In another specific embodiment, the non-small cell lung cancer is a non-small cell lung cancer with an EGFR actionable mutation, and the patient has previously failed EGFR-TKI treatment and has previously failed PD-1 / PD-L1 antibody treatment and chemotherapy.

[0032] In embodiment 3 of the method, the cancer is cervical cancer. In a specific embodiment, the cervical cancer is recurrent or metastatic cervical cancer.

[0033] In embodiment 4 of the method, the cancer is ovarian cancer. In a specific embodiment, the ovarian cancer is recurrent or metastatic ovarian cancer. In another specific embodiment, the ovarian cancer is platinum-resistant ovarian cancer.

[0034] In embodiment 5 of the method, the cancer is urothelial carcinoma. In specific embodiments, the urothelial carcinoma is locally advanced or metastatic urothelial carcinoma.

[0035] In embodiment 6 of the method, the cancer is prostate cancer. In a specific embodiment, the prostate cancer is locally advanced or metastatic urothelial carcinoma. In another specific embodiment, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0036] In embodiment 7 of the method, the immunoconjugate of formula (I) is immunoconjugate A.

[0037] In embodiment 8 of the method, the patient is administered 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof and 5 mg / kg of immunoconjugate A, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered once every three weeks, and the immunoconjugate A is administered once every three weeks. For example, the human patient is administered 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof on day 1 of a 3-week cycle, and 5 mg / kg of immunoconjugate A is administered on day 1 of a 3-week cycle.

[0038] In embodiment 9 of the method, the patient is administered 400 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof and 5 mg / kg of immunoconjugate A, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered once every six weeks and the immunoconjugate A is administered once every two weeks. For example, the human patient is administered 400 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof on day 1 of a 6-week cycle, and 5 mg / kg of immunoconjugate A is administered on days 1, 15, and 29 of the 6-week cycle.

[0039] In embodiment 10 of the method, the patient is administered 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof, 5 mg / kg of immunoconjugate A, and a platinum-containing chemotherapeutic agent, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, the immunoconjugate A is administered once every 3 weeks, and the platinum-containing chemotherapeutic agent is administered once every 3 weeks. For example, on day 1 of a 3-week cycle, the human patient is administered 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof, on day 1 of a 3-week cycle, 5 mg / kg of immunoconjugate A is administered, and on day 1 of a 3-week cycle, the platinum-containing chemotherapeutic agent is administered.

[0040] In embodiment 11 of the method, 400 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof, 5 mg / kg of immunoconjugate A, and a platinum-containing chemotherapeutic agent are administered to the patient, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered once every 6 weeks, immunoconjugate A is administered once every 2 weeks, and the platinum-containing chemotherapeutic agent is administered once every 3 weeks. For example, the human patient is administered 400 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof on day 1 of a 6-week cycle, 5 mg / kg of immunoconjugate A is administered on days 1, 15, and 29 of a 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of a 6-week cycle.

[0041] In embodiment 12 of the method, 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof, 5 mg / kg of immunoconjugate A, and carboplatin or cisplatin are administered to the patient, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, immunoconjugate A is administered once every 3 weeks, and carboplatin or cisplatin is administered once every 3 weeks. For example, on day 1 of a 3-week cycle, 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof is administered to the human patient, on day 1 of a 3-week cycle, 5 mg / kg of immunoconjugate A is administered, and on day 1 of a 3-week cycle, carboplatin or cisplatin is administered.

[0042] In a second aspect, the present disclosure provides a kit comprising:

[0043] (a) an immunoconjugate of formula (I); and

[0044] (b) anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0045] In some embodiments, the present disclosure provides a kit comprising:

[0046] (a) an immunoconjugate of formula (I); and

[0047] (b) anti-human PD-1 antibody or antigen-binding fragment thereof.

[0048] In embodiment 1 of the kit, the kit further comprises instructions for administering the immunoconjugate of formula (I) and the anti-human PD-1 antibody or antigen-binding fragment thereof to a human patient.

[0049] In a third aspect, the present disclosure provides a combination for treating a cell proliferative disorder, such as cancer, in a human patient, comprising:

[0050] (a) an immunoconjugate of formula (I); and

[0051] (b) cell proliferative disorders treated with anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0052] In some embodiments, the present disclosure provides a combination for treating a cell proliferative disorder, such as cancer, in a human patient comprising:

[0053] (a) an immunoconjugate of formula (I); and

[0054] (b) anti-human PD-1 antibody or antigen-binding fragment thereof.

[0055] In a fourth aspect, the present disclosure provides a pharmaceutical combination for treating a cell proliferative disorder, such as cancer, in a human patient, the pharmaceutical combination comprising:

[0056] (a) an immunoconjugate of formula (I); and

[0057] (b) anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0058] In some embodiments, the present disclosure provides a pharmaceutical combination for treating a cell proliferative disorder, such as cancer, in a human patient, comprising:

[0059] (a) an immunoconjugate of formula (I); and

[0060] (b) anti-human PD-1 antibody or antigen-binding fragment thereof.

[0061] In a fifth aspect, the present disclosure provides a use of a pharmaceutical combination for the preparation of a medicament for treating a cell proliferative disorder, such as cancer, in a human patient, the pharmaceutical combination comprising:

[0062] (a) an immunoconjugate of formula (I); and

[0063] (b) anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0064] In some embodiments, the present disclosure provides a use of a pharmaceutical combination for the preparation of a medicament for treating a cell proliferative disorder, such as cancer, in a human patient, the pharmaceutical combination comprising:

[0065] (a) an immunoconjugate of formula (I); and

[0066] (b) anti-human PD-1 antibody or antigen-binding fragment thereof.

[0067] In certain embodiments of the first, second, third, fourth, or fifth aspects, the anti-human PD-1 antibody or antigen-binding fragment thereof comprises three light chain CDRs as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and three heavy chain CDRs as shown in SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO. 8.

[0068] In certain embodiments of the first, second, third, fourth, or fifth aspects, the anti-human PD-1 antibody or antigen-binding fragment thereof comprises V L A region comprising the amino acid sequence shown in SEQ ID NO: 4, and V H A region comprising the amino acid sequence shown in SEQ ID NO:9.

[0069] In certain embodiments of the first, second, third, fourth, or fifth aspect, the anti-human PD-1 antibody or antigen-binding fragment thereof comprises a light chain comprising or consisting of the amino acid sequence shown in SEQ ID NO: 5, and a heavy chain comprising or consisting of the amino acid sequence shown in SEQ ID NO: 10.

[0070] In certain embodiments of the first, second, third, fourth, or fifth aspect, the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab.

[0071] In certain embodiments of the first, second, third, fourth, or fifth aspect, the anti-human PD-1 antibody or antigen-binding fragment thereof is nivolumab.

[0072] In certain embodiments of the first, second, third, fourth, or fifth aspect, the anti-human PD-1 antibody or antigen-binding fragment thereof is cemiplimab.

[0073] In certain embodiments of the first, second, third, fourth, or fifth aspect, the anti-human PD-1 antibody or antigen-binding fragment thereof is dostalimab.

[0074] Detailed description of the invention

[0075] Definitions and Abbreviations

[0076] The following lists the definitions of various terms used herein. These definitions apply to the terms as used in this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0077] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly used in the art.

[0078] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one elements. Furthermore, the use of the term "including" as well as other forms such as "include," "includes," and "included" is non-limiting.

[0079] As used herein, the term "about" in quantitative terms refers to plus or minus 10% of the value it modifies (rounded to the nearest integer if the value is not divisible, e.g., number of molecules or nucleotides).

[0080] "Antibody-drug conjugate," "ADC," or "immunoconjugate" refers to an antibody molecule, or antigen-binding fragment thereof, that is covalently or non-covalently bound, with or without a linker, to one or more biologically active molecules. The term "antibody" is used herein in the broadest sense and includes polyclonal and monoclonal antibodies, e.g., whole antibodies, and functional (antigen-binding) fragments thereof. The term includes genetically engineered and / or otherwise modified immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific (e.g., bispecific) antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, and tandem tri-scFv.

[0081] As used herein, the terms "at least one" item or "one or more" items each include a single item selected from the list as well as a set of two or more items selected from the list.

[0082] The terms "administration" or "administering" refer to the act of injecting or otherwise physically delivering a substance (e.g., an anti-PD-1 antibody) that exists outside the body to a patient, such as by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0083] As used herein, unless otherwise indicated, "antibody fragment" or "antigen binding fragment" refers to an antibody fragment that retains the ability to specifically bind to an antigen, for example, an antibody fragment that retains one or more CDR regions and the ability to specifically bind to an antigen. An antibody that "specifically binds" to PD-1 means that the antibody exhibits binding preference for PD-1 over other proteins (as the case may be), but such specificity does not require absolute binding specificity. If the binding of the antibody is decisive for the presence of the target protein in the sample, for example, it will not produce undesirable results such as false positives, the antibody is considered to be "specific" for its intended target. The antibody or its binding fragment will bind to the target protein with an affinity that is at least twice as great as that with a non-target protein, preferably at least 10 times greater, more preferably at least 20 times greater, and most preferably at least 100 times greater.

[0084] Antigen binding portions include, for example, Fab, Fab', F(ab')2, Fd, Fv, fragments including CDRs and single-chain variable region fragment antibodies (scFv), as well as polypeptides that bind to the antigen, which contain at least a portion of an immunoglobulin that is sufficient to confer specificity to the antigen (e.g., PD-1). Immunoglobulins can be divided into different categories based on the amino acid sequence of the constant region of the antibody heavy chain. There are five main types of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, several of which can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different types of immunoglobulins are well known. The antigen-binding fragments of full-length antibodies can be used to prepare the immunoconjugates of the present disclosure. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; recombinant IgG fragments (rIgG); diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv or sFv); single-domain antibodies (e.g., sdAb, sdFv, nanobodies); and multispecific antibodies formed from antibody fragments. In certain embodiments, the fragment is a single-chain antibody fragment comprising a heavy chain variable region and / or a light chain variable region, such as an scFv.

[0085] An "antigen" is a structure to which an antibody can selectively bind. A target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other natural or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, the antigen is associated with a cell, e.g., present on or in a cell, such as a cancer cell.

[0086] The terms "advanced solid malignancies" and "advanced solid tumors" are used interchangeably and refer to tumors that cannot be radically resected. Advanced solid tumors include, but are not limited to, metastatic tumors in the bone, brain, breast, liver, lung, lymph nodes, pancreas, prostate, and soft tissue (sarcomas).

[0087] As used herein, the term "antibody" refers to any form of immunoglobulin molecules that exhibit desired biological or binding activity. Therefore, it is used in the broadest sense, specifically including but not limited to monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies. "Parent antibody" refers to an antibody obtained by being exposed to an antigen by the immune system before the antibody is modified for a specific purpose, such as an antibody humanization used as a human therapeutic drug. As used herein, the term "antibody" includes not only complete polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen-binding portion that competes for specific binding with a complete antibody, a fusion protein comprising an antigen-binding portion, and any other modified configuration of the immunoglobulin molecule comprising an antigen recognition site.

[0088] Typically, the basic antibody structural unit comprises a tetramer. Each tetramer comprises two pairs of identical polypeptide chains, each pair having a "light" chain (approximately 25 kDa) and a "heavy" chain (approximately 50-70 kDa). The amino-terminal portion of each chain includes a variable region of approximately 100 to 110 or more amino acids that is primarily responsible for antigen recognition. The variable regions of each light / heavy chain pair form the antibody's binding site. Thus, in general, a complete antibody has two binding sites. The carboxyl-terminal portion of the heavy chain can define the constant region primarily responsible for effector function. Typically, human light chains are divided into kappa light chains and lambda light chains. Furthermore, human heavy chains are typically classified as μ, δ, γ, α, or ε, and define the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. In both light and heavy chains, the variable and constant regions are connected by a "J" region of approximately 12 or more amino acids, while the heavy chain also includes a "D" region of approximately 10 or more amino acids. See generally, Fundamental Immunology, Chapter 7, Paul, W., ed., 2nd ed., Raven Press, NY (1989).

[0089] A "biotherapeutic agent" is a biological molecule, such as an antibody or fusion protein, that blocks ligand / receptor signaling in any biological pathway that supports tumor maintenance and / or growth or suppresses anti-tumor immune responses.

[0090] As used herein, the term "carrier" includes vehicles, excipients, and diluents and refers to a material, composition, or vehicle that participates in carrying or transporting an agent from one organ or body part to another organ or body part of a patient, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0091] As used herein, the term "comprising" may include the embodiments of "consisting of" and "consisting essentially of." As used herein, the terms "comprise," "include," "having," "has," "may," "contain," or variations thereof, are intended to be open transitional phrases, terms, or words that require the presence of specified ingredients / steps and allow for the presence of other ingredients / steps. However, such descriptions should be construed as also describing compositions or methods as "consisting of" and "consisting essentially of" the enumerated components, allowing only the indicated components or compounds, and any acceptable carriers or fluids, to be present, and excluding other components or compounds.

[0092] "CDR" refers to the V H One of the three hypervariable regions (H1, H2, or H3) within the non-framework region of the β-sheet framework, or the antibody V L One of the three hypervariable regions (L1, L2 or L3) within the non-framework region of the β-sheet framework. Therefore, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the most highly variable regions within the antibody variable domain. Structurally, Chothia defines CDR region sequences as residues that are not part of the conserved β-sheet framework and are therefore able to adapt to different conformations. Both terms are well known in the art. CDR region sequences have also been defined by AbM, Contact and IMGT. The positions of CDRs within canonical antibody variable regions have been determined by comparing multiple structures (Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-48; Morea et al., 2000, Methods, 20:267-79). Because the number of residues in different antibody hypervariable regions is not equal, the additional residues relative to the canonical position are usually numbered with a, b, c etc. next to the residue numbering in the canonical variable region numbering scheme (Al-Lazikani et al., supra). This nomenclature is well known to those skilled in the art. The corresponding relationship between the numbering systems (including, for example, the Kabat numbering system and the IMGT unique numbering system) is well known to those skilled in the art, and is shown in Table 1 below. In certain embodiments, the CDRs are defined by the Kabat numbering system. In other embodiments, the CDRs are defined by the IMGT numbering system. In other embodiments, the CDRs are defined by the AbM numbering system. In other embodiments, the CDRs are defined by the Chothia numbering system. In other embodiments, the CDRs are defined by the Contact numbering system.

[0093] Table 1. Correspondence between CDR numbering systems

[0094] "Chemotherapeutic agents" are compounds that can be used to treat cancer. Classifications of chemotherapeutic agents include, but are not limited to, alkylating agents (including platinum-containing chemotherapeutic agents), antimetabolites, kinase inhibitors, spindle poison alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogestins, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and antisense oligonucleotides that inhibit the expression of genes associated with abnormal cell proliferation or tumor growth. Chemotherapeutic agents that can be used in the methods of treatment of the present disclosure include cytostatic and / or cytotoxic agents.

[0095] A "chimeric antibody" refers to an antibody in which a portion of its heavy and / or light chain contains a sequence derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder is derived from another species (e.g., mouse) or belongs to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0096] As used herein, the terms "combination therapy" and "therapeutic combination" refer to treatments in which at least one anti-human PD-1 antibody (or antigen-binding fragment thereof) and an immunoconjugate of Formula (I), and optionally an additional therapeutic agent, are administered to a patient in a coordinated manner over an overlapping period of time. The period of treatment with at least one anti-human PD-1 antibody (or antigen-binding fragment thereof) ("anti-PD-1 treatment") is the time a patient receives treatment with the anti-human PD-1 antibody (or antigen-binding fragment thereof); that is, the total time from the initial administration of the anti-human PD-1 antibody (or antigen-binding fragment thereof) to the last day of the treatment cycle. Similarly, the period of treatment with the immunoconjugate of Formula (I) ("immunoconjugate treatment with Formula (I)") is the time a patient receives treatment with the immunoconjugate of Formula (I); that is, the total time from the initial administration of the immunoconjugate of Formula (I) to the last day of the treatment cycle. In the methods and therapeutic combinations described herein, the anti-PD-1 treatment overlaps with the immunoconjugate treatment with Formula (I) by at least one day. In certain embodiments, the anti-PD-1 therapy and the immunoconjugate therapy of Formula (I) are performed together. In some embodiments, the anti-PD-1 therapy begins before the immunoconjugate therapy of Formula (I). In some embodiments, the immunoconjugate therapy of Formula (I) begins before the anti-PD-1 therapy. In some embodiments, the anti-PD-1 therapy is terminated before the immunoconjugate therapy of Formula (I) is terminated. In some embodiments, the immunoconjugate therapy of Formula (I) is terminated before the anti-PD-1 therapy is terminated.

[0097] The terms "complementarity determining region" and "CDR", synonymous with "hypervariable region" or "HVR", refer to subregions within an antibody variable domain that confer specificity and / or affinity to an antibody for its antigen. Generally speaking, there are three CDRs (HCDR1, HCDR2, and HCDR3) in each heavy chain variable domain, and three CDRs (LCDR1, LCDR2, and LCDR3) in each light chain variable domain. "Framework region" ("FR") refers to the non-CDR portions of a variable domain. Generally speaking, there are four FRs in each full-length heavy chain variable domain, and four FRs in each full-length light chain variable domain. For a particular CDR or FR, its precise amino acid sequence boundaries can be readily determined according to any of several known schemes, including the scheme described by Kabat et al., 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (the "Kabat" numbering scheme); Al-Lazikani et al., JMB 273:927-948 (1997) (the "Chothia" numbering scheme); MacCallum et al., J. Mol. Biol., 262:732-745 (1996) (the "Contact" numbering scheme); Lefranc et al., Dev Comp Immunol, 27(1):55-77 (2003) (the "IMGT" numbering scheme); and Honegger and Pluckthun, J. Mol. Biol., 309(3):657-70 (2001) (the "Aho" numbering scheme).

[0098] For a specific CDR or FR, its boundaries may vary depending on the scheme used for determination. For example, the Kabat scheme is based on sequence alignment, while the Chothia scheme is based on structural information. The numbering of both the Kabat and Chothia schemes is based on the most common antibody region sequence lengths, with insertions represented by inserted letters, such as "30a". The two schemes place certain insertions and deletions ("indels") in different positions, resulting in numbering differences. The Contact scheme is based on complex crystal structure analysis and is similar to the Chothia numbering scheme in many respects. Unless otherwise stated, the CDRs of antibodies referred to herein can be determined according to any one of the Kabat, Chothia, IMGT and Contact methods.

[0099] "Conservatively modified variants" or "conservative substitutions" refer to replacing an amino acid in a protein with an amino acid having other similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone conformation, and rigidity), such that such changes can often be made without changing the biological activity or other desired properties of the protein, such as antigen affinity and / or specificity. In general, those skilled in the art recognize that the replacement of a single amino acid in a non-essential region of a polypeptide will not substantially change its biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, the Benjamin / Cummings Pub. Co., page 224 (4th edition)). In addition, replacement of amino acids with similar structure or function is unlikely to destroy biological activity. Exemplary conservative substitutions are shown in Table 2 below.

[0100] Table 2. Exemplary conservative amino acid substitutions

[0101] As used herein, the term "DAR" or "drug-to-antibody ratio" refers to: (a) the number of linker / drug moieties attached to an antibody in a single antibody-drug conjugate molecule (i.e., "n"), which is an integer from 0 to 10, such as an integer from 1 to 10; or (b) the average number of linker / drug moieties attached to an antibody in a composition comprising more than one antibody-drug conjugate molecule (i.e., "n"). ), which is an integer or decimal from 0 to 10, such as an integer or decimal from 1 to 10. Therefore, in one embodiment, for the antibody-drug conjugates of the present disclosure, the DAR is an integer or decimal from 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, or 0 to 1. In some embodiments, for the antibody-drug conjugates of the present disclosure, the DAR is an integer or decimal of 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 9-10. In some embodiments, for the antibody-drug conjugates of the present disclosure, the DAR is an integer or decimal of 1-8, 1-4, 2-5, 3-6, 4-7, 5-8, or 6-8. In other embodiments, for the antibody-drug conjugates of the present disclosure, the DAR is an integer or decimal of 1-3, 2-4, 3-5, 4-6, 5-7, or 6-8. In other embodiments, for the antibody-drug conjugates of the present disclosure, the DAR is an integer or decimal of 1-2, 2-3, 3-4, 4-5, 5-6, 5-7, or 7-8. Similarly, for a composition comprising an antibody-drug conjugate of the present disclosure, the DAR of the composition is the average of the DARs of all antibody-drug conjugate molecules present in the composition. Thus, for a composition comprising an antibody-drug conjugate of the disclosure, the DAR of the composition is an integer or fractional number of 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, or 0-1. In some embodiments, for a composition comprising an antibody-drug conjugate of the disclosure, the DAR of the composition is an integer or decimal of 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 9-10. In additional embodiments, for the disclosed antibody-drug conjugate compositions, the DAR of the composition is an integer or decimal of 1-4, 2-5, 3-6, 4-7, 5-8, or 6-8.In other embodiments, for compositions comprising an antibody-drug conjugate of the present disclosure, the DAR of the composition is an integer or decimal of 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, or 6 to 8. In further embodiments, for compositions comprising an antibody-drug conjugate of the present disclosure, the DAR of the composition is an integer or decimal of 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, or 7 to 8. As used above, "composition" is understood to include pharmaceutical compositions.

[0102] The therapeutic agents and compositions provided by the present disclosure can be administered by any suitable enteral route or parenteral route. The term "enteral route" refers to administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, oral and rectal routes, or intragastric routes. "Parenteral route" refers to routes of administration other than the enteral route. Examples of parenteral routes include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardial, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal, subcutaneous or topical administration. The therapeutic agents and compositions provided by the present disclosure can be administered using any suitable method, such as by oral intake, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump and osmotic pump. Suitable routes of administration and methods can vary according to a variety of factors, such as the specific therapeutic agent used, the desired absorption rate, the specific formulation or dosage form used, the type or severity of the disease being treated, the specific site of action and the patient's condition, and can be easily selected by those skilled in the art.

[0103] "Homology" refers to the sequence similarity between two polypeptide sequences when they are optimally aligned. When a certain position in the two compared sequences is occupied by the same amino acid monomer subunit, for example, if a certain position in the light chain CDR of two different Abs is occupied by alanine, the two Abs are homologous at that position. The percentage of homology is the number of matching positions shared by the two sequences divided by the number of positions compared × 100. For example, when the two compared sequences are optimally aligned, 8 out of 10 positions of the two sequences match, then the two sequences are 80% homologous. Typically, the comparison is performed when the two sequences are aligned to produce the maximum percentage of homology. For example, the comparison can be performed using the BLAST algorithm, where the parameters of the algorithm are selected to provide the maximum match between the sequences over the entire length of each reference sequence.

[0104] The following references are related to the BLAST algorithm that is frequently used for sequence analysis: BLAST ALGORITHMS: Altschul, SF et al. (1990) J. Mol. Biol., 215:403-410; Gish, W. et al. (1993) Nature Genet., 3:266-272; Madden, TL et al. (1996) Meth. Enzymol., 266:131-141; Altschul, SF et al. (1997) Nucleic Acids Res., 25:3389-3402; Zhang et al. (1997) Genome Res., 7:649-656; Wootton, JC et al. (1993) Comput. Chem., 17:149-163; Hancock, JM et al. (1994) Comput. Appl. Biosci., 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, MO et al., "A model of evolutionary change in proteins.", in Atlas of Protein Sequence and Structure (1978), vol. 5, suppl. 3, MO Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, RM et al., "Matrices for detecting distant relationships.", in Atlas of Protein Sequence and Structure (1978) Vol. 5, Suppl. 3, MO Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, D.C.; Altschul, S. F. (1991) J. Mol. Biol., 219: 555-565; States, DJ et al. (1991) Methods, 3: 66-70; Henikoff, S. et al. (1992) Proc. Natl. Acad. Sci. USA, 89: 10915-1919; Altschul, S. F. et al. (1993) J. Mol. Evol., 36: 290-300; ALIGNMENT STATISTICS: Karlin, S. et al. (1990) Proc. Natl. Acad. Sci. USA, 87: 2264-2268; Karlin, S. et al. (1993) Proc.Natl. Acad. Sci. USA, 90: 5873-5877; Dembo, A. et al. (1994) Ann. Prob., 22: 2022-2039; and Altschul, SF, “Evaluating the statistical significance of multiple distinct local alignments.” In Theoretical and Computational Methods in Genome Research (S. Suhai, ed.) (1997), pp. 1-14, Plenum, New York.

[0105] A "human antibody" refers to an antibody comprising human immunoglobulin sequences or derivatives thereof. If produced in a mouse, mouse cell, or hybridoma derived from a mouse cell, a human antibody may contain murine carbohydrate chains. Similarly, a "mouse antibody" or a "rat antibody" refers to an antibody comprising only mouse or rat immunoglobulin sequences, or derivatives thereof, respectively.

[0106] "Humanized antibody" refers to an antibody form comprising sequences from non-human (e.g., mouse) antibodies and human antibodies. These antibodies contain minimal sequences derived from non-human immunoglobulins. Typically, the humanized antibody comprises substantially all of at least one, typically two variable domains, wherein all or substantially all of the hypervariable region loops correspond to the hypervariable region loops of non-human immunoglobulins, and all or substantially all of the FR regions are FR regions of human immunoglobulin sequences. Optionally, the humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. When it is necessary to distinguish between parent rodent antibodies and humanized antibodies, the prefix "hum," "hu," or "h" can be added to the antibody clone name. The humanized form of a rodent antibody generally comprises the same CDR sequence as the parent rodent antibody, although for purposes of increasing affinity, increasing the stability of the humanized antibody, or other reasons, some amino acid substitutions may be included.

