Antibody and Taxon Combination Therapy

Abstract

The present invention provides a combination therapy for reducing or preventing tumor progression or treating cancer in a subject, the combination therapy comprising the administration of a binding agent that binds to human CD137 and human PD-L1, and a taxane chemotherapeutic agent.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to combination therapies using binding agents that bind to human CD137 and human PD-L1 in combination with taxane chemotherapeutic agents to reduce or prevent tumor progression or to treat cancer. [Background technology]

[0002] Background of the Invention CD137 (4-1BB, TNFRSF9) is a member of the tumor necrosis factor (TNF) receptor (TNFR) family. CD137 binds to CD8 + T cells and CD4 + It is a costimulatory molecule on the surface of T cells, regulatory T cells (Tregs), natural killer (NK) and NKT cells, B cells, and neutrophils. CD137 is not constitutively expressed on T cells but is induced upon T cell receptor (TCR) activation. Stimulation via its natural ligand, 4-1BBL, or agonist antibodies results in signaling using TNFR-associated factor (TRAF)-2 and TRAF-1 as adaptors. Initial signaling by CD137 involves a K-63 polyubiquitination reaction that ultimately activates the nuclear factor (NF)-κB and mitogen-activated protein (MAP)-kinase pathways. Signaling leads to increased T cell costimulation, proliferation, cytokine production, and maturation, and to CD8 +T cell survival is prolonged. Agonistic antibodies against CD137 have been shown to promote T cell-mediated anti-tumor control in various preclinical models (Murillo et al. 2008 Clin. Cancer Res. 14(21): 6895-6906 (Non-Patent Document 1)). Antibodies that stimulate CD137 can induce T cell survival and proliferation, thereby enhancing anti-tumor immune responses. Antibodies that stimulate CD137 have been disclosed in the prior art, including the human IgG4 antibody urelumab (WO2005035584 (Patent Document 1)) and the human IgG2 antibody utomilumab (Fisher et al. 2012 Cancer Immunol. Immunother. 61: 1721-1733 (Non-Patent Document 2)).

[0003] Programmed cell death ligand 1 (PD-L1, PDL1, CD274, B7H1) is a 33 kDa single-pass type I membrane protein. Three PD-L1 isoforms have been described based on alternative splicing. PD-L1 belongs to the immunoglobulin (Ig) superfamily and contains one Ig-like C2-type domain and one Ig-like V-type domain. Freshly isolated T and B cells express only trace amounts of PD-L1, whereas CD14 + A small proportion of monocytes (approximately 16%) constitutively express PD-L1, however, interferon-γ (IFNγ) is known to upregulate PD-L1 on tumor cells.

[0004] PD-L1 acts by 1) tolerizing tumor-reactive T cells by binding to the PD-L1 receptor, programmed cell death protein 1 (PD-1) (CD279), on activated T cells; and 2) by PD-1 signaling via tumor cell-expressed PD-L1 to CD8 +PD-L1 interferes with antitumor immunity by rendering tumor cells resistant to T cell- and Fas ligand-mediated lysis; 3) by tolerizing T cells through reverse signaling via T cell-expressed CD80 (B7.1); and 4) by promoting the development and maintenance of induced T regulatory cells. PD-L1 is expressed in many human cancers, including melanoma, ovarian, lung, and colon cancers (Latchman et al., 2004 Proc Natl Acad Sci USA 101, 10691-6).

[0005] PD-L1 blocking antibodies have shown clinical activity in several types of cancer known to overexpress PD-L1 (including melanoma and NSCLC). For example, atezolizumab is a humanized IgG1 monoclonal antibody against PD-L1. Atezolizumab is currently undergoing clinical trials as an immunotherapy for several indications, including various types of solid tumors (see, for example, Rittmeyer et al., 2017 Lancet 389:255-265), and has been approved for the treatment of non-small cell lung cancer and bladder cancer. The PD-L1 antibody avelumab (Kaufman et al., Lancet Oncol. 2016;17(10):1374-1385) has been approved by the FDA for the treatment of adult and pediatric patients aged 12 years or older with metastatic Merkel cell carcinoma and is undergoing clinical trials in several cancer indications, including bladder cancer, gastric cancer, head and neck cancer, mesothelioma, NSCLC, ovarian cancer, and kidney cancer. The PD-L1 antibody durvalumab has been approved for the treatment of locally advanced or metastatic urothelial cancer and is in clinical development in several solid tumors and hematological cancers (see, e.g., Massard et al., 2016 J Clin Oncol. 34(26):3119-25). Additional anti-PD-L1 antibodies are described, for example, in WO2004004771.

[0006] Horton et al. (J Immunother Cancer. 2015; 3(Suppl 2):O10 (Non-Patent Document 7)) discloses the combination of an agonist 4-1BB antibody with a PD-L1 neutralizing antibody. WO2019 / 025545 (Patent Document 3) provides binding agents, such as a bispecific antibody that binds to human PD-L1 and human CD137.

[0007] However, despite these advances in the art, there is a great need for improved therapies that target PD-L1 and CD137. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO2005035584 [Patent Document 2] WO2004004771 [Patent Document 3] WO2019 / 025545 [Non-patent literature]

[0009] [Non-Patent Document 1] Murillo et al. 2008 Clin. Cancer Res. 14(21): 6895-6906 [Non-patent document 2] Fisher et al. 2012 Cancer Immunol. Immunother. 61: 1721-1733 [Non-patent document 3] Latchman et al., 2004 Proc Natl Acad Sci USA 101, 10691-6 [Non-patent document 4] Rittmeyer et al., 2017 Lancet 389:255-265 [Non-Patent Document 5] Kaufman et al Lancet Oncol. 2016;17(10):1374-1385 [Non-patent document 6] Massard et al., 2016 J Clin Oncol. 34(26):3119-25 [Non-Patent Document 7] Horton et al., J Immunother Cancer. 2015; 3(Suppl 2):O10 Summary of the Invention

[0010] An object of the present invention is a method for reducing or preventing tumor progression or treating cancer in a subject, comprising: i) a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1; and ii) Taxane chemotherapy agents and providing a subject with a combination treatment with

[0011] The amount of binding agent administered at each dose and / or in each treatment cycle is: a) about 0.3 to 5 mg / kg body weight or about 25 to 400 mg in total; and / or b) Approximately 2.1×10 -9 ~3.4×10 -8 mol / kg body weight or a total of approximately 1.7 × 10 -7 ~2.7×10 -6 mol That's fine too.

[0012] It is a further object of the present invention to provide a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1 for use in the treatment of cancer or in reducing or preventing tumor progression, wherein the binding agent is used in combination with a taxane chemotherapeutic agent.

[0013] Another aspect of the invention provides a taxane chemotherapeutic agent for use in the treatment of cancer or in reducing or preventing tumor progression, the taxane chemotherapeutic agent being used in combination with a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1.

[0014] Finally, it is an object of the present invention to provide a composition comprising a taxane chemotherapeutic agent and a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1. [Brief explanation of the drawings]

[0015] [Figure 1] Schematic diagram of the predicted mechanism of action of the CD137xPD-L1 bispecific antibody. (A) PD-L1 is expressed on the surface of antigen-presenting cells (APCs) and tumor cells. Binding of PD-L1 to T cells expressing the negative regulatory molecule PD-1 effectively neutralizes T cell activation signals, ultimately resulting in T cell inhibition. (B) Upon addition of the CD137xPD-L1 bispecific antibody, the inhibitory PD-1:PD-L1 interaction is blocked by the PD-L1-specific arm. At the same time, the bispecific antibody mediates agonistic signaling to CD137 expressed on T cells through cell-cell interactions, resulting in potent T cell costimulation. [Figure 2] Schematic diagram of clinical trial design. [Figure 3] Dose escalation; best percent change in tumor size from baseline, all patients. Data cutoff: September 29, 2020. Five patients did not have post-baseline scans. aMinimum duration of response (5 weeks) per RECIST v1.1 was not reached. bPR not confirmed on subsequent scan. NE, not evaluable; NSCLC, non-small cell lung cancer; PD, progressive; PD-(L)1, programmed cell death (ligand) 1; PR, partial response; SD, stable disease; SoD, sum of diameters; uPR, unconfirmed partial response. [Figure 4]Dose escalation; best change in tumor size from baseline, NSCLC patients. Data cutoff: September 29, 2020. aPR not confirmed on subsequent scan. bPD-L1 expression was assessed in archival tumor specimens. BOR, best overall response; CR, complete response; ICI, immune checkpoint inhibitor; NA, not available; PD, progressive; PD-(L)1, programmed cell death (ligand) 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumor; SD, stable disease; SoD, sum of diameters; TPS, tumor proportion score; uPR, unconfirmed partial response. [Figure 5] Expansion Cohort 1: A) Best change in tumor size from baseline, B) Change in target lesion SoD from baseline. Data cutoff: October 12, 2020. *Indicates patients with ongoing treatment. aPR was not confirmed on subsequent scans. bPD-L1 expression was assessed in tumor biopsies obtained before the start of GEN1046 treatment (22C3 pharmDx assay, HistoGeneX, Belgium). All patients who underwent at least one post-baseline tumor assessment (schedule every 6 weeks) and were therefore evaluable for clinical benefit were included. Six of 12 patients are still receiving treatment. Of the remaining 12 patients not shown, three patients had clinical progression before the first response assessment, and nine patients are still receiving treatment and never had their first response assessment. BOR and time point response were assessed using RECIST 1.1; NA: assessment after first PD. BOR, best overall response; ICI, immune checkpoint inhibitor; NA, not available; NE, not evaluable; NSCLC, non-small cell lung cancer; PD, progressive disease; PD-(L)1, programmed cell death (ligand) 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SoD, sum of diameters; TPS, tumor proportion score; uPR, unconfirmed partial response. [Figure 6]Model-predicted maximum trimer formation and receptor occupancy for PD-L1 when administered at a 100 mg dose once every three weeks (1Q3W). [Figure 7] The MC38 syngeneic tumor model was established by subcutaneous inoculation of 1 x 106 MC38 cells into C57BL / 6 mice. When tumors reached a mean volume of 64 mm3, mice were randomized and treated with mbsIgG2a-PD-L1x4-1BB (0.5 mg / kg; 2 QW x 3), docetaxel (10 mg / kg; 1 QW x 3), alone or in combination, or PBS. A. Data shown are median tumor volumes per treatment group (n = 10). Data from animals that reached termination criteria were saved for later analysis. Growth curves were terminated if <50% of animals within a treatment group remained alive. Arrows indicate the day of treatment. B. Kaplan-Meier curves show progression-free survival, defined as the percentage of mice with tumor volumes <500 mm3. After all animals had progressed to tumor volumes greater than 500 mm3, Mantel-Cox analysis was used to compare survival between treatment groups (Table 14). DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description of the Invention definition In the context of the present invention, the term "binding agent" refers to any agent capable of binding to a desired antigen. In certain embodiments of the present invention, the binding agent is an antibody, an antibody fragment, or a construct thereof. The binding agent may also include synthetic, modified, or non-natural moieties, particularly non-peptide moieties. Such moieties may, for example, link the desired antigen-binding functionality or antigen-binding region, e.g., an antibody or antibody fragment. In one embodiment, the binding agent is a synthetic construct comprising an antigen-binding CDR or variable region.

[0017] The term "immunoglobulin" refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of low molecular weight light (L) chains and one pair of heavy (H) chains, with all four chains interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)). Briefly, each heavy chain typically comprises a heavy chain variable region (herein referred to as V H or VH) and a heavy chain constant region (herein referred to as C H The heavy chain constant region is typically composed of three domains, CH1, CH2, and CH3. The hinge region is the region between the CH1 and CH2 domains of the heavy chain and is highly flexible. Disulfide bonds in the hinge region are part of the interaction between the two heavy chains in an IgG molecule. Each light chain typically contains a light chain variable region (herein referred to as V L or VL) and a light chain constant region (herein referred to as C L or CL). The light chain constant region is typically composed of one domain, CL. The VH and VL regions may be further divided into hypervariable regions (or hypervariable regions that are hypervariable in sequence and / or can be in the form of structure-defined loops), also called complementarity-determining regions (CDRs), interspersed with conserved regions called framework regions (FRs). Each VH and VL is typically composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (Chothia and Lesk J. Mol. Biol. 196, 901-917 (1987)). Unless otherwise specified or contradicted by context, CDR sequences herein are identified using DomainGapAlign according to the IMGT rules (Lefranc MP., Nucleic Acids Research 1999;27:209-212 and Ehrenmann F., Kaas Q. and Lefranc M.-P. Nucleic Acids Res., 38, D301-307 (2010); see also Internet http address www.imgt.org / . Unless otherwise specified or contradicted by the context, the amino acid positions of the constant region in the present invention are designated according to EU numbering (Edelman et al., Proc Natl Acad Sci US A. 1969 May;63(1):78-85; Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition. 1991 NIH Publication No. 91-3242).

[0018] The terms "amino acid" and "amino acid residue" are sometimes used interchangeably herein and should not be understood as limiting. Amino acids are organic compounds that contain an amine (-NH2) and a carboxyl (-COOH) functional group in addition to a side chain (R group) specific to each amino acid. In the context of the present invention, amino acids can be classified based on their structure and chemical characteristics. Accordingly, amino acid classes can be reflected in one or both of the following tables:

[0019] Table 1. Major classifications based on the structure and general chemical characterization of the R group. TIFF2023551980000001.tif52128

[0020] Table 2. Alternative physical and functional classifications of amino acid residues TIFF2023551980000002.tif88128

[0021] Substitution of one amino acid for another may be classified as conservative or non-conservative substitution. In the context of the present invention, a "conservative substitution" refers to the substitution of one amino acid with another amino acid having similar structural and / or chemical characteristics. Such substitution of one amino acid residue with another amino acid residue of the same class as defined in either of the two tables above: for example, leucine may be substituted with isoleucine, since both leucine and isoleucine are aliphatic branched hydrophobic substances. Similarly, aspartic acid may be substituted with glutamic acid, since both aspartic acid and glutamic acid are small, negatively charged residues.

[0022] As used herein, the term "amino acid corresponding to position ..." refers to the amino acid position number of the human IgG1 heavy chain. Corresponding amino acid positions in other immunoglobulins may be found by alignment with human IgG1. Thus, an amino acid or segment in one sequence that "corresponds to" an amino acid or segment in another sequence is an amino acid or segment that aligns with the other amino acid or segment using a standard sequence alignment program, e.g., ALIGN, ClustalW, or the like, typically using default settings, and that has at least 50%, at least 80%, at least 90%, or at least 95% identity to the human IgG1 heavy chain. Techniques for aligning sequences or segments within a sequence, thereby determining positions within a sequence that correspond to amino acid positions according to the invention, are considered well known in the art.

[0023] In the context of the present invention, the term "antibody" (Ab) refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of either thereof, which has the ability to specifically bind to an antigen under typical physiological conditions with a fairly long half-life, e.g., at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 4 hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or more, about 3 days, 4 days, 5 days, 6 days, 7 days, or more, or any other relevant, functionally defined period (e.g., a period sufficient to induce, promote, enhance, and / or modulate a physiological response associated with antibody-antigen binding and / or a period sufficient for the antibody to enhance effector activity). The variable regions of the heavy and light chains of an immunoglobulin molecule contain binding domains that interact with an antigen. As used herein, the term "antigen-binding region" refers to the region that interacts with an antigen and includes both the VH and VL regions. The term "antibody" as used herein includes not only monospecific antibodies but also multispecific antibodies that contain multiple, e.g., two or more, e.g., three or more, different antigen-binding regions. The constant region of an antibody (Ab) can mediate the binding of immunoglobulins to various cells of the immune system (e.g., effector cells) and host tissues or host factors, including complement system components, such as C1q, the first component of the classical pathway of complement activation. As mentioned above, the term "antibody" as used herein includes antigen-binding fragments, i.e., antibody fragments that retain the ability to specifically bind to antigens, unless otherwise specified or clearly contradicted by the context. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.Examples of antigen-binding fragments encompassed within the term "antibody" include: (i) Fab' or Fab fragments, monovalent fragments consisting of the VL, VH, CL, and CH1 domains, or the monovalent antibodies described in WO2007059782 (Genmab); (ii) F(ab')2 fragments, bivalent fragments in which two Fab fragments are linked by a disulfide bridge at the hinge region; (iii) Fd fragments, consisting essentially of the VH and CH1 domains; (iv) Fv fragments, consisting essentially of the VL and VH domains of a single arm of an antibody; and (v) domain antibodies, consisting essentially of a VH domain (Holt et al; Trends Biotechnol. 2003 Nov; 21 (11):484-90), also known as dAb fragments (Ward et al., Nature 341 , 544-546(1989));(vi) camelid or nanobody molecules (Revets et al; Expert Opin Biol Ther. 2005 Jan; 5 (1):111-24), and (vii) isolated complementarity-determining regions (CDRs). Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, the VL and VH regions pair to form a monovalent molecule (known as a single-chain antibody or single-chain Fv (scFv)). See, e.g., Bird et al., Science 242 , 423-426(1988) and Huston et al., PNAS USA 85The fragments may be joined using recombinant techniques by synthetic linkers that allow them to be produced as a single protein chain forming a single chain (see, e.g., J. Immunol., 5879-5883 (1988)). Such single-chain antibodies are included within the term antibody unless otherwise specified or clearly indicated by context. While such fragments are generally included within the meaning of antibody, they are a unique feature of the present invention, collectively and individually exhibiting distinct biological properties and utilities. These and other useful antibody fragments and bispecific forms of such fragments in the context of the present invention are further discussed herein. The term antibody, unless otherwise specified, should also be understood to include polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides, e.g., chimeric antibodies and humanized antibodies, as well as antibody fragments (antigen-binding fragments) that retain the ability to specifically bind to an antigen, provided by any known technique, e.g., enzymatic cleavage, peptide synthesis, and recombinant techniques. The antibodies produced may have any isotype. As used herein, the term "isotype" refers to the immunoglobulin class (e.g., IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM) encoded by heavy chain constant region genes. When a particular isotype, e.g., IgG1, is referred to herein, the term is not limited to a particular isotype sequence, e.g., a particular IgG1 sequence, but is used to indicate that the sequence of the antibody is more similar to that isotype, e.g., IgG1, than to other isotypes. Thus, for example, the IgG1 antibodies of the present invention may be sequence variants of native IgG1 antibodies that include altered constant regions.

[0024] In the context of the present invention, the term "bispecific antibody" or "bs" refers to an antibody having two different antigen-binding regions defined by different antibody sequences. In some embodiments, the different antigen-binding regions bind to different epitopes on the same antigen. However, in preferred embodiments, the different antigen-binding regions bind to different target antigens. The bispecific antibody may be any form of bispecific antibody, including any of the bispecific antibody formats described herein below.

[0025] The term "full-length," when used in the context of antibodies, indicates that the antibody is not a fragment and contains all of the domains of a particular isotype that are normally found in nature for that particular isotype, e.g., the VH, CH1, CH2, CH3, hinge, VL, and CL domains for an IgG1 antibody. In certain embodiments, a full-length antibody contains two heavy chains and two light chains. Each chain contains a constant (C) region and a variable (V) region, which can be divided into domains designated CHI, CH2, CH3, and VH for the heavy chain, and CL and VL for the light chain. Preferably, the domains of the heavy chain are arranged in the following natural antibody order: VH-CH1-CH2-CH3, meaning that the VH domain is adjacent to the CHI domain, followed by the CH2 domain, which is followed by the CH3 domain. Preferably, the light chain domains are also present in the following natural antibody order: VL-CL, meaning that the VL domain is adjacent to the CL domain.

[0026] As used herein, the term "human antibody" is intended to include antibodies having variable and framework regions derived from human germline immunoglobulin sequences and human immunoglobulin constant domains. The human antibodies of the present invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations, insertions, or deletions introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another non-human species, such as a mouse, have been grafted onto human framework sequences.

