Methods of treatment and uses of pharmaceutical combinations comprising conjugates

Abstract

Methods of treatment and uses involving pharmaceutical combinations comprising the conjugates. Specifically, the present invention relates to pharmaceutical compositions, kits, therapeutic combinations and uses thereof for the treatment of cell proliferative disorders (e.g., cancer), and methods of treating cell proliferative disorders (e.g., cancer).

Description

Therapeutic methods and uses of pharmaceutical combinations comprising conjugates

[0001] This application is based on and claims priority to a PCT application No. PCT / CN2023 / 105235, filed on June 30, 2023, and a CN application No. 202410821898.2, filed on June 24, 2024, the contents of which are incorporated herein in their entirety.

[0002] The present disclosure relates to therapeutic methods and uses of pharmaceutical combinations comprising conjugates. In particular, the present disclosure relates to pharmaceutical compositions, kits, and pharmaceutical combinations comprising immunoconjugates. The present disclosure also relates to methods of treating a cell proliferative disorder, in particular non-small cell lung cancer (NSCLC), in a patient.

[0003] PD-1 is considered an important player in immune regulation and maintenance of peripheral tolerance. PD-1 is expressed at moderate levels 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] The two known ligands of PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in various human tissues that form cancers. In large samples such as ovarian cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, and melanoma, expression of PD-L1 was shown to be associated with poor prognosis and decreased overall survival, regardless of subsequent treatment.

[0005] Likewise, in breast cancer and melanoma, PD-1 expression on tumor-infiltrating lymphocytes marked dysfunctional T cells and was associated with poor prognosis in renal cancer. Thus, it has been proposed that tumor cells expressing PD-L1 interact with T cells expressing PD-1 to attenuate T cell activation and evade immune surveillance, resulting in impaired immune responses against tumors.

[0006] Immune checkpoint therapy targeting the PD-1 axis has made breakthrough progress in clinical responses in a variety of human cancers. Immuno-therapy targeting the PD-1 axis includes monoclonal antibodies against 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 monoclonal antibodies that bind to the PD-L1 ligand (MPDL3280A; TECENTRIQ TM(atezolizumab), Genentech, San Francisco, CA, USA). Both treatment modalities have been shown to have anti-tumor effects in a number of cancer types.

[0007] It has been suggested that the efficacy of such antibodies can 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 signal transduction that is expressed in a variety of tumor types. Trop-2 is expressed in normal trophoblast layers to enable trophoblast cell growth, migration, and proliferation. Trop-2 is associated with a variety of cellular signaling pathways, including intracellular calcium transduction, MAPK signaling pathway, RAF, NF-κΒ, and cyclin D / E, among others.

[0009] It has been shown that Trop-2 is upregulated in cancer cells compared to normal cells. This increase in expression has been observed in a number of different tumor types, including breast cancer, colon cancer, non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma, thyroid cancer, and hepatobiliary cancer, which increases the likelihood of Trop-2 as a pan-cancer tumor agnostic biomarker. The reason for the upregulation of Trop-2 in cancer cells is not known; however, it is postulated that Trop-2 has a key regulatory role in cell proliferation and invasion, which means that overexpression would lead to selective tumor progression. In fact, preclinical data indicates that Trop-2 overexpression stimulates tumor growth, while Trop-2 knockdown inhibits tumor growth.

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

[0011] The success of targeting Trop-2 by antibody-drug conjugates (ADCs) in metastatic breast cancer (MBC) and urothelial cancers and ongoing trials in NSCLC have established Trop-2 targeting as a highly effective strategy and several Trop-2 targeting treatments, such as anti-Trop-2 antibodies and Trop-2 targeting ADCs, have recently been developed for the clinic. Subsequently, several early clinical trials have demonstrated that Trop-2-based ADCs have good safety and clinical benefit in a variety of tumor types. This includes clinical benefit and tolerability in tumor types with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and small cell cancer. An example of an immunoconjugate currently in early clinical trials is immunoconjugate A:

[0012] wherein Ab is an anti-Trop-2 antibody (sacituzumab), described in U.S. Patent Publication 20200347075.

[0013] Given its involvement in several traditional molecular pathways associated with cancer development, Trop-2 can play a role in tumor progression. Trop-2 overexpression is associated with poor prognosis in pancreatic cancer, perihilar cholangiocarcinoma, cervical cancer, gastric cancer, and other diseases. In a Meta-analysis including 2569 patients, increased Trop-2 expression was associated with poor overall and disease-free survival outcomes in several solid tumors. Considering the expression pattern of Trop-2 and the associated poor prognostic outcomes, Trop-2 is a rational 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 monotherapies, the combination of these therapeutics with different mechanisms of action and non-overlapping toxicities has the potential to provide more significant and prolonged responses in many cancer types.

[0015]

[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 said patient:

[0017] (a) an anti-human PD-1 antibody or antigen binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI);

[0018] (b) an immunoconjugate of Formula (I):

[0019] wherein,

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

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

[0022] wherein the amounts of (a) and (b) together are effective to treat the cell proliferative disorder.

[0023] In some embodiments, the present disclosure provides a method of treating a cell proliferative disorder, e.g., cancer, in a patient, comprising administering to the patient:

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

[0025] (b) an immunoconjugate of Formula (I):

[0026] wherein,

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

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

[0029] wherein the amounts of (a) and (b) together are effective to treat the cell proliferative disorder.

[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 cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, non-Hodgkin’s lymphoma, renal 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. Further, in some embodiments of the above method, the cancer has an elevated level of PD-L1 expression, e.g., a cancer having a tumor proportion score (TPS) of >1%, 1-49%, or >50%, or a combined positive score (CPS) of >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 particular embodiment, the non-small cell lung cancer is advanced or metastatic non-small cell lung cancer. In another particular embodiment, the patient is in need of first line treatment and the non-small cell lung cancer does not have EGFR mutations and ALK fusion genes. In another particular embodiment, the non-small cell lung cancer is non-small cell lung cancer with operable mutations in EGFR and the patient has failed prior EGFR-TKI treatment. In another particular embodiment, the non-small cell lung cancer has a 19del mutation and / or has a 21L858R mutation. In another particular embodiment, the non-small cell lung cancer is non-small cell lung cancer with operable mutations in EGFR and the patient has failed prior EGFR-TKI treatment and has failed prior PD-1 / PD-L1 antibody treatment and chemotherapy.

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

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

[0034] In Embodiment 5 of the method, the cancer is urothelial cancer. In a particular embodiment, the urothelial cancer is locally advanced or metastatic urothelial cancer.

[0035] In Embodiment 6 of the method, the cancer is prostate cancer. In a particular embodiment, the prostate cancer is locally advanced or metastatic urothelial cancer. In another particular 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 immunoconjugate A is administered once every three weeks. For example, a 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 on Day 1 of a 3 week cycle.

[0038] In an 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 immunoconjugate A, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered once every six weeks and immunoconjugate A is administered once every 2 weeks. For example, a 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 immunoconjugate A on days 1, 15, and 29 of a 6 week cycle.

[0039] In an 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 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, immunoconjugate A is administered once every 3 weeks, and the platinum-containing chemotherapeutic agent is administered once every 3 weeks. For example, a 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 immunoconjugate A on day 1 of a 3 week cycle, and the platinum-containing chemotherapeutic agent on day 1 of a 3 week cycle.

[0040] In an embodiment 11 of the method, the patient is administered 400 mg of the anti- human PD-1 antibody or antigen-binding fragment thereof, 5 mg / kg immunoconjugate A, and a platinum-containing chemotherapeutic agent, 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, a 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 immunoconjugate A on days 1, 15, and 29 of a 6 week cycle, and the platinum-containing chemotherapeutic agent on days 1 and 22 of a 6 week cycle.

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

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

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

[0044] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum- containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

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

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

[0047] (b) an 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 use in the treatment of a cell proliferative disorder, e.g., cancer, in a human patient, comprising:

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

[0051] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum- containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

[0052] In some embodiments, the present disclosure provides a combination for use in the treatment of a cell proliferative disorder, e.g., cancer, in a human patient, comprising:

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

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

[0055] In a fourth aspect, the present disclosure provides a pharmaceutical combination for use in the treatment of a cell proliferative disorder, e.g., cancer, in a human patient, the pharmaceutical combination comprising:

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

[0057] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum- containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

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

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

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

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

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

[0063] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

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

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

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

[0067] In certain embodiments of the first, second, third, fourth, or fifth aspect, the anti-human PD-1 antibody or antigen-binding fragment thereof comprises three light chain CDRs as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and three heavy chain CDRs as set forth 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 aspect, the anti-human PD-1 antibody or antigen-binding fragment thereof comprises a light chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 5 and a heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 10. L region comprising the amino acid sequence set forth in SEQ ID NO: 4, and a V H region comprising the amino acid sequence set forth 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 set forth in SEQ ID NO: 5 and a heavy chain comprising or consisting of the amino acid sequence set forth 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 dostarlimab.

[0074] Detailed description of the invention

[0075] Definitions and abbreviations

[0076] The following list defines various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances.

[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 more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0079] As used herein, the term "about" in the context of a term or numerical designation means plus or minus 10% of the value being modified (rounded to the nearest whole number if the value being modified is not divisible, e.g., number of molecules or nucleotides).

[0080] An "antibody-drug conjugate," "ADC," or "immunoconjugate" refers to an antibody molecule or antigen-binding fragment thereof covalently or non-covalently bound to one or more biologically active molecules, with or without a linker. The term "antibody" is used in the broadest sense and includes polyclonal and monoclonal antibodies, e.g., intact 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 term "at least one" or "one or more" each includes a single item selected from a list and a collection of two or more items selected from the list.

[0082] The term "administering" or "administration" refers to the act of injecting or otherwise physically delivering a substance (e.g., an anti-PD-1 antibody) that is present outside of the body to a patient, e.g., 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 noted, an "antibody fragment" or "antigen binding fragment" refers to a fragment of an antibody that retains the ability to specifically bind to an antigen, e.g., a fragment that retains one or more CDR regions and the ability to specifically bind to an antigen. An antibody "specifically binds" to PD-1 means that the antibody exhibits preferential binding to PD-1 over other proteins, as the case can be, but such specificity does not require absolute binding specificity. An antibody is considered to be "specific" for its intended target if its binding is determinative for the presence of the target protein in a sample, e.g., does not produce false positives, etc. An antibody or binding fragment thereof will bind to the target protein with an affinity that is at least two-fold greater, preferably at least 10-fold greater, more preferably at least 20-fold greater, and most preferably at least 100-fold greater than the affinity for non-target proteins.

[0084] Antigen binding moieties 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 an antigen that contain at least a portion of an immunoglobulin sufficient to confer antigen (e.g., PD-1) specificity. Depending on the amino acid sequence of the constant region of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions that correspond to the different classes of immunoglobulins are called a, d, e, g, and m, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. Antigen binding fragments of a full-length antibody can be used to prepare 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 multi-specific 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, e.g., scFv.

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

[0086] “Advanced solid malignancy” and “advanced solid tumor” are used interchangeably to refer to a tumor that cannot be resected with curative intent. Advanced solid tumors include, but are not limited to, metastatic tumors in bone, brain, breast, liver, lung, lymph node, pancreas, prostate, and soft tissue (sarcomas).

[0087] As used herein, the term "antibody" refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is 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. A "parental antibody" refers to an antibody obtained by exposure of the immune system to an antigen prior to modification of the antibody for a particular use, such as humanization of an antibody for use as a human therapeutic. As used herein, the term "antibody" includes not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion, fusion protein comprising an antigen binding portion, and any other modified configuration of an immunoglobulin molecule that comprises an antigen recognition site.

[0088] Generally, a basic antibody structural unit includes a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The variable region of each light / heavy chain pair forms the antibody binding site. Thus, in general, an intact antibody has two binding sites. The carboxy-terminal portion of the heavy chain can define a constant region primarily responsible for effector functions. Generally, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define a Fundamental Immunology (Fundamental Immunology), Ch. 7, Paul, W., ed., Second Edition, Raven Press, N.Y. (1989).

[0089] A "biological therapeutic agent" refers to 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 inhibits anti-tumor immune responses.

[0090] The term "carrier" as used herein includes carriers, excipients, and diluents, and refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.

[0091] As used herein, the term "comprising" can include the embodiments "consisting of and "consisting essentially of." The terms "comprise," "include," "having," "has," "may," "contain," "containing," or variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or methods "consisting of and "consisting essentially of the enumerated components, only allowing the presence of the named components or compounds, and any acceptable carriers or fluids, and excluding other components or compounds.

[0092] "CDR" refers to one of the three hypervariable regions within the antibody V H one of the three hypervariable regions within the non- framework region of a β-sheet framework, or antibody V L one of the three hypervariable regions within the non- framework region of a β-sheet framework. Thus, CDRs are variable region sequences interspersed among framework region sequences. CDR regions are well known to those skilled in the art and have been defined, for example, by Kabat as the regions of greatest hypervariability within antibody variable domains. Structurally, Chothia has defined CDR region sequences as the residues that are not part of the conserved β-sheet framework, thus enabling them to adopt different conformations. Both of these 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 a number of 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 within different antibody hypervariable regions varies, additional residues relative to the canonical position are typically numbered with a, b, c, etc. next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al., supra). This nomenclature is also well known to those skilled in the art. The correspondence between 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 some embodiments, the CDRs are as defined by the Kabat numbering system. In other embodiments, the CDRs are as defined by the IMGT numbering system. In other embodiments, the CDRs are as defined by the AbM numbering system. In other embodiments, the CDRs are as defined by the Chothia numbering system. In other embodiments, the CDRs are as defined by the Contact numbering system.

[0093] Table 1. Correspondence between CDR numbering systems

[0094] A "chemotherapeutic agent" is a compound useful in the treatment of cancer. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents (including platinum-containing chemotherapeutics), antimetabolites, kinase inhibitors, spindle poisons plant 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 expression of genes associated with abnormal cell proliferation or tumor growth. Chemotherapeutic agents useful in the treatment methods of the disclosure include cytostatic and / or cytotoxic agents.

[0095] A "chimeric antibody" refers to an antibody having a portion of its heavy and / or light chains containing sequences derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) 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 the administration of 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, to a patient concomitantly, that is, within the same overall treatment protocol. The period of treatment with at least one of the anti-human PD-1 antibodies (or antigen binding fragment thereof) ("anti-PD-1 treatment") is the time period during which the patient receives treatment with the anti-human PD-1 antibody (or antigen binding fragment thereof); that is, the total length of 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 of Formula (I) treatment") is the time period during which the patient receives treatment with the immunoconjugate of Formula (I); that is, the total length of 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 and the immunoconjugate of Formula (I) treatment overlap at least one day. In certain embodiments, the anti-PD-1 treatment and the immunoconjugate of Formula (I) treatment are concurrent. In some embodiments, the anti-PD-1 treatment begins prior to the immunoconjugate of Formula (I) treatment. In some embodiments, the immunoconjugate of Formula (I) treatment begins prior to the anti-PD-1 treatment. In some embodiments, the anti-PD-1 treatment ends prior to the termination of the immunoconjugate of Formula (I) treatment. In some embodiments, the immunoconjugate of Formula (I) treatment ends prior to the termination of the anti-PD-1 treatment.

[0097] The terms "complementarity determining region" and "CDR," are synonymous with "hypervariable region" or "HVR," and refer to subregions within antibody variable domains that impart specificity and / or affinity of an antibody for its antigen. Generally, there are three CDRs in each heavy chain variable domain (HCDR1, HCDR2, and HCDR3) and three CDRs in each light chain variable domain (LCDR1, LCDR2, and LCDR3). "Framework regions" ("FRs") refer to the portions of the variable domains that are not CDRs. Generally, there are four FRs in each full-length heavy chain variable domain and four FRs in each full-length light chain variable domain. The precise amino acid sequence boundaries of a particular CDR or FR 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) ("Kabat numbering scheme"); Al-Lazikani et al., JMB 273 927-948 (1997) ("Chothia numbering scheme"); MacCallum et al., J. Mol. Biol., 262:732-745 (1996) ("Contact" numbering scheme); Lefranc et al., Dev Comp Immunol, 27(l):55-77 (2003) ("IMGT" numbering scheme); and Honegger and Pluckthun, J. Mol. Biol., 309(3):657-70 (2001) ("Aho" numbering scheme).

[0098] The boundaries of a particular CDR or FR can vary depending on which scheme is used to determine them. For example, the Kabat scheme is based on sequence alignment, while the Chothia scheme is based on structural information. Both the Kabat and Chothia numbering schemes are based on the most common antibody region sequence lengths, with insertions denoted by inserted letters, e.g., "30a." The two schemes place certain insertions and indels at different positions, resulting in numbering differences. The Contact scheme is based on complex crystal structure analysis and is similar in many respects to the Chothia numbering scheme. Unless otherwise specified, the CDRs of an antibody referred to herein can be determined according to any of the Kabat, Chothia, IMGT, and Contact methods.

