Combination therapies for treatment of cancer

Abstract

To provide methods, pharmaceutical compositions and kits for treating a cellular proliferative disorder (e.g., cancer).SOLUTION: Provided are methods comprising administering: (a) an anti-human PD-1 antibody or an antigen binding fragment thereof; and (b) an immunoconjugate of Formula (I) [wherein Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10].SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to combination therapies useful in the treatment of cancer. In particular, the present disclosure relates to combination therapies comprising antibodies and immunoconjugates that bind to Programmed Cell Death Protein 1 (PD-1) or antigen-binding fragments thereof. [Background technology]

[0002] PD-1 is recognized as playing an important role in immune regulation and the maintenance of peripheral immune tolerance. PD-1 is moderately expressed on naive T cells, B cells, and NKT cells, and is upregulated by T / B cell receptor signaling in lymphocytes, monocytes, and myeloid cells.

[0003] Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers occurring in a variety of tissues. In large sample sets, including ovarian, renal, colorectal, pancreatic, liver and melanoma, expression of PD-L1 has been shown to correlate with poor prognosis and reduced overall survival, regardless of subsequent treatment.

[0004] Similarly, expression of PD-1 on tumor-infiltrating lymphocytes has been found to characterize dysfunctional T cells in breast cancer and melanoma, and to correlate 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, thereby contributing to a reduced immune response against the tumor.

[0005] Immune checkpoint therapy targeting the PD-1 axis has led to dramatic improvements in clinical responses in multiple human cancers. TM(pembrolizumab) (Merck and Co., Inc., Kenilworth, NJ, USA) and OPDIVO TM (nivolumab) (Bristol-Myers Squibb Company, Princeton, NJ, USA)] and a monoclonal antibody that binds to the PD-L1 ligand [MPDL3280A; TECENTRIQ TM (atezolizumab) (Genentech, San Francisco, CA, USA). Both therapeutic approaches have demonstrated antitumor effects in many types of cancer.

[0006] It has been proposed that the efficacy of such antibodies may be enhanced when administered in combination with other approved or experimental cancer treatments (e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other unregulated signaling pathways within tumors, and other immune enhancing agents).

[0007] Trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein involved in calcium signaling and is expressed in several tumor types. Trop-2 is expressed in normal trophoblast cells and enables trophoblast cell growth, migration and proliferation. Trop-2 has been implicated in several cell signaling pathways, including intracellular calcium transport, MAPK signaling pathway, RAF, NF-κB and cyclin D / E, among others.

[0008] It has been shown that Trop-2 is upregulated in cancer cells when compared to its normal cell counterparts. This increased expression has been seen in many different types of tumors, including breast, colon, non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma, thyroid and hepatobiliary carcinoma, raising the possibility of Trop-2 as an agnostic biomarker of tumors. The reason for Trop-2 upregulation in cancer cells is unclear; however, Trop-2 is hypothesized to have an important regulatory effect on cell proliferation and invasion, meaning that overexpression may lead to selective tumor progression. Indeed, preclinical data suggest that overexpression of Trop-2 stimulates tumor growth, whereas knockdown of Trop-2 inhibits tumor growth.

[0009] In particular, in breast cancer, elevated Trop-2 expression has been associated with decreased survival. Expression of the Trop-2 gene has been detected in all breast cancer subtypes, with higher levels observed in HR+ / HER2- and triple-negative breast cancers (TNBC) compared to HER2+ disease. Genomic analysis of TNBC has confirmed that Trop-2 is also an attractive candidate for targeted therapy, leading to further investigation of Trop-2 as a novel therapeutic target.

[0010] Successful targeting of Trop-2 via antibody-drug conjugates (ADCs) in metastatic breast cancer (MBC) and urothelial carcinoma, and ongoing trials in NSCLC, have established Trop-2 targeting as a valid and beneficial strategy, and several Trop-2-targeted therapeutics, such as anti-Trop-2 antibodies and Trop-2-targeted ADCs, have been recently developed for clinical use. Subsequently, multiple early-phase clinical trials have demonstrated a favorable safety profile and clinical benefits associated with Trop-2-based ADCs across multiple tumor types. This includes clinical benefit and tolerability in tumor types with limited treatment options (e.g., triple-negative breast cancer, platinum-resistant urothelial carcinoma, and small cell lung cancer). An example of an immunoconjugate currently undergoing early-phase clinical trials is immunoconjugate A: [ka] [wherein Ab is an anti-Trop-2 antibody (sacituzumab) and is described in U.S. Patent Publication No. 20200347075] It is.

[0011] Trop-2 may play a role in tumor progression, given its involvement in several molecular pathways traditionally associated with cancer development. High expression of Trop-2 correlates with poor prognosis in pancreatic, hilar cholangiocarcinoma, cervical and gastric cancers. In a meta-analysis including 2,569 patients, elevated expression of Trop-2 was associated with decreased overall disease-free survival in several solid tumors. Given the expression pattern of Trop-2 and the associated poor prognosis, Trop-2 is a reasonable prognostic marker and therapeutic target. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent Publication No. 20200347075 Summary of the Invention [Problem to be solved by the invention]

[0013] Given the encouraging results shown by both anti-human PD-1 antibodies and immunoconjugates as monotherapy for cancer treatment, combinations of these therapeutic agents, which have different mechanisms of action and non-overlapping toxicities, have the potential to provide more significant and long-lasting responses in many types of cancer. [Means for solving the problem]

[0014] In a first aspect, the disclosure provides a method of treating a cell proliferative disorder (e.g., cancer) in a patient, the method comprising administering to the patient: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof; and (b) Formula (I): [ka] [During the ceremony, Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10. An immunoconjugate represented by the formula: administering wherein the amounts of (a) and (b) present in the composition, together, are effective to treat ovarian cancer, cervical cancer, prostate cancer, or urothelial cancer.

[0015] In one embodiment (embodiment No. 1) of this method, 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 carcinoma, non-Hodgkin's lymphoma, renal cancer, Hodgkin's lymphoma, mesothelioma, ovarian cancer, small cell lung cancer, esophageal cancer, anal cancer, bile duct cancer, colorectal cancer, cervical cancer, thyroid cancer, or salivary cancer. Furthermore, in some embodiments of the above method, the cancer expresses high levels of PD-L1, for example, a cancer having a tumor with a tumor proportion score (TPS) of 1% or more, 10% or more, or 50% or more. For example, the level of PD-L1 TPS is confirmed by an FDA approved test.

[0016] In embodiment No. 2 of this method, the cancer to be treated is selected from ovarian cancer, cervical cancer, prostate cancer and urothelial cancer.

[0017] In embodiment No. 3 of this method, the cancer is cervical cancer. In a particular embodiment, the cervical cancer is recurrent or metastatic cervical cancer.

[0018] In embodiment No. 4 of this 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.

[0019] In embodiment No. 5 of this method, the cancer is urothelial carcinoma. In a particular embodiment, the urothelial carcinoma is locally advanced or metastatic urothelial carcinoma.

[0020] In embodiment No. 6 of this method, the cancer is prostate cancer. In a particular embodiment, the prostate cancer is locally advanced or metastatic urothelial carcinoma. In another particular embodiment, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0021] In embodiment No. 7 of this method, the immunoconjugate of formula (I) is Immunoconjugate A.

[0022] In embodiment No. 8 of this method, the patient is administered 200 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof and 5 mg of Immunoconjugate A, where 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 three week cycle and 5 mg of Immunoconjugate A on day 1 of a three week cycle.

[0023] In embodiment No. 9 of this method, the patient is administered 400 mg of the anti-human PD-1 antibody or antigen-binding fragment thereof and 5 mg of Immunoconjugate A, where the anti-human PD-1 antibody or antigen-binding fragment thereof is administered once every six weeks and Immunoconjugate A is administered once every two 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 six week cycle and 5 mg of Immunoconjugate A on days 1, 15, and 29 of a six week cycle.

[0024] In a second aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (a) an immunoconjugate of formula (I); and (b) an anti-human PD-1 antibody or an antigen-binding fragment thereof; A kit comprising:

[0025] In embodiment No. 1 of this kit, the kit further comprises an immunoconjugate of Formula (I) and instructions for administering the anti-human PD-1 antibody or antigen-binding fragment thereof to a human patient.

[0026] In a third aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (a) an immunoconjugate of formula (I); and (b) an anti-human PD-1 antibody or an antigen-binding fragment thereof; The present invention provides a therapeutic combination for treating a cell proliferative disorder (e.g., cancer) in a human patient, comprising:

[0027] In certain embodiments of the first, second, or third aspect, the anti-human PD-1 antibody, or antigen-binding fragment thereof, comprises the three light chain CDRs of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and the three heavy chain CDRs of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8.

[0028] In certain embodiments of the first, second, or third aspect, the anti-human PD-1 antibody, or antigen-binding fragment thereof, comprises a V L region and V comprising the amino acid sequence set forth in SEQ ID NO:9 H Area, including.

[0029] In certain embodiments of the first, second, or third aspect, the anti-human PD-1 antibody, or antigen-binding fragment thereof, comprises a light chain that comprises, or consists of, the amino acid sequence set forth in SEQ ID NO:5, and a heavy chain that comprises, or consists of the amino acid sequence set forth in SEQ ID NO:10.

[0030] In certain embodiments of the first, second or third aspect, the anti-human PD-1 antibody, or antigen-binding fragment thereof, is pembrolizumab.

[0031] In certain embodiments of the first, second or third aspect, the anti-human PD-1 antibody, or antigen-binding fragment thereof, is nivolumab.

[0032] In a particular embodiment of the first, second or third aspect, the anti-human PD-1 antibody, or antigen-binding fragment thereof, is cemiplimab.

[0033] In certain embodiments of the first, second or third aspect, the anti-human PD-1 antibody, or antigen-binding fragment thereof, is dostarlimab. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Definitions and Abbreviations Set forth below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout the specification and claims, unless limited in specific instances, either individually or as part of a larger group.

[0035] 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.

[0036] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms such as "include," "includes," and "included" are not limiting.

[0037] As used herein, the term "about" in quantitative terms indicates plus or minus 10% of the value it modifies (if the value cannot be subdivided, such as the number of molecules or nucleotides, it is rounded up to the nearest integer).

[0038] "Antibody drug conjugate" or "ADC" or "immunoconjugate" refers to an antibody molecule or antigen-binding fragment thereof, covalently or non-covalently linked, with or without a linker, to one or more biologically active molecules. The term "antibody" is used herein in the broadest sense and includes polyclonal and monoclonal antibodies, such as intact antibodies and functional (antigen-binding) fragments thereof. The term includes engineered and / or otherwise modified forms of 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-scFvs and tandem tri-scFvs.

[0039] As used herein, the terms "at least one" or "one or more" items each encompass not only a single item selected from a list, but also mixtures of two or more items selected from a list.

[0040] The terms "administration" or "administering" refer to the act of injecting or otherwise physically delivering an exogenous substance (e.g., an anti-PD-1 antibody) to a patient, such as by oral delivery, mucosal delivery, intradermal delivery, intravenous delivery, subcutaneous delivery, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0041] As used herein, unless otherwise indicated, 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 that "specifically binds" to PD-1 is an antibody that exhibits preferential binding to PD-1 (optionally), although this specificity does not require absolute binding specificity. An antibody is considered to be "specific" for its intended target if its binding determines the presence of the target protein in a sample without undesirable results, e.g., false positives. An antibody or binding fragment thereof binds to a target protein with an affinity that is at least 2-fold stronger, preferably at least 10-fold stronger, more preferably at least 20-fold stronger, and most preferably at least 100-fold stronger, compared to its affinity for a non-target protein.

[0042] Antigen-binding moieties include, for example, Fab, Fab', F(ab')2, Fd, Fv, fragments containing the CDRs, and single chain variable fragment antibodies (scFv), and polypeptides that contain at least a portion of an immunoglobulin sufficient to confer specific antigen binding to an antigen (e.g., PD-1). Depending on the antibody amino acid sequence of the constant region of the antibody's heavy chain, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). The heavy chain constant regions corresponding to the various classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of the various classes of immunoglobulins are well known. Antigen-binding fragments of full-length antibodies can be used to generate the immunoconjugates of the present disclosure. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, recombinant IgG (rlgG) fragments, diabodies, linear antibodies, single chain antibody molecules (e.g., scFv or sFv), single domain antibodies (e.g., sdAb, sdFv, nanobodies), and multispecific antibodies formed from antibody fragments. In certain embodiments, the fragment is a single chain antibody fragment comprising the variable heavy chain region and / or the variable light chain region, such as an scFv.

[0043] An "antigen" is a structure to which an antibody can selectively bind. A target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other natural or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, the antigen is associated with a cell, e.g., present on the surface or inside a cell (e.g., a cancer cell).

[0044] "Advanced solid tumor malignancy" and "advanced solid tumor" are used interchangeably to refer to tumors that are not amenable to curative resection. Advanced solid tumors include, but are not limited to, metastatic tumors of bone, brain, breast, liver, lung, lymph nodes, pancreas, prostate, and soft tissue (sarcomas).

[0045] As used herein, the term "antibody" refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. It is therefore used in the broadest sense and specifically includes, but is not limited to, monoclonal antibodies (which includes full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, and chimeric antibodies. A "parent antibody" is an antibody obtained by exposure of the immune system to an antigen prior to modification of the antibody for its intended use (e.g., 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 any antigen-binding portion thereof that competes with the intact antibody for specific binding, unless otherwise specified, fusion proteins containing an antigen-binding portion, and any other modified configuration of an immunoglobulin molecule that contains an antigen recognition site.

[0046] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer comprises two identical pairs of polypeptide chains, where each pair has one "light" chain (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain contains a variable region of about 100-110 or more amino acids that are primarily responsible for antigen recognition. The variable regions of each light / heavy chain pair form the antibody binding site. Thus, an intact antibody generally has two binding sites. The carboxy-terminal portion of the heavy chain may define a constant region that is primarily responsible for effector function. Typically, human light chains are classified as kappa light chains and lambda light chains. Furthermore, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. Fundamental Immunology See Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)).

[0047] "Biotherapeutic agent" means a biological molecule (e.g., an antibody or a fusion protein) that blocks ligand / receptor signaling in any physiological pathway that supports tumor maintenance and / or growth or suppresses anti-tumor immune responses.

[0048] The term "carrier" as used herein includes carriers, excipients and diluents and means a material, composition or vehicle (e.g., liquid or solid fillers, diluents, excipients, solvents or encapsulating material) that is involved in the transport or transportation of a pharmaceutical agent from one organ or part of the body to another organ or part of the patient's body.

[0049] As used herein, the term "comprising" can include the embodiments "consisting of" and "consisting essentially of." The terms "comprise(s)," "include(s)," "having," "has," "may," "contain(s)," and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified components / steps and allow for the presence of other components / steps. However, such descriptions should also be construed as describing compositions or processes as "consisting of" and "consisting essentially of" the listed components, whereby only the specified components or compounds are permitted to be present, along with any acceptable carriers or fluids, and other components or compounds are excluded.

[0050] "CDR" is the antibody V H One of the three hypervariable regions (H1, H2, or H3) within the non-framework regions of the β-sheet framework, or LIt indicates one of three hypervariable regions (L1, L2, or L3) in the non-framework regions of the β-sheet framework. Thus, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and are defined, for example, by Kabat as the most hypervariable regions in antibody variable domains. CDR region sequences are also structurally defined by Chothia as residues that are not part of the conserved β-sheet framework and therefore can adapt to various conformations. Both terms are well recognized in the art. CDR region sequences are also defined by AbM, Contact, and IMGT. The positions of CDRs in canonical antibody variable regions have been determined by comparison of multiple structures (Al-Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea et al., 2000, Methods 20:267-79). Since the number of residues in the hypervariable regions varies among antibodies, additional residues relative to the canonical position are conventionally numbered a, b, c, etc., next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al., supra). Such nomenclature is likewise familiar to those of skill in the art. Correspondences between numbering systems, including, for example, Kabat numbering and the IMGT specific numbering system, are familiar to those of skill in the art and are shown in Table 1 below. In some embodiments, the CDRs are defined by the Kabat numbering system. In other embodiments, the CDRs are defined by the IMGT numbering system. In yet other embodiments, the CDRs are defined by the AbM numbering system. In yet other embodiments, the CDRs are defined by the Chothia numbering system. In yet other embodiments, the CDRs are defined by the Contact numbering system.

[0051] [Table 1]

[0052] 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 chemotherapeutic agents), antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogesterone agents, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and antisense oligonucleotide agents that inhibit the expression of genes involved in abnormal cell or tumor growth. Chemotherapeutic agents useful in the therapeutic methods of the present disclosure include cytostatic and / or cytotoxic agents.