[0107] A "complete" antibody comprises an antigen binding site and CL and at least heavy chain constant regions CH1, CH2, and CH3. The constant region may comprise a human constant region or an amino acid sequence variant thereof. In certain embodiments, the complete antibody has one or more effector functions.

[0108] As used herein, the term "immune response" relates to any one or more of the following responses: specific immune response, nonspecific immune response, specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation and cytokine expression.

[0109] As used herein, the term "immune response" relates to any one or more of the following responses: specific immune response, nonspecific immune response, specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation and cytokine expression.

[0110] The term "isolated" when used in reference to an antibody or fragment thereof refers to a purified state, in this context, meaning that the defined molecule is substantially free of other biomolecules, such as nucleic acids, proteins, lipids, carbohydrates, or other materials, such as cell debris and growth medium. Generally, the term "isolated" does not imply the complete absence or freeness of such materials, or of water, buffers, or salts, unless such amounts substantially interfere with the experimental or therapeutic use of the binding compounds as described herein.

[0111] As used herein, "Kabat" refers to the immunoglobulin alignment and numbering system originated by Elvin A Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.).

[0112] As used herein, "monoclonal antibody" or "mAb" or "Mab" refers to a substantially homologous antibody group, i.e., an antibody molecule comprising the group, which is identical in amino acid sequence except for the presence of a small amount of possible naturally occurring mutations. In contrast, conventional (polyclonal) antibody preparations typically include a large number of different antibodies having different amino acid sequences within their variable domains, particularly in the CDRs, which are typically specific for different epitopes. The modifier "monoclonal" represents the characteristic of an antibody that is obtained from a substantially homologous antibody group and should not be construed as requiring the antibody to be produced by any ad hoc method. For example, the monoclonal antibodies used in accordance with the present disclosure can first be prepared by the hybridoma method described by Kohler et al. (1975) Nature 256:495, or by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, by Clackson et al. (1991) Nature, 352:624-628 and Marks et al. (1991) J. Mol. Biol, 222:581-597. See also Presta (2005) J. Allergy Clin. Immunol., 116:731.

[0113] "PD-1 antagonist" refers to any compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells or NKT cells), and preferably also blocks the binding of PD-L2 expressed in cancer cells to PD-1 expressed by immune cells. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the methods, compositions and uses for treating human subjects disclosed herein, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of human PD-1 and PD-L2 to human PD-1. The amino acid sequence of human PD-1 is available in NCBI Locus No.: NP_005009. The amino acid sequences of human PD-L1 and PD-L2 are available in NCBI Locus No.: NP_054862 and NP_079515, respectively.

[0114] "Pembrolizumab" (formerly known as MK-3475, SCH 900475, and lambrolizumab), alternatively referred to herein as "pembro," is a humanized IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013), including the heavy and light chain amino acid sequences and CDRs described in Table 3. Pembrolizumab is approved by the U.S. FDA as described in the prescribing information (Merck & Co., Inc., Rahway, NJ USA; initially approved in the U.S. in 2014, updated in February 2023). The term pembrolizumab includes mAbs having the structure described above (supra) but excluding the C-terminal lysine in the heavy chain.

[0115] As used herein, "pembrolizumab variant" refers to a monoclonal antibody comprising heavy and light chain sequences identical to those of pembrolizumab, except that it has three, two, or one conservative amino acid substitutions outside the light chain CDRs and six, five, four, three, two, or one conservative amino acid substitutions outside the heavy chain CDRs, e.g., the variant positions are located in the framework region or the constant region, and it optionally has a deletion of the heavy chain C-terminal lysine residue. In other words, pembrolizumab and pembrolizumab variants comprise the same CDR sequences, but differ from each other by having conservative amino acid substitutions at no more than three or six other positions in their full-length light and heavy chain sequences, respectively. Pembrolizumab variants are substantially the same as pembrolizumab with respect to the following properties: binding affinity for PD-1 and the ability to block binding of PD-L1 and PD-L2 to PD-1.

[0116] "Platinum chemotherapy" (also known as platinum-based chemotherapy) refers to the use of platinum coordination complexes as chemotherapy agents to treat cancer. Platinum-based chemotherapy agents are alkylating agents that cross-link DNA, resulting in ineffective DNA mismatch repair, often leading to apoptosis. Examples of platinum-based chemotherapy agents include cisplatin, carboplatin, and oxaliplatin.

[0117] As used herein, the term "patient" (or "subject") refers to a mammal that has been the subject of treatment, observation, or experiment. The mammal can be male or female. The mammal can be one or more selected from humans, bovines (e.g., cows), porcines (e.g., pigs), ovines (e.g., sheep), caprines (e.g., goats), equines (e.g., horses), canines (e.g., domestic dogs), felines (e.g., domestic cats), lagomorphs (rabbits), rodents (e.g., rats or mice), and raccoons (e.g., raccoons). In certain embodiments, the patient is a human.

[0118] As used herein, the term "a patient in need thereof" refers to a patient diagnosed with or suspected of having a cell proliferative disorder as defined herein, such as cancer.

[0119] The term "pharmaceutically acceptable carrier" refers to any inactive substance that is suitable for use in the formulation of a therapeutic agent. The carrier can be an anti-adherent, adhesive, coating agent, disintegrant, filler or diluent, preservative (such as an antioxidant, antibacterial or antifungal agent), sweetener, absorption delaying agent, wetting agent, emulsifier, buffer, etc. The example of a suitable pharmaceutically acceptable carrier includes water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), dextrose, vegetable oil (such as olive oil), saline, buffer, buffered saline solution, and isotonic agents, such as sugar, polyols, sorbitol, and sodium chloride.

[0120] The term "pharmaceutically acceptable salt" refers to a salt that has similar efficacy to the parent compound and is not biologically or otherwise undesirable (e.g., has neither toxicity nor other harmfulness to its receptor). Therefore, one embodiment of the present disclosure provides a pharmaceutically acceptable salt of the disclosed compounds. As used herein, the term "salt" refers to any one of the following salts: acidic salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. The salts of the disclosed compounds can be formed by methods known to those of ordinary skill in the art, such as reacting the disclosed compounds with an amount of acid or base (e.g., equivalent) in a medium (e.g., a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization.

[0121] Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthenate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. Suitable salts include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed in, for example, P. Stahl et al., Camille G. (ed.), Handbook of Pharmaceutical Salts. Properties, Selection and Use (2002) Zurich: Wiley VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1): 1-19; P. Gould, International J. of Pharmaceutics (1986) 33: 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996) Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC, website). The disclosures of these are hereby incorporated by reference.

[0122] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts of organic bases (e.g., organic amines) such as dicyclohexylamine, tert-butylamine, choline salts, and amino acid salts such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides (e.g., decyl, lauryl and stearoyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromide), and others. Compounds carrying acidic moieties can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Additionally, where acid (-COOH) or alcohol groups are present, pharmaceutically acceptable esters may be used to alter the solubility or hydrolysis characteristics of the compound.

[0123] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the disclosure and are considered equivalent to the free forms of the corresponding compounds for purposes of the disclosure.

[0124] In addition, when the compounds of the present disclosure contain both a basic moiety (such as, but not limited to, aliphatic primary, secondary, tertiary or cyclic amines, aryl or heteroaryl amines, pyridines or imidazoles) and an acidic moiety (such as, but not limited to, tetrazoles or carboxylic acids), zwitterions ("inner salts") may be formed and are included within the term "salt" as used herein. It is understood that certain compounds of the present disclosure may exist as zwitterions and have both anionic and cationic centers and a net neutral charge in the same compound. Such zwitterions are included in the present disclosure.

[0125] As used herein, "RECIST 1.1 criteria" refers to the definition of target lesions or non-target lesions as set forth in Eisenhauer, EA et al., Eur. J. Cancer 45:228-247 (2009), as appropriate based on the context of the response being measured.

[0126] When referring to a specific anti-tumor response to a treatment described herein, a "responder patient" is a patient who exhibits an anti-tumor response.

[0127] A "sustained response" refers to a persistent therapeutic effect after cessation of a treatment described herein. In some embodiments, a sustained response has a duration at least as long as the duration of treatment, or a duration at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

[0128] As used herein, the term "simultaneous administration" related to drug administration refers to administering drugs so that each drug is present in the patient's body at the same time. In addition to the concomitant administration of drugs (via the same or alternative routes), simultaneous administration can also include administering the drugs (via the same or alternative routes) at different times.

[0129] A "sustained response" refers to a therapeutic effect that persists after cessation of a treatment described herein. In some embodiments, a sustained response has a duration that is at least the same as the duration of treatment, or at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

[0130] As used herein, "treating" a cell proliferative disorder refers to administering a combination therapy of an anti-human PD-1 antibody (or antigen-binding fragment thereof) and an immunoconjugate of Formula (I) to a patient suffering from or diagnosed with a cell proliferative disorder (e.g., cancer) to achieve at least one positive therapeutic effect, such as a reduced number of cancer cells, a reduced tumor size, a reduced tumor burden, a reduced rate of cancer cell infiltration of peripheral organs, or a reduced rate of tumor metastasis or tumor growth, including administration by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. Typically, the agents of the treatment method are administered in an amount effective to alleviate one or more disease symptoms in the patient or population being treated, to any clinically measurable degree, whether by inducing regression of such symptoms or by inhibiting the progression of such symptoms. The amount of the agent effective to alleviate any particular disease symptom in the treatment method may vary according to factors such as the patient's disease state, age, and weight, and the ability of the combination therapy to elicit the desired response in the patient. Whether disease symptoms have been alleviated can be assessed by any clinical measurement commonly used by a physician or other skilled health care provider to determine the severity or progression of the symptoms. "Treatment" can include one or more of the following effects: inducing / increasing an anti-tumor immune response, reducing the amount of one or more tumor markers, stopping or delaying the growth of a tumor or blood cancer or the progression of a disease such as cancer, stabilizing the disease, inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more cancerous lesions or tumors, reducing the level of one or more tumor markers, improving or eliminating the clinical manifestations of the disease, reducing the severity or duration of clinical symptoms, prolonging the survival rate of the treated disease relative to the expected survival of a similar untreated patient, and inducing complete or partial remission of a cancerous condition, wherein the disease is cancer, more specifically, non-small cell lung cancer.

[0131] The amount of therapeutic agent effective to alleviate the symptoms of any particular disease may vary depending on factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the patient. Whether disease symptoms have subsided can be assessed by any clinical measurement commonly used by a physician or other skilled health care provider to determine the severity or progression of the symptoms.

[0132] Positive therapeutic effects in cancer can be measured in many ways (See, WA Weber, J. Nucl. Med. 50: 1S-10S (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, T / C ≤ 42% is the minimum level of anti-tumor activity. T / C < 10% is considered a high level of anti-tumor activity, where T / C (%) = median tumor volume of treated subjects / median tumor volume of reference subjects × 100. In some embodiments, the treatment achieved by the disclosed therapy is any one of PR, CR, OR, PFS, DFS, and OS. PFS, also known as "progression-free survival," represents the length of time during and after the treatment period without tumor growth, and includes the time the patient experiences CR or PR and the time the patient experiences SD. DFS refers to the length of time during and after the treatment period during which the patient remains disease-free. OS refers to an increase in life expectancy compared to a natural or untreated individual or patient. In some embodiments, the response to the disclosed therapy is any one of PR, CR, PFS, DFS, or OR as assessed using the RECIST 1.1 response criteria. The therapeutic regimen for the disclosed therapy that is effective in treating a cancer patient may vary depending on factors such as the patient's disease state, age, and weight, and the ability of the therapy to elicit an anti-cancer response in the patient. Although an embodiment of any aspect of the present disclosure may not be effective in achieving a positive therapeutic effect in every patient, it should achieve a positive therapeutic effect in a statistically significant number of patients, as determined by any statistical test known in the art, such as Student's-test, chi-square test, or the like. 2 -test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and Wilcoxon-test.

[0133] The terms "therapeutic regimen," "dosing protocol," and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination therapies of the present disclosure.

[0134] "Tumor," as it applies to a patient diagnosed with or suspected of having cancer, refers to a malignant or potentially malignant neoplasm or mass of tissue of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that does not typically contain cysts or areas of fluid. Different types of solid tumors are named after the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) do not typically form solid tumors (American Institute for Cancer Research, Dictionary of Cancer Terms).

[0135] "Tumor burden," also known as "tumor load," refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor throughout the body (including lymph nodes and bone marrow). Tumor burden can be determined by various methods known in the art, such as by measuring the size of the tumor when removed from the patient (e.g., using calipers) or while in vivo using imaging techniques (e.g., ultrasound, bone scan, CT or MRI scan).

[0136] The term "tumor size" refers to the overall size of a tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by various methods known in the art, such as by measuring the size of the tumor while removed from the patient (e.g., using calipers) or while in vivo using imaging techniques (e.g., bone scans, ultrasound, CT or MRI scans).

[0137] As used herein, "variable region" refers to the segment of the IgG chain that is variable in sequence between different antibodies. The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, alone or in combination. The variable region of the heavy chain may be referred to as "V H The variable region of the light chain may be referred to as "V L ”.

[0138] Typically, the variable regions of both the heavy and light chains contain three hypervariable regions, also known as complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FRs). The CDRs are typically arranged within the framework regions to bind to specific epitopes. Generally, from N-terminus to C-terminus, both the light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. As described herein, the light chain CDRs are CDRL1, CDRL2, and CDRL3, respectively, and the heavy chain CDRs are CDRH1, CDRH2, and CDRH3, respectively. Generally, the amino acid assignments for each domain are consistent with the definitions in: Sequences of Proteins of Immunological Interest, Kabat et al., National Institutes of Health, Bethesda, Md., 5th edition, NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem., 32: 1-75; Kabat et al. (1977) J. Biol. Chem., 252: 6609-6616; Chothia et al. (1987) J Mol. Biol., 196: 901-917; or Chothia et al. (1989) Nature, 342: 878-883.

[0139] When used in connection with an antibody (e.g., an anti-PD-1 antibody, or an anti-TROP2 antibody) or an amino acid region within the antibody, the term "variant" may refer to a peptide or polypeptide comprising one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions compared to a native or unmodified sequence. For example, a variant of an anti-PD-1 antibody may be produced by one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to the amino acid sequence of a native or previously unmodified anti-PD-1 antibody. Variants may be naturally occurring or may be artificially constructed. Polypeptide variants may be prepared from corresponding nucleic acid molecules encoding the variants. In specific embodiments, antibody variants (e.g., anti-PD-1 antibody variants) at least retain the functional activity of the antibody. In some embodiments, anti-PD-1 antibody variants bind to PD-1 and / or antagonize PD-1 activity.

[0140] When aspects or embodiments of the present disclosure are described in terms of Markush groups or other alternative groupings, the disclosure encompasses not only the entire group listed as a whole, but also each individual member of the group and all possible subgroups of the main group, as well as the main group lacking one or more members. The disclosure also contemplates the explicit exclusion of one or more of any group members in the claims.

[0141] All ranges disclosed herein are inclusive of the stated endpoints and are independently combinable (e.g., a range of "50 mg to 500 mg" includes the endpoints 50 mg and 500 mg, and all intermediate values). The endpoints of the ranges and any values ​​disclosed herein are not limited to the exact ranges or values; they are sufficiently imprecise to include values ​​approximating these ranges and / or values.

[0142] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event of conflict, the present specification, including definitions, will control. Throughout the specification and claims, the word "comprise" or variations thereof, such as "comprises" or "comprising," will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless the context requires otherwise, singular terms shall include pluralities, and plural terms shall include the singular. The term "eg" or any examples following "for example" are not intended to be exhaustive or limiting.

[0143] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0144] The following abbreviations are used herein and are defined as follows:

[0145] Additional abbreviations may be defined throughout the disclosure.

[0146] The present disclosure relates to therapeutic combinations, wherein the therapeutic combination comprises: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (b) an immunoconjugate of formula (I).

[0147] The present disclosure relates to methods of treating a cell proliferative disorder as defined herein, wherein the method comprises administering to a human patient in need thereof a combination therapy comprising (a) an anti-human PD-1 antibody (or antigen-binding fragment thereof); and (b) an immunoconjugate of formula (I).

[0148] In some embodiments of the methods and therapeutic combinations, the anti-human-PD-1 antibody is pembrolizumab, and the immunoconjugate of formula (I) is a compound of formula I.

[0149] In some preferred embodiments, the immunoconjugate of formula (I) is immunoconjugate A, which is described in U.S. Patent Publication No. 20200347075. Immunoconjugate A has the following structure:

[0150] wherein n is an integer or decimal from 1 to 8; and

[0151] Ab1 is sacituzumab.

[0152] PD-1 antagonists or anti-human PD-1 monoclonal antibodies for use in the present disclosure

[0153] Examples of mAbs that bind to human PD-1 that can be used in the methods, compositions, kits, and uses of the present disclosure are described in US 7,521,051, US 8,008,449, and US 8,354,509. Specific anti-human PD-1 mAbs that can be used as PD-1 antagonists in the methods, compositions, kits, and uses of the present disclosure include: pembrolizumab (formerly known as MK-3475, SCH 900475, and lamprolizumab), a humanized IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013), which includes the heavy and light chain amino acid sequences shown in Table 3, and humanized antibodies h409A11, h409A16, and h409A17 described in WO 2008 / 156712.

[0154] Other examples of PD-1 antagonists that can be used in the methods, compositions, kits, and uses of the present disclosure include, but are not limited to, nivolumab ( Bristol-Myers Squibb Company, Princeton, NJ, USA), cemipril imab ( Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Sanofi-Aventis US LLC., Bridgewater, NJ) and dostalimumab ( GlaxoSmithKline LLC, Philadelphia, PA).

[0155] Provided herein are PD-1 antagonists or anti-human PD-1 monoclonal antibodies that can be used in any of the methods, compositions, kits, and uses disclosed herein, including any chemical compound or biological molecule that blocks the binding of PD-L1 to PD-1 and preferably also blocks the binding of PD-L2 to PD-1.

[0156] Any monoclonal antibody that binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and its ligands PD-L1 or PD-L2 can be used. In some embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1. In other embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L2. In other embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1 and the interaction between PD-1 and PD-L2.

[0157] In certain embodiments, the anti-human PD-1 monoclonal antibody is selected from pembrolizumab, nivolumab, cemiplizumab, dostalimab, pidilizumab (US Pat. No. 7,332,582), AMP-514 (MedImmune LLC, Gaithersburg, MD), PDR001 (US Pat. No. 9,683,048), tislelizumab BGB-A317 (US Pat. No. 8,735,553), and INCMGA00012 or MGA012 (MacroGenics, Rockville, MD). In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab. In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab. In another embodiment, the anti-human PD-1 monoclonal antibody is nivolumab. In another embodiment, the anti-human PD-1 monoclonal antibody is cemiplizumab. In yet another embodiment, the anti-human PD-1 monoclonal antibody is pidilizumab. In one embodiment, the anti-human PD-1 monoclonal antibody is AMP-514. In another embodiment, the anti-human PD-1 monoclonal antibody is PDR001. In another embodiment, the anti-human PD-1 monoclonal antibody is BGB-A317. In another embodiment, the anti-human PD-1 monoclonal antibody is MGA012.

[0158] In some embodiments, the anti-human PD-1 antibodies or antigen-binding fragments thereof for use in the methods and uses disclosed herein comprise the three light chain CDRs of CDRL1, CDRL2, and CDRL3 and / or the three heavy chain CDRs of CDRH1, CDRH2, and CDRH3.

[0159] In one embodiment, CDRL1 has the amino acid sequence set forth in SEQ ID NO: 1 or a variant of the amino acid sequence set forth in SEQ ID NO: 1, CDRL2 has the amino acid sequence set forth in SEQ ID NO: 2 or a variant of the amino acid sequence set forth in SEQ ID NO: 2, and CDRL3 has the amino acid sequence set forth in SEQ ID NO: 3 or a variant of the amino acid sequence set forth in SEQ ID NO: 3.

[0160] In one embodiment of the anti-human PD-1 antibody or antigen-binding fragment thereof, CDRH1 has the amino acid sequence set forth in SEQ ID NO: 6 or a variant of the amino acid sequence set forth in SEQ ID NO: 6, CDRH2 has the amino acid sequence set forth in SEQ ID NO: 7 or a variant of the amino acid sequence set forth in SEQ ID NO: 7, and CDRH3 has the amino acid sequence set forth in SEQ ID NO: 8 or a variant of the amino acid sequence set forth in SEQ ID NO: 8.

[0161] In one embodiment of the anti-human PD-1 antibody or antigen-binding fragment thereof, the three light chain CDRs have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and the three heavy chain CDRs have the amino acid sequences shown in SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8.

[0162] In an alternative embodiment of the anti-human PD-1 antibody or antigen-binding fragment thereof, CDRL1 has the amino acid sequence set forth in SEQ ID NO: 11 or a variant of the amino acid sequence set forth in SEQ ID NO: 11, CDRL2 has the amino acid sequence set forth in SEQ ID NO: 12 or a variant of the amino acid sequence set forth in SEQ ID NO: 12, and CDRL3 has the amino acid sequence set forth in SEQ ID NO: 13 or a variant of the amino acid sequence set forth in SEQ ID NO: 13.

[0163] In one embodiment of the anti-human PD-1 antibody or antigen-binding fragment thereof, CDRH1 has the amino acid sequence set forth in SEQ ID NO: 16 or a variant of the amino acid sequence set forth in SEQ ID NO: 16, CDRH2 has the amino acid sequence set forth in SEQ ID NO: 17 or a variant of the amino acid sequence set forth in SEQ ID NO: 17, and CDRH3 has the amino acid sequence set forth in SEQ ID NO: 18 or a variant of the amino acid sequence set forth in SEQ ID NO: 18.

[0164] In an alternative embodiment of the anti-human PD-1 antibody or antigen-binding fragment thereof, the three light chain CDRs have the amino acid sequences shown in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and the three heavy chain CDRs have the amino acid sequences shown in SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18.

[0165] In a further embodiment, CDRL1 has the amino acid sequence set forth in SEQ ID NO:21 or a variant of the amino acid sequence set forth in SEQ ID NO:21, CDRL2 has the amino acid sequence set forth in SEQ ID NO:22 or a variant of the amino acid sequence set forth in SEQ ID NO:22, and CDRL3 has the amino acid sequence set forth in SEQ ID NO:23 or a variant of the amino acid sequence set forth in SEQ ID NO:23.

[0166] In another embodiment of the anti-human PD-1 antibody or antigen-binding fragment thereof, CDRH1 has the amino acid sequence set forth in SEQ ID NO: 24 or a variant of the amino acid sequence set forth in SEQ ID NO: 24, CDRH2 has the amino acid sequence set forth in SEQ ID NO: 25 or a variant of the amino acid sequence set forth in SEQ ID NO: 25, and CDRH3 has the amino acid sequence set forth in SEQ ID NO: 26 or a variant of the amino acid sequence set forth in SEQ ID NO: 26.

[0167] In another embodiment of the anti-human PD-1 antibody or antigen-binding fragment thereof, the three light chain CDRs have the amino acid sequences shown in SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23, and the three heavy chain CDRs have the amino acid sequences shown in SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26.

[0168] In a sub-embodiment of the above anti-human PD-1 embodiment, the anti-human PD-1 antibody or antigen-binding fragment is an antibody.

[0169] Some anti-human PD-1 antibodies and antigen-binding fragments disclosed herein comprise a light chain variable region and a heavy chain variable region. In some embodiments, the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 4 or a variant thereof, and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 9 or a variant thereof. In further embodiments, the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 14 or a variant thereof, and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 19 or a variant thereof. In other embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 27 or a variant of the amino acid sequence of SEQ ID NO: 27, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 28 or a variant of the amino acid sequence of SEQ ID NO: 28, the amino acid sequence of SEQ ID NO: 29 or a variant of the amino acid sequence of SEQ ID NO: 29, or the amino acid sequence of SEQ ID NO: 30 or a variant of the amino acid sequence of SEQ ID NO: 30. In these embodiments, the light chain variable region or heavy chain variable region sequence is identical to the reference sequence except for one, two, three, four, or five amino acid substitutions. In some embodiments, the substitutions are located in the framework regions (i.e., outside the CDRs). In some embodiments, the one, two, three, four, or five amino acid substitutions are conservative substitutions.

[0170] In one embodiment of the methods, kits, or uses disclosed herein, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 4, and a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 9. In another embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 14, and a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 19. In one embodiment of the compositions, methods, kits, and uses disclosed herein, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 28, and a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 27. In another embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region comprising, or consisting of, the amino acid sequence of SEQ ID NO: 29, and a heavy chain variable region comprising, or consisting of, the amino acid sequence of SEQ ID NO: 27. In yet another embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region comprising, or consisting of, the amino acid sequence of SEQ ID NO: 30, and a heavy chain variable region comprising, or consisting of, the amino acid sequence of SEQ ID NO: 27.