[0099] A "conservatively modified variant" or "conservative substitution" refers to the replacement of 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, etc.) such that such changes often can be made without altering 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 substitution 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., p. 224 (4th ed.)). Moreover, substitution of amino acids with similar structural or functional properties is less likely to disrupt 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 0-10, such as an integer from 1-10; 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., or ), which is an integer or decimal number from 0 to 10, e.g., an integer or decimal number from 1 to 10. Thus, in one embodiment, for an antibody-drug conjugate of the disclosure, the DAR is an integer or decimal number 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 an antibody-drug conjugate of the disclosure, the DAR is an integer or decimal number from 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, 6 to 10, 6 to 9, 6 to 8, 6 to 7, 7 to 10, 7 to 9, 7 to 8, 8 to 10, 8 to 9, or 9 to 10. In some embodiments, for an antibody-drug conjugate of the disclosure, the DAR is an integer or decimal number from 1 to 8, 1 to 4, 2 to 5, 3 to 6, 4 to 7, 5 to 8, or 6 to 8. In other embodiments, for an antibody-drug conjugate of the disclosure, the DAR is an integer or decimal number from 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, or 6 to 8. In other embodiments, for an antibody-drug conjugate of the disclosure, the DAR is an integer or decimal number from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 5 to 7, or 7 to 8. Likewise, for a composition comprising an antibody-drug conjugate of the 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 decimal number 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 a composition comprising an antibody-drug conjugate of the disclosure, the DAR of the composition is an integer or decimal number from 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, 6 to 10, 6 to 9, 6 to 8, 6 to 7, 7 to 10, 7 to 9, 7 to 8, 8 to 10, 8 to 9, or 9 to 10. In further embodiments, for a composition of an antibody-drug conjugate of the disclosure, the DAR of the composition is an integer or decimal number from 1 to 4, 2 to 5, 3 to 6, 4 to 7, 5 to 8, or 6 to 8.In other embodiments, for a composition comprising an antibody-drug conjugate of the present disclosure, the DAR of the composition is an integer or a decimal number from 1-3, 2-4, 3-5, 4-6, 5-7, or 6-8. In further embodiments, for a composition comprising an antibody-drug conjugate of the present disclosure, the DAR of the composition is an integer or a decimal number from 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8. As used above, “composition” shall be understood to mean a pharmaceutical composition, as used above.

[0102] The therapeutic agents and compositions provided by the present disclosure can be administered by any suitable enteral or parenteral route of administration. The term “enteral route of administration” refers to administration via any portion of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal routes, or intragastric routes. A “parenteral route of administration” refers to a route of administration other than an enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and sternal, subcutaneous, or topical administration. The therapeutic agents and compositions of the present disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. Suitable routes of administration and methods can vary depending on a variety of factors, such as the particular therapeutic agent used, the rate of absorption desired, the particular formulation or dosage form used, the type or severity of the disease being treated, the particular site of action, and the patient’s condition, and can be readily selected by one of skill in the art.

[0103] “Homology” refers to the sequence similarity between two polypeptide sequences when optimally aligned. Two Abs are homologous at a position if that position in both of the sequences being compared is occupied by the same amino acid monomer subunit, e.g., if both of the light chain CDRs of two different Abs have an alanine at a certain position, then the two Abs are homologous at that position. The percent homology is the number of matching positions divided by the number of positions compared x 100. For example, if two sequences being compared have 8 matches out of 10 positions when optimally aligned, then the two sequences have 80% homology. Typically, the comparison is made over the full length of the sequences being compared when the sequences are aligned to give the greatest percent homology. The comparison can be made, for example, by the BLAST algorithm, in which the parameters of the algorithm are selected to give the maximum match between the sequences over the entire length of the respective reference sequences.

[0104] The following references relate to the BLAST algorithm, which is frequently used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F. et al. (1990) J. Mol. Biol., 215:403-410; Gish, W. et al. (1993) Nature Genet., 3:266-272; Madden, T.L. et al. (1996) Meth. Enzymol., 266:131-141; Altschul, S.F. et al. (1997) Nucleic Acids Res., 25:3389-3402; Zhang et al. (1997) Genome Res., 7:649-656; Wootton, J.C. et al. (1993) Comput. Chem., 17:149-163; Hancock, J.M. et al. (1994) Comput. Appl. Biosci., 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O. et al., “A model of evolutionary change in proteins.” In Atlas of Protein Sequence and Structure (1978), vol. 5, suppl. 3, M.O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R.M. et al., “Matrices for detecting distant relationships.” In Atlas of Protein Sequence and Structure (1978) vol. 5, suppl. 3, M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, D.C.; Altschul, S.F. (1991) J. Mol. Biol., 219:555-565; States, D.J. 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.Dembo, A. et al. (1994) Ann. Prob., 22:2022-2039; and Altschul, S. F., "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. Human antibodies can contain murine carbohydrate chains if produced in mice, mouse cells, or hybridomas derived from mouse cells. Similarly, a "mouse antibody" or "rat antibody" refers to an antibody comprising only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

[0106] A "humanized antibody" refers to a form of antibody that contains sequences from non-human (e.g., murine) antibodies as well as human antibodies. These antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody contains substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable region loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. When the parent rodent antibody and the humanized antibody need to be distinguished, the prefix "hum," "hu" or "h" can be added to the antibody clone name. The humanized form of a rodent antibody generally contains the same CDR sequences as the parent rodent antibody, although some amino acid substitutions can be included for increasing affinity, increasing stability of the humanized antibody, or for other reasons.

[0107] An "intact" antibody comprises an antigen binding site as well as a CL and at least heavy chain constant regions CH1, CH2 and CH3. The constant regions can include human constant regions or amino acid sequence variants thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0108] The term "immune response" as used herein relates to any one or more of the following responses: specific immune response, non-specific immune response, specific and non-specific 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] The term "immune response" as used herein relates to any one or more of the following responses: specific immune response, non-specific immune response, specific and non-specific 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" as used when referring to an antibody or fragment thereof refers to the state of purification, in this case, the defined molecule is substantially free of other biological molecules, such as nucleic acids, proteins, lipids, saccharides, or other materials, such as cellular debris and growth media. Generally, the term "isolated" does not mean that such materials are completely absent or free from water, buffers, or salts, unless their content substantially interferes with the experimental or therapeutic use of the binding compound as described herein.

[0111] "Kabat" as used herein refers to the immunoglobulin alignment and numbering system initiated 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, a "monoclonal antibody" or "mAb" or "Mab" refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence, except for possible naturally occurring mutations that can be present, except for possibly naturally occurring mutations that can be present. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, that specifically bind to different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure can be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or can be made by recombinant DNA methods (see, e.g., U.S. Patent 4816567). The "monoclonal antibodies" can also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature, 352:624-628 and Marks et al. (1991) J. Mol. Biol, 222:581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol., 116:731.

[0113] A "PD-1 antagonist" refers to any compound or biological molecule that blocks the binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell, or NKT cell), and preferably also blocks the binding of PD-L2 expressed on a cancer cell to PD-1 expressed on an immune cell. 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 therapeutic methods of treatment of a human individual, compositions, and uses of the disclosure, 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 human PD-1 amino acid sequence is found at NCBI Locus No.: NP_005009. The human PD-L1 and PD-L2 amino acid sequences are found at NCBI Locus Nos.: NP_054862 and NP_079515, respectively.

[0114] “Pembrolizumab” (formerly known as MK-3475, SCH 900475, and lambrolizumab) is alternatively referred to herein as “pembro” and is a humanized IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013), which includes the heavy and light chain amino acid sequences and CDRs described in Table 3. As used herein, “pembro” includes the mAb having the structure described above (Id.) but not including the C-terminal lysine in the heavy chain. Pembrolizumab has been approved by the U.S. FDA as described in the prescribing information (Merck & Co., Inc., Rahway, NJ USA; U.S. first approval 2014, updated February 2023). The term pembrolizumab includes the mAb having the structure described above (Id.) but not including the C-terminal lysine in the heavy chain.

[0115] As used herein, “pembrolizumab variant” refers to a monoclonal antibody comprising the same heavy and light chain sequences as pembrolizumab heavy and light chain sequences, except for 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 in the framework regions or constant regions, and which 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, respectively, in their full-length light and heavy chain sequences. Pembrolizumab variants are substantially identical to pembrolizumab with respect to the following properties: binding affinity for PD-1 and the ability to block the binding of each of PD-L1 and PD-L2 to PD-1.

[0116] “Platinum-containing chemotherapy” (also referred to as platinum agents) refers to the treatment of cancer using platinum coordination complexes as chemotherapeutic agents. Platinum-containing chemotherapeutic agents are alkylating agents that cross-link DNA, which leads to inefficient DNA mismatch repair, often resulting in apoptosis. Examples of platinum agents include cisplatin, carboplatin, and oxaliplatin.

[0117] As used herein, the term “patient” (or “subject”) refers to a mammal that has been the object of treatment, observation or experiment. The mammal can be male or female. The mammal can be one or more selected from the group consisting of a human, a bovine (e.g., a cow), a porcine (e.g., a pig), an ovine (e.g., a sheep), a caprine (e.g., a goat), an equine (e.g., a horse), a canine (e.g., a domestic dog), a feline (e.g., a domestic cat), a leporine (a rabbit), a rodent (e.g., a rat or a mouse), a procyonid (Procyon lotor) (e.g., a raccoon). In particular embodiments, the patient is a human.

[0118] The term "patient in need thereof as used herein 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 suitable for use in a formulation for delivering a therapeutic agent. The carrier can be an antiadherent, a binder, a coating agent, a disintegrant, a filler or diluent, a preservative (such as an antioxidant, an antibacterial or an antifungal agent), a sweetener, an absorption delaying agent, a wetting agent, an emulsifying agent, a buffer, and the like. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), dextrose, vegetable oils (e.g., olive oil), saline, buffers, buffered saline solutions, and isotonic agents, such as sugars, polyols, sorbitol, and sodium chloride.

[0120] The term "pharmaceutically acceptable salt" refers to a salt that has similar efficacy as the parent compound and is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise harmful to the recipient thereof). Accordingly, one embodiment of the present disclosure provides a pharmaceutically acceptable salt of a compound of the present disclosure. As used herein, the term "salt" denotes 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. Salts of the compounds of the present disclosure can be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the present disclosure with an amount of acid or base (e.g., an equivalent) in a medium (e.g., a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0121] Exemplary acid addition salts include acetate, ascorbate, benzoate, besylate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthylenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also referred to as tosylate), and the like. Suitable salts include acid addition salts, e.g., that can be formed 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 that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.), 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, D.C., on the Internet). These disclosures are incorporated herein by reference thereto.

[0122] Exemplary basic salts include ammonium salts, alkali metal salts of sodium, lithium, and potassium, alkaline earth metal salts of calcium and magnesium, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (for example, methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (for example, dimethyl, diethyl, and dibutyl sulfates), long chain halides (for example, decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (for example, benzyl and phenethyl bromides), and others. Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (for example sodium or potassium), alkaline earth metal salts (for example calcium or magnesium), and salts with suitable organic ligands such as quaternary ammonium salts. In addition, where an acid (-COOH) or alcohol group is present, pharmaceutically acceptable esters can be used to alter the solubility or hydrolysis characteristics of the compound.

[0123] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the disclosure, and all acid, base salts, and quaternary amines are meant to be encompassed by the term "salt" as used herein.

[0124] Furthermore, where the compounds of the disclosure contain both a basic moiety, such as but not limited to, aliphatic primary, secondary, tertiary or cyclic amines, aromatic or heteroaromatic amines, pyridines or imidazoles, and an acidic moiety, such as but not limited to, tetrazoles or carboxylic acids, zwitterions ("inner salts") can be formed and are included within the scope of the term "salt" as used herein. It is understood that certain compounds of the disclosure can exist in a zwitterionic form and simultaneously possess both an anionic and cationic center within the same compound and a net neutral charge. Such zwitterions are included within the disclosure.

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

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

[0127] A "sustained response" refers to a continued therapeutic effect 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 a duration that is at least 1.5, 2.0, 2.5, or 3 times longer than the duration of treatment.

[0128] The term "concurrent administration" as used herein in connection with the administration of a drug means that the drugs are administered such that each drug is present in the body of the patient at the same time. In addition to concomitant administration of the drugs (via the same or alternative routes), concurrent administration can also include administration of the drugs at different times (by the same or alternative routes).

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

[0130] "Treating" a cell proliferative disorder as used herein means administering the combination therapy of an anti-human PD-1 antibody (or antigen-binding fragment thereof) and an immunoconjugate of Formula (I) to a patient having a cell proliferative disorder (e.g., cancer) 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 into peripheral organs, or a reduced rate of tumor metastasis or tumor growth, including by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. Generally, the agents of the method of treatment are administered in amounts effective to reduce one or more symptoms of the disease in the patient or population receiving treatment, to any clinically measurable degree, whether by inducing regression of such symptoms or by inhibiting progression of such symptoms. The amount of an agent in the method of treatment that is effective to reduce any particular symptom of the disease can vary according to factors such as the patient's disease state, age, and weight, and the ability of the combination therapy to elicit a desired response in the patient. Whether a disease symptom has been reduced can be assessed by any clinically measurable means typically employed by a physician or other skilled health care provider to judge the severity or progression state of the symptom. "Treatment" can include one or more of the following effects: inducing / increasing an anti-tumor immune response, reducing the number of one or more tumor markers, halting or delaying the growth of a tumor or a 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, ameliorating or eliminating the clinical manifestations of the disease, reducing the severity or duration of clinical symptoms, prolonging survival of the treated disease relative to the expected survival of a similar untreated patient, and inducing a complete or partial remission of a cancerous disorder, wherein the disease is cancer, more specifically, non-small cell lung cancer.

[0131] The dosage of a therapeutic agent that effectively relieves symptoms of any specific disease can vary depending on factors such as the patient's disease state, age, weight, and the drug's ability to elicit the 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 healthcare provider to determine the severity or progression of the symptoms.

[0132] The effectiveness of treatment in cancer can be measured using many methods (See, W.A. Weber, J. Nucl. Med. 50: 1S-10S (2009)). For example, regarding tumor growth inhibition, according to NCI criteria, a T / C ≤ 42% is the minimum level of antitumor activity. A T / C < 10% is considered a high level of antitumor activity, where T / C (%) = median tumor volume of the treated subject / median tumor volume of the reference subject × 100. In some embodiments, the treatment achieved by the therapy disclosed herein is any one of PR, CR, OR, PFS, DFS, and OS. PFS, also known as “progression-free survival,” represents the duration of treatment without tumor growth and includes the time a patient experiences CR or PR as well as the time a patient experiences SD. DFS refers to the duration of treatment and the time a patient remains disease-free. OS refers to the extended life expectancy compared to naturally occurring or untreated individuals or patients. In some embodiments, the response to the therapy disclosed herein is any one of PR, CR, PFS, DFS, or OR, as assessed using RECIST 1.1 response criteria. Treatment regimens for cancer patients effectively treated with the therapy disclosed herein may vary based on factors such as the patient's disease status, age, and weight, and the ability of the therapy to elicit an anticancer response in that patient. While embodiments of any aspect of this disclosure may not effectively achieve 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, etc. 2 - Tests, based on Mann and Whitney's U-test, Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test, and Wilcoxon-test.

[0133] The terms “treatment regimen,” “dosing protocol,” and “dosing regimen” are used interchangeably and refer to the dosage and timing of administration of each therapeutic agent in the combination therapy disclosed herein.

[0134] “Tumor,” when applied to a patient diagnosed 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 of, or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cell that forms them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) usually do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0135] “Tumor burden,” also referred to 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 tumors throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by various methods known in the art, for example, by measuring the size of a tumor when removed from the patient (e.g., using calipers) or in vivo using imaging techniques (e.g., ultrasound, bone scan, CT or MRI scan).

[0136] The term “tumor size” refers to the total 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, for example, by measuring the size of a tumor when removed from the patient (e.g., using calipers) or in vivo using imaging techniques (e.g., bone scan, ultrasound, CT or MRI scan).

[0137] “Variable region,” as used herein, refers to the segment of an IgG chain that is variable in sequence between different antibodies. The “variable region” of an antibody refers to either 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 can be referred to as “V H ”. The variable region of the light chain can be referred to as “V L ”.

[0138] Generally, the variable regions of both heavy and light chains contain three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FRs). The CDRs are typically arranged in a framework region, which is capable of binding an epitope. Generally, from N-terminus to C-terminus, both the light chain and the heavy chain variable domains comprise 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 assignment of amino acids to each domain is consistent with the definition set forth in: Sequences of Proteins of Immunological Interest, Kabat et al., U.S. Department of Health and Human Services, Bethesda, Md., 5th Ed., 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] The term "variant," 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, can refer to a peptide or polypeptide that comprises 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 as compared to a native or unmodified sequence. For example, a variant of an anti-PD-1 antibody can result from 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 can be naturally occurring or can be artificially constructed. Polypeptide variants can be prepared from corresponding nucleic acid molecules encoding the variant. In particular embodiments, an antibody variant (e.g., an anti-PD-1 antibody variant) retains at least the functional activity of the antibody. In some embodiments, an anti-PD-1 antibody variant binds PD-1 and / or antagonizes PD-1 activity.