[0053] "Chimeric antibody" refers to antibodies in which a portion of the heavy and / or light chain contains sequences derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chains are derived from another species (e.g., mouse) or belong to another antibody class or subclass, and also to fragments of such antibodies so long as they exhibit the desired biological activity.

[0054] As used herein, the terms "combination therapy" and "therapeutic combination" refer to a treatment in which at least one anti-human PD-1 antibody (or antigen-binding fragment thereof) and an immunoconjugate of Formula (I) and optionally an additional therapeutic agent are each administered to a patient in a coordinated manner over overlapping time periods. The duration of treatment with at least one anti-human PD-1 antibody (or antigen-binding fragment thereof) ("anti-PD-1 treatment") is the period during which a patient receives treatment with an anti-human PD-1 antibody (or antigen-binding fragment thereof); i.e., the period from the first administration of an anti-human PD-1 antibody (or antigen-binding fragment thereof) to the last day of a treatment cycle. Similarly, the duration of treatment with an immunoconjugate of Formula (I) ("immunoconjugate treatment of Formula (I)") is the period during which a patient receives treatment with an immunoconjugate of Formula (I); i.e., the period from the first administration of an immunoconjugate of Formula (I) to the last day of a treatment cycle. In the methods and combination treatments described herein, the anti-PD-1 treatment overlaps with the immunoconjugate of Formula (I) treatment for at least one day. In certain embodiments, the anti-PD-1 treatment and the immunoconjugate of Formula (I) treatment are coextensive. In some embodiments, the anti-PD-1 treatment is initiated prior to the immunoconjugate of Formula (I) treatment. In some embodiments, the immunoconjugate of Formula (I) treatment is initiated prior to the anti-PD-1 treatment. In some embodiments, the anti-PD-1 treatment is terminated prior to the termination of the immunoconjugate of Formula (I) treatment. In some embodiments, the immunoconjugate of Formula (I) treatment is terminated prior to the termination of the anti-PD-1 treatment.

[0055] The terms "complementarity determining region" and "CDR" are synonymous with "hypervariable region" or "HVR" and refer to subregions within an antibody variable domain that confer specificity and / or affinity of the antibody for its antigen. Generally, there are three CDRs (HCDR1, HCDR2, and HCDR3) in each heavy chain variable domain and three CDRs (LCDR1, LCDR2, and LCDR3) in each light chain variable domain. "Framework region" ("FR") refers to the non-CDR portions of the variable domain. 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 given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by: Kabat et al., 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (the "Kabat" numbering scheme); Al-Lazikani et al., JMB 273,927-948 (1997) (the "Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996) (the "contact" numbering scheme); Lefranc et al., Dev Comp Immunol. 27(l):55-77 (2003) (the "IMGT" numbering scheme); and Honegger and Pluckthun, J Mol Biol, 309(3):657-70 (2001) (the "Aho" numbering scheme).

[0056] The boundaries of a given CDR or FR may vary depending on the scheme used to identify it. For example, the Kabat scheme is based on sequence alignment, while the Chothia scheme is based on structural information. The numbering for both the Kabat and Chothia schemes is based on the length of the sequence of the most common antibody region, with insertions adjusted with an insertion letter such as "30a". The two schemes place certain insertions and deletions ("indels") at different positions, resulting in different numbering. The contact scheme is based on the analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. Unless otherwise indicated, the CDRs of the antibodies referred to herein may be identified according to any of the Kabat, Chothia, IMGT and contact methods.

[0057] "Conservatively modified variants" or "conservative substitutions" refer to the substitution of amino acids in a protein with other amino acids having similar properties (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.), such that such changes can often be made without altering the biological activity or other desired properties of the protein. Those skilled in the art will generally recognize that single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to destroy biological activity. Exemplary conservative substitutions are set forth in Table 2 below.

[0058] [Table 2]

[0059] The term "DAR" or "drug antibody ratio" as used herein refers to: (a) the number of linkers / drug moieties attached to an antibody in a single antibody drug conjugate molecule, which is an integer between 0 and 10; or (b) the average number of linkers / drug moieties attached to an antibody in a composition comprising two or more antibody drug conjugate molecules, which is a decimal number between 0 and 10. Thus, in one embodiment, for an antibody drug conjugate of the present disclosure, the DAR is an integer between 0 and 10, 0 and 9, 0 and 8, 0 and 7, 0 and 6, 0 and 5, 0 and 4, 0 and 3, 0 and 2, and 0 and 1. In an additional embodiment, for an antibody drug conjugate of the present disclosure, the DAR is an integer between 1 and 8, 1 and 4, 2 and 5, 3 and 6, 4 and 7, 5 and 8, and 6 and 8. In another embodiment, for an antibody drug conjugate of the present disclosure, the DAR is an integer between 1 and 3, 2 and 4, 3 and 5, 4 and 6, 5 and 7, and 6 and 8. In further embodiments, for an antibody-drug conjugate of the present disclosure, the DAR is an integer between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, and 7 and 8. Similarly, for a composition comprising an antibody-drug conjugate of the present disclosure, the DAR for 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 present disclosure, the DAR of the composition is a decimal number between 0 and 8, 0 and 7, 0 and 6, 0 and 5, 0 and 4, 0 and 3, 0 and 2, and 0 and 1. In additional embodiments, for a composition comprising an antibody-drug conjugate of the present disclosure, the DAR of the composition is a decimal number between 1 and 4, 2 and 5, 3 and 6, 4 and 7, 5 and 8, and 6 and 8. In another embodiment, for a composition comprising an antibody-drug conjugate of the present disclosure, the DAR of the composition is a decimal number between 1 and 3, 2 and 4, 3 and 5, 4 and 6, 5 and 7, and 6 and 8. In further embodiments, for compositions comprising an antibody-drug conjugate of the present disclosure, the DAR of the composition is a decimal number between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, and 7 and 8. The term "composition" as used above is understood to encompass pharmaceutical compositions.

[0060] The therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral or parenteral route of administration. The term "enteral route" of administration refers to administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal and rectal routes, or intragastric routes. The term "parenteral route" of administration refers to a route of administration other than the 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 intrasternal, 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 pumps, and osmotic pumps. The appropriate route and method of administration can vary depending on many factors, such as the particular therapeutic agent used, the desired rate of absorption, the particular formulation or dosage form used, the type or severity of the disease being treated, the particular site of action and the condition of the patient, and can be readily selected by one of ordinary skill in the art.

[0061] "Homology" refers to the sequence similarity between two polypeptide sequences when they are optimally aligned. If both positions of two compared sequences are occupied by the same amino acid monomer subunit, for example, if a position in the light chain CDR of two different Abs is occupied by alanine, then the two Abs are homologous at that position. The percentage of homology is the number of homologous positions shared by two sequences divided by the total number of positions compared x 100. For example, if 8 out of 10 positions in two sequences match when the two sequences are optimally aligned, the two sequences are 80% homologous. In general, the comparison is performed when the two sequences are aligned to obtain the maximum percentage of homology. For example, the comparison can be performed by the BLAST algorithm, where the parameters of the algorithm are selected to obtain the maximum match between the respective sequences over the entire length of the respective reference sequences.

[0062] The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST ALGORITHMS: Altschul, SF, et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, TL, et al., (1996) Meth. Enzymol. 266:131-141; Altschul, SF, et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, JC, et al., (1993) Comput. Chem. 17:149-163; Hancock, JM et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, MO, et al., “A model of evolutionary change in proteins.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. MO Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, RM, et al., “Matrices for detecting distant relationships.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.” MO Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, SF, (1991) J. Mol. Biol. 219:555-565; States, DJ, et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, SF, et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, 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. .

[0063] A "human antibody" refers to an antibody that contains human immunoglobulin protein sequences or derivatives thereof. A human antibody may contain mouse glycosylation if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, a "mouse antibody" or a "rat antibody" refers to an antibody that contains only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

[0064] "Humanized antibody" refers to a form of an antibody that contains sequences from a non-human (e.g., murine) antibody and sequences from a human antibody. Such antibodies contain minimal sequences derived from a non-human immunoglobulin. Generally, the humanized antibody contains substantially all of at least one (typically two) variable domain, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are of a human immunoglobulin sequence. The humanized antibody may further contain at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin. The prefixes "hum", "hu" or "h" may be added to the antibody clone name when necessary to distinguish the humanized antibody from the parent rodent antibody. The humanized forms of rodent antibodies generally contain the same CDR sequences as the parent rodent antibody, but may contain certain amino acid substitutions to improve affinity, to improve the stability of the humanized antibody, or for other reasons.

[0065] An "intact" antibody is one that comprises an antigen-binding site as well as a CL and at least a heavy chain constant region, CH1, CH2, and CH3. The constant region may comprise a human constant region or an amino acid sequence variant thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0066] As used herein, the term "immune response" relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific responses, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, activation of immune cells, proliferation of immune cells, differentiation of immune cells, and expression of cytokines.

[0067] As used herein, the term "immune response" relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific responses, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, activation of immune cells, proliferation of immune cells, differentiation of immune cells, and expression of cytokines.

[0068] The term "isolated" as used in reference to an antibody or fragment thereof refers to a purified state, and in such context means that the specified molecule is substantially free of other biological molecules (e.g., nucleic acids, proteins, lipids, carbohydrates) or other substances (e.g., cellular debris or growth medium). In general, the term "isolated" is not intended to indicate the complete absence of such substances, or the absence of water, buffers, or salts, unless present in amounts that would substantially interfere with the experimental or therapeutic uses of the binding compounds described herein.

[0069] As used herein, "Kabat" refers to the immunoglobulin alignment and numbering system developed by Elvin A. Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.).

[0070] "Monoclonal antibody" or "mAb" or "Mab" as used herein 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 may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically contain a large number of different antibodies having different amino acid sequences in the variable domains (especially the CDRs), which are often specific for different epitopes. The modifier "monoclonal" indicates the nature of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. ((1975) Nature 256: 495), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). "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. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0071] "PD-1 antagonist" means any compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to immune cell-expressed PD-1. 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, compositions and uses disclosed herein in which a human individual is the subject of treatment, the PD-1 antagonist blocks human PD-L1 from binding to human PD-1, and preferably blocks both human PD-L1 and PD-L2 from binding to human PD-1. The amino acid sequence of human PD-1 can be found in NCBI Locus No.: NP_005009. The amino acid sequences of human PD-L1 and PD-L2 can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.

[0072] "Pembro" (previously known as MK-3475, SCH900475, and lambro), alternatively referred to herein as "pembro", is a humanized IgG4 mAb having the structure set forth in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and containing the heavy and light chain amino acid sequences and CDRs set forth in Table 3. Pembrolizumab is approved by the US FDA as set forth in the prescribing information for KEYTRUDA® (Merck & Co., Inc., Rahway, NJ USA; first approved in the US 2014, updated February 2023). The term "pembrolizumab" also encompasses mAbs having the structure above (Id.) but that do not contain a C-terminal lysine in the heavy chain.

[0073] As used herein, "pembrolizumab variant" refers to a monoclonal antibody that contains heavy and light chain sequences that are identical to those in pembrolizumab, except that it has 3, 2, or 1 conservative amino acid substitutions at positions outside the light chain CDRs and 6, 5, 4, 3, 2, or 1 conservative amino acid substitutions outside the heavy chain CDRs, e.g., the variant positions are located in framework or constant regions, and optionally the C-terminal lysine residue of the heavy chain is deleted. In other words, pembrolizumab and pembrolizumab variants contain identical CDR sequences but differ from each other by having conservative amino acid substitutions at only 3 or 6 other positions in their full-length light and heavy chain sequences, respectively. Pembrolizumab variants are substantially similar to pembrolizumab with respect to the following properties: affinity for PD-1 and ability to block the binding of each of PD-L1 and PD-L2 to PD-1.

[0074] "Platinum-containing chemotherapy" (also known as platins) refers to the use of chemotherapeutic agents that are coordination complexes of platinum, used to treat cancer. Platinum-containing chemotherapeutic agents are alkylating agents that cross-link DNA, and as a result of this cross-linking, DNA mismatch repair is ineffective, generally leading to apoptosis. Examples of platins include cisplatin, carboplatin, and oxaliplatin.

[0075] The term "patient" (alternatively, "subject") as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of human, bovine (e.g., cows), porcine (e.g., pigs), ovine (e.g., sheep), caprine (e.g., goats), equine (e.g., horses), canine (e.g., domestic dogs), feline (e.g., domestic cats), lagomorph (rabbits), rodent (e.g., rats or mice), and Procyon lotor (e.g., raccoons). In certain embodiments, the patient is a human.

[0076] As used herein, the term "patient in need thereof" refers to a patient diagnosed with or suspected of suffering from a cell proliferative disorder (e.g., cancer) as defined herein.

[0077] The term "pharmaceutical acceptable carrier" refers to any inert material suitable for use in a formulation for delivering a therapeutic agent. Carriers can be anti-adherents, binders, coatings, disintegrants, bulking agents or diluents, preservatives (e.g., antioxidants, antibacterial or antifungal agents), sweeteners, absorption retardants, wetting agents, emulsifiers and buffers, etc. Examples of suitable pharmaceutical acceptable carriers include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), glucose, vegetable oils (e.g., olive oil), saline, buffers, buffered saline, and isotonic agents (e.g., sugars, polyhydric alcohols, sorbitol, and sodium chloride).

[0078] The term "pharmaceutically acceptable salt" refers to a salt that has the same effectiveness as the parent compound and is not biologically or otherwise undesirable (e.g., not toxic or harmful to the recipient) (this includes internal salts such as zwitterions). Thus, an embodiment of the present disclosure provides a pharmaceutically acceptable salt of a compound of the present disclosure. The term "salt" as used herein refers to any of the following: acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. Salts of compounds of the present disclosure can be formed by methods known to those skilled in the art, for example, by reacting a compound of the present disclosure with a specific amount (e.g., an equivalent amount) of acid or base in a medium (e.g., a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0079] Representative acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, and toluenesulfonate (also known as tosylate). Suitable salts include, for example, acid addition salts that may be formed by mixing a solution of the compound with a solution of a pharma- ceutically acceptable acid (e.g., hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid). Additionally, acids that are generally considered suitable for forming pharma- ceutically useful salts from basic pharmaceutical compounds are discussed, for example, in 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 in The Orange Book (Food & Drug Administration, Washington, DC on their website), the disclosures of which are incorporated herein by reference.

[0080] Representative basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) (e.g., dicyclohexylamine, t-butylamine, choline) and salts with amino acids (e.g., arginine, lysine), etc. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate and dibutyl sulfate), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like. Compounds having an acidic moiety can be mixed with a suitable pharma- ceutically acceptable salt to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands (e.g., quaternary ammonium salts), etc. Also, when an acid group (-COOH) or an alcohol group is present, pharma- ceutically acceptable esters can be used to modify the solubility or hydrolysis characteristics of the compound.

[0081] All such acid salts and base salts are intended to be pharma- ceutically acceptable salts within the scope of this disclosure, and all acid salts and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this disclosure.

[0082] Additionally, when a compound of the present disclosure contains both a basic moiety (such as, but not limited to, a primary, secondary, tertiary or cyclic aliphatic amine, an aromatic or heteroaryl amine, a pyridine or an imidazole) and an acidic moiety (such as, but not limited to, a tetrazole or a carboxylic acid), a zwitterion ("inner salt") may be formed, which is also encompassed by the term "salt" as used herein. It is understood that certain compounds of the present disclosure may exist in zwitterionic form, having both anionic and cationic centers within the same compound, with a net neutral charge. Such zwitterions are encompassed within the scope of the present disclosure.

[0083] As used herein, "RECIST 1.1 response criteria" means the definitions set forth in Eisenhauer, EA et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or non-target lesions, as appropriate, based on the context in which response is being measured.

[0084] "Responder patient," when referring to a specific anti-tumor response to a treatment described herein, means that the patient exhibited an anti-tumor response.

[0085] "Durable response" refers to a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, a sustained response refers to a duration at least as long as the treatment period or at least 1.5, 2.0, 2.5, or 3 times longer than the treatment period.

[0086] The term "simultaneous administration" as used herein with respect to administration of drugs refers to administration of drugs such that the individual drugs are present in the patient's body at the same time. Simultaneous administration can include concomitant administration of drugs (by the same or different routes), as well as administration of drugs at different times (by the same or different routes).

[0087] "Durable response" refers to a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, a sustained response refers to a duration at least as long as the treatment period or at least 1.5, 2.0, 2.5, or 3 times longer than the treatment period.