[0027] As used herein, the term "humanized antibody" refers to a genetically engineered non-human antibody containing a human antibody constant domain and a non-human variable domain that has been modified to contain a high level of sequence homology to the human variable domain. This can be accomplished by joining the six non-human antibody complementarity-determining regions (CDRs) that together form the antigen-binding site with homologous human acceptor framework regions (FRs) (see WO92 / 22653 and EP0629240). To fully reproduce the binding affinity and specificity of the parent antibody, it may be necessary to substitute (backmutate) framework residues from the parent antibody (i.e., non-human antibody) into the human framework regions. Structural homology modeling can help identify amino acid residues in the framework regions that are important for the binding properties of the antibody. Thus, a humanized antibody may comprise non-human CDR sequences, primarily human framework regions optionally containing one or more amino acid backmutations to non-human amino acid sequences, and a fully human constant region. Optionally, further amino acid modifications may be applied, although the modifications are not necessarily back mutations, to obtain humanized antibodies with favorable characteristics, e.g., affinity and biochemical properties.

[0028] As used herein, unless contradicted by context, the term "Fc region" refers to an antibody region consisting of two Fc sequences of an immunoglobulin heavy chain, said Fc sequences including at least a hinge region, a CH2 domain, and a CH3 domain.

[0029] As used herein, the term "Fc region" refers to the region of an antibody that, from the N-terminus to the C-terminus, comprises at least the hinge, CH2, and CH3 regions. The Fc region of an antibody may mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and components of the complement system.

[0030] As used herein, the term "hinge region" refers to the hinge region of an immunoglobulin heavy chain. Thus, for example, the hinge region of a human IgG1 antibody corresponds to amino acids 216 to 230 according to the EU numbering system set forth in Kabat (Kabat, EA et al., Sequences of proteins of immunological interest. 5th Edition - US Department of Health and Human Services, NIH publication No. 91-3242, pp. 662, 680, 689 (1991)). However, the hinge region may also refer to any hinge region of the other subtypes described herein.

[0031] As used herein, the term "CH1 region" or "CH1 domain" refers to the CH1 region of an immunoglobulin heavy chain. Thus, for example, the CH1 region of a human IgG1 antibody corresponds to amino acids 118-215 according to the Eu numbering system set forth in Kabat (ibid.). However, the CH1 region may also be the CH1 region of any of the other subtypes described herein.

[0032] As used herein, the term "CH2 region" or "CH2 domain" refers to the CH2 region of an immunoglobulin heavy chain. Thus, for example, the CH2 region of a human IgG1 antibody corresponds to amino acids 231-340 according to the Eu numbering system set forth in Kabat (ibid.). However, the CH2 region may also be the CH2 region of any of the other subtypes described herein.

[0033] As used herein, the term "CH3 region" or "CH3 domain" refers to the CH3 region of an immunoglobulin heavy chain. Thus, for example, the CH3 region of a human IgG1 antibody corresponds to amino acids 341-447 according to the Eu numbering system set forth in Kabat (ibid.). However, the CH3 region may also be the CH3 region of any of the other subtypes described herein.

[0034] The term "full length," when used in the context of an antibody, indicates that the antibody is not a fragment, but contains all of the domains of a particular isotype that are normally found in nature for that isotype, e.g., in the case of an IgG1 antibody, the VH, CH1 region, CH2 region, CH3 region, hinge, VL, and CL domains.

[0035] As used herein, the terms "binding" or "capable of binding" in the context of antibody binding to a given antigen or epitope typically refer to binding of an antibody to a given antigen or epitope with a binding affinity of about 10% or more when measured using biolayer interferometry (BLI) or, for example, when measured using surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument using the antigen as the ligand and the antibody as the analyte. -7 M or less, e.g., about 10 -8 M or less, e.g., about 10 -9 M or less, about 10 -10 M or less, or about 10 -11 M or even less K D The antibody binds with an affinity corresponding to a K for binding to a non-specific antigen other than the designated antigen or a closely related antigen (e.g., BSA, casein). DK that is at least 1 / 10, for example at least 1 / 100, for example at least 1 / 1,000, for example at least 1 / 10,000, for example at least 1 / 100,000 D The amount of increased affinity corresponds to the antibody's K D As a result, the K D is very low (i.e., the antibody is highly specific), the affinity for the antigen may be at least 10,000-fold less than the affinity for a non-specific antigen.

[0036] As used herein, "k" d " (sec -1 The term k ) refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is k off Also called value.

[0037] As used herein, "K D The term "" (M) refers to the dissociation equilibrium constant of a particular antibody-antigen interaction.

[0038] The term "PD-L1," as used herein, refers to the programmed death-ligand 1 protein. PD-L1 is found in humans and other species; therefore, the term "PD-L1" is not limited to human PD-L1, unless contradicted by context. The human PD-L1 sequence can be found under Genbank accession number NP_054862.1. The sequence of human PD-L1 is also set forth in SEQ ID NO:25, in which amino acids 1-18 are predicted to be a signal peptide. The mature polypeptide sequence is set forth in SEQ ID NO:26.

[0039] The term "PD-1," as used herein, refers to the human programmed cell death-1 protein, also known as CD279 (UniProtKB Q15116).

[0040] The term "programmed cell death-1 (PD-1) pathway" or "PD-1 pathway" refers to a molecular signaling pathway involving the cell surface receptor PD-1 and its ligands PD-L1 and PD-L2. Activation of this pathway induces immune tolerance, whereas inhibition can relieve T cell suppression, thereby leading to immune activation.

[0041] As used herein, the term "CD137" refers to the human cluster of differentiation 137 protein. CD137 (4-1BB), also known as TNFRSF9, is the receptor for the ligand TNFSF9 / 4-1BBL. CD137 is thought to be involved in T cell activation. Human CD137 has the UniProt accession number Q07011. The sequence of human CD137 is also shown in SEQ ID NO:23, with amino acids 1-23 predicted to be a signal peptide. The mature sequence of human CD137 is shown in SEQ ID NO:24.

[0042] The term "treatment" refers to the administration of an effective amount of a therapeutically active antibody as provided by the present invention, optionally in combination with a taxane chemotherapeutic agent, for the purpose of alleviating, ameliorating, arresting, or eradicating (curing) a symptom or disease state.

[0043] The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences (i.e., % homology = number of identical positions / total number of positions × 100). The percent identity between two nucleotide or amino acid sequences can be determined, for example, using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci. 4, 11-17 (1988), incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. Furthermore, the percent identity between two amino acid sequences can be determined using the algorithm of Needleman and Wunsch, J. Mol. Biol. 48, 444-453 (1970)).

[0044] In the context of the present invention, the following notation is used to describe mutations, unless otherwise specified: i) A substitution of an amino acid at a certain position is written, for example, K409R, which means that lysine at position 409 of the protein is substituted with arginine. ii) For certain variants, a specific three-letter or one-letter notation is used, with the symbols Xaa and X indicating any amino acid residue. Thus, a substitution of lysine at position 409 with arginine is indicated by K409R, and a substitution of lysine at position 409 with any amino acid residue is indicated by K409X. In the case of a deletion of lysine at position 409, this is indicated by K409*.

[0045] In the context of the present invention, "inhibition of binding of PD-L1 to PD-1" refers to a detectably significant reduction in the binding of PD-L1 to PD-1 in the presence of an antibody capable of binding to PD-L1. Typically, inhibition refers to at least about a 10% reduction in the binding between PD-L1 and PD-1 caused by the presence of an anti-PD-L1 antibody, such as at least about a 15%, such as at least about a 20%, such as at least a 40% reduction. Inhibition of binding of PD-L1 to PD-1 can be determined by any suitable technique. In one embodiment, inhibition is determined as described in Example 6 of WO2019 / 025545.

[0046] Resistance to treatment with a binding substance of the present invention, failure to respond to treatment with a binding substance of the present invention, and / or relapse from treatment with a binding substance of the present invention and / or other therapeutic substances can be assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST criteria v1.1). The RECIST criteria are shown in the table below.

[0047] Table 3. Definition of response (RECIST v1.1) TIFF2023551980000003.tif156161

[0048] "Best overall response" is the best response recorded from the start of treatment until disease progression / relapse (the smallest measurement recorded since treatment began is used as the criterion for PD). Subjects with a CR or PR are considered to have an objective response. Subjects with a CR, PR, or SD are considered to have controlled disease. Subjects with NE are counted as non-responders. "Best overall response" is the best response recorded from the start of treatment until disease progression / relapse (the smallest measurement recorded since treatment began is used as the criterion for PD). Subjects with a CR, PR, or SD are considered to have controlled disease. Subjects with NE are counted as non-responders.

[0049] "Duration of response (DOR)" is defined as the time from the first documented objective tumor response (CR or PR) to the date of first PD or death from the underlying cancer, with the confirmed best overall response being CR or PR.

[0050] "Progression-free survival (PFS)" is defined as the number of days from Day 1 of Cycle 1 to first documented progression or death from any cause.

[0051] "Overall survival (OS)" is defined as the number of days from day 1 of cycle 1 to death from any cause. If the subject is not known to have died, OS is adjusted to the last day the subject was known to be alive (on or before the cutoff date).

[0052] "Taxane chemotherapeutic agent" includes taxanes, as well as chemotherapeutic agents that are taxane derivatives, eg, semi-synthetic taxane derivatives or synthetic taxane derivatives.

[0053] In the context of the present invention, the term "treatment regimen" refers to a structured treatment plan designed to improve and maintain health.

[0054] In a first aspect, the present invention provides a method for reducing or preventing tumor progression or treating cancer in a subject, comprising: I) a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1; and ii) Taxane chemotherapy agents providing a subject with a combination treatment with

[0055] Preferably, the binding agent and taxane chemotherapeutic agent are administered to the subject in at least one treatment cycle, e.g., in multiple treatment cycles, e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten treatment cycles.

[0056] More preferably, the binding agent is a binding agent wherein the first binding domain binds to human CD137 having the sequence set forth in SEQ ID NO:24 and / or the second binding domain binds to human PD-L1 having the sequence set forth in SEQ ID NO:26.

[0057] The binding agent may be one that, upon binding to human CD137, activates human CD137 and, upon binding to PD-L1, inhibits the binding of human PD-L1 to human PD-1. In a specific embodiment, the binding agent used in accordance with the invention binds to human PD-L1 such that the binding of human PD-L1 to human PD-1 is inhibited or blocked, and by binding to human PD-L1, the binding agent also mediates conditional 4-1BB costimulation, for example, to enhance T cell and NK cell function.

[0058] In the method according to the invention, the binding agent comprises: a) the first binding region comprises, consists of, or consists essentially of a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:1, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:5; and b) the second antigen-binding region comprises, consists of, or consists essentially of a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:8, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:12. It can also be something like this.

[0059] In the method according to the invention, the binding agent comprises: a) the first binding region comprises, consists of, or consists essentially of a heavy chain variable region (VH) comprising the CDR1 sequence shown in SEQ ID NO:2, the CDR2 sequence shown in SEQ ID NO:3, and the CDR3 sequence shown in SEQ ID NO:4, and a light chain variable region (VL) comprising the CDR1 sequence shown in SEQ ID NO:6, the CDR2 sequence shown as GAS, and the CDR3 sequence shown in SEQ ID NO:7; and b) the second antigen-binding region comprises, consists of, or consists essentially of a heavy chain variable region (VH) comprising the CDR1 sequence set forth in SEQ ID NO:9, the CDR2 sequence set forth in SEQ ID NO:10, and the CDR3 sequence set forth in SEQ ID NO:11, and a light chain variable region (VL) comprising the CDR1 sequence set forth in SEQ ID NO:13, the CDR2 sequence set forth as DDN, and the CDR3 sequence set forth in SEQ ID NO:14; It can also be something like this.

[0060] Furthermore, in the method according to the invention, the binding agent comprises: a) the first binding region comprises, consists of, or consists essentially of a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO:1, and a light chain variable region (VL) region comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO:5; and b) the second binding region comprises, consists of, or consists essentially of a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO:8, and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO:12. It can also be something like this.

[0061] In the method according to the invention, the binding agent comprises: a) the first binding region comprises, consists of, or consists essentially of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:5; and b) the second binding region comprises, consists of, or consists essentially of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:8 and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:12; It is something.

[0062] The binding agent may in particular be an antibody, eg a multispecific antibody, or eg a bispecific antibody.

[0063] The binding agent may also be in the form of a full-length antibody or an antibody fragment.

[0064] More preferably, the antibody is a human or humanized antibody.

[0065] Each variable region may comprise three complementarity determining regions (CDR1, CDR2, and CDR3) and four framework regions (FR1, FR2, FR3, and FR4).

[0066] The complementarity determining regions and framework regions may be arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0067] The binding substance is i) a polypeptide comprising, consisting of, or consisting essentially of said first heavy chain variable region (VH) and first heavy chain constant region (CH); and ii) a polypeptide comprising, consisting of, or consisting essentially of said second heavy chain variable region (VH) and second heavy chain constant region (CH). may include:

[0068] In the method according to the invention, the binding agent comprises: i) a polypeptide comprising said first light chain variable region (VL) and further comprising a first light chain constant region (CL), and ii) a polypeptide comprising said second light chain variable region (VL) and further comprising a second light chain constant region (CL). It may comprise, consist of, or consist essentially of.

[0069] The binding agent may be an antibody comprising a first binding arm and a second binding arm, the first binding arm comprising: i) a polypeptide comprising the first heavy chain variable region (VH) and the first heavy chain constant region (CH); and ii) a polypeptide comprising the first light chain variable region (VL) and the first light chain constant region (CL). and the second binding arm comprises, consists of, or consists essentially of iii) a polypeptide comprising the second heavy chain variable region (VH) and the second heavy chain constant region (CH); and iv) a polypeptide comprising the second light chain variable region (VL) and the second light chain constant region (CL). Comprising, consisting of, or consisting essentially of.

[0070] The binding substance is i) a first heavy chain and a first light chain comprising an antigen-binding region capable of binding to CD137; and ii) a second heavy chain and a second light chain comprising said antigen-binding region capable of binding to PD-L1; It may comprise, consist of, or consist essentially of.

[0071] The binding substance is i) a first heavy chain and a first light chain comprising an antigen-binding region capable of binding to CD137, wherein the first heavy chain comprises a first heavy chain constant region and the first light chain comprises a first light chain constant region; and ii) a second heavy chain and a second light chain comprising an antigen-binding region capable of binding to PD-L1, wherein the second heavy chain comprises a second heavy chain constant region and the second light chain comprises a second light chain constant region. It may comprise, consist of, or consist essentially of.

[0072] Each of the first heavy chain constant region (CH) and the second heavy chain constant region (CH) may comprise one or more of a heavy chain constant 1 (CH1) region, a hinge region, a heavy chain constant 2 (CH2) region, and a heavy chain constant 3 (CH3) region, preferably at least the hinge region, the CH2 region, and the CH3 region.

[0073] The first heavy chain constant region (CH) and the second heavy chain constant region (CH) may each comprise a CH3 region, and the two CH3 regions comprise asymmetric mutations.

[0074] In the first heavy chain constant region (CH), at least one of the amino acids at a position corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 of a human IgG1 heavy chain according to EU numbering may be substituted, and in the second heavy chain constant region (CH), at least one of the amino acids at a position corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 of a human IgG1 heavy chain according to EU numbering may be substituted. In a specific embodiment, the first heavy chain and the second heavy chain are not substituted at the same positions.

[0075] The binding substance may be (i) in which the amino acid at the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering is L in the first heavy chain constant region (CH) and the amino acid at the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering is R in the second heavy chain constant region (CH), or (ii) in which the amino acid at the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering is R in the first heavy chain and the amino acid at the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering is L in the second heavy chain.

[0076] In the methods according to the present invention, the binding substance may be a binding substance that induces Fc-mediated effector function to a lower extent compared to another antibody, where the other antibody comprises the same first and second antigen-binding regions and two heavy chain constant regions (CHs) comprising human IgG1 hinge, CH2, and CH3 regions.

[0077] In particular, the methods may use binding agents in which the first and second heavy chain constant regions (CH) have been modified such that the antibody induces Fc-mediated effector function to a lesser extent compared to an otherwise identical antibody comprising unmodified first and second heavy chain constant regions (CH). In particular, each of the unmodified first and second heavy chain constant regions (CH), or both the unmodified first and second CH, can comprise, consist of, or consist essentially of the amino acid sequence set forth in SEQ ID NO:15.

[0078] Fc-mediated effector function may be determined by measuring binding of a binding agent to Fcγ receptors, binding to C1q, or induction of Fc-mediated cross-linking of Fcγ receptors. In particular, Fc-mediated effector function may be determined by measuring binding of a binding agent to C1q.

[0079] The first heavy chain constant region and the second heavy chain constant region of the binding agent may be modified so that binding of the antibody to C1q is reduced compared to the wild-type antibody, preferably by at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or 100%, and C1q binding is preferably measured by ELISA.

[0080] The binding agent used in the methods provided herein may be a binding agent in which, in at least one of the first heavy chain constant region (CH) and the second heavy chain constant region (CH), one or more amino acids at positions corresponding to positions L234, L235, D265, N297, and P331 of a human IgG1 heavy chain according to EU numbering are not L, L, D, N, and P, respectively.

[0081] In a binding agent for use according to the invention, the positions corresponding to positions L234 and L235 of a human IgG1 heavy chain according to EU numbering may be F and E in said first and second heavy chains, respectively.

[0082] In particular, the positions corresponding to positions L234, L235, and D265 of the human IgG1 heavy chain according to EU numbering may be F, E, and A in said first and second heavy chain constant regions (HC), respectively.

[0083] The binding substance used in the methods according to the present invention may be a binding substance in which the positions corresponding to positions L234 and L235 of the human IgG1 heavy chain according to EU numbering in both the first heavy chain constant region and the second heavy chain constant region are F and E, respectively, and wherein (i) the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering in the first heavy chain constant region is L and the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering in the second heavy chain is R, or (ii) the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering in the first heavy chain constant region is R and the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering in the second heavy chain is L.

[0084] The binding substance used in the methods according to the present invention may be a binding substance in which the positions corresponding to positions L234, L235, and D265 of the human IgG1 heavy chain according to EU numbering in both the first heavy chain constant region and the second heavy chain constant region are F, E, and A, respectively, and wherein (i) the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering in the first heavy chain constant region is L and the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering in the second heavy chain constant region is R, or (ii) the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering in the first heavy chain is R and the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering in the second heavy chain is L.

[0085] The binding agent used in the method according to the present invention may be one in which the constant region of the first heavy chain and / or the second heavy chain comprises: a) the sequence shown in SEQ ID NO: 15 [IgG1-FC]; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 10 substitutions compared to the amino acid sequence defined in a) or b), for example at most 9 substitutions, at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most 2, or at most 1 substitution. The binding agent may comprise, consist essentially of, or consist of an amino acid sequence selected from the group consisting of:

[0086] The binding agent used in the method according to the invention may be one in which the constant region of the first heavy chain or the second heavy chain, e.g. the second heavy chain, is a) the sequence shown in SEQ ID NO: 16 [IgG1-F405L]; b) a subsequence of a sequence defined in a), e.g., a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 9 substitutions compared to the amino acid sequence defined in a) or b), for example at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most 2, or at most 1 substitution. The binding agent may comprise, consist essentially of, or consist of an amino acid sequence selected from the group consisting of:

[0087] The binding agent used in the method according to the invention may be one in which the constant region of the first heavy chain or the second heavy chain, e.g. the first heavy chain, is a) the sequence shown in SEQ ID NO: 17 [IgG1-F409R] b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 10 substitutions compared to the amino acid sequence defined in a) or b), for example at most 9 substitutions, at most 8 substitutions, at most 7 substitutions, at most 6 substitutions, at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. The binding agent may comprise, consist essentially of, or consist of an amino acid sequence selected from the group consisting of:

[0088] The binding agent used in the method according to the present invention may be one in which the constant region of the first heavy chain and / or the second heavy chain comprises: a) the sequence shown in SEQ ID NO: 18 [IgG1-Fc_FEA]; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 7 substitutions compared to the amino acid sequence defined in a) or b), for example at most 6 substitutions, at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. The binding agent may comprise, consist essentially of, or consist of an amino acid sequence selected from the group consisting of:

[0089] The binding agent used in the method according to the invention may be one in which the constant region of said first heavy chain and / or second heavy chain, e.g. the second heavy chain, is a) the sequence shown in SEQ ID NO:20 [IgG1-Fc_FEAL], b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 6 substitutions compared to the amino acid sequence defined in a) or b), for example at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. The binding agent may comprise, consist essentially of, or consist of an amino acid sequence selected from the group consisting of:

[0090] The binding agent used in the method according to the invention may be one in which the constant region of said first heavy chain and / or second heavy chain, e.g. the first heavy chain, is a) the sequence shown in SEQ ID NO: 19 [IgG1-Fc_FEAR]; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 6 substitutions compared to the amino acid sequence defined in a) or b), for example at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. The binding agent may comprise, consist essentially of, or consist of an amino acid sequence selected from the group consisting of:

[0091] The binding agent used in the methods according to the invention may comprise a kappa (κ) light chain constant region.