[0171] In yet another embodiment, the methods, kits or uses disclosed herein comprise a L domain and / or V H domain of an anti-human PD-1 antibody or antigen-binding protein, the V L domain and / or V H The domain has the same structure as the above V L domain or V H One of the domains has at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or 50% sequence identity and exhibits specific binding to PD-1. In other embodiments, the anti-human PD-1 antibody or antigen binding protein of the present method comprises V L domain and / or V H A domain having up to 1, 2, 3, 4, 5 or more amino acid substitutions and exhibiting specific binding to PD-1.

[0172] In any of the above embodiments, the PD-1 antagonist can be a full-length anti-PD-1 antibody or an antigen-binding fragment thereof that specifically binds to human PD-1. In certain embodiments, the PD-1 antagonist is a full-length anti-PD-1 antibody selected from any immunoglobulin class, including IgM, IgG, IgD, IgA, and IgE. Preferably, the anti-antibody is an IgG antibody. Any isotype of IgG can be used, including IgG1, IgG2, IgG3, and IgG4. Different constant domains can be attached to the V L and V H Region. For example, if the specific intended use of the antibodies (or fragments) disclosed herein is to require altered effector functions, heavy chain constant domains other than IgG1 may be used. Although IgG1 antibodies provide long half-life and effector functions such as recruitment activation and antibody-dependent cellular toxicity, these activities may not be desirable for all uses of the antibody. In this case, for example, an IgG4 constant domain may be used.

[0173] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of the amino acid residue sequence set forth in SEQ ID NO: 5, and a heavy chain comprising or consisting of the amino acid residue sequence set forth in SEQ ID NO: 10. In alternative embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of the amino acid residue sequence set forth in SEQ ID NO: 15, and a heavy chain comprising or consisting of the amino acid residue sequence set forth in SEQ ID NO: 20. In further embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of the amino acid residue sequence set forth in SEQ ID NO: 32, and a heavy chain comprising or consisting of the amino acid residue sequence set forth in SEQ ID NO: 31. In other embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 33 and a heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 31. In still other embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 34 and a heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 31. In some compositions, methods, kits, and uses disclosed herein, the PD-1 antagonist is nivolumab or a biosimilar of nivolumab. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is cemiplizumab. In another such embodiment, the agent is dostalimumab.

[0174] Generally, the amino acid sequence variants of the anti-PD-1 antibodies and antigen-binding fragments disclosed herein will have an amino acid sequence that is identical to the reference antibody or antigen-binding fragment (e.g., heavy chain, light chain, V chain, H 、V L or humanized sequence) have at least 75% amino acid sequence identity, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95%, 98 or 99%. Sequence identity or homology is defined herein as the percentage of amino acid residues in the candidate sequence that are identical to the anti-PD-1 residues after aligning the sequences and introducing gaps (if necessary), without considering any conservative substitutions as part of the sequence identity. N-terminal, C-terminal or internal extension deletions or insertions should not be construed as affecting sequence identity or homology.

[0175] Sequence identity refers to the degree to which the amino acids of two polypeptides are identical at equivalent positions when the two sequences are optimally aligned. Sequence identity can be determined using the BLAST algorithm, wherein the parameters of the algorithm are selected to give the maximum match between each sequence over the entire length of each reference sequence. The following references relate to BLAST algorithms that are frequently used for sequence analysis: BLAST ALGORITHMS: Altschul, SF et al. (1990) J. Mol. Biol., 215:403-410; Gish, W. et al. (1993) Nature Genet., 3:266-272; Madden, TL et al. (1996) Meth. Enzymol., 266:131-141; Altschul, SF et al. (1997) Nucleic Acids Res., 25:3389-3402; Zhang et al. (1997) Genome Res., 7:649-656; Wootton, JC et al. (1993) Comput. Chem., 17:149-163; Hancock, JM et al. (1994) Comput. Appl. Biosci., 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, MO et al., "A model of evolutionary change in proteins.", in Atlas of Protein Sequence and Structure (1978) Vol. 5, Suppl. 3, MO Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, RM et al., "Matrices for detecting distant relationships.", in Atlas of Protein Sequence and Structure, (1978) Vol. 5, Suppl. 3, MO Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, SF (1991) J. Mol. Biol., 219: 555-565; States, DJ et al. (1991) Methods, 3: 66-70; Henikoff, S. et al. (1992) Proc. Natl. Acad. Sci. USA, 89: 10915-1919; Altschol, SF et al. (1993) J. Mol. Evol., 36:290-300; ALIGNMENT STATISTICS: Karlin, S. et al. (1990) Proc. Natl. Acad. Sci. USA, 87:2264-2268; Karlin, S. et al. (1993) Proc. Natl. Acad. Sci. USA, 90:5873-5877; Dembo, A. et al. (1994) Ann. Prob., 22:2022-2039; and Altschul, SF, “Evaluating the statistical significance of multiple distinct local alignments.”, In Theoretical and Computational Methods in Genome Research (S. Suhai, ed.) (1997), pp. 1-14, Plenum, New York.

[0176] Likewise, any class of light chain can be used in the compositions and methods herein. Specifically, kappa, lambda, or variants thereof can be used in the compositions of the invention and the compositions, methods, kits, and uses disclosed herein.

[0177] Table 3. Exemplary PD-1 antibody sequences

[0178] Table 4. Other PD-1 antibodies and antigen-binding fragments useful in the methods and uses disclosed herein.

[0179] In embodiments of the therapeutic combinations, pharmaceutical compositions, methods, kits, and uses disclosed herein, the anti-human PD-1 antibody (or its antigen-binding fragment) is an anti-PD-1 monoclonal antibody. In some specific aspects of these embodiments, the anti-human PD-1 antibody (or its antigen-binding fragment) is selected from nivolumab, pembrolizumab, pidilizumab, and AMP-224. In some specific aspects of these embodiments, the anti-human PD-1 antibody (or its antigen-binding fragment) is selected from nivolumab and pembrolizumab. In a more specific aspect, the anti-human PD-1 antibody (or its antigen-binding fragment) is nivolumab. In another more specific aspect, the anti-human PD-1 antibody (or its antigen-binding fragment) is pembrolizumab.

[0180] In embodiments of the therapeutic combinations, methods, kits, and uses disclosed herein, the anti-human PD-1 antibody is pembrolizumab. In other such embodiments, the anti-human PD-1 antibody is nivolumab. In other such embodiments, the anti-human PD-1 antibody is pidilizumab. In other such embodiments, the anti-human PD-1 antibody is tislelizumab. In other such embodiments, the anti-human PD-1 antibody is AMP-514. In other such embodiments, the anti-human PD-1 antibody is cemiplizumab. In other such embodiments, the anti-human PD-1 antibody is dostalimumab.

[0181] Immunoconjugate of formula (I)

[0182] The immunoconjugates useful in the present disclosure are those of formula (I):

[0183] wherein Ab is an antibody that binds to Trop-2; and

[0184] n is an integer from 1 to 10.

[0185] In certain embodiments, the immunoconjugates useful in the present disclosure are immunoconjugates of formula (I):

[0186] where n is an integer from 1 to 10; and

[0187] Ab is an antibody that binds to Trop-2, which comprises:

[0188] (i) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 39; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and

[0189] (ii) a light chain variable region comprising LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0190] In certain embodiments, the immunoconjugates useful in the present disclosure are immunoconjugates of formula (I):

[0191] where n is an integer from 1 to 10; and

[0192] Ab is an antibody that binds to Trop-2 and includes:

[0193] (a) a heavy chain variable region having the amino acid sequence of SEQ ID No: 37; and

[0194] (b) A light chain variable region having the amino acid sequence of SEQ ID No: 38.

[0195] In certain embodiments, the immunoconjugates useful in the present disclosure are immunoconjugates of formula (I):

[0196] where n is an integer from 1 to 10; and

[0197] Ab is an antibody that binds to Trop-2 and includes:

[0198] (i) a heavy chain variable region having the amino acid sequence of SEQ ID No: 35; and

[0199] (ii) a light chain variable region having the amino acid sequence of SEQ ID No: 36.

[0200] In a preferred embodiment, the immunoconjugate of formula (I) is immunoconjugate A, which is described in U.S. Patent Publication No. 20200347075. Immunoconjugate A has the following structure:

[0201] where n is an integer from 1 to 8; and

[0202] Ab1 is taciturnumab.

[0203] In other preferred embodiments, a composition comprising an immunoconjugate of formula (I) is administered, wherein

[0204] The DAR of the composition is an integer or decimal from 0 to 8, and

[0205] Ab1 is taciturnumab.

[0206] In certain embodiments, the DAR of the composition is an integer or decimal of 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 9-10. In some embodiments, the DAR of the composition is an integer or decimal of 1-8, 1-4, 2-5, 3-6, 4-7, 5-8, or 6-8. In some embodiments, the DAR of the composition is an integer or decimal of 1-3, 2-4, 3-5, 4-6, 5-7, or 6-8. In some embodiments, the DAR of the composition is an integer or decimal of 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8. In some embodiments, the DAR of the composition is an integer or decimal of 5-8.

[0207] In some embodiments, the composition has a DAR of 5.1, 5.2, 5.3, 5.4, 5.5, 5.5, 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, 7.9, 8.0.

[0208] In some embodiments of the present disclosure, the anti-Trop-2 antibody of the immunoconjugate of formula (I) is saccharotuzumab (or hRS7), which is described in U.S. Patent Publication No. 2012 / 0237518. This antibody can also be obtained by screening from a vector design and construction of an antibody library displaying the antibody, which is disclosed in CN103476941A, or by screening Sorrento Therapeutics, Inc. library.

[0209] Table 5 shows the SEQ ID NOs of the heavy and light chain complementarity determining regions (HCDR and LCDR), heavy and light chain variable domains (VH and VL), and amino acid sequences of the heavy and light chains (HC and LC) of taciturn.

[0210] Table 5 Amino acid sequence list of Taciturn ("Ab1")

[0211] In certain embodiments, the immunoconjugate of formula (I) comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 linkers / drug moieties per antibody (i.e., n is 1-10). In certain embodiments, the immunoconjugate of formula (I) comprises one or more (e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2) linkers / drug moieties.

[0212] In a specific embodiment, the immunoconjugate of Formula (I) comprises about 6 to about 8 linker / drug moieties per antibody (i.e., n is about 6 to about 8). In a specific embodiment, the immunoconjugate of Formula (I) is immunoconjugate A, and n is 6-8.

[0213] The immunoconjugate of formula (I) comprises an antibody or fragment thereof that is specific for human TROP-2 and is therefore an excellent targeting moiety for delivering conjugated payloads to cells (e.g., TROP-2 positive cells). In certain embodiments, the immunoconjugate used in the disclosed therapeutic regimens is any anti-TROP-2 immunoconjugate described in U.S. Patent Publication No. 20200347075.

[0214] Uses of the disclosed combination therapy

[0215] Treatment or prevention of cell proliferative disorders

[0216] The combination therapies disclosed herein are potentially useful for treating diseases or conditions including, but not limited to, cell proliferative disorders. Cell proliferative disorders include, but are not limited to, cancer, benign papillomatous hyperplasia, and gestational trophoblastic disease. The terms "cancer," "cancerous," or "malignant" refer to or describe the physiological condition in mammals that is characterized by unregulated cell growth.

[0217] Thus, in one aspect, the present disclosure relates to a method of treating a cell proliferative disorder, comprising administering to a patient in need thereof a combination therapy comprising (a) an anti-human PD-1 antibody (or antigen-binding fragment thereof); and (b) an immunoconjugate of formula (I), wherein the amounts administered are such that together they are effective to treat the cell proliferative disorder.

[0218] In some embodiments, the present disclosure relates to a method for treating a cell proliferative disorder, comprising administering to a patient in need thereof a combination therapy comprising (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof), a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKIs); and (b) an immunoconjugate of formula (I), wherein the amounts administered are such that the above-mentioned components (a) and (b) together are effective to treat the cell proliferative disorder.

[0219] In some embodiments, the present disclosure provides a kit comprising:

[0220] (a) an immunoconjugate of formula (I); and

[0221] (b) anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0222] In some embodiments, the present disclosure provides a kit comprising:

[0223] (a) an immunoconjugate of formula (I); and

[0224] (b) anti-human PD-1 antibody or antigen-binding fragment thereof.

[0225] In embodiment 1 of the kit, the kit further comprises instructions for administering the immunoconjugate of formula (I) and the anti-human PD-1 antibody or antigen-binding fragment thereof to a human patient.

[0226] In some embodiments, the present disclosure provides a combination for treating a cell proliferative disorder, such as cancer, in a human patient comprising:

[0227] (a) an immunoconjugate of formula (I); and

[0228] (b) cell proliferative disorders treated with anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0229] In some embodiments, the present disclosure provides a combination for treating a cell proliferative disorder, such as cancer, in a human patient comprising:

[0230] (a) an immunoconjugate of formula (I); and

[0231] (b) Cell proliferative disorders involving anti-human PD-1 antibodies or antigen-binding fragments thereof.

[0232] In some embodiments, the present disclosure provides a pharmaceutical combination for treating a cell proliferative disorder, such as cancer, in a human patient, comprising:

[0233] (a) an immunoconjugate of formula (I); and

[0234] (b) cell proliferative disorders treated with anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0235] In some embodiments, the present disclosure provides a pharmaceutical combination for treating a cell proliferative disorder, such as cancer, in a human patient, comprising:

[0236] (a) an immunoconjugate of formula (I); and

[0237] (b) Cell proliferative disorders involving anti-human PD-1 antibodies or antigen-binding fragments thereof.

[0238] In some embodiments, the present disclosure provides a use of a pharmaceutical combination for the preparation of a medicament for treating a cell proliferative disorder, such as cancer, in a human patient, the pharmaceutical combination comprising:

[0239] (a) an immunoconjugate of formula (I); and

[0240] (b) cell proliferative disorders treated with anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0241] In some embodiments, the present disclosure provides a use of a pharmaceutical combination for the preparation of a medicament for treating a cell proliferative disorder, such as cancer, in a human patient, the pharmaceutical combination comprising:

[0242] (a) an immunoconjugate of formula (I); and

[0243] (b) anti-human PD-1 antibody or antigen-binding fragment thereof.

[0244] In some embodiments, the pharmaceutical combination or kit comprises:

[0245] (a) an immunoconjugate of formula (I); and

[0246] (b) anti-human PD-1 antibody or antigen-binding fragment thereof.

[0247] In some embodiments, the pharmaceutical combination or kit comprises:

[0248] (a) an immunoconjugate of formula (I);

[0249] (b) an anti-human PD-1 antibody or an antigen-binding fragment thereof; and

[0250] (c) Platinum-containing chemotherapeutic agents.

[0251] In some embodiments, the pharmaceutical combination or kit comprises:

[0252] (a) an immunoconjugate of formula (I); and

[0253] (b) Platinum-containing chemotherapeutic agents.

[0254] In some embodiments, the pharmaceutical combination or kit comprises:

[0255] (a) an immunoconjugate of formula (I); and

[0256] (b) EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

[0257] In some embodiments, the platinum-containing chemotherapeutic agent is carboplatin or cisplatin; preferably carboplatin.

[0258] In some embodiments, the EGFR-tyrosine kinase inhibitor is osimertinib.

[0259] In some embodiments, the cell proliferative disorder is non-small cell lung cancer.

[0260] In some embodiments, the non-small cell lung cancer is EGFR wild-type; in some embodiments, the non-small cell lung cancer is EGFR mutant.

[0261] In some embodiments, the non-small cell lung cancer is ALK fusion gene negative non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is ALK fusion gene positive non-small cell lung cancer.

[0262] In some embodiments, the non-small cell lung cancer is squamous cell carcinoma; in some embodiments, the non-small cell lung cancer is non-squamous cell carcinoma.

[0263] In some embodiments, the non-small cell lung cancer has an elevated PD-L1 expression level, for example, a tumor proportion score (TPS) ≥ 1%, or a TPS of 1%-49%, or a TPS ≥ 50%.

[0264] In some embodiments, the non-small cell lung cancer has no elevated PD-L1 expression level, for example, has a tumor proportion score (TPS) of <1%.

[0265] In some embodiments, the non-small cell lung cancer has a 19del mutation and / or a 21L858R mutation.

[0266] In some embodiments, the non-small cell lung cancer has central nervous system metastases; in some embodiments, the non-small cell lung cancer does not have central nervous system metastases.

[0267] In some embodiments, the non-small cell lung cancer has not received treatment, has received first-line treatment, has received two or more lines of treatment, or has received three or more lines of treatment.

[0268] In some embodiments, the non-small cell lung cancer has been previously treated with only first-generation EGFR TKIs and not with second-generation or third-generation EGFR TKIs.

[0269] In some embodiments, the non-small cell lung cancer has been previously treated with only first-generation or second-generation EGFR TKIs and has not been treated with third-generation EGFR TKIs.

[0270] In some embodiments, the non-small cell lung cancer has been previously treated with a third generation EGFR TKI.

[0271] In some embodiments, the non-small cell lung cancer is EGFR wild-type and ALK fusion gene negative non-small cell lung cancer.

[0272] In some embodiments, the non-small cell lung cancer is an EGFR-mutated non-small cell lung cancer that has failed previous EGFR-TKI treatment.

[0273] In some embodiments, the non-small cell lung cancer is EGFR wild-type squamous cell carcinoma.

[0274] In some embodiments, the non-small cell lung cancer is an EGFR wild-type non-squamous cell lung cancer.

[0275] In some embodiments, the non-small cell lung cancer is EGFR wild-type and has a TPS < 1%.

[0276] In some embodiments, the non-small cell lung cancer is EGFR wild-type and has a TPS of 1%-49%.

[0277] In some embodiments, the non-small cell lung cancer is EGFR wild-type and has a TPS of ≥50%.

[0278] In some embodiments, the non-small cell lung cancer is EGFR mutant and has previously failed treatment with first-generation or second-generation EGFR TKIs.

[0279] In some embodiments, the non-small cell lung cancer is EGFR mutant and has previously failed treatment with a third-generation EGFR TKI.

[0280] In some embodiments, the non-small cell lung cancer is EGFR mutant and has central nervous system metastasis.

[0281] In some embodiments, the non-small cell lung cancer is EGFR mutant and has no central nervous system metastasis.

[0282] In certain embodiments, the cell proliferative disorder is selected from cancer, benign papillomatous hyperplasia, benign neoplastic disease, and gestational trophoblastic disease. In specific embodiments, the gestational trophoblastic disease is selected from hydatidiform mole and gestational trophoblastic tumor (e.g., invasive hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor).

[0283] In a specific embodiment, the cell proliferative disorder being treated is cancer. Thus, in one embodiment, provided herein is a method of treating cancer in a patient, the method comprising administering to the patient a combination therapy comprising (a) an anti-human PD-1 antibody (or antigen-binding fragment thereof); and (b) an immunoconjugate of formula (I), wherein the amounts administered are such that together they are effective in treating the cancer.

[0284] In a specific embodiment, the amount administered is effective to treat cancer in a human patient. In another specific embodiment, the amount administered is effective to inhibit the replication of cancer cells or the metastasis of cancer cells in a patient.

[0285] In one embodiment, the cancer is metastatic. In another embodiment, the cancer is recurrent. In another embodiment, the cancer is refractory. In yet another embodiment, the cancer is both recurrent and refractory.

[0286] In one embodiment, the patient has previously received treatment for cancer. In another embodiment, the patient has not previously received treatment for cancer.

[0287] In one embodiment, the patient has previously received systemic treatment for the cancer. In another embodiment, the patient has not previously received systemic treatment for the cancer.

[0288] In other embodiments, the cancer is present in an adult patient; in other embodiments, the cancer is present in a pediatric patient.

[0289] The compositions, methods, kits and uses provided herein can be used to treat cancer. Cancers that can be treated using the compositions, methods, kits and uses disclosed herein include, but are not limited to: (1) Cardiac: sarcomas (angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; (2) Lung: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma, non-small cell; (3) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, type II ... (4) Genitourinary tract: kidney (adenocarcinoma, Wilms' tumor [Nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), and urothelial carcinoma; (5) Liver: hepatocytes. (6) Bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondral tumor (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid and giant cell tumor; (7) Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, reproductive (8) Gynecological: uterus (endometrial cancer), cervix (cervical cancer, preeclampsia or cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulocyte tumor, Severe-Leyden cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma), breast cancer;(9) Hematologic: Hematologic (myeloid leukemia [acute and chronic], acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelomonocytic (CMML), myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, lipoma, hemangioma, fibroma, keloid, psoriasis; and (11) Adrenal: neuroblastoma. Examples of cancers that can be treated using the compounds, compositions, and methods described herein include thyroid cancer, anaplastic thyroid cancer, epidermal cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), sarcoma, tetracarcinoma, liver cancer, and multiple myeloma.

[0290] As used herein, the term "cancer cell" includes any cell affected by any of the above-mentioned diseases.

[0291] In a specific embodiment, the cancer being treated is selected from the group consisting of non-small cell lung cancer, prostate cancer, ovarian cancer, cervical cancer, or urothelial cancer. In a specific embodiment, the cancer is selected from the group consisting of non-small cell lung cancer, recurrent cervical cancer, metastatic cervical cancer, locally advanced urothelial cancer, metastatic urothelial cancer, platinum-sensitive recurrent ovarian cancer, or metastatic castration-resistant prostate cancer.

[0292] In one embodiment, provided herein are methods of treating unresectable or metastatic melanoma in a human patient. In some embodiments, the methods comprise treating resected high-risk stage III melanoma.

[0293] In certain embodiments, the cancer is selected from lung cancer. In specific embodiments, the lung cancer is selected from non-small cell lung cancer, bronchogenic carcinoma, and pleuropulmonary blastoma.

[0294] In one embodiment, provided herein is a method for treating metastatic non-small cell lung cancer (NSCLC) in a human patient. In some embodiments, the NSCLC is non-squamous. In other embodiments, the NSCLC is squamous. In certain embodiments of the method for treating NSCLC, the patient's tumor has no EGFR or ALK genomic aberrations. In certain embodiments of the method for treating NSCLC, the patient's tumor has EGFR or ALK genomic aberrations and has disease progression before receiving the combined therapy described herein, while receiving treatment for EGFR or ALK aberrations or after. In a specific embodiment, the treated NSCLC has no EGFR mutations and ALK fusion genes. In a specific embodiment, the treated NSCLC has an EGFR actionable mutation, and the patient has failed previous EGFR-TKI treatment. In another specific embodiment, the non-small cell lung cancer has a 19del mutation and / or has a 21L858R mutation. In another specific embodiment, the non-small cell lung cancer is non-small cell lung cancer with an EGFR actionable mutation, and the patient has previously failed EGFR-TKI treatment and has previously failed PD-1 / PD-L1 antibody treatment and chemotherapy.

[0295] In a specific embodiment, the cancer is selected from malignant mesothelioma.In a specific embodiment, the cancer is selected from epithelial mesothelioma and sarcoid.

[0296] In one embodiment, provided herein are methods for treating refractory and classical Hodgkin lymphoma (cHL) in a human patient. In certain embodiments, the patient has relapsed after 1, 2, 3, or more lines of treatment for cHL. In specific embodiments, the patient is an adult patient. In alternative embodiments, the patient is a pediatric patient.

[0297] In one embodiment, provided herein are methods for treating urothelial carcinoma in a human patient. In certain embodiments, the urothelial carcinoma is locally advanced or metastatic urothelial carcinoma. In certain embodiments, the patient is not suitable for cisplatin-containing chemotherapy. In further embodiments, the patient has disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. In specific embodiments, the patient's tumor expresses PD-L1 (CPS ≥ 10).

[0298] In one embodiment, provided herein are methods for treating unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors in human patients. In specific embodiments, the patient has disease progression after previous anticancer therapy.

[0299] In one embodiment, provided herein are methods for treating unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient colorectal cancer in a human patient. In a specific embodiment, the patient has disease progression following prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

[0300] In one embodiment, provided herein is a method for treating recurrent locally advanced or metastatic gastric cancer or recurrent locally advanced or metastatic gastroesophageal junction adenocarcinoma in a human patient. In a specific embodiment, the patient's tumor expresses PD-L1 [combined positive score (CPS) ≥ 1]. In some embodiments, the patient has disease progression while or after receiving two or more lines of treatment including fluoropyrimidine-containing and platinum-containing chemotherapy. In some embodiments, the patient has disease progression while or after receiving two or more lines of treatment including HER2 / neu targeted therapy.

[0301] In certain embodiments, the cancer is selected from lymphoma. In specific embodiments, the cancer is selected from Hodgkin lymphoma (e.g., refractory classical Hodgkin lymphoma), non-Hodgkin lymphoma, and cutaneous T-cell lymphoma.

[0302] In one embodiment, provided herein are methods for treating non-Hodgkin lymphoma (NHL) in a human patient. In one embodiment, the NHL is a low-grade lymphoma. In another embodiment, the NHL is a high-grade lymphoma. In certain embodiments, the NHL is selected from the group consisting of primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma, mycosis fungoides, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodular marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Sezary syndrome syndrome, primary central nervous system lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, anaplastic large cell lymphoma (primary cutaneous), anaplastic large cell lymphoma (systemic), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma / leukemia, extranodal NK / T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, gamma / delta splenic T-cell lymphoma, subcutaneous panniculitis-like T-cell, and Burkitt lymphoma.

[0303] In one embodiment, provided herein are methods of treating cancer in a human patient, including wherein the patient has a tumor with a high mutational burden.