[0088] As used herein, "treat" or "treating" a cell proliferative disorder means administering a combination therapy of an anti-human PD-1 antibody (or antigen-binding fragment thereof) and an immunoconjugate of Formula (I) to a patient suffering from or diagnosed with a cell proliferative disorder (e.g., cancer) to achieve at least one positive therapeutic effect (e.g., a reduction in the number of cancer cells, a reduction in tumor size, a reduction in tumor burden, a reduction in the rate of cancer cell invasion into peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth), including administration by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or by any other physical delivery method described herein or known in the art. Typically, the agents of the treatment method are administered in an amount effective to alleviate one or more disease symptoms in the patient or population being treated by inducing a clinically measurable regression of such one or more disease symptoms or inhibiting its progression. The amount of the agent of the therapeutic method effective to alleviate any particular disease symptom may vary depending on factors such as the patient's condition, age and weight, and the ability of the therapeutic combination to induce the desired response in the patient. Whether the disease symptom is alleviated can be evaluated by clinical measurements that are usually used by doctors or other skilled medical providers to evaluate the severity or progression of the condition. "Treatment" may include one or more of the following: inducing / increasing an anti-tumor immune response, reducing the number of one or more tumor markers, stopping or slowing the growth of tumors or blood cancers or the progression of a disease such as cancer, stabilizing the disease, inhibiting the growth or survival of tumor cells, removing or reducing the size of one or more cancerous lesions or tumors, reducing the level of one or more tumor markers, improving or suppressing the clinical symptoms of the disease, reducing the severity or duration of clinical symptoms, prolonging the survival of treated patients compared to the expected survival of similar untreated patients, and inducing a complete or partial remission of the cancerous condition (wherein the disease is cancer, more particularly non-small cell lung cancer).

[0089] The amount of therapeutic agent effective to alleviate any particular disease symptom may vary depending on factors such as the condition, age, and weight of the patient and the ability of the agent to elicit a desired response in the patient. Alleviation of a disease symptom can be assessed by clinical measurements routinely used by a physician or other skilled medical provider to assess the severity or progression of the condition.

[0090] Positive therapeutic effects in cancer can be measured in many ways (see WA Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, T / C≦42% is the minimum level of antitumor activity. T / C<10% is considered to be a high level of antitumor activity, where T / C(%)=median treated tumor volume / median control tumor volume×100. In some embodiments, the treatment achieved by the therapy of the present disclosure is any of PR, CR, OR, PFS, DFS and OS. PFS, also referred to as "time to tumor progression", refers to the period during and after treatment during which the cancer does not grow, including the time the patient experienced CR or PR, as well as the time the patient experienced SD. DFS refers to the period during and after treatment during which the patient is disease-free. OS refers to the extension of life expectancy compared to naive or untreated individuals or patients. In some embodiments, the response to the therapy of the present disclosure is either PR, CR, PFS, DFS or OR as assessed using RECIST 1.1 response criteria. The treatment regimen for the therapy of the present disclosure that is effective in treating cancer patients may vary depending on factors such as the patient's condition, age and weight, and the ability of the therapy to induce an anti-cancer response in the patient. Although an embodiment of any of the aspects of the present disclosure may not be effective in achieving a positive therapeutic effect in every patient, it may be possible to achieve a positive therapeutic effect by any statistical test known in the art (e.g., Student's t-test, chi-test, etc.). 2This should be the case in a statistically significant number of patients as determined by the ANOVA test, the Mann and Whitney U test, the Kruskal-Wallis test (H test), the Jonckheere-Terpstra test, and the Wilcoxon test.

[0091] The terms "treatment regimen," "dosing protocol," and "dosing regimen" are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in the combination therapy of the present disclosure.

[0092] "Tumor" as applied to a patient diagnosed with or suspected of having cancer refers to a malignant or potentially malignant neoplasm or mass of tissue of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that does not usually contain cysts or areas of liquid. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) do not generally form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0093] "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 total size of the tumor throughout the body, including lymph nodes and bone marrow. Tumor burden can be ascertained by a variety of methods known in the art, such as by measuring the size of the tumor when removed from the patient, e.g., with calipers, or while in the body, using imaging techniques (e.g., ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI) scan).

[0094] 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 ascertained by various methods known in the art, such as by measuring the dimensions of the tumor when removed from the patient, for example, with calipers, or when in vivo, using imaging techniques (e.g., bone scan, ultrasound, CT, or MRI scan).

[0095] As used herein, "variable region" refers to the segment of an IgG chain that is variable in sequence among different antibodies. The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain is referred to as "V H The light chain variable region is sometimes called the "V L "It is sometimes referred to as "

[0096] Typically, both heavy and light chain variable regions contain three hypervariable regions (also called complementarity determining regions (CDRs)) located within relatively conserved framework regions (FRs). The CDRs are usually aligned with the framework regions and allow binding to a specific epitope. Generally, from N-terminus to C-terminus, both light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. As referred to herein, the light chain CDRs are CDRL1, CDRL2 and CDRL3, respectively, and the heavy chain CDRs are CDRH1, CDRH2 and CDRH3, respectively. The assignment of amino acids to each domain generally follows the definitions in "Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, 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."

[0097] The term "variant," when used with respect to an antibody (e.g., an anti-PD-1 antibody or an anti-TROP2-antibody) or an amino acid region within an antibody, can refer to a peptide or polypeptide that contains one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions compared to the native or unmodified sequence. For example, an anti-PD-1 antibody variant 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 the native or unmodified anti-PD-1 antibody. Variants can occur naturally or can be artificially constructed. Polypeptide variants can be prepared from the corresponding nucleic acid molecule encoding the variant. In certain embodiments, an antibody variant (e.g., an anti-PD-1 antibody variant) retains at least the functional activity of the antibody. In some embodiments, the anti-PD-1 antibody variants bind to PD-1 and / or antagonize PD-1 activity.

[0098] When aspects or embodiments of the disclosure are described in terms of a Markush group or other group of alternatives, the disclosure encompasses not only the entire group listed as a whole (but also each member of the group individually, and all possible subgroups of the main group), but also the main group absent one or more of the group members. The disclosure further contemplates the explicit exclusion of any one or more of the group members in the claims.

[0099] All ranges disclosed herein are inclusive of the recited endpoints and are independently combinable (e.g., the range "50 mg to 500 mg" includes the endpoints 50 mg and 500 mg, and all intermediate values). The endpoints of the ranges and any values ​​disclosed herein are not limited to exact ranges or values; they are imprecise enough to include values ​​that are approximations of those ranges and / or values.

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the event of a conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word "comprise" or variations thereof, such as "comprises" or "comprising," is understood to mean 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 include the plural, and plural terms include the singular. Examples following the terms "eg" or "for example" are not intended to be exhaustive or limiting.

[0101] Representative 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 are not intended to be limiting.

[0102] The following abbreviations are used herein and are defined as follows: [Table 3] TIFF2025016419000006.tif223158

[0103] Additional abbreviations may be defined throughout this disclosure.

[0104] The present disclosure relates to a therapeutic combination, wherein the therapeutic combination comprises: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (b) an immunoconjugate represented by Formula (I).

[0105] The present disclosure relates to a method of treating a cell proliferative disorder, as defined herein, comprising administering to a human patient in need of such treatment a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (b) an immunoconjugate represented by Formula (I).

[0106] In some embodiments of the methods and therapeutic combinations, the anti-human PD-1 antibody is pembrolizumab and the immunoconjugate of Formula (I) is a compound of Formula I.

[0107] In a preferred embodiment, the immunoconjugate of formula (I) is Immunoconjugate A, which is described in U.S. Patent Publication No. 20200347075. Immunoconjugate A has the structure: [ka] [Where: n is an integer or decimal number from 1 to 8; and Ab is sacituzumab. has.

[0108] PD-1 antagonists or anti-human PD-1 monoclonal antibodies useful in the present disclosure Examples of mAbs that bind human PD-1 and are useful in the methods, compositions, kits, and uses of the present disclosure are described in US 7,521,051, US 8,008,449, and US 8,354,509. Particular anti-human PD-1 mAbs useful as PD-1 antagonists in the methods, compositions, kits, and uses of the present disclosure include: pembrolizumab (formerly known as MK-3475, SCH 900475, and lambrolizumab), a humanized IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and having heavy and light chain amino acid sequences as shown in Table 3, and humanized antibodies h409A11, h409A16, and h409A17, described in WO2008 / 156712.

[0109] Additional examples of PD-1 antagonists useful in the methods, compositions, kits, and uses of the disclosure include, but are not limited to, nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO®, Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Sanofi-Aventis US LLC., Bridgewater, NJ), and dostallimab (JEMPERLI®, GlaxoSmithKline LLC, Philadelphia, PA).

[0110] Provided herein are PD-1 antagonists or anti-human PD-1 monoclonal antibodies that may be used in any of the methods, compositions, kits and uses disclosed herein, which include any compound or biological molecule that blocks PD-L1 from binding to PD-1, and preferably also blocks PD-L2 from binding to PD-1.

[0111] Any monoclonal antibody that binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and its ligands PD-L1 or PD-L2 can be used. In some embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1. In another embodiment, 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 yet another embodiment, 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.

[0112] 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 (MedImmune 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 yet another embodiment, the anti-human PD-1 monoclonal antibody is BGB-A317. In yet another embodiment, the anti-human PD-1 monoclonal antibody is MGA012.

[0113] In some embodiments, an anti-human PD-1 antibody, or antigen-binding fragment thereof, for use in the methods and uses disclosed herein comprises the three light chain CDRs, CDRL1, CDRL2, and CDRL3, and / or the three heavy chain CDRs, CDRH1, CDRH2, and CDRH3.

[0114] In one embodiment, CDRL1 has the amino acid sequence set forth in SEQ ID NO:1 or a variant of the amino acid sequence set forth in SEQ ID NO:1, CDRL2 has the amino acid sequence set forth in SEQ ID NO:2 or a variant of the amino acid sequence set forth in SEQ ID NO:2, and CDRL3 has the amino acid sequence set forth in SEQ ID NO:3 or a variant of the amino acid sequence set forth in SEQ ID NO:3.

[0115] In one embodiment of the anti-human PD-1 antibody, or antigen-binding fragment thereof, CDRH1 has the amino acid sequence set forth in SEQ ID NO:6, or a variant of the amino acid sequence set forth in SEQ ID NO:6, CDRH2 has the amino acid sequence set forth in SEQ ID NO:7, or a variant of the amino acid sequence set forth in SEQ ID NO:7, and CDRH3 has the amino acid sequence set forth in SEQ ID NO:8, or a variant of the amino acid sequence set forth in SEQ ID NO:8.

[0116] 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.

[0117] In alternative embodiments of the anti-human PD-1 antibody, or antigen-binding fragment thereof, CDRL1 has the amino acid sequence set forth in SEQ ID NO:11, or a variant of the amino acid sequence set forth in SEQ ID NO:11, CDRL2 has the amino acid sequence set forth in SEQ ID NO:12, or a variant of the amino acid sequence set forth in SEQ ID NO:12, and CDRL3 has the amino acid sequence set forth in SEQ ID NO:13, or a variant of the amino acid sequence set forth in SEQ ID NO:13.

[0118] 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.

[0119] In alternative embodiments 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] In subembodiments of the above anti-human PD-1 embodiments, the anti-human PD-1 antibody or antigen-binding fragment is an antibody.

[0124] Some anti-human PD-1 antibodies and antigen-binding fragments disclosed herein comprise a light chain variable region and a heavy chain variable region. In some embodiments, the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:4 or a variant 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 such embodiments, the light chain variable region sequence or the heavy chain variable region sequence is identical to the reference sequence except for having 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the substitutions are in the framework regions (i.e., outside the CDRs). In some embodiments, 1, 2, 3, 4, or 5 of the amino acid substitutions are conservative substitutions.

[0125] 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 that comprises or consists of the amino acid sequence set forth in SEQ ID NO:4, and a heavy chain variable region that comprises or consists of the amino acid sequence set forth in SEQ ID NO:9. In a further embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region that comprises or consists of the amino acid sequence set forth in SEQ ID NO:14, and a heavy chain variable region that comprises or consists of the amino acid sequence set forth 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 that comprises or consists of the amino acid sequence set forth in SEQ ID NO:28, and a heavy chain variable region that comprises or consists of the amino acid sequence set forth in SEQ ID NO:27. In a further embodiment, the anti-human PD-1 antibody or antigen-binding fragment comprises a light chain variable region that comprises or consists of the amino acid sequence set forth in SEQ ID NO:29, and a heavy chain variable region that comprises or consists of the amino acid sequence set forth in SEQ ID NO:27. In another embodiment, the antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:30, and a heavy chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:27.

[0126] In another embodiment, the method, kit or use disclosed herein comprises any one of the above-described V L Domain or V H V that shows at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or 50% sequence identity to one of the domains L Domain and / or V HIn another embodiment, the anti-human PD-1 antibody or antigen binding protein of the method comprises an anti-human PD-1 antibody or antigen binding protein having a V domain and exhibiting specific binding to PD-1. In another embodiment, the anti-human PD-1 antibody or antigen binding protein of the method comprises an anti-human PD-1 antibody or antigen binding protein having up to one, two, three, four, or five or more amino acid substitutions. L Domain and V H domain and exhibits specific binding to PD-1.

[0127] In any of the above embodiments, the PD-1 antagonist may 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 class of immunoglobulin, including IgM, IgG, IgD, IgA, and IgE. Preferably, the antibody is an IgG antibody. Any isotype of IgG may be used, including IgG1, IgG2, IgG3, and IgG4. Different constant domains may be used in combination with the V and VL antibodies provided herein. L Area and V H For example, if a particular intended use of the antibodies (or fragments) disclosed herein requires altered effector functions, heavy chain constant domains other than IgG1 may be used. Although IgG1 antibodies offer long half-life and effector functions (e.g., complement activation and antibody-dependent cellular cytotoxicity), such activities may not be desirable for all applications of the antibody. In such cases, for example, an IgG4 constant domain can be used.

[0128] In a particular embodiment, 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 an alternative embodiment, 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 a further embodiment, 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 a further embodiment, 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 yet further 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 pembrolizumab or a pembrolizumab biosimilar. In some compositions, methods, kits and uses disclosed herein, the PD-1 antagonist is nivolumab or a nivolumab biosimilar. 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.

[0129] Generally, amino acid sequence variants of the anti-PD-1 antibodies and antigen-binding fragments disclosed herein are similar to those of the reference antibody or antigen-binding fragment (e.g., heavy chain, light chain, V H , V L, or a humanized sequence). Identity or homology with respect to a sequence is defined herein as the percentage of amino acid residues in a candidate sequence that are identical to the anti-PD-1 residues after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percentage sequence identity, without considering conservative substitutions as part of the sequence identity. None of the antibody sequences, N-terminal, C-terminal or internal extensions, deletions, or insertions shall be construed as affecting sequence identity or homology.

[0130] Sequence identity refers to the degree to which the amino acids of two polypeptides are identical at equivalent positions when the two sequences are optimally aligned.Sequence identity can be determined using the BLAST algorithm, where the parameters of the algorithm are selected to maximize the match between the respective sequences over the entire length of each reference sequence. The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST ALGORITHMS: Altschul, SF, et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, TL, et al., (1996) Meth. Enzymol. 266:131-141; Altschul, SF, et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, JC, et al., (1993) Comput. Chem. 17:149-163; Hancock, JM et al. al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, MO, et al., "A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. MO Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, RM, et al., "Matrices for detecting distant relationships." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3." MO Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, SF, (1991) J. Mol. Biol. 219:555-565; States, DJ, et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, SF, et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, SF "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York. .

[0131] Similarly, any class of light chain may be used in the compositions and methods herein. In particular, Kappa, Lambda or variants thereof are useful in the compositions of the invention and the compositions, methods, kits and uses disclosed herein.

[0132] [Table 4] TIFF2025016419000009.tif248163TIFF2025016419000010.tif26163

[0133] [Table 5] TIFF2025016419000012.tif208169

[0134] In embodiments of the 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 certain 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 certain aspects of these embodiments, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is selected from nivolumab and pembrolizumab. In a further particular aspect, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is nivolumab. In a further particular aspect, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is pembrolizumab.

[0135] In embodiments of the compositions, methods, kits, and uses disclosed herein, the anti-human PD-1 antibody is pembrolizumab. In another such embodiment, the anti-human PD-1 antibody is nivolumab. In another such embodiment, the anti-human PD-1 antibody is pidilizumab. In another such embodiment, the anti-human PD-1 antibody is tislelizumab. In another such embodiment, the anti-human PD-1 antibody is AMP-514. In another such embodiment, the anti-human PD-1 antibody is cemiplimab. In another such embodiment, the anti-human PD-1 antibody is dostarlimab.