[0140] When aspects or embodiments of the present disclosure are described in terms of a Markush group or other alternative grouping, the present disclosure is not intended to be limited to the whole group listed as a whole, but also to each individual member of the group and all possible subgroups of the main group, as well as to the main group missing one or more members. The present disclosure also contemplates explicitly excluding any one or more members of a group.

[0141] All ranges disclosed herein are inclusive of the endpoints and independently combinable (e.g., ranges of "50 mg to 500 mg" is inclusive of the endpoints 50 mg and 500 mg, as well as all intermediate values of the range, unless the context clearly dictates otherwise). The endpoints and any values disclosed in this application are not limited to the precise values stated. They are sufficiently imprecise to include values approximating these.

[0142] Unless defined otherwise, 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. If a conflict arises between the definitions of terms in this section and the patent, patent application, or other filing, including any provisional application(s), that can be filed with the present application, the terms in this section prevail. In the entire description and claims of this specification, the word "comprise" or variations 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 otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Any reference to an example herein is intended to refer to an example-fied implementation, and not to a limitation of aspects of the present disclosure.

[0143] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can 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 with the following meanings:

[0145] Additional abbreviations can 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 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 the 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 20200347075. Immunoconjugate A has the following structure:

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

[0151] Ab1is sacituzumab.

[0152] PD-1 antagonists or anti-human PD-1 monoclonal antibodies for use in the methods, compositions, kits, and uses of the present disclosure

[0153] Examples of mAbs that bind human PD-1 useful for 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 useful for the methods, compositions, kits, and uses of the present disclosure as PD-1 antagonists include: pembrolizumab (formerly known as MK-3475, SCH 900475, and lamprolizumab), which is a humanized IgG4 mAb having the 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 the humanized antibodies h409A11, h409A16, and h409A17 described in WO 2008 / 156712.

[0154] Other examples of PD-1 antagonists useful for the methods, compositions, kits, and uses of the present disclosure include, but are not limited to: nivolumab (Opdivo®; Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (Libtayo®; Sanofi-Aventis U.S. LLC., Bridgewater, NJ), and dostarlimab (PF-06957018; Pfizer Inc., New York, NY). Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (Libtayo®; Sanofi-Aventis U.S. LLC., Bridgewater, NJ), and dostarlimab (PF-06957018; Pfizer Inc., New York, NY). Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Sanofi-Aventis U.S. LLC., Bridgewater, NJ) and dostarlimab (PF-06957018; Pfizer Inc., New York, NY). 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 ligand, 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 the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, pidilizumab (U.S. Pat. No. 7,332,582), AMP-514 (Medlmmune LLC, Gaithersburg, MD), PDR001 (U.S. Pat. No. 9,683,048), tislelizumab BGB-A317 (U.S. 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 cemiplimab. 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 antibody or antigen-binding fragment thereof for use in the methods and uses disclosed herein comprises three light chain CDRs of CDRL1, CDRL2, and CDRL3 and / or 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 thereof, CDRL2 has the amino acid sequence set forth in SEQ ID NO: 2 or a variant thereof, and CDRL3 has the amino acid sequence set forth in SEQ ID NO: 3 or a variant thereof.

[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 thereof, CDRH2 has the amino acid sequence set forth in SEQ ID NO: 7 or a variant thereof, and CDRH3 has the amino acid sequence set forth in SEQ ID NO: 8 or a variant thereof.

[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 set forth 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 set forth 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 thereof, CDRL2 has the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof, and CDRL3 has the amino acid sequence set forth in SEQ ID NO: 13 or a variant thereof.

[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 one alternative embodiment of the anti-human PD-1 antibody or antigen-binding fragment thereof, the three light chain CDRs have the amino acid sequences set forth 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 set forth 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 yet 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 set forth 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 set forth in SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26.

[0168] In one subembodiment of the above anti-human PD-1 embodiments, the anti- human PD-1 antibody or antigen-binding fragment is an antibody.

[0169] Some of the 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 of the amino acid sequence set forth in SEQ ID NO: 4, and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 9 or a variant of the amino acid sequence set forth in SEQ ID NO: 9. In further embodiments, the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 14 or a variant of the amino acid sequence set forth in SEQ ID NO: 14, and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 19 or a variant of the amino acid sequence set forth in SEQ ID NO: 19. In further embodiments, the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 27 or a variant of the amino acid sequence set forth in SEQ ID NO: 27, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 28 or a variant of the amino acid sequence set forth in SEQ ID NO: 28, the amino acid sequence set forth in SEQ ID NO: 29 or a variant of the amino acid sequence set forth in SEQ ID NO: 29, or the amino acid sequence set forth in SEQ ID NO: 30 or a variant of the amino acid sequence set forth in 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 having one, two, three, four, or five amino acid substitutions. In some embodiments, the substitutions are in the framework region (i.e., outside of 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 containing or consisting of the amino acid sequence shown in SEQ ID NO: 4, and a heavy chain variable region containing or consisting of the amino acid sequence shown in SEQ ID NO: 9. In another embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region containing or consisting of the amino acid sequence shown in SEQ ID NO: 14, and a heavy chain variable region containing or consisting of the amino acid sequence shown in 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 containing or consisting of the amino acid sequence shown in SEQ ID NO: 28, and a heavy chain variable region containing or consisting of the amino acid sequence shown in SEQ ID NO: 27. In another embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region containing or consisting of the amino acid sequence shown in SEQ ID NO: 29, and a heavy chain variable region containing or consisting of the amino acid sequence shown in SEQ ID NO: 27. In yet another embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region containing or consisting of the amino acid sequence shown in SEQ ID NO: 30, and a heavy chain variable region containing or consisting of the amino acid sequence shown in SEQ ID NO: 27.

[0171] In yet another embodiment, the methods, kits, or uses disclosed herein include having V L Domain and / or V H Anti-human PD-1 antibody or antigen-binding protein with the V domain L Domain and / or V H The structural domain has the same characteristics as the above V L Domain or V H One of the structural domains exhibits at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75%, or 50% sequence homology and demonstrates specific binding to PD-1. In other embodiments, the anti-human PD-1 antibody or antigen-binding protein of this method comprises V L Domain and / or V H The domain has at most 1, 2, 3, 4, 5 or more amino acid substitutions and exhibits 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 of the immunoglobulin classes, including IgM, IgG, IgD, IgA, and IgE. Preferably, the antibody is an IgG antibody. IgG of any isotype can be used, including IgGl, IgG2, IgG3, and IgG4. Different constant domains can be appended to the V L and V H domains provided herein. For example, if the particular intended use of the antibodies (or fragments) disclosed herein is one that requires altered effector function, then a heavy chain constant domain other than IgGl can be used. While IgGl antibodies provide long half-lives and effector functions, such as complement activation and antibody-dependent cellular cytotoxicity, these activities can not be desired for all uses of the antibodies. In such cases, for example, an IgG4 constant domain can 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 sequence of amino acid residues set forth in SEQ ID NO: 5, and a heavy chain comprising or consisting of the sequence of amino acid residues set forth in SEQ ID NO: 10. In some alternative embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of the sequence of amino acid residues set forth in SEQ ID NO: 15, and a heavy chain comprising or consisting of the sequence of amino acid residues set forth in SEQ ID NO: 20. In yet some embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of the sequence of amino acid residues set forth in SEQ ID NO: 32, and a heavy chain comprising or consisting of the sequence of amino acid residues 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 sequence of amino acid residues set forth in SEQ ID NO: 33, and a heavy chain comprising or consisting of the sequence of amino acid residues 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 sequence of amino acid residues set forth in SEQ ID NO: 34, and a heavy chain comprising or consisting of the sequence of amino acid residues 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 cemiplimab. In another such embodiment, the agent is dostarlimab.

[0174] Generally, the amino acid sequence variants of the anti-PD-1 antibodies and antigen binding fragments disclosed herein will 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% to the amino acid sequence of the reference antibody or antigen binding fragment (e.g., heavy chain, light chain, V H L or humanized sequence). Identity or homology with respect to a sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the anti-PD-1 residues, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Gaps in the carboxy- and amino-termini or internal gaps are not to be considered in the calculation of sequence identity.​

[0175] Sequence identity refers to the extent 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, with parameters of the algorithm selected to give the maximum match between the sequences over their entire length. The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F. et al. (1990) J. Mol. Biol., 215:403-410; Gish, W. et al. (1993) Nature Genet., 3:266-272; Madden, T.L. et al. (1996) Meth. Enzymol., 266:131-141; Altschul, S.F. et al. (1997) Nucleic Acids Res., 25:3389-3402; Zhang et al. (1997) Genome Res., 7:649-656; Wootton, J.C. et al. (1993) Comput. Chem., 17:149-163; Hancock, J.M. et al. (1994) Comput. Appl. Biosci., 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O. et al., “A model of evolutionary change in proteins.” In Atlas of Protein Sequence and Structure (1978) Vol. 5, Suppl. 3, M.O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M. et al., “Matrices for detecting distant relationships.” In Atlas of Protein Sequence and Structure, (1978) Vol. 5, Suppl. 3, M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F. (1991) J. Mol. Biol., 219:555-565; States, D.J. et al. (1991) Methods, 3:66-70; Henikoff, S. et al. (1992) Proc. Natl. Acad. Sci. USA, 89:10915-1919; Altschol, S.F. et al. (1993) J. Mol. Evol.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, S. F., "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. In particular, kappa, lambda, or variants thereof can be used in the compositions of the application 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 antigen-binding fragment thereof) is an anti-PD-1 monoclonal antibody. In particular aspects of these embodiments, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, and AMP-224. In specific aspects of these embodiments, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is selected from the group consisting of nivolumab and pembrolizumab. In a more specific aspect, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is nivolumab. In another more specific aspect, the anti-human PD-1 antibody (or antigen-binding fragment thereof) 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 talizumab. In other such embodiments, the anti-human PD-1 antibody is AMP-514. In other such embodiments, the anti-human PD-1 antibody is cibisatamab. In other such embodiments, the anti-human PD-1 antibody is dostarlimab.

[0181] Immunoconjugates of Formula (I)

[0182] Immunoconjugates of Formula (I) are useful in the present disclosure:

[0183] wherein Ab is an antibody that binds 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] wherein n is an integer from 1 to 10; and

[0187] Ab is an antibody that binds Trop-2, comprising:

[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 a LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; a LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0190] In certain embodiments, the immunoconjugate useful for the present disclosure is an immunoconjugate of formula (I):

[0191] wherein n is an integer from 1-10; and

[0192] Ab is an antibody that binds Trop-2, comprising:

[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 immunoconjugate useful for the present disclosure is an immunoconjugate of formula (I):

[0196] wherein n is an integer from 1-10; and

[0197] Ab is an antibody that binds Trop-2, comprising:

[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 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:

[0201] wherein n is an integer from 1-8; and

[0202] Ab1 is sacituzumab.

[0203] In other preferred embodiments, the composition comprising the immunoconjugate of formula (I) is administered in combination with an antibody that binds Trop-2, wherein

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

[0205] Ab1 is sacituzumab.

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

[0207] In some embodiments, the DAR of the composition is an integer or decimal number from 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 disclosure, the anti-Trop-2 antibody of the immunoconjugate of Formula (I) is sacituzumab (or hRS7), which is described in U.S. Patent Publication No. 2012 / 0237518. This antibody can also be obtained by screening from vectors designed, constructed from antibody libraries displaying antibodies, which are disclosed in CN103476941A, or can be obtained by screening the library of Sorrento Therapeutics, Inc. .

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

[0210] Table 5 List of amino acid sequences of sacituzumab (‘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 one particular embodiment, the immunoconjugate of Formula (I) comprises about 6 to about 8 linkers / drug moieties per antibody (i.e., n is about 6 to about 8). In one particular 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 specific for human Trop-2, and thus can be used to deliver the conjugated payload to an excellent targeting moiety to a cell (e.g., Trop-2 positive cell). In certain embodiments, the immunoconjugate used in the therapeutic regimen of the present disclosure is any anti-TROP-2 immunoconjugate described in U.S. Patent Publication No. 20200347075.

[0214] Use of the combination therapy of the present disclosure

[0215] Treatment or prevention of a cell proliferative disorder

[0216] The combination therapy disclosed herein is potentially useful in the treatment of a disease or disorder, including but not limited to, a cell proliferative disorder. Cell proliferative disorders include, but are not limited to, cancer, benign papillary hyperplasia, and gestational trophoblastic disease. The terms “cancer,” “cancerous,” or “malignant” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0217] Thus, in one aspect, the present disclosure relates to a method of treating a cell proliferative disorder, the method 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 together effective to treat the cell proliferative disorder.

[0218] In some embodiments, 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), a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI); and (b) an immunoconjugate of Formula (I), wherein the amounts administered are effective together 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) an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

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

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

[0224] (b) an 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 use in treating a cell proliferative disorder, such as a cancer, in a human patient, comprising:

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

[0228] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof cell proliferative disorder, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

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

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

[0231] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof cell proliferative disorder.

[0232] In some embodiments, the present disclosure provides a pharmaceutical combination for use in the treatment of a cell proliferative disorder, e.g., cancer, in a human patient, the pharmaceutical combination comprising:

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

[0234] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof cell proliferative disorder, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

[0235] In some embodiments, the present disclosure provides a pharmaceutical combination for use in the treatment of a cell proliferative disorder, e.g., cancer, in a human patient, the pharmaceutical combination comprising:

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

[0237] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof cell proliferative disorder.

[0238] In some embodiments, the present disclosure provides a pharmaceutical combination for use in the treatment of a cell proliferative disorder, e.g., cancer, in a human patient, the pharmaceutical combination comprising:

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

[0240] (b) an anti-human PD-1 antibody or antigen-binding fragment thereof cell proliferative disorder, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

[0241] In some embodiments, the present disclosure provides a pharmaceutical combination for use in the treatment of a cell proliferative disorder, e.g., cancer, in a human patient, the pharmaceutical combination comprising:

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

[0243] (b) an 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) an 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 antigen binding fragment thereof; and

[0250] (c) a platinum-containing chemotherapeutic agent.

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

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

[0253] (b) a platinum-containing chemotherapeutic agent.

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

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

[0256] (b) an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

[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 level of PD-L1 expression, for example, a tumor proportion score (TPS) of > 1%, or a TPS of 1-49%, or a TPS of > 50%.

[0264] In some embodiments, the non-small cell lung cancer has a PD-L1 expression level that is not elevated, e.g., has a tumor proportion score (TPS) <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 a central nervous system metastasis; in some embodiments, the non-small cell lung cancer does not have a central nervous system metastasis.

[0267] In some embodiments, the non-small cell lung cancer is treatment naive, or has received first line treatment, or has received more than second line treatment, or has received more than third line treatment.

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

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

[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 an 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 mutant and prior EGFR-TKI treatment failed non-small cell lung cancer.

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

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

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

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

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

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

[0279] In some embodiments, the non-small cell lung cancer is EGFR-mutant and has failed prior 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 particular embodiments, the cell proliferative disorder is selected from cancer, benign papillary hyperplasia, benign neoplastic disease, and gestational trophoblastic disease. In specific embodiments, the gestational trophoblastic disease is selected from hydatidiform mole and gestational trophoblast tumor (e.g., invasive hydatidiform mole, choriocarcinoma, placental site trophoblast tumor, and epithelioid trophoblast tumor).

[0283] In a specific embodiment, the cell proliferative disorder being treated is cancer. Accordingly, 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 amount administered is effective to treat the cancer together.

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

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

[0287] In one embodiment, the patient has previously received a systemic treatment for the cancer. In another embodiment, the patient has not previously received a 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: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; (2) Pulmonary: bronchogenic carcinoma (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, carcinoid carcinoma, vasoactive intestinal peptide tumor), small bowel (adenocarcinoma, lymphoma, carcinoid carcinoma, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectum; (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, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma), and urothelial carcinoma; (5) Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (6) Bone: osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastioma, chondromyxofibroma, osteoid, and giant cell tumors; (7) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, neurglioma), brain (astrocytoma, spongioblastoma, neurglioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, neurglioma, sarcoma); (8) Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig’s cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast cancer;(9) blood: blood (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, moles dysplastic nevi, lipoma, angioma, fibroma, kelomd, psoriasis; and (11) adrenal gland: 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, carcinosarcoma, liver cancer, and multiple myeloma.

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

[0291] In a particular embodiment, the cancer being treated is selected from non-small cell lung cancer, prostate cancer, ovarian cancer, cervical cancer, or urothelial cancer. In a particular embodiment, the cancer is selected from 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 include treating a high-risk stage III melanoma that has been resected.

[0293] In particular embodiments, the cancer is selected from lung cancer. In particular embodiments, the lung cancer is selected from non-small cell lung cancer, bronchial tumors, and pleuropulmonary blastoma.