[0304] In a specific embodiment, the cancer is selected from brain cancer and spinal cancer. In a specific embodiment, the brain cancer and spinal cancer are selected from anaplastic astrocytoma, glioblastoma, astrocytoma and neuroblastic neuroblastoma (also known as olfactory blastoma). In a specific embodiment, the brain cancer is selected from astrocytoma (e.g., pilocytic astrocytoma, pituitary giant cell astrocytoma, diffuse astrocytoma, multiform xanthoastrocytoma, anaplastic astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma and primary pediatric glioblastoma), oligodendroglioma (e.g., oligodendroglioma and anaplastic oligodendroglioma ), oligoastrocytoma (e.g., oligoastrocytoma and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, brain cell tumor / malignant glioma, visual pathway and hypothalamic glioma, and primary central nervous system lymphoma. In the particular case of these embodiments, the brain cancer is selected from glioma, glioblastoma multiforme, paraganglioma and suprabasal protoneurodermal tumor (sPNET). In one embodiment, the brain cancer or spinal cancer is a metastatic brain tumor or tumor.

[0305] In a specific embodiment, the cancer is selected from head and neck cancer, including recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, hypopharyngeal cancer, oral cancer (e.g., squamous cell carcinoma, lymphoma and sarcoma), lip cancer, oropharyngeal cancer, salivary gland cancer, cancer of the larynx (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma) and cancer of the eye or eye cancer. In a specific embodiment, the eye cancer is selected from intraocular melanoma and retinoblastoma. In one embodiment, provided herein is a method for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in a human patient. In some embodiments, the patient has previously received platinum-containing chemotherapy. In certain embodiments, the patient has disease progression during or after platinum-containing chemotherapy.

[0306] In a specific embodiment, the cancer is selected from leukemia and blood cancer. In a specific embodiment, the cancer is selected from myeloproliferative neoplasms, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), post-MPN AML, post-MDS AML, del (5q)-associated high-risk MDS or AML, blast stage chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langers cell histiocytosis, hairy cell leukemia and plasma cell neoplasms including plasmacytoma and multiple myeloma. The leukemia mentioned herein can be acute or chronic.

[0307] In certain embodiments, the cancer is selected from skin cancer. In certain embodiments, the skin cancer is selected from melanoma, squamous cell carcinoma, and basal cell carcinoma. In specific embodiments, the skin cancer is unresectable or metastatic melanoma.

[0308] In certain embodiments, the cancer is selected from cancers of the reproductive system. In specific embodiments, the cancer is selected from breast cancer, cervical cancer, vaginal cancer, ovarian cancer, endometrial cancer, prostate cancer, penile cancer, and testicular cancer. In certain examples of these embodiments, the cancer is a breast cancer selected from ductal carcinoma and phyllodes tumor. In certain examples of these embodiments, the breast cancer can be male breast cancer or female breast cancer. In some cases of these embodiments, the breast cancer is triple-negative breast cancer. In other cases, the breast cancer is ER+ / HER2- breast cancer. In certain examples of these embodiments, the cancer is cervical cancer selected from squamous cell carcinoma and adenocarcinoma.

[0309] In a specific embodiment, the cancer is selected from cancers of the gastrointestinal system. In a specific embodiment, the cancer is selected from esophageal cancer, gastric cancer (also referred to as gastric cancer), gastrointestinal carcinoid tumors, pancreatic cancer, gallbladder cancer, colorectal cancer and anal cancer. In the case of these embodiments, the cancer is selected from esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphoma, gastrointestinal lymphoma, solid pseudopapillary tumors of the pancreas, pancreatic blastoma, islet cell tumors, pancreatic cancer including acinar cell carcinoma and ductal adenocarcinoma, gallbladder adenocarcinoma, colorectal adenocarcinoma, microsatellite stable colorectal cancer, late microsatellite stable colorectal cancer, metastatic microsatellite stable colorectal cancer and anal squamous cell carcinoma.

[0310] In certain embodiments, the cancer is selected from liver cancer and bile duct cancer. In certain embodiments, the cancer is liver cancer (also known as hepatocellular carcinoma). In certain embodiments, the cancer is bile duct cancer (also known as cholangiocarcinoma); in the case of these embodiments, bile duct cancer is selected from intrahepatic bile duct cancer and extrahepatic bile duct cancer.

[0311] In a specific embodiment, the cancer is selected from kidney cancer and bladder cancer. In a specific embodiment, the cancer is a kidney cancer selected from renal cell carcinoma, Wilms' tumor, and transitional cell carcinoma. In a specific embodiment, the cancer is a bladder cancer selected from urothelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0312] In a particular embodiment, the cancer is selected from bone cancer. In a specific embodiment, the bone cancer is selected from osteosarcoma, malignant fibrous histiocytoma of bone, Ewing's sarcoma, chordoma (cancer of the bones along the spine).

[0313] In a particular embodiment, the cancer is selected from a sarcoma. In a specific embodiment, the sarcoma is selected from a central chondrosarcoma, a central and periosteal chondrocytoma, a fibrosarcoma, a clear cell sarcoma of the tendon sheath, and a Kaposi's sarcoma.

[0314] In certain embodiments, the cancer is selected from adenocarcinoma.In specific embodiments, the cancer is selected from adrenocortical carcinoma, pheochromocytoma, paraganglioma, pituitary tumor, thymoma and thymic carcinoma.

[0315] In a specific embodiment, the cancer is selected from thyroid cancer.In a specific embodiment, the thyroid cancer is selected from medullary thyroid cancer, papillary thyroid cancer, and follicular thyroid cancer.

[0316] In certain embodiments, the cancer is selected from a germ cell tumor. In specific embodiments, the cancer is selected from a malignant extracranial germ cell tumor and a malignant extragonadal germ cell tumor. In specific instances of these embodiments, the malignant extragonadal germ cell tumor is selected from a non-seminoma and a seminoma.

[0317] In a particular embodiment, the cancer is selected from cardiac tumors. In a specific embodiment, the cardiac tumor is selected from malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0318] In embodiments, the cancer is a metastatic tumor, such as liver metastases from colorectal or pancreatic cancer; and brain metastases from lung or breast cancer.

[0319] In some embodiments, the cancer shows high expression of PD-L1 [(Tumor Proportion Score (TPS) ≥ 50%)] and has not been previously treated with platinum-containing chemotherapy. In alternative embodiments, the patient has a tumor that expresses PD-L1 (TPS ≥ 1%) and has been previously treated with platinum-containing chemotherapy. In specific embodiments, the patient has had disease progression while or after receiving platinum-containing chemotherapy.

[0320] In certain embodiments, the PD-L1 TPS is determined by an FDA-approved test.

[0321] In certain embodiments, the cancer is classified as a stage III cancer or a stage IV cancer. In some instances of these embodiments, the cancer is unresectable.

[0322] Administration and dosage

[0323] The present disclosure relates to methods for treating cell proliferative disorders, comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof), a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKIs); and (b) an immunoconjugate of formula (I), wherein the amounts administered are effective together to treat or prevent the cell proliferative disorder.

[0324] The present disclosure relates to methods of treating a cell proliferative disorder, comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or antigen-binding fragment thereof); and (b) an immunoconjugate of formula (I), wherein the amounts administered are such that together they are effective to treat or prevent the cell proliferative disorder.

[0325] The immunoconjugate of formula (I) and the anti-human PD-1 antibody (or its antigen-binding fragment) are each (together with a pharmaceutically acceptable carrier or excipient) typically formulated into a dosage form suitable for administration to a patient via a desired route of administration. For example, dosage forms include those suitable for (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable carriers or excipients will vary depending on the specific dosage form selected. In addition, suitable pharmaceutically acceptable carriers or excipients may be selected to perform a specific function in the composition. In embodiments, the immunoconjugate of formula (I) and / or the anti-human PD-1 antibody (or its antigen-binding fragment) may be formulated into a dosage form that allows systemic use, i.e., distribution within the patient's body; examples of such systemic administration include oral administration, intravenous administration, and subcutaneous administration. In other embodiments, the immunoconjugate of formula (I), the anti-human PD-1 antibody (or its antigen-binding fragment), platinum-containing chemotherapeutic agent, and / or EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can be formulated into a dosage form that allows for targeted or separate use, i.e., the immunoconjugate of formula (I) and / or the anti-human PD-1 antibody (or its antigen-binding fragment) is administered only to the part of the patient's body to be treated; examples of such targeted administration include intratumoral injection.

[0326] In some embodiments, at least one therapeutic agent in the combination therapy (the anti-PD-1 antibody or its binding fragment, and the immunoconjugate of Formula (I)) is administered using the same dosage regimen (therapeutic dose, frequency and duration) that is typically used when the agent is used as a monotherapy for the same condition. In other embodiments, the patient receives a lower total amount of at least one therapeutic agent in the combination therapy than when the agent is used as a monotherapy, for example, a smaller dose, a lower dosing frequency and / or a shorter treatment duration.

[0327] In embodiments of the compositions, methods, kits, and uses disclosed herein, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered by intravenous infusion or subcutaneous injection, and the immunoconjugate of formula (I) is administered by intravenous infusion or subcutaneous injection. In specific embodiments, the anti-human PD-1 antibody (or antigen-binding fragment thereof) and the immunoconjugate of formula (I) are each administered by intravenous infusion.

[0328] When administering the combination therapy of the present disclosure to a patient, the agents comprising the combination may be administered in any order, such as sequentially, synchronously, together, simultaneously, etc. In such a combination therapy, the amounts of the various agents may be different amounts (different doses) or the same amount (same dose). Thus, for non-limiting illustrative purposes, the immunoconjugate of formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) may be present in a fixed amount (dose) in a single dosage unit.

[0329] In one embodiment, the immunoconjugate of formula (I) is administered during a time period when the anti-human PD-1 antibody (or antigen-binding fragment thereof) exerts its prophylactic or therapeutic effect, or vice versa.

[0330] In another embodiment, the immunoconjugate of formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) are administered at doses commonly used when such agents are used as monotherapy for treating cancer.

[0331] In another embodiment, the immunoconjugate of formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) are administered at doses lower than those typically used when such agents are used as monotherapy for treating cancer.

[0332] In another embodiment, the immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) act synergistically and are administered at doses lower than those typically used when such agents are used as monotherapy for treating cancer.

[0333] The immunoconjugate of formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) can act additively or synergistically. A synergistic combination can allow one or both of these agents to be used at lower doses and / or to be administered less frequently. Lower doses or less frequent administration of these drugs can reduce the toxicity of the therapy without reducing the efficacy of the therapy.

[0334] In one embodiment, administration of an immunoconjugate of Formula (I) and an anti-human PD-1 antibody (or antigen-binding fragment thereof) inhibits cancer resistance to one or both of these agents.

[0335] In some embodiments, the combination therapy of the present disclosure is administered for a period of time until the patient shows no symptoms of the disease or condition. In some embodiments, the combination therapy of the present disclosure is administered for a period of time until the patient is cured of the disease or condition. In some embodiments, the combination therapy of the present disclosure is administered for a period of time until the patient shows resistance to the therapy. In some embodiments, the combination therapy of the present disclosure is administered for a period of time until the patient shows side effects that require termination of therapy.

[0336] In some embodiments, the patient is fasted for at least 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, or 12 hours prior to administration of one or more components of the combination therapy. In some embodiments, the patient is fasted for at least 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, or 12 hours after administration of one or more components of the combination therapy.

[0337] The disclosed combination therapies can be used before or after tumor resection surgery, and can be used before, during, or after radiation therapy.

[0338] In some embodiments, the combination therapy of the present disclosure is administered to a patient who has not been previously treated with a biological or chemotherapeutic agent, i.e., a patient who has never been treated with a In other embodiments, the combination therapy is administered to patients who have not achieved a durable response to previous treatment with the biologic or chemotherapeutic agent, ie, treatment-experienced patients.

[0339] Products provided as a therapeutic combination may include a composition comprising an anti-human PD-1 antibody (or antigen-binding fragment thereof) and a composition comprising an immunoconjugate of formula (I) in separate forms, such as a kit or any form designed to be administered separately in a simultaneous or separate dosing schedule.

[0340] In some embodiments, the dosage of the drug is 50 mg to 500 mg, 50 mg to 450 mg, 50 mg to 400 mg, 50 mg to 350 mg, 50 mg to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 500 mg, 100 mg to 450 mg, 100 mg to 400 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, 100 mg to 150 mg, 150 mg to 500 mg, 150 mg to 450 mg, 150 mg to 400 mg, 150 mg to 350 mg, 150 mg to 300 mg, 150 mg to 250 mg, 150 mg to 20 or an antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered to the patient at a dose of 200 mg to 400 mg.

[0341] In some embodiments, the anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is administered subcutaneously or intravenously at a dose of about 10, about 20, about 50, about 80, about 100, about 200, about 300, about 400, about 500, about 1000, or about 2500 mg / patient weekly, biweekly, three-weekly, four-weekly, five-weekly, six-weekly, monthly, bimonthly, or quarterly.

[0342] In some specific methods, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is about 0.01 mg / kg to about 50 mg / kg, about 0.05 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.2 mg / kg to about 9 mg / kg, about 0.3 mg / kg to about 8 mg / kg, about 0.4 mg / kg to about 7 mg / kg, about 0.5 mg / kg to about 6 mg / kg, about 0.6 mg / kg to about 5 mg / kg, about 0.7 mg / kg to about 4 mg / kg, about 0.8 mg / kg to about 3 mg / kg, about 0.9 mg / kg to about 2 mg / kg, about 1.0 mg / kg to about 1.5 mg / kg, about 1.0 mg / kg to about 2.0 mg / kg, about 1.0 mg / kg to about 3.0 mg / kg, or about 2.0 mg / kg to about 4.0 mg / kg.

[0343] In some specific methods, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 150 mg to about 250 mg, about 175 mg to about 250 mg, about 200 mg to about 250 mg, about 150 mg to about 240 mg, about 175 mg to about 240 mg, or about 200 mg to about 240 mg. In some embodiments, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.

[0344] In another embodiment, the PD-1 antagonist in this therapy is pembrolizumab or a pembrolizumab variant, which is administered in a liquid medication at a dose selected from 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / kg Q2W, 5 mg / kg Q2W, 10 mg / kg Q2W, 1 mg / kg Q3W, 2 mg / kg Q3W, 3 mg / kg Q3W, 5 mg / kg Q3W, or 10 mg / kg Q3W. In other embodiments, the PD-1 antagonist in this therapy is pembrolizumab or a pembrolizumab variant, which is administered in a liquid medication at a fixed dose, for example, 200 mg Q3W or 400 mg Q6W.

[0345] In some embodiments, the PD-1 antagonist in this therapy is pembrolizumab, which is administered at a dose and frequency of 400 mg Q6W.

[0346] In some embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or an antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg of pembrolizumab once every three weeks or six weeks. In one embodiment, the human patient is administered about 200 mg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered about 240 mg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered 2 mg / kg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered 400 mg of pembrolizumab once every six weeks.

[0347] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered 200 mg of pembrolizumab once every three weeks.

[0348] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered 400 mg of pembrolizumab once every six weeks.

[0349] In some embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 200 mg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 240 mg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 400 mg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered 480 mg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered 2 mg / kg of pembrolizumab once every six weeks.

[0350] In some embodiments, pembrolizumab is provided as a liquid drug comprising 25 mg / ml pembrolizumab, 7% (w / v) sucrose, and 0.02% (w / v) polysorbate 80 in 10 mM histidine buffer, pH 5.5. In other embodiments, pembrolizumab is provided as a liquid drug comprising about 125 to about 200 mg / mL of pembrolizumab or an antigen-binding fragment thereof; about 10 mM histidine buffer; about 10 mM L-methionine or a pharmaceutically acceptable salt thereof; about 7% (w / v) sucrose; and about 0.02% (w / v) polysorbate 80.

[0351] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg of pembrolizumab once every three weeks. In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 400 mg of pembrolizumab once every six weeks.

[0352] In some embodiments, the selected dose of pembrolizumab is administered by IV infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion over a period of 25-40 minutes, or about 30 minutes. In other embodiments, the selected dose of pembrolizumab is administered by subcutaneous injection.

[0353] In some embodiments, the selected dose of pembrolizumab is administered subcutaneously. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient is 320mg to 420mg, 340mg to 420mg, 345mg to 415mg, 350mg to 410mg, 355mg to 405mg, 360mg to 400mg, 365mg to 395mg, 370mg to 390mg, 375mg to 385mg, or 379mg to 381mg. In one embodiment, pembrolizumab is administered by subcutaneous injection at a dosage of about 280mg to about 450mg. In a further embodiment, pembrolizumab is administered by subcutaneous injection at a dosage of about 300mg to about 450mg. In another embodiment, pembrolizumab is administered subcutaneously at a dosage of about 320mg to about 450mg.

[0354] In certain embodiments, pembrolizumab is administered subcutaneously to the patient, wherein pembrolizumab is part of a composition and is present in the composition at a concentration of 130 mg / mL. In certain embodiments, pembrolizumab is administered subcutaneously to the patient, wherein the pembrolizumab is part of a composition and is present in the composition at a concentration of 165 mg / mL. In certain embodiments, pembrolizumab is administered subcutaneously to the patient by two injections. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient via a prefilled syringe is 380 mg. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient via two prefilled syringes is 380 mg.

[0355] In one embodiment, the selected dose of pembrolizumab is administered by subcutaneous injection at a dose that is at least about 1.6 times higher than a dose of 200 mg or 2 mg / kg. In one embodiment, the subcutaneous dose is administered once every three weeks. In one embodiment, the subcutaneous dose is administered once every six weeks. In one embodiment, the bioavailability of the subcutaneous dose of pembrolizumab is at least 63%. In one embodiment, the bioavailability of the subcutaneous dose of pembrolizumab is at least 64%. In one embodiment, the bioavailability of the subcutaneous dose of pembrolizumab is at least 66%.

[0356] In other embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is nivolumab, and the human patient is administered about 240 mg or about 3 mg / kg of nivolumab once every two weeks. In a specific embodiment, the human patient is administered about 240 mg of nivolumab once every two weeks. In a specific embodiment, the human patient is administered about 3 mg / kg of nivolumab once every two weeks. In other embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is nivolumab, and the human patient is administered about 480 mg of nivolumab once every four weeks.

[0357] The immunoconjugate of formula (I) and a pharmaceutically acceptable carrier or excipient are generally formulated into a dosage form suitable for administration to a patient via the desired route of administration. For example, the dosage form includes a sterile solution, a suspension, and a powder for reconstitution. Suitable pharmaceutically acceptable carriers or excipients will vary depending on the specific dosage form selected. In addition, suitable pharmaceutically acceptable carriers or excipients may be selected for specific functions. In an embodiment, the immunoconjugate of formula (I) may be formulated into a dosage form that allows systemic use, i.e., the distribution of the immunoconjugate of formula (I) in the patient's body; examples of such systemic administration include subcutaneous administration and intravenous administration. In another embodiment, the immunoconjugate of formula (I) may be formulated into a dosage form that allows targeted or separate use, i.e., the immunoconjugate of formula (I) is administered only to the part of the patient's body to be treated; examples of such targeted administration include intratumoral injection. In certain embodiments, the dose is provided intravenously or subcutaneously. In certain embodiments, the dosage of the immunoconjugate of formula (I) is 1.0 mg / kg to 6.0 mg / kg, 1.0 mg / kg to 5.5 mg / kg, 1.0 mg / kg to 5.0 mg / kg, 1.0 mg / kg to 4.5 mg / kg, 1.0 mg / kg to 4.0 mg / kg, 1.0 mg / kg to 3.5 mg / kg, 1.0 mg / kg to 3.0 mg / kg, 1.0 mg / kg to 2.5 mg / kg, 1.0mg / kg to 2.0mg / kg, 1.0mg / kg to 1.5mg / kg, 1.5mg / kg to 6.0mg / kg, 1.5mg / kg to 5.5mg / kg, 1.5mg / kg to 5.0mg / kg, 1.5mg / kg to 4.5mg / kg, 1.5mg / kg to 4.0mg / kg, 1.5mg / kg to 3.5mg / kg, 1.5mg / kg to 3.0mg / kg, 1.5mg / kg g to 2.5mg / kg, 1.5mg / kg to 2.0mg / kg, 2.0mg / kg to 6.0mg / kg, 2.0mg / kg to 5.5mg / kg, 2.0mg / kg to 5.0mg / kg, 2.0mg / kg to 4.5mg / kg, 2.0mg / kg to 4.0mg / kg, 2.0mg / kg to 3.5mg / kg, 2.0mg / kg to 3.0mg / kg, 2.0mg / kg to 2.5mg / kg g / kg, 2.5mg / kg to 6.0mg / kg, 2.5mg / kg to 5.5mg / kg, 2.5mg / kg to 5.0mg / kg, 2.5mg / kg to 4.5mg / kg, 2.5mg / kg to 4.0mg / kg, 2.5mg / kg to 3.5mg / kg, 2.5mg / kg to 3.0mg / kg, 3.0mg / kg to 6.0mg / kg, 3.0mg / kg to 5.5mg / kg, 3.0mg / kg to 5.0mg / kg, 3.0mg / kg to 4.5mg / kg, 3.0mg / kg to 4.0mg / kg, 3.0mg / kg to 3.5mg / kg, 3.5mg / kg to 6.0mg / kg, 3.5mg / kg to 5.5mg / kg, 3.5mg / kg to 5.0mg / kg, 3.5mg / kg to 4.5mg / kg, 3.5mg / kg to 4.0mg / kg, 4.0mg / kg to 6 In certain embodiments, the dosage of the immunoconjugate of formula (I) is 3.0 mg / kg to 5.0 mg / kg. In certain embodiments, the total dosage during the therapeutic interval is typically at least 0.25 mg / kg body weight, more typically at least 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.50 mg / kg, 1.75 mg / kg, 2.00 mg / kg, 2.25 mg / kg, 2.50 mg / kg, 2.75 mg / kg, 3.00 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.00 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, 5.50 mg / kg, 5.75 mg / kg, 6.00 mg / kg, 6.25 mg / kg, 6.50 mg / kg, 6.75 mg / kg, and 7.00 mg / kg. In other embodiments, the immunoconjugate of formula (I) is administered subcutaneously or intravenously at 2.00 mg / kg, 2.25 mg / kg, 2.50 mg / kg, 2.75 mg / kg, 3.00 mg / kg, 3.25 mg / kg, 3.75 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, 5.50 mg / kg, 5.75 mg / kg or 6.00 mg / kg weekly, biweekly, "every three weeks," "every four weeks," monthly, "every six weeks," "every two months or quarterly." In a specific embodiment, the immunoconjugate of formula (I) is administered at 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg or 5.50 mg / kg.50 mg / kg every 3 weeks. In a specific embodiment, the immunoconjugate of formula (I) is administered at 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg every 3 weeks, every 4 weeks, or every 6 weeks. In another specific embodiment, the immunoconjugate of formula (I) is administered at 5.00 mg / kg every 3 weeks, every 4 weeks, or every 6 weeks.

[0358] In one embodiment, in the combined therapy of the present disclosure, the immunoconjugate of formula (I) is administered at a dosage of 0.25 mg / kg to 10 mg / kg. In some embodiments, the immunoconjugate of formula (I) is administered at a dosage of 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 8, 9 or 10 mg / kg as a single dose, or any combination thereof as multiple doses. In certain embodiments, the immunoconjugate of formula (I) is administered at a dosage of 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75 or 6 mg / kg. In other embodiments, the immunoconjugate of formula (I) is administered at a dosage of 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5, 5.25 or 5.5 mg / kg. In a specific embodiment, the immunoconjugate of formula (I) is administered at a dosage of 5 mg / kg. In some embodiments, the immunoconjugate of formula (I) is administered within a repetitive cycle of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks. In a specific embodiment, the immunoconjugate of formula (I) is administered within a cycle of three weeks. In another specific embodiment, the immunoconjugate of formula (I) is administered within a cycle of four weeks. In another specific embodiment, the immunoconjugate of formula (I) is administered within a cycle of six weeks. The treatment regimen can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more dosing cycles (for example, 3 or more cycles, or 4 or more cycles). In certain embodiments, the immunoconjugate of formula (I) is administered within one, two, three, four, five, six or seven days of the cycle. The administration day can be continuous, or can be spaced apart by one, two, three, four, five or six days, one week, two weeks, three weeks or four weeks, or any combination therebetween. In a specific embodiment, the immunoconjugate of formula (I) is administered only on the 1st day of each cycle (for example, a 3-week cycle). In a specific embodiment, the immunoconjugate of formula (I) is administered on the 1st and 8th day of each cycle (for example, a 3-week cycle). In a specific embodiment, the immunoconjugate of formula (I) is administered on the 1st, 8th and 15th day of each cycle (for example, a 4-week cycle or a 6-week cycle). In a specific embodiment, the immunoconjugate of formula (I) is administered on the first day of a 3-week cycle. In another specific embodiment, the immunoconjugate of formula (I) is administered on the first day of a 4-week cycle. In another embodiment, the immunoconjugate of formula (I) is administered on days 1, 15, and 29 of a 6-week cycle.In other embodiments, the immunoconjugate of formula (I) is administered at 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg or 5.50 mg / kg every 2 weeks, every 3 weeks, every 4 weeks or every 6 weeks. In a specific embodiment, the immunoconjugate of formula (I) is administered at 4.00 mg / kg every 2 weeks. In another specific embodiment, the immunoconjugate of formula (I) is administered at 4.00 mg / kg every 3 weeks. In a specific embodiment, the immunoconjugate of formula (I) is administered at 5.00 mg / kg every 2 weeks. In another specific embodiment, the immunoconjugate of formula (I) is administered at 5.00 mg / kg every 3 weeks.