[0136] An immunoconjugate represented by formula (I) Immunoconjugates useful in the present disclosure have formula (I): [ka] [During the ceremony, Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10. It is an immunoconjugate represented by the formula:

[0137] In certain embodiments, the immunoconjugates useful in the present disclosure have formula (I): [ka] [During the ceremony, n is an integer from 1 to 10; and Ab is (i) a heavy chain variable region comprising: HCDR1 comprising the amino acid sequence of SEQ ID NO: 39; HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and HCDR3 comprising the amino acid sequence of SEQ ID NO: 41; and (ii) a light chain variable region comprising: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44; and is an antibody that binds to Trop-2. It is an immunoconjugate represented by the formula:

[0138] In certain embodiments, the immunoconjugates useful in the present disclosure have formula (I): [ka] [During the ceremony, n is an integer from 1 to 10; and Ab is (i) a heavy chain variable region having the amino acid sequence of SEQ ID NO: 37; and (ii) a light chain variable region having the amino acid sequence of SEQ ID NO: 38; and is an antibody that binds to Trop-2. It is an immunoconjugate represented by the formula:

[0139] In certain embodiments, the immunoconjugates useful in the present disclosure have formula (I): [ka] [During the ceremony, n is an integer from 1 to 10; and Ab is (i) a heavy chain having the amino acid sequence of SEQ ID NO: 35; and (ii) a light chain having the amino acid sequence of SEQ ID NO: 36; and is an antibody that binds to Trop-2. It is an immunoconjugate represented by the formula:

[0140] In a preferred embodiment, the immunoconjugate represented by formula (I) is Immunoconjugate A, described in U.S. Patent Publication No. 20200347075. Immunoconjugate A has the structure: [ka] [Where: n is an integer from 1 to 8; and Ab1 is sacituzumab. has.

[0141] In another preferred embodiment, the compound of formula (I) [ka] a composition comprising an immunoconjugate represented by Where: the average "n" in the composition is a decimal number from 1 to 8; and Ab1 is sacituzumab.

[0142] In some embodiments of the present disclosure, the anti-Trop-2 antibody of the immunoconjugate of formula (I) is sacituzumab (or hRS7), as described in U.S. Patent Publication No. 2012 / 0237518. This antibody can also be obtained by screening the construction of an antibody library displaying the antibody by carrier design, as disclosed in CN103476941A, or by screening the G-MAB® library of Sorrento Therapeutics, Inc.

[0143] Table 5 shows the sequence numbers of the heavy and light chain complementarity determining regions (HCDRs and LCDRs), the heavy and light chain variable domains (VH and VL), and the amino acid sequences of the heavy and light chains (HC and LC) of sacituzumab.

[0144] [Table 6] TIFF2025016419000020.tif34169

[0145] In certain embodiments, an immunoconjugate of Formula (I) comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linker / drug moieties per antibody (i.e., n is 1 to 10). In certain embodiments, an immunoconjugate of Formula (I) comprises one or more (e.g., 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2) linker / drug moieties.

[0146] In certain embodiments, the immunoconjugate of Formula (I) comprises about 6 to about 8 linker / drug moieties per antibody (i.e., n is about 6 to about 8). In certain embodiments, the immunoconjugate of Formula (I) is immunoconjugate A and n is 6 to 8.

[0147] The immunoconjugates of formula (I) comprise an antibody or fragment thereof that is specific for human Trop-2 and can therefore be used as an excellent targeting moiety for delivering conjugated payloads to cells (e.g., Trop-2 positive cells). In certain embodiments, the immunoconjugates used in the therapeutic regimens of the present disclosure are any of the anti-Trop-2 immunoconjugates described in U.S. Patent Publication No. 20200347075.

[0148] Uses of the Combination Therapies of the Present Disclosure Treatment or prevention of cell proliferative disorders The combination therapies disclosed herein are potentially useful in the treatment of diseases or disorders such as, but not limited to, cell proliferative disorders, including, but not limited to, cancer, benign papillomatosis, and gestational trophoblastic disease. The terms "cancer," "cancerous," or "malignant" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell proliferation.

[0149] Accordingly, in one aspect, the disclosure relates to a method of treating a cell proliferative disorder, the method comprising administering to a patient in need of such treatment a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (b) an immunoconjugate represented by Formula (I), wherein the amounts administered are together effective to treat the cell proliferative disorder.

[0150] In certain embodiments, the cell proliferative disorder is selected from cancer, benign papillomatosis, benign neoplastic disorder, and gestational trophoblastic disease, hi certain embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform mole, and gestational trophoblastic neoplasia (e.g., invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor).

[0151] In certain embodiments, the cell proliferative disorder to be treated is cancer.

[0152] 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 represented by Formula (I); wherein the amounts administered are together effective to treat the cancer.

[0153] In certain embodiments, the amount administered is effective to treat cancer in a human patient, hi another specific embodiment, the amount administered is effective to inhibit cancer cell replication or metastasis of cancer cells in the patient.

[0154] In one embodiment, the cancer is metastatic. In another embodiment, the cancer is recurrent. In another embodiment, the cancer is refractory. In yet another embodiment, the cancer is both recurrent and refractory.

[0155] In one embodiment, the patient has previously been treated for cancer, hi another embodiment, the patient has not previously been treated for cancer.

[0156] In one embodiment, the patient has previously undergone systemic treatment for cancer. In another embodiment, the patient has not previously undergone systemic treatment for cancer.

[0157] In another embodiment, the cancer is in an adult patient; in an additional embodiment, the cancer is in a pediatric patient.

[0158] The compositions, methods, kits and uses provided herein are useful for treating cancer. Cancers that may be treated using the compositions, methods, kits and uses disclosed herein include, but are not limited to, the following: (1) Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; (2) Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma, non-small cell (3) Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, 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, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), and urothelial carcinoma; (5) Liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (6) Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (cytoplasmic Reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, giant cell tumor;(7) nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);(8) Gynecology: uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast; (9) Hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelomonocytic (CMML), myeloid cell proliferation (10) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, lenticular dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and (11) Adrenal gland: neuroblastoma. Examples of cancers that may be treated using the compounds, compositions and methods described herein include thyroid cancer, anaplastic thyroid cancer, epidermoid cancer, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), sarcoma, tetracarcinoma, hepatocellular carcinoma, and multiple myeloma.

[0159] As used herein, the term "cancer cell" includes a cell afflicted with any one of the above-identified conditions.

[0160] In certain embodiments, the cancer to be treated is selected from the following: non-small cell lung cancer, prostate cancer, ovarian cancer, cervical cancer, or urothelial cancer. In certain embodiments, the cancer is selected from the following: 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.

[0161] In one embodiment, provided herein are methods of treating unresectable or metastatic melanoma in a human patient. In some embodiments, the methods include treating resected high-risk stage III melanoma.

[0162] In certain embodiments, the cancer is selected from lung cancer, hi certain embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, bronchial tumor, and pleuropulmonary blastoma.

[0163] In one embodiment, provided herein is a method of treating metastatic non-small cell lung cancer (NSCLC) in a human patient. In some embodiments, the NSCLC is non-squamous. In another embodiment, the NSCLC is squamous. In certain embodiments of the method of treating NSCLC, the patient's tumor does not have an EGFR or ALK genomic abnormality. In certain embodiments of the method of treating NSCLC, the patient's tumor has an EGFR or ALK genomic abnormality and has progressed at or after receiving a treatment for an EGFR or ALK abnormality prior to receiving the combination therapy described herein. In certain embodiments, the NSCLC being treated does not have an EGFR mutation and an ALK fusion gene. In certain embodiments, the NSCLC being treated has an EGFR actionable mutation and the patient has failed a previous EGFR-TKI treatment and has failed a previous treatment with a combination of a PD-1 / PD-L1 antibody and chemotherapy.

[0164] In certain embodiments, the cancer is selected from the group consisting of malignant mesothelioma, hi certain embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoid.

[0165] In one embodiment, provided herein is a method of treating refractory classical Hodgkin's lymphoma (cHL) in a human patient. In certain embodiments, the patient has relapsed after one, two, three or more cHL therapies. In certain embodiments, the patient is an adult patient. In alternative embodiments, the patient is a pediatric patient.

[0166] In one embodiment, provided herein is a method for urothelial carcinoma in a human patient. In certain embodiments, the urothelial carcinoma is locally advanced or metastatic urothelial carcinoma. In certain embodiments, the patient is not suitable for receiving cisplatin-containing chemotherapy. In further embodiments, the patient progresses during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. In certain embodiments, the patient's tumor expresses PD-L1 (CPS≧10).

[0167] In one embodiment, provided herein is a method of treating an unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumor in a human patient, hi certain embodiments, the patient has progressed disease after prior anti-cancer treatment.

[0168] In one embodiment, provided herein is a method of treating unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient colorectal cancer in a human patient. In certain embodiments, the patient has progressed disease after prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

[0169] 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 certain embodiments, the patient's tumor expresses PD-L1 [combined positive score (CPS) > 1]. In some embodiments, the patient has disease progression on or after two or more prior lines of therapy including fluoropyrimidine and platinum-containing chemotherapy. In some embodiments, the patient has disease progression on or after two or more prior lines of therapy including HER2 / neu targeted therapy.

[0170] In certain embodiments, the cancer is selected from lymphoma. In certain embodiments, the cancer is selected from the group consisting of Hodgkin's lymphoma (e.g., classical refractory Hodgkin's lymphoma), non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.

[0171] 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 an indolent lymphoma. In another embodiment, the NHL is an aggressive lymphoma. In a particular embodiment, the NHL is a primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma, mycosis fungoides, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), lymph node marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Sezary syndrome, primary The tumor is selected from: 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, extranodal nasal-type NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma / delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and Burkitt's lymphoma.

[0172] In one embodiment, a method of treating cancer in a human patient is provided, wherein the patient has a tumor with a high mutational burden.

[0173] In certain embodiments, the cancer is selected from brain and spinal cancer. In certain embodiments, the brain and spinal cancer is selected from the group consisting of anaplastic astrocytoma, glioblastoma, astrocytoma, and olfactory neuroblastoma (also known as olfactory blastoma). In certain embodiments, the brain cancer is selected from the group consisting of astrocytic tumors (e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumors (e.g., oligodendroglioma and anaplastic oligodendroglioma), oligoastrocytoma (e.g., glioma ... For example, oligoastrocytoma and anaplastic oligoastrocytoma), ependymoma (for example, 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 certain examples of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and supratentorial primitive neuroectodermal tumor (sPNET). In one embodiment, the brain or spinal cancer is a metastatic brain tumor.

[0174] In certain embodiments, the cancer is selected from head and neck cancer (including recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)), nasopharyngeal cancer, nasal and paranasal sinus cancer, hypopharyngeal cancer, oral cavity cancer (e.g., squamous cell carcinoma, lymphoma, sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumor, laryngeal cancer (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma) and eye cancer or ocular cancer. In certain embodiments, the eye cancer is selected from the group consisting of 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 been treated with platinum-containing chemotherapy. In certain embodiments, the patient has disease progression during or after platinum-containing chemotherapy.

[0175] In certain embodiments, the cancer is selected from leukemia and blood cancer. In certain embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPN), post-MPN AML, post-MDS AML, del(5q)-related high-risk MDS or AML, chronic myelogenous leukemia in blast phase, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms (e.g., plasmacytoma and multiple myeloma). The leukemias referred to herein can be acute or chronic.

[0176] In certain embodiments, the cancer is selected from skin cancer. In certain embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma. In certain embodiments, the skin cancer is unresectable melanoma or metastatic melanoma.

[0177] In certain embodiments, the cancer is selected from cancers of the reproductive system. In certain embodiments, the cancer is selected from the group consisting of breast cancer, cervical cancer, vaginal cancer, ovarian cancer, endometrial cancer, prostate cancer, penile cancer and testicular cancer. In certain examples of these embodiments, the cancer is breast cancer selected from the group consisting of ductal carcinoma and phyllodes tumor. In certain examples of these embodiments, the breast cancer can be male breast cancer or female breast cancer. In some examples of these embodiments, the breast cancer is triple negative breast cancer. In another example, the breast cancer is ER+ / HER2- breast cancer. In certain examples of these embodiments, the cancer is cervical cancer selected from the group consisting of squamous cell carcinoma and adenocarcinoma.

[0178] In certain embodiments, the cancer is selected from cancers of the gastrointestinal system. In certain embodiments, the cancer is selected from the group consisting of esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid tumors, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In exemplary of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphoma, gastrointestinal lymphoma, solid pseudopapillary tumor of the pancreas, pancreatoblastoma, islet cell tumor, pancreatic cancer (e.g., acinar cell carcinoma and tubular adenocarcinoma), gallbladder adenocarcinoma, colorectal adenocarcinoma, microsatellite stable colorectal cancer, advanced microsatellite stable colorectal cancer, metastatic microsatellite stable colorectal cancer, and anal squamous cell carcinoma.

[0179] In certain embodiments, the cancer is selected from liver cancer and cholangiocarcinoma. In certain embodiments, the cancer is liver cancer (also known as hepatocellular carcinoma). In certain embodiments, the cancer is bile duct cancer (also known as cholangiocarcinoma); in examples of these embodiments, the cholangiocarcinoma is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

[0180] In certain embodiments, the cancer is selected from kidney cancer and bladder cancer. In certain embodiments, the cancer is kidney cancer selected from the group consisting of renal cell carcinoma, Wilms' tumor, and transitional cell carcinoma. In certain embodiments, the cancer is bladder cancer selected from the group consisting of urothelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0181] In certain embodiments, the cancer is selected from bone cancer, hi certain embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing's sarcoma, and chordoma (cancer of the bones along the spine).

[0182] In certain embodiments, the cancer is selected from a sarcoma, hi certain embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of the tendon sheath, and Kaposi's sarcoma.

[0183] In certain embodiments, the cancer is selected from an adenocarcinoma, hi certain embodiments, the cancer is selected from the group consisting of an adrenocortical cancer (also known as adrenocortical carcinoma or adrenal cortical carcinoma), a pheochromocytoma, a paraganglioma, a pituitary tumor, a thymoma, and a thymic carcinoma.

[0184] In certain embodiments, the cancer is selected from thyroid cancer, hi certain embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid cancer, papillary thyroid cancer, and follicular thyroid cancer.

[0185] In certain embodiments, the cancer is selected from a germ cell tumor. In certain embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In certain examples of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of non-seminomas and seminomas.

[0186] In certain embodiments, the cancer is selected from a cardiac tumor, hi certain embodiments, the cardiac tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0187] In embodiments, the cancer is a metastatic tumor, such as liver metastases from colorectal or pancreatic cancer, and brain metastases from lung or breast cancer.

[0188] In some embodiments, the cancer has 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 certain embodiments, the patient has progressed disease during or after receiving platinum-containing chemotherapy.

[0189] In certain embodiments, PD-L1 TPS is determined by an FDA-approved test.

[0190] In certain embodiments, the cancer is classified as stage III cancer or stage IV cancer. In some examples of these embodiments, the cancer is not surgically resectable.

[0191] Administration and Dosage The present disclosure relates to a method of treating a cell proliferative disorder, the method comprising administering to a patient in need of such treatment a combination therapy comprising: (a) an anti-human PD-1 antibody (or an antigen-binding fragment thereof); and (b) an immunoconjugate represented by Formula (I), wherein the amounts administered, together, are effective to treat or prevent the cell proliferative disorder.

[0192] Thus, in one aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof; (b) a pharma- ceutically acceptable carrier; and (c) Formula (I): [ka] [During the ceremony, Ab is an antibody that binds to Trop-2; and n is a decimal number from 0 to 10 and represents the average number of linker / payload moieties attached to each antibody for multiple immunoconjugates represented by Formula (I). A plurality of immunoconjugates represented by the formula: and providing a pharmaceutical composition comprising wherein the amounts of (a) and (b) present in the composition, together, are effective to treat ovarian cancer, cervical cancer, prostate cancer, or urothelial cancer.

[0193] The immunoconjugate of formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof), respectively, are typically formulated (together with a pharma- ceutically acceptable carrier or excipient) into a dosage form adapted for administration to a patient by a desired route of administration. For example, dosage forms include (1) dosage forms adapted for oral administration (e.g., tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets); and (2) dosage forms adapted for parenteral administration (e.g., sterile solutions, suspensions, and powders for reconstitution). Suitable pharma- ceutically acceptable carriers or excipients will vary depending on the particular mode of administration selected. In addition, suitable pharma- ceutically acceptable carriers or excipients can be selected for a particular function that they may serve in the composition. In embodiments, the immunoconjugates of Formula (I) and / or anti-human PD-1 antibodies (or antigen-binding fragments thereof) can be formulated into dosage forms that allow for systemic use (i.e., distribution throughout a patient's body); examples of such systemic administration include oral administration, intravenous administration, and subcutaneous administration. In further embodiments, the immunoconjugates of Formula (I) and / or anti-human PD-1 antibodies (or antigen-binding fragments thereof) can be formulated into dosage forms that allow for targeted or isolated use (i.e., administration of the immunoconjugates of Formula (I) and / or anti-human PD-1 antibodies (or antigen-binding fragments thereof) only to the portion of a patient's body that is to be treated); examples of such targeted administration include intratumoral injection.