[0294] In one embodiment, provided herein are methods of 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 methods of treating NSCLC, the patient's tumor is free of EGFR or ALK genomic aberrations. In certain embodiments of the methods of treating NSCLC, the patient's tumor has EGFR or ALK genomic aberrations and has disease progression while on or after treatment for the EGFR or ALK aberration prior to receiving the combination therapy described herein. In a particular embodiment, the NSCLC being treated is free of EGFR mutations and ALK fusion genes. In a particular embodiment, the NSCLC being treated has an EGFR operable mutation and the patient has failed prior EGFR-TKI therapy. In another particular embodiment, the non-small cell lung cancer has a 19del mutation and / or has a 21 L858R mutation. In another particular embodiment, the non-small cell lung cancer is a non-small cell lung cancer with an EGFR operable mutation and the patient has failed prior EGFR-TKI therapy and has failed prior PD-1 / PD-L1 antibody therapy and chemotherapy.

[0295] In particular embodiments, the cancer is selected from the group consisting of malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelioid mesothelioma and sarcoidosis.

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

[0297] In one embodiment, provided herein are methods of 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 eligible for platinum-containing chemotherapy. In further embodiments, the patient has disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. In particular embodiments, the patient's tumor expresses PD-L1 (CPS > 10).

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

[0299] In one embodiment, provided herein is a method of treating unresectable or metastatic microsatellite-high (MSI-H) or mismatch repair deficient colorectal cancer in a human patient. In a particular embodiment, the patient has disease progression after prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

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

[0301] In a particular embodiment, the cancer is selected from lymphoma. In a specific embodiment, the cancer is selected from Hodgkin's lymphoma (e.g., refractory classical Hodgkin's lymphoma), non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.

[0302] In one embodiment, provided herein is a method of treating non-Hodgkin's 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 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 the mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Sezary syndrome, primary central nervous system lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma / leukemia, nasal-type extranodal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma / delta splenic T-cell lymphoma, subcutaneous panniculitis-like T-cell, and Burkitt's lymphoma.

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

[0304] In particular embodiments, the cancer is selected from brain and spinal cord cancers. In specific embodiments, the brain and spinal cord cancers are selected from anaplastic astrocytoma, glioblastoma, astrocytoma, and neuroblastic neurocytoma (also known as olfactory mother cell tumor). In specific embodiments, the brain cancer is selected from astrocytoma (e.g., pilocytic astrocytoma, pituitary giant cell astrocytoma, diffuse astrocytoma, pleomorphic 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, cerebral astrocytoma / malignant glioma, visual pathway and hypothalamic glioma, and primary central nervous system lymphoma. In particular instances of these embodiments, the brain cancer is selected from neuroglioma, glioblastoma multiforme, paraganglioma, and supratentorial primitive neuroectodermal tumor (sPNET). In one embodiment, the brain or spinal cord cancer is a metastatic brain tumor or tumor.

[0305] In particular embodiments, the cancer is selected from head and neck cancer, including recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), nasopharyngeal cancer, cancer of the nasal cavity and paranasal sinuses, hypopharyngeal cancer, oral cavity 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 ocular cancer. In specific embodiments, the ocular cancer is selected from intraocular melanoma and retinoblastoma. In one embodiment, provided herein is a method of 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 treatment. In certain embodiments, the patient has disease progression during or after platinum-containing chemotherapy.

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

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

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

[0309] In particular embodiments, the cancer is selected from a cancer of the gastrointestinal system. In particular embodiments, the cancer is selected from esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In instances of these embodiments, the cancer is selected from esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid, gastrointestinal stromal tumor, gastric lymphoma, gastrointestinal lymphoma, pancreatic solid-pseudopapillary tumor, pancreatic blastoma, islet cell tumor, pancreatic carcinoma including acinar cell carcinoma and ductal adenocarcinoma, gallbladder adenocarcinoma, colorectal adenocarcinoma, microsatellite stable colorectal cancer, advanced microsatellite stable colorectal cancer, metastatic microsatellite stable colorectal cancer, and anal squamous cell carcinoma.

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

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

[0312] In particular embodiments, the cancer is selected from bone cancer. In specific embodiments, the bone cancer is selected from osteosarcoma, malignant fibrous histiocytoma of bone, Ewing's sarcoma, chordoma (cancer of the bone along the spinal column).

[0313] In particular embodiments, the cancer is selected from sarcoma. In specific embodiments, the sarcoma is selected from central chondrosarcoma, central and periosteal chondroblastoma, fibrosarcoma, tenosynovial clear cell sarcoma, and Kaposi sarcoma.

[0314] In particular 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 particular embodiments, the cancer is selected from thyroid cancer. In specific embodiments, the thyroid cancer is selected from medullary thyroid carcinoma, papillary thyroid carcinoma, and follicular thyroid carcinoma.

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

[0317] In particular embodiments, the cancer is selected from cardiac tumor. In specific embodiments, 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, for example, a liver metastasis from a colorectal or pancreatic cancer; and a brain metastasis from a lung or breast cancer.

[0319] In some embodiments, the cancer exhibits high PD-L1 expression [(tumor proportion score (TPS) > 50%)] and has not been previously treated with platinum-containing chemotherapy. In alternative embodiments, the patient has a tumor with PD-L1 expression (TPS > 1%) and has been previously treated with platinum-containing chemotherapy. In particular embodiments, the patient has disease progression while on or after treatment with platinum-containing chemotherapy.

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

[0321] In particular embodiments, the cancer is classified as a stage III cancer or a stage IV cancer. In some instances of these embodiments, the cancer is not surgically resectable.

[0322] Dosing and Doses

[0323] 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), a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor (EGFR-TKI); and (b) an immunoconjugate of Formula (I), in amounts that together are effective 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), in amounts that together are effective to treat or prevent the cell proliferative disorder.

[0325] The immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen binding fragment thereof) are each (with a pharmaceutically acceptable carrier or excipient) typically formulated in a dosage form that is suitable for administration to a patient by the 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 particular dosage form selected. In addition, suitable pharmaceutically acceptable carriers or excipients can be selected for a particular function in the composition. In embodiments, the immunoconjugate of Formula (I) and / or the anti-human PD-1 antibody (or antigen binding fragment thereof) can be formulated in a dosage form that allows for systemic use, i.e., distribution throughout the patient's body; examples of such systemic administration include oral administration, intravenous administration, and subcutaneous administration. In further embodiments, the immunoconjugate of Formula (I), the anti-human PD-1 antibody (or antigen binding fragment thereof), the platinum-containing chemotherapeutic agent, and / or the EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can be formulated in a dosage form that allows for targeted or localized use, i.e., administration of the immunoconjugate of Formula (I) and / or the anti-human PD-1 antibody (or antigen binding fragment thereof) to only the body part of the patient 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 binding fragment thereof, and the immunoconjugate of Formula (I)) is administered using the same dosage regimen (therapeutic dose, frequency, and duration) typically used when the agent is used as monotherapy to treat the same condition. In other embodiments, the patient receives at least one therapeutic agent in the combination therapy in a total amount that is less than when the agent is used as monotherapy, e.g., a smaller dose, a lower frequency of administration, and / or a shorter duration of treatment.

[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 particular 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 the combination therapy of the disclosure is administered to a patient, the agents comprising the combination can be administered in any order, e.g., sequentially, synchronously, together, simultaneously, etc. In such combination therapy, the amounts of the various agents can be different amounts (different dosages) or the same amount (the same dosage). Thus, for the purpose of non-limiting illustration, the immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) can be present in a fixed amount (dosage) in a single dosage unit.

[0329] In one embodiment, the immunoconjugate of Formula (I) is administered during the time period when the anti-human PD-1 antibody (or antigen-binding fragment thereof) exerts its prophylactic or therapeutic effect, and 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 the usual dosages of such agents when 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 less than the usual dosages of such agents when 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 less than the usual dosages of such agents when 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 the agents to be used at a lower dosage, and / or administered less frequently. A lower dosage 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, the administration of the immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) inhibits the resistance of a cancer to one or both of the agents.

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

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

[0337] The combination therapy of the present disclosure can be used prior to or after tumor resection surgery, and can be used prior to, during, or after radiation therapy.

[0338] In some embodiments, the patient to whom the combination therapy of the present disclosure is administered has not been previously treated with a biological or chemical therapeutic agent, i.e., is treatment-naive. In other embodiments, the patient to whom the combination therapy is administered has not achieved a durable response after being previously treated with the biological or chemical therapeutic agent, i.e., is treatment-experienced.

[0339] The products provided as a therapeutic combination can include a composition comprising an anti-human PD-1 antibody (or antigen-binding fragment thereof) and a composition comprising the immunoconjugate of Formula (I) in separate form, for example in the form of a kit designed to enable separate administration, either simultaneously or according to separate dosing regimens, or in any form.

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

[0341] In some embodiments, the anti-PD-1 antibody (e.g., 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 per week, every two weeks, every three weeks, every 4 weeks, every 5 weeks, every 6 weeks, every month, every two months, or every quarter.

[0342] In some particular 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 particular 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 the therapy is pembrolizumab or a pembrolizumab variant, which is administered in a liquid medicament 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 the therapy is pembrolizumab or a pembrolizumab variant, which is administered in a liquid medicament at a fixed dose, e.g., 200 mg Q3W or 400 mg Q6W.

[0345] In some embodiments, the PD-1 antagonist in the 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., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is pembrolizumab, and about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg of pembrolizumab is administered to the human patient once every three weeks or once every six weeks. In one embodiment, about 200 mg of pembrolizumab is administered to the human patient once every three weeks. In one embodiment, about 240 mg of pembrolizumab is administered to the human patient once every three weeks. In one embodiment, 2 mg / kg of pembrolizumab is administered to the human patient once every three weeks. In one embodiment, 400 mg of pembrolizumab is administered to the human patient once every six weeks.

[0347] 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 200 mg of pembrolizumab is administered to the human patient once every three weeks.

[0348] 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 400 mg of pembrolizumab is administered to the human patient 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 about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg of pembrolizumab is administered to the human patient once every six weeks. In one embodiment, about 200 mg of pembrolizumab is administered to the human patient once every six weeks. In one embodiment, about 240 mg of pembrolizumab is administered to the human patient once every six weeks. In one embodiment, about 400 mg of pembrolizumab is administered to the human patient once every six weeks. In one embodiment, 480 mg of pembrolizumab is administered to the human patient once every six weeks. In one embodiment, 2 mg / kg of pembrolizumab is administered to the human patient once every six weeks.

[0350] In some embodiments, provided is pembrolizumab as a liquid drug comprising 25 mg / ml pembrolizumab, 7% (w / v) sucrose, 0.02% (w / v) polysorbate 80 in 10 mM histidine buffer, pH 5.5. In other embodiments, provided is pembrolizumab 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 about 200 mg of pembrolizumab is administered to the human patient 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 about 400 mg of pembrolizumab is administered to the human patient 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 320 mg to 420 mg, 340 mg to 420 mg, 345 mg to 415 mg, 350 mg to 410 mg, 355 mg to 405 mg, 360 mg to 400 mg, 365 mg to 395 mg, 370 mg to 390 mg, 375 mg to 385 mg, or 379 mg to 381 mg. In one embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 280 mg to about 450 mg. In a further embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 300 mg to about 450 mg. In yet another embodiment, pembrolizumab is administered subcutaneously at a dose of about 320 mg to about 450 mg.

[0354] In certain embodiments, the 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 130 mg / mL. In certain embodiments, the 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, the pembrolizumab is administered subcutaneously to the patient by two injections. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient by a pre-filled syringe is 380 mg. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient by two pre-filled syringes is 380 mg.

[0355] In one embodiment, a selected dose of pembrolizumab is administered by subcutaneous injection at a dose that is at least about 1.6-fold 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, about 240 mg or about 3 mg / kg of nivolumab is administered to the human patient once every two weeks. In a particular embodiment, about 240 mg of nivolumab is administered to the human patient once every two weeks. In a particular embodiment, about 3 mg / kg of nivolumab is administered to the human patient 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, about 480 mg of nivolumab is administered to the human patient once every four weeks.

[0357] The immunoconjugate of Formula (I), and a pharmaceutically acceptable carrier or excipient are typically formulated into a dosage form suitable for administration to a patient by the desired route of administration. For example, the dosage form includes sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable carriers or excipients will vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable carriers or excipients can be selected for a particular function. In embodiments, the immunoconjugate of Formula (I) can be formulated into a dosage form that allows for systemic use, i.e., distribution of the immunoconjugate of Formula (I) throughout the body of the patient; examples of such systemic administration include subcutaneous administration and intravenous administration. In further embodiments, the immunoconjugate of Formula (I) can be formulated into a dosage form that allows for targeted or localized use, i.e., administration of the immunoconjugate of Formula (I) to only the body part of the patient to be treated; examples of such targeted administration include intratumoral injection. In certain embodiments, the dosage 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, 1.0 mg / kg to 2.0 mg / kg, 1.0 mg / kg to 1.5 mg / kg, 1.5 mg / kg to 6.0 mg / kg, 1.5 mg / kg to 5.5 mg / kg, 1.5 mg / kg to 5.0 mg / kg, 1.5 mg / kg to 4.5 mg / kg, 1.5 mg / kg to 4.0 mg / kg, 1.5 mg / kg to 3.5 mg / kg, 1.5 mg / kg to 3.0 mg / kg, 1.5 mg / kg to 2.5 mg / kg, 1.5 mg / kg to 2.0 mg / kg, 2.0 mg / kg to 6.0 mg / kg, 2.0 mg / kg to 5.5 mg / kg, 2.0 mg / kg to 5.0 mg / kg, 2.0 mg / kg to 4.5 mg / kg, 2.0 mg / kg to 4.0 mg / kg, 2.0 mg / kg to 3.5 mg / kg, 2.0 mg / kg to 3.0 mg / kg, 2.0 mg / kg to 2.5 mg / kg, 2.5 mg / kg to 6.0 mg / kg, 2.5 mg / kg to 5.5 mg / kg, 2.5 mg / kg to 5.0 mg / kg, 2.5 mg / kg to 4.5 mg / kg, 2.5 mg / kg to 4.0 mg / kg, 2.5 mg / kg to 3.5 mg / kg, 2.5 mg / kg to 3.0 mg / kg, 3.0 mg / kg to 6.0 mg / kg, 3.0 mg / kg to 5.5 mg / kg, 3.0 mg / kg to 5.0 mg / kg, 3.0 mg / kg to 4.5 mg / kg, 3.0 mg / kg to 4.0 mg / kg, 3.0 mg / kg to 3.5 mg / kg, 3.5 mg / kg to 6.0 mg / kg, 3.5 mg / kg to 5.5 mg / kg, 3.5 mg / kg to 5.0 mg / kg, 3.5 mg / kg to 4.5 mg / kg, 3.5 mg / kg to 4.0 mg / kg, 4.0 mg / kg to 6.0 mg / kg, 4.0 mg / kg to 5.5 mg / kg, 4.0 mg / kg to 5.0 mg / kg, 4.0 mg / kg to 4.5 mg / kg, 4.5 mg / kg to 6.0 mg / kg, 4.5 mg / kg to 5.5 mg / kg, 4.5 mg / kg to 5.0 mg / kg, 5.0 mg / kg to 6.0 mg / kg, 5.0 mg / kg to 5.5 mg / kg, or 5.5 mg / kg to 6.0 mg / kg. In certain embodiments, the dose of the immunoconjugate of Formula (I) is 3.0 mg / kg to 5.0 mg / kg. In certain embodiments, the total dose per treatment 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 3 weeks," "every 4 weeks," monthly, "every 6 weeks," "every two months or quarterly." In a particular 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. In a particular 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 particular 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, the immunoconjugate of Formula (I) is administered in the combination therapies of the present disclosure at a dose of 0.25 mg / kg to 10 mg / kg. In some embodiments, the immunoconjugate of Formula (I) is administered at a dose 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 as multiple doses in any combination thereof. In certain embodiments, the immunoconjugate of Formula (I) is administered at a dose 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 dose of 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5, 5.25, or 5.5 mg / kg. In a particular embodiment, the immunoconjugate of Formula (I) is administered at a dose of 5 mg / kg. In some embodiments, the immunoconjugate of Formula (I) is administered over a repeating cycle of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In a particular embodiment, the immunoconjugate of Formula (I) is administered over a three-week cycle. In another particular embodiment, the immunoconjugate of Formula (I) is administered over a four-week cycle. In still another particular embodiment, the immunoconjugate of Formula (I) is administered over a six-week cycle. 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 cycles of administration (e.g., 3 or more cycles, or 4 or more cycles). In certain embodiments, the immunoconjugate of Formula (I) is administered on one, two, three, four, five, six, or seven days of the cycle. The days of administration can be consecutive, or can be separated by one, two, three, four, five, or six days, one week, two weeks, three weeks, or four weeks, or any combination thereof. In particular embodiments, the immunoconjugate of Formula (I) is administered only on day 1 of each cycle (e.g., a 3-week cycle). In particular embodiments, the immunoconjugate of Formula (I) is administered on days 1 and 8 of each cycle (e.g., a 3-week cycle). In particular embodiments, the immunoconjugate of Formula (I) is administered on days 1, 8, and 15 of each cycle (e.g., a 4-week cycle or a 6-week cycle). In a particular embodiment, the immunoconjugate of Formula (I) is administered on the first day of a 3-week cycle. In another particular 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 particular embodiment, the immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 2 weeks. In another particular embodiment, the immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 3 weeks. In a particular embodiment, the immunoconjugate of Formula (I) is administered at 5.00 mg / kg every 2 weeks. In another particular 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 in a cycle of every week, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every month, every two months, or every quarter.