[0092] The binding agent used in the methods according to the invention may comprise a lambda (λ) light chain constant region.

[0093] The binding agent used in the method according to the present invention may be a binding agent wherein said first light chain constant region is a kappa (κ) light chain constant region.

[0094] The binding agent used in the method according to the present invention may be a binding agent wherein said second light chain constant region is a lambda (λ) light chain constant region.

[0095] The binding agent used in the method according to the present invention may be a binding agent wherein said first light chain constant region is a lambda (λ) light chain constant region.

[0096] The binding agent used in the method according to the invention may be a binding agent in which the second light chain constant region is a kappa (κ) light chain constant region.

[0097] The binding agent used in the method according to the invention is one in which the kappa (κ) light chain is a) the sequence shown in SEQ ID NO:21; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 10 substitutions compared to the amino acid sequence defined in a) or b), for example at most 9 substitutions, at most 8 substitutions, at most 7 substitutions, at most 6 substitutions, at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. The binding agent may comprise an amino acid sequence selected from the group consisting of:

[0098] The binding agent used in the method according to the invention is one in which the lambda (λ) light chain is a) the sequence shown in SEQ ID NO:22; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 10 substitutions compared to the amino acid sequence defined in a) or b), for example at most 9 substitutions, at most 8 substitutions, at most 7 substitutions, at most 6 substitutions, at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. The binding agent may comprise an amino acid sequence selected from the group consisting of:

[0099] The binding agent may be of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

[0100] In particular, the binding agent may be a full-length IgG1 antibody.

[0101] In a currently preferred embodiment, the antibody is of the IgG1m(f) allotype.

[0102] It is further preferred that the binding agent or antibody is acasunlimab or a biosimilar thereof.

[0103] Taxanes are a class of diterpenes, some of which are used or being developed for use as chemotherapeutic agents, including paclitaxel and docetaxel, that cause stabilization of cellular microtubules, thereby inhibiting cell division, resulting in antitumor activity. Taxanes have the molecular formula C 20 H 36 and the following chemical structure: TIFF2023551980000004.tif40128.

[0104] The taxane chemotherapeutic agent may be selected from the group consisting of docetaxel, paclitaxel, cabazitaxel, and tesetaxel, among others.

[0105] Paclitaxel was first approved by the FDA in 1992 and is sold under the trade names Taxol and Abraxane. The molecular formula for paclitaxel is C 47 H 51 NO 14 and has the following chemical structure: I have TIFF2023551980000005.tif44128.

[0106] Docetaxel was first approved by the FDA in 1996 and is sold under the trade name Taxotere. The molecular formula of docetaxel is C 43 H 53 NO 14 and has the following chemical structure: I have TIFF2023551980000006.tif39128.

[0107] Cabazitaxel was first approved by the FDA in 2010 and is sold under the trade name Jevtana. The molecular formula of cabazitaxel is C 45 H 57 NO 14 and has the following chemical structure: I have TIFF2023551980000007.tif49128.

[0108] Tesetaxel is an orally bioavailable semisynthetic taxane derivative with the chemical formula C 46 H 60 FN 3 O 13 The chemical formula of tesetaxel is: TIFF2023551980000008.tif53128.

[0109] In a currently preferred embodiment, the taxane chemotherapeutic agent is docetaxel.

[0110] The amount of binding agent administered at each dose and / or in each treatment cycle is: a) about 0.3 to 15 mg / kg body weight or about 25 to 1200 mg in total; and / or b) Approximately 2.1×10 -9 ~1.2×10 -7 mol / kg body weight or a total of approximately 1.7 × 10 -7 ~8.1×10 -6 mol That's fine too.

[0111] The amount of binding agent administered at each dose and / or in each treatment cycle may also be a) about 0.3 to 10 mg / kg body weight or about 25 to 800 mg in total; and / or b) Approximately 2.1×10 -9 ~6.8×10 -8 mol / kg body weight or a total of approximately 1.7 × 10 -7 ~5.4×10 -6 mol That's fine too.

[0112] Furthermore, the amount of binding agent administered at each dose and / or in each treatment cycle may be: a) about 0.3 to 5 mg / kg body weight or about 25 to 400 mg in total; and / or b) Approximately 2.1×10 -9 ~3.4×10 -8 mol / kg body weight or a total of approximately 1.7 × 10 -7 ~2.7×10 -6 mol That's fine too.

[0113] In certain embodiments, the amount of binding agent administered at each dose and / or in each treatment cycle is: a) about 1.25 mg / kg body weight or about 100 mg in total; and / or b) Approximately 8.5×10 -9 mol / kg body weight or a total of approximately 6.8 × 10 -7 mol That's fine too.

[0114] The amount of taxane chemotherapeutic agent administered at each dose and / or in each treatment cycle is about 10-200 mg / m 2 , e.g., 20-40 mg / m 2 , 30-50 mg / m 2 , 40-100 mg / m 2 , 50-100mg / m 2 , 50-80 mg / m 2 , 50-70 mg / m 2 , 50-60 mg / m2 , 50-110 mg / m 2 , 60-100mg / m 2 , 60-100mg / m 2 , 60-90 mg / m 2 , 70-80 mg / m 2 , 80-200 mg / m 2 , 90-180 mg / m 2 , 90-110 mg / m 2 , 100-175 mg / m 2 , or, for example, about 170-180 mg / m 2 That's fine too.

[0115] In certain embodiments, the taxane chemotherapeutic agent is docetaxel, and the amount administered at each dose and / or in each treatment cycle is about 50-60 mg / m 2 , e.g., about 55 mg / m 2 is.

[0116] In other embodiments, the taxane chemotherapeutic agent is docetaxel and the amount administered at each dose and / or in each treatment cycle is about 70-80 mg / m 2 , for example about 75 mg / m 2 is.

[0117] It should be understood that in treatment regimens according to the present invention, the amount of taxane chemotherapeutic agent may initially be administered as indicated above, and then may be reduced to avoid or reduce side effects. Dose reduction may be specifically in accordance with labeling and / or established local medical practice. For example, initially, the amount of taxane chemotherapeutic agent administered at each dose and / or in each treatment cycle may be about 50-60 mg / m 2 , for example, about 55 mg / m 2 or about 70-80 mg / m 2 , for example, about 75 mg / m 2 However, later, the amount administered at each dose and / or in each treatment cycle may be 20-40 mg / m 2 , e.g., 35 mg / m 2may be reduced to

[0118] The binding agents and / or taxane chemotherapeutic agents used in accordance with the present invention may be administered, in particular by systemic administration.

[0119] Preferably, the binding agent and / or taxane chemotherapeutic agent is administered to the subject by intravenous injection or infusion.

[0120] At least one dose of the binding agent and at least one dose of said taxane chemotherapeutic agent may be administered in each treatment cycle.

[0121] Each treatment cycle may be 1 week (7 days), 2 weeks (14 days), 3 weeks (21 days), or 4 weeks (28 days).

[0122] In certain embodiments of the invention, each dose is administered or infused once a week, once every two weeks (1Q2W), once every three weeks (1Q3W), or once every four weeks (1Q4W).

[0123] The binding agent and taxane chemotherapeutic agent may be administered on the same day.

[0124] In certain embodiments, each dose of the binding agent is infused over a period of at least 30 minutes, eg, at least 60 minutes, at least 90 minutes, at least 120 minutes, or at least 240 minutes.

[0125] In the method according to the invention, administration of the binding agent is preferably carried out at least 30 minutes, such as at least 1 hour or such as at least 2 hours before administration of the taxane chemotherapeutic agent.

[0126] With respect to dosing of binding agents and taxane chemotherapeutic agents according to the invention, it should be understood that administration of multiple smaller doses over a short period of time, e.g., within 2-24 hours, e.g., within 2-12 hours, or on the same day, may be considered equivalent to administration of a larger single dose. For example, four infusions of 25 mg of binding agent on the same day may be considered equivalent to a single 100 mg dose provided by continuous infusion.

[0127] In a currently preferred treatment regimen, one dose of the binding agent and / or one dose of the taxane chemotherapeutic agent is administered on day 1 of each treatment cycle.

[0128] In particular, one dose of the binding agent may be administered every three weeks (1Q3W), for example, on day 1 of each three-week treatment cycle.

[0129] It is currently preferred that one dose of the taxane chemotherapeutic agent is administered every three weeks (1Q3W), for example, on day 1 of each three-week treatment cycle.

[0130] The method of any one of the preceding claims, wherein each dose of the taxane chemotherapeutic agent is premedicated with, for example, a steroid, for example, to reduce the incidence and severity of fluid retention and the severity of hypersensitivity reactions. The steroid premedication can be, for example, an oral corticosteroid, for example, about 8 mg of dexamethasone, administered twice daily for three days starting one day before administration of the taxane chemotherapeutic agent.

[0131] The subjects treated in accordance with the present invention are preferably human subjects.

[0132] The tumor or cancer is preferably a solid tumor.

[0133] The tumor or cancer may be selected from the group consisting of melanoma, ovarian cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), colorectal cancer, head and neck cancer, gastric cancer, breast cancer, kidney cancer, urothelial cancer, bladder cancer, esophageal cancer, pancreatic cancer, liver cancer, thymoma and thymic carcinoma, brain cancer, glioma, adrenocortical carcinoma, thyroid cancer, other skin cancers, sarcoma, multiple myeloma, leukemia, lymphoma, myelodysplastic syndrome, ovarian cancer, endometrial or uterine carcinoma, prostate cancer, penile cancer, cervical cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Merkel cell carcinoma, and mesothelioma.

[0134] In certain embodiments, the tumor or cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (NSCLC), urothelial carcinoma (cancer of the bladder, ureter, urethra, or renal pelvis), endometrial cancer (EC), breast cancer (e.g., triple-negative breast cancer (TNBC)), squamous cell carcinoma of the head and neck (SCCHN) (e.g., cancer of the oral cavity, pharynx, or larynx), and cervical cancer.

[0135] The tumor or cancer may in particular be lung cancer.

[0136] The lung cancer may be non-small cell lung cancer (NSCLC), for example, squamous or non-squamous NSCLC.

[0137] Lung cancer is the most common malignant tumor and the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for 85–90% of all lung cancer cases (Jemal et al., 2011). The 5-year survival rate for NSCLC is approximately 18% (SEER, 2018). The major histological subtypes of NSCLC include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large cell carcinoma, carcinoid tumor, and other less common subtypes, with adenocarcinoma being the most common.

[0138] Standard treatment for patients with advanced or metastatic NSCLC who have progressed on or are no longer candidates for targeted therapy typically includes platinum-based chemotherapy. Platinum combinations have been shown to produce overall response rates (ORR) of approximately 25-35%, time to progression (TTP) of 4-6 months, and median survival times of 8-10 months.

[0139] Tumor gene mutations / alterations have been identified and influence therapy selection. Identifying specific mutations or alterations in tumor genes, such as anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), c-ROS oncogene 1 (ROS1), BRAF, KRAS, and programmed cell death ligand-1 (PD-L1), can help select potentially effective targeted therapies while avoiding the use of therapies unlikely to provide clinical benefit (NCCN, 2018c). Activating-sensitivity EGFR mutations predict response to EGFR tyrosine kinase inhibitors (TKIs) (e.g., gefitinib, erlotinib, afatinib, and osimertinib). Similarly, TKIs (e.g., alectinib, ceritinib, and crizotinib) are effective treatments for ALK and ROS1 mutations and are approved as first-line therapy for each mutation. Checkpoint inhibitor antibodies that block the interaction between PD1 and PD-L1 (e.g., pembrolizumab and nivolumab) have also been shown to be effective treatments, either alone or in combination with chemotherapy, for treating patients with advanced or metastatic NSCLC whose tumors express PD-L1.

[0140] Despite the availability of multiple treatment options, the prognosis for patients with stage IV NSCLC is ultimately poor, and lung cancer remains the number one cause of cancer death in both men and women. Cure rates decline with each line of therapy, either when patients succumb to their cancer or when they experience a decline in health that precludes further treatment.

[0141] The lung cancer may be NSCLC, and the NSCLC does not have an epidermal growth factor (EGFR)-sensitizing mutation and / or an anaplastic lymphoma (ALK) translocation / ROS1 rearrangement. An EGFR-sensitizing mutation refers to a mutation that confers sensitivity to an EGFR tyrosine kinase inhibitor (TKI), such as the approved tyrosine kinase inhibitors erlotinib, osimertinib, gefintinib, olmutinib, nazartinib, and avitinib.

[0142] The epidermal growth factor receptor (EGFR) amino acid sequence is provided herein as SEQ ID NO:27.

[0143] The amino acid sequence of the epidermal growth factor receptor (EGFR) sensitivity-increasing mutation is: i) an in-frame deletion, and optionally an insertion, of one or more amino acids at positions 746 to 751, e.g., any of the deletions and insertions defined in Table 4; ii) a single amino acid substitution at any one of positions 709, 715, 719, 720, 768, 858, and 861, e.g., any of the deletions and insertions defined in Table 5; and iii) In-frame duplications and / or insertions selected from the duplications / insertions defined in Table 6 The amino acid numbers refer to the amino acid numbers of SEQ ID NO:27.

[0144] (Table 4) In-frame deletions within exon 19 of the human EGFR gene (modified from Shigematsu et al., Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers, JNCI: Journal of the National Cancer Institute, Volume 97, Issue 5, 2 March 2005). del = deletion; ins = insertion. TIFF2023551980000009.tif91128

[0145] Table 5. Single-base substitutions and resulting amino acid changes within exon 21 of the human EGFR gene (adapted from Shigematsu et al., Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers, JNCI: Journal of the National Cancer Institute, Volume 97, Issue 5, 2 March 2005) TIFF2023551980000010.tif76128

[0146] (Table 6) In-frame duplications and / or insertions within exon 20 of the human EGFR gene (adapted from Shigematsu et al., Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers, JNCI: Journal of the National Cancer Institute, Volume 97, Issue 5, 2 March 2005). ins = insertion. TIFF2023551980000011.tif68128

[0147] The non-small cell lung cancer may be characterized by at least one mutation in the EGFR amino acid sequence selected from L747S, D761Y, T790M, C797S, T854A, e.g., T790M, C797S, D761Y, and double mutations T790M / D761Y and T790 / C797S, and / or the subject undergoing treatment may have at least one mutation in the EGFR amino acid sequence selected from L747S, D761Y, T790M, C797S, T854A, e.g., T790M, C797S, D761Y, and double mutations T790M / D761Y and T790 / C797S. The amino acid numbers refer to the amino acid numbers of SEQ ID NO: 27.

[0148] Non-small cell lung cancer is i. Wild-type human EGFR; for example, human EGFR comprising the sequence set forth in SEQ ID NO:27 or a mature polypeptide thereof; and ii. A human EGFR that is a variant of the EGFR of item i and does not have any sensitivity-increasing mutations when compared with the EGFR of item i. The antibody may be characterized by expression of an epidermal growth factor receptor (EGFR) selected from the group consisting of:

[0149] Non-small cell lung cancer is i) an in-frame deletion, and optionally an insertion, of one or more amino acids at positions 746 to 751, e.g., any of the deletions and insertions defined in Table 4; ii) a single amino acid substitution at any one of positions 709, 715, 719, 720, 768, 858, and 861, e.g., any of the deletions and insertions defined in Table 5; and iii) In-frame duplications and / or insertions selected from the duplications / insertions defined in Table 6 The cancer may be not characterized by an epidermal growth factor receptor (EGFR) sensitivity-increasing mutation selected from the group consisting of: The amino acid numbers refer to the amino acid numbers of SEQ ID NO: 27. Similarly, a subject receiving treatment according to the present invention may be a subject who does not have such an EGFR sensitivity-increasing mutation.

[0150] The non-small cell lung cancer may be a cancer that is not characterized by a mutation in the EGFR amino acid sequence selected from L747S, D761Y, T790M, C797S, T854A, for example, T790M, C797S, D761Y, and double mutations T790M / D761Y and T790 / C797S. The amino acid numbers refer to the amino acid numbers of SEQ ID NO: 27. Similarly, the subject receiving treatment according to the present invention may not have any of the mutations.

[0151] Non-small cell lung cancers and / or subjects undergoing treatment according to the invention may be characterized as having a mutation in the gene encoding ALK tyrosine kinase (ALK) (UniProt Q9UM73) that causes rearrangement of the gene encoding ALK with a gene encoding a fusion partner to form a fusion oncogene.

[0152] Non-small cell lung cancer may be characterized by a mutation in the gene encoding ALK that causes a rearrangement between the gene encoding ALK and the gene encoding Echinoderm microtubule-associated protein-like 4 (EMAPL4) (EML4) (UniProt Q9HC35) (to form the EML4-ALK fusion oncogene), and / or a subject receiving treatment according to the invention may have a mutation in the gene encoding ALK that causes a rearrangement between the gene encoding ALK and the gene encoding Echinoderm microtubule-associated protein-like 4 (EMAPL4) (EML4) (UniProt Q9HC35) (to form the EML4-ALK fusion oncogene).

[0153] Non-small cell lung cancer is characterized by mutations in the gene encoding ALK tyrosine kinase (ALK), i. KIF5B (UniProt P33176), which encodes kinesin-1 heavy chain (KINH); ii. KLC1 (UniProt Q07866), which encodes kinesin light chain 1 (KLC1); iii. TFG (UniProt Q92734), which encodes the protein TFG; iv. TPR (UniProt P12270), which encodes the nuclear protein TPR; v. HIP1 (UniProtKB-O00291), which encodes Huntington-interacting protein 1 (HIP-1); vi. STRN (UniProtKB-O43815), which encodes striatin; vii. DCTN1 (UniProt Q14203), which encodes dynactin subunit 1; viii. SQSTM1 (UniProtKB-Q13501), which encodes sequestosome-1; ix. NPM1 (UniProt P06748), which encodes nucleophosmin; BCL11A (UniProt Q9H165), encoding xB-cell lymphoma / leukemia 11A, and xi. BIRC6 (UniProt Q13490), encoding a baculoviral IAP repeat-containing protein and / or a subject being treated according to the invention may be characterized by a mutation in the gene encoding ALK that causes a rearrangement of the ALK-encoding gene with a gene selected from the group consisting of KIF5B-ALK fusion oncogene, KLC1-ALK fusion oncogene, TFG-ALK fusion oncogene, TPR-ALK fusion oncogene, HIP1-ALK fusion oncogene, STRN-ALK fusion oncogene, DCTN1-ALK fusion oncogene, SQSTM1-ALK fusion oncogene, NPM1-ALK fusion oncogene, BCL11A-ALK fusion oncogene, and BIRC6-ALK fusion oncogene.

[0154] The non-small cell lung cancer may be characterized by expression of wild-type human ALK tyrosine kinase, eg, human ALK tyrosine kinase comprising the sequence provided in UniProt Q9HC35, or the mature polypeptide thereof.