[0194] 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 (dosage, frequency, and duration of treatment) as is typically used when that therapeutic agent is used as a monotherapy to treat the same condition. In another embodiment, the patient is administered at least one of the therapeutic agents in the combination therapy in a lower total amount (e.g., a lower dosage, less frequent administration, and / or shorter duration of treatment) than when that therapeutic agent is used as a monotherapy.

[0195] 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 certain embodiments, the human PD-1 antibody (or antigen-binding fragment thereof) and the immunoconjugate of Formula (I) are each administered by intravenous infusion.

[0196] When the combination therapy of the present disclosure is administered to a patient, the agents comprising the combination can be administered in any order, for example, sequentially, simultaneously, together, or simultaneously. The amounts of the various agents in such combination therapy can be different amounts (different dosage amounts) or can be the same amounts (same dosage amounts). Thus, for non-limiting illustrative purposes, the immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) can be present in fixed amounts (dosage amounts) in a single dosage unit.

[0197] In one embodiment, the immunoconjugate of Formula (I) is administered during the period during which the anti-human PD-1 antibody (or antigen-binding fragment thereof) exerts its prophylactic or therapeutic effect, or vice versa.

[0198] In another embodiment, the immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) are administered in dosages typically used when such agents are used as monotherapy to treat cancer.

[0199] In another embodiment, the immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) are administered at doses lower than those typically used when such agents are used as monotherapy to treat cancer.

[0200] In yet another embodiment, the immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) act synergistically and are administered at doses lower than those typically used when such agents are used as monotherapy to treat cancer.

[0201] The immunoconjugate of Formula (I) and the anti-human PD-1 antibody (or antigen-binding fragment thereof) may act additively or synergistically. A synergistic combination may allow for the use of lower dosages of one or both of these agents and / or less frequent administration of one or both of these agents. Lower dosages or less frequent administration of these agents may reduce the toxicity of the treatment without reducing the efficacy of the treatment.

[0202] In one embodiment, administration of an immunoconjugate of Formula (I) and an anti-human PD-1 antibody (or an antigen-binding fragment thereof) can inhibit resistance of a cancer to either or both of these agents.

[0203] In some embodiments, the combination therapy of the present disclosure is administered for a period of time until the patient no longer exhibits symptoms of the disease or disorder. In some embodiments, the combination therapy of the present disclosure is administered for a period of time until the patient is cured of the disease or disorder. In some embodiments, the combination therapy of the present disclosure is administered for a period of time until the patient exhibits resistance to the therapy. In some embodiments, the combination therapy of the present disclosure is administered for a period of time until the patient exhibits side effects that require discontinuation of the treatment.

[0204] In some embodiments, the patient fasts for at least 1, 2, 3, 4, 6, 8, 12 hours before one or more components of the combination therapy are administered, hi some embodiments, the patient is required to fast for at least 1, 2, 3, 4, 6, 8, 12 hours after one or more components of the combination therapy are administered.

[0205] The combination therapy of the present disclosure can be used before or after surgery to remove the tumor, and can be used before, during, or after radiation therapy.

[0206] In some embodiments, the combination therapy of the present disclosure is administered to patients who have not been previously treated with a biotherapeutic or chemotherapeutic agent (i.e., treatment-naive). In other embodiments, the combination therapy is administered to patients who have failed to achieve a durable response after previous treatment with a biotherapeutic or chemotherapeutic agent (i.e., treatment-experienced).

[0207] An article of manufacture 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 an immunoconjugate of Formula (I) in separate forms, for example in the form of a kit, or in any form designed to allow for simultaneous separate administration or separate administration on separate dosing schedules.

[0208] In some embodiments, the anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof is administered subcutaneously or intravenously at about 10, about 20, about 50, about 80, about 100, about 200, about 300, about 400, about 500, about 1000, or about 2500 mg per patient once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once per month, once every two months, or four times per year.

[0209] In certain methods, the dose of the anti-PD-1 antibody (e.g., an 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.

[0210] In certain methods, the dose of the anti-PD-1 antibody (e.g., an 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., an 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.

[0211] In another embodiment, the PD-1 antagonist in the treatment is pembrolizumab or a pembrolizumab variant, which is administered as a liquid medicament at a dose selected from the group consisting of 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 another embodiment, the PD-1 antagonist in the treatment is pembrolizumab or a pembrolizumab variant, which is administered as a liquid medicament at a fixed dose, such as 200 mg Q3W or 400 mg Q6W.

[0212] 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 the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg of pembrolizumab, or about 2 mg / kg of pembrolizumab once every three weeks or once every six weeks. In one embodiment, the human patient is administered about 200 mg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered about 240 mg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered 2 mg / kg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered 400 mg of pembrolizumab once every six weeks.

[0213] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered 200 mg of pembrolizumab once every three weeks.

[0214] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered 400 mg of pembrolizumab once every six weeks.

[0215] In some embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg of pembrolizumab, or about 2 mg / kg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 200 mg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 240 mg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 400 mg of pembrolizumab once every six weeks. In one embodiment, the human patient is administered 480 mg of pembrolizumab once every six weeks. In one embodiment, a human patient is administered 2 mg / kg pembrolizumab once every six weeks.

[0216] In some embodiments, pembrolizumab is provided as a liquid formulation comprising 25 mg / mL pembrolizumab in 10 mM histidine buffer (pH 5.5), 7% (w / v) sucrose, and 0.02% (w / v) polysorbate 80. In another embodiment, pembrolizumab is provided as a liquid formulation comprising about 125 to about 200 mg / mL pembrolizumab or an antigen-binding fragment thereof; about 10 mM histidine buffer; about 10 mM L-methionine or a pharma- ceutically acceptable salt thereof; about 7% (w / v) sucrose; and about 0.02% (w / v) polysorbate 80.

[0217] In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg of pembrolizumab every three weeks. In certain embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered about 400 mg of pembrolizumab every six weeks.

[0218] 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 over a period of about 30 minutes. In another embodiment, the selected dose of pembrolizumab is administered by subcutaneous injection.

[0219] In some embodiments, the selected dose of pembrolizumab is administered subcutaneously. In certain embodiments, the amount of pembrolizumab administered subcutaneously to a 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 a further embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 320 mg to about 450 mg.

[0220] In certain embodiments, pembrolizumab is administered subcutaneously to a patient, where pembrolizumab is part of a composition and is present in the composition at a concentration of 130 mg / mL. In certain embodiments, pembrolizumab is administered subcutaneously to a patient, where pembrolizumab is part of a composition and is present in the composition at a concentration of 165 mg / mL. In certain embodiments, pembrolizumab is administered subcutaneously to a patient in two injections. In certain embodiments, the amount of pembrolizumab administered subcutaneously to a patient is 380 mg in one prefilled syringe. In certain embodiments, the amount of pembrolizumab administered subcutaneously to a patient is 380 mg in two prefilled syringes.

[0221] In one embodiment, the selected dose of pembrolizumab is administered by subcutaneous injection at a dose at least about 1.6 times higher than a 200 mg dose or a 2 mg / kg dose. In one embodiment, the subcutaneous dose is administered once every 3 weeks. In one embodiment, the subcutaneous dose is administered once every 6 weeks. In one embodiment, the bioavailability of the subcutaneous pembrolizumab dose is at least 63%. In one embodiment, the bioavailability of the subcutaneous pembrolizumab dose is at least 64%. In one embodiment, the bioavailability of the subcutaneous pembrolizumab dose is at least 66%.

[0222] In another embodiment of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is nivolumab, and the human patient is administered about 240 mg of nivolumab, or about 3 mg / kg of nivolumab, and the nivolumab is administered once every two weeks. In one particular embodiment, the human patient is administered about 240 mg of nivolumab once every two weeks. In one particular embodiment, the human patient is administered about 3 mg / kg of nivolumab once every two weeks. In another embodiment of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is nivolumab, and the human patient is administered about 480 mg of nivolumab once every four weeks.

[0223] The immunoconjugate of formula (I) and the pharma- ceutically acceptable carrier or excipient are typically formulated into a dosage form adapted for administration to a patient by a desired route of administration. For example, dosage forms include sterile solutions, suspensions, and powders for reconstitution. Suitable pharma- ceutically acceptable carriers or excipients vary depending on the particular dosage form selected. Furthermore, suitable pharma- ceutically acceptable carriers or excipients can be selected for a particular function. In an embodiment, 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 patient's body); examples of such systemic administration include subcutaneous administration and intravenous administration. In a further embodiment, the immunoconjugate of formula (I) can be formulated into a dosage form that allows for targeted or isolated use (i.e., administration of the immunoconjugate of formula (I) only to the part of the patient's body that is to be treated); examples of such targeted administration include intratumoral injection. In certain embodiments, the dose is provided intravenously or subcutaneously. The total dose for the treatment interval is generally at least 0.25 mg / kg body weight, more generally 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, 4.00 mg / kg, 5.00 mg / kg, 6.00 mg / kg, 7.00 mg / kg, 8.00 mg / kg, 9.00 mg / kg, 10.00 mg / kg, 11.00 mg / kg, 12.00 mg / kg, 13.00 mg / kg, 14.00 mg / kg, 15.00 mg / kg, 16.00 mg / kg, 17.00 mg / kg, 18.00 mg / kg, 19.00 mg / kg, 20.00 mg / kg, 21.00 mg / kg, 22.00 mg / kg, 23.00 mg / kg, 24.00 mg / kg, 25.00 mg / kg, 26.00 mg / kg, 27.00 mg / kg, 28.00 mg / kg, 29.00 mg / kg, 30.00 mg / kg, 31.00 mg / kg, 32.00 mg / kg, 33.00 mg / kg, 34.00 mg / kg, 35.00 mg / kg, 36.00 mg / kg, 37.00 mg / kg, 38.00 mg / kg, 39.00 mg / kg, 40.00 mg / kg kg, 3.25mg / kg, 3.50mg / kg, 3.75mg / kg, 4.00mg / kg, 4.25mg / kg, 4.50mg / kg, 4.75mg / kg, 5.00mg / kg, 5.25mg / kg, 5.50mg / kg, 5.75mg / kg, 6.00mg / kg, 6.25mg / kg, 6.50mg / kg, 6.75mg / kg and 7.00mg / kg.In another embodiment, 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, 3.50 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 or 6.00 mg / kg once per week, once every two weeks, "once every three weeks," "once every four weeks," once per month, "once every six weeks," once every two months or four times per year. In certain embodiments, 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 once every three weeks. In certain embodiments, 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 once every three weeks, four weeks, or six weeks. In another specific embodiment, the immunoconjugate of Formula (I) is administered at 5.00 mg / kg once every three weeks, four weeks, or six weeks.

[0224] In one embodiment, in the combination therapy of the present disclosure, the immunoconjugate of formula (I) is administered at a dose of 0.25 mg / kg to 10 mg / kg. In some embodiments, the immunoconjugate of formula (I) can be 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, either as a single dose or in any combination thereof in multiple doses. 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 another embodiment, the immunoconjugate of Formula (I) is administered at a dose of 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.

[0225] In some embodiments, the immunoconjugate of Formula (I) is 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 immunoconjugate of Formula (I) is administered in a 3-week cycle. In another particular embodiment, the immunoconjugate of Formula (I) is administered in a 4-week cycle. In yet another particular embodiment, the immunoconjugate of Formula (I) is administered in a 6-week cycle. The treatment regimen may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administration cycles (e.g., 3 or more cycles, or 4 or more cycles). In certain embodiments, the immunoconjugate of Formula (I) is administered on days 1, 2, 3, 4, 5, 5, 6, or 7 of the cycle. The administration days may be consecutive or may have 1, 2, 3, 4, 5, or 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks between them, or any combination thereof. In certain embodiments, the immunoconjugate of Formula (I) is administered only on day 1 of each cycle (e.g., a 3-week cycle). In certain embodiments, the immunoconjugate of Formula (I) is administered on days 1 and 8 of each cycle (e.g., a 3-week cycle). In certain 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 certain embodiments, the immunoconjugate of Formula (I) is administered on day 1 of a 3-week cycle. In another specific embodiment, the immunoconjugate of Formula (I) is administered on day 1 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 another 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 once every 2 weeks, once every 3 weeks, once every 4 weeks, or once every 6 weeks.In a particular embodiment, the immunoconjugate of Formula (I) is administered at 5.00 mg / kg once every two weeks. In another particular embodiment, the immunoconjugate of Formula (I) is administered at 5.00 mg / kg once every three weeks.

[0226] The immunoconjugate of Formula (I) can be administered initially according to a dosing schedule described herein, followed by a different dosing schedule (e.g., to increase or decrease the frequency of administration) described herein. In some embodiments, the immunoconjugate of Formula (I) is administered weekly for the first 1, 2, 3, 4, 5, or 6, 7, 8, 9, 10, 11, or 12 weeks, and then once every 3 weeks. In certain embodiments, the immunoconjugate of Formula (I) is administered weekly for the first 2, 3, 4, 5, or 6 weeks, and then once every 3 weeks. In certain embodiments, the immunoconjugate of Formula (I) is administered weekly for the first 1, 2, 3, 4, 5, or 6 weeks, and then once every 4 weeks.

[0227] The immunoconjugates of formula (I) can be administered via parenteral administration. As used herein, "parenteral administration" of an immunoconjugate includes any route of administration characterized by physically breaking through a patient's tissue and administering the immunoconjugate through said breakthrough in the tissue, thus generally resulting in administration directly into the bloodstream, into a muscle, or into an internal organ. Thus, parenteral administration includes, but is not limited to, administration of the immunoconjugate by injecting the immunoconjugate, administration of the immunoconjugate by applying the immunoconjugate through a surgical incision, administration of the immunoconjugate by applying the immunoconjugate through a non-surgical wound that penetrates the tissue, and the like. In particular, parenteral administration is intended to include, but is not limited to, the following: subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intratumoral, and intrasynovial injection or infusion; and kidney dialysis infusion techniques. In certain embodiments, the immunoconjugate of Formula (I) is administered intravenously. In another particular embodiment, the immunoconjugate of Formula (I) is administered subcutaneously. Local perfusion is also contemplated. In some embodiments, the infusion can be administered by one route (e.g., intravenously) for the first dose, and then by another route for subsequent doses.

[0228] In certain embodiments, the immunoconjugate of formula (I) is administered by intravenous (IV) infusion. The infusion can be performed over a period of about 0.1 to about 4 hours (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 120, or 180 minutes). In certain embodiments, the infusion time is 30 minutes. The infusion time can be extended as necessary to accommodate the therapeutic tolerance of an individual patient. When the immunoconjugate is administered in two or more doses, in some embodiments, the infusion time for the first dose is longer than the infusion time for the subsequent doses, or, alternatively, the infusion time for the first dose is shorter than the infusion time for the subsequent doses.

[0229] In one embodiment, a method of treating a cell proliferative disorder is provided, the method comprising administering to a patient in need of such treatment a combination therapy comprising: (a) an anti-human PD-1 antibody (or antigen-binding fragment thereof); and (b) an immunoconjugate represented by Formula (I); where the anti-human PD-1 antibody (or antigen-binding fragment thereof) and the immunoconjugate represented by Formula (I) are each administered on day 1 of a three-week cycle ("Combination Regimen 1").

[0230] In a specific embodiment, for combination regimen 1, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered every 3 week cycle at a dose of 200 mg, and the immunoconjugate of Formula (I) is administered every 3 week cycle at a dose of 5 mg / kg.

[0231] In a specific embodiment, for combination regimen 1, the anti-human PD-1 antibody is pembrolizumab.

[0232] In certain embodiments, for combination regimen 1, the immunoconjugate of Formula (I) is immunoconjugate A.

[0233] In another specific embodiment, for combination regimen 1, the anti-human PD-1 antibody is pembrolizumab and the immunoconjugate of Formula (I) is immunoconjugate A.

[0234] In certain embodiments, for combination regimen 1, the immunoconjugate of Formula (I) is immunoconjugate A.

[0235] In another embodiment, combination regimen 1 is administered for 1 to 4 cycles.

[0236] In one embodiment, combination regimen 1 is administered to a patient to treat cancer, wherein the cancer is prostate cancer, ovarian cancer, cervical cancer, or urothelial cancer.

[0237] In certain embodiments, combination regimen 1 is administered to a patient to treat cancer, wherein the cancer is metastatic castration-resistant prostate cancer.

[0238] In another specific embodiment, combination regimen 1 is administered to a patient to treat cancer, wherein the cancer is platinum-resistant ovarian cancer.