[0360] In some embodiments, the immunoconjugate of Formula (I) is administered 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 once every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks.

[0361] In some embodiments, the immunoconjugate of Formula (I) is administered 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 twice every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks.

[0362] In some embodiments, the immunoconjugate of Formula (I) is administered 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, three times every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks.

[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 at 3.0 mg / kg twice every 2 weeks.

[0365] In some embodiments, the immunoconjugate A is administered at 3.0 mg / kg three times every 2 weeks.

[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 at 4.0 mg / kg twice 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 at 2.25 mg / kg twice every 3 weeks.

[0371] In some embodiments, the immunoconjugate A is administered at 2.25 mg / kg three times every 3 weeks.

[0372] 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; for 1, 2, 3, 4, 5, or 6 cycles, followed by 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; for 1, 2, 3, 4, 5, or 6 cycles; with each cycle being 6 weeks.

[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; for 1, 2, 3, 4, 5, or 6 cycles, followed by 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; for 1, 2, 3, 4, 5, or 6 cycles; with each cycle being 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 once every 2 weeks; every 6 weeks is a cycle.

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

[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; every 6 weeks is a cycle.

[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; every 6 weeks is a cycle.

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

[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; every 6 weeks is a cycle.

[0381] The immunoconjugate of Formula (I) can be administered according to a first dosing regimen described herein, followed by administration according to a different dosing regimen described herein (e.g., to increase or decrease the frequency of administration). In some embodiments, the immunoconjugate of Formula (I) is administered weekly for a first 1, 2, 3, 4, 5, or 6, 7, 8, 9, 10, 11, or 12 week period, followed by administration once every 3 weeks. In certain embodiments, the immunoconjugate of Formula (I) is administered once weekly for a first 2, 3, 4, 5, or 6 week period, followed by administration once every 3 weeks. In certain embodiments, the immunoconjugate of Formula (I) is administered once weekly for a first 1, 2, 3, 4, 5, or 6 week period, followed by administration once every 4 weeks. The immunoconjugate of Formula (I) can be administered by parenteral administration. As used herein, "parenteral administration" of an immunoconjugate includes any route of administration characterized by physical breach of a patient's tissue and administration of the immunoconjugate via the breach in tissue, and thus it generally results in direct administration into the bloodstream, into muscle, or into an internal organ. Thus, parenteral administration includes, but is not limited to, administration of the immunoconjugate by injection of the immunoconjugate, administration of the immunoconjugate by surgical incision, administration of the immunoconjugate through a tissue-penetrating non-surgical wound, and the like. In particular, the parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intratumoral, and intra synovial injection or infusion; and renal dialysis infusion techniques. In a particular embodiment, the immunoconjugate of Formula (I) is administered intravenously. In another particular embodiment, the immunoconjugate of Formula (I) is administered subcutaneously. Regional infusion is also contemplated. In some embodiments, a first dose infusion can be administered by one route (e.g., intravenous), and subsequent doses can be administered by another route. In certain embodiments, the immunoconjugate of Formula (I) can be administered by intravenous (IV) infusion. The infusion can be carried out over a period of time 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 lengthened as needed to accommodate the treatment tolerance of the individual patient. 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, there is provided a method of treating a cell proliferative disorder, the method 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 anti-human PD-1 antibody (or 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 one particular embodiment, for Combination Regimen 1, 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. In another particular embodiment, for Combination Regimen 1, 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 4 mg / kg per 3-week cycle.

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

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

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

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

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

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

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

[0391] (a) the non-small cell lung cancer is EGFR mutation-negative, and ALK fusion gene-positive; or

[0392] (b) the non-small cell lung cancer is EGFR operably mutant, and the patient has failed prior EGFR-TKI treatment.

[0393] In one embodiment, there is provided a method of treating a cell proliferative disorder, the method 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 anti-human PD-1 antibody (or 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 particular embodiment, for Combination Regimen 2, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered as 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 particular embodiment, for Combination Regimen 2, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered as 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 particular embodiment, for Combination Regimen 2, the anti-human PD-1 antibody is pembrolizumab.

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

[0397] In another particular 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 for 1 to 4 cycles.

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

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

[0401] (a) the non-small cell lung cancer is EGFR mutation-negative and ALK fusion gene-positive; or

[0402] (b) the non-small cell lung cancer is EGFR operably mutated and the patient has failed prior EGFR-TKI treatment.

[0403] In one embodiment, there is provided a method of treating non-small cell lung cancer, 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 dosing amounts and dosing frequencies of the anti-human PD-1 antibody (or antigen-binding fragment thereof) and the immunoconjugate of Formula (I) are as described in any one of the above.

[0404] In one embodiment, the non-small cell lung cancer is as described in any one of the 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 at a frequency of once every 1-4 weeks, and the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of once every 1-10 weeks; preferably once every 2-8 weeks.

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

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

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

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

[0411] In one embodiment, the non-small cell lung cancer is as described in any one of the 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 at a frequency of once every 1-5 weeks, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of once every 1-10 weeks (preferably once every 2-8 weeks), and the platinum-containing chemotherapeutic agent is administered at a frequency of once every 1-5 weeks.

[0414] In some embodiments, the immunoconjugate of Formula (I) and the platinum- containing chemotherapeutic agent are each administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m 2 to 150 mg / m 2 .

[0415] In some embodiments, the immunoconjugate of Formula (I) and the platinum- containing chemotherapeutic agent are each administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m

[0416] In some embodiments, the immunoconjugate of Formula (I) and the platinum- containing chemotherapeutic agent are each administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m

[0417] In some embodiments, the immunoconjugate of Formula (I) and the platinum- containing chemotherapeutic agent are each administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m

[0418] In some embodiments, the immunoconjugate of Formula (I) and the platinum- containing chemotherapeutic agent are each administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m

[0419] In some embodiments, the immunoconjugate of Formula (I) and the platinum- containing chemotherapeutic agent are each administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m

[0420] In some embodiments, the immunoconjugate of Formula (I) and the platinum- containing chemotherapeutic agent are each administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m

[0421] wherein the immunoconjugate of Formula (I) and the platinum-containing chemotherapeutic agent are each administered in 6 week cycles, 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 2 phases, wherein,

[0424] In the first phase, the immunoconjugate of Formula (I) is administered in 3 week cycles and is administered on day 1 of each 3 week cycle and the platinum-containing chemotherapeutic agent is administered in 3 week cycles and is administered on day 1 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 2 phases, wherein,

[0427] In the first phase, the immunoconjugate of Formula (I) is administered in 3 week cycles and is administered on days 1 and 8 of each 3 week cycle and the platinum-containing chemotherapeutic agent is administered in 3 week cycles and is administered on day 1 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, the cisplatin is administered at a dose of 75 mg / m 2 , 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

[0434] In some embodiments, in the first phase, 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 phase, 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 in a cycle that is weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, bimonthly, 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 antigen binding fragment thereof, 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 antigen binding fragment thereof 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 chemotherapeutic 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, 22 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 chemotherapeutic 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 2 phases, wherein,

[0446] In phase 1, the immunoconjugate of Formula (I) is administered in 3 week cycles and on day 1 of each 3 week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered in 6 week cycles and on day 1 of each 6 week cycle, and the platinum-containing chemotherapeutic agent is administered in 3 week cycles and on day 1 of each 3 week cycle;

[0447] In phase 2, the immunoconjugate of Formula (I) is administered in 2 week cycles and on day 1 of each 2 week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered in 6 week cycles and on day 1 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 2 phases, wherein,

[0449] In phase 1, the immunoconjugate of Formula (I) is administered in 3 week cycles and on days 1 and 8 of each 3 week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered in 6 week cycles and on day 1 of each 6 week cycle, and the platinum-containing chemotherapeutic agent is administered in 3 week cycles and on day 1 of each 3 week cycle;

[0450] In phase 2, the immunoconjugate of Formula (I) is administered in 2 week cycles and on day 1 of each 2 week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered in 6 week cycles and on day 1 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 phase, 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 phase, 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 phase, 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 phase, 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 1-5 weeks and a dose of 1-10 mg / kg, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of 1-10 weeks (preferably 2-8 weeks) and a dose of 100-800 mg, and the platinum-containing chemotherapeutic agent is administered at a frequency of once every 1-5 weeks and a bioavailability of 1-10 mg / ml / min.

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

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

[0464] In some embodiments, the immunoconjugate of Formula (I) is administered at a frequency of once every 3 weeks and a dose of 4 mg / kg, and the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of once every 6 weeks and a dose of 400 mg / kg, and the platinum-containing chemotherapeutic agent is administered at a frequency of once every 3 weeks and a bioavailability of AUC 5 mg / ml / min.

[0465] In some embodiments, the immunoconjugate of Formula (I) is administered at a frequency of once every 3 weeks and a dose of 4 mg / kg, and the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of once every 6 weeks and a dose of 400 mg / kg, and the platinum-containing chemotherapeutic agent is administered at a frequency of once every 3 weeks and a bioavailability of AUC 5 mg / ml / min; after 2 cycles, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of once every 6 weeks and a dose of 400 mg, the immunoconjugate of Formula (I) is administered at a frequency of once every 2 weeks and a dose of 4 mg / kg; every 6 weeks is one cycle.

[0466] In some embodiments, there is provided a method of treating non-small cell lung cancer, 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 dosing amounts and dosing frequencies of the platinum-containing chemotherapeutic agent and the immunoconjugate of formula (I) are as described in any one of the above.

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

[0468] In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with EGFR-sensitizing mutations and prior EGFR-TKI treatment failure.

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

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

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

[0472] In some embodiments, wherein the immunoconjugate of formula (I) is administered at a frequency of once every 3 weeks, and the platinum-containing chemotherapeutic agent is administered at a frequency of once every 3 weeks.

[0473] In some embodiments, the immunoconjugate of formula (I) is administered at a frequency of twice every 3 weeks and at a dose of 2.25 mg / kg, and the platinum-containing chemotherapeutic agent is administered at a frequency of once every 3 weeks and at a dose of AUC 5 mg / ml / min.

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

[0475] In some embodiments, the immunoconjugate of Formula (I) is administered at a dose of 3.4 mg / kg once every 3 weeks and the platinum-containing chemotherapeutic agent is administered at a dose of AUC 5 mg / ml / min once every 3 weeks; after 2 cycles, the immunoconjugate of Formula (I) is administered at a dose of 4 mg / kg once every 2 weeks; every 6 weeks is one cycle.

[0476] In some embodiments, the immunoconjugate of Formula (I) is administered at a dose of 3.4 mg / kg once every 3 weeks and the platinum-containing chemotherapeutic agent is administered at a dose of AUC 5 mg / ml / min once every 3 weeks; after 2 cycles, the immunoconjugate of Formula (I) is administered at a dose of 4 mg / kg once every 2 weeks; every 6 weeks is one cycle.

[0477] In some embodiments, there is provided a method of treating non-small cell lung cancer, 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 and the dose of the immunoconjugate of Formula (I) and EGFR-tyrosine kinase inhibitor are as described in any one of the above.

[0478] In some embodiments, the non-small cell lung cancer is as described in any one of the 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 EGFR 19del or 21 L858R sensitive mutation non-small cell lung cancer.

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

[0482] In some embodiments, the immunoconjugate of Formula (I) is administered once every 1-5 weeks and the EGFR-tyrosine kinase inhibitor is administered at a frequency of 3 times a day, 2 times a day, 1 time a day, 1 time 2 days, or 1 time 3 days.

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

[0484] In some embodiments, wherein the immunoconjugate of Formula (I) is administered at a frequency of once every 2 weeks, and the EGFR-tyrosine kinase inhibitor is administered at a frequency of once a day.

[0485] In some embodiments, the immunoconjugate of Formula (I) is administered at a frequency of once every 2 weeks and at a dose of 3 mg / kg, and the EGFR-tyrosine kinase inhibitor is administered at a frequency of once a day and at a dose of 80 mg.

[0486] In some embodiments, the immunoconjugate of Formula (I) is administered at a frequency of once every 2 weeks and at a dose of 4 mg / kg, and the EGFR-tyrosine kinase inhibitor is administered at a frequency of once a day and at a dose of 80 mg.

[0487] In some embodiments, the immunoconjugate of Formula (I) is administered in a cycle of every week, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every month, every two months, or every quarter, and the EGFR-tyrosine kinase inhibitor is administered in a cycle of every day, 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 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.

[0489] In some embodiments:

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

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

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

[0493] In some embodiments:

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

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

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

[0497] In some embodiments:

[0498] (i) the immunoconjugate of Formula (I) is administered 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 of the therapeutic agents in the combination therapy (the anti-PD-1 antibody or binding fragment thereof, and the immunoconjugate of Formula (I)) is administered using the same dosage regimen (therapeutic dose, frequency, and duration) typically employed when the agent is used as monotherapy for the same condition. In other embodiments, the patient receives at least one of the therapeutic agents in the combination therapy in a total amount less than when the agent is used as monotherapy, e.g., a smaller dose, a lower frequency of doses, 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 anti-cancer agents, wherein the additional anti-cancer agent is used to prevent, treat, control, ameliorate, 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 anti-cancer agents to prevent, treat, control, ameliorate, or reduce the risk of cancer. These additional therapeutic agents can be administered simultaneously or sequentially with the combination therapies of the disclosure by the usual routes and in the usual doses.

[0504] Thus, in one aspect, the disclosure provides a pharmaceutical composition comprising: (a) an immunoconjugate of Formula (I); (b) an anti-human PD-1 antibody (or 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 together are effective to treat cancer.

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

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

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

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

[0509] wherein:

[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 portions connected to the antibody for each of the multiple formulas (I);

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

[0513] In one embodiment, the antibody in the pharmaceutical composition is sacitrus bromide.

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

[0515] This article also provides combination therapies, including administering a pharmaceutical composition to a patient 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 dosages of (a), (b), and (c) together are effective in treating cancer.

[0516] When administered in combination with an additional therapeutic agent, the additional therapeutic agent may be administered in repeated cycles of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In one particular embodiment, the additional therapeutic agent is administered in a three-week cycle. In another particular embodiment, the additional therapeutic agent is administered in a four-week cycle. In yet another particular embodiment, the additional therapeutic agent is administered in a six-week cycle. In some embodiments, the additional therapeutic agent is administered on one, two, three, four, five, six, or seven days of the cycle. Dosing days may be consecutive, 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 a specific implementation, the additional therapeutic agent is administered on days 1, 8, and 15 of a 3-week, 4-week, or 6-week cycle.

[0517] The additional therapeutic agent(s) can 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 will be appreciated that the above description of additional therapeutic agents can overlap. It will also be appreciated 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 on an individual patient basis.

[0518] When the therapeutic combinations disclosed herein are used with one or more additional therapeutic agents, the anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or the immunoconjugate of Formula (I) can be administered simultaneously with, prior to, 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 separately by the same or different routes of administration, or in the same pharmaceutical composition as the other agents.

[0519] The weight ratio of the anti-human PD-1 antibody (or antigen-binding fragment thereof) to the immunoconjugate of Formula (I) can vary, depending on the therapeutically effective dosage of each agent. In general, a therapeutically effective dosage of each agent will be used. Combinations comprising at least an anti-human PD-1 antibody (or antigen-binding fragment thereof), an immunoconjugate of Formula (I), and one or more additional therapeutic agents will generally include a therapeutically effective dosage of each therapeutic agent. In such combinations, the anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or the immunoconjugate of Formula (I) and the additional therapeutic agent(s) disclosed herein can be administered to a patient simultaneously or sequentially. Further, one element can be administered prior to, simultaneously with, or following administration of the additional therapeutic agent(s). In one embodiment, a combination comprising at least an anti-human PD-1 antibody (or antigen-binding fragment thereof), an immunoconjugate of Formula (I), and one or more additional therapeutic agents will comprise a dosage of each element that, when administered together, is effective to treat cancer.

[0520] In one embodiment, the present disclosure provides a combined preparation of an anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or 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 the treatment of a cell proliferative disorder, e.g., cancer.

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

[0522] Anti-viral compounds that can be used in combination with the treatments 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 treatments disclosed herein include B7 costimulatory molecules, interleukin-2, interferon-gamma, GM-CSF, CTLA-4 antagonists, OX-40 / OX-40 ligand, CD40 / CD40 ligand, sargramostim, levamisole, vaccinia virus, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxin, mineral oil, surface active agents such as lipolecithin, pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions. Adjuvants such as aluminum hydroxide or phosphate can be added to increase the ability of the vaccine to trigger, enhance, or prolong the 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, imidazoquinolines, resiquimod, and retinoic acid-inducible gene I (RIG-I) agonists such as poly I:C.