[0155] The non-small cell lung cancer may be characterized by not having a mutation in the gene encoding ALK tyrosine kinase (ALK) that causes rearrangement of ALK with a fusion partner to form a fusion oncogene, and / or the subject does not have such a mutation.

[0156] The non-small cell lung cancer may be characterized by not having a mutation in the gene encoding Echinoderm microtubule-associated protein-like 4 (EMAPL4) (EML4) (UniProt Q9HC35) that causes a rearrangement between the gene encoding ALK tyrosine kinase (ALK) (UniProt Q9HC35) and ALK to form the EML4-ALK fusion oncogene, and / or the subject may not have such a mutation.

[0157] The non-small cell lung cancer may be characterized by the absence of a mutation in any gene selected from the group consisting of the gene encoding ALK tyrosine kinase (ALK), the gene encoding Echinoderm microtubule-associated protein-like 4 (EMAPL4) (EML4) (UniProt Q9HC35).

[0158] Non-small cell lung cancer is - epidermal growth factor receptor (EGFR) mutations that increase susceptibility, - mutations in the gene encoding ALK tyrosine kinase (ALK), leading to rearrangements between EML4 and ALK and the formation of the EML4-ALK fusion oncogene; - a mutation in the EGFR amino acid sequence that induces or confers resistance to one or more EGFR tysrosine kinase inhibitors (EGFR-TKIs) in the subject; and the subject may have been treated with a programmed cell death-1 (PD-1) / programmed cell death-1 (PD-1) inhibitor (e.g., nivolumab, genolimuzumab, atezolizumab, durvalumab, or avelumab) or with chemotherapy (e.g., chemotherapy including a platinum, taxane, pemetrexed, and / or gemcitabine), and may have failed such previous treatment.

[0159] Non-small cell lung cancer is - epidermal growth factor receptor (EGFR) mutations that increase susceptibility, - a mutation in the EGFR amino acid sequence that induces or confers resistance to one or more EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the subject; - Mutations in the gene encoding ALK tyrosine kinase (ALK), leading to rearrangements between EML4 and ALK and the formation of the EML4-ALK fusion oncogene and the subject may have been treated with an EGFR inhibitor (e.g., erlotinib, osimertinib, gefintinib, olmutinib, nazartinib, and avitinib) or with a PD-1 / PD-L1 inhibitor (e.g., nivolumab, genolimu- zumab, atezolizumab, durvalumab, or avelumab), and may have failed such prior treatment.

[0160] The subject has received up to four systemic conditioning regimens for advanced / metastatic disease to treat lung cancer and has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

[0161] Prior to receiving treatment according to the present invention, the subject has received platinum-based chemotherapy to treat lung cancer, or the subject may be ineligible for platinum-based therapy and have received treatment with an alternative chemotherapy, for example, a gemcitabine-containing regimen.

[0162] The subject may have received prior treatment with a checkpoint inhibitor, e.g., an agent that targets programmed cell death-1 (PD-1) / programmed cell death-ligand 1 (PD-L1), e.g., a PD-1 / PD-L1 inhibitor, to treat lung cancer. Preferably, the subject should have received only one prior treatment with a PD-1 / PD-L1 inhibitor, alone or in combination.

[0163] In particular, the subject may have experienced disease progression during or after treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. Further, the subject may have experienced disease progression during or after their last prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor.

[0164] Inhibitors of PD-1 and / or PD-L1 may include, inter alia, antibodies or antigen-binding fragments thereof capable of binding to PD-L1.

[0165] Known inhibitors of PD-1 and / or PD-L1 include pembrolizumab (Merck & Co), CBT-501 (genolimuzumab; Genor Bio / CBT Pharma), nivolumab (BMS), REGN2810 (cemiplimab; Regeneron), BGB-A317 (tislelizumab; BeiGene / Celgene), Amp-514 (MEDI0680) (Amplimmune), TSR-042 (dostallimab; Tesaro / AnaptysBio), JNJ-63723283 / JNJ-3283 (Johnson & Johnson), PF-06801591 (Pfizer), JS-001 (tripolibamab / toriparimab; Shanghai Junshi Bio), SHR-1210 / INCSHR-1210 (camrelizumab; Incyte corp), PDR001 (spartalizumab; Novartis), BCD-100 (BioCad), AGEN2034 (Agenus), IBI-308 (sintilimab; Innovent Biologics), RG7446 / MPDL-3280A (atezolizumab; Roche), MSB-0010718C (avelumab; Merck Serono / Pfizer), and MEDI-4736 (durvalumab; AstraZeneca), KN-035 (embafolimab; 3DMed / Alphamab Co.).

[0166] In particular, the subject may have experienced disease progression, eg, radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

[0167] Alternatively, a subject undergoing treatment according to the present invention may have not previously been treated with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor, e.g., any of the PD-1 / PD-L1 inhibitors listed above, to treat said lung cancer.

[0168] In other embodiments, the tumor or cancer is endometrial cancer. Endometrial cancer (EC) is the most common gynecological malignancy in the United States and other developed countries, and its incidence has been increasing worldwide. In the United States, an estimated 60,000 new cases and over 10,000 deaths were reported in 2016. In 2012, 527,600 women were diagnosed with uterine EC worldwide. The majority of EC cases are identified at an early stage and treated by surgery with or without radiation therapy or chemotherapy. However, the prognosis for patients with advanced disease is poor, with a 5-year survival rate of less than 50% for patients with lymph node metastasis and less than 20% for patients with peritoneal or distant metastasis.

[0169] Multiagent chemotherapy is the preferred treatment for metastatic, recurrent, or high-risk disease; however, there is no consensus regarding a standard regimen. Carboplatin and paclitaxel are increasingly being used in the first-line setting for advanced / metastatic or recurrent EC. Response rates to carboplatin and paclitaxel range from 40% to 62%, with overall survival (OS) ranging from approximately 13 to 29 months. Patients who progress during combination therapy or cannot tolerate multiagent chemotherapy may receive single-agent therapy, but chemotherapy options in this setting have only produced modest activity, particularly in the second-line and later settings. Response rates to single agents range from 21% to 36% in the first-line setting and from 4% to 27% in the second-line setting (NCCN, 2018d).

[0170] Most recently, pembrolizumab demonstrated antitumor activity in patients with locally advanced or metastatic PD-L1-positive EC who had experienced progression during or after standard therapy.

[0171] In particular, subjects or endometrial cancers treated according to the present invention may have epithelial endometrial histology, including endometrioid carcinoma, serous carcinoma, squamous cell carcinoma, clear cell carcinoma, or carcinosarcoma.

[0172] The subject may have received up to four systemic conditioning regimens for advanced / metastatic disease to treat said endometrial cancer and may have experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

[0173] The subject may have not been previously treated with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor, to treat said endometrial cancer. For example, the PD-1 / PD-L1 inhibitor is selected from the list of PD-1 / PD-L1 inhibitors above.

[0174] According to other embodiments, the tumor or cancer is a urothelial cancer, including cancer of the bladder, ureter, urethra, or renal pelvis.

[0175] The subject may have received up to four systemic conditioning regimens for advanced / metastatic disease to treat said urothelial cancer and may have experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

[0176] The subject may have received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor; e.g., any one of the PD-1 / PD-L1 inhibitors listed above, to treat the urothelial cancer.

[0177] Furthermore, the subject may have previously undergone platinum-based chemotherapy, i.e., chemotherapy using agents that are coordination compounds of platinum, to treat the urothelial cancer. Examples of platinum-based chemotherapy include treatment with cisplatin, oxaliplatin, and carboplatin.

[0178] Subjects may be ineligible for platinum-based therapy and have been treated with alternative chemotherapy, for example, a gemcitabine-containing regimen.

[0179] In another embodiment according to the present invention, the tumor or cancer is breast cancer, for example, triple-negative breast cancer (TNBC).TNBC generally refers to breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).TNBC may be particularly HER2-negative, for example, as determined by measuring protein expression by fluorescent in situ hybridization (FISH) or immunohistochemistry.

[0180] The subject may have received at least one systemic conditioning regimen for locally advanced / metastatic disease to treat said breast cancer, for example, at least one systemic conditioning regimen including an anthracycline-containing, taxane-containing, antimetabolite-containing, or microtubule inhibitor-containing regimen.

[0181] In a further embodiment, the subject may have received up to four systemic conditioning regimens for locally advanced / metastatic disease to treat said breast cancer, including at least one systemic conditioning regimen including, for example, an anthracycline-containing, taxane-containing, antimetabolite-containing, or microtubule inhibitor-containing regimen.

[0182] The subject may have received prior treatment with a checkpoint inhibitor to treat breast cancer, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor; e.g., any one of the PD- / PD-L1 inhibitors listed above.

[0183] The subject may have experienced disease progression, e.g., radiographically confirmed disease progression, during or after prior treatment with a checkpoint inhibitor to treat breast cancer.

[0184] In other embodiments, the subject may be a subject who has not been previously treated with a checkpoint inhibitor to treat breast cancer, e.g., a subject who has not been treated with an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor; e.g., a PD- / PD-L1 inhibitor listed above.

[0185] The tumor or cancer may be head and neck cancer, such as squamous cell carcinoma of the head and neck (SCCHN). SCCHN is a leading cause of death, with over 600,000 cases diagnosed annually worldwide. In 2018, approximately 64,690 people in the United States developed oral, pharyngeal, or laryngeal cancer, resulting in an estimated 13,740 deaths during the same period. Head and neck cancer can occur in the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyroid, and salivary glands. Smoking and alcohol significantly increase the risk of developing head and neck cancer. Furthermore, human papillomavirus (HPV) infection is causally associated with squamous cell carcinoma of the oropharynx (particularly the tonsils and base of the tongue), and recent evidence suggests that HPV may also be associated with a higher risk of laryngeal squamous cell carcinoma. Patients with localized HPV-positive head and neck cancer have improved outcomes in terms of response to treatment, PFS, and OS compared with HPV-negative tumors.

[0186] Treatment of head and neck cancer is complex and requires a multidisciplinary approach. The prognosis for patients with recurrent or metastatic SCCHN is generally poor, with median survival ranging from approximately 6 to 12 months, depending on the patient's performance status and disease-related factors. For appropriate patients, first-line therapy includes cetuximab and cisplatin or carboplatin plus 5-fluorouracil (5-FU). The addition of cetuximab has been associated with improved survival (10.1 vs. 7.4 months) and mPFS (3.3 vs. 5.6 months) compared with platinum and 5-FU alone. Single-agent chemotherapy is recommended for patients with poor performance status. To date, the most commonly used single agents have included platinum compounds, taxanes, nab-paclitaxel, methotrexate, fluorouracil, and cetuximab.

[0187] In the United States and some other countries, pembrolizumab and nivolumab are approved for patients with progressive disease (PD) after platinum-containing chemotherapy. Data from trials exploring single-agent activity of PD-1 targets have appeared promising, but response rates remain low.

[0188] In particular, the tumor or cancer may be a recurrence of metastatic SCCHN.

[0189] In particular embodiments relating to SCCHN, the tumor or cancer is a cancer of the oral cavity, pharynx, or larynx.

[0190] The subject may have received up to four systemic conditioning regimens for recurrent / metastatic disease to treat SCCHN and may have experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

[0191] The subject may have undergone treatment with platinum-based chemotherapy to treat SCCHN, for example, treatment with cisplatin, oxaliplatin, and carboplatin.

[0192] Alternatively, the subject may not be eligible for platinum-based therapy and may have received alternative chemotherapy to treat SCCHN.

[0193] The subject may have previously been treated with a checkpoint inhibitor to treat SCCHN, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor; e.g., a PD- / PD-L1 inhibitor listed above.

[0194] The subject may have experienced disease progression, eg, radiographically confirmed disease progression, during or after prior treatment with a checkpoint inhibitor.

[0195] In other embodiments, the subject may be a subject who has not received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor, e.g., a subject who has not received treatment with any of the PD- / PD-L1 inhibitors listed above.

[0196] In a further embodiment, the tumor or cancer is cervical cancer. Cervical cancer poses a significant medical problem worldwide, with an estimated incidence of over 500,000 new cases. In the United States, it is estimated that approximately 12,800 new cases and 4,210 deaths will occur in 2017. The median age at diagnosis of cervical cancer in the United States is 49 years old, and is younger in developing countries. In the United States, the five-year survival rate for patients diagnosed with localized disease is 91%, but the prognosis for patients with advanced disease remains poor. The five-year survival rate for advanced / metastatic disease is less than 35%.

[0197] First-line treatment for recurrent or metastatic cervical cancer consists of bevacizumab in combination with paclitaxel and a platinum (cisplatin or carboplatin) or paclitaxel and topotecan. Despite a 48% ORR and a median OS of approximately 18 months, nearly all patients relapse after this first-line treatment. Regarding second-line therapy, pembrolizumab is approved in the United States for the treatment of patients with recurrent or metastatic cervical cancer whose disease has progressed during or after chemotherapy and whose tumors express PD-L1, as confirmed by an FDA-approved test. No other approved therapies are available. However, patients are often treated with single-agent modalities, including, but not limited to, pemetrexed, topotecan, docetaxel, nab-paclitaxel, vinorelbine, and, in some cases, bevacizumab. Response rates with single-agent treatment are very low (range: 0-15%), and for this reason cervical cancer remains a population with a very high unmet medical need.

[0198] The cervical cancer may be, in particular, a cervical cancer of squamous cell, adenocarcinoma, or adenosquamous histology.

[0199] A subject to be treated according to the present invention may have received at least one systemic conditioning regimen for recurrent / metastatic disease to treat said cervical cancer, e.g., chemotherapy in combination with a treatment targeting vascular endothelial growth factor A, e.g., chemotherapy in combination with treatment with bevacizumab, and have experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

[0200] Subjects treated according to the present invention may have received up to four systemic conditioning regimens for recurrent / metastatic disease, including chemotherapy in combination with treatment targeting vascular endothelial growth factor A, e.g., chemotherapy in combination with treatment with bevacizumab.

[0201] In some embodiments, the subject treated in accordance with the present invention has not been previously treated with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor, e.g., has not been treated with any of the PD- / PD-L1 inhibitors listed above.

[0202] Preferably, the subject is female.

[0203] A further aspect of the invention provides a composition, e.g., a pharmaceutical composition, comprising a taxane chemotherapeutic agent and a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1.

[0204] Preferably, the amount of binding agent in the composition is about 25-1200 mg, or about 1.7 x 10 -7 ~8.1×10 -6 mol, e.g., 25 to 1200 mg or 1.7 × 10 -7 ~8.1×10 -6 mol; approximately 25 to 800 mg or approximately 1.7 × 10 -7 ~5.4×10 -6 mol, e.g., 25-800 mg or 1.7 × 10 -7 ~5.4×10 -6 mol, or approximately 25 to 400 mg or approximately 1.7 × 10 -7 ~2.7×10 -6 mol, e.g., 25-400 mg or 1.7 × 10 -7 ~2.7×10 -6 It is mol.

[0205] The amount of binding agent administered in the composition is, in particular, about 25 to 320 mg or about 1.7 x 10 -7 ~2.2×10 -6 mol, e.g., 25-320 mg or 1.7 × 10 -7 ~2.2×10 -6 mol; approximately 30 to 320 mg or approximately 2.4 × 10 -7 ~2.2×10 -6mol; e.g., 30-320 mg or 2.4 × 10 -7 ~2.2×10 -6 mol approx. 40-260 mg or approx. 2.7 × 10 -7 ~1.8×10 -6 mol, e.g., 40-260 mg or 2.7 × 10 -7 ~1.8×10 -6 mol; approximately 50 to 200 mg or approximately 3.4 × 10 -7 ~1.4×10 -6 mol, e.g., 50-200 mg or 3.4 x 10 -7 ~1.4×10 -6 mol; approximately 60 to 140 mg or approximately 4.1 × 10 -7 ~9.5×10 -7 mol, e.g., 60-140 mg or 4.1 x 10 -7 ~9.5×10 -7 mol; approximately 70 to 140 mg or approximately 4.8 × 10 -7 ~9.5×10 -7 mol, e.g., 70-140 mg or 4.8 x 10 -7 ~9.5×10 -7 mol; approximately 80 to 120 mg or approximately 5.5 × 10 -7 ~8.2×10 -7 mol, e.g., 80-120 mg or 5.5 × 10 -7 ~8.2×10 -7 mol; approximately 90-110 mg or approximately 6.1 × 10 -7 ~7.5×10 -7 mol, e.g., 90-110 mg or 6.1 x 10 -7 ~7.5×10 -7 mol; approximately 95 to 105 mg or approximately 6.5 × 10 -7 ~7.2×10 -7 mol, e.g., 95-105 mg or 6.5 x 10 -7 ~7.2×10 -7 mol; approximately 65 to 120 mg or approximately 4.4 × 10 -7 ~8.2×10 -7 mol, e.g., 65-120 mg or 4.4 × 10 -7 ~8.2×10 -7 mol; approximately 70 to 100 mg or approximately 4.8 × 10-7 ~6.8×10 -7 mol, e.g., 70-100 mg or 4.8 x 10 -7 ~6.8×10 -7 mol; or approximately 75-90 mg or approximately 5.1 × 10 -7 ~6.1×10 -7 mol, e.g., 75-90 mg or 5.1 x 10 -7 ~6.1×10 -7 Mol is also acceptable.

[0206] The composition or pharmaceutical composition can be prepared by conventional techniques, e.g., by the method described in Remington: The Science and Practice of Pharmacy, 1999. th The pharmaceutical compositions may be formulated using carriers, excipients, and / or diluents, as well as any other ingredients suitable for pharmaceutical compositions, including known adjuvants, according to the techniques disclosed in "The Antibody and Antibody Conjugates of the Invention," Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. Pharmaceutically acceptable carriers or diluents, as well as any known adjuvants and excipients, must be suitable for the antibody or antibody conjugate of the invention and the selected method of administration. The suitability of carriers and other ingredients for pharmaceutical compositions is determined based on the absence of a significant adverse effect on the desired biological properties of the selected compound or pharmaceutical composition of the invention (e.g., less than a significant effect on antigen binding [e.g., 10% or less relative inhibition, 5% or less relative inhibition, etc.]).

[0207] Pharmaceutical compositions of the present invention may include diluents, fillers, salts, buffers, surfactants (e.g., non-ionic surfactants such as Tween-20 or Tween-80), stabilizers (e.g., sugars or protein-free amino acids), preservatives, solubilizers, and / or other materials suitable for inclusion in pharmaceutical compositions.

[0208] Pharmaceutically acceptable carriers include any and all suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, antioxidants and absorption delaying agents, and the like that are physiologically compatible with the compounds of the present invention.

[0209] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, saline, phosphate buffered saline, ethanol, dextrose, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, corn oil, peanut oil, cottonseed oil, and sesame oil, carboxymethylcellulose colloidal solution, tragacanth gum, and injectable organic esters such as ethyl oleate, and / or various buffer solutions. Other carriers are well known in the pharmaceutical field.

[0210] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injection solutions or dispersions.The use of such media and agents for pharmaceutically active substances is well known in the art.Except where conventional media or agents are incompatible with active compounds, they are intended to be used in the pharmaceutical compositions of the present invention.

[0211] The pharmaceutical compositions of the present invention may also contain pharmaceutically acceptable antioxidants, such as (1) water-soluble antioxidants, e.g., ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, e.g., ascorbic acid palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, e.g., citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0212] The pharmaceutical compositions of the present invention may also include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, glycerol, or sodium chloride in the composition.

[0213] The pharmaceutical compositions of the present invention may also contain one or more auxiliary agents suitable for the selected route of administration, such as preservatives, wetting agents, emulsifiers, dispersing agents, antiseptics, or buffers, which can enhance the shelf life or effectiveness of the compositions.The combination of compounds of the present invention may also be prepared using carriers that protect the compounds from rapid release, such as sustained-release formulations, including implants, transdermal patches, and microencapsulated delivery systems.Such carriers may include gelatin, glyceryl monostearate, glyceryl distearate, biodegradable biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid alone or with polylactic acid wax, or other materials well known in the art.Methods for preparing such formulations are generally known to those skilled in the art.See, for example, Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0214] In one embodiment, the binding substance used according to the present invention can be formulated to be suitable for dispersal in vivo.Pharmaceutically acceptable carriers for parenteral administration include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions.The use of such media and agents for pharmaceutically active substances is known in the art.Unless conventional media or agents are incompatible with the active compound, their use in the compositions of the present invention is contemplated.Other active compounds or therapeutic compounds can also be incorporated into the composition.