[0239] In another specific embodiment, combination regimen 1 is administered to a patient to treat cancer, wherein the cancer is recurrent or metastatic cervical cancer.

[0240] In another specific embodiment, combination regimen 1 is administered to a patient to treat cancer, wherein the cancer is locally advanced or metastatic urothelial carcinoma.

[0241] In one embodiment, a method of treating a cell proliferative disorder is provided, the method comprising administering to a patient in need of such treatment a combination therapy comprising: (a) an anti-human PD-1 antibody (or antigen-binding fragment thereof); and (b) an immunoconjugate represented by Formula (I); where the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered on day 1, and the immunoconjugate represented by Formula (I) is administered on days 1, 15, and 29 of a 6 week cycle ("Combination Regimen 2").

[0242] In a specific embodiment, for combination regimen 2, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a single dose of 400 mg on day 1 of each 6-week cycle, and the immunoconjugate of Formula (I) is administered at a dose of 5 mg / kg on days 1, 15, and 29, respectively, of each 6-week cycle.

[0243] In a specific embodiment, for combination regimen 2, the anti-human PD-1 antibody is pembrolizumab.

[0244] In certain embodiments, for combination regimen 2, the immunoconjugate of Formula (I) is immunoconjugate A.

[0245] In another specific embodiment, for combination regimen 2, the anti-human PD-1 antibody is pembrolizumab and the immunoconjugate of Formula (I) is immunoconjugate A.

[0246] In another embodiment, combination regimen 2 is administered for 1 to 4 cycles.

[0247] In one embodiment, combination regimen 2 is administered to a patient to treat cancer, wherein the cancer is prostate cancer, ovarian cancer, cervical cancer, or urothelial cancer.

[0248] In certain embodiments, combination regimen 2 is administered to a patient to treat cancer, wherein the cancer is metastatic castration-resistant prostate cancer.

[0249] In another specific embodiment, combination regimen 2 is administered to a patient to treat cancer, wherein the cancer is platinum-resistant ovarian cancer.

[0250] In another specific embodiment, combination regimen 2 is administered to a patient to treat cancer, wherein the cancer is recurrent or metastatic cervical cancer.

[0251] 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 (dosage, frequency, and duration of treatment) as would normally be employed if that therapeutic agent were used as a monotherapy to treat the same condition. In another embodiment, the patient is administered at least one therapeutic agent in the combination therapy in a lower total amount (e.g., a lower dose, a lower dosage, and / or a shorter duration of treatment) than if that therapeutic agent were used as a monotherapy.

[0252] Additional medications 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, where the additional anti-cancer agents are used to prevent, treat, control, ameliorate, or reduce the risk of a particular disease or condition, such as a cell proliferative disorder. In one embodiment, the therapeutic combinations disclosed herein are combined with one or more additional anti-cancer agents for use in preventing, treating, controlling, ameliorating, or reducing the risk of cancer. Such additional therapeutic agents can be administered simultaneously or sequentially with the combination therapies disclosed herein, by a route and in an amount commonly used for that therapeutic agent.

[0253] Accordingly, 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 pharma- ceutically acceptable salt thereof; and (d) a pharma- ceutically acceptable carrier. In one embodiment, the amounts of (a), (b), and (c) present in the pharmaceutical composition, together, are effective to treat cancer.

[0254] Further provided herein is a combination therapy comprising administering to a patient a pharmaceutical composition comprising: (a) an immunoconjugate of Formula (I); (b) an anti-human PD-1 antibody (or antigen-binding fragment thereof); and (c) an additional therapeutic agent, or a pharma- ceutical acceptable salt thereof. In one embodiment, the dosages of (a), (b), and (c) together are effective to treat cancer.

[0255] When co-administered with an additional therapeutic agent, the additional therapeutic agent can be administered in a repeated cycle 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 3-week cycle. In another particular embodiment, the additional therapeutic agent is administered in a 4-week cycle. In yet another particular embodiment, the additional therapeutic agent is administered in a 6-week cycle. In a particular embodiment, the additional therapeutic agent is administered on days 1, 2, 3, 4, 5, 5, 6, or 7 of the cycle. The administration days can be consecutive or can have 1, 2, 3, 4, 5, or 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks between them, or any combination thereof. In a particular 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 certain embodiments, the additional therapeutic agent is administered on day 1 of a 3 week cycle. In another particular embodiment, the additional therapeutic agent is administered on day 1 of a 4 week cycle. In certain embodiments, the additional therapeutic agent is administered on days 1, 8, and 15 of a 3 week cycle, a 4 week cycle, or a 6 week cycle.

[0256] The additional therapeutic agent may be one or more agents selected from the group consisting of STING agonists, poly ADP-ribose polymerase (PARP) inhibitors, mitogen-activated protein kinase (MEK) inhibitors, cyclin-dependent kinase (CDK) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, tryptophan 2,3-dioxygenase (TDO) selective inhibitors, antiviral compounds, antigens, adjuvants, anticancer drugs, 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, smoothen inhibitors, alkylating agents, antitumor antibiotics, antimetabolites, retinoids and immunomodulators (including, but not limited to, anticancer vaccines). It is understood that the above descriptions of additional therapeutic agents may overlap. It is also understood that the therapeutic combination is subject to optimization. The best combination to use an anti-human PD-1 antibody (or antigen-binding fragment thereof), an immunoconjugate of Formula (I), and one or more additional therapeutic agents will be determined based on the needs of an individual patient.

[0257] When the therapeutic combinations disclosed herein are used contemporaneously with one or more additional therapeutic agents, the anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or immunoconjugate of Formula (I) can be administered simultaneously with, before or after, the one or more additional therapeutic agents. Either the anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or immunoconjugate of Formula (I) can be administered separately from the other agent, by the same or a different route of administration, or in the same pharmaceutical composition as the other agent.

[0258] The weight ratio of anti-human PD-1 antibody (or antigen-binding fragment thereof) and immunoconjugate of Formula (I) can vary and depends on the therapeutically effective dose of each agent. Generally, a therapeutically effective dose of each is used. A combination comprising at least one anti-human PD-1 antibody (or antigen-binding fragment thereof), immunoconjugate of Formula (I), and one or more additional therapeutic agents generally comprises a therapeutically effective dose of each therapeutic agent. In such combinations, the anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or immunoconjugate of Formula (I) disclosed herein and the additional therapeutic agent can be administered separately or together. Furthermore, administration of one component can be prior to, simultaneous with, or subsequent to administration of the additional therapeutic agent. In one embodiment, a combination comprising at least one anti-human PD-1 antibody (or antigen-binding fragment thereof), immunoconjugate of Formula (I), and one or more additional therapeutic agents comprises a dose of each component such that the amounts administered together are effective to treat cancer.

[0259] In one embodiment, the disclosure provides an anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or an immunoconjugate of Formula (I) and at least one additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy, in one embodiment, the treatment is treatment of a cell proliferative disorder, such as cancer.

[0260] The present disclosure further provides the use of an immunoconjugate of Formula (I) for treating a cell proliferative disorder, wherein the patient has previously (e.g., within 24 hours) been treated with an anti-human PD-1 antibody (or antigen-binding fragment thereof). In one embodiment, the immunoconjugate of Formula (I) is administered within 30 minutes after administration of the anti-human PD-1 antibody (or antigen-binding fragment thereof) is completed. The present disclosure further provides the use of an anti-human PD-1 antibody (or antigen-binding fragment thereof) for treating a cell proliferative disorder, wherein the patient has previously (e.g., within 24 hours) been treated with an immunoconjugate of Formula (I). In one embodiment, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered within 30 minutes after administration of the immunoconjugate of Formula (I) is completed.

[0261] Anti-viral compounds that may be used in combination with the therapeutic combinations 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.

[0262] Antigens and adjuvants that can be used in combination with the therapeutic combinations disclosed herein include B7 costimulatory molecules, interleukin-2, interferon-γ, GM-CSF, CTLA-4 antagonists, OX-40 / OX-40 ligand, CD40 / CD40 ligand, sargramostim, levamisole, vaccinia virus, bacillus Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxins, mineral oil, surfactants such as lipolecithin, Pluronic® polyols, polyanions, peptides, and oil or hydrocarbon emulsions. Adjuvants such as aluminum hydroxide or aluminum phosphate can be added to enhance the ability of the vaccine to induce, enhance, or prolong an immune response. Further substances, such as cytokines, chemokines and bacterial nucleic acid sequences, e.g., CpG, Toll-like receptor (TLR) 9 agonists and further agonists for TLR2, TLR4, TLR5, TLR7, TLR8, TLR7 / 8, TLR9 and TLR8 / 9, e.g., lipoproteins, lipopolysaccharide (LPS), monophosphoryl lipid A, lipoteichoic acid, imiquimod, resiquimod, as well as retinoic acid-inducible gene I (RIG-I) agonists, e.g., poly I:C, used separately or in combination, are also potential adjuvants.

[0263] Chemotherapeutic agents that can be used in combination with the therapeutic combinations disclosed herein include abiraterone acetate, altretamine, anhydrovinblastine, aroplatin, asparaginase (also known as L-asparaginase and Erwinia L-asparaginase), auristatins, 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-L-proline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'deoxy-8'-norbin-caleukoblastine, dinaciclib, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine Dolastatins, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and the taxanes, ifosfamide, liarozole, lonidamine, lomustine, MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, the taxanes, nilutamide, olaparib, onapristone, oxaliplatin, paclitaxel, prednimustine, procarbazine, RPR109881, selumetinib, stramstine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine, and pharmaceutical acceptable salts thereof.

[0264] 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 alanine ((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-aminopropanoic acid, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in International Patent Publication No. WO 02 / 068470), pasireotide (also known as SO230, described in International Patent Publication No. WO 02 / 010192), and sorafenib.

[0265] Examples of topoisomerase II inhibitors include, but are not limited to, etoposide and teniposide.

[0266] 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 chemotherapeutic agents (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 agent. In a particular embodiment, the additional therapeutic agent is cisplatin. In another particular embodiment, the additional therapeutic agent is carboplatin. In certain embodiments, when co-administered with carboplatin, the dose of carboplatin is about AUC 1 mg / mL / min to AUC 10 mg / mL / min and is administered intravenously. In certain embodiments, when co-administered with carboplatin, the dose of carboplatin is about AUC 5 mg / mL / min and is administered intravenously. In another embodiment, when co-administered with cisplatin, the dose of cisplatin is about 10 mg / mL. 2 ~150mg / m 2 and is administered intravenously. In certain embodiments, when co-administered with cisplatin, the dose of cisplatin is 75 mg / m 2 and is administered intravenously.

[0267] Examples of antitumor antibiotics include, but are not limited to, doxorubicin, bleomycin, daunorubicin, daunorubicin liposome (daunorubicin citrate liposome), mitoxantrone, epirubicin, idarubicin, and mitomycin C.

[0268] Examples of antimetabolites include, but are not limited to, clarivine, 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), and cytarabine serotonin (sold under the trade name DEPOCYT). TM These include cyclosporine (sold under the trade name DACOGEN®), 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.

[0269] Examples of retinoids include, but are not limited to, alitretinoin, tretinoin, isotretinoin, and bexarotene.

[0270] In one embodiment, a method of treating a cell proliferative disorder is provided, the method comprising administering to a patient in need of such treatment a combination therapy comprising: (a) an anti-human PD-1 antibody (or antigen-binding fragment thereof); (b) an immunoconjugate represented by Formula (I); and (c) a platinum-based chemotherapeutic agent; wherein the anti-human PD-1 antibody (or antigen-binding fragment thereof), the immunoconjugate represented by Formula (I), and the platinum-based chemotherapeutic agent are each administered on day 1 of a 3-week cycle ("Combination Regimen 3").

[0271] In a specific embodiment, for combination regimen 3, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered every 3 week cycle at a dose of 200 mg, and the immunoconjugate of Formula (I) is administered every 3 week cycle at a dose of 5 mg / kg.

[0272] In a specific embodiment, for combination regimen 3, the anti-human PD-1 antibody is pembrolizumab.

[0273] In certain embodiments, for combination regimen 3, the immunoconjugate of Formula (I) is immunoconjugate A.

[0274] In another specific embodiment, for combination regimen 3, the anti-human PD-1 antibody is pembrolizumab and the immunoconjugate of Formula (I) is immunoconjugate A.

[0275] In another specific embodiment, for combination regimen 3, the platinum-based chemotherapeutic agent is cisplatin or carboplatin.

[0276] In another specific embodiment, for combination regimen 3, the anti-human PD-1 antibody is pembrolizumab, the immunoconjugate represented by Formula (I) is immunoconjugate A, and the platinum-based chemotherapeutic agent is carboplatin.

[0277] In a particular embodiment, for combination regimen 3, the anti-human PD-1 antibody is pembrolizumab, the immunoconjugate represented by Formula (I) is immunoconjugate A, and the platinum-based chemotherapeutic agent is cisplatin.

[0278] In another embodiment, combination regimen 3 is administered for 1 to 4 cycles.

[0279] In one embodiment, combination regimen 3 is administered to a patient to treat cancer, wherein the cancer is prostate cancer, ovarian cancer, cervical cancer, or urothelial cancer.

[0280] In certain embodiments, combination regimen 3 is administered to a patient to treat cancer, wherein the cancer is metastatic castration-resistant prostate cancer.

[0281] In another specific embodiment, combination regimen 3 is administered to a patient to treat cancer, wherein the cancer is platinum-resistant ovarian cancer.

[0282] In another specific embodiment, combination regimen 3 is administered to a patient to treat cancer, wherein the cancer is recurrent or metastatic cervical cancer.

[0283] In one embodiment, a method of treating a cell proliferative disorder is provided, the method comprising administering to a patient in need of such treatment a combination therapy comprising: (a) an anti-human PD-1 antibody (or antigen-binding fragment thereof); (b) an immunoconjugate represented by Formula (I); and (c) a platinum-based chemotherapeutic agent; wherein the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered on day 1; the immunoconjugate represented by Formula (I) is administered on days 1, 15, and 29; and the platinum-based chemotherapeutic agent is administered on days 1 and 22 of a 6 week cycle ("Combination Regimen 4").

[0284] In a specific embodiment, for combination regimen 4, an anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered at a dose of 400 mg every 6 week cycle, and an immunoconjugate of Formula (I) is administered at a dose of 5 mg / kg on days 1, 15, and 29 of each 6 week cycle.

[0285] In a specific embodiment, for combination regimen 4, the anti-human PD-1 antibody is pembrolizumab.

[0286] In certain embodiments, for combination regimen 4, the immunoconjugate of Formula (I) is immunoconjugate A.

[0287] In another specific embodiment, for combination regimen 4, the anti-human PD-1 antibody is pembrolizumab and the immunoconjugate of Formula (I) is immunoconjugate A.

[0288] In another specific embodiment, for combination regimen 4, the platinum-based chemotherapeutic agent is carboplatin or cisplatin.

[0289] In another specific embodiment, for combination regimen 4, the anti-human PD-1 antibody is pembrolizumab, the immunoconjugate represented by Formula (I) is immunoconjugate A, and the platinum-based chemotherapeutic agent is carboplatin, administered at a dose of AUC 5 mg / mL / min for each dose administered.

[0290] In a particular embodiment, for combination regimen 4, the anti-human PD-1 antibody is pembrolizumab, the immunoconjugate represented by Formula (I) is Immunoconjugate A, and the platinum-based chemotherapeutic agent is cisplatin, which is administered at a dose of 75 mg / m 2 is administered at a dose of

[0291] In one embodiment, combination regimen 4 is administered to a patient to treat cancer, wherein the cancer is prostate cancer, ovarian cancer, cervical cancer, or urothelial cancer.

[0292] In certain embodiments, combination regimen 4 is administered to a patient to treat cancer, wherein the cancer is metastatic castration-resistant prostate cancer.

[0293] In another specific embodiment, combination regimen 4 is administered to a patient to treat cancer, wherein the cancer is platinum-resistant ovarian cancer.

[0294] In another specific embodiment, combination regimen 4 is administered to a patient to treat cancer, wherein the cancer is recurrent or metastatic cervical cancer.

[0295] Further embodiments Further embodiments of the present disclosure include the compositions, combinations, uses and methods described above, where it is understood that each embodiment can be combined with one or more other embodiments, so long as such combinations of embodiments are consistent with the description of the embodiment. Furthermore, it should be understood that the embodiments provided above are understood to encompass all embodiments, including those resulting from combinations of embodiments.