[0524] Chemotherapeutic agents that can be used in combination with the treatment disclosed herein include abiraterone acetate, altretamine, anhydrovinblastine, arnirubicin, 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'- didehydro-4'deoxy-8'-norvincaleukoblastine, dinaciclib, docetaxel, docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cytarabine, cytosine arabinoside, dacarbazine (DTIC), dactinomycin, decitabine-doxorubicin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyl urea and hydroxyl urea, and taxol alkaloids, ifosfamide, leunotoside, loperamide, lomustine, MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, mycophenolic acid, sertenef, streptozocin, mitomycin, methotrexate, taxane, nilutamide, olaparib, onasem, oxaliplatin, paclitaxel, prednimustine, procarbazine, RPR109881, semaxaner, stramustine phosphate, tamoxifen, tasonemine, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, 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. WO 01 / 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- pyridinylmethyl)amino]-3-pyridinecarboxamide, and described in International Patent Publication No. WO 02 / 068470), pegaptanib (also known as SO 230, and described in International Patent Publication No. WO 02 / 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 chemotherapeutics (e.g., aroplatin, 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 chemotherapeutic. In a particular embodiment, the additional therapeutic agent is cisplatin. In another particular embodiment, the additional therapeutic agent is carboplatin. In particular embodiments, 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 particular 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 to 150 mg / m 2 , administered intravenously. In a particular 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, daunorubicin liposomal (daunorubicin citrate liposome), mitoxantrone, epirubicin, idarubicin, and mitomycin C.

[0529] Examples of antimetabolites include, but are not limited to, cladribine (sold under the trade name Cladribine), 5-fluorouracil, 6-thioguanine, pemetrexed (sold under the trade name Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C)), cytarabine liposomal (also known as Liposomal Ara-C, sold under the trade name DepoCyt M), decitabine (sold under the trade name Dacogen®), hydroxyurea, and fludarabine, floxuridine, cladribine (also known as 2-chlorodeoxyadenosine (2-CdA)), methotrexate (also known as amethopterin, methotrexate sodium (MTX)), and pentostatin. sold under the trade name Cladribine), 5-fluorouracil, 6-thioguanine, pemetrexed (sold under the trade name Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C)), cytarabine liposomal (also known as Liposomal Ara-C, sold under the trade name DepoCyt M), decitabine (sold under the trade name Dacogen®), hydroxyurea, and fludarabine, floxuridine, cladribine (also known as 2-chlorodeoxyadenosine (2-CdA)), methotrexate (also known as amethopterin, methotrexate sodium (MTX)), and pentostatin. TM sold under the trade name Cladribine), 5-fluorouracil, 6-thioguanine, pemetrexed (sold under the trade name Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C)), cytarabine liposomal (also known as Liposomal Ara-C, sold under the trade name DepoCyt M), decitabine (sold under the trade name Dacogen®), hydroxyurea, and fludarabine, floxuridine, cladribine (also known as 2-chlorodeoxyadenosine (2-CdA)), methotrexate (also known as amethopterin, methotrexate sodium (MTX)), and pentostatin. sold under the trade name Cladribine), 5-fluorouracil, 6-thioguanine, pemetrexed (sold under the trade name Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C)), cytarabine liposomal (also known as Liposomal Ara-C, sold under the trade name DepoCyt M), decitabine (sold under the trade name Dacogen®), hydroxyurea, and fludarabine, floxuridine, cladribine (also known as 2-chlorodeoxyadenosine (2-CdA)), methotrexate (also known as amethopterin, methotrexate sodium (MTX)), and pentostatin.

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

[0531] In one embodiment, there is provided a method of treating a cell proliferative disorder, the method comprising administering to a patient in need thereof a combination therapy comprising: (a) an anti-human PD-1 antibody (or 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 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 one particular 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 one particular embodiment, for Combination Regimen 3, the anti-human PD-1 antibody is pembrolizumab.

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

[0535] In another particular 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 particular embodiment, for Combination Regimen 3, the platinum-based chemotherapeutic agent is cisplatin or carboplatin.

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

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

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

[0540] In another embodiment, Combination Regimen 3 is administered for 1 to 4 cycles.

[0541] In another embodiment, Combination Regimen 3 is administered for 1 to 4 cycles.

[0542] In another embodiment, Combination Regimen 3 is administered for 1 to 4 cycles.

[0543] In another embodiment, Combination Regimen 3 is administered for 1 to 4 cycles.

[0544] In another embodiment, Combination Regimen 3 is administered for 1 to 4 cycles.

[0545] In another embodiment, Combination Regimen 3 is administered for 1 to 4 cycles.

[0546] In another embodiment, Combination Regimen 3 is administered for 1 to 4 cycles.

[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 chemotherapeutic agent is cisplatin at a dose of 75 mg / m2 per administration.

[0548] In one particular embodiment, combination regimen 3 is administered as follows:

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

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

[0551] (iii) carboplatin is administered 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 particular embodiment, combination regimen 3 is administered as follows:

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

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

[0556] (iii) cisplatin is administered at a dose of about 75 mg / m 2 on day 1 of a 3 week cycle; 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 a cancer, wherein the cancer is non-small cell lung cancer.

[0559] In one particular embodiment, combination regimen 3 is administered to a patient to treat a cancer, wherein the cancer is non-small cell lung cancer, and:

[0560] (a) the non-small cell lung cancer is EGFR mutation-negative, and ALK fusion gene-positive; or

[0561] (b) the non-small cell lung cancer is EGFR mutation-positive, and the patient has failed prior EGFR-TKI treatment.

[0562] In one particular embodiment, combination regimen 4 is administered as follows:

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

[0564] (ii) On day 1 of a 6-week cycle, administer the said anti-human PD-1 antibody or its antigen-binding fragment at a dose of approximately 400 mg;

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

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

[0567] In another specific implementation, combined scheme 4 is applied as follows:

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

[0569] (ii) On day 1 of a 6-week cycle, administer the said anti-human PD-1 antibody or its antigen-binding fragment at a dose of approximately 400 mg;

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

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

[0572] In one implementation, a patient is given combination regimen 4 to treat cancer, wherein the cancer is non-small cell lung cancer.

[0573] In one particular implementation, combination regimen 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 described herein does not have EGFR mutations or the ALK fusion gene; or

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

[0576] Other implementation plans

[0577] Further embodiments of this disclosure include the compositions, combinations, uses, and methods described above, wherein it should be understood that each embodiment may be combined with one or more other embodiments such that such combinations are consistent with the description of the embodiments. It should also be further understood that the embodiments provided above are to be construed as including all embodiments, including embodiments resulting from combinations of embodiments.

[0578] Reagent test kit

[0579] The present disclosure also provides articles of manufacture, e.g., 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 a 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, e.g., vials or ampoules made of non-reactive glass or plastic.

[0580] In one embodiment, the kit includes means for separately storing the compositions, e.g., containers, divided bottles, or divided foil packets. The kits of the present disclosure can be used for administration of different dosage forms, e.g., oral and parenteral, for administration of the separate compositions at different dosage intervals, or for infusing the separate compositions into separate, relatively close, locations in the body. To assist with compliance, the kits of the present disclosure generally include instructions for administration.

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

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

[0583] (b) an immunoconjugate of Formula (I):

[0584] wherein:

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

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

[0587] wherein the amounts of (a) and (b) in the kit together are effective to treat cancer.

[0588] In one embodiment, for a 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 a kit of the present disclosure, the immunoconjugate of Formula (I) contained in the kit is immunoconjugate A.

[0590] General Methods

[0591] Standard procedures in molecular biology are described in Sambrook, Fritsch and Maniatis (1982 & 1989 2nd Edition, 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 procedures 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, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (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, N.J., pp. 384-391). 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. (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; U.S. 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 antigen is not necessary for antibody production. Animals can be immunized with cells bearing the antigen of interest. Spleen cells 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 for 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 ndFluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, are available for use as, for example, diagnostic reagents (Molecular Probes y (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).

[0597] Standard methods for describing histology of the immune system 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, Phila, PA; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0598] Software packages and databases sequences are available for determining, for example, antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments (see, e.g., GenBank, Vector NTI® Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); MacVector® (Accelrys, Inc., San Diego, CA); DNA Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); (TimeLogic Corp., Crystal Bay, Nevada); Menne, et al. (2000) Bioinformatics 16:741-742; Menne, et al. (2000) Bioinformatics Applications Note 16:741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68:177-181; 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 in any way to limit.

[0600] Example 1

[0601] Preparation of immunoconjugate A

[0602] Immunoconjugate A can be prepared using the methods 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 a combination therapy for patients with NSCLC

[0605] The study consists of 3 phases, including a screening period, a treatment period, and a survival follow-up period, as follows:

[0606] • The screening period is within 28 days prior to the first dose of study treatment.

[0607] • During the treatment period, subjects will receive immunoconjugate A monotherapy or combination with osimertinib in 28-day cycles and immunoconjugate A in combination with pembrolizumab ± chemotherapy or immunoconjugate A in combination with chemotherapy in 21- or 42-day cycles until meeting any study treatment discontinuation criteria. Any subject discontinuing study treatment is required to complete an end-of-treatment (EOT) visit within 30 days of the last dose of study treatment or prior to starting a new anticancer therapy, whichever occurs first, should be close to the 30-day visit after the last dose of study treatment.

[0608] • Adverse events within 30 days after the last dose of study treatment will be recorded, regardless of whether new anti-neoplastic therapy is initiated (serious adverse events will be recorded up to 90 days after the last dose of study treatment, or 30 days after the last dose of study treatment if the subject initiates new anti-cancer therapy, whichever occurs first).

[0609] • Subjects will be followed for survival by phone every 3 months (± 14 days) after the last dose to obtain survival information and new anti-cancer therapy information until the subject decides to withdraw from the study, is lost to follow-up, dies, or the study ends, whichever occurs first. Subjects who discontinue study treatment for reasons other than disease progression will continue to have tumor assessments until disease progression occurs, new anti-cancer therapy is initiated, 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 require approximately 3 years from the time the first subject (or legally authorized representative) provides written informed consent until the last subject visit.

[0611] Dosing cohorts and duration:

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

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

[0614] Cohorts 1 and 2: Enrolled subjects have NSCLC requiring first-line treatment; no actionable EGFR mutations and ALK fusion genes; PD-L1 TPS > 1%. Eligible subjects will be randomized 1 : 1 to cohorts 1 and 2 to receive the following study treatment (Note: In the expansion phase, subjects are planned to be randomized 1 : 1 into 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, Q3W) + pembrolizumab (200 mg, Q3W), every 3 weeks as a cycle.

[0616] • Cohort 2: Immunoconjugate A (5 mg / kg, Q2W) + pembrolizumab (400 mg, Q6W) for 6 weeks per cycle.

[0617] Cohorts 3 and 4: Enrolled subjects with NSCLC requiring first-line treatment; no actionable EGFR mutations and ALK fusion genes. Eligible subjects were randomized 1 : 1 to Cohorts 3 and 4 to receive the following study treatment (Note: In the expansion phase, subjects are planned to be randomized 1 : 1 into either cohort, with cohort stratification by squamous 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, Q3W) for 3 weeks per cycle for 4 cycles or 6 weeks per cycle for 2 cycles, followed by immunoconjugate A + pembrolizumab.

[0619] • Cohort 4: Immunoconjugate A + pembrolizumab + cisplatin (75 mg / m 2 Q3W) for 3 weeks per cycle for 4 cycles or 6 weeks per cycle for 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 Cohorts 1 and 2 data. If the 5 mg / kg Q2W or Q3W dose is tolerated in Cohorts 1 and 2, the safety run-in phase for Cohorts 3 and 4 will start at immunoconjugate A 4 mg / kg Q2W or Q3W (a dose level that is lower than the dose level deemed tolerated in Cohorts 1 and 2) in combination with pembrolizumab plus carboplatin or cisplatin.

[0621] Cohorts 5 and 6: Enrolled subjects with NSCLC with actionable EGFR mutations who failed prior EGFR-TKI treatment. Eligible subjects were randomized 1 : 1 to Cohorts 5 and 6, stratified by cohort by prior treatment with only first or second generation EGFR-TKI vs. third generation EGFR-TKI and PD-L1 TPS <1% vs. TPS 1%-49% vs. TPS > 50%. The dose 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 for 3 weeks per cycle for 4 cycles or 6 weeks per cycle for 2 cycles, followed by immunoconjugate A + pembrolizumab.

[0623] • Cohort 6: Immunoconjugate A + carboplatin or cisplatin every 3 weeks for a cycle, for a total of 4 cycles, or every 6 weeks for a cycle, for a total of 2 cycles, followed by immunoconjugate A.

[0624] Immunoconjugate A: Immunoconjugate A is administered intravenously on Day 1 of each cycle every 3 weeks for a cycle (Cohort 1; and further applicable to Cohorts 3, 4, 5, and 6 as determined by SRC), or on Days 1, 15, and 29 of each cycle every 6 weeks for a cycle (Cohort 2; and further applicable to Cohorts 3, 4, 5, and 6). The first infusion duration for each patient is 90 (+ 15) minutes, and infusion-related adverse events (AEs) are monitored. If no infusion-related AEs occur, the duration of subsequent infusions can be adjusted to 60 (+ 15) minutes. If infusion-related AEs occur or to ensure the safety of the subject during infusion, the investigator can adjust the infusion duration to 90 (+ 15) minutes.

[0625] Pembrolizumab: Pembrolizumab is administered intravenously at 200 mg for 30 minutes on Day 1 of each cycle every 3 weeks for a cycle (Cohort 1; and further applicable to Cohorts 3, 4, 5, and 6), or at 400 mg for 30 minutes on Day 1 of each cycle every 6 weeks for a cycle (Cohort 2; and further applicable to Cohorts 3, 4, 5, and 6).

[0626] Carboplatin: Carboplatin is administered intravenously at AUC 5 mg / mL / min on Day 1 of each cycle every 3 weeks for a cycle, or on Days 1 and 22 of each cycle every 6 weeks for a cycle. Cohort 3 carboplatin cycle calculations will be consistent with the calculations for immunoconjugate A and pembrolizumab in the determination cohort (Cohort 1 or 2). Regardless of how cycles are calculated, carboplatin will be administered once every 3 weeks for a total of 4 doses over 12 weeks.

[0627] Cisplatin: Cisplatin is administered intravenously at 75 mg / M 2 Cisplatin: Cisplatin is administered intravenously at 75 mg / M

[0628] Combined dosing sequence:

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

[0630] • When immunoconjugate A and chemotherapy are administered on the same day, study treatments will be administered sequentially. Intravenous infusion of immunoconjugate A is performed first, followed by intravenous infusion of chemotherapy at least 30 minutes later.

[0631] • If the investigator assesses that the subject is still benefiting clinically, the subject is allowed to continue study treatment beyond the initial definition of disease progression according to RECIST 1.1. The conclusion of clinical benefit can be made by the investigator based on radiological findings and clinical condition assessment that no intolerable toxicity or worsening symptoms due to disease progression (PD) has occurred. The subject can be reconsented to by describing any reasonably foreseeable risks or discomforts in the informed consent form (ICF).

[0632] Dose and administration

[0633] Infusion duration: The infusion time for each subject’s first infusion of immunoconjugate A is 90 (± 15) minutes, and infusion-related AEs are monitored. If no infusion-related AEs occur, the duration of subsequent infusions can be adjusted to 60 (+ 15) minutes. If infusion-related AEs occur or to ensure the safety of the infusion of study drug, the investigator can adjust the infusion time 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, immunoconjugate A is administered at least 30 minutes after the completion of the pembrolizumab infusion. When immunoconjugate A is used in combination with pembrolizumab and chemotherapy, pembrolizumab intravenous infusion is performed first, followed by intravenous infusion of immunoconjugate A at least 30 minutes later, and intravenous infusion of carboplatin or cisplatin at least 30 minutes later (the maximum interval between immunoconjugate A and chemotherapy is allowed to be +1 day only).

[0636] When immunoconjugate A and chemotherapy (cisplatin or carboplatin) are administered on the same day, intravenous infusion of immunoconjugate A is performed first, followed by intravenous infusion of chemotherapy at least 30 minutes later.

[0637] Adverse Reaction Monitoring: On Day 1 of Cycle 1, following completion of all infusions, subjects will be monitored for adverse reactions for at least 90 minutes. If no infusion-related AEs occur, subjects will be monitored for adverse reactions for at least 60 minutes following completion of study treatment (except where clinical symptoms require close monitoring).

[0638] Pre-treatment measures for infusion-related reactions for Immunoconjugate A: Pre-treatment is required within 30 to 60 minutes prior to Immunoconjugate A infusion following completion of pembrolizumab. Subjects are recommended to pre-medicate with diphenhydramine (or equivalent dose of an antihistamine), acetaminophen (or equivalent dose of an analgesic) ± other treatment regimens recommended by the investigator according to institutional standards or local guidelines.

[0639] The study is divided into two parts, Part 1 is a safety run-in phase to evaluate dose levels; Part 2 is an expansion phase to further explore efficacy and safety based on the safe and tolerable dose range determined from Part 1.