[0359] In some embodiments, the immunoconjugate of formula (I) and the anti-human PD-1 antibody or antigen-binding fragment thereof are each administered weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every two months, or quarterly.

[0360] In some embodiments, the immunoconjugate of Formula (I) is administered once every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks at 1 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2 mg / kg, 2.25 mg / kg, 2.5 mg / kg, 2.75 mg / kg, 3 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg.

[0361] In some embodiments, the immunoconjugate of Formula (I) is administered twice every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks at 1 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2 mg / kg, 2.25 mg / kg, 2.5 mg / kg, 2.75 mg / kg, 3 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg.

[0362] In some embodiments, the immunoconjugate of Formula (I) is administered three times every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks at 1 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2 mg / kg, 2.25 mg / kg, 2.5 mg / kg, 2.75 mg / kg, 3 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg.

[0363] In some embodiments, the immunoconjugate A is administered at 3.0 mg / kg once every 2 weeks.

[0364] In some embodiments, the immunoconjugate A is administered twice at 3.0 mg / kg every 2 weeks.

[0365] In some embodiments, the immunoconjugate A is administered three times every two weeks at 3.0 mg / kg.

[0366] In some embodiments, the immunoconjugate A is administered at 4.0 mg / kg once every 2 weeks.

[0367] In some embodiments, the immunoconjugate A is administered twice at 4.0 mg / kg every 2 weeks.

[0368] In some embodiments, the immunoconjugate A is administered at 4.0 mg / kg three times every 2 weeks.

[0369] In some embodiments, the immunoconjugate A is administered at 2.25 mg / kg once every 3 weeks.

[0370] In some embodiments, the immunoconjugate A is administered twice at 2.25 mg / kg every 3 weeks.

[0371] In some embodiments, the immunoconjugate A is administered three times every three weeks at 2.25 mg / kg.

[0372] In some embodiments, the immunoconjugate of formula (I) is administered once, twice, or three times at 1 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2 mg / kg, 2.25 mg / kg, 2.5 mg / kg, 2.75 mg / kg, 3 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks; After 5 or 6 cycles, the immunoconjugate of formula (I) is administered once, twice or three times at 1 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2 mg / kg, 2.25 mg / kg, 2.5 mg / kg, 2.75 mg / kg, 3 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg or 5.50 mg / kg every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks or every 6 weeks; every 6 weeks is one cycle.

[0373] In some embodiments, the immunoconjugate of formula (I) is administered at a dose of 1 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2 mg / kg, 2.25 mg / kg, 2.5 mg / kg, 2.75 mg / kg, 3 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg or 5.50 mg / kg, once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 5 weeks or once every 6 weeks; 1, 2, 3, 4, After 5 or 6 cycles, the immunoconjugate of formula (I) is administered at a dosage of 1 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2 mg / kg, 2.25 mg / kg, 2.5 mg / kg, 2.75 mg / kg, 3 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg or 5.50 mg / kg, once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 5 weeks or once every 6 weeks; one cycle is 6 weeks.

[0374] In some embodiments, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the immunoconjugate of Formula (I) is administered at a dose of about 4 mg / kg.

[0375] In some embodiments, the immunoconjugate A is administered at 2.25 mg / kg once every 3 weeks; after 1, 2, or 3 cycles, the immunoconjugate A is administered at 4.0 mg / kg every 2 weeks; and one cycle is every 6 weeks.

[0376] In some embodiments, the immunoconjugate A is administered twice at 2.25 mg / kg every 3 weeks; after 1, 2, or 3 cycles, the immunoconjugate A is administered once every 2 weeks at 4.0 mg / kg; and one cycle is every 6 weeks.

[0377] In some embodiments, the immunoconjugate A is administered at 3.0 mg / kg once every 2 weeks; after 1, 2, or 3 cycles, the immunoconjugate A is administered at 4.0 mg / kg once every 2 weeks; and one cycle is every 6 weeks.

[0378] In some embodiments, the immunoconjugate A is administered at 2.25 mg / kg once every 3 weeks; after two cycles, the immunoconjugate A is administered at 4.0 mg / kg once every 2 weeks; and one cycle is every 6 weeks.

[0379] In some embodiments, the immunoconjugate A is administered twice at 2.25 mg / kg every 3 weeks; after two cycles, the immunoconjugate A is administered once every 2 weeks at 4.0 mg / kg; and one cycle is every 6 weeks.

[0380] In some embodiments, the immunoconjugate A is administered at 3.0 mg / kg once every 2 weeks; after two cycles, the immunoconjugate A is administered at 4.0 mg / kg once every 2 weeks; and one cycle is every 6 weeks.

[0381] The immunoconjugate of the formula (I) can be administered for the first time according to a dosing regimen as described herein, and then administered according to different dosing regimens as described herein (for example, to increase or reduce the frequency of administration). In some embodiments, during the first 1, 2, 3, 4, 5 or 6, 7, 8, 9, 10, 11 or 12 weeks, the immunoconjugate of the formula (I) is administered weekly, then administered once every 3 weeks. In certain embodiments, during the first 2, 3, 4, 5 or 6 weeks, the immunoconjugate of the formula (I) is administered once weekly, then administered once every 3 weeks. In certain embodiments, during the first 1, 2, 3, 4, 5 or 6 weeks, the immunoconjugate of the formula (I) is administered once weekly, then administered once every 4 weeks. The immunoconjugate of formula (I) can be administered by parenteral administration. As used herein, "parenteral administration" of immunoconjugate includes any route of administration, characterized in that the immunoconjugate is administered via the physical destruction of patient tissues and the destruction in tissues, so it generally results in direct administration to the bloodstream, muscle or internal organs. Therefore, parenteral administration includes, but is not limited to, administering the immunoconjugate by injection, administering the immunoconjugate by surgical incision, administering the immunoconjugate by tissue penetrating non-surgical wound, etc. In particular, the parenteral administration is expected to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intratumoral and intrasynovial injection or infusion; and renal dialysis infusion technology. In a specific embodiment, the immunoconjugate of formula (I) is administered intravenously. In another specific embodiment, the immunoconjugate of formula (I) is administered subcutaneously. It is also expected to include regional infusion. In some embodiments, the first dose infusion can be administered by one route (e.g., intravenous), followed by subsequent doses by another route. In certain embodiments, the immunoconjugate of formula (I) can be administered by intravenous (IV) infusion. The infusion can be performed over a period of about 0.1 to about 4 hours (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 120, or 180 minutes). In a specific embodiment, the infusion time is 30 minutes. The infusion time can be extended as needed to accommodate the treatment tolerance of individual patients. When the immunoconjugate is administered in more than one dose, in some embodiments, the infusion time for the first dose is longer than the infusion time for subsequent doses, or alternatively, the infusion time for the first dose is shorter than the infusion time for subsequent doses.

[0382] In one embodiment, a method of treating a cell proliferative disorder is provided, comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (b) an immunoconjugate of formula (I); wherein the anti-human PD-1 antibody (or an antigen-binding fragment thereof) and the immunoconjugate of formula (I) are each administered on day 1 of a 3-week cycle ("Combination Regimen 1").

[0383] In a specific embodiment, for combination regimen 1, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a dose of 200 mg per 3-week cycle, and the immunoconjugate of formula (I) is administered at a dose of 5 mg / kg per 3-week cycle. In another specific embodiment, for combination regimen 1, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a dose of 200 mg per 3-week cycle, and the immunoconjugate of formula (I) is administered at a dose of 4 mg / kg per 3-week cycle.

[0384] In a specific embodiment, for Combination Regimen 1, the anti-human PD-1 antibody is pembrolizumab.

[0385] In a specific embodiment, for Combination Regimen 1, the immunoconjugate of Formula (I) is immunoconjugate A.

[0386] In another specific embodiment, for Combination Regimen 1, the anti-human PD-1 antibody is pembrolizumab, and the immunoconjugate of Formula (I) is immunoconjugate A.

[0387] In a specific embodiment, for Combination Regimen 1, the immunoconjugate of Formula (I) is immunoconjugate A.

[0388] In another embodiment, said Combination Regimen 1 is administered in 1 to 4 cycles.

[0389] In one embodiment, Combination Regimen 1 is administered to a patient to treat cancer, wherein the cancer is non-small cell lung cancer.

[0390] In a specific embodiment, Combination Regimen 1 is administered to a patient to treat cancer, wherein the cancer is non-small cell lung cancer, and:

[0391] (a) The non-small cell lung cancer has no EGFR mutation and ALK fusion gene; or

[0392] (b) The non-small cell lung cancer has an actionable EGFR mutation, and the patient has previously failed EGFR-TKI treatment.

[0393] In one embodiment, a method of treating a cell proliferative disorder is provided, comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (b) an immunoconjugate of formula (I); wherein the anti-human PD-1 antibody (or an antigen-binding fragment thereof) is administered on day 1, and the immunoconjugate of formula (I) is administered on days 1, 15, and 29 of a 6-week cycle ("Combination Regimen 2").

[0394] In a specific embodiment, for combination regimen 2, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a single dose of 400 mg on day 1 of each 6-week cycle, and the immunoconjugate of formula (I) is administered at a dose of 5 mg / kg on days 1, 15, and 29 of each 6-week cycle. In another specific embodiment, for combination regimen 2, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a single dose of 400 mg on day 1 of each 6-week cycle, and the immunoconjugate of formula (I) is administered at a dose of 4 mg / kg on days 1, 15, and 29 of each 6-week cycle.

[0395] In a specific embodiment, for Combination Regimen 2, the anti-human PD-1 antibody is pembrolizumab.

[0396] In a specific embodiment, for Combination Regimen 2, the immunoconjugate of Formula (I) is immunoconjugate A.

[0397] In another specific embodiment, for Combination Regimen 2, the anti-human PD-1 antibody is pembrolizumab, and the immunoconjugate of Formula (I) is immunoconjugate A.

[0398] In another embodiment, Combination Regimen 2 is administered in 1 to 4 cycles.

[0399] In one embodiment, Combination Regimen 2 is administered to a patient to treat cancer, wherein the cancer is non-small cell lung cancer.

[0400] In a specific embodiment, Combination 2 is administered to a patient to treat cancer, wherein the cancer is non-small cell lung cancer, and:

[0401] (a) The non-small cell lung cancer has no EGFR mutation and ALK fusion gene; or

[0402] (b) The non-small cell lung cancer has an actionable EGFR mutation, and the patient has previously failed EGFR-TKI treatment.

[0403] In one embodiment, a method for treating non-small cell lung cancer is provided, comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (b) an immunoconjugate of formula (I); wherein the dosage and frequency of administration of the anti-human PD-1 antibody (or an antigen-binding fragment thereof) and the immunoconjugate of formula (I) are as described above.

[0404] In one embodiment, the non-small cell lung cancer is as described above.

[0405] In one embodiment, the non-small cell lung cancer is EGFR wild-type, ALK fusion gene negative, and PD-L1 TPS ≥ 1%.

[0406] In one embodiment, the immunoconjugate of formula (I) is administered once every 1 to 4 weeks, and the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 1 to 10 weeks; preferably once every 2 to 8 weeks.

[0407] In one embodiment, the immunoconjugate of formula (I) is administered at a frequency of once every 1 to 4 weeks and a dose of 1 to 10 mg / kg, and the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a frequency of once every 1 to 10 weeks (preferably once every 2 to 8 weeks) and a dose of 100 to 800 mg.

[0408] In one embodiment, the immunoconjugate of formula (I) is administered once every 2 weeks, and the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 6 weeks.

[0409] In one embodiment, the immunoconjugate of formula (I) is administered once every 2 weeks at a dose of 4 mg / kg, and the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 6 weeks at a dose of 400 mg / kg.

[0410] In one embodiment, a method for treating non-small cell lung cancer is provided, comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); (b) an immunoconjugate of formula (I); and (c) a platinum-containing chemotherapeutic agent; wherein the dosage and frequency of administration of the anti-human PD-1 antibody (or an antigen-binding fragment thereof), the platinum-containing chemotherapeutic agent, and the immunoconjugate of formula (I) are as described above.

[0411] In one embodiment, the non-small cell lung cancer is as described above.

[0412] In one embodiment, the non-small cell lung cancer is EGFR wild-type and ALK fusion gene negative.

[0413] In one embodiment, the immunoconjugate of formula (I) is administered once every 1 to 5 weeks, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 1 to 10 weeks (preferably once every 2 to 8 weeks), and the platinum-containing chemotherapeutic agent is administered once every 1 to 5 weeks.

[0414] In some embodiments, the dosage is about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / mL 2 Up to 150 mg / m 2 The platinum-containing chemotherapeutic agent is administered at a dose of .

[0415] In some embodiments, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every two months, or quarterly.

[0416] In some embodiments, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 3-week cycle, and each is administered on day 1 and / or day 8 of each 3-week cycle;

[0417] Preferably, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 3-week cycle, and each is administered on day 1 of each 3-week cycle;

[0418] Preferably, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 3-week cycle, and the immunoconjugate of formula (I) is administered on the 1st and 8th day of each 3-week cycle, and the platinum-containing chemotherapeutic agent is administered on the 1st day of each 3-week cycle.

[0419] In some embodiments, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 6-week cycle, wherein the immunoconjugate of formula (I) is administered on days 1, 8, 22, and / or 29 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle;

[0420] wherein the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 6-week cycle, wherein the immunoconjugate of formula (I) is administered on days 1, 8, 22, and 29 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle;

[0421] The immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 6-week cycle, wherein the immunoconjugate of formula (I) is administered on days 1 and 22 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle.

[0422] In some embodiments, the immunoconjugate of Formula (I) and the platinum-containing chemotherapeutic agent are administered in 1, 2, 3, or 4 phases.

[0423] In some embodiments, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are administered in two phases, wherein:

[0424] In the first stage, the immunoconjugate of formula (I) is administered in a 3-week cycle and on the first day of each 3-week cycle, and the platinum-containing chemotherapy agent is administered in a 3-week cycle and on the first day of each 3-week cycle;

[0425] In the second phase, the immunoconjugate of formula (I) is administered in 2-week cycles and is administered on day 1 of each 2-week cycle.

[0426] In some embodiments, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are administered in two phases, wherein:

[0427] In the first stage, the immunoconjugate of formula (I) is administered in a 3-week cycle and is administered on the 1st and 8th days of each 3-week cycle, and the platinum-containing chemotherapy agent is administered in a 3-week cycle and is administered on the 1st day of each 3-week cycle;

[0428] In the second phase, the immunoconjugate of formula (I) is administered in 2-week cycles and is administered on day 1 of each 2-week cycle.

[0429] In some embodiments, each phase lasts 2-24 weeks, 4-24 weeks, 6-24 weeks, 8-24 weeks, 10-24 weeks, 12-24 weeks, 14-24 weeks, 16-24 weeks, 18-24 weeks, 20-24 weeks, or 22-24 weeks.

[0430] In some embodiments, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, the carboplatin is administered at a dose of AUC 5 mg / mL / min, or,

[0431] The immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min.

[0432] In some embodiments, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg and the cisplatin is administered at a dose of 75 mg / m 2 Dosage administration, or

[0433] The immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg, and the cisplatin is administered at a dose of 75 mg / m 2 Dosage administration.

[0434] In some embodiments, in the first stage, the immunoconjugate of formula (I) is administered at a dose of about 3 mg / kg and the carboplatin is administered at a dose of AUC 5 mg / mL / min;

[0435] In the second phase, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg.

[0436] In some embodiments, in the first stage, the immunoconjugate of formula (I) is administered at a dose of about 2.25 mg / kg and the carboplatin is administered at a dose of AUC 5 mg / mL / min;

[0437] In the second phase, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg.

[0438] In some embodiments, the number of cycles is 1-4.

[0439] In some embodiments, the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are each administered weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every two months, or quarterly.

[0440] In some embodiments, the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are each administered in a 3-week cycle, and each is administered on day 1 of each 3-week cycle.

[0441] In some embodiments, the immunoconjugate of formula (I), the anti-human PD-1 antibody or its antigen-binding fragment, and the platinum-containing chemotherapeutic agent are each administered in a 6-week cycle, wherein the immunoconjugate of formula (I) is administered on days 1, 8, 22, and / or 29 of each 6-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered on day 1 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle;

[0442] Preferably, the immunoconjugate of formula (I) is administered on days 1, 8, 22, and 29 of each 6-week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each 6-week cycle, and the platinum-containing chemotherapy agent is administered on days 1 and 22 of each 6-week cycle;

[0443] Preferably, the immunoconjugate of formula (I) is administered on days 1 and 22 of each 6-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered on day 1 of each 6-week cycle, and the platinum-containing chemotherapy agent is administered on days 1 and 22 of each 6-week cycle.

[0444] In some embodiments, the immunoconjugate of Formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are administered in 1, 2, 3, or 4 phases.

[0445] In some embodiments, the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are administered in two phases, wherein:

[0446] In the first stage, the immunoconjugate of formula (I) is administered in a 3-week cycle and on the first day of each 3-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered in a 6-week cycle and on the first day of each 6-week cycle, and the platinum-containing chemotherapy agent is administered in a 3-week cycle and on the first day of each 3-week cycle;

[0447] In the second stage, the immunoconjugate of formula (I) is administered in a 2-week cycle and is administered on the 1st day of each 2-week cycle, and the anti-human PD-1 antibody or its antigen-binding fragment is administered in a 6-week cycle and is administered on the 1st day of each 6-week cycle.

[0448] In some embodiments, the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are administered in two phases, wherein:

[0449] In the first stage, the immunoconjugate of formula (I) is administered in a 3-week cycle and is administered on the 1st and 8th days of each 3-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered in a 6-week cycle and is administered on the 1st day of each 6-week cycle, and the platinum-containing chemotherapy agent is administered in a 3-week cycle and is administered on the 1st day of each 3-week cycle;

[0450] In the second stage, the immunoconjugate of formula (I) is administered in a 2-week cycle and is administered on the 1st day of each 2-week cycle, and the anti-human PD-1 antibody or its antigen-binding fragment is administered in a 6-week cycle and is administered on the 1st day of each 6-week cycle.

[0451] In some embodiments, each phase lasts 2-24 weeks, 4-24 weeks, 6-24 weeks, 8-24 weeks, 10-24 weeks, 12-24 weeks, 14-24 weeks, 16-24 weeks, 18-24 weeks, 20-24 weeks, or 22-24 weeks.

[0452] In some embodiments, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min, or,

[0453] The immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min.

[0454] In some embodiments, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min, or,

[0455] The immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min.

[0456] In some embodiments, in the first stage, the immunoconjugate of formula (I) is administered at a dose of about 3 mg / kg, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min;

[0457] In the second stage, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, and the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg.

[0458] In some embodiments, in the first stage, the immunoconjugate of formula (I) is administered at a dose of about 2.25 mg / kg, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min;

[0459] In the second stage, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, and the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg.

[0460] In some embodiments, the number of cycles is 1-4.

[0461] In some embodiments, the immunoconjugate of formula (I) is administered at a frequency of once every 1 to 5 weeks and a dose of 1 to 10 mg / kg, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a frequency of once every 1 to 10 weeks (preferably once every 2 to 8 weeks) and a dose of 100 to 800 mg, and the platinum-containing chemotherapeutic agent is administered at a frequency of once every 1 to 5 weeks and a dose with a bioavailability of 1 to 10 mg / ml / min.

[0462] In some embodiments, the immunoconjugate of formula (I) is administered at a frequency of 1 to 5 weeks and a dose of 1 to 10 mg / kg, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a frequency of 1 to 10 weeks (preferably once every 2 to 8 weeks) and a dose of 100 to 800 mg, and the platinum-containing chemotherapy agent is administered at a frequency of 1 to 5 weeks and an AUC of 1 to 10 mg / ml / min; after 1 to 5 cycles, the immunoconjugate of formula (I) is administered at a frequency of 1 to 5 weeks and a dose of 1 to 10 mg / kg, and the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a frequency of 1 to 10 weeks (preferably once every 2 to 8 weeks) and a dose of 100 to 800 mg; one cycle is 6 weeks.

[0463] In some embodiments, the immunoconjugate of formula (I) is administered once every 3 weeks, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 6 weeks, and the platinum-containing chemotherapeutic agent is administered once every 3 weeks.

[0464] In some embodiments, the immunoconjugate of Formula (I) is administered once every three weeks at a dose of 4 mg / kg, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every six weeks at a dose of 400 mg / kg, and the platinum-containing chemotherapeutic agent is administered once every three weeks at a dose of AUC 5 mg / ml / min.

[0465] In some embodiments, the immunoconjugate of Formula (I) is administered once every three weeks at a dose of 4 mg / kg, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered once every six weeks at a dose of 400 mg / kg, and the platinum-containing chemotherapy agent is administered once every three weeks at a dose of 5 mg / ml / min AUC; after two cycles, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered once every six weeks at a dose of 400 mg, and the immunoconjugate of Formula (I) is administered once every two weeks at a dose of 4 mg / kg; one cycle consists of six weeks.

[0466] In some embodiments, a method of treating non-small cell lung cancer is provided, comprising administering to a patient in need thereof a combination therapy comprising: (a) an immunoconjugate of formula (I); and (b) a platinum-containing chemotherapeutic agent; wherein the dosage and frequency of administration of the platinum-containing chemotherapeutic agent and the immunoconjugate of formula (I) are as described above.

[0467] In some embodiments, the non-small cell lung cancer is as described above.

[0468] In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with an EGFR sensitive mutation and has previously failed EGFR-TKI treatment.

[0469] In some embodiments, the immunoconjugate of formula (I) is administered once every 1 to 5 weeks, and the platinum-containing chemotherapeutic agent is administered once every 1 to 5 weeks.

[0470] In some embodiments, the immunoconjugate of formula (I) is administered once every 1 to 5 weeks at a dose of 1 to 10 mg / kg, and the platinum-containing chemotherapeutic agent is administered once every 1 to 5 weeks at a dose of AUC 1 to 10 mg / ml / min.

[0471] In some embodiments, the immunoconjugate of formula (I) is administered at a frequency of once every 1 to 5 weeks and a dose of 1 to 10 mg / kg, and the platinum-containing chemotherapeutic agent is administered at a frequency of once every 1 to 5 weeks and a dose of AUC 1 to 10 mg / ml / min; after 1 to 5 cycles, the immunoconjugate of formula (I) is administered at a frequency of once every 1 to 5 weeks and a dose of 1 to 10 mg / kg; every 6 weeks is one cycle.

[0472] In some embodiments, the immunoconjugate of formula (I) is administered once every three weeks and the platinum-containing chemotherapeutic agent is administered once every three weeks.

[0473] In some embodiments, the immunoconjugate of formula (I) is administered twice three weeks at a dose of 2.25 mg / kg, and the platinum-containing chemotherapeutic agent is administered once three weeks at a dose of AUC 5 mg / ml / min.

[0474] In some embodiments, the immunoconjugate of formula (I) is administered once every three weeks at a dose of 3 mg / kg, and the platinum-containing chemotherapeutic agent is administered once every three weeks at a dose of AUC 5 mg / ml / min.

[0475] In some embodiments, the immunoconjugate of formula (I) is administered at a frequency of twice three weeks and a dose of 2.25 mg / kg, and the platinum-containing chemotherapy agent is administered at a frequency of once three weeks and a dose of AUC 5 mg / ml / min; after two cycles, the immunoconjugate of formula (I) is administered at a frequency of once two weeks and a dose of 4 mg / kg; one cycle is six weeks.

[0476] In some embodiments, the immunoconjugate of formula (I) is administered once every three weeks at a dose of 3 mg / kg, and the platinum-containing chemotherapeutic agent is administered once every three weeks at a dose of AUC 5 mg / ml / min; after two cycles, the immunoconjugate of formula (I) is administered once every two weeks at a dose of 4 mg / kg; one cycle is six weeks.

[0477] In some embodiments, a method of treating non-small cell lung cancer is provided, comprising administering to a patient in need thereof a combination therapy comprising: (a) an immunoconjugate of formula (I); and (b) an EGFR-tyrosine kinase inhibitor; wherein the frequency of administration and the dosage of the immunoconjugate of formula (I) and the EGFR-tyrosine kinase inhibitor are as described above.

[0478] In some embodiments, the non-small cell lung cancer is as described above.

[0479] In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer.

[0480] In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with EGFR 19del or 21L858R sensitive mutations.

[0481] In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with EGFR 19del or 21L858R sensitive mutation and has not received previous systemic treatment.

[0482] In some embodiments, the immunoconjugate of formula (I) is administered once every 1 to 5 weeks, and the EGFR-tyrosine kinase inhibitor is administered three times a day, twice a day, once a day, once every two days, or once every three days.

[0483] In some embodiments, the immunoconjugate of formula (I) is administered at a frequency of once every 1 to 5 weeks and a dose of 1 to 10 mg / kg, and the EGFR-tyrosine kinase inhibitor is administered at a frequency of 3 times a day, 2 times a day, once a day, once every 2 days, or once every 3 days and a dose of 30 to 150 mg.

[0484] In some embodiments, the immunoconjugate of formula (I) is administered once every two weeks, and the EGFR-tyrosine kinase inhibitor is administered once a day.

[0485] In some embodiments, the immunoconjugate of formula (I) is administered once every two weeks at a dose of 3 mg / kg, and the EGFR-tyrosine kinase inhibitor is administered once a day at a dose of 80 mg.