[0215] Injectable pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier may be an aqueous or non-aqueous solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. It is often preferable to include isotonic agents, such as sugars, polyalcohols such as glycerol, mannitol, sorbitol, or sodium chloride, in the compositions. Prolonged absorption of injectable compositions can be achieved by including absorption-delaying agents, such as monostearate salts and gelatin, in the compositions. Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent with one of the components or a combination of components, for example, as listed above, as needed, and then carrying out sterilization microfiltration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains basic dispersion medium and other components that are required, for example, other components that are required from those listed above.For the sterile powder that is used to prepare sterile injectable solution, the example of preparation method is vacuum drying and freeze-drying (lyophilization), which produces the powder of active ingredient and any other desired components from the solution of active ingredient and any other desired components that has been previously sterilized by filtration.

[0216] Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent with one of the above-listed components or a combination of the above-listed components as needed, and then carrying out sterilization microfiltration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains basic dispersion medium and other components that are required from above-listed components.For the sterile powder that is used to prepare sterile injectable solution, the example of preparation method is vacuum drying and freeze-drying (lyophilization), which produces the powder of active ingredient and any other desired components from the solution of active ingredient and any other desired components that has been previously sterilized by filtration.

[0217] In one embodiment, the composition according to the present invention comprises about 5.5 x 10 -7 mol or approximately 80 mg, e.g., 5.5 x 10 -7 mol or 80 mg of said binding agent.

[0218] In a currently preferred embodiment, the composition according to the present invention comprises about 6.8 x 10 -7 mol or about 100 mg of the binding agent, e.g., 6.8×10 -7 mol or 100 mg of said binding agent.

[0219] In the composition according to the invention, the binding agent may be as defined above, for example, the binding agent may comprise any of the variable and constant regions defined above.

[0220] In the composition according to the invention, the taxane chemotherapeutic agent is preferably as defined above. The present invention further comprises unit dosage forms of the binding agents or compositions disclosed above.

[0221] Preferably, the unit dosage form is a unit dosage form for systemic administration. In certain embodiments, the unit dosage form is for injection or infusion into a subject, for example, intravenous injection or infusion.

[0222] In the composition or unit dosage form, the binding substance is preferably present in an aqueous solution, for example, 0.9% NaCl (saline). The volume of the unit dosage form may be 50 to 500 mL, for example, 50 to 250 mL, 50 to 500 mL, 100 to 500 mL, or 100 to 250 mL.

[0223] In yet a further aspect, the present application provides a binding agent comprising a first binding region that binds to human CD137 and a second binding region that binds to human PD-L1 for use in treating cancer or for use in reducing or preventing tumor progression, wherein the binding agent is used in combination with a taxane chemotherapeutic agent.

[0224] The binding agent for use according to the present invention is preferably a binding agent as defined above, for example said binding agent may comprise any of the variable and constant regions defined above.

[0225] With respect to binding agents for use according to the present invention, the taxane chemotherapeutic agent may be as defined above. In a currently preferred embodiment, the taxane chemotherapeutic agent is docetaxel.

[0226] The binding agent and taxane chemotherapeutic agent may be present in a composition as defined above.

[0227] Furthermore, the present invention provides a taxane chemotherapeutic agent for use in the treatment of cancer or in reducing or preventing tumor progression, the taxane chemotherapeutic agent being used in combination with a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1.

[0228] The binding agent may be as defined above, for example, the binding agent may comprise any of the variable and constant regions defined above.

[0229] The taxane chemotherapeutic agent may be as defined above. In a currently preferred embodiment, the taxane chemotherapeutic agent is docetaxel.

[0230] The binding agent and taxane chemotherapeutic agent may be present in a composition as defined above.

[0231] Finally, the present invention provides a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1 for the manufacture of a medicament for use in the treatment of cancer or for use in reducing or preventing tumor progression, wherein the medicament is for use in combination with a taxane chemotherapeutic agent.

[0232] The binding agent may be as defined above, for example, the binding agent may comprise any of the variable and constant regions defined above.

[0233] The taxane chemotherapeutic agent may be as defined above. In a currently preferred embodiment, the taxane chemotherapeutic agent is docetaxel.

[0234] The binding agent and taxane chemotherapeutic agent may be present in a composition as defined above.

[0235] Additional items of this disclosure include: 1. A method for reducing or preventing tumor progression or treating cancer in a subject, comprising: I) a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1; and ii) Taxane chemotherapy agents providing to said subject a combination treatment with 2. The method of item 1, comprising administering the binding agent and the taxane chemotherapeutic agent to the subject in at least one treatment cycle. 3. The method of any of the preceding items, wherein the first binding region binds to human CD137 having the sequence set forth in SEQ ID NO:24, and / or the second binding region binds to human PD-L1 having the sequence set forth in SEQ ID NO:26. 4. The method of any of the preceding items, wherein the binding agent activates human CD137 upon binding to human CD137 and inhibits the binding of human PD-L1 to human PD-1 upon binding to PD-L1. 5. a) the first binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:1 and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:5; and b) the second antigen-binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:8, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:12; 1. The method of any of the preceding items. 6. a) the first binding region comprises a heavy chain variable region (VH) comprising the CDR1 sequence shown in SEQ ID NO:2, the CDR2 sequence shown in SEQ ID NO:3, and the CDR3 sequence shown in SEQ ID NO:4, and a light chain variable region (VL) comprising the CDR1 sequence shown in SEQ ID NO:6, the CDR2 sequence shown as GAS, and the CDR3 sequence shown in SEQ ID NO:7; and b) the second antigen-binding region comprises a heavy chain variable region (VH) comprising the CDR1 sequence shown in SEQ ID NO:9, the CDR2 sequence shown in SEQ ID NO:10, and the CDR3 sequence shown in SEQ ID NO:11, and a light chain variable region (VL) comprising the CDR1 sequence shown in SEQ ID NO:13, the CDR2 sequence shown as DDN, and the CDR3 sequence shown in SEQ ID NO:14; 1. The method of any of the preceding items. 7. a) the first binding region comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO:1, and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO:5; and b) the second binding region comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO:8, and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO:12; 1. The method of any of the preceding items. 8. a) the first binding region comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:5; and b) the second binding region comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:8 and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:12; 1. The method of any of the preceding items. 9. The method of any of the preceding items, wherein the binding agent is an antibody, a multispecific antibody, e.g., a bispecific antibody. 10. The method of any of the preceding items, wherein the binding agent is in the form of a full-length antibody or an antibody fragment. 11. Any of the methods of items 5 to 10, wherein each variable region comprises three complementarity-determining regions (CDR1, CDR2, and CDR3) and four framework regions (FR1, FR2, FR3, and FR4). 12. The method of item 11, wherein the complementarity determining regions and the framework regions are arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. 13. i) a polypeptide comprising, consisting of, or consisting essentially of a first heavy chain variable region (VH) and a first heavy chain constant region (CH); and ii) a polypeptide comprising, consisting of, or consisting essentially of a second heavy chain variable region (VH) and a second heavy chain constant region (CH). 2. The method of any of the preceding items, comprising: 14. i) a polypeptide comprising a first light chain variable region (VL) and further comprising a first light chain constant region (CL), and ii) a polypeptide comprising a second light chain variable region (VL) and further comprising a second light chain constant region (CL). 2. The method of any of the preceding items, comprising: 15. The binding agent is an antibody comprising a first binding arm and a second binding arm, wherein the first binding arm is i) a polypeptide comprising the first heavy chain variable region (VH) and the first heavy chain constant region (CH); and ii) a polypeptide comprising the first light chain variable region (VL) and the first light chain constant region (CL). and the second binding arm comprises iii) a polypeptide comprising the second heavy chain variable region (VH) and the second heavy chain constant region (CH); and iv) a polypeptide comprising the second light chain variable region (VL) and the second light chain constant region (CL). 2. The method of any of the preceding items, comprising: 16. i) a first heavy chain and a first light chain comprising an antigen-binding region capable of binding to CD137; and ii) a second heavy chain and a second light chain comprising an antigen-binding region capable of binding to PD-L1; 2. The method of any of the preceding items, comprising: 17. The binding substance is i) a first heavy chain and a first light chain comprising an antigen-binding region capable of binding to CD137, wherein the first heavy chain comprises a first heavy chain constant region and the first light chain comprises a first light chain constant region; and ii) a second heavy chain and a second light chain comprising an antigen-binding region capable of binding to PD-L1, wherein the second heavy chain comprises a second heavy chain constant region and the second light chain comprises a second light chain constant region. 2. The method of any of the preceding items, comprising: 18. The method of any of items 13 to 17, wherein the first heavy chain constant region (CH) and the second heavy chain constant region (CH) each comprise one or more of a heavy chain constant 1 (CH1) region, a hinge region, a heavy chain constant 2 (CH2) region, and a heavy chain constant 3 (CH3) region, preferably at least a hinge region, a CH2 region, and a CH3 region. 19. The method of any of items 13 to 18, wherein the first heavy chain constant region (CH) and the second heavy chain constant region (CH) each comprise a CH3 region, and the two CH3 regions comprise asymmetric mutations. 20. The method of any of Items 13 to 19, wherein the first heavy chain constant region (CH) has a substitution of at least one amino acid at a position corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 of a human IgG1 heavy chain according to EU numbering, and the second heavy chain constant region (CH) has a substitution of at least one amino acid at a position corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 of a human IgG1 heavy chain according to EU numbering, and wherein the first heavy chain and the second heavy chain do not have substitutions at the same positions. 21. The method of item 20, wherein (i) the amino acid at the position corresponding to F405 of human IgG1 heavy chain according to EU numbering is L in the first heavy chain constant region (CH) and the amino acid at the position corresponding to K409 of human IgG1 heavy chain according to EU numbering is R in the second heavy chain constant region (CH), or (ii) the amino acid at the position corresponding to K409 of human IgG1 heavy chain according to EU numbering is R in the first heavy chain and the amino acid at the position corresponding to F405 of human IgG1 heavy chain according to EU numbering is L in the second heavy chain. 22. The method of any of the preceding items, wherein the binding agent induces Fc-mediated effector function to a reduced extent compared to another antibody, wherein the other antibody comprises the same first and second antigen-binding regions and two heavy chain constant regions (CHs) comprising human IgG1 hinge, CH2, and CH3 regions. 23. The method of item 22, wherein the first heavy chain constant region (CH) and the second heavy chain constant region (CH) have been modified so as to induce Fc-mediated effector function to a lesser extent compared to an otherwise identical antibody comprising unmodified first and second heavy chain constant regions (CH). 24. The method of item 23, wherein each of the unmodified first heavy chain constant region (CH) and second heavy chain constant region (CH) comprises the amino acid sequence shown in SEQ ID NO: 15. 25. The method of any of items 23 to 24, wherein the Fc-mediated effector function is measured by binding to Fcγ receptors, binding to C1q, or induction of Fc-mediated cross-linking of Fcγ receptors. 26. The method of item 25, wherein the Fc-mediated effector function is measured by binding to C1q. 27. The first heavy chain constant region and the second heavy chain constant region are modified such that binding of the antibody to C1q is reduced compared to a wild-type antibody, preferably by at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or 100%; C1q binding is preferably measured by ELISA. Use any of the methods listed in items 22 to 26. 28. The method of any of the preceding items, wherein in at least one of the first heavy chain constant region (CH) and the second heavy chain constant region (CH), one or more amino acids at positions corresponding to positions L234, L235, D265, N297, and P331 of a human IgG1 heavy chain according to EU numbering are not L, L, D, N, and P, respectively. 29. The method of item 28, wherein the positions corresponding to positions L234 and L235 of the human IgG1 heavy chain according to EU numbering are F and E in the first heavy chain and the second heavy chain, respectively. 30. The method of item 28 or 29, wherein the positions corresponding to positions L234, L235, and D265 of the human IgG1 heavy chain according to EU numbering are F, E, and A in the first heavy chain constant region (HC) and the second heavy chain constant region (HC), respectively. 31. The method of any of Items 28 to 30, wherein the positions corresponding to positions L234 and L235 of the human IgG1 heavy chain according to EU numbering in both the first heavy chain constant region and the second heavy chain constant region are F and E, respectively, and wherein i) the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering in the first heavy chain constant region is L and the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering in the second heavy chain is R, or (ii) the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering in the first heavy chain constant region is R and the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering in the second heavy chain is L. 32. The method of any of Items 28 to 31, wherein the positions corresponding to positions L234, L235, and D265 of the human IgG1 heavy chain according to EU numbering in both the first heavy chain constant region and the second heavy chain constant region are F, E, and A, respectively, and wherein (i) the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering in the first heavy chain constant region is L and the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering in the second heavy chain constant region is R, or (ii) the position corresponding to K409 of the human IgG1 heavy chain according to EU numbering in the first heavy chain is R and the position corresponding to F405 of the human IgG1 heavy chain according to EU numbering in the second heavy chain is L. 33. The constant region of the first heavy chain and / or the second heavy chain comprises: a) the sequence shown in SEQ ID NO: 15 [IgG1-FC]; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 10 substitutions compared to the amino acid sequence defined in a) or b), for example at most 9 substitutions, at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most 2, or at most 1 substitution. 33. The method of any of items 13 to 32, comprising, consisting essentially of, or consisting of an amino acid sequence selected from the group consisting of: 34. The constant region of the first heavy chain or the second heavy chain, e.g., the second heavy chain, comprises: a) the sequence shown in SEQ ID NO: 16 [IgG1-F405L]; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 9 substitutions compared to the amino acid sequence defined in a) or b), for example at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most 2, or at most 1 substitution. 34. The method of any of items 13 to 33, comprising, consisting essentially of, or consisting of an amino acid sequence selected from the group consisting of: 35. The constant region of the first heavy chain or the second heavy chain, e.g., the first heavy chain, comprises: a) the sequence shown in SEQ ID NO: 17 [IgG1-F409R]; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 10 substitutions compared to the amino acid sequence defined in a) or b), for example at most 9 substitutions, at most 8 substitutions, at most 7 substitutions, at most 6 substitutions, at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. 35. The method of any of items 13 to 34, comprising, consisting essentially of, or consisting of an amino acid sequence selected from the group consisting of: 36. The constant region of the first heavy chain and / or the second heavy chain comprises: a) the sequence shown in SEQ ID NO: 18 [IgG1-Fc_FEA]; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 7 substitutions compared to the amino acid sequence defined in a) or b), for example at most 6 substitutions, at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. 36. The method of any of items 13 to 35, comprising, consisting essentially of, or consisting of an amino acid sequence selected from the group consisting of: 37. The constant region of the first heavy chain and / or the second heavy chain, e.g., the second heavy chain, comprises: a) the sequence shown in SEQ ID NO:20 [IgG1-Fc_FEAL], b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 6 substitutions compared to the amino acid sequence defined in a) or b), for example at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. 37. The method of any of items 13 to 36, comprising, consisting essentially of, or consisting of an amino acid sequence selected from the group consisting of: 38. The constant region of the first heavy chain and / or the second heavy chain, e.g., the first heavy chain, comprises: a) the sequence shown in SEQ ID NO: 19 [IgG1-Fc_FEAR]; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 6 substitutions compared to the amino acid sequence defined in a) or b), for example at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. 38. The method of any of items 13 to 37, comprising, consisting essentially of, or consisting of an amino acid sequence selected from the group consisting of: 39. The method of any of the preceding items, wherein the binding agent comprises a kappa (κ) light chain constant region. 40. The method of any of the preceding items, wherein the binding agent comprises a lambda (λ) light chain constant region. 41. The method of any of the preceding items, wherein the first light chain constant region is a kappa (κ) light chain constant region. 42. The method of any of the preceding items, wherein the second light chain constant region is a lambda (λ) light chain constant region. 43. The method of any of the preceding items, wherein the first light chain constant region is a lambda (λ) light chain constant region. 44. The method of any of the preceding items, wherein the second light chain constant region is a kappa (κ) light chain constant region. 45. The kappa (κ) light chain is: a) the sequence shown in SEQ ID NO:21; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 10 substitutions compared to the amino acid sequence defined in a) or b), for example at most 9 substitutions, at most 8 substitutions, at most 7 substitutions, at most 6 substitutions, at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. 45. The method of any of items 39 to 44, comprising an amino acid sequence selected from the group consisting of: 46. ​​The lambda (λ) light chain: a) the sequence shown in SEQ ID NO:22; b) a subsequence of the sequence in a), for example, a subsequence in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive amino acids are deleted starting from the N-terminus or C-terminus of the sequence defined in a); and c) a sequence having at most 10 substitutions compared to the amino acid sequence defined in a) or b), for example at most 9 substitutions, at most 8 substitutions, at most 7 substitutions, at most 6 substitutions, at most 5 substitutions, at most 4 substitutions, at most 3 substitutions, at most 2 substitutions, or at most 1 substitution. 46. ​​The method according to any of items 40 to 45, comprising an amino acid sequence selected from the group consisting of: 47. The method of any of the preceding items, wherein the binding agent is of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 48. The method of any of the preceding items, wherein the binding agent is a full-length IgG1 antibody. 49. The method of any of the preceding items, wherein the antibody is of the IgG1m(f) allotype. 50. The method of any of the preceding items, wherein the antibody is akasunlimab or a biosimilar thereof. 51. The method of any of the preceding items, wherein the taxane is selected from the group consisting of docetaxel, paclitaxel, cabazitaxel, and tesetaxel. 52. The method of any of the preceding items, wherein the taxane chemotherapy agent is docetaxel. 53. The amount of binding agent administered at each dose and / or in each treatment cycle is a) about 0.3 to 15 mg / kg body weight or about 25 to 1200 mg in total; and / or b) Approximately 2.1×10 -9 ~1.2×10 -7 mol / kg body weight or a total of approximately 1.7 × 10 -7 ~8.1×10 -6 mol The method of any of the preceding items, 54. The amount of binding agent administered at each dose and / or in each treatment cycle is a) about 0.3 to 10 mg / kg body weight or about 25 to 800 mg in total; and / or b) Approximately 2.1×10 -9 ~6.8×10 -8 mol / kg body weight or a total of approximately 1.7 × 10 -7 ~5.4×10 -6 mol The method of any of the preceding items, 55. The amount of binding agent administered at each dose and / or in each treatment cycle is a) about 0.3 to 5 mg / kg body weight or about 25 to 400 mg in total; and / or b) Approximately 2.1×10 -9 ~3.4×10 -8 mol / kg body weight or a total of approximately 1.7 × 10 -7 ~2.7×10 -6 mol The method of any of the preceding items, 56. The amount of binding agent administered at each dose and / or in each treatment cycle is a) about 1.25 mg / kg body weight or about 100 mg in total; and / or b) Approximately 8.5×10 -9 mol / kg body weight or a total of approximately 6.8 × 10 -7 mol The method of any of the preceding items, 57. The amount of taxane chemotherapy administered at each dose and / or in each treatment cycle is about 10-200 mg / m 2 , e.g., 20-40 mg / m 2 , 30-50 mg / m 2 , 40-100 mg / m 2 , 50-100mg / m 2 , 50-80 mg / m 2 , 50-70 mg / m 2 , 50-60 mg / m 2 , 50-110 mg / m 2 , 60-100mg / m 2 , 60-100mg / m 2 , 60-90 mg / m 2 , 70-80 mg / m 2 , 80-200 mg / m 2 , 90-180 mg / m 2 , 90-110 mg / m 2 , 100-175 mg / m 2 , or, for example, about 170-180 mg / m 2 The method of any of the preceding items, 58. The taxane chemotherapy agent is docetaxel, and the amount administered at each dose and / or in each treatment cycle is about 50-60 mg / m 2 , e.g., about 55 mg / m 2The method of any of the preceding items, 59. The taxane chemotherapy agent is docetaxel, and the amount administered at each dose and / or in each treatment cycle is about 70-80 mg / m 2 , for example about 75 mg / m 2 The method of any of the preceding items, 60. The method of any of the preceding items, wherein the binding agent and / or the taxane chemotherapeutic agent are administered by systemic administration. 61. The method of any of the preceding items, wherein the binding agent and / or the taxane chemotherapeutic agent is administered by intravenous injection or infusion. 62. The method of any of the preceding items, wherein in each treatment cycle, at least one dose of the binding agent and at least one dose of a taxane chemotherapeutic agent are administered. 63. The method of any of the preceding items, wherein each treatment cycle is 3 weeks (21 days). 64. The method of any of the preceding items, wherein the binding agent and the taxane chemotherapeutic agent are administered on the same day. 65. The method of any of the preceding items, wherein each dose of the binding agent is infused over a period of at least 30 minutes, e.g., at least 60 minutes, at least 90 minutes, at least 120 minutes, or at least 240 minutes. 66. The method of any of the preceding items, wherein administration of the binding agent occurs at least 30 minutes, such as at least 1 hour, or such as at least 2 hours, before administration of the taxane chemotherapeutic agent. 67. The method of any of the preceding items, wherein one dose of the binding agent and / or one dose of the taxane chemotherapeutic agent is administered on day 1 of each treatment cycle. 68. The method of any of the preceding items, wherein one dose of the binding agent is administered every three weeks (1Q3W), e.g., on day 1 of each three-week treatment cycle. 69. The method of any of the preceding items, wherein one dose of the taxane chemotherapeutic agent is administered every three weeks (1Q3W), e.g., on day 1 of each three-week treatment cycle. 70. Any of the preceding methods, wherein each dose of taxane chemotherapy is preceded by steroid premedication, e.g., oral corticosteroid premedication, e.g., about 8 mg of dexamethasone twice daily for three days starting one day before administration of the taxane chemotherapy. 71. The method of any of the preceding items, wherein the subject is a human subject. 72. The method of any of the preceding items, wherein the tumor or cancer is a solid tumor. 73. The method of any of the preceding items, wherein the tumor or cancer is selected from the group consisting of melanoma, ovarian cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), colorectal cancer, head and neck cancer, gastric cancer, breast cancer, kidney cancer, urothelial cancer, bladder cancer, esophageal cancer, pancreatic cancer, liver cancer, thymoma and thymic cancer, brain cancer, glioma, adrenocortical carcinoma, thyroid cancer, other skin cancers, sarcoma, multiple myeloma, leukemia, lymphoma, myelodysplastic syndrome, ovarian cancer, endometrial cancer, prostate cancer, penile cancer, cervical cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Merkel cell carcinoma, and mesothelioma. 74. The method of any of the preceding items, wherein the tumor or cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (NSCLC), urothelial carcinoma (cancer of the bladder, ureter, urethra, or renal pelvis), endometrial cancer (EC), breast cancer (e.g., triple-negative breast cancer (TNBC)), squamous cell carcinoma of the head and neck (SCCHN) (e.g., cancer of the oral cavity, pharynx, or larynx), and cervical cancer. 75. The method of any of the preceding items, wherein the tumor or cancer is lung cancer. 76. The method of item 75, wherein the lung cancer is non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC. 77. The method of item 56, wherein the NSCLC does not have epidermal growth factor (EGFR) sensitivity-increasing mutations and / or anaplastic lymphoma (ALK) translocations / ROS1 rearrangements. 78. Any of the methods of items 75-77, wherein the subject has received up to four systemic conditioning regimens for advanced / metastatic disease and experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment. 79. The method of item 78, wherein the subject has undergone platinum-based chemotherapy. 80. The method of item 78, wherein the subject is ineligible for platinum-based therapy and has been treated with an alternative chemotherapy, e.g., a gemcitabine-containing regimen. 81. The method of any of the preceding items, wherein the subject has received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 82. The method of any of the preceding items, wherein the subject has experienced disease progression during or after treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 83. The method of any of the preceding items, wherein the subject has experienced disease progression during or after their last prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 84. The method of any of items 78-83, wherein the subject has experienced disease progression, e.g., radiographically confirmed disease progression, during or after their last systemic conditioning treatment. 85. The method of any of the preceding items, wherein the subject has not received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 86. The method of any of the preceding items, wherein the tumor or cancer is endometrial cancer. 87. The object is: Epithelial endometrial histology, including endometrioid carcinoma, serous carcinoma, squamous cell carcinoma, clear cell carcinoma, or carcinosarcoma 87. The method of item 86, comprising: 88. The method of item 86 or 87, wherein the subject has received up to four systemic conditioning regimens for advanced / metastatic disease and experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment. 89. The method of any of paragraphs 86-88, wherein the subject has not received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 90. The method of any of the preceding items, wherein the tumor or cancer is urothelial cancer, including cancer of the bladder, ureter, urethra, or renal pelvis. 91. The method of item 90, wherein the subject has received up to four systemic conditioning regimens for advanced / metastatic disease and experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment. 92. The method of item 90 or 91, wherein the subject has received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 93. The method of item 90 or 91, wherein the subject has undergone platinum-based chemotherapy. 94. The method of any of items 90 or 91, wherein the subject is ineligible for platinum-based therapy and has been treated with an alternative chemotherapy, e.g., a gemcitabine-containing regimen. 95. The method of any of the preceding items, wherein the tumor or cancer is breast cancer, e.g., triple-negative breast cancer (TNBC). 96. The method of item 95, wherein the TNBC is HER2-negative, for example, HER2-negative as determined by measuring protein expression by fluorescent in situ hybridization (FISH) or immunohistochemistry, progesterone receptor-negative, and estrogen receptor-negative. 97. The method of item 95 or 76, wherein the subject has received at least one systemic conditioning regimen for locally advanced / metastatic disease, e.g., at least one systemic conditioning regimen including an anthracycline-containing, taxane-containing, antimetabolite-containing, or microtubule inhibitor-containing regimen. 98. The object is: Up to four systemic conditioning regimens for locally advanced / metastatic disease, including at least one systemic conditioning regimen containing an anthracycline-, taxane-, antimetabolite-, or microtubule-inhibitor-containing regimen The method described in item 97, wherein the patient has undergone 99. The method of any of items 95-98, wherein the subject has received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 100. The method of item 99, wherein the subject has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the pretreatment with a checkpoint inhibitor. 101. The method of any of items 95-98, wherein the subject has not received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 102. The method of any of the preceding items, wherein the tumor or cancer is a head and neck cancer, e.g., squamous cell carcinoma of the head and neck (SCCHN). 103. The method of item 102, wherein the tumor or cancer is recurrent or metastatic SCCHN. 104. The method of item 102 or 103, wherein the tumor or cancer is a cancer of the oral cavity, pharynx, or larynx. 105. Any of the methods of items 102-104, wherein the subject has received up to four systemic conditioning regimens for recurrent / metastatic disease and experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment. 106. The method of item 105, wherein the subject has undergone platinum-based chemotherapy. 107. The method of item 105, wherein the subject is ineligible for platinum-based therapy and is receiving alternative chemotherapy. 108. The method of any of items 102-107, wherein the subject has received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 109. The method of item 108, wherein the subject has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the pretreatment with a checkpoint inhibitor. 110. The method of any of items 102-107, wherein the subject has not received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 111. The method of any of the preceding items, wherein the tumor or cancer is cervical cancer. 112. The method of item 111, wherein the cervical cancer is squamous cell, adenocarcinoma, or adenosquamous histology cervical cancer. 113. The method of item 111 or 112, wherein the subject has received at least one systemic conditioning regimen for recurrent / metastatic disease, e.g., chemotherapy in combination with a treatment targeting vascular endothelial growth factor A, e.g., chemotherapy in combination with treatment with bevacizumab, and has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment. 114. The object is: Up to four systemic conditioning regimens for recurrent / metastatic disease, including chemotherapy in combination with vascular endothelial growth factor A-targeted treatment, e.g., chemotherapy in combination with treatment with bevacizumab The method of item 113, wherein the patient has undergone 115. The method of any of paragraphs 111-114, wherein the subject has not received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor. 116. A composition comprising a taxane chemotherapeutic agent and a binding agent comprising a first binding region that binds to human CD137 and a second binding region that binds to human PD-L1. 117. The amount of binding substance in the composition is 25 to 400 mg or 1.7 × 10 -7 ~2.7×10 -6 117. The composition according to item 116, wherein the total amount of the 118. The composition according to item 116, comprising about 80 mg of the binding substance. 119. The composition of any of items 116 to 118, wherein the binding substance is as defined in any of items 3 to 50. 120. The composition of any of items 116 to 119, wherein the taxane chemotherapy drug is as defined in any of items 51 to 52. 121. The composition of any of items 116 to 120, which is for systemic administration. 122. The composition of any of items 116 to 121, which is for injection or infusion, for example, for intravenous injection or infusion. 123. Any of the compositions of item 122, wherein the binding agent and the taxane chemotherapeutic agent are present in a volume of 50 to 500 mL, e.g., 100 to 250 mL, of an aqueous solution, e.g., 0.9% NaCl (saline). 124. A binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1 for use in treating cancer or for use in reducing or preventing tumor progression, wherein the binding agent is used in combination with a taxane chemotherapy agent. 125. A binding substance for use according to item 124, as defined in any of items 3 to 50. 126. A binding substance for use according to item 124 or 125, wherein the taxane chemotherapeutic agent is as defined in any of items 51 to 52. 127. A taxane chemotherapeutic agent for use in the treatment of cancer or in reducing or preventing tumor progression, the taxane chemotherapeutic agent being used in combination with a binding agent comprising a first binding domain that binds to human CD137 and a second binding domain that binds to human PD-L1. 128. A taxane chemotherapeutic agent for use according to item 127, wherein the binding agent is as defined in any of items 3 to 50. 129. A taxane chemotherapeutic agent for use according to item 127 or 128, as defined in any of the items.