[0296] kit The disclosure further provides articles of manufacture (e.g., kits) that include one or more containers (e.g., single-use or multi-use containers) containing a pharmaceutical composition of an immunoconjugate of Formula (I) described herein in the dosages described herein, a pharmaceutical composition of an anti-human PD-1 antibody (or antigen-binding fragment thereof) described herein in the dosages described herein, optionally an additional therapeutic agent, and instructions for use in accordance with the treatment regimens described herein. The immunoconjugate of Formula (I), the anti-human PD-1 antibody (or antigen-binding fragment thereof) and the additional therapeutic agent can be packaged together or separately in suitable packaging, such as vials or ampoules made of non-reactive glass or plastic.

[0297] In one embodiment, the kit includes a means for separately holding the compositions, such as a container, a divided bottle, or a divided foil packet. The kit of the present disclosure can be used to administer different dosage forms (e.g., oral and parenteral dosage forms) for administering the separate compositions at different dosage intervals, or can be used to titrate the separate compositions against each other. To aid in compliance, the kit of the present disclosure typically includes instructions for administration.

[0298] In one embodiment, the present disclosure provides: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof; and (b) Formula (I): [ka] [During the ceremony, Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10. An immunoconjugate represented by the formula: A kit comprising: wherein the amounts of (a) and (b) present in the composition, together, are effective to treat ovarian cancer, cervical cancer, prostate cancer, or urothelial cancer.

[0299] In one embodiment of the kit of the disclosure, the anti-human PD-1 antibody or antigen-binding fragment included in the kit is pembrolizumab.

[0300] In another embodiment, for a kit of the present disclosure, the immunoconjugate of Formula (I) contained in the kit is Immunoconjugate A.

[0301] Common methods Standard methods in molecular biology are described in: Sambrook, Fritsch and Maniatis (1982 & 1989 2 nd 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 rded., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA). Standard methods are also described in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning and DNA mutagenesis in bacterial cells (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugate and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0302] Protein purification methods, including immunoprecipitation, chromatography, electrophoresis, centrifugation and crystallization, have been 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, and glycosylation of proteins are described (see, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, NJ, pp. 384-391). The generation, purification and fragmentation of polyclonal and monoclonal antibodies have been 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 are available for characterizing ligand / receptor interactions (see, e.g., Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0303] 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. Patent No. 6,329,511).

[0304] An alternative to humanization is to use human antibody libraries displayed on phage or 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).

[0305] It is not necessary to purify an antigen to generate antibodies. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be 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).

[0306] Methods for flow cytometry, including fluorescence-activated cell sorting (FACS), are available (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 nd ed.; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).

[0307] Standard methods for immune system histology have been 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).

[0308] Software packages and databases 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); DeCypher® (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). EXAMPLES

[0309] Working Example The following examples illustrate representative embodiments of the present disclosure and are not intended to be limiting in any way.

[0310] Example 1 Preparation of Immunoconjugate A Immunoconjugate A can be made using the methods described in U.S. Patent Publication No. 20200347075, where Immunoconjugate A is referred to as "ADC-A."

[0311] Example 2 Preparation of Pembrolizumab Pembrolizumab can be made, for example, according to the methods described in International Publication No. WO2008 / 156712.

[0312] Example 3 A study of immunoconjugate A and pembrolizumab as combination therapy in subjects with various cancers This study consists of three periods, including a screening period, a treatment period, and a survival follow-up period, as follows:

[0313] *The screening period is up to 28 days prior to the first administration of the study intervention.

[0314] * During the treatment period, subjects will receive immunoconjugate A in combination with pembrolizumab in 42-day cycles until any of the study intervention discontinuation criteria are met. Subjects who discontinue the study intervention must complete an End of Treatment (EOT) visit within 30 days after the last dose of study intervention or before initiating a new anti-cancer therapy (whichever occurs first, which should be closer to 30 days after the last dose of study intervention).

[0315] * After completion of treatment, each subject will be followed for 30 days after discontinuation of all study interventions for adverse event monitoring, regardless of initiation of new anti-cancer therapy (for serious adverse events, follow-up will be for 90 days after discontinuation of all study interventions or for 30 days after discontinuation of all study interventions if the subject starts a new anti-cancer therapy, whichever occurs first); and for immune-related adverse events, collected for up to 90 days after the last dose of pembrolizumab or for 30 days after discontinuation of all study interventions if the subject starts a new anti-cancer therapy that is an immunotherapy (IO) agent, whichever occurs first).

[0316] *Subjects will continue to have survival follow-up visits by telephone every 90 days (± 14 days) for vital information and new anticancer treatments after the last dose of study intervention until the subject decides to withdraw from the study, is lost to follow-up, dies, or the end of the study. Subjects who discontinue study intervention for reasons other than disease progression will continue to have tumor evaluations until disease progression, new anticancer treatment is initiated, the subject decides to withdraw from the study, is lost to follow-up, or dies.

[0317] The study is estimated to last approximately 3 years from the time the first subject (or their legally authorized representative) provides written informed consent until the last visit of the last subject.

[0318] Intervention group and duration A total of four cohorts are planned for this study: *Cohort A: 2L or 3L recurrent or metastatic cervical cancer (CC) *Cohort B: 1L locally advanced or metastatic urothelial carcinoma (UC) *Cohort C: 2L platinum-sensitive recurrent ovarian cancer (OC) *Cohort D: 2L+ metastatic castration-resistant prostate cancer (mCRPC).

[0319] Subjects receive immunoconjugate A in combination with pembrolizumab. A pembrolizumab infusion is administered on day 1 of each 42-day cycle, and an immunoconjugate A infusion is administered on days 1, 15, and 29 of each 42-day cycle. An immunoconjugate A infusion is administered at least 30 minutes after the pembrolizumab infusion on day 1 of each cycle.

[0320] For all cohorts, delays in administration of Immunoconjugate A and pembrolizumab should not exceed 21 and 42 days, respectively (calculated from the scheduled date of infusion). Delays in administration of Immunoconjugate A >21 days or pembrolizumab >42 days should be discussed with the medical monitor.

[0321] An interim futility analysis of tumor response data will be performed. If there is no objective response after enrollment of the first 20 subjects for Cohort A or Cohort D, or if 3 or fewer of the first 20 subjects for Cohort B or 2 or fewer of the first 20 subjects for Cohort C achieve a confirmed or unconfirmed objective response, further enrollment may be paused for that cohort. If there is at least 1 response (confirmed or unconfirmed) for Cohort A or Cohort D, at least 4 responses (confirmed or unconfirmed) for Cohort B, or at least 3 responses (confirmed or unconfirmed) for Cohort C, enrollment into that cohort will continue up to a maximum of 40 subjects.

[0322] Usage / Dosage Infusion duration: The first infusion of immunoconjugate A will be administered over 90 (± 15) minutes to each subject. The infusion of pembrolizumab will be administered over 30 minutes. If pembrolizumab and immunoconjugate A are administered on the same day, pembrolizumab will be administered first, followed by the immunoconjugate A infusion at least 30 minutes apart. Infusion-related AEs will be monitored throughout the infusion. If no infusion-related AEs occur, the time of subsequent infusions of immunoconjugate A may be adjusted to 60 (+ 15) minutes. If an infusion-related AE occurs or if the investigator determines that the safety associated with immunoconjugate A infusions can be improved, the infusion time of immunoconjugate A may be adjusted to 90 (± 15) minutes.

[0323] Monitoring for adverse reactions: After the first infusion of study intervention (pembrolizumab and immunoconjugate A), subjects will be monitored for adverse reactions in the clinical setting for at least 90 minutes after completion of the study intervention infusion. If no infusion-related AEs occur, subjects will be monitored for adverse reactions for at least 60 minutes after completion of the study intervention infusion for subsequent infusions of the study intervention (excluding close monitoring for clinical symptoms).

[0324] Premedication for Immunoconjugate A infusion-related reactions: Premedication will occur after completion of the pembrolizumab infusion and within 30-60 minutes prior to the Immunoconjugate A infusion on Day 1 of each cycle if the pembrolizumab and Immunoconjugate A infusions are administered on the same day. Premedication will occur within 30-60 minutes prior to the Immunoconjugate A infusion on Days 15 and 29 of each cycle if the Immunoconjugate A infusion is administered on that day. Subjects are encouraged to receive a planned pretreatment regimen of diphenhydramine (or an equivalent dose of an antihistamine), acetaminophen (or an equivalent dose of an analgesic), and any other pretreatment regimens recommended by the investigator (as appropriate) in accordance with institutional standards and guidelines.

[0325] Dose-limiting (DLT) observation DLT is defined as any of the following toxicities related to the study intervention occurring during the DLT evaluation period (Days 1-28 of Cycle 1): Grade 3 or higher treatment-related non-hematologic toxicity causing an infusion delay of more than 2 weeks (infusions on Days 15 and 29 of Cycle 1) during the 28-day DLT evaluation period will be considered a DLT. Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V5.0.

[0326] blood system * Grade 4 neutropenia lasting more than 7 days; *Febrile neutropenia; * Grade 4 decreased platelet count; * Grade 3 or greater thrombocytopenia accompanied by clinically significant bleeding.

[0327] non-blood system * In case of liver toxicity: * An increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times the upper limit of normal (ULN) with a concomitant increase in total bilirubin greater than two times the ULN in the absence of an alternative etiology; * AST or ALT >5x ULN for more than 3 days if baseline levels are ≤3x ULN; AST or ALT >8x ULN for more than 3 days if baseline levels are >3x ULN; * Grade 4 increase in AST or ALT; * Grade 3 or greater treatment-related non-hematologic, non-hepatic toxicity, except for: * Grade 3 nausea, vomiting, or diarrhea lasting less than 72 hours and receiving appropriate symptomatic treatment; * Grade 3 fatigue lasting less than 7 days; * Grade 3 oral mucosal inflammation lasting less than 7 days and receiving appropriate symptomatic treatment; * Grade 3 rash lasting less than 7 days and receiving appropriate symptomatic treatment; * Grade 3 fever (no clinically significant fever source) lasting less than 7 days and receiving appropriate symptomatic treatment; * Grade 3 laboratory abnormalities (asymptomatic), no medical intervention required; * Grade 3 autoimmune thyroiditis or other endocrine abnormality, manageable with endocrine therapy and not requiring initiation of systemic corticosteroids; * Grade 3 tumor flare (defined as localized pain, inflammation, or rash confined to the site of a known or suspected tumor); * Grade 3 hypersensitivity / infusion reaction lasting 6 hours or less.

[0328] If any toxicity other than those listed above is observed during the DLT evaluation period, the decision as to whether or not the toxicity should be considered a DLT will be based on the opinion of the investigator in consultation with the medical monitor.

[0329] The starting dose of Immunoconjugate A for subjects during the safety run-in period is 5 mg / kg q2w. If the mTPI design requires tapering, the dose of Immunoconjugate A will be reduced to 4 mg / kg, and if Immunoconjugate A is still not well tolerated, no further dose reductions will be permitted and the study will be terminated.

[0330] Dose escalation and de-escalation decisions will be based on the mTPI design and will depend on the number of subjects enrolled and the number of DLTs observed at the current dose level.

[0331] In Table 3-1, columns indicate the number of subjects treated at the current dose level and rows indicate the number of subjects experiencing a DLT. The table entries are dose-finding decisions; E, S, D, and DU represent dose escalation, continuation at the same dose, dose de-escalation, and removal of a dose from the study due to unacceptable toxicity, respectively.

[0332] When adding subjects to a particular dose level in response to a "stay" decision, the number of additional subjects enrolled is limited to minimize exposure to doses that may be unacceptably toxic (denoted as DU in Table 3-1). Second, to determine how many more subjects can be enrolled at that dose level, one can count the diagonal (downward and to the right) steps from the current cell to the first cell marked DU.

[0333] A D or DU decision at the 4 mg / kg dose level will stop the study. An E decision at the 5 mg / kg dose level will result in continuation at that level. After 12 subjects have been enrolled at the initial dose, if the mTPI table indicates "S" to continue at the current dose, dose exploration will stop. Otherwise, if "D" or "DU" is indicated, up to 12 new subjects may be enrolled at the lower dose.

[0334] The dose with the estimated DLT rate closest to 30% will be used in the dose-finding phase. Note that although the target toxicity rate used to develop the guidelines in Table 3-1 was 30%, the percentage of subjects with observed DLTs may be slightly above or below 30%.

[0335] The number of subjects enrolled at a dose, but not yet fully evaluable for DLT assessment, must not exceed the number of remaining subjects at risk of developing a DLT before the dose is considered unacceptably toxic. Dose exploration will end after 12 subjects have been treated at any of the selected doses, as long as the decision based on Table 3-1 is "continue" or "escalate." The dose with the estimated DLT rate closest to 30% may be treated as the preliminary RP2D. The totality of data will be considered before deciding which dose to advance to the next phase.

[0336] [Table 7]

[0337] A safety run-in analysis will be conducted in the first 12 subjects enrolled in any of these four cohorts to determine the safety and tolerability of immunoconjugate A (5 mg / kg, q2w) in combination with pembrolizumab. Enrollment will occur while the SRC reviews data from the 12 subjects during the safety run-in period. Subsequent enrollment may continue if the safety and tolerability of the combination treatment is confirmed. Safety and tolerability of the first 12 subjects treated with immunoconjugate A in combination with pembrolizumab will be evaluated as follows:

[0338] Subjects in any of the four cohorts will be treated with 5 mg / kg immunoconjugate A on days 1, 15, and 29 in combination with 400 mg pembrolizumab on day 1 of each cycle. The dose of immunoconjugate A will be tapered according to the rules outlined in the mTPI design, using the immunoconjugate A dose level definitions outlined in Table 3-2. The number of subjects enrolled at a dose, but not yet fully evaluable for DLT assessment, must not exceed the number of remaining subjects at risk of developing a DLT before the dose is deemed unacceptably toxic. Dose exploration will end after 12 subjects have been treated at any of the selected doses, as long as the decision based on Table 3-1 is "continue" or "escalate." The dose with the estimated DLT rate closest to 30% may be treated as the preliminary RP2D. The totality of the data will be considered before deciding which dose to advance to the next phase.

[0339] [Table 8]

[0340] Definition of end of research Completion of the study will be confirmed when any of the following criteria are met:

[0341] *All subjects have completed the EOT visit and data regarding clinical benefit and / or overall survival are deemed mature by the sponsor.

[0342] *The primary analysis is complete, and the sponsor has initiated a separate extension study to ensure access to the study intervention for subjects still on treatment.

[0343] Study population Prospective approval of protocol deviations from recruitment and enrollment criteria, also known as protocol waivers or exemptions, will not be permitted.

[0344] The study population will consist of subjects suffering from selected solid tumors. Subjects must be able to provide written consent and must meet all of the inclusion criteria and none of the exclusion criteria.

[0345] Recruitment criteria 1. A subject is eligible to participate in this study only if all of the following criteria apply to him / her:

[0346] age 2. Subjects must be at least 18 years of age at the time they sign the informed consent.

[0347] Subject type and disease characteristics 3. For subjects with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 assessed within 7 days prior to the start of study intervention, an ECOG performance status score of 2 is permitted for patients with urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy (Cohort B).

[0348] 4. Subjects with expected survival of 3 months or longer.

[0349] 5. Cohort A : Subjects with 2L or 3L recurrent or metastatic cervical cancer a. Histologically or cytologically confirmed recurrent or metastatic cervical carcinoma with squamous cell, adenocarcinoma, or adenosquamous histology; b. Subjects who have experienced disease progression during or after treatment with platinum-based doublet chemotherapy; NOTE: Prior treatment with bevacizumab is not required if bevacizumab is not standard of care or if the subject is not eligible for bevacizumab treatment according to local criteria; c. Subjects who have received 1 or 2 prior systemic therapy regimens for recurrent and / or metastatic cervical cancer. Chemotherapy administered as adjuvant or neoadjuvant therapy or chemotherapy combined with radiation therapy should not be counted as systemic therapy regimens. Monotherapy with PD-1 / PD-L1 inhibitors for recurrent or metastatic cervical cancer should be counted.

[0350] 6. Cohort B : Subjects with 1L locally advanced or metastatic urothelial carcinoma Histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra. Subjects with mixed histology are eligible if they have >50% urothelial component and <10% plasmacytoid component (pathology will be assessed locally). Subjects with non-urothelial carcinoma of the urinary tract are not permitted; b. Subjects who are ineligible for cisplatin-containing chemotherapy, defined as meeting at least one of the following criteria: *ECOG performance status; * Creatinine clearance (calculated or measured) less than 60 mL / min, but greater than 30 mL / min. Subjects with creatinine clearance (calculated or measured) less than 30 mL / min or subjects receiving dialysis will be excluded from this study; * Hearing loss of grade 2 or greater; *Peripheral neuropathy grade 2 or greater; * New York Heart Association Class III heart failure; c. No prior systemic chemotherapy for advanced / unresectable (inoperable) or metastatic urothelial carcinoma. Use of nivolumab in the neoadjuvant setting with recurrence >12 months after completion of treatment is permitted; NOTE: Low-dose chemotherapy (e.g., low-dose cisplatin, cisplatin plus 5FU, mitomycin plus 5FU, or cisplatin plus paclitaxel) given concomitantly with radiation to the primary tumor site is not considered systemic therapy.