[0486] In some embodiments, the immunoconjugate of formula (I) is administered at a frequency of 4 mg / kg once every two weeks, and the EGFR-tyrosine kinase inhibitor is administered at a frequency of 80 mg once a day.

[0487] In some embodiments, the immunoconjugate of formula (I) is administered weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every two months, or quarterly, and the EGFR-tyrosine kinase inhibitor is administered daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, or every week.

[0488] In some embodiments, the immunoconjugate of formula (I) is administered in 2-week cycles, and each is administered on day 1 of each 2-week cycle, and the EGFR-tyrosine kinase inhibitor is administered every day.

[0489] In some embodiments:

[0490] (i) administering the immunoconjugate of formula (I) at a dose of about 3 mg / kg on day 1 of a 2-week cycle;

[0491] (ii) administering osimertinib at a dose of about 80 mg daily;

[0492] (iv) The number of cycles is 1 to 4.

[0493] In some embodiments:

[0494] (i) administering the immunoconjugate of formula (I) at a dose of about 4 mg / kg on day 1 of a 2-week cycle;

[0495] (ii) administering osimertinib at a dose of about 80 mg daily;

[0496] (iv) The number of cycles is 1 to 4.

[0497] In some embodiments:

[0498] (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on day 1 of a 2-week cycle;

[0499] (ii) administering osimertinib at a dose of about 80 mg daily;

[0500] (iv) The number of cycles is 1 to 4.

[0501] In some embodiments, at least one therapeutic agent in the combination therapy (the anti-PD-1 antibody or its binding fragment, and the immunoconjugate of Formula (I)) is administered using the same dosage regimen (therapeutic dose, frequency, and duration) that is typically used when the agent is used as a monotherapy for the same condition. In other embodiments, the patient receives a lower total amount of at least one therapeutic agent in the combination therapy than when the agent is used as a monotherapy, for example, a smaller dose, a less frequent dose, and / or a shorter duration of treatment.

[0502] Additional therapeutic agents

[0503] The therapeutic combinations and combination therapies disclosed herein can be used in combination with one or more additional therapeutic agents, including but not limited to, additional anticancer agents, wherein the additional anticancer agents are used to prevent, treat, control, improve or reduce the risk of a particular disease or condition (e.g., a cell proliferative disorder). In one embodiment, the therapeutic combinations disclosed herein are combined with one or more additional anticancer agents for preventing, treating, controlling, improving or reducing the risk of cancer. These additional therapeutic agents can be administered simultaneously or sequentially with the combination therapies disclosed herein by their commonly used routes and dosages.

[0504] Therefore, in one aspect, the present disclosure provides a pharmaceutical composition comprising: (a) an immunoconjugate of formula (I); (b) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (c) an additional therapeutic agent or a pharmaceutically acceptable salt thereof, and (d) a pharmaceutically acceptable carrier. In one embodiment, the amounts of (a), (b), and (c) in the pharmaceutical composition are together effective for treating cancer.

[0505] In one embodiment, provided herein is a pharmaceutical composition comprising:

[0506] (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof;

[0507] (b) a pharmaceutically acceptable carrier; and

[0508] (c) a plurality of immunoconjugates of formula (I):

[0509] in:

[0510] Ab is an antibody that binds Trop-2; and

[0511] n is a decimal from 0 to 10 and represents the average number of linker / payload moieties attached to each antibody used in the plurality of immunoconjugates of Formula (I);

[0512] The amounts of (a) and (c) in the composition are together effective for treating cancer.

[0513] In one embodiment, for the pharmaceutical composition, the antibody is taciturnumab.

[0514] In another embodiment, for the pharmaceutical composition, the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab.

[0515] Also provided herein is a combination therapy comprising administering to a patient a pharmaceutical composition comprising: (a) an immunoconjugate of formula (I); (b) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (c) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof. In one embodiment, the amounts of (a), (b), and (c) administered together are effective for treating cancer.

[0516] When administered in combination with an additional therapeutic agent, the additional therapeutic agent may be administered in a repeating cycle of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In a specific embodiment, the additional therapeutic agent is administered in a three-week cycle. In another specific embodiment, the additional therapeutic agent is administered in a four-week cycle. In yet another specific embodiment, the additional therapeutic agent is administered in a six-week cycle. In certain embodiments, the additional therapeutic agent is administered on one, two, three, four, five, six, or seven days of the cycle. The administration days may be continuous, or may be one, two, three, four, five, or six days, one week, two weeks, three weeks, or four weeks, or any combination thereof. In a specific embodiment, the additional therapeutic agent is administered only on Day 1 of each cycle (e.g., a 2-week cycle, a 3-week cycle, or a 4-week cycle). In a specific embodiment, the additional therapeutic agent is administered on Day 1 of a 3-week cycle. In another specific embodiment, the additional therapeutic agent is administered on Day 1 of a 4-week cycle. In specific embodiments, the additional therapeutic agent is administered on days 1, 8, and 15 of a 3-week cycle, a 4-week cycle, or a 6-week cycle.

[0517] The additional therapeutic agent may be one or more agents selected from the group consisting of: STING agonists, poly ADP ribose polymerase (PARP) inhibitors, mitogen-activated protein kinase (MEK) inhibitors, cyclin-dependent kinase (CDK) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, tryptophan 2,3-dioxygenase (TDO) selective inhibitors, antiviral compounds, antigens, adjuvants, anticancer agents, CTLA-4, LAG-3 and PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, Smoothened inhibitors, alkylating agents, antitumor antibiotics, antimetabolites, retinoids and immunomodulatory agents including but not limited to anticancer vaccines. It should be understood that the description of the additional therapeutic agents above may overlap. It will also be understood that the therapeutic combinations are optimized, and that the optimal combination of the anti-human PD-1 antibody (or antigen-binding fragment thereof), the immunoconjugate of Formula (I), and one or more additional therapeutic agents will be determined based on the needs of the individual patient.

[0518] When the therapeutic combination disclosed herein is used concurrently with one or more additional therapeutic agents, the anti-human PD-1 antibody (or antigen-binding antibody or fragment thereof) and / or the immunoconjugate of Formula (I) can be administered concurrently with, before, or after the one or more additional therapeutic agents. Any of the anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or the immunoconjugate of Formula (I) can be administered alone, by the same or different routes of administration, or together with other agents in the same pharmaceutical composition.

[0519] The weight ratio of the anti-human PD-1 antibody (or its antigen-binding fragment) to the immunoconjugate of formula (I) can vary, depending on the therapeutically effective dose of each agent. In general, a therapeutically effective dose of each agent will be used. A combination comprising at least an anti-human PD-1 antibody (or its antigen-binding fragment), an immunoconjugate of formula (I) and one or more additional therapeutic agents generally includes a therapeutically effective dose of each therapeutic agent. In such a combination, the anti-human PD-1 antibody (or its antigen-binding fragment) and / or the immunoconjugate of formula (I) disclosed herein and the additional therapeutic agent can be administered alone or in combination. In addition, one component can be administered before, simultaneously with, or after the administration of the additional therapeutic agent. In one embodiment, a combination comprising at least one anti-human PD-1 antibody (or its antigen-binding fragment), an immunoconjugate of formula (I) and one or more additional therapeutic agents will contain a dose of each component that is administered at such a dose that together they are effective for treating cancer.

[0520] In one embodiment, the present disclosure provides a combination preparation of an anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or an immunoconjugate of formula (I), and at least one additional therapeutic agent, for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is for a cell proliferative disorder, such as cancer.

[0521] The present disclosure also provides the use of an immunoconjugate of formula (I) for treating a cell proliferative disorder, wherein the patient has previously (e.g., within 24 hours) received treatment with an anti-human PD-1 antibody (or an antigen-binding fragment thereof). In one embodiment, the immunoconjugate of formula (I) is administered within 30 minutes after the administration of the anti-human PD-1 antibody (or its antigen-binding fragment) is completed. The present disclosure also provides the use of an anti-human PD-1 antibody (or its antigen-binding fragment) for treating a cell proliferative disorder, wherein the patient has previously (e.g., within 24 hours) received treatment with an immunoconjugate of formula (I). In one embodiment, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered within 30 minutes after the administration of the immunoconjugate of formula (I) is completed.

[0522] Antiviral compounds that can be used in combination with the therapies disclosed herein include hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors.

[0523] Antigens and adjuvants that can be used in combination with the therapeutic combinations disclosed herein include B7 co-stimulatory molecules, interleukin-2, interferon-γ, GM-CSF, CTLA-4 antagonists, OX-40 / OX-40 ligand, CD40 / CD40 ligand, sargramostim, levamisole, vaccinia virus, Bacillus Calmette-Guérin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxin, mineral oil, surfactants such as lipophosphatidylcholine, pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions. Adjuvants, such as aluminum hydroxide or aluminum phosphate, can be added to increase the ability of the vaccine to trigger, enhance, or prolong an immune response. Additional materials, used alone or in combination, are also potential adjuvants, such as cytokines, chemokines, and bacterial nucleic acid sequences, such as CpG, Toll-like receptor (TLR) 9 agonists, and additional agonists for TLR 2, TLR 4, TLR 5, TLR 7, TLR 8, TLR 7 / 8, TLR9, and TLR 8 / 9, including lipoproteins, lipopolysaccharide (LPS), monophosphoryl lipid A, lipoteichoic acid, imiquimod, resiquimod, and retinoic acid-inducible gene 1 (RIG-I) agonists such as poly I:C.

[0524] Chemotherapeutic agents that can be used in combination with the therapeutic combinations disclosed herein include abiraterone acetate, atitinamine, anhydrovinblastine, acitretin, asparaginase (also known as L-asparaginase and Erwinia L-asparaginase), auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-prolyl-tert-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-dihydro-4'-deoxy-8'-norvin-caleukoblastine, dinaciclib, docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophytoxin , cyclophosphamide, cytarabine, dacarbazine (DTIC), dactin, daunorubicin, decitabine-dolestatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea and taxanes, ifosfamide, riozosine, anisodamine, lomustine, MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizocin, sertenef, streptozotocin, mitomycin, methotrexate, taxanes, nilutamide, olaparib, onask, oxaliplatin, paclitaxel, prednimustine, procarbazine, RPR109881, selumetinib, stramustine phosphate, tamoxifen, tasonemin, paclitaxel, tretinoin, vinblastine, vincristine, vinca desulphate and vinflunine, and pharmaceutically acceptable salts thereof.

[0525] Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark AVASTIN by Genentech / Roche), axitinib (described in PCT International Patent Publication No. WO01 / 002369), Brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, and described in International Patent Publication No. WO02 / 068470), pasireotide (also known as SO 230, and described in International Patent Publication No. WO02 / 010192) and sorafenib.

[0526] Examples of topoisomerase II inhibitors include, but are not limited to, etoposide and teniposide.

[0527] Examples of alkylating agents include, but are not limited to, 5-azacytidine, decitabine, temozolomide, dactinomycin (also known as actinomycin-D), melphalan, altretamine, carmustine, bendamustine, busulfan, platinum-based chemotherapy agents (e.g., alloplatin, cisplatin, carboplatin, and oxaliplatin), lomustine, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine, mechlorethamine, streptozocin, thiotepa, and pharmaceutically acceptable salts thereof. In one embodiment, the additional therapeutic agent is a platinum-based chemotherapy agent. In a specific embodiment, the additional therapeutic agent is cisplatin. In another specific embodiment, the additional therapeutic agent is carboplatin. In a specific embodiment, when administered in combination with carboplatin, the dose of carboplatin is about AUC 1 mg / mL / min to AUC 10 mg / mL / min, administered intravenously. In a specific embodiment, when administered in combination with carboplatin, the dose of carboplatin is AUC 5 mg / mL / min, administered intravenously. In other embodiments, when administered in combination with cisplatin, the dose of cisplatin is about 10 mg / m 2 Up to 150 mg / m 2 In a specific embodiment, when administered in combination with cisplatin, the dose of cisplatin is 75 mg / m 2 , administered intravenously.

[0528] Examples of antitumor antibiotics include, but are not limited to, doxorubicin, bleomycin, daunorubicin, liposomal daunorubicin (daunorubicin citrate liposome), mitoxantrone, epirubicin, idarubicin, and mitomycin C.

[0529] Examples of antimetabolites include, but are not limited to, meclopramide, 5-fluorouracil, 6-thioguanine, pemetrexed (trade name arabinoside (also known as arabinosylcytosine (Ara-C)), liposomal cytarabine (also known as Liposomal Ara-C, sold under the trade name DepoCyt TM Sold under the trade name of (marketed in Japan), hydroxyurea and fludarabine, floxuridine, cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), methotrexate (also known as methotrexate, methotrexate sodium (MTX)), and pentostatin.

[0530] Examples of retinoids include, but are not limited to, alitretinoin, tretinoin, isotretinoin, and bexarotene.

[0531] In one embodiment, a method of treating a cell proliferative disorder is provided, comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); (b) an immunoconjugate of formula (I); and (c) a platinum-based chemotherapeutic agent, wherein the anti-human PD-1 antibody (or an antigen-binding fragment thereof), the immunoconjugate of formula (I), and the platinum-based chemotherapeutic agent are each administered on day 1 of a 3-week cycle. ("Combination Regimen 3")

[0532] In a specific embodiment, for Combination Regimen 3, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a dose of 200 mg per 3-week cycle, and the immunoconjugate of Formula (I) is administered at a dose of 5 mg / kg per 3-week cycle.

[0533] In a specific embodiment, for Combination Regimen 3, the anti-human PD-1 antibody is pembrolizumab.

[0534] In a specific embodiment, for Combination Regimen 3, the immunoconjugate of Formula (I) is immunoconjugate A.

[0535] In another specific embodiment, for Combination Regimen 3, the anti-human PD-1 antibody is pembrolizumab, and the immunoconjugate of Formula (I) is immunoconjugate A.

[0536] In another specific embodiment, for Combination Regimen 3, the platinum chemotherapeutic agent is cisplatin or carboplatin.

[0537] In another specific embodiment, for Combination Regimen 3, the anti-human PD-1 antibody is pembrolizumab, the immunoconjugate of Formula (I) is immunoconjugate A, and the platinum chemotherapeutic agent is carboplatin.

[0538] In a specific embodiment, for Combination Regimen 3, the anti-human PD-1 antibody is pembrolizumab, the immunoconjugate of Formula (I) is immunoconjugate A, and the platinum chemotherapeutic agent is cisplatin.

[0539] In another embodiment, Combination Regimen 3 is administered for 1 to 4 cycles.

[0540] In one embodiment, a method of treating a cell proliferative disorder is provided, comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); (b) an immunoconjugate of formula (I); and (c) a platinum-based chemotherapeutic agent, wherein the anti-human PD-1 antibody (or an antigen-binding fragment thereof) is administered on day 1; the immunoconjugate of formula (I) is administered on days 1, 15, and 29; and the platinum-based chemotherapeutic agent is administered on days 1 and 22 of a 6-week cycle ("Combination Regimen 4").

[0541] In a specific embodiment, for Combination Regimen 4, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a dose of 400 mg / kg on days 1, 15, and 29 of each 6-week cycle, and the immunoconjugate of Formula (I) is administered at a dose of 5 mg / kg on days 1, 15, and 29 of each 6-week cycle.

[0542] In a specific embodiment, for Combination Regimen 4, the anti-human PD-1 antibody is pembrolizumab.

[0543] In a specific embodiment, for Combination Regimen 4, the immunoconjugate of Formula (I) is immunoconjugate A.

[0544] In another specific embodiment, for Combination Regimen 4, the anti-human PD-1 antibody is pembrolizumab, and the immunoconjugate of Formula (I) is immunoconjugate A.

[0545] In another specific embodiment, for Combination Regimen 4, the platinum chemotherapeutic agent is carboplatin or cisplatin.

[0546] In another specific embodiment, for Combination Regimen 4, the anti-human PD-1 antibody is pembrolizumab, the immunoconjugate of Formula (I) is immunoconjugate A, and the platinum chemotherapy agent is carboplatin, administered at a dose of AUC 5 mg / mL / min.

[0547] In certain embodiments, for Combination Regimen 4, the anti-human PD-1 antibody is pembrolizumab, the immunoconjugate of Formula (I) is immunoconjugate A, and the platinum-based chemotherapy agent is cisplatin, administered at a dose of 75 mg / m2 per administration.

[0548] In a specific embodiment, Combination 3 is administered as follows:

[0549] (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on day 1 of a 3-week cycle;

[0550] (ii) administering the anti-human PD-1 antibody or antigen-binding fragment thereof at a dose of about 200 mg on day 1 of a 3-week cycle;

[0551] (iii) carboplatin at a dose of about AUC 5 mg / ml / min on day 1 of a 3-week cycle; and

[0552] (iv) The number of cycles is 1 to 4.

[0553] In another specific embodiment, Combination Regimen 3 is administered as follows:

[0554] (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on day 1 of a 3-week cycle;

[0555] (ii) administering the anti-human PD-1 antibody or antigen-binding fragment thereof at a dose of about 200 mg on day 1 of a 3-week cycle;

[0556] (iii) About 75 mg / m2 on day 1 of a 3-week cycle 2 cisplatin at a dose of ; and

[0557] (iv) The number of cycles is 1 to 4.

[0558] In one embodiment, Combination Regimen 3 is administered to a patient to treat cancer, wherein the cancer is non-small cell lung cancer.

[0559] In a specific embodiment, Combination 3 is administered to a patient to treat cancer, wherein the cancer is non-small cell lung cancer, and:

[0560] (a) The non-small cell lung cancer has no EGFR mutation and ALK fusion gene; or

[0561] (b) The non-small cell lung cancer has an actionable EGFR mutation, and the patient has previously failed EGFR-TKI treatment.

[0562] In a specific embodiment, Combination Regimen 4 is administered as follows:

[0563] (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on days 1, 15, and 29 of a 6-week cycle;

[0564] (ii) administering the anti-human PD-1 antibody or antigen-binding fragment thereof at a dose of about 400 mg on day 1 of a 6-week cycle;

[0565] (iii) carboplatin at a dose of about AUC 5 mg / ml / min on days 1 and 22 of a 6-week cycle; and

[0566] (iv) The number of cycles is 1 to 4.

[0567] In another specific embodiment, Combination Regimen 4 is administered as follows:

[0568] (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on days 1, 15, and 29 of a 6-week cycle;

[0569] (ii) administering the anti-human PD-1 antibody or antigen-binding fragment thereof at a dose of about 400 mg on day 1 of a 6-week cycle;

[0570] (iii) cisplatin at a dose of about 75 mg / m2 on days 1 and 22 of a 6-week cycle; and

[0571] (iv) The number of cycles is 1 to 4.

[0572] In one embodiment, Combination Regimen 4 is administered to a patient to treat cancer, wherein the cancer is non-small cell lung cancer.

[0573] In a specific embodiment, Combination 4 is administered to a patient to treat cancer, wherein the cancer is non-small cell lung cancer, and:

[0574] (a) The non-small cell lung cancer has no EGFR mutation and ALK fusion gene; or

[0575] (b) The non-small cell lung cancer has an actionable EGFR mutation, and the patient has previously failed EGFR-TKI treatment.

[0576] Additional embodiments

[0577] Additional embodiments of the present disclosure include the compositions, combinations, uses, and methods described above, wherein it is understood that each embodiment can be combined with one or more other embodiments so that such a combination is consistent with the description of the embodiments. It should also be further understood that the embodiments provided above are understood to include all embodiments, including those resulting from combining the embodiments.

[0578] Reagent test kit

[0579] The present disclosure also provides articles of manufacture, such as kits, comprising one or more containers (e.g., single-use or multi-use containers) comprising a pharmaceutical composition of an immunoconjugate of formula (I) described herein at a dose described herein, a pharmaceutical composition of an anti-human PD-1 antibody (or antigen-binding fragment thereof) described herein at a dose described herein, optionally an additional therapeutic agent, and instructions for use according to the treatment regimen described herein. The immunoconjugate of formula (I), the anti-human PD-1 antibody (or antigen-binding fragment thereof), and the additional therapeutic agent can be packaged together or separately in suitable packaging, such as a vial or ampoule made of non-reactive glass or plastic.

[0580] In one embodiment, the kit includes a device for separately storing the compositions, such as a container, a divided bottle, or a divided foil package. The kit of the present disclosure can be used for administration of different dosage forms, such as oral and parenteral, for administration of the separate compositions at different dosage intervals, or for instillation of the separate compositions relative to each other. To assist compliance, the kit of the present disclosure typically includes instructions for administration.

[0581] In one embodiment, the present disclosure provides a kit comprising:

[0582] (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof; and

[0583] (b) Immunoconjugates of formula (I):

[0584] in:

[0585] Ab is an antibody that binds Trop-2; and

[0586] n is an integer from 1 to 10;

[0587] The amounts of (a) and (b) in the kit together are effective for treating cancer.

[0588] In one embodiment, for the kit of the present disclosure, the anti-human PD-1 antibody or antigen-binding fragment contained in the kit is pembrolizumab.

[0589] In another embodiment, for the kit of the present disclosure, the immunoconjugate of formula (I) contained in the kit is immunoconjugate A.

[0590] General approach

[0591] Sambrook, Fritsch and Maniatis (1982 & 1989 2 describe standard methods in molecular biology. ndEdition,2001 3 rd Edition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3 rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA). Standard methods are also found in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0592] Methods for protein purification are described, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, NJ, pp. 384-391). The production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterizing ligand / receptor interactions are available (see, e.g., Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0593] Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter, et al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1999) J. Biol. Chem. 274:27371-27378). al. (1997) J. Biol. Chem. 272: 10678-10684; Chothia et al. (1989) Nature 342: 877-883; Foote and Winter (1992) J. Mol. Biol. 224: 487-499; US Pat. No. 6, 329, 511).

[0594] An alternative approach to humanization is the use of human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).

[0595] Purification of the antigen is not necessary for the production of antibodies. Animals can be immunized with cells carrying the antigen of interest. Splenocytes are then isolated from the immunized animal and fused with a myeloma cell line to produce hybridomas (see, e.g., Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithamana et al. (1999) J. Immunol. 163:5157-5164).

[0596] Methods of flow cytometry are available, including fluorescence activated cell sorting (FACS) (see, e.g., Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2 nded.; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, are available for use, for example, as diagnostic reagents (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).

[0597] Standard methods for immune system histology are described (see, e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Philadelphia, PA; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0598] Software packages and database sequences are available for determining, for example, antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments (see, for example, GenBank, Vector Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); von Heijne (1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res. 14:4683-4690). Example

[0599] The following examples illustrate representative embodiments of the present disclosure but are not meant to be limiting in any way.

[0600] Example 1

[0601] Preparation of immunoconjugate A

[0602] Immunoconjugate A can be prepared using the method described in US Patent Publication No. 20200347075, wherein Immunoconjugate A is referred to as "BT001021".

[0603] Example 2

[0604] Study of Immunoconjugate A and Pembrolizumab as Combination Therapy for Patients with NSCLC

[0605] This study consists of three phases, including a screening phase, a treatment phase, and a survival follow-up phase, as follows:

[0606] The screening period was within 28 days before the first dose of study treatment.

[0607] During the treatment period, subjects will receive immunoconjugate A as monotherapy or in combination with osimertinib in 28-day cycles, and immunoconjugate A in combination with pembrolizumab ± chemotherapy or immunoconjugate A in combination with chemotherapy in 21-day or 42-day cycles until any study treatment discontinuation criteria are met. Any subject who discontinues study treatment will need to complete an end-of-treatment (EOT) visit within 30 days after the last dose of study treatment or before starting new anticancer treatment (whichever occurs first, which should be close to 30 days after the last dose of study treatment).

[0608] After the end of treatment, regardless of whether new anti-cancer treatment is started, adverse events within 30 days after the last dose of study treatment will be recorded (serious adverse events will be recorded until 90 days after the last dose of study treatment, or 30 days after the last dose of study treatment if the subject starts a new anti-cancer treatment, whichever occurs first).

[0609] Survival follow-up will continue every 3 months (±14 days) after the last dose to obtain survival information and new anticancer treatment information by telephone until the subject decides to withdraw from the study, is lost to follow-up, dies, or the study is terminated, whichever occurs first. Subjects who discontinue study treatment for reasons other than disease progression will continue to have tumor assessments until disease progression, initiation of new anticancer treatment, the subject decides to withdraw from the study, is lost to follow-up, or dies, whichever occurs first.

[0610] It is estimated that the study will take approximately 3 years from the time the first subject (or his or her legally authorized representative) provides written informed consent to the last visit of the last subject.

[0611] Dosing groups and duration:

[0612] A total of six cohorts are planned for the immunoconjugate A / pembrolizumab combination study. Cohorts 1 and 2 will be evaluated initially. Dosing regimens for Cohorts 3, 4, 5, and 6 will be determined based on preliminary safety, efficacy, and PK data from Cohorts 1 and 2.

[0613] The starting dose for the safety run-in period for Cohorts 1 and 2 will be based on studies of the immunoconjugate A + pembrolizumab combination in selected advanced solid tumors. It is estimated that the safety run-in period for Cohorts 1 and 2 in this study will begin with 5 mg / kg Q2W or Q3W of immunoconjugate A plus pembrolizumab. However, if this dose is not tolerated with the investigational immunoconjugate A, the next lower dose (4 mg / kg Q2W or Q3W of immunoconjugate A) will be evaluated in this study based on PK, efficacy, and safety data.