[0236] array (Table 7) TIFF2023551980000012.tif186170TIFF2023551980000013.tif243170TIFF20235519800 00014.tif244170TIFF2023551980000015.tif242170TIFF2023551980000016.tif185170

[0237] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention. [Example]

[0238] Example 1: Generation of CD137 antibody Antibodies CD137-005 and CD137-009 were produced as described in Example 1 of WO2016 / 110584. Briefly, rabbits were immunized with a protein mixture containing a human CD137-Fc fusion protein. Single B cells were sorted from the blood and screened for the production of CD137-specific antibodies by ELISA and flow cytometry. RNA was extracted from the B cells that screened positively and sequenced. The heavy and light chain variable regions were gene synthesized and cloned into a human IgG1κ or IgG1λ expression vector containing a human IgG1 heavy chain with the following amino acid mutations: L234F, L235E, D265A, and F405L(FEAL) or F405L(FEAL). The numbers for the amino acid positions are according to EU numbering (corresponding to SEQ ID NO: 20). The variable region sequences of the chimeric CD137 antibody (CD137-009) are shown in the sequence listing herein, SEQ ID NO:28 and SEQ ID NO:29.

[0239] Example 2: Humanization of rabbit (chimeric) CD137 antibody Humanized antibody sequences from rabbit anti-CD137-009 were generated at Antitope (Cambridge, UK). The humanized antibody sequences were generated using germline humanization (CDR grafting) technology. Humanized V-region genes were designed based on human germline sequences with the closest homology to the rabbit antibody VH and Vκ amino acid sequences. A series of seven VH and three Vκ (VL) germline humanized V-region genes were designed. Structural models of the non-human parent antibody V-regions were generated using the Swiss PDB and analyzed to identify amino acids in the V-region framework that may be important for the binding properties of the antibody. These amino acids were targeted for incorporation into antibodies grafted with one or more variant CDRs. The germline sequences used as the basis for the humanization design are listed in Table 8.

[0240] Table 8. Best-matched human germline V and J segment sequences TIFF2023551980000017.tif40164

[0241] Variant sequences with the lowest incidence of potential T cell epitopes were then selected using iTope™ and TCED™ (T Cell Epitope Database), in silico technologies under Antitope's intellectual property rights (Perry, LCA, Jones, TD and Baker, MP New Approaches to Prediction of Immune Responses to Therapeutic Proteins during Preclinical Development (2008). Drugs in R&D 9 (6): 385-396; 20 Bryson, CJ, Jones, TD and Baker, MP Prediction of Immunogenicity of Therapeutic Proteins (2010). Biodrugs 24 (1): 1-8). Finally, the nucleotide sequences of the designed variants were codon-optimized.

[0242] The variable region sequences of the humanized CD137 antibody (CD137-009-HC7LC2) are shown in the sequence listing herein, SEQ ID NO: 1 and SEQ ID NO: 5.

[0243] Example 3: Generation of PD-L1 antibodies Immunization and hybridoma generation were performed at Aldevron GmbH (Freiburg, Germany). cDNA encoding amino acids 19-238 of human PD-L1 was cloned into an expression plasmid under Aldevron's intellectual property rights. Antibody PD-L1-547 was generated by immunizing OmniRat animals (transgenic rats expressing a diverse antibody repertoire with fully human idiotypes; Ligand Pharmaceuticals Inc., San Diego, USA) with intradermal application of human PD-L1 cDNA-coated gold particles using a handheld particle bombardment device ("gene gun"). Serum samples were collected after each series of immunizations and tested by flow cytometry against HEK cells transiently transfected with the above expression plasmid to express human PD-L1. Antibody-producing cells were isolated and fused with mouse myeloma cells (Ag8) according to standard procedures. RNA from hybridomas producing PD-L1-specific antibodies was extracted and sequenced. The heavy and light chain variable regions (SEQ ID NOs: 8 and 12) were gene synthesized and cloned into a human IgG1λ expression vector containing a human IgG1 heavy chain containing the following amino acid mutations: L234F, L235E, D265A, and K409R (FEAR). Amino acid position numbers are according to EU numbering (corresponding to SEQ ID NO: 19).

[0244] Example 4: Generation of bispecific antibodies by 2-MEA-induced Fab arm exchange Bispecific IgG1 antibodies were generated by Fab arm exchange under controlled reducing conditions. The basis of this method is the use of complementary CH3 domains to promote heterodimer formation under specific assay conditions, as described in WO2011 / 131746. To create an antibody pair with complementary CH3 domains, F405L and K409R (EU numbering) mutations were introduced into the relevant antibodies.

[0245] To generate bispecific antibodies, two parental complementary antibodies, each at a final concentration of 0.5 mg / mL, were incubated with 75 mM 2-mercaptoethylamine-HCl (2-MEA) in a total volume of 100 μL of PBS for 5 h at 31°C. The reduction reaction was stopped by removing the reducing agent 2-MEA using a spin column (Microcon centrifugal filter, 30k, Millipore) according to the manufacturer's protocol.

[0246] Bispecific antibodies were generated by combining the following antibodies from Examples 1 and 3: - CD137-009-FEAL antibody in combination with PD-L1-547-FEAR antibody - PD-L1-547-FEAL antibody in combination with CD137-009-FEAR antibody - GEN1046 (PD-L1-547-FEAL antibody in combination with CD137-009-HC7LC2-FEAR antibody (CD137 binding arm: SEQ ID NO: 1, 5, 21, 19; PD-L1 binding arm: SEQ ID NO: 18, 12, 22, 20), - b12-FEAL antibody in combination with PD-L1-547-FEAR antibody, CD137-009-FEAR, or CD137-009-HC7LC2-FEAR antibody, using the gp120-specific antibody b12 (Barbas, CF. J Mol Biol. 1993 Apr 5;230(3):812-23) as the first arm. - PD-L1-547-FEAL or CD137-009-FEAL with the b12-FEAR antibody.

[0247] Example 5: Pharmacodynamic evaluation of GEN1046 in peripheral blood in patients with advanced solid tumors To investigate the biological activity of various dose levels of GEN1046 in patients with advanced tumors, blood and serum samples were collected at baseline and multiple time points during treatment. Based on the mechanism of action of GEN1046, biologically active dose levels were expected to modulate circulating levels of interferon-γ and induce proliferation of peripheral CD8 T cells.

[0248] Serum samples were collected from patients at baseline and at multiple time points after GEN1046 administration (Day 1 [2 and 4-6 hours post-dose], Day 2, Day 3, Day 8, and Day 15) in Cycles 1 and 2 to determine serum levels of interferon-γ (IFN-γ). Serum levels of IFN-γ were measured by a Meso Scale Discovery (MSD) multiplex immunoassay (catalog number K15209G) according to the manufacturer's instructions.

[0249] To measure peripheral modulation of immune cell subsets, peripheral blood immunophenotyping was performed on whole blood collected in EDTA tubes at baseline and multiple time points (days 2, 3, 8, and 15) after GEN1046 administration in cycles 1 and 2. 100 μL of whole blood was added to fluorochrome-conjugated monoclonal antibodies that specifically bind to cell surface antigens: CD45RA-FITC (clone LEU-18, BD Biosciences, catalog number 335039), CCR7-BV510 (clone 3D12, BD Biosciences, catalog number 563449), and CD8-PerCP-Cy5.5 (clone RPA-T8, BD Biosciences, catalog number 560662). After incubation on ice, the stained samples were treated with FACS Lysing Solution (BD Biosciences, catalog number 349202) to lyse red blood cells. Excess antibody and cell debris were removed by washing with Stain Buffer (BD Biosciences, Cat. No. 554656). After lysis / washing, cells were fixed and permeabilized by incubation with Permeabilizing Solution 2 buffer (BD Biosciences, Cat. No. 340973). Cells were then washed, resuspended in Stain Buffer, and incubated on ice with an antibody against Ki67 (BV421 B56, BD Biosciences, Cat. No. 562899) to detect proliferating cells. After incubation, excess antibody was removed by washing with Stain Buffer. Cells were resuspended in Stain Buffer and stained and acquired within 1 hour on a BD FACSCanto™ II flow cytometer (Becton Dickinson).

[0250] Administration of GEN1046 to cancer patients modulated circulating levels of IFN-γ and proliferating effector memory CD8 T cells (Table 1). IFN-γ levels increased more than two-fold in the first treatment cycle across all dose levels tested. The largest increases were detected at the 50 mg and 80 mg dose levels, with most patients (75%) in the 80 mg cohort experiencing a more than two-fold increase (Table 1). GEN1046 significantly increased Ki67 + CD8 + CD45RA - CCR7 - It also induced the proliferation of effector memory CD8+ T cells as measured by an increase in the frequency of T cells. The increase in the frequency of proliferating CD8+ T cells was comparable to the changes observed with modulation of circulating levels of IFNγ. + The greatest and more consistent modulation of effector memory T cells was observed in patients in the 80 mg cohort. Notably, the magnitude of changes in circulating levels of both IFN-γ and proliferating effector memory CD8 T cells was smaller in the 400 mg cohort compared to the 25-200 mg cohort. These results demonstrate that GEN1046 induces an immune response characterized by modulation of immune effector cells and soluble factors critical for the generation of antitumor immune responses, with the 80 mg dose level producing a large magnitude of response.

[0251] Table 9. GEN1046 Modulation of Peripheral Pharmacodynamic Endpoints in Cancer Patients: Peak Fold Change from Baseline by Dose Level During Cycle 1 a TIFF2023551980000018.tif89162Preliminary data as of January 27, 2020. n: number of patients per dose cohort; Min: smallest measured value; Q1: 25th percentile; Q3: 75th percentile; Max: largest measured value. a Pharmacodynamic evaluations, including changes in circulating levels of interferon-γ and effector memory T cells, were performed using blood samples from patients with advanced solid tumors enrolled in the dose-escalation phase of an open-label, multicenter safety study of GEN1046 (NCT03917381). b Circulating levels of interferon-γ in serum samples were measured at baseline and at multiple time points after GEN1046 administration (Day 1 [2 hours and 4-6 hours post-dose], Day 2, Day 3, Day 8, and Day 15) in Cycles 1 and 2. Interferon-γ levels in serum samples were determined by Meso Scale Discovery (MSD) multiplex immunoassay. c Peripheral blood immunophenotyping was performed on whole blood collected at baseline and at multiple time points (days 2, 3, 8, and 15) after GEN1046 administration in cycles 1 and 2. Proliferation (Ki67 + ) effector memory CD8 T cells (CD8 + CD45RA - CCR7 - The frequency of erythrocytes (e.g., erythrocytes ... and thymocytes) was assessed in whole blood samples by flow cytometry.