[0351] 7. Cohort C : Subjects with 2L platinum-sensitive recurrent ovarian cancer a. Histologically or cytologically confirmed high-grade serous component, high-grade predominantly serous, mixed endometrioid Mullerian with clear cells, or low-grade serous ovarian, primary peritoneal, or fallopian tube carcinoma; b. Known breast cancer susceptibility gene (BRCA) wild type; NOTE: Subjects will be asked to provide a genetic report of confirmed BRCA wild type based on tumor tissue prior to the first dose of study intervention; otherwise, a tumor block or slide (either archival tissue or fresh biopsy sample is acceptable) will be asked to be tested at screening to confirm BRCA wild type; c. Have received two previous courses of platinum-containing therapy and have disease that is considered platinum-sensitive after the penultimate (near-last) platinum course (time between the penultimate platinum regimen and disease progression is greater than 6 months). For the last line of platinum-containing therapy, subjects must have received at least 4 cycles of treatment; NOTE: Prior bevacizumab, anti-PD-1 / PD-L1 immunotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors (if used for frontline maintenance) are permitted. d. Subjects have responded (complete or partial response) and are maintaining a response to their last platinum regimen and are enrolled in the study within 8 weeks of completing their last platinum regimen.

[0352] 8. Cohort D : Subjects with 2L+ metastatic castration-resistant prostate cancer a. Histologically or cytologically confirmed diagnosis of mCRPC; b. Subjects with measurable (soft tissue) prostate cancer on CT or MRI scan per PCWG modified RECIST 1.1 or subjects with bone metastases detectable by total body bone scintigraphy per PCWG guidance; c. Subjects who have received up to two prior next-generation anti-hormonal therapies; d. Subjects who have received only one prior chemotherapy regimen for castration-resistant disease and have received docetaxel for mCRPC and may have progressed during or after such treatment. Subjects who are intolerant to docetaxel are not eligible; NOTE: Subjects who have previously received taxane therapy in the adjuvant or hormone-sensitive setting are permitted, provided treatment was completed ≥12 months prior to screening, with no early discontinuation due to intolerance and no failure during 6 treatment cycles; e. Subjects with progression of prostate cancer within 6 months prior to screening as determined by the investigator using one of the following: * PSA progression using local laboratory values, defined by an increase in PSA level of at least 2 with an interval of at least 1 week between each assessment (wherein PSA level at screening was required to be ≥2 ng / mL); *Soft-tissue radiographic disease progression based on PCWG modified RECIST 1.1 or RECIST 1.1 criteria, with or without PSA progression; * Radiographic bone disease progression, defined as the appearance of two or more new bone lesions on bone scan, with or without PSA progression; NOTE: Subjects with prostate cancer disease confined to the prostate gland without evidence of metastasis cannot be reliably imaged and therefore are not eligible for this study.

[0353] 8. Subject has at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria; Note: For Cohort C, subjects without measurable disease per RECIST 1.1 are eligible to enroll, and for Cohort D, subjects with disease per PCWG modified RECIST 1.1 are eligible to enroll.

[0354] 9. For both TROP2 and PD-L1 testing, subjects able to provide tumor blocks or slides prior to the first dose of study intervention (for archival tumor tissue: formalin-fixed paraffin-embedded tissue block or approximately 8-10 unstained and formalin-fixed paraffin-embedded archived cut slides). For Cohort C, subjects are required to provide additional archival tumor tissue (tumor block or approximately 5-8 additional unstained slides or 20 additional unstained slides if coarse needle biopsy is used) for HRD testing prior to the first dose of study intervention. If fewer unstained slides are required, the decision to enroll the subject may be made on an individual basis after consultation with the Medical Monitor. b. Subjects unable to provide archival tumor blocks or slides must agree to provide a fresh biopsy prior to receiving any study intervention. In the investigator's opinion, tumor suitable for biopsy must be accessible, not previously irradiated, not from a target lesion, and free of contraindications to biopsy. Fine needle aspirates, brushing and punch biopsies, cell pellets from pleural effusions, forceps and wash samples are not acceptable.

[0355] 10. Subjects have relatively good organ and bone marrow function (no blood transfusions, recombinant human thrombopoietin, or colony-stimulating factor therapy within 2 weeks prior to screening), as defined as: a. Absolute neutrophil count ≥ 1.5 × 109 / L, platelet count ≥ 100 × 109 / L, and hemoglobin ≥ 9 g / dL; b. Serum bilirubin ≤1.5 × ULN, AST, ALT, and alkaline phosphatase ≤2.5 × ULN, except for subjects with liver metastases (ALT and AST ≤5 × ULN, serum bilirubin ≤2 × ULN) and subjects with liver and / or bone metastases (alkaline phosphatase ≤5 × ULN, serum albumin ≥30 g / L); NOTE: For subjects with Gilbert's syndrome, investigators should discuss this with the medical monitor on an individual basis; c. Creatinine clearance calculated by the Cockcroft-Gault formula, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, or the Modification of Diet in Renal Disease (MDRD) formula, ≥ 50 mL / min; d. International normalized ratio (INR), activated partial thromboplastin time (aPTT), and prothrombin time (PT) less than 1.5 x ULN.

[0356] 11. Subjects must have resolved (i.e., improved to Grade 0 or Grade 1, or to the level specified in the eligibility criteria) from all toxicities from previous treatment, except for toxicities not considered a safety risk (e.g., alopecia, vitiligo, and other asymptomatic laboratory abnormalities). Subjects with Grade 2 or less neuropathy will be evaluated on an individual basis after consultation with the medical monitor.

[0357] Gender and contraception / barrier requirements 12. Contraceptive use by men and women must be consistent with local regulations regarding contraceptive methods for those participating in clinical research; NOTE: The reliability of sexual abstinence for enrollment eligibility of men and / or women must be evaluated in relation to the duration of the clinical study and the subjects' preferred usual lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptom-temperature, or postovulation methods) and withdrawal are not acceptable methods of contraception.

[0358] a. Male Subject: * Male subjects must agree to use highly effective contraception from the time they sign the Informed Consent Form (ICF) until at least 6 months after the last dose of the study intervention and must refrain from donating sperm during this period; b. Female Subjects: * Female subjects are eligible to participate if they are not pregnant, not lactating, and meet at least one of the following criteria: * Not a woman of childbearing potential (WOCBP); or * WOCBP who agree to follow contraceptive instructions from signing the ICF until at least 6 months after the last dose of study intervention.

[0359] Informed consent 13. Subject is able to provide signed informed consent, including adherence to the requirements and restrictions set forth in the ICF and in this protocol.

[0360] Exclusion criteria Subjects will be excluded from the study if they meet any of the following criteria:

[0361] Medical conditions 1. Subjects with active or untreated central nervous system (CNS) metastases and / or carcinomatous meningitis are not eligible, but subjects with previously treated brain metastases may participate if their CNS disease has been stable for at least 4 weeks prior to the first dose of study intervention and they have discontinued use of corticosteroids for this indication for at least 2 weeks prior to initiating treatment in this study.

[0362] 2. Subjects with a known additional malignancy that is ongoing or has required active treatment within the past 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has received potentially curative therapy, or cervical carcinoma in situ.

[0363] 3. Subjects with clinically significant cardiovascular disease, including: a. QTcF interval >480 ms; b. Left ventricular ejection fraction less than 50%; c. Decompensated heart failure (New York Heart Association class III to class IV); d. poorly controlled hypertension (defined as diastolic blood pressure >100mmHg and / or systolic blood pressure >160mmHg); e. Myocardial infarction or unstable angina occurring within 6 months prior to the first administration of the study intervention; f. Serious cardiac arrhythmias, such as ventricular arrhythmias requiring medication or second- or third-degree atrioventricular block, not including asymptomatic atrial fibrillation where the heart rate is controlled.

[0364] 4. Subject has severe and / or uncontrolled concomitant illness such as decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorder, active inflammatory bowel disease or gastrointestinal perforation.

[0365] 5. Subjects diagnosed with active hepatitis B (hepatitis B surface antigen positive or hepatitis B core antibody positive and hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) >500 IU / mL or >2000 copies / mL) or hepatitis C (hepatitis C antibody positive and hepatitis C virus [HCV]-RNA above ULN detection).

[0366] 6. Subject has known prior positive test results or medical history for Human Immunodeficiency Virus (HIV).

[0367] 7. Subjects known to have active tuberculosis.

[0368] 8. Subject has undergone any major surgical procedure (as defined by the investigator) within 30 days of administration of the first study intervention or is currently in recovery from previous surgery.

[0369] 9. Known allergy or hypersensitivity to pembrolizumab or immunoconjugate A, or to any of the excipients in pembrolizumab or immunoconjugate A.

[0370] 10. Subject has a history of interstitial lung disease (ILD) or a history of non-infectious pneumonia requiring steroids, or has current or suspected ILD / pneumonitis, where imaging studies at screening cannot exclude ILD / pneumonitis.

[0371] 11. Subject has a history of allogeneic tissue / solid organ transplant.

[0372] 12. Subject has an autoimmune disease that required systemic therapy within the past 2 years or required immunosuppressive therapy during the study.

[0373] Note: Subjects with controlled type 1 diabetes, euthyroiditis or hypothyroidism well controlled with hormone replacement therapy (HRT), or skin conditions not requiring systemic treatment (e.g., vitiligo, psoriasis) are eligible.

[0374] Prior / concomitant therapy 13. Subject has been previously treated with TROP2 targeted therapy.

[0375] 14. Subject has been previously treated at any time with a previous topoisomerase I-containing antibody-drug conjugate for early stage or metastatic disease.

[0376] 15. Previous exposure to experimental anti-tumor vaccines or any agents targeting T cell costimulatory or immune checkpoint pathways, except for anti-PD-1 / PD-L1 inhibitors.

[0377] NOTE: Subjects who have previously received anti-PD-1 and / or anti-PD-L1 antibodies are permitted to enroll in the study if they meet the following criteria: * Not having experienced toxicity leading to permanent discontinuation of prior immunotherapy (IMT); *All AEs while undergoing previous IMT must have resolved to Grade ≤1 or baseline prior to screening for this study; * Have not experienced grade ≥3 irAEs or any grade neurological or ocular AEs while receiving prior IMT.

[0378] NOTE: Subjects with endocrine AEs of any grade will be permitted to enroll if they are stable on appropriate replacement therapy and asymptomatic; * Not requiring the use of additional immunosuppressants other than corticosteroids to manage AEs, not experiencing recurrence of AEs upon rechallenge, and not currently requiring a maintenance dose of prednisone or equivalent >10 mg per day.

[0379] 16. Subjects who have been vaccinated with a live vaccine within 30 days prior to the first dose or who are scheduled to be vaccinated with a live vaccine during the study period. Patients who require coronavirus disease 2019 (COVID-19) vaccination during the study intervention should receive a non-live vaccine (e.g., vaccines based on mRNA or replication-incompetent fully inactivated / genetically modified viruses).

[0380] 17.Subject requires use of strong inhibitors or inducers of CYP3A4 for at least 14 days prior to the first dose of the study intervention and throughout the study.

[0381] 18. Subjects who have received any chemotherapy, radiation therapy, immunotherapy, or biological therapy within 4 weeks prior to the first administration of the study intervention; or any small molecule tyrosine kinase inhibitor, antitumor hormonal therapy, systemic immune stimulants (including, but not limited to, interferon and interleukin-2), or traditional Chinese medicine approved for antitumor treatment within 2 weeks prior to the first administration of the study intervention. Palliative radiation to known metastatic sites within 2 weeks prior to the first administration of the study intervention.

[0382] 19. Subject has received systemic anti-infective treatment within 1 week prior to the first dose of study intervention.

[0383] 20. Subjects with a disease requiring systemic corticosteroid therapy (dose greater than 10 mg / day of prednisolone or equivalent doses of similar drugs) or another immunosuppressive therapy within 14 days prior to the first dose of the study intervention. However, subjects requiring intranasal, inhaled, topical application to the skin, or local injection of glucocorticoids (e.g., intra-articular injection) or requiring glucocorticoids as prophylaxis for hypersensitivity may be enrolled.

[0384] Previous / concurrent clinical research experience 21.Subject is participating in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.

[0385] Other Exclusions 22. Prior to administration of the first dose, the subject's condition rapidly deteriorates, e.g., significant change in physical fitness or decline in ECOG such that the subject no longer meets the inclusion criteria.

[0386] 23. Investigators will take into consideration other circumstances that may interfere with the evaluation of the study intervention or the safety of subjects or the interpretation of the study results.

[0387] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in carrying out the methods and uses disclosed herein.

Claims

1. 1. A method of treating cancer in a patient, comprising administering to the patient: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof; and (b) Formula (I): 【Chemistry 1】 [During the ceremony, Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10. An immunoconjugate represented by the formula: administering wherein the amounts of (a) and (b) present in the composition together are effective to treat ovarian cancer, cervical cancer, prostate cancer, or urothelial cancer.

2. 2. The method of claim 1, wherein n is 6 to 8.

3. The antibody, (i) a heavy chain variable region comprising: HCDR1 comprising the amino acid sequence of SEQ ID NO: 39; HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and HCDR3 comprising the amino acid sequence of SEQ ID NO: 41; and (ii) a light chain variable region comprising: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44; The method of claim 1 or 2, comprising:

4. The antibody, (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37; and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 38; The method according to any one of claims 1 to 3, comprising:

5. The antibody, (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 35; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 36; The method according to any one of claims 1 to 4, comprising:

6. The method of any one of claims 1 to 5, wherein the antibody is sacituzumab.

7. The method of any one of claims 1 to 6, wherein the immunoconjugate of Formula (I) is administered to the patient at a dose of 1.0 mg / kg to 6.0 mg / kg.

8. The method of any one of claims 1 to 7, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is selected from nivolumab, cemiplimab, dostallimab, pidilizumab, tislelizumab, and pembrolizumab.

9. The method of claim 8, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab.

10. 10. The method of any one of claims 1 to 9, 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.

11. The method of any one of claims 1 to 10, wherein the immunoconjugate of Formula (I) and the anti-human PD-1 antibody or antigen-binding fragment thereof are each administered in a three-week cycle, and each is administered on day 1 of each three-week cycle.

12. The method of any one of claims 1 to 10, 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.

13. 12. The method of claim 11, 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.

14. 13. The method of claim 12, 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.

15. The method according to any one of claims 11 to 14, wherein the number of cycles is from 1 to 4.

16. The method of any one of claims 1 to 15, further comprising administering to the patient an additional anti-cancer agent.

17. 17. The method of claim 16, wherein the additional anti-cancer agent is a platinum-containing chemotherapeutic agent.

18. The method according to any one of claims 1 to 17, wherein the cancer to be treated is selected from ovarian cancer, cervical cancer, prostate cancer and urothelial cancer.

19. 19. The method of claim 18, wherein the ovarian cancer is platinum-resistant ovarian cancer.

20. 19. The method of claim 18, wherein the cervical cancer is recurrent or metastatic cervical cancer.

21. 20. The method of claim 18, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

22. 19. The method of claim 18, wherein the urothelial carcinoma is locally advanced or metastatic urothelial carcinoma.

23. 1. A pharmaceutical composition comprising: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof; (b) a pharma- ceutically acceptable carrier; and (c) Formula (I): 【Chemistry 2】 [During the ceremony, Ab is an antibody that binds to Trop-2; and n is a decimal number from 0 to 10 and represents the average number of linker / payload moieties attached to each antibody for multiple immunoconjugates represented by Formula (I). a plurality of immunoconjugates represented by Including, wherein the amounts of (a) and (b) present in the composition, together, are effective to treat ovarian cancer, cervical cancer, prostate cancer, or urothelial cancer.

24. 24. The pharmaceutical composition of claim 23, wherein the antibody is sacituzumab.

25. The pharmaceutical composition according to claim 23 or 24, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab.

26. A kit comprising: (a) an amount of an anti-human PD-1 antibody or antigen-binding fragment thereof; and (b) a particular amount of a compound of formula (I): 【Chemistry 3】 [During the ceremony, Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10. An immunoconjugate represented by the formula: Including, wherein the amounts of (a) and (b) present in the composition together are effective to treat ovarian cancer, cervical cancer, prostate cancer, or urothelial cancer.

27. The kit of claim 26, 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.

28. The kit of claim 26 or 27, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is pembrolizumab.

29. The kit according to any one of claims 26 to 28, wherein the immunoconjugate represented by formula (I) is immunoconjugate A.

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