[0614] Cohorts 1 and 2: Eligible subjects will be randomized 1:1 to Cohorts 1 and 2 to receive the following treatment: NSCLC requiring first-line treatment; no actionable EGFR mutations or ALK fusions; PD-L1 TPS ≥ 1%. Eligible subjects will be randomized 1:1 to Cohorts 1 and 2 to receive the following treatment (Note: In the expansion phase, subjects will be randomized 1:1 to either cohort, stratified by squamous cell carcinoma vs. non-squamous cell carcinoma and PD-L1 TPS 1%-49% vs. TPS ≥ 50%):

[0615] Cohort 1: Immunoconjugate A (5 mg / kg, every 3 weeks) + pembrolizumab (200 mg, every 3 weeks), every 3 weeks.

[0616] Cohort 2: Immunoconjugate A (5 mg / kg, every 2 weeks) + pembrolizumab (400 mg, every 6 weeks), with a 6-week cycle.

[0617] Cohorts 3 and 4: Enroll the following subjects: NSCLC patients requiring first-line treatment; no actionable EGFR mutations and ALK fusion genes. Eligible subjects will be randomly assigned 1:1 to Cohorts 3 and 4 to receive the following study treatment (Note: In the extension phase, subjects are planned to be randomized 1:1 to either cohort, stratified by squamous cell carcinoma vs. non-squamous cell carcinoma and PD-L1 TPS <1% vs. TPS ≥50%):

[0618] Cohort 3: Immunoconjugate A + pembrolizumab + carboplatin (AUC 5 mg / mL / min, every 3 weeks) every 3 weeks for 4 cycles or every 6 weeks for 2 cycles, followed by immunoconjugate A + pembrolizumab.

[0619] Cohort 4: Immunoconjugate A + pembrolizumab + cisplatin (75 mg / m 2 ,Q3W), every 3 weeks for a total of 4 cycles, or every 6 weeks for a total of 2 cycles, followed by immunoconjugate A + pembrolizumab.

[0620] NOTE: The dosing frequency and dose of immunoconjugate A and pembrolizumab in Cohorts 3 and 4 will be determined based on data from Cohorts 1 and 2. If the 5 mg / kg Q2W or Q3W dose is tolerated in Cohorts 1 and 2, the safety run-in period for Cohorts 3 and 4 is expected to begin with immunoconjugate A 4 mg / kg Q2W or Q3W (a dose level that is lower than the dose level considered tolerated in Cohorts 1 and 2) in combination with pembrolizumab plus carboplatin or cisplatin.

[0621] Cohorts 5 and 6: Enroll patients with NSCLC harboring actionable EGFR mutations who have failed prior EGFR-TKI therapy. Eligible subjects will be randomized 1:1 to Cohorts 5 and 6, stratified by prior treatment with only first- or second-generation EGFR-TKIs versus third-generation EGFR-TKIs and PD-L1 TPS <1% versus TPS 1%-49% versus TPS ≥50%. The doses of immunoconjugate A and platinum in Cohorts 5 and 6 will be based on data from Cohorts 3 and 4.

[0622] Cohort 5: Immunoconjugate A + pembrolizumab + carboplatin or cisplatin every 3 weeks for 4 cycles or every 6 weeks for 2 cycles, followed by immunoconjugate A + pembrolizumab.

[0623] Cohort 6: Immunoconjugate A plus carboplatin or cisplatin every 3 weeks for 4 cycles or every 6 weeks for 2 cycles, followed by immunoconjugate A.

[0624] Immunoconjugate A: Immunoconjugate A was administered intravenously on day 1 of each 3-week cycle (cohort 1; and further applied to cohorts 3, 4, 5, and 6 as determined by SRC), or on days 1, 15, and 29 of each 6-week cycle (cohort 2; and further applied to cohorts 3, 4, 5, and 6). The first infusion duration for each patient was 90 (±15) minutes, and infusion-related adverse events (AEs) were monitored. If no infusion-related AEs occurred, the subsequent infusion duration could be adjusted to 60 (+15) minutes. In the event of an infusion-related AE or to ensure the safety of the subject's infusion, the researcher could adjust the infusion duration to 90 (±15) minutes.

[0625] Pembrolizumab: 200 mg of pembrolizumab administered intravenously over 30 minutes on day 1 of each 3-week cycle (Cohort 1; and further applicable to Cohorts 3, 4, 5, and 6) or 400 mg of pembrolizumab administered intravenously over 30 minutes on day 1 of each 6-week cycle (Cohort 2; and further applicable to Cohorts 3, 4, 5, and 6).

[0626] Carboplatin: Carboplatin at an AUC of 5 mg / mL / min will be administered intravenously on day 1 of each 3-week cycle or on days 1 and 22 of each 6-week cycle. Cohort 3 carboplatin cycle calculations will be consistent with those for immunoconjugate A and pembrolizumab in the assay cohorts (cohorts 1 or 2). Regardless of the cycle calculation, carboplatin will be administered every 3 weeks for 12 weeks for a total of 4 doses.

[0627] Cisplatin: 75 mg / mL on day 1 of a 3-week cycle or on days 1 and 22 of a 6-week cycle. 2 Cisplatin is administered intravenously. Cohort 3 carboplatin cycle calculations will be consistent with those for immunoconjugate A and pembrolizumab in the assay cohorts (cohorts 1 or 2). Regardless of the cycle calculation, cisplatin will be administered every 3 weeks for 12 weeks, totaling 4 doses.

[0628] Order of combined administration:

[0629] When pembrolizumab, immunoconjugate A, and chemotherapy are administered on the same day, study treatments will be administered sequentially: pembrolizumab will be administered intravenously first, followed by an intravenous infusion of immunoconjugate A, at least 30 minutes later, and when combined with chemotherapy, carboplatin or cisplatin will be administered intravenously, at least 30 minutes later (a maximum interval of +1 day is allowed between immunoconjugate A and chemotherapy).

[0630] When immunoconjugate A and chemotherapy are administered on the same day, study treatments will be administered sequentially: immunoconjugate A will be administered intravenously first, followed by chemotherapy, with at least 30 minutes between administrations.

[0631] Subjects may continue study treatment beyond the initial definition of progressive disease as determined by RECIST 1.1 if the investigator assesses continued clinical benefit. A conclusion of clinical benefit may be made if the investigator assesses no intolerable toxicity or worsening symptoms due to progressive disease (PD) based on radiographic findings and clinical symptoms. Subjects may be readmitted with an Informed Consent Form (ICF) describing any reasonably foreseeable risks or discomfort.

[0632] Dosage and administration

[0633] Infusion duration: Each subject will receive their first infusion of immunoconjugate A for 90 (±15) minutes and will be monitored for infusion-related AEs. If no infusion-related AEs occur, the subsequent infusion duration can be adjusted to 60 (±15) minutes. If an infusion-related AE occurs, or to ensure the safety of the study drug infusion, the investigator may adjust the infusion duration of immunoconjugate A to 90 (±15) minutes.

[0634] Pembrolizumab is infused over 30 minutes.

[0635] When pembrolizumab and immunoconjugate A are administered on the same day, administer immunoconjugate A at least 30 minutes after the completion of the pembrolizumab infusion. When immunoconjugate A is used in combination with pembrolizumab and chemotherapy, administer pembrolizumab intravenously first, followed by an intravenous infusion of immunoconjugate A at least 30 minutes later, and then by an intravenous infusion of carboplatin or cisplatin at least 30 minutes later (a maximum interval of only +1 day is allowed between immunoconjugate A and chemotherapy).

[0636] When immunoconjugate A and chemotherapy (cisplatin or carboplatin) were administered on the same day, immunoconjugate A was administered intravenously first, followed by chemotherapy, with at least 30 minutes between administrations.

[0637] Adverse reaction monitoring: On Day 1 of the first cycle, after all infusions are completed, monitor subjects for adverse reactions for at least 90 minutes. If no infusion-related AEs occur, monitor subjects for adverse reactions for at least 60 minutes after completion of study treatment (unless clinical symptoms require close monitoring).

[0638] Pretreatment measures for immunoconjugate A infusion-related reactions: Pretreatment is required 30 to 60 minutes after completion of pembrolizumab and before infusion of immunoconjugate A. It is recommended that subjects pre-treat with diphenhydramine (or an equivalent dose of antihistamine) and acetaminophen (or an equivalent dose of analgesic) ± other treatment options recommended by the investigator according to institutional standards or local guidelines.

[0639] The study is divided into two parts. The first part is the safety lead-in phase to evaluate the dose level; the second part is the extension phase to further explore the efficacy and safety based on the safe and tolerable dose range determined in the first part.

[0640] End of study

[0641] The study will be terminated when the following conditions are met:

[0642] All subjects have completed or discontinued study treatment, and the sponsor considers the overall survival benefit data for this study to be mature.

[0643] The primary analysis has been completed; the sponsor has opened a separate extension study to ensure that remaining subjects can continue to receive treatment.

[0644] Research group

[0645] No prior approval of protocol deviations from recruitment and enrollment criteria (also known as protocol waivers) was permitted. The study population was subjects with advanced or metastatic non-small cell lung cancer. Subjects had to be able to provide written informed consent, meet all inclusion criteria, and not meet any exclusion criteria.

[0646] Inclusion criteria

[0647] Subjects were selected only if they met all of the following criteria:

[0648] 1. Regardless of gender, the subject must be at least 18 years old on the day of signing the informed consent form;

[0649] 2. Subjects with histologically or cytologically confirmed NSCLC, locally advanced (stage IIIB / IIIC) or metastatic (stage IV) NSCLC according to the 8th edition of the TNM staging for lung cancer published by the International Union Against Cancer and the American Joint Committee on Cancer, who are not suitable for definitive surgery and / or radiotherapy (with or without concurrent chemotherapy);

[0650] 3. Subjects in Cohorts 1, 2, 3, and 4 with non-squamous or mixed histology NSCLC should be confirmed to be EGFR wild-type and ALK fusion-negative by tumor histology; have no known alterations in driver genes such as ROS1, NTRK, and BRAF; and have no actionable genomic alterations for other approved targeted therapies. For patients with squamous NSCLC, if prior EGFR and ALK status is unknown, no corresponding testing is required before enrollment in this study, and the genetic status will be considered negative.

[0651] Subjects in Cohorts 5 and 6 should have actionable genomic mutations confirmed by tumor histology, cytology, or blood samples;

[0652] 4. The study will include the following 6 cohorts:

[0653] a) Cohort 1 and Cohort 2: Subjects with locally advanced or metastatic NSCLC who do not have actionable EGFR mutations and ALK fusion genes, no known ROS1, NTRK, BRAF gene alterations or other actionable gene mutations for which there are approved therapies, and who meet all of the following criteria: i) no prior systemic therapy; ii) no prior treatment with PD-1 / PD-L1 antibodies; iii) PD-L1 TPS ≥ 1% as determined by central laboratory testing, such as the PD-L1 IHC 22C3 PharmDx assay. Subjects who have previously received adjuvant, neoadjuvant, or definitive chemotherapy and have experienced disease progression > 6 months after completing treatment are allowed to be enrolled;

[0654] b) Cohorts 3 and 4: Subjects with locally advanced or metastatic NSCLC who do not have actionable EGFR mutations and ALK fusion genes, no known ROS1, NTRK, BRAF gene alterations, or other actionable gene mutation kinases for which approved therapies exist, and who have not previously received systemic therapy, including the use of PD-1 / PD-L1 antibodies. Subjects who have previously received adjuvant, neoadjuvant, or definitive chemotherapy and have experienced disease progression >6 months after completing treatment are allowed to be included;

[0655] c) Cohorts 5 and 6: Subjects with actionable EGFR mutations, including exon 19 deletion mutations or exon 21 point mutations (L858R), who have previously failed EGFR-TKI treatment and meet all of the following criteria: i) Failure of first- or second-generation EGFR-TKIs, with exon 20 T790M mutation negativity confirmed by tumor histology after treatment failure; or failure of third-generation EGFR-TKI treatment, regardless of T790M mutation status; ii) No previous chemotherapy or PD-1 / PD-L1 antibody treatment for locally advanced or metastatic NSCLC; Subjects who have previously received adjuvant, neoadjuvant, or definitive chemotherapy and have experienced disease progression >6 months after completing treatment are allowed to be included;

[0656] 5. Subjects were able to provide tumor tissue blocks or sections before the first dose of study treatment (archive tumor tissue: formalin-fixed paraffin-embedded tissue blocks, approximately 10 unstained sections for Cohorts 1, 2, 3, 4, and 5, and approximately 5 unstained sections for Cohort 6).

[0657] a) If fewer than 10 unstained sections (Cohorts 1, 2, 3, 4, and 6) or 5 unstained sections (Cohort 5) were available, the decision to enroll the subject was made on a case-by-case basis after discussion with the medical monitor.

[0658] b) Subjects who are unable to provide archived tumor tissue blocks or sections agree to provide fresh biopsy specimens before receiving study treatment;

[0659] 6. Subjects must have at least one radiographically measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; brain metastases are not considered target lesions.

[0660] 7. The subject's ECOG performance status score was 0 or 1 within 7 days before the start of study treatment;

[0661] 8. Subjects with an expected survival period of ≥ 3 months;

[0662] 9. Subjects with adequate organ function as shown by the following laboratory values ​​(no blood transfusion, recombinant human thrombopoietin, or colony-stimulating factor treatment within 2 weeks prior to screening) (Table 3-4):

[0663] Table 3-4 Appropriate organ function laboratory values

[0664] 10. Left ventricular ejection fraction (LVEF) ≥ 50%, as determined by echocardiography (ECHO) or multi-portal acquisition (MUGA) scanning;

[0665] 11. Subjects must have recovered from all toxicities caused by previous treatment (improved to < Grade 2 based on the CTCAE 5.0 criteria, or reached the level specified in the eligibility criteria), except for toxicities that are not considered to be safety risks (e.g., alopecia, vitiligo, and other asymptomatic laboratory abnormalities);

[0666] 12. The contraceptive measures used by male and female subjects must comply with local regulations regarding contraceptive methods for clinical research subjects;

[0667] NOTE: The reliability of abstinence in the eligibility of males and / or females needs to be evaluated based on the duration of the clinical study and the subjects' preferred and usual lifestyle. Periodic abstinence (e.g., calendar method, ovulation method, symptom-temperature method, or postovulation method) and withdrawal are not acceptable methods of contraception.

[0668] a. Male subjects:

[0669] Male subjects must agree to use highly effective contraceptive measures from the time they sign the Informed Consent Form (ICF) to at least 6 months after the last dose of study treatment and must not donate sperm during this period.

[0670] b. Female subjects:

[0671] Female subjects eligible for participation in the study must be non-pregnant, non-breastfeeding, and meet at least one of the following conditions:

[0672] Women of childbearing potential (WOCBP)

[0673] or

[0674] WOCBP who agrees to follow contraceptive guidelines from the time they sign the ICF until at least 6 months after the last dose of study treatment; and

[0675] 13. Subjects should voluntarily participate in the study, sign the ICF, and be able to comply with the medical consultations and related procedures specified in the protocol.

[0676] Exclusion criteria

[0677] Subjects who meet any of the following criteria are not eligible for inclusion in this study:

[0678] Medical conditions

[0679] 1. Subjects with mixed SCLC histopathological features;

[0680] 2. Subjects with a known history of previous malignant tumors, unless the subject has received potentially curative treatment and has no signs of recurrence within 3 years of such treatment;

[0681] Note: The 3-year disease-free period does not apply to the NSCLC tumors under investigation in this study. This period also does not apply to patients with basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, cervical cancer in situ, or other carcinoma in situ that has been definitively resected.

[0682] 3. Subjects known to have meningeal metastases, brainstem metastases, spinal cord metastases and / or compressed or active CNS metastases. Subjects with locally treated brain metastases can be enrolled if they are clinically stable for at least 4 weeks before the first dose of study treatment and have stopped steroid treatment for at least 14 days; according to this definition, brain metastases should have been stable before the first dose of study drug. For subjects in whom CNS metastases are first discovered at screening, the treating investigator should consider delaying study treatment to document the stability of CNS metastases using repeated imaging after at least 4 weeks (in this case, all screening activities may need to be repeated);

[0683] 4. Subjects with grade 2 or higher peripheral neuropathy who received platinum treatment in this study;

[0684] 5. Subjects with a history of esophageal varices, severe ulcers, gastrointestinal perforation, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months before the first dose of study treatment;

[0685] 6. Subjects with arteriovenous thromboembolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis (except venous thrombosis caused by intravenous catheterization during previous chemotherapy, which has been resolved by the investigator) and pulmonary embolism within 6 months before the first dose of the study intervention;

[0686] 7. Subjects with active inflammatory bowel disease or a history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or chronic diarrhea);

[0687] 8. Subjects with clinically significant cardiovascular diseases, such as:

[0688] a) Severe or uncontrolled heart disease or clinical symptoms requiring treatment within 6 months prior to the first dose of the study treatment, including: congestive heart failure classified as Class III-IV by the New York Heart Association (NYHA), unstable angina that cannot be controlled by drugs, serious arrhythmias requiring medical treatment (except atrial fibrillation or paroxysmal supraventricular tachycardia), and myocardial infarction;

[0689] b) have a history of myocarditis or cardiomyopathy; and

[0690] c) baseline QTc interval >480ms;

[0691] 9. Subjects with a history of interstitial lung disease (ILD) / non-infectious pneumonia requiring steroid treatment, or currently suffering from ILD / pneumonia, or subjects whose suspected ILD / pneumonia cannot be excluded by imaging examination at screening;

[0692] 10. Subjects with uncontrolled systemic diseases judged by the investigator:

[0693] a) Subjects with uncontrolled hypertension (systolic blood pressure > 160 mmHg and / or diastolic blood pressure > 100 mmHg) under drug intervention, a history of unstable hypertension, or a history of poor compliance with antihypertensive treatment;

[0694] b) Subjects with uncontrolled diabetes mellitus (fasting glucose ≥ 10 mmol / L and / or HbA1c ≥ 8%);

[0695] c) Subjects with clinical symptoms or pleural effusion, pericardial effusion or ascites requiring repeated drainage;

[0696] 11. Subjects with autoimmune diseases who have required systemic treatment (e.g., use of disease symptom relievers, corticosteroids, or immunosuppressive drugs) in the past 2 years. Hormone replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed;

[0697] 12. Subjects with active hepatitis B or hepatitis C.

[0698] Note: HBV-DNA testing is required for subjects who are positive for hepatitis B surface antigen (HBsAg) and / or hepatitis B core antibody (HBcAb); HBV-DNA ≥ 500 IU / mL or above the detection limit (if the detection limit is higher than 500 IU / mL) is considered to be active hepatitis B. Active hepatitis C is defined as positive for hepatitis C antibodies and HCV-RNA above the detection limit.

[0699] 13. Subjects with known poorly controlled human immunodeficiency virus (HIV) infection. HIV-infected participants with a history of Kaposi's sarcoma and / or multicentric Castleman's disease are included. HIV-infected individuals must have well-controlled HIV on antiretroviral therapy (ART) and meet all of the following criteria:

[0700] a) Participants on ART must have a CD4+ T cell count >350 cells / mm at screening 3 ;

[0701] b) Participants on ART must have achieved and maintained virological suppression, defined as HIV RNA levels less than 50 or LLOQ (below the limit of detection) as demonstrated using a locally available assay, at screening and for at least 12 weeks prior to screening; and

[0702] c) Participants on ART must have remained on a stable regimen with no changes in medication or dose modification for at least 4 weeks prior to study entry (Day 1).

[0703] 14. Subjects known to have active pulmonary tuberculosis;

[0704] 15. Subjects who have received any chemotherapy, radiotherapy, immunotherapy, or biological therapy within 4 weeks prior to the first dose of study treatment; subjects who have received small molecule TKI, anti-tumor hormone therapy, systemic immunostimulants (including but not limited to interferon, IL-2), or approved anti-tumor Chinese medicine preparations within 2 weeks prior to the first dose of study treatment; subjects who have received palliative radiotherapy for known metastatic sites within 2 weeks prior to the first dose of study treatment;

[0705] Note: Subjects who have previously received anti-PD-1 or anti-PD-L1 antibodies can be enrolled in the corresponding study cohort if they meet the following conditions:

[0706] No previous toxicity leading to permanent discontinuation of immunotherapy (IMT).

[0707] All AEs previously experienced while receiving IMT have recovered to ≤ Grade 1 or baseline before study screening.

[0708] No previous grade ≥3 irAEs or neurological or ocular AEs of any grade while receiving IMT.

[0709] NOTE: Subjects experiencing any grade endocrine AE who remain stable and asymptomatic on appropriate alternative treatment may be enrolled.

[0710] The AE does not require the use of immunosuppressants other than corticosteroids to manage the AE, the AE does not recur if re-administered, and maintenance doses of >10 mg / day of prednisone or equivalent are not currently required;

[0711] 16. Subjects who have received other clinical investigational drugs or major surgery within 4 weeks before the first dose of study treatment;

[0712] 17. Subjects who have received more than 30 Gy of radiation therapy to the lung within 6 months before the first dose of study treatment;

[0713] 18. Subjects who require systemic use of strong inhibitors or inducers of cytochrome P4503A4 (CYP3A4) within 2 weeks or 5 half-lives before the first dose of study treatment and during the study;

[0714] 19. Subjects who have received continuous high-dose systemic corticosteroids (low-dose corticosteroids are allowed, such as ≤10 mg / day of prednisone or equivalent dose, if the dose has been stable for at least 4 weeks) or other immunosuppressive treatments within 2 weeks before the first dose of study treatment;

[0715] 20. Subjects who have received live vaccines or live attenuated vaccines within 4 weeks before the first dose of study treatment, or who plan to receive live vaccines during the study;

[0716] 21. Subjects with severe infections (including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia) within 4 weeks prior to the first dose of study treatment, or concomitant infections requiring systemic antibiotic treatment within 2 weeks prior to the first dose of study treatment;

[0717] 22. Subjects with a history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation;

[0718] 23. Subjects with known allergy or hypersensitivity to pembrolizumab or immunoconjugate A, or excipients of pembrolizumab or immunoconjugate A.

[0719] 24. Subjects who are pregnant or breastfeeding, or anticipate becoming pregnant or giving birth to a child during the expected duration of this study;

[0720] 25. Subjects whose condition rapidly deteriorates, such as severe changes in performance status, during screening prior to the first dose of study treatment; and

[0721] 26. Subjects with other conditions that the researcher deems unsuitable for participation in this study.

[0722] Example 3

[0723] Study on the combination of immunoconjugate A and various drugs in the treatment of NSCLC

[0724] The patient types and dosing regimens for each cohort of this study are as follows:

[0725] Cohort 1: First-line NSCLC patients with wild-type EGFR and negative ALK fusion genes, and PD-L1 TPS ≥ 1%, were enrolled. They received immunoconjugate A at a dose of 4 mg / kg (based on patient weight) every two weeks plus pembrolizumab at a dose of 400 mg every six weeks.

[0726] Cohort 3: First-line NSCLC subjects with wild-type EGFR were enrolled. In the first stage, the subjects received immunoconjugate A + pembrolizumab + carboplatin. The dose of immunoconjugate A was 2.25 mg / kg based on the patient's body weight, administered twice every 3 weeks, on the 1st and 8th day of every 3 weeks; pembrolizumab 400 mg was administered once every 6 weeks; carboplatin was administered at a dose to achieve AUC 5 mg / ml / min, administered once every 3 weeks; the duration of the first stage was 6 to 24 weeks (e.g., 6, 12, 18 or 24 weeks); after the first stage, the subjects entered the second stage, in which they received immunoconjugate A + pembrolizumab. The dose of immunoconjugate A was 4 mg / kg based on the patient's body weight, administered once every 2 weeks; pembrolizumab 400 mg was administered once every 6 weeks. Some subjects in Cohort 3 had squamous cell carcinoma and some had non-squamous cell carcinoma; Cohort 3 included subjects with PD-L1 TPS < 1%, subjects with TPS 1%-49%, and subjects with TPS ≥ 50%.

[0727] Cohort 4: First-line NSCLC subjects with wild-type EGFR were enrolled. In the first stage, the subjects received immunoconjugate A + pembrolizumab + carboplatin. The dose of immunoconjugate A was 3 mg / kg based on the patient's body weight, administered once every 3 weeks; pembrolizumab 400 mg was administered once every 6 weeks; carboplatin was administered at a dose to achieve AUC 5 mg / ml / min, administered once every 3 weeks; the duration of the first stage was 6 to 24 weeks (e.g., 6, 12, 18 or 24 weeks); after the first stage, the subjects entered the second stage, in which they received immunoconjugate A + pembrolizumab. The dose of immunoconjugate A was 4 mg / kg based on the patient's body weight, administered once every 2 weeks; pembrolizumab 400 mg was administered once every 6 weeks. Some subjects in Cohort 4 had squamous cell carcinoma and some had non-squamous cell carcinoma; Cohort 4 included subjects with PD-L1 TPS < 1%, subjects with TPS 1%-49%, and subjects with TPS ≥ 50%.

[0728] Cohort 5 enrolled NSCLC patients with EGFR mutations who had previously failed EGFR-TKI therapy. In the first phase, patients received immunoconjugate A plus carboplatin. Immunoconjugate A was administered at a dose of 2.25 mg / kg (based on patient body weight) twice every three weeks. Carboplatin was administered once every three weeks at a dose that achieved an AUC of 5 mg / ml / min. The duration of the first phase was 6 to 24 weeks (e.g., 6, 12, 18, or 24 weeks). Following the first phase, patients entered the second phase, receiving immunoconjugate A monotherapy at a dose of 4 mg / kg (based on patient body weight) once every two weeks. Cohort 5 included patients previously treated with only first- or second-generation EGFR TKIs, as well as those previously treated with third-generation EGFR TKIs. Cohort 5 also included patients with and without central nervous system metastases.