[0252] Example 6: Preliminary Data from Dose Escalation: Study design : The clinical trial for GCT1046-01 (ClinicalTrials.gov Identifier: NCT03917381) was designed as a two-part study, including an ongoing dose-escalation part and a planned expansion part.

[0253] This study was designed as an open-label, multicenter, Phase I / IIa safety study of GEN1046 (DuoBody® - PD-L1x4-1BB). The study consisted of two parts: first-in-human (FIH) dose escalation (Phase I) and expansion (Phase IIa). Figure 2 shows a schematic diagram of the clinical trial design.

[0254] Dose escalation Dose escalation was designed to evaluate GEN1046 in subjects with solid malignancies with the goal of determining the maximum tolerated dose (MTD) or maximum administered dose (MAD) and / or recommended phase 2 dose (RP2D).

[0255] For dose escalation, subjects were required to be male or female, aged 18 years or older, and to have measurable disease per RECIST 1.1.

[0256] Subjects were required to have metastatic or unresectable histologically or cytologically confirmed non-CNS solid tumors, for which standard therapies likely to provide clinical benefit are unavailable or who are not candidates for such available therapies, and who, in the opinion of the investigator, may benefit from experimental therapy with GEN1046.

[0257] In dose escalation, subjects received GEN1046 infusions once every three weeks (1Q3W) until protocol-defined criteria for treatment discontinuation, e.g., radiographic disease progression or clinical progression, were met. GEN1046 was administered using an iv infusion over a minimum of 60 minutes on day 1 of each 3-week treatment cycle (21 days). The conceptual design of this study is shown in Figure 2.

[0258] The 1Q3W dose escalation was designed to potentially (depending on data collected during the study) evaluate GEN1046 at seven main dose levels: a constant 25 mg, 80 mg, 200 mg, 400 mg, 800 mg, 1200 mg, and 1600 mg, and six optional intermediate dose levels: a constant 50 mg, 140 mg, 300 mg, 600 mg, 1000 mg, and 1400 mg.

[0259] The recommended phase 2 dose (RP2D) was based on a review of available safety and dosing information and could be less than the maximum tolerated dose (MTD).

[0260] Increase The purpose of the expansion is to provide further data on the safety, tolerability, MoA, PK, and antitumor activity of the selected dose / schedule.

[0261] The expansion is designed to begin recruitment in up to six tumor types (seven parallel cohorts): NSCLC, EC, UC, TNBC, SCCHN, and cervical cancer. Further expansion cohorts for additional tumor types may be established based on preliminary efficacy signals generated in dose escalation. The sponsor will determine the priority for establishing disease-specific expansion cohorts based on data generated in dose escalation.

[0262] NSCLC expansion cohort The NSCLC expansion cohort must include subjects with squamous histology as well as subjects with non-squamous histology.

[0263] Because response rates and other disease-related outcomes may differ in PD-1 / PD-L1-naive versus PD-1 / L1-pretreated populations, NSCLC patients were divided into different cohorts to ensure sufficient evidence of preliminary efficacy. Cohort 2 aims to explore preliminary efficacy in PD-1 / L1-naive NSCLC patients for whom SOC with PD-1 / L1 inhibitors is limited or unavailable. If preliminary clinical evidence, as confirmed by DMC review of the totality of the data, suggests substantial improvement over available therapies in populations with high unmet medical need (e.g., PD-L1-poor or -negative), sponsors may request that Cohort 2 be established in regions where access to PD-1 / L1 inhibitors is not restricted.

[0264] UC expansion cohort The UC cohort was designed to include both platinum-based chemotherapy eligible and ineligible subjects.

[0265] SCCHN and TNBC growth cohort The SCCHN and TNBC cohorts may include subjects who have received prior treatment with a PD-1 / PD-L1 inhibitor, as well as subjects who have not received prior treatment with a PD-1 / L1 inhibitor.

[0266] Inclusion criteria Subjects are eligible for inclusion in the study only if all of the following criteria are met:

[0267] Subjects must be male or female, aged 18 years or older, and must have measurable disease according to RECIST 1.1.

[0268] Subjects must have a histologically or cytologically confirmed diagnosis of relapsed or refractory, advanced and / or metastatic NSCLC, EC, UC, TNBC, SCCHN, or cervical cancer that is no longer a candidate for or has refused standard therapy (if the subject was available and eligible for each treatment) and has failed anti-cancer therapy as follows:

[0269] Expansion cohort 1 (NSCLC): pretreated with PD-1 / L1 NSCLC subjects who have received up to four systemic conditioning regimens (adjuvant and maintenance therapy are considered part of one line of treatment) for advanced / metastatic disease and have radiographic disease progression during or after the last conditioning therapy.

[0270] Subjects with NSCLC of all histologies may be enrolled. Subjects with a histologic or cytologic diagnosis of non-squamous NSCLC must be free of epidermal growth factor receptor (EGFR) sensitizing mutations and / or anaplastic lymphoma (ALK) translocations / ROS1 rearrangements. EGFR sensitizing mutations are those amenable to treatment with approved tyrosine kinase inhibitors (TKIs). Documentation of EGFR and ALK status must be available per local assessment. If documentation of EGFR and ALK status is not available, sponsor medical monitor approval is required prior to enrollment.

[0271] Subjects must have received platinum-based therapy (or alternative chemotherapy due to platinum ineligibility, eg, gemcitabine-containing regimens).

[0272] Subjects must have received prior treatment with a PD-1 / L1 inhibitor, alone or in combination, and must have radiographic disease progression while on treatment. Sponsor approval is required for subjects with SD or BOR of PD while on a CPI-containing regimen with treatment duration up to 16 weeks.

[0273] Expansion Cohort 2 (NSCLC) - PD-1 / L1 naive NSCLC subjects who have received up to four systemic conditioning regimens for metastatic disease (maintenance therapy is considered part of one line of treatment) and have radiographic disease progression during or after the last conditioning regimen.

[0274] Subjects with NSCLC of all histologies may be enrolled. Subjects with a histologic or cytologic diagnosis of non-squamous NSCLC must not have epidermal growth factor receptor (EGFR) sensitizing mutations and / or anaplastic lymphoma kinase (ALK) translocations / ROS1 rearrangements. EGFR sensitizing mutations are those amenable to treatment with approved tyrosine kinase inhibitors (TKIs). Documentation of EGFR and ALK status must be available per local assessment. If documentation of EGFR and ALK status is not available, sponsor medical monitor approval is required prior to enrollment.

[0275] Subjects must have received platinum-based therapy (or alternative chemotherapy due to platinum ineligibility, eg, gemcitabine-containing regimens).

[0276] Subjects must have received prior treatment with a PD-1 / L1 inhibitor. It should not happen .

[0277] Expansion Cohort 3 (UC): UC subjects who have received up to four systemic conditioning regimens (adjuvant and maintenance therapy are considered part of one line of treatment) for locally advanced / metastatic disease and have radiographic disease progression (of the bladder, ureter, urethra, or renal pelvis) during or after the last conditioning regimen.

[0278] Subjects must have received prior treatment with a PD-1 / L1 inhibitor, alone or in combination, and must have radiographic disease progression while on treatment. Sponsor approval is required for subjects with SD or BOR of PD while on a CPI-containing regimen with treatment duration up to 16 weeks.

[0279] Regional results from the most recent PD-L1 trial (if available) must be provided prior to enrollment.

[0280] Cohort 3a: For subjects eligible to receive platinum-based therapy: Subjects must have received platinum-based chemotherapy.

[0281] Cohort 3b: For subjects not eligible for platinum-based therapy: Subjects must not be eligible for platinum-based or cisplatin-containing chemotherapy.

[0282] Expansion Cohort 4 (EC): EC subjects who have received up to four systemic conditioning regimens (maintenance therapy is considered part of one line of treatment) for advanced / metastatic disease and have radiographic disease progression during or after their last conditioning regimen.

[0283] Subjects must have epithelial endometrial histology, including endometrioid carcinoma, serous carcinoma, squamous cell carcinoma, clear cell carcinoma, or carcinosarcoma. Sarcomas and mesenchymal ECs are excluded.

[0284] Subjects must have received prior treatment with a PD-1 / L1 inhibitor. It should not happen (Established local labels / access must be respected).

[0285] Expansion Cohort 5 (TNBC): TNBC determined to be HER2-negative [HER2 negative by FISH] assay (HER2 to CEP17 non-amplified ratio <2.0, single-probe mean HER2 gene copy number <4 signals / cell); or Alternatively, HER2 protein expression by IHC result is 1+ negative or IHC 0- negative according to regional evaluation and ER and PgR negative status (defined as <1% hormone receptor-expressing cells by IHC analysis).Subjects who have received up to four systemic conditioning regimens (maintenance therapy is considered part of one line of treatment), including but not limited to anthracycline-, taxane-, antimetabolite-, or microtubule-inhibitor-containing regimens, for locally advanced / metastatic disease and have radiographic disease progression during or after the last conditioning regimen.

[0286] Subjects with a prior history of phenotypically distinct breast cancer must have confirmed TNBC in a biopsy obtained after the subject's last prior systemic therapy.

[0287] Cohort 5a - Subjects who have received prior PD-1 / L1 inhibitor therapy: Subjects must have received prior treatment with a PD-1 / L1 inhibitor, alone or in combination, and must have had radiographic disease progression while on treatment.

[0288] Cohort 5b - PD-1 / L1 inhibitor-naive subjects: Subjects must have received prior treatment with a PD-1 / L1 inhibitor. It should not happen .

[0289] Expansion Cohort 6 (SCCHN): Subjects with recurrent or metastatic SCCHN (oral cavity, pharynx, larynx) who have received up to four systemic conditioning regimens (maintenance therapy is considered part of one line of treatment) for recurrent / metastatic disease and have radiographic PD during or after the last conditioning regimen.

[0290] Subjects must have disease progression during or after prior treatment with platinum-based chemotherapy (alternative combination chemotherapy is permitted if the subject's platinum-ineligible status is documented).

[0291] Cohort 6a - Subjects who have received prior PD-1 / L1 inhibitor therapy: Subjects must have received prior treatment with a PD-1 / L1 inhibitor, alone or in combination, and must have radiographic disease progression while on treatment. Sponsor approval is required for subjects with SD or BOR of PD while on a CPI-containing regimen with treatment duration up to 16 weeks.

[0292] Cohort 6b - PD-1 / L1 inhibitor-naive subjects: Subjects must have received prior treatment with a PD-1 / L1 inhibitor. It should not happen .

[0293] Expansion Cohort 7 (Cervical Cancer): Cervical cancer subjects who have received up to four systemic conditioning regimens for recurrent / metastatic disease, including a combination of chemotherapy and bevacizumab (according to applicable labeling), unless the subject is bevacizumab-ineligible according to local criteria, and who have radiographic disease progression during or after the last conditioning regimen (chemotherapy administered in the adjuvant or neoadjuvant setting or in combination with radiation therapy must not have been included in the previous line of therapy).

[0294] Subjects must have cervical cancer of squamous cell, adenocarcinoma, or adenosquamous histology.

[0295] Subjects must have received prior treatment with a PD-1 / L1 inhibitor. It should not happen (Established local labels / access must be respected).

[0296] result Dose escalation The following preliminary results were obtained during dose escalation: Table 10 shows the best overall response (RECIST v1.1) by dose level at enrollment and dosing for a total of 30 patients (data extraction date: February 3, 2020).

[0297] Tables 11 and 12 show the objective response rate and confirmed objective response rate, respectively, by dose level at enrollment and dosing for a total of 61 patients (RECIST v1.1) (data cutoff: October 12, 2020).

[0298] The best percent change in tumor size from baseline for all patients is shown in Figure 3. Disease control occurred in 40 / 61 (65.6%) patients in the dose-escalation phase. Partial responses (PRs) were observed in four patients with triple-negative breast cancer, ovarian cancer, or non-small cell lung cancer (NSCLC). Thirty-six patients maintained stable disease.

[0299] The clinical activity (best change in tumor size from baseline) observed in NSCLC patients is shown in Figure 4 (data cutoff: October 12, 2020). Of the six NSCLC patients, all of whom had previously received checkpoint immunotherapy, two had an unconfirmed PR, two maintained stable disease, and two experienced progression.

[0300] Table 10. Best overall response by dose level (RECIST v1.1) TIFF2023551980000019.tif19388

[0301] Table 11. Objective Response Rate - Dose Escalation TIFF2023551980000020.tif21895

[0302] Table 12. Confirmed Response Rate - Dose Escalation TIFF2023551980000021.tif223110

[0303] Increase: Expansion Cohort 1: As of October 12, 2020, 24 patients were enrolled in Expansion Cohort 1. Expansion Cohort 1 includes patients with NSCLC (pretreated with PD-1 / L1). Twelve patients with confirmed progression on or after checkpoint inhibitor therapy were available for evaluation after baseline (Figure 5).

[0304] Conclusion: GEN1046 is a first-in-class, next-generation PD-L1x4-1BB bispecific antibody with an acceptable safety profile and promising early clinical activity, unlike existing 4-1BB agonists.

[0305] In the dose-escalation phase of this Phase I / IIa study, GEN1046 demonstrated a manageable safety profile and preliminary clinical activity in a heavily pretreated advanced solid tumor population.

[0306] Most adverse events were mild to moderate. Treatment-related grade 3 transaminase elevations resolved with corticosteroids. No treatment-related bilirubin or grade 4 transaminase elevations were observed. Six patients experienced dose-limiting toxicities (DLTs). The maximum tolerated dose (MTD) was not reached.

[0307] Clinical benefit was observed across different dose levels in patients, including those who were resistant to previous immunotherapy and those with tumors that were generally insensitive to immune checkpoint inhibitors (ICIs).

[0308] Disease control was achieved in 65.6% of patients, including partial responses in triple-negative breast cancer (1), ovarian cancer (1), and ICI-pretreated NSCLC (2).

[0309] Modulation of pharmacodynamic endpoints was observed across a wide range of dose levels, demonstrating biological activity.

[0310] Encouraging preliminary responses were observed in an expansion cohort currently enrolling patients with NSCLC who had received prior checkpoint immunotherapy exposure.

[0311] Example 7: Pharmacokinetic / Pharmacodynamic Model We developed an integrated semi-mechanistic PK / PD (pharmacokinetic / pharmacodynamic) model that assumes distribution of GEN1046 to the central and peripheral PK compartments, as well as distribution to the tumor and lymphatic compartments. The model utilizes PK and pharmacodynamic data from the literature and physiological parameters to parameterize PD-L1 and 4-1BB expression and T cell trafficking to these compartments. The model compartments consist of well-mixed 2D and 3D spaces and free drug movement between all compartments. Furthermore, the model incorporates the dynamic binding of GEN1046 to PD-L1 and 4-1BB to predict trimer formation (crosslinking with PD-L1 and 4-1BB) and receptor occupancy (RO) for PD-L1 and 4-1BB in the tumor. Simulations showed that trimer formation was optimal at an 80 mg dose. The model-predicted RO for PD-L1 and 4-1BB in the tumor appeared to be sufficient at doses of 80–140 mg. Increasing the dose to ≥200 mg reduced trimer formation. Furthermore, based on available clinical pharmacodynamic data, dose levels ≤200 mg demonstrated greater magnitude and consistent modulation of peripheral pharmacodynamic endpoints (IFNγ and expanded Ki67+ effector memory CD8+ T cells). Considering PK / pharmacodynamic modeling predictions and available clinical data, the optimal dose of GEN1046 was predicted to be in the range of 80–140 mg. A 100 mg dose administered 1 Q3W maintained maximal trimer formation and mean RO(%) for PD-L1 at reasonable levels throughout the entire dosing interval.

[0312] The model-predicted maximum trimer formation and receptor occupancy for 100 mg 1Q3W PDL1 is shown in FIG.

[0313] Example 8: Combination of GEN1046 and docetaxel in the MC38 syngeneic mouse tumor model method MC38 mouse colon carcinoma cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO. MC38 cells were harvested from cell cultures growing in logarithmic phase and quantified.

[0314] MC38 cells (1 × 10 dissolved in 100 μL PBS) 6 100 tumor cells) were injected subcutaneously into the right lower flank of female C57BL / 6 mice (obtained from Vital River Laboratories Research Models and Services; 6–8 weeks old at the start of the experiment).

[0315] Tumor growth was assessed three times a week using calipers. Tumor volume (mm) was calculated from caliper measurements. 3 ) to ([length] x [width] 2 ) / 2, where length is the longest tumor dimension and width is the longest tumor dimension perpendicular to the length.

[0316] 64mm before treatment 3 Mice were randomized into groups (n=10 / group) with a mean tumor volume of 10 μL / g body weight. On the day of treatment, mice were injected intraperitoneally with mbsIgG2a-PD-L1x4-1BB (0.5 mg / kg; injection volume of 10 μL / g body weight; two doses weekly for 3 weeks [2QW x 3]), docetaxel (10 mg / kg; injection volume of 10 μL / g body weight; QW x 3), a combination of mbsIgG2a-PD-L1x4-1BB (0.5 mg / kg; 2QW x 3) and docetaxel (10 mg / kg; two separate injections in an injection volume of 10 μL / g body weight [mbsIgG2a-PD-L1x4-1BB followed by docetaxel 30 minutes later]; QW x 3), or PBS in an injection volume of 10 μL / g body weight (Table 13).

[0317] Mice were monitored daily for clinical signs of disease. After randomization, they were weighed three times a week. When tumor volumes reached 1500 mm 3 Experiments were terminated for individual mice when the body weight exceeded 100 mg / kg / day or when the animals reached a humane endpoint (e.g., when mice showed >20% weight loss, tumor ulceration [>75%], severe clinical signs were observed, and / or tumor growth prevented the mice from physical activity).

[0318] Table 13: Treatment groups and dosing regimens TIFF2023551980000022.tif84164 a 2QW x 3: 2 doses per week for 3 weeks

[0319] result Rapid tumor growth was observed in MC38-bearing mice treated with PBS (Figure 7A). Tumor growth in mice treated with docetaxel (10 mg / kg; QW × 3) or mbsIgG2a-PD-L1x4-1BB (0.5 mg / kg; 2 QW × 3) was comparable to that in the PBS-treated group (Figure 7A). However, tumor growth was delayed in mice treated with the combination of mbsIgG2a-PD-L1x4-1BB (0.5 mg / kg; 2 QW × 3) and docetaxel (10 mg / kg; QW × 3) (Figure 7A). Kaplan-Meier analysis showed that treatment with the combination of mbsIgG2a-PD-L1x4-1BB and docetaxel significantly reduced tumor volume above 500 mm compared with the PBS treatment group (p<0.01) and compared with mbsIgG2a-PD-L1x4-1BB or docetaxel alone (p<0.05; Mantel-Cox; Figure 7B, Table 14). 3 The combination of docetaxel and mbsIgG2a-PD-L1x4-1BB induced a significant prolongation of progression-free survival, defined as the percentage of mice with smaller tumors. These findings are therefore consistent with enhanced antitumor activity of the combination of docetaxel and mbsIgG2a-PD-L1x4-1BB. Furthermore, the combination treatment was well tolerated, as no significant weight loss was observed.

[0320] Table 14. Mantel-Cox analysis of progression-free survival induced by mbsIgG2a-PD-L1x4-1BB, docetaxel (either alone or in combination) in the MC38 model in C57BL / 6 mice. TIFF2023551980000023.tif93161 1 <500mm 3 A tumor volume of 500 mm was used as the cutoff for progression-free survival. Mantel-Cox analysis was performed to determine whether all animals had a tumor volume of 500 mm. 3 This was performed after the tumor volume had progressed to more than 100 mg / kg.