[0640] End of Study

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

[0642] All subjects have completed or discontinued study treatment, and the sponsor believes that overall survival benefit data for the study is mature.

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

[0644] Study Population

[0645] No pre-approval for protocol deviations that deviate from the enrollment and inclusion criteria (also known as protocol exemptions) is allowed. The study population is subjects with advanced or metastatic non-small cell lung cancer. Subjects must be able to provide a written informed consent and meet all inclusion criteria and do not meet any exclusion criteria.

[0646] Inclusion Criteria

[0647] Subjects are eligible for inclusion in the study if they meet all of the following criteria:

[0648] 1. Subjects must be 18 years of age or older on the day of signing the informed consent form, regardless of gender;

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

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

[0651] Subjects in Cohorts 5 and 6 should be confirmed to contain EGFR actionable genomic mutations by tumor histology, cytology or blood sample;

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

[0653] a) Cohorts 1 and 2: Locally advanced or metastatic NSCLC subjects who have no actionable EGFR mutations and ALK fusion genes, no known alterations in ROS1, NTRK, BRAF genes or other actionable genomic mutations for approved therapies, who meet all of the following criteria: i) have not received systemic treatment previously; ii) have not been treated with a PD-1 / PD-L1 antibody previously; iii) PD-L1 TPS > 1% as determined by a central laboratory test, such as the PD-L1 IHC 22C3 PharmDx assay. Enrollment of subjects who received adjuvant, neoadjuvant therapy or definitive chemotherapy with disease progression > 6 months after completion of treatment is allowed;

[0654] b) Cohorts 3 and 4: Locally advanced or metastatic NSCLC subjects who have no actionable EGFR mutations and ALK fusion genes, no known alterations in ROS1, NTRK, BRAF genes or other actionable genomic mutations for approved therapies, who have not received systemic treatment previously, including the use of a PD-1 / PD-L1 antibody. Enrollment of subjects who received adjuvant, neoadjuvant therapy or definitive chemotherapy with disease progression > 6 months after completion of treatment is allowed;

[0655] c) Cohort 5 and Cohort 6: Subjects with EGFR actionable mutations, including exon 19 deletion mutation or exon 21 point mutation (L858R), who have failed prior EGFR-TKI therapy, who meet all of the following criteria: i) have failed prior first- or second-generation EGFR-TKIs, and, following treatment failure, exon 20 T790M mutation is confirmed to be negative by tumor histology; or have failed a third-generation EGFR-TKI, irrespective of T790M mutation status; ii) have no prior chemotherapy or PD-1 / PD-L1 antibody therapy for locally advanced or metastatic NSCLC; subjects who received adjuvant, neoadjuvant, or definitive chemotherapy are allowed to be enrolled if they have experienced disease progression > 6 months after completion of treatment;

[0656] 5. Subjects are able to provide a tumor tissue block or sections (archival tumor tissue: formalin-fixed paraffin-embedded tissue block, about 10 unstained sections for Cohorts 1, 2, 3, 4, and 5, and about 5 unstained sections for Cohort 6) prior to the first dose of study treatment.

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

[0658] b) Subjects who are unable to provide an archival tumor tissue block or sections agree to provide a fresh biopsy specimen prior to receiving study treatment;

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

[0660] 7. Subjects have an ECOG performance status score of 0 or 1 assessed within 7 days prior to the start of study treatment;

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

[0662] 9. Subjects with adequate organ function as shown by the following laboratory values (within 2 weeks prior to screening, without receiving a transfusion, recombinant human thrombopoietin, or colony-stimulating factor treatment):

[0663] Table 3-4 Laboratory values for adequate organ function

[0664] 10. Left ventricular ejection fraction (LVEF) > 50% by echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan;

[0665] 11. Subjects must have recovered from all toxicities resulting from prior therapy (improvement to < Grade 2 based on CTCAE 5.0 criteria, or to levels specified in the inclusion criteria, except for toxicities not considered a safety risk (e.g., alopecia, vitiligo, and other asymptomatic laboratory abnormalities);

[0666] 12. Contraceptive use in male and female subjects must meet the requirements for methods of contraception in subjects participating in clinical studies according to local regulations;

[0667] Note: The reliability of abstinence needs to be assessed in male and / or female enrollment eligibility according to the duration of the clinical study and the subject’s preferred and customary lifestyle. Regular abstinence (e.g., coitus interruptus, calendar, ovulation, symptothermal, or post-ovulation methods), and withdrawal method are not acceptable methods of contraception.

[0668] a. Male subjects:

[0669] • Male subjects must agree to use a highly effective method of contraception from the time of signing the informed consent form (ICF) until at least 6 months after the last dose of study treatment and not to donate sperm during this period.

[0670] b. Female subjects:

[0671] • Female subjects eligible to participate in the study need to be not pregnant, not breastfeeding, and at least one of the following:

[0672] Women of childbearing potential (WOCBP)

[0673] or

[0674] WOCBP who agree to follow the contraception guidelines from the time of signing the ICF until at least 6 months after the last dose of study treatment; and

[0675] 13. Subjects should volunteer to participate in the study, sign the ICF, and be able to comply with the scheduled visits and related procedures as specified in the protocol.

[0676] Exclusion Criteria

[0677] Subjects meeting any of the following criteria are not to be enrolled in the study:

[0678] Medical Conditions

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

[0680] 2. Subjects with a known history of prior malignancy unless the subject has received potentially curative treatment and is without evidence of recurrence for 3 years following such treatment;

[0681] Note: The 3-year time requirement without evidence of disease does not apply to NSCLC tumors under investigation for this study. This time requirement also does not apply to subjects with a basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other carcinoma in situ that is definitively resected;

[0682] 3. Subjects known to have meningeal metastases, brain stem metastases, spinal cord metastases, and / or active CNS metastases. Subjects with brain metastases that have been treated locally can be enrolled if they are clinically stable for at least 4 weeks prior to the first dose of study treatment and are off steroids for at least 14 days; according to this limitation, subjects should have stable brain metastases prior to the first dose of study drug. For subjects who have a first discovery of CNS metastases at the time of screening, the treating investigator should consider delaying study treatment to document stability of the CNS metastases with repeat imaging at least 4 weeks later (in this case, it can be necessary to repeat all screening activities);

[0683] 4. Subjects with > Grade 2 peripheral neuropathy and receiving platinum treatment in this study;

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

[0685] 6. Subjects with a history of arterial-venous thromboembolic events, such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis (except for venous thrombosis caused by venous catheterization in prior chemotherapy, which has been resolved by the investigator's judgment), and pulmonary embolism within 6 months prior to the first dose of study intervention;

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

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

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

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

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

[0691] 9. Subjects with a medical history of interstitial lung disease (ILD) / non-infectious pneumonitis requiring steroid treatment, or who currently have ILD / pneumonitis, or who cannot be ruled out as having suspected ILD / pneumonitis by imaging at screening;

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

[0693] a) Subjects with uncontrolled hypertension (systolic blood pressure > 160 mmHg and / or diastolic blood pressure > 100 mmHg) under medical intervention, a history of unstable hypertension, or a history of poorly compliant antihypertensive therapy;

[0694] b) Subjects with uncontrolled diabetes (fasting glucose > 10 mmol / L and / or HbAlc > 8%) under medical intervention;

[0695] c) Subjects with clinically symptomatic or requiring repeated drainage of pleural effusion, pericardial effusion, or ascites;

[0696] 11. Subjects with an autoimmune disease requiring systemic treatment (e.g., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) within the last 2 years. Hormone replacement therapy (e.g., thyroid hormone, insulin, or physiologic corticosteroid replacement therapy for adrenocortical 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: For subjects positive for hepatitis B surface antigen (HBsAg) and / or hepatitis B core antibody (HBcAb), testing for HBV-DNA is required; HBV-DNA > 500 IU / mL or above the lower limit of detection (if the lower limit is higher than 500 IU / mL) is considered active hepatitis B. Active hepatitis C is defined as positive for hepatitis C antibody and HCV-RNA above the lower limit of detection;

[0699] 13. Subjects with known human immunodeficiency virus (HIV) infection that is not well controlled. Participants who are HIV-infected with a history of Kaposi’s sarcoma and / or multicentric Castleman’s disease are included. HIV-infected subjects must have well-controlled HIV while on antiretroviral therapy (ART) and meet all of the following criteria:

[0700] a) Participants in ART must have CD4+ T-cell count > 350 cells / mm3 at screening 3 ;

[0701] b) Participants in ART must have completed and maintained virologic suppression, defined as HIV RNA levels below 50 or LLOQ (lower limit of quantification) confirmed using locally available assays, at screening and within at least 12 weeks prior to screening; and

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

[0703] 14. Subjects with known active tuberculosis;

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

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

[0706] • No toxicity from prior immunotherapy (IMT) that led to permanent discontinuation of the treatment.

[0707] • All AEs from prior IMT have recovered to ≤ Grade 1 or baseline prior to study screening.

[0708] • No Grade ≥ 3 irAEs or any grade neurologic or ocular AEs occurred from prior IMT.

[0709] Note: Subjects who have experienced endocrine AEs of any grade are included if they remain stable and asymptomatic on appropriate replacement therapy.

[0710] • No need for other immunosuppressive agents than corticosteroids to manage AEs if re-administration of the AE does not lead to recurrence and there is no current need for maintenance of > 10 mg / day of prednisone or equivalent dose;

[0711] 16. Subjects who received other investigational medicinal products or major surgery within 4 weeks prior to first dose of study treatment;

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

[0713] 18. Subjects who require systemic use of strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) within 2 weeks or 5 half-lives prior to the first dose of study treatment and during the study;

[0714] 19. Subjects who received a continuous high dose of systemic corticosteroids within 2 weeks prior to the first dose of study treatment (low dose corticosteroids, e.g., <10 mg / day of prednisone or equivalent, are permitted provided they have been stable for at least 4 weeks) or other immunosuppressive therapy;

[0715] 20. Subjects who were vaccinated with a live vaccine or live attenuated vaccine within 4 weeks prior to the first dose of study treatment or who plan to receive a live vaccine during the study;

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

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

[0718] 23. Subjects known to be hypersensitive to pembrolizumab or Immunoconjugate A, or to components of pembrolizumab or Immunoconjugate A.

[0719] 24. Subjects who are pregnant or breastfeeding, or expecting to become pregnant or conceive a child during the projected duration of the study;

[0720] 25. Subjects with rapidly deteriorating conditions, e.g., severe changes in performance status, during the screening process prior to the first dose of study treatment; and

[0721] 26. Subjects with other conditions that, in the investigator's opinion, do not make the subject an appropriate candidate for participation in the study.

[0722] Example 3

[0723] Study of Immunoconjugate A in combination with various classes of drugs for the treatment of NSCLC

[0724] The patient types and their dosing regimens for each cohort of the study are shown below:

[0725] Cohort 1: First-line NSCLC subjects enrolled with EGFR wild-type and ALK fusion gene negative, with subjects having PD-L1 TPS >1%. Subjects receive treatment with Immunoconjugate A + pembrolizumab, with Immunoconjugate A dosed at 4 mg / kg based on patient body weight, once every 2 weeks; and pembrolizumab dosed at 400 mg once every 6 weeks.

[0726] Cohort 3: First-line NSCLC subjects enrolled EGFR wild-type, in the first phase, the subjects receive treatment of immunoconjugate A + pembrolizumab + carboplatin, the dose of immunoconjugate A is 2.25 mg / kg based on patient weight, 3 weeks twice, on the 1st and 8th day of every 3 weeks; pembrolizumab 400 mg, 6 weeks once; carboplatin is administered at a dose to achieve AUC 5 mg / ml / min, 3 weeks once; the duration of the first phase is 6-24 weeks (for example, 6, 12, 18, or 24 weeks); after the first phase, enter the second phase, in which the subjects receive treatment of immunoconjugate A + pembrolizumab, the dose of immunoconjugate A is 4 mg / kg based on patient weight, 2 weeks once; pembrolizumab 400 mg, 6 weeks once. Some subjects in cohort 3 have squamous cell carcinoma, and some have non-squamous cell carcinoma; cohort 3 includes subjects with PD-L1 TPS <1%, subjects with TPS 1%-49%, and subjects with TPS≥50%.

[0727] Cohort 4: First-line NSCLC subjects enrolled EGFR wild-type, in the first phase, the subjects receive treatment of immunoconjugate A + pembrolizumab + carboplatin, the dose of immunoconjugate A is 3 mg / kg based on patient weight, 3 weeks once; pembrolizumab 400 mg, 6 weeks once; carboplatin is administered at a dose to achieve AUC 5 mg / ml / min, 3 weeks once; the duration of the first phase is 6-24 weeks (for example, 6, 12, 18, or 24 weeks); after the first phase, enter the second phase, in which the subjects receive treatment of immunoconjugate A + pembrolizumab, the dose of immunoconjugate A is 4 mg / kg based on patient weight, 2 weeks once; pembrolizumab 400 mg, 6 weeks once. Some subjects in cohort 4 have squamous cell carcinoma, and some have non-squamous cell carcinoma; cohort 4 includes subjects with PD-L1 TPS <1%, subjects with TPS 1%-49%, and subjects with TPS≥50%.

[0728] Cohort 5: NSCLC subjects with EGFR mutations and prior failure of EGFR-TKI treatment enroll in the study, in the first phase, subjects receive treatment with immunoconjugate A + carboplatin, immunoconjugate A is administered at a dose of 2.25 mg / kg based on patient body weight, given twice in 3 weeks; carboplatin is administered at a dose to achieve an AUC of 5 mg / ml / min, given once in 3 weeks; the duration of the first phase is 6-24 weeks (e.g., 6, 12, 18, or 24 weeks); following the first phase, subjects enter the second phase, in which they receive monotherapy with immunoconjugate A, immunoconjugate A is administered at a dose of 4 mg / kg based on patient body weight, given once in 2 weeks. Cohort 5 includes subjects who were previously treated with only first- or second-generation EGFR TKIs, as well as subjects who were treated with a third-generation EGFR TKI. Cohort 5 includes subjects with central nervous system metastases, as well as subjects without central nervous system metastases.

[0729] Cohort 6: NSCLC subjects with EGFR mutations and prior failure of EGFR-TKI treatment enroll in the study, in the first phase, subjects receive treatment with immunoconjugate A + carboplatin, immunoconjugate A is administered at a dose of 3 mg / kg based on patient body weight, given once in 3 weeks; carboplatin is administered at a dose to achieve an AUC of 5 mg / ml / min, given once in 3 weeks; the duration of the first phase is 6-24 weeks (e.g., 6, 12, 18, or 24 weeks); following the first phase, subjects enter the second phase, in which they receive monotherapy with immunoconjugate A, immunoconjugate A is administered at a dose of 4 mg / kg based on patient body weight, given once in 2 weeks. Cohort 6 includes subjects who were previously treated with only first- or second-generation EGFR TKIs, as well as subjects who were treated with a third-generation EGFR TKI. Cohort 6 includes subjects with central nervous system metastases, as well as subjects without central nervous system metastases.

[0730] Cohort 7: NSCLC subjects with EGFR mutations enroll in the study, subjects receive treatment with immunoconjugate A + osimertinib, immunoconjugate A is administered at a dose of 4 mg / kg based on patient body weight, given once in 2 weeks; osimertinib is administered at a dose of 80 mg, given once daily. Cohort 7 includes subjects with a 19del mutation and / or with a 21 L858R mutation; Cohort 7 includes subjects with central nervous system metastases, as well as subjects without central nervous system metastases.

[0731] Cohort 7-1: Enrolled subjects with EGFR-mutant NSCLC, subjects received treatment of immunoconjugate A + osimertinib, the dose of immunoconjugate A was 3 mg / kg based on body weight, once every 2 weeks; the dose of osimertinib was 80 mg, once a day. Cohort 7-1 included subjects with 19del mutation and / or with 21L858R mutation; Cohort 7-1 included subjects with central nervous system metastasis, and subjects without central nervous system metastasis.

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

[0733] 1. Age ≥ 18 years at the time of signing informed consent, gender not limited;

[0734] 2. Histologically or cytologically confirmed NSCLC, and locally advanced or metastatic (stage IV) NSCLC who are not suitable for curative surgery and / or curative radiotherapy;

[0735] 3. Histologically confirmed EGFR wild type and EGFR activating mutation confirmed by histological, cytological or hematological samples;

[0736] 4. a) EGFR wild type and ALK fusion gene negative, locally advanced or metastatic NSCLC without systemic treatment in the past; c) EGFR sensitive mutation, who had received EGFR-TKI treatment and treatment failure, who had received anti-PD-1 / PD-L1 antibody and platinum-containing chemotherapy treatment failure; d) EGFR sensitive mutation, who had not received systemic treatment or had received EGFR-TKI treatment and treatment failure;

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

[0738] 6. At least one image measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 standard;

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

[0740] 8. The expected survival of the subject was ≥ 3 months;

[0741] 9. Adequate organ function;

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

[0743] 11. Male and female subjects must use contraception in accordance with the requirements of local regulations for the method of contraception for subjects in clinical studies.