[0729] Cohort 6: NSCLC subjects with EGFR mutations who have failed prior EGFR-TKI therapy were enrolled. In the first phase, subjects received immunoconjugate A plus carboplatin at a dose of 3 mg / kg of body weight every 3 weeks and carboplatin at a dose that achieved an AUC of 5 mg / ml / min every 3 weeks. The duration of the first phase was 6 to 24 weeks (e.g., 6, 12, 18, or 24 weeks). Following the first phase, subjects entered the second phase, in which they received immunoconjugate A monotherapy at a dose of 4 mg / kg of body weight every 2 weeks. Cohort 6 included subjects previously treated with only first- or second-generation EGFR TKIs, as well as subjects treated with third-generation EGFR TKIs. Cohort 6 included subjects with and without central nervous system metastases.

[0730] Cohort 7: NSCLC subjects with EGFR mutations were enrolled and received immunoconjugate A plus osimertinib. Immunoconjugate A was administered at a dose of 4 mg / kg (based on patient body weight) every two weeks, followed by osimertinib at a dose of 80 mg once daily. Cohort 7 included subjects with 19del mutations and / or 21L858R mutations, as well as subjects with and without central nervous system metastases.

[0731] Cohort 7-1 enrolled NSCLC subjects with EGFR mutations and received immunoconjugate A plus osimertinib. Immunoconjugate A was administered at a dose of 3 mg / kg (based on patient body weight) every two weeks, followed by osimertinib at a dose of 80 mg daily. Cohort 7-1 included subjects with 19del mutations and / or 21L858R mutations, as well as subjects with and without central nervous system metastases.

[0732] The inclusion criteria for patients in this study were:

[0733] 1. Applicants must be ≥18 years old when signing the informed consent form, regardless of gender;

[0734] 2. Locally advanced or metastatic (stage IV) NSCLC confirmed by histology or cytology and not suitable for radical surgery and / or radical radiotherapy;

[0735] 3. EGFR wild type confirmed by histology and EGFR activating mutation confirmed by tumor histology, cytology or hematology samples;

[0736] 4. a) Locally advanced or metastatic NSCLC with wild-type EGFR and negative ALK fusion genes, who have not received prior systemic treatment; c) Patients with EGFR-sensitizing mutations who have received and failed EGFR-TKI therapy, or who have previously failed anti-PD-1 / PD-L1 antibodies and platinum-based chemotherapy; d) Patients with EGFR-sensitizing mutations who have not received prior systemic treatment or who have received and failed EGFR-TKI therapy;

[0737] 5. The subject is able to provide tumor tissue blocks or sections before the first dose of study treatment;

[0738] 6. According to the Response Evaluation in Solid Tumors (RECIST) v1.1 criteria, there is at least one radiographically measurable lesion;

[0739] 7. Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1 within 7 days of the first dose of study treatment;

[0740] 8. The subject's expected survival period is ≥ 3 months;

[0741] 9. Have adequate organ function;

[0742] 10. The patient must have recovered from all toxicities caused by previous treatment;

[0743] 11. The contraceptive measures used by male and female subjects must comply with local regulations on contraceptive methods for clinical research subjects.

[0744] 12. The subjects voluntarily participate in this study, sign the informed consent form, and are able to comply with the visits and related procedures specified in the protocol.

[0745] The exclusion criteria for this study were:

[0746] 1. Histopathological type contains small cell carcinoma components;

[0747] 2. Subjects with a known history of malignant tumors;

[0748] 3. Subjects known to have meningeal metastasis, brainstem metastasis, spinal cord metastasis and / or compression, or active CNS metastasis;

[0749] 4. Subjects who have previously developed grade 2 or higher peripheral neuropathy while receiving platinum-containing treatment;

[0750] 5. History of esophageal varices, severe ulcers, gastrointestinal perforation, gastrointestinal obstruction, intra-abdominal abscess or acute gastrointestinal bleeding within 6 months before the first dose of study treatment;

[0751] 6. Arteriovenous thrombosis events occurring within 6 months before the first dose of study treatment;

[0752] 7. Active or clear history of inflammatory bowel disease;

[0753] 8. Subjects with clinically significant cardiovascular disease;

[0754] 9. Patients with a history of interstitial lung disease (ILD) or non-infectious pneumonia requiring steroid treatment;

[0755] 10. Uncontrollable systemic diseases, including hypertension and diabetes that cannot be controlled by drugs, and effusions requiring repeated drainage, as determined by the investigator;

[0756] 11. Patients with active autoimmune diseases that required systemic treatment within the past 2 years;

[0757] 12. Diagnosed with active hepatitis B or C;

[0758] 13. Subjects with known poorly controlled human immunodeficiency virus (HIV) infection;

[0759] 14. Known active pulmonary tuberculosis;

[0760] 15. Patients who have received other clinical investigational drugs or undergone major surgery within 4 weeks before the first dose of study treatment;

[0761] 16. Lung lesions received radiotherapy with a total dose exceeding 30 Gy within 6 months before the first dose of study treatment;

[0762] 17. Patients who need to systemically use strong inhibitors or inducers of cytochrome P4503A4 enzyme (CYP3A4) within 2 weeks or 5 half-lives before the first dose of study treatment and during the study;

[0763] 18. Continuous administration of high-dose systemic corticosteroids within 2 weeks before the first dose of study treatment;

[0764] 19. Vaccination with live or attenuated vaccines within 4 weeks before the first dose of study treatment;

[0765] 20. Severe infection occurred within 4 weeks before the first dose of study treatment;

[0766] 21. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation;

[0767] 22. Subjects with known allergic or hypersensitivity reactions to pembrolizumab or conjugate A, or the excipients of pembrolizumab or conjugate A.

[0768] Although preferred embodiments of the present disclosure are shown and described herein, it will be apparent to those skilled in the art that these embodiments are exemplary only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in implementing the methods and uses disclosed herein.

Claims

1. A method of treating a cell proliferative disorder, such as cancer, in a patient, comprising administering to the patient: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor; and (b) an immunoconjugate of formula (I): in: Ab is an antibody that binds to Trop-2, and n is an integer selected from 1-10; The amounts of (a) and (b) administered are together effective to treat the condition.

2. The method of claim 1, comprising administering to the patient: (a) the anti-human PD-1 antibody or an antigen-binding fragment thereof; and (b) the immunoconjugate of formula (I).

3. The method of claim 1 or 2, wherein n is selected from 6-8.

4. The method of any one of claims 1 to 3, wherein the antibody that binds to Trop-2 comprises: (i) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence of SEQ ID NO: 39, HCDR2 comprising the amino acid sequence of SEQ ID NO: 40, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and (ii) a light chain variable region comprising LCDR1 comprising the amino acid sequence of SEQ ID NO:42, LCDR2 comprising the amino acid sequence of SEQ ID NO:43, and LCDR3 comprising the amino acid sequence of SEQ ID NO:

44.

5. The method of any one of claims 1-4, wherein the antibody that binds to Trop-2 comprises: (i) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 37, and (ii) a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:

38.

6. The method of any one of claims 1-5, wherein the antibody that binds Trop-2 comprises: (i) a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 35, and (ii) a light chain comprising the amino acid sequence shown in SEQ ID NO:

36.

7. The method of any one of claims 1-6, wherein the antibody that binds Trop-2 is sacituzumab.

8. The method of any one of claims 1-7, wherein the immunoconjugate of formula (I) is administered to the patient at a dose of 1.0 mg / kg to 6.0 mg / kg.

9. The method of any one of claims 1-8, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is selected from nivolumab, cemiplimab, dostarlimab, pidilizumab, tislelizumab, and pembrolizumab.

10. The method of any one of claims 1-9, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab.

11. The method of any one of claims 1-10, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered to the patient at a dose of 50 mg to 500 mg.

12. The method of any one of claims 1-11, wherein the immunoconjugate of formula (I) and the anti-human PD-1 antibody or antigen-binding fragment thereof are each administered weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every two months, or quarterly.

13. The method of any one of claims 1-12, wherein the immunoconjugate of formula (I) and the anti-human PD-1 antibody or antigen-binding fragment thereof are each administered in a 3-week cycle, and each is administered on day 1 of each 3-week cycle.

14. The method of any one of claims 1-12, wherein the immunoconjugate of formula (I) and the anti-human PD-1 antibody or antigen-binding fragment thereof are each administered in a 6-week cycle, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each 6-week cycle, and the immunoconjugate of formula (I) is administered on days 1, 15, and 29 of each 6-week cycle.

15. The method of claim 13, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg and the immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg.

16. The method of claim 14, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg and the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg.

17. The method of claim 14, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg and the immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg.

18. The method of any one of claims 11-17, wherein the number of cycles is 1-4.

19. The method of any one of claims 1-18, wherein the platinum-containing chemotherapeutic agent is carboplatin or cisplatin; preferably carboplatin.

20. The method of any one of claims 1-19, wherein the dosage is about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / mL / min. 2 Up to 150 mg / m 2 The platinum-containing chemotherapeutic agent is administered at a dose of 21. The method of any one of claims 1-20, wherein the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every two months, or quarterly.

22. The method of any one of claims 1-21, wherein the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 3-week cycle, and each is administered on day 1 and / or day 8 of each 3-week cycle; Preferably, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 3-week cycle, and each is administered on the first day of each 3-week cycle; Preferably, the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 3-week cycle, and the immunoconjugate of formula (I) is administered on the 1st day and the 8th day of each 3-week cycle, and the platinum-containing chemotherapeutic agent is administered on the 1st day of each 3-week cycle.

23. The method of any one of claims 1-21, wherein the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 6-week cycle, wherein the immunoconjugate of formula (I) is administered on days 1, 8, 22, and / or 29 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle; The immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 6-week cycle, wherein the immunoconjugate of formula (I) is administered on days 1, 8, 22, and 29 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle; The immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are each administered in a 6-week cycle, wherein the immunoconjugate of formula (I) is administered on days 1 and 22 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle.

24. The method of any one of claims 1-21, wherein the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are administered in 1, 2, 3 or 4 phases.

25. The method of claim 24, wherein the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are administered in two stages, wherein: In the first stage, the immunoconjugate of formula (I) is administered in a 3-week cycle and on the first day of each 3-week cycle, and the platinum-containing chemotherapy agent is administered in a 3-week cycle and on the first day of each 3-week cycle; In the second phase, the immunoconjugate of formula (I) is administered in 2-week cycles and is administered on day 1 of each 2-week cycle.

26. The method of claim 24, wherein the immunoconjugate of formula (I) and the platinum-containing chemotherapeutic agent are administered in two stages, wherein: In the first stage, the immunoconjugate of formula (I) is administered in a 3-week cycle on the 1st and 8th day of each 3-week cycle, and the platinum-containing chemotherapy agent is administered in a 3-week cycle on the 1st day of each 3-week cycle; In the second phase, the immunoconjugate of formula (I) is administered in 2-week cycles and is administered on day 1 of each 2-week cycle.

27. The method of any one of claims 24-26, wherein each phase lasts 2-24 weeks, 4-24 weeks, 6-24 weeks, 8-24 weeks, 10-24 weeks, 12-24 weeks, 14-24 weeks, 16-24 weeks, 18-24 weeks, 20-24 weeks, or 22-24 weeks.

28. The method of claim 22 or 23, wherein the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg and the carboplatin is administered at a dose of AUC 5 mg / mL / min, or, The immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min.

29. The method of claim 22 or 23, wherein the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg and the cisplatin is administered at a dose of 75 mg / m 2 Dosage administration, or The immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg, and the cisplatin is administered at a dose of 75 mg / m 2 Dosage administration.

30. The method of claim 25, wherein: In the first stage, the immunoconjugate of formula (I) is administered at a dose of about 3 mg / kg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min; In the second phase, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg.

31. The method of claim 26, wherein: In the first stage, the immunoconjugate of formula (I) is administered at a dose of about 2.25 mg / kg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min; In the second phase, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg.

32. The method of any one of claims 21-31, wherein the number of cycles is 1-4.

33. The method of any one of claims 1-20, wherein the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are each administered weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every two months, or quarterly.

34. The method of claim 33, wherein the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are each administered in a 3-week cycle, and each is administered on day 1 of each 3-week cycle.

35. The method of any one of claims 1-21, 33, wherein the immunoconjugate of formula (I), the anti-human PD-1 antibody or its antigen-binding fragment, and the platinum-containing chemotherapeutic agent are each administered in a 6-week cycle, wherein the immunoconjugate of formula (I) is administered on days 1, 8, 22, and / or 29 of each 6-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered on day 1 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle; Preferably, the immunoconjugate of formula (I) is administered on days 1, 8, 22 and 29 of each 6-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered on day 1 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle; Preferably, the immunoconjugate of formula (I) is administered on days 1 and 22 of each 6-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered on day 1 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle.

36. The method of any one of claims 1-21, 33-35, wherein the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are administered in 1, 2, 3 or 4 stages.

37. The method of claim 36, wherein the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are administered in two stages, wherein: In the first stage, the immunoconjugate of formula (I) is administered in a 3-week cycle and on the first day of each 3-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered in a 6-week cycle and on the first day of each 6-week cycle, and the platinum-containing chemotherapy agent is administered in a 3-week cycle and on the first day of each 3-week cycle; In the second stage, the immunoconjugate of formula (I) is administered in a 2-week cycle and is administered on the 1st day of each 2-week cycle, and the anti-human PD-1 antibody or its antigen-binding fragment is administered in a 6-week cycle and is administered on the 1st day of each 6-week cycle.

38. The method of claim 36, wherein the immunoconjugate of formula (I), the anti-human PD-1 antibody or antigen-binding fragment thereof, and the platinum-containing chemotherapeutic agent are administered in two stages, wherein: In the first stage, the immunoconjugate of formula (I) is administered in a 3-week cycle and is administered on the 1st and 8th days of each 3-week cycle, the anti-human PD-1 antibody or its antigen-binding fragment is administered in a 6-week cycle and is administered on the 1st day of each 6-week cycle, and the platinum-containing chemotherapy agent is administered in a 3-week cycle and is administered on the 1st day of each 3-week cycle; In the second stage, the immunoconjugate of formula (I) is administered in a 2-week cycle, and on the first day of each 2-week cycle, The anti-human PD-1 antibody or its antigen-binding fragment is administered in a 6-week cycle and is administered on the first day of each 6-week cycle.

39. The method of any one of claims 36-38, wherein each phase lasts 2-24 weeks, 4-24 weeks, 6-24 weeks, 8-24 weeks, 10-24 weeks, 12-24 weeks, 14-24 weeks, 16-24 weeks, 18-24 weeks, 20-24 weeks, or 22-24 weeks.

40. The method of claim 34, wherein the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min, or, The immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg, the anti-human PD-1 antibody or its antigen-binding fragment is administered at a dose of about 200 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min.

41. The method of claim 35, wherein the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min, or, The immunoconjugate of formula (I) is administered at a dose of about 5 mg / kg, the anti-human PD-1 antibody or its antigen-binding fragment is administered at a dose of about 400 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min.

42. The method of claim 37, wherein: In the first stage, the immunoconjugate of formula (I) is administered at a dose of about 3 mg / kg, the anti-human PD-1 antibody or its antigen-binding fragment is administered at a dose of about 400 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min; In the second stage, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, and the anti-human PD-1 antibody or its antigen-binding fragment is administered at a dose of about 400 mg.

43. The method of claim 38, wherein: In the first stage, the immunoconjugate of formula (I) is administered at a dose of about 2.25 mg / kg, the anti-human PD-1 antibody or its antigen-binding fragment is administered at a dose of about 400 mg, and the carboplatin is administered at a dose of AUC 5 mg / mL / min; In the second stage, the immunoconjugate of formula (I) is administered at a dose of about 4 mg / kg, and the anti-human PD-1 antibody or its antigen-binding fragment is administered at a dose of about 400 mg.

44. The method of any one of claims 33-43, wherein the number of cycles is 1-4.

45. The method of claim 34, wherein: (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on day 1 of a 3-week cycle; (ii) administering the anti-human PD-1 antibody or antigen-binding fragment thereof at a dose of about 200 mg on day 1 of a 3-week cycle; (iii) on day 1 of a 3-week cycle, administering carboplatin at a dose of about AUC 5 mg / ml / min; and (iv) The number of cycles is 1 to 4.

46. ​​The method of claim 34, wherein: (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on day 1 of a 3-week cycle; (ii) administering the anti-human PD-1 antibody or antigen-binding fragment thereof at a dose of about 200 mg on day 1 of a 3-week cycle; (iii) cisplatin at a dose of about 75 mg / m2 on day 1 of a 3-week cycle; and (iv) The number of cycles is 1 to 4.

47. The method of claim 35, wherein: (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on days 1, 15 and 29 of a 6-week cycle; (ii) administering the anti-human PD-1 antibody or antigen-binding fragment thereof at a dose of about 400 mg on day 1 of a 6-week cycle; (iii) carboplatin at a dose of about AUC 5 mg / ml / min on days 1 and 22 of a 6-week cycle; and (iv) The number of cycles is 1 to 4.

48. The method of claim 35, wherein: (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on days 1, 15 and 29 of a 6-week cycle; (ii) administering the anti-human PD-1 antibody or antigen-binding fragment thereof at a dose of about 400 mg on day 1 of a 6-week cycle; (iii) on days 1 and 22 of a 6-week cycle at a dose of approximately 75 mg / m 2 administration of cisplatin at a dose of 100 mg / kg; and (iv) The number of cycles is 1 to 4.

49. The method of any one of claims 1-48, comprising administering to the patient: (a) the EGFR-tyrosine kinase inhibitor; and (b) an immunoconjugate of formula (I); in, The EGFR-tyrosine kinase inhibitor is osimertinib.

50. The method of claim 49, wherein the immunoconjugate of formula (I) is administered weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every two months, or quarterly, and the EGFR-tyrosine kinase inhibitor is administered daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, or weekly.

51. The method of claim 49 or 50, wherein the immunoconjugate of formula (I) is administered in a 2-week cycle, and each is administered on day 1 of each 2-week cycle, and the EGFR-tyrosine kinase inhibitor is administered every day.

52. The method of claim 51, wherein: (i) administering the immunoconjugate of formula (I) at a dose of about 3 mg / kg on day 1 of a 2-week cycle; (ii) administering osimertinib at a dose of about 80 mg per day; (iv) The number of cycles is 1 to 4.

53. The method of claim 51, wherein: (i) administering the immunoconjugate of formula (I) at a dose of about 4 mg / kg on day 1 of a 2-week cycle; (ii) administering osimertinib at a dose of about 80 mg per day; (iv) The number of cycles is 1 to 4.

54. The method of claim 51, wherein: (i) administering the immunoconjugate of formula (I) at a dose of about 5 mg / kg on day 1 of a 2-week cycle; (ii) administering osimertinib at a dose of about 80 mg per day; (iv) The number of cycles is 1 to 4.

55. The method of any one of claims 1-54, wherein the condition being treated is non-small cell lung cancer.

56. The method of claim 55, wherein: (a) The non-small cell lung cancer has no EGFR mutation and ALK fusion gene; or (b) The non-small cell lung cancer has an EGFR actionable mutation and the patient has previously failed EGFR-TKI treatment.

57. The method of any one of claims 1 to 18, wherein: The immunoconjugate of formula (I) is administered at a frequency of once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 5 weeks or once every 6 weeks and a dose of 1 to 10 mg / kg, and the anti-human PD-1 antibody (or its antigen-binding fragment) is administered at a frequency of once every 1 to 10 weeks (preferably 2 to 8 weeks) and a dose of 100 to 800 mg; Preferably, the disease is non-small cell lung cancer that is EGFR wild-type and ALK fusion gene negative.

58. The method of any one of claims 33-48, wherein: The immunoconjugate of formula (I) is administered once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 5 weeks or once every 6 weeks at a dose of 1 to 10 mg / kg, the anti-human PD-1 antibody (or its antigen-binding fragment) is administered once every 1 to 10 weeks (preferably 2 to 8 weeks) at a dose of 100 to 800 mg, and the platinum-containing chemotherapeutic agent is administered once every 1 to 5 weeks at an AUC of 1 to 10 mg / ml / min; after 1 to 5 cycles, the immunoconjugate of formula (I) is administered once every 1 to 5 weeks at a dose of 1 to 10 mg / kg, and the anti-human PD-1 antibody (or its antigen-binding fragment) is administered once every 1 to 10 weeks (preferably 2 to 8 weeks) at a dose of 100 to 800 mg; one cycle is 6 weeks; Preferably, the disease is non-small cell lung cancer that is EGFR wild-type and ALK fusion gene negative.

59. The method of any one of claims 19-32, wherein: The immunoconjugate of formula (I) is administered at a frequency of once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 5 weeks or once every 6 weeks and a dose of 1 to 10 mg / kg, and the platinum-containing chemotherapy agent is administered at a frequency of once every 1 to 5 weeks and a dose of AUC 1 to 10 mg / ml / min; after 1 to 5 cycles, the immunoconjugate of formula (I) is administered at a frequency of once every 1 to 5 weeks and a dose of 1 to 10 mg / kg; one cycle is 6 weeks; Preferably, the disease is non-small cell lung cancer with EGFR sensitive mutation and previous EGFR-TKI treatment failure.

60. The method of any one of claims 49-54, wherein: The immunoconjugate of formula (I) is administered at a frequency of once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks and a dose of 1 to 10 mg / kg, and the EGFR-tyrosine kinase inhibitor is administered at a frequency of 3 times a day, 2 times a day, once a day, once every 2 days, or once every 3 days and a dose of 30 to 150 mg; Preferably, the disease is EGFR-mutated non-small cell lung cancer.

61. A pharmaceutical composition comprising: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor; (b) a pharmaceutically acceptable carrier; and (c) a plurality of immunoconjugates of formula (I): in: Ab is an antibody that binds Trop-2; and is an integer or decimal from 0 to 10 and represents the average value of the number n of linker / payload moieties attached to each antibody used in the plurality of immunoconjugates of formula (I); The amounts of (a) and (c) in the pharmaceutical composition are together effective for treating a cell proliferative disorder such as cancer.

62. The pharmaceutical composition of claim 61, wherein (1) The anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab; (2) The platinum-containing chemotherapy agent is cisplatin or carboplatin; (3) The EGFR-tyrosine kinase inhibitor is osimertinib; and / or (4) The immunoconjugate of formula (I) is immunoconjugate A.

63. A pharmaceutical composition comprising: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof; (b) a pharmaceutically acceptable carrier; and (c) a plurality of immunoconjugates of formula (I): in: Ab is an antibody that binds Trop-2; and is a decimal from 0 to 10 and represents the average number n of linker / payload moieties attached to each antibody used in the plurality of immunoconjugates of Formula (I); The amounts of (a) and (c) in the pharmaceutical composition are together effective for treating a cell proliferative disorder such as cancer.

64. The pharmaceutical composition of claim 63, wherein the antibody that binds TROP-2 is taciturnumab.

65. The pharmaceutical composition of claim 63 or 64, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab.

66. A kit comprising: (a) a certain amount of anti-human PD-1 antibody or an antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor; as well as (b) an amount of an immunoconjugate of formula (I): in: Ab is an antibody that binds Trop-2; and n is an integer from 0 to 10; The amounts of (a) and (c) in the kit are together effective for treating a cell proliferative disorder such as cancer.

67. A kit comprising: (a) a certain amount of anti-human PD-1 antibody or an antigen-binding fragment thereof; as well as (b) an amount of an immunoconjugate of formula (I): in: Ab is an antibody that binds to Trop-2; and n is an integer from 0 to 10; The amounts of (a) and (c) in the kit are together effective for treating a cell proliferative disorder such as cancer.

68. The kit of claim 66 or 67, further comprising instructions for administering the immunoconjugate of formula (I) and the anti-human PD-1 antibody or antigen-binding fragment thereof to a human patient.

69. The kit of any one of claims 66-68, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab.

70. The kit of any one of claims 66-69, wherein the immunoconjugate of formula (I) is immunoconjugate A.

71. The kit of claim 66, wherein The EGFR-tyrosine kinase inhibitor is osimertinib; and / or the immunoconjugate of formula (I) is immunoconjugate A.

72. A pharmaceutical combination for treating a cell proliferative disorder such as cancer in a human patient, the pharmaceutical combination comprising: (a) an immunoconjugate of formula (I); and (b) anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors; The immunoconjugate of formula (I), anti-human PD-1 antibody or antigen-binding fragment thereof, platinum-containing chemotherapeutic agent, and / or EGFR-tyrosine kinase inhibitor is as described in any one of claims 1-71.

73. Use of a pharmaceutical combination for the preparation of a medicament for treating a cell proliferative disorder such as cancer in a human patient, the pharmaceutical combination comprising: (a) an immunoconjugate of formula (I); and (b) anti-human PD-1 antibodies or antigen-binding fragments thereof, platinum-containing chemotherapeutic agents, and / or EGFR-tyrosine kinase inhibitors; The immunoconjugate of formula (I), anti-human PD-1 antibody or antigen-binding fragment thereof is as described in any one of claims 1-72.

Images