[0321] These results provide a rationale for evaluating the combination of GEN1046 and docetaxel in cancer patients to enhance antitumor efficacy and enhance survival.

[0322] Example 9: Combination with docetaxel In the dose-escalation portion of this study, no MTD was determined, and doses up to 1200 mg Q3W were safely administered. Dose determination was based on the completeness of available clinical efficacy and safety data, as well as the magnitude and consistency of immunomodulation and PK / PD model predictions of PD endpoints. Initial safety data indicated that the occurrence of the most frequent adverse events, e.g., ALT / AST elevation, was not dose-dependent, and therefore, a lower starting dose of GEN1046 was not required for safety reasons. Preliminary efficacy was observed at doses of 80 to 200 mg Q3W (Example 6). Clinical pharmacokinetic endpoints indicated that at dose levels ≦200 mg Q3W, there was a significant increase in proliferation (Ki67 + ) Effector Memory CD8 + Consistent modulation of T cell and circulating levels of IFNγ was found. These results were consistent with predicted optimal trimer formation and average receptor occupancy for PD-L1 blockade in tumors, observed at doses ranging from 80 to 140 mg Q3W using mechanistic modeling. The most frequent adverse event reported in patients receiving GEN1046 was transaminase elevation, followed by hyperthyroidism, fatigue, nausea, asthenia, and neutropenia. 75 mg / m 2 Mild or moderate transaminase increases have been reported in patients with NSCLC receiving docetaxel, but these are not common side effects. Other common docetaxel side effects overlap with those seen with GEN1046 and include fatigue, nausea, asthenia, and decreased neutrophil counts. However, these events are less common with GEN1046 than with docetaxel, and the majority of events are mild or moderate.

[0323] The combination of GEN1046 and docetaxel was initially evaluated in patients with metastatic NSCLC who had progressed on platinum-based chemotherapy and PD-L1 inhibitor therapy. GEN1046 was administered in combination with docetaxel (Taxotere®) via IV infusion on day 1 of each 3-week treatment cycle until disease progression or until one of the predefined treatment criteria was met. The docetaxel infusion began at least 30 minutes after GEN1046 administration. The GEN1046 dose was fixed at 100 mg based on the limited potential for additive toxicity from the combination and the apparent lack of dose-dependent association of GEN1046 with adverse events and efficacy. The GEN1046 dose was fixed at 55 mg / m depending on the number of previously observed dose-limiting toxicities. 2 or 75 mg / m 2 Docetaxel was administered at a dose of 75 mg / m. 2 The GEN1046 dose of 100 mg 1Q3W used in the combination treatment was the recommended phase 2 dose (RP2D) determined in the dose escalation portion of the study.

[0324] The following inclusion criteria were applied to the combination group (NSCLC): GEN1046 plus docetaxel. ●Subjects with NSCLC of any histology may be enrolled. Subjects with a histological or cytological diagnosis of non-squamous NSCLC must be free of EGFR-sensitizing mutations and / or ALK translocations / ROS1 rearrangements. EGFR-sensitizing mutations are those amenable to treatment with approved TKIs. Documentation of EGFR and ALK status must be available per local assessment. If documentation of EGFR and ALK status is not available, sponsor medical monitor approval is required prior to enrollment. ● The subject has progressed during / after treatment with anti-PD1 / ligand 1 (L1) monoclonal antibody (mAb) administered as monotherapy or in combination. ●Subjects have progressed during / after platinum-doublet chemotherapy for metastatic disease with or without anti-PD1 / ligand 1 (L1) monoclonal antibody mAb.

[0325] Disease progression during / after PD-anti-PD1 / ligand 1 (L1)1 treatment progression is defined by fulfilling the following criteria: - Have received at least two doses of an approved anti-PD-1 / L1 mAb. - Prior evidence of disease progression (PD) during / after anti-PD-1 / L1 as defined by RECIST 1.1.

[0326] Preliminary results: As of November 2021, a total of 12 patients had been enrolled and were receiving GEN1046 and docetaxel: 6 patients received 55 mg / m 2 Docetaxel was administered to six patients at a dose of 75 mg / m 2 Four patients continued treatment: one patient received 55 mg / m 2 Docetaxel was administered at a dose of 75 mg / m in three patients. 2 Docetaxel was administered. A total of eight patients discontinued treatment. The primary reasons for discontinuation were radiographically documented disease progression (five subjects), subject discontinuation due to disease progression per serious adverse event (SAE) reporting (one subject), subject requesting discontinuation of study treatment (one subject), and discontinuation due to respiratory failure due to disease progression (one subject).

[0327] Table 15. Cumulative GEN1046 treatment-related adverse events by grade. A 55 mg / m 2 Docetaxel, B 75 mg / m 2 Docetaxel. A TIFF2023551980000024.tif132158B TIFF2023551980000025.tif182158

[0328] Table 16. Docetaxel treatment-related adverse events by grade. A 55 mg / m 2 Docetaxel, B 75 mg / m 2 Docetaxel. A TIFF2023551980000026.tif117158B TIFF2023551980000027.tif95158

[0329] Toxicities of particular concern: Hepatotoxicity: No drug-related hepatotoxicity was reported for GEN1046 or docetaxel. Myelosuppression: There were no new side effects of neutropenia during the DLT period. There were no significant differences in anemia between dose levels. Immune-related toxicities: None reported for GEN1046.

[0330] There were no dose reductions or discontinuations during the DLT period. Docetaxel was discontinued during one infusion site extravasation (55 mg / m2) event.

[0331] efficacy: Preliminary efficacy data are available for GEN1046 and 75 mg / m 2 The first post-baseline scan in one of the six patients showed a response according to RECIST v1.1 criteria.

[0332] overview: ●Medication was administered to 12 subjects. At either dose level of docetaxel (55 mg / m 2 or 75 mg / m 2 ) but no dose-limiting toxicities were reported. There were no serious adverse events related to GEN1046 during the dose-limiting toxicity period. High dose of 75 mg / m 2 Docetaxel is manageable. There was no immune-related toxicity and the data did not suggest additive or synergistic toxicity. • The combination is manageable and well tolerated. GEN1046 and 75mg / m 2 Preliminary indication of response in subjects dosed with docetaxel.

Claims

1. 1. A method for reducing or preventing tumor progression or treating cancer in a subject, comprising: I) a binding agent comprising a first binding region that binds to human CD137 and a second binding region that binds to human PD-L1; and ii) Taxane chemotherapy agents For use in the method, comprising providing to the subject a combination treatment with The binding agent comprises or said binding agent and said taxane chemotherapeutic agent in combination; Medicine.

2. The pharmaceutical composition of claim 1, wherein the method comprises administering to the subject the binding agent and the taxane chemotherapeutic agent in at least one treatment cycle.

3. a) the first binding region comprises a heavy chain variable region (VH) comprising the CDR1 sequence shown in SEQ ID NO:2, the CDR2 sequence shown in SEQ ID NO:3, and the CDR3 sequence shown in SEQ ID NO:4, and a light chain variable region (VL) comprising the CDR1 sequence shown in SEQ ID NO:6, the CDR2 sequence shown as GAS, and the CDR3 sequence shown in SEQ ID NO:7; b) the second antigen-binding region comprises a heavy chain variable region (VH) comprising the CDR1 sequence shown in SEQ ID NO:9, the CDR2 sequence shown in SEQ ID NO:10, and the CDR3 sequence shown in SEQ ID NO:11, and a light chain variable region (VL) comprising the CDR1 sequence shown in SEQ ID NO:13, the CDR2 sequence shown as DDN, and the CDR3 sequence shown in SEQ ID NO:14; The pharmaceutical composition according to claim 1 or 2.

4. a) the first binding region comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:5; and b) the second binding region comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:8 and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:12; The pharmaceutical composition according to any one of claims 1 to 3.

5. The method of any one of claims 1 to 4, wherein the binding substance is an antibody, a multispecific antibody, for example a bispecific antibody.

6. The method of any one of claims 1 to 5, wherein the binding agent is in the form of a full-length antibody or an antibody fragment.

7. i) a polypeptide comprising, consisting of, or consisting essentially of a first heavy chain variable region (VH) and a first heavy chain constant region (CH) comprising the amino acid sequence set forth in SEQ ID NO:19 or SEQ ID NO:20; and ii) a polypeptide comprising, consisting of, or consisting essentially of a second heavy chain variable region (VH) and a second heavy chain constant region (CH) comprising the amino acid sequence shown in SEQ ID NO:20 or SEQ ID NO:

19. The pharmaceutical composition according to any one of claims 1 to 6, comprising:

8. i) a polypeptide comprising a first light chain variable region (VL) and further comprising a first light chain constant region (CL) comprising the amino acid sequence set forth in SEQ ID NO:21 or SEQ ID NO:22; and ii) a polypeptide comprising a second light chain variable region (VL) and further comprising a second light chain constant region (CL) comprising the amino acid sequence shown in SEQ ID NO:22 or SEQ ID NO:

21. The pharmaceutical composition according to any one of claims 1 to 7, comprising:

9. The pharmaceutical agent according to any one of claims 1 to 8, wherein the antibody is akasunlimab or a biosimilar thereof.

10. The pharmaceutical agent according to any one of claims 1 to 9, wherein the taxane chemotherapeutic agent is selected from the group consisting of docetaxel, paclitaxel, cabazitaxel, and tesetaxel, preferably the taxane chemotherapeutic agent is docetaxel.

11. The amount of the binding agent administered at each dose and / or in each treatment cycle is a) about 0.3-15 mg / kg body weight or about 25-1200 mg in total; and / or b) Approximately 2.1×10 -9 ~1.2×10 -7 mol / kg body weight or about 1.7 × 10 -7 ~8.1×10 -6 Mol The pharmaceutical composition according to any one of claims 1 to 10,

12. The amount of the binding agent administered at each dose and / or in each treatment cycle is a) about 0.3-10 mg / kg body weight or about 25-800 mg in total; and / or b) Approximately 2.1×10 -9 ~6.8×10 -8 mol / kg body weight or about 1.7 × 10 -7 ~5.4×10 -6 Mol The pharmaceutical composition according to any one of claims 1 to 11,

13. The amount of the binding agent administered at each dose and / or in each treatment cycle is a) about 0.3-5 mg / kg body weight or about 25-400 mg in total; and / or b) Approximately 2.1×10 -9 ~3.4×10 -8 mol / kg body weight or about 1.7 × 10 -7 ~2.7×10 -6 Mol The pharmaceutical composition according to any one of claims 1 to 12,

14. The amount of the binding agent administered at each dose and / or in each treatment cycle is a) about 1.25 mg / kg body weight or about 100 mg in total; and / or b) Approximately 8.5×10 -9 mol / kg body weight or about 6.8 × 10 -7 Mol The pharmaceutical composition according to any one of claims 1 to 13,

15. The amount of the taxane chemotherapeutic agent administered at each dose and / or in each treatment cycle is about 10 to 200 mg / m 2 , e.g., 20-40 mg / m 2 , 30–50 mg / m 2 , 40–100 mg / m 2 , 50–100 mg / m 2 , 50–80 mg / m 2 , 50–70 mg / m 2 , 50–60 mg / m 2 , 50–110 mg / m 2 , 60–100 mg / m 2 , 60–100 mg / m 2 , 60–90 mg / m 2 , 70–80 mg / m 2 , 80–200 mg / m 2 , 90–180 mg / m 2 , 90–110 mg / m 2 , 100–175 mg / m 2 , or, for example, about 170-180 mg / m 2 The pharmaceutical agent according to any one of claims 1 to 14,

16. The taxane chemotherapeutic agent is docetaxel, and the amount administered at each dose and / or in each treatment cycle is about 50-60 mg / m 2 , for example about 55 mg / m 2 or the amount administered in each dose and / or in each treatment cycle is about 70-80 mg / m 2 , such as about 75 mg / m 2 .

17. A pharmaceutical according to any one of claims 1 to 16, wherein in the method, the binding substance and / or the taxane chemotherapeutic agent are administered by systemic administration, preferably by intravenous injection or infusion.

18. The method according to any one of claims 1 to 17, wherein in each treatment cycle at least one dose of said binding agent and at least one dose of a taxane chemotherapeutic agent are administered, preferably each treatment cycle being of 3 weeks (21 days).

19. The pharmaceutical composition of any one of claims 1 to 18, wherein in said method, said binding agent and said taxane chemotherapeutic agent are administered on the same day.

20. A pharmaceutical agent described in any one of claims 1 to 19, wherein in the method, each dose of the binding agent is infused over a period of at least 30 minutes, such as at least 60 minutes, at least 90 minutes, at least 120 minutes or at least 240 minutes, and preferably administration of the binding agent is at least 30 minutes, such as at least 1 hour or such as at least 2 hours, prior to administration of the taxane chemotherapeutic agent.

21. The method of claim 20, wherein one dose of the binding agent is administered every three weeks (1Q3W), e.g., on day 1 of each three-week treatment cycle, and / or one dose of the taxane chemotherapeutic agent is administered every three weeks (1Q3W), e.g., on day 1 of each three-week treatment cycle. The pharmaceutical composition according to any one of claims 1 to 20.

22. A pharmaceutical agent described in any one of claims 1 to 21, in which the method comprises administering each dose of taxane chemotherapy agent prior to steroid premedication, e.g., premedication with an oral corticosteroid, e.g., about 8 mg of dexamethasone twice daily for three days starting one day prior to administration of the taxane chemotherapy agent.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the subject is a human subject.

24. the tumor or cancer is a solid tumor; Preferably, the tumor or cancer is selected from the group consisting of melanoma, ovarian cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), colorectal cancer, head and neck cancer, gastric cancer, breast cancer, kidney cancer, urothelial cancer, bladder cancer, esophageal cancer, pancreatic cancer, liver cancer, thymoma and thymic cancer, brain cancer, glioma, adrenal cortical carcinoma, thyroid cancer, other skin cancers, sarcoma, multiple myeloma, leukemia, lymphoma, myelodysplastic syndrome, ovarian cancer, endometrial cancer, prostate cancer, penile cancer, cervical cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Merkel cell carcinoma, and mesothelioma; More preferably, the tumor or cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (NSCLC)), urothelial carcinoma (cancer of the bladder, ureter, urethra, or renal pelvis), endometrial carcinoma (EC), breast cancer (e.g., triple-negative breast cancer (TNBC)), squamous cell carcinoma of the head and neck (SCCHN) (e.g., cancer of the oral cavity, pharynx, or larynx), and cervical cancer. The pharmaceutical composition according to any one of claims 1 to 23.

25. The method of any one of claims 1 to 24, wherein the tumor or cancer is lung cancer, preferably non-small cell lung cancer (NSCLC), such as squamous or non-squamous NSCLC.

26. The pharmaceutical agent of claim 25, wherein the NSCLC does not have an epidermal growth factor receptor (EGFR) sensitivity increasing mutation and / or an anaplastic lymphoma karyogram (ALK) translocation / ROS1 rearrangement.

27. The pharmaceutical agent of claim 25 or 26, wherein the subject has received up to four systemic conditioning regimens for progressive / metastatic disease and has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

28. the subject has received platinum-based chemotherapy, or The subject is ineligible for platinum-based therapy and has been treated with an alternative chemotherapy, e.g., a gemcitabine-containing regimen. The pharmaceutical composition according to claim 27.

29. The pharmaceutical agent of any one of claims 1 to 28, wherein the subject has undergone prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor, and preferably the subject has experienced disease progression during or after treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor.

30. The method of any one of claims 27 to 29, wherein the subject has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

31. The pharmaceutical agent of any one of claims 1 to 28, wherein the subject has not been previously treated with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor.

32. the tumor or cancer is endometrial cancer; Preferably, the subject is Epithelial endometrial histology, including endometrioid carcinoma, serous carcinoma, squamous cell carcinoma, clear cell carcinoma, or carcinosarcoma having The pharmaceutical composition according to any one of claims 1 to 24.

33. The pharmaceutical agent of claim 32, wherein the subject has received up to four systemic conditioning regimens for progressive / metastatic disease and has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

34. The pharmaceutical agent of claim 32 or 33, wherein the subject has not been previously treated with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor.

35. The pharmaceutical agent of any one of claims 1 to 24, wherein the tumor or cancer is urothelial cancer, including cancer of the bladder, ureter, urethra, or renal pelvis.

36. The pharmaceutical agent of claim 35, wherein the subject has received up to four systemic conditioning regimens for progressive / metastatic disease and has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

37. The pharmaceutical agent of claim 35 or 36, wherein the subject has been pre-treated with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor.

38. the subject has received platinum-based chemotherapy, or The subject is ineligible for platinum-based therapy and has been treated with an alternative chemotherapy, e.g., a gemcitabine-containing regimen. The pharmaceutical composition according to claim 35 or 36.

39. The pharmaceutical agent of any one of claims 1 to 24, wherein the tumor or cancer is breast cancer, such as triple-negative breast cancer (TNBC).

40. The subject has received at least one systemic conditioning regimen for locally advanced / metastatic disease, e.g., at least one systemic conditioning regimen including an anthracycline-containing, taxane-containing, antimetabolite-containing, or microtubule inhibitor-containing regimen; Preferably, the subject is Up to four systemic conditioning regimens for locally advanced / metastatic disease, including at least one systemic conditioning regimen containing an anthracycline-containing, taxane-containing, antimetabolite-containing, or microtubule inhibitor-containing regimen I have received The pharmaceutical composition of claim 39.

41. The pharmaceutical of claim 39 or 40, wherein the subject has undergone pre-treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor, and preferably the subject has experienced disease progression, e.g., radiographically confirmed disease progression, during or after said pre-treatment with a checkpoint inhibitor.

42. The pharmaceutical agent of claim 39 or 40, wherein the subject has not been previously treated with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor.

43. The pharmaceutical agent of any one of claims 1 to 24, wherein the tumor or cancer is a head and neck cancer, for example, squamous cell carcinoma of the head and neck (SCCHN), preferably, the tumor or cancer is recurrent or metastatic SCCHN.

44. The pharmaceutical agent of claim 43, wherein the subject has received up to four systemic conditioning regimens for recurrent / metastatic disease and has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment.

45. the subject has received platinum-based chemotherapy, or The subject is ineligible for platinum-based therapy and is receiving an alternative chemotherapy. The medicament according to claim 43.

46. The pharmaceutical agent of any one of claims 43 to 45, wherein the subject has undergone pre-treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor, and preferably the subject has experienced disease progression, e.g., radiographically confirmed disease progression, during or after said pre-treatment with a checkpoint inhibitor.

47. The pharmaceutical agent of any one of claims 43 to 45, wherein the subject has not received prior treatment with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor.

48. The pharmaceutical agent according to any one of claims 1 to 24, wherein the tumor or cancer is cervical cancer, preferably the cervical cancer is cervical cancer of squamous cell, adenocarcinoma, or adenosquamous histology.

49. the subject has received at least one systemic conditioning regimen for recurrent / metastatic disease, e.g., chemotherapy in combination with a treatment targeting vascular endothelial growth factor A, e.g., chemotherapy in combination with a treatment with bevacizumab, and has experienced disease progression, e.g., radiographically confirmed disease progression, during or after the last systemic conditioning treatment; Preferably, the subject is Up to four systemic conditioning regimens for recurrent / metastatic disease, including chemotherapy in combination with a vascular endothelial growth factor A-targeted treatment, e.g., chemotherapy in combination with a treatment with bevacizumab I have received The pharmaceutical composition of claim 48.

50. The pharmaceutical agent of claim 48 or 49, wherein the subject has not been previously treated with a checkpoint inhibitor, e.g., an agent that targets PD-1 / PD-L, e.g., a PD-1 / PD-L1 inhibitor.

51. A composition comprising a taxane chemotherapeutic agent and a binding agent comprising a first binding region that binds to human CD137 and a second binding region that binds to human PD-L1.

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