[0744] 12. The subject voluntarily enrolls in the study, signs the informed consent form, and is able to comply with the scheduled visits and related procedures.

[0745] Exclusion criteria for this study are:

[0746] 1. Pathohistological type contains small cell carcinoma component;

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

[0748] 3. Subjects with known meningeal metastases, brainstem metastases, spinal cord metastases and / or compression, or active CNS metastases;

[0749] 4. Subjects who have experienced > Grade 2 peripheral neuropathy with prior platinum-containing therapy;

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

[0751] 6. Arteriovenous thrombotic event that occurred within 6 months prior to the first dose of study treatment;

[0752] 7. Active or history of documented 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 pneumonitis requiring steroid treatment;

[0755] 10. Uncontrolled systemic diseases, including uncontrolled hypertension and diabetes mellitus, and uncontrolled effusions requiring repeated drainage, according to the Investigator’s judgment;

[0756] 11. Active autoimmune disease requiring systemic treatment and requiring systemic treatment within the past 2 years;

[0757] 12. Diagnosis of active hepatitis B or C;

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

[0759] 14. Known active tuberculosis;

[0760] 15. Received other investigational drugs within 4 weeks prior to the first dose of study treatment or major surgery within 4 weeks prior to the first dose of study treatment;

[0761] 16. Received radiation therapy to the lung of > 30 Gy total dose within 6 months prior to the first dose of study treatment;

[0762] 17. Subjects who require systemic use of strong inhibitors or inducers of cytochrome P450 3A4 enzyme (CYP3A4) within 2 weeks or 5 half-lives prior to the first dose of study treatment and during the study;

[0763] 18. Subjects who have received high-dose systemic corticosteroids within 2 weeks prior to the first dose of study treatment;

[0764] 19. Subjects who have been vaccinated with a live or attenuated vaccine within 4 weeks prior to the first dose of study treatment;

[0765] 20. Subjects who have had a serious infection within 4 weeks prior to the first dose of study treatment;

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

[0767] 22. Subjects known to be allergic or hypersensitive to pembrolizumab or conjugate A, or to a component of pembrolizumab or conjugate A.

[0768] While the preferred embodiments of the present disclosure are shown and described herein, it is to be understood that these embodiments are merely exemplary of the principles of the present disclosure. Numerous modifications, changes, and adaptations will occur to those skilled in the art without departing from the spirit and scope of the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein can be employed in practicing the methods and uses disclosed herein.

Claims

A method of treating a cell proliferative disorder, e.g., cancer, in a patient, comprising administering to said patient: (a) an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor; and (b) an immunoconjugate of Formula (I): wherein: Ab is an antibody that binds Trop-2, and n is an integer selected from 1-10; wherein the amounts of (a) and (b) are administered together in amounts that are collectively effective to treat said disorder. The method of claim 1, comprising administering to said patient: (a) said anti-human PD-1 antibody or antigen-binding fragment thereof; and (b) said immunoconjugate of Formula (I). The method of claim 1 or 2, wherein n is selected from 6-8. The method of any one of claims 1-3, wherein said antibody that binds Trop-2 comprises: (i) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 39, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 40, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41, and (ii) a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 42, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 43, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:

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

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

36. The method of any one of claims 1-6, wherein said antibody that binds Trop-2 is sacituzumab. The method of any one of claims 1-7, wherein said immunoconjugate of Formula (I) is administered to said patient at a dose of 1.0 mg / kg to 6.0 mg / kg. The method of any one of claims 1-8, wherein said anti-human PD-1 antibody or antigen-binding fragment thereof is selected from nivolumab, cemiplimab, dostarlimab, pidilizumab, tislelizumab, and pembrolizumab. The method of any one of claims 1-9, wherein said anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab. 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. 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 in a cycle of every week, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every month, every two months, or every quarter. 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. 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. 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. 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. 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. The method of any one of claims 11-17, wherein the number of cycles is 1-4. The method of any one of claims 1-18, wherein the platinum-containing chemotherapeutic agent is carboplatin or cisplatin; preferably carboplatin. The method of any one of claims 1-19, wherein the platinum-containing chemotherapeutic agent is administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m 2 150 mg / m 2 2. The method of any one of claims 1-19, wherein the platinum-containing chemotherapeutic agent is administered at a dose of about AUC 1 mg / mL / min to AUC 10 mg / mL / min or 10 mg / m The method of any one of claims 1-20, wherein the immunoconjugate of Formula (I) and the platinum-containing chemotherapeutic agent are each administered in a cycle of every week, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every month, every two months, or every quarter. 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 day 1 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 days 1 and 8 of each 3-week cycle, and the platinum-containing chemotherapeutic agent is administered on day 1 of each 3-week cycle. 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 6 week cycles, 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; wherein the immunoconjugate of Formula (I) and the platinum-containing chemotherapeutic agent are each administered in 6 week cycles, 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; wherein the immunoconjugate of Formula (I) and the platinum-containing chemotherapeutic agent are each administered in 6 week cycles, 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. 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. The method of claim 24, wherein the immunoconjugate of Formula (I) and the platinum-containing chemotherapeutic agent are administered in two stages, wherein, In Phase 1, the immunoconjugate of Formula (I) is administered in 3 week cycles and is administered on day 1 of each 3 week cycle, and the platinum-containing chemotherapeutic agent is administered in 3 week cycles and is administered on day 1 of each 3 week cycle; in Phase 2, the immunoconjugate of Formula (I) is administered in 2 week cycles and is administered on day 1 of each 2 week cycle. The method of claim 24, wherein the immunoconjugate of Formula (I) and the platinum-containing chemotherapeutic agent are administered in two stages, wherein, In Phase 1, the immunoconjugate of Formula (I) is administered in 3 week cycles and is administered on days 1 and 8 of each 3 week cycle, and the platinum-containing chemotherapeutic agent is administered in 3 week cycles and is administered on day 1 of each 3 week cycle; in Phase 2, the immunoconjugate of Formula (I) is administered in 2 week cycles and is administered on day 1 of each 2 week cycle. The method of any one of claims 24-26, each phase lasting 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. 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. The method of claim 22 or 23, wherein the immunoconjugate of Formula (I) is administered at a dose of about 4 mg / kg, the cisplatin is administered at a dose of 75 mg / m 2 or, the immunoconjugate of Formula (I) is administered at a dose of about 5 mg / kg, the cisplatin is administered at a dose of 75 mg / m 2 . The method of claim 25, wherein, In the first phase, 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. The method of claim 26, wherein, In the first phase, 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. The method of any one of claims 21-31, wherein the number of cycles is 1-4. 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 in a cycle that is weekly, every 1.5 weeks, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, bimonthly, or quarterly. 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. The method of any one of claims 1-21, 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 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 antigen-binding fragment thereof 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 antigen-binding fragment thereof 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, 22 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 chemotherapeutic agent is administered on days 1 and 22 of each 6-week cycle. 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 each administered in 1, 2, 3, or 4 phases. 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 2 phases, wherein, In phase 1, the immunoconjugate of Formula (I) is administered in a 3-week cycle and on day 1 of each 3-week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered in a 6-week cycle and on day 1 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered in a 3-week cycle and on day 1 of each 3-week cycle; in phase 2, the immunoconjugate of Formula (I) is administered in a 2-week cycle and on day 1 of each 2-week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered in a 6-week cycle and on day 1 of each 6-week cycle. 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 2 phases, wherein, In phase 1, the immunoconjugate of Formula (I) is administered in a 3-week cycle and on days 1 and 8 of each 3-week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered in a 6-week cycle and on day 1 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered in a 3-week cycle and on day 1 of each 3-week cycle; In phase 1, the immunoconjugate of Formula (I) is administered in a 3-week cycle and on days 1 and 8 of each 3-week cycle, the anti-human PD-1 antibody or antigen-binding fragment thereof is administered in a 6-week cycle and on day 1 of each 6-week cycle, and the platinum-containing chemotherapeutic agent is administered in a 3-week cycle and on day 1 of each 3-week cycle; In the second phase, the immunoconjugate of Formula (I) is administered on a 2 week cycle and on day 1 of each 2 week cycle, and the anti-human PD-1 antibody or antigen-binding fragment thereof is administered on a 6 week cycle and on day 1 of each 6 week cycle. The method of any one of claims 36-38, each phase lasting 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. 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 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. 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 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. The method of claim 37, wherein, In the first phase, 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; in the second phase, 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. The method of claim 38, wherein, In the first phase, 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; in the second phase, 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. The method of any one of claims 33-43, wherein the number of cycles is 1-4. The method of claim 34, wherein: (i) about 5 mg / kg of the immunoconjugate of Formula (I) on day 1 of a 3 week cycle; (ii) about 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof on day 1 of a 3 week cycle; (iii) about AUC 5 mg / ml / min of carboplatin on day 1 of a 3 week cycle; and (iv) for 1 to 4 cycles. The method of claim 34, wherein: (i) about 5 mg / kg of the immunoconjugate of Formula (I) on day 1 of a 3 week cycle; (ii) about 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof on day 1 of a 3 week cycle; (iii) about 75 mg / m2of cisplatin on day 1 of a 3 week cycle; and (iv) for 1 to 4 cycles. The method of claim 35, wherein: (i) about 5 mg / kg of the immunoconjugate of Formula (I) on days 1, 15, and 29 of a 6 week cycle; (ii) about 400 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof on day 1 of a 6 week cycle; (iii) about AUC 5 mg / ml / min of carboplatin on days 1 and 22 of a 6 week cycle; and (iv) for 1 to 4 cycles. The method of claim 35, wherein: (i) about 5 mg / kg of the immunoconjugate of Formula (I) on days 1, 15, and 29 of a 6 week cycle; (ii) about 400 mg of the anti-human PD-1 antibody or antigen binding fragment thereof on day 1 of a 6 week cycle; (iii) about 75 mg / m2of cisplatin on days 1 and 22 of a 6 week cycle; and (iv) for 1 to 4 cycles. 2 (i) about 5 mg / kg of the immunoconjugate of Formula (I) on days 1, 15, and 29 of a 6 week cycle; (ii) about 400 mg of the anti-human PD-1 antibody or antigen binding fragment thereof on day 1 of a 6 week cycle; (iii) about 75 mg / m2of cisplatin on days 1 and 22 of a 6 week cycle; and (iv) for 1 to 4 cycles. 2 (i) about 5 mg / kg of the immunocon The method of any one of claims 1-48, comprising administering to the patient: (a) the EGFR-tyrosine kinase inhibitor; and (b) the immunoconjugate of Formula (I); wherein, The EGFR-tyrosine kinase inhibitor is osimertinib. The method of claim 49, wherein the immunoconjugate of Formula (I) is administered in a weekly, every 1.5 week, every 2 week, every 3 week, every 4 week, every 5 week, every 6 week, monthly, bimonthly, or quarterly cycle, and the EGFR-tyrosine kinase inhibitor is administered in a daily, every 2 day, every 3 day, every 4 day, every 5 day, every 6 day, or weekly cycle. 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 daily. The method of claim 51, wherein: (i) about 3 mg / kg of the immunoconjugate of Formula (I) on day 1 of a 2 week cycle; (ii) about 80 mg of osimertinib daily; (iv) for 1 to 4 cycles. The method of claim 51, wherein: (i) about 4 mg / kg of the immunoconjugate of Formula (I) on day 1 of a 2 week cycle; (ii) about 80 mg of osimertinib daily; (iv) for 1 to 4 cycles. The method of claim 51, wherein: (i) about 5 mg / kg of the immunoconjugate of Formula (I) on day 1 of a 2 week cycle; (ii) about 80 mg of osimertinib daily; (iv) for 1 to 4 cycles. The method of any one of claims 1-54, wherein the disorder being treated is non-small cell lung cancer. The method of claim 55, wherein: (a) the non-small cell lung cancer is EGFR mutation- and ALK fusion gene- negative; or (b) the non-small cell lung cancer has an operable mutation in EGFR, and the patient has failed prior EGFR-TKI therapy. (a) the non-small cell lung cancer is EGFR mutation- and ALK fusion gene- negative; or (b) the non-small cell lung cancer has an operable mutation in EGFR, and the patient has failed prior EGFR-TKI therapy. The method of any one of claims 1-18, 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 at a dose of 1-10 mg / kg, and the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of once in 1-10 weeks (preferably 2-8 weeks) and at a dose of 100-800 mg; preferably the disorder is non-small cell lung cancer that is EGFR wild-type and ALK fusion gene negative. The method of any one of claims 33-48, 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 at a dose of 1-10 mg / kg, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of once in 1-10 weeks (preferably 2-8 weeks) and at a dose of 100-800 mg, and the platinum-containing chemotherapeutic agent is administered at a frequency of once in 1-5 weeks and at a dose of AUC 1-10 mg / ml / min; after 1-5 cycles, the immunoconjugate of Formula (I) is administered at a frequency of once in 1-5 weeks and at a dose of 1-10 mg / kg, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a frequency of once in 1-10 weeks (preferably 2-8 weeks) and at a dose of 100-800 mg; each 6 weeks constitutes one cycle; preferably the disorder is non-small cell lung cancer that is EGFR wild-type and ALK fusion gene negative. 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 at a dose of 1-10 mg / kg, and the platinum-containing chemotherapeutic agent is administered at a frequency of once in 1-5 weeks and at a dose of AUC 1-10 mg / ml / min; after 1-5 cycles, the immunoconjugate of Formula (I) is administered at a frequency of once in 1-5 weeks and at a dose of 1-10 mg / kg; each 6 weeks constitutes one cycle; preferably the disorder is non-small cell lung cancer that is EGFR wild-type and ALK fusion gene negative. 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 at a dose of 1-10 mg / kg, and the EGFR-tyrosine kinase inhibitor is administered at a frequency of 3 times a day, 2 times a day, 1 time a day, 1 time in 2 days, or 1 time in 3 days, and at a dose of 30-150 mg; preferably the disorder is non-small cell lung cancer that is EGFR mutant. a pharmaceutical composition comprising: (a) an anti-human PD-1 antibody or 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): wherein: Ab is an antibody that binds Trop-2; and Ab is an antibody that binds Trop-2; and is an integer or decimal number from 0 to 10 and represents the average value of the number n of linker / payload moieties attached to each antibody for the plurality of immunoconjugates of formula (I); wherein the amounts of (a) and (c) in the pharmaceutical composition together are effective for treating a cell proliferative disorder, e.g., cancer. 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 chemotherapeutic agent is cisplatin or carboplatin; (3) the EGFR-tyrosine kinase inhibitor is osimertinib; and / or (4) the immunoconjugate of Formula (I) is immunoconjugate A. A pharmaceutical composition comprising: (a) an anti-human PD-1 antibody or antigen-binding fragment thereof; (b) a pharmaceutically acceptable carrier; and (c) a plurality of immunoconjugates of Formula (I): wherein: Ab is an antibody that binds Trop-2; and is a number from 0 to 10, and represents the average value of the number n of linker / payload moieties attached to each antibody for the plurality of immunoconjugates of formula (I); wherein the amounts of (a) and (c) together are effective for treating a cell proliferative disorder, e.g., cancer, in the pharmaceutical composition. The pharmaceutical composition of claim 63, wherein the antibody that binds TROP-2 is sacituzumab. The pharmaceutical composition of claim 63 or 64, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab. A kit comprising: (a) an amount of an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor; and (b) an amount of an immunoconjugate of Formula (I): wherein: Ab is an antibody that binds Trop-2; and n is an integer from 0 to 10; wherein the amounts of (a) and (c) in the kit together are effective to treat a cell proliferative disorder, e.g., cancer. A kit comprising: (a) an amount of an anti-human PD-1 antibody or antigen-binding fragment thereof; and (b) an amount of an immunoconjugate of Formula (I): wherein: Ab is an antibody that binds Trop-2; and n is an integer from 0 to 10; wherein the amounts of (a) and (c) in the kit together are effective to treat a cell proliferative disorder, e.g., cancer. 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. The kit of any one of claims 66-68, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab. The kit of any one of claims 66-69, wherein the immunoconjugate of Formula (I) is immunoconjugate A. The kit of claim 66, wherein, The EGFR-tyrosine kinase inhibitor is osimertinib; and / or the immunoconjugate of Formula (I) is immunoconjugate A. A pharmaceutical combination for use in the treatment of a cell proliferative disorder, such as cancer, in a human patient, said pharmaceutical combination comprising: (a) an immunoconjugate of Formula (I); and (b) an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor; 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 being as described in any one of claims 1-71. The use of a pharmaceutical combination for the manufacture of a medicament for the treatment of a cell proliferative disorder, such as cancer, in a human patient, said pharmaceutical combination comprising: (a) an immunoconjugate of Formula (I); and (b) an anti-human PD-1 antibody or antigen-binding fragment thereof, a platinum-containing chemotherapeutic agent, and / or an EGFR-tyrosine kinase inhibitor; the immunoconjugate of Formula (I), anti-human PD-1 antibody or antigen-binding fragment thereof being as described in any one of claims 1-72.