Method for treating solid tumor

Abstract

CD73 catalyzes the formation of extracellular adenosine, which promotes an immunosuppressive tumor environment. CD73 is overexpressed in stromal cells and various types of tumor cells. A method of treating a solid tumor is provided. In particular, a method is provided for treating solid tumors, such as advanced solid tumors, by using an anti-CD73 antibody or antigen-binding fragment thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 346,195, filed on May 26, 2022, under 35 U.S.C. §119(e), the contents of which are incorporated by reference in their entirety into the disclosure of this application. Technical Field

[0002] The present application relates to a method for treating solid tumors. In particular, a method for treating solid tumors (e.g., advanced solid tumors) by using an anti-CD73 antibody or an antigen-binding fragment thereof is provided. Background Art

[0003] CD73, cluster of differentiation 73, also known as 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase, is an enzyme used to convert AMP to adenosine. CD73 catalyzes the formation of extracellular adenosine, which contributes to the immunosuppressive tumor environment. CD73 is overexpressed in stromal cells and multiple types of tumor cells, as well as Treg, M2 and myeloid-derived suppressor cells (MDSC).

[0004] Preclinical evidence shows that CD73 inhibition prevents adenosine-mediated lymphocyte suppression, enhances the activity of CD8+ effector cells, and reduces both MDSCs and Tregs. Several anti-CD73 antibodies are being developed as potential anticancer drugs, but none has been approved for clinical use. Summary of the invention

[0001] This application meets clinical treatment needs by using CD73 antibodies.

[0002] In one aspect, the present application provides a method for treating solid tumors, comprising administering a CD73 antibody or an antigen-binding fragment thereof to a subject in need thereof at a dose of about 2 to about 50 mg / kg body weight. In one aspect, the present application provides a method for treating solid tumors, comprising administering a CD73 antibody or an antigen-binding fragment thereof to a subject in need thereof at a dose of about 2 to about 20 mg / kg body weight.

[0003] In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 40 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 40 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 35 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 15 to about 35 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 15 to about 30 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 20 to about 30 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 15 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 10 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 10 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 5 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 20 mg / kg body weight.

[0004] In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), or once a month. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject once every three weeks (Q3W). In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of 20 mg / kg or 30 mg / kg, once every three weeks (Q3W).

[0005] In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered intravenously to the subject.

[0006] In some embodiments, the CD73 antibody or antigen-binding fragment thereof is selected from the group consisting of a full-length antibody, Fab, Fab', F(ab')2, scFv, and sdAb. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is a full-length antibody.

[0007] In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 in the heavy chain variable region (VH) as shown in SEQ ID NO: 1, wherein CDR1, CDR2, and CDR3 are according to the Kabat numbering scheme. In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises: (1) HCDR1 comprising the amino acid sequence as shown in SEQ ID NO: 3 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 3; (2) HCDR2 comprising the amino acid sequence as shown in SEQ ID NO: 4 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 4; and (3) HCDR3 comprising the amino acid sequence as shown in SEQ ID NO: 5 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 5. In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence as shown in SEQ ID NO:1, or an amino acid sequence having at least 90% identity to SEQ ID NO:1.

[0008] In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises LCDR1, LCDR2, and LCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 in the light chain variable region (VL) as shown in SEQ ID NO:2, wherein CDR1, CDR2, and CDR3 are according to the Kabat numbering scheme. In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises: (1) LCDR1 comprising the amino acid sequence as shown in SEQ ID NO:6 or an amino acid sequence having one or more substitutions compared to SEQ ID NO:6; (2) LCDR2 comprising the amino acid sequence as shown in SEQ ID NO:7 or an amino acid sequence having one or more substitutions compared to SEQ ID NO:7; and (3) LCDR3 comprising the amino acid sequence as shown in SEQ ID NO:8 or an amino acid sequence having one or more substitutions compared to SEQ ID NO:8. In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) comprising the amino acid sequence as shown in SEQ ID NO:2, or an amino acid sequence that is at least 90% identical to SEQ ID NO:2.

[0009] In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises: (1) HCDR1, HCDR2 and HCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2 and CDR3 in the heavy chain variable region (VH) as shown in SEQ ID NO:1, and (2) LCDR1, LCR2 and LCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2 and CDR3 in the light chain variable region (VL) as shown in SEQ ID NO:2, wherein CDR1, CDR2 and CDR3 are according to the Kabat numbering scheme. In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises: (1) HCDR1 comprising the amino acid sequence as shown in SEQ ID NO:3, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:3; (2) HCDR2 comprising the amino acid sequence as shown in SEQ ID NO:4, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:4; (3) HCDR3 comprising the amino acid sequence as shown in SEQ ID NO:5, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:5; (4) LCDR1 comprising the amino acid sequence as shown in SEQ ID NO:6, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:6; (5) LCDR2 comprising the amino acid sequence as shown in SEQ ID NO:7, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:7; and (6) LCDR3 comprising the amino acid sequence as shown in SEQ ID NO:8, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:8.

[0010] In some embodiments, the CD73 antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence as shown in SEQ ID NO:1, or an amino acid sequence that is at least 90% identical to SEQ ID NO:1, and (2) a light chain variable region (VL) comprising an amino acid sequence as shown in SEQ ID NO:2, or an amino acid sequence that is at least 90% identical to SEQ ID NO:2.

[0011] In some embodiments, the CD73 antibody or antigen-binding fragment thereof is selected from the group consisting of uliledlimab (I-Mab Biopharma), oleclumab (AstraZeneca), CPI-006 (Corvus Pharma), BMS-986179 (Bristol-Myers Squibb), AB-680 (Arcus Biosciences), NZV-930 (SRF373, Surface Oncolohgy / Novartis), JAB-BX102 (Jacobio), AK119 (Akesobio), Sym024 (Symphogen), IBI 325 (Innovent), BR 101 (Hisun BioRay), and LY3475070 (Eli Lilly).

[0012] In some embodiments, the solid tumor is selected from the group consisting of acute lymphoblastic leukemia, multiple myeloma, glioma, mesothelioma, ovarian cancer, sarcoma, cervical cancer, bladder cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymphoma, melanoma, Skin cancer (basal cell carcinoma), pancreatic cancer, prostate cancer, uterine cancer and thyroid cancer. In some embodiments, lung cancer includes non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In some embodiments, the solid tumor is an advanced solid tumor. In some embodiments, the solid tumor is a metastatic solid tumor. In some embodiments, the solid tumor is a recurrent solid tumor. In certain embodiments, the solid tumor is a refractory solid tumor. In some embodiments, the solid tumor is in phase III or IV. In some embodiments, the method further comprises administering a PD-L1 antagonist to the subject.

[0013] In some embodiments, the CD73 antibody or antigen-binding fragment thereof and the PD-L1 antagonist are administered simultaneously. In some embodiments, the CD73 antibody or antigen-binding fragment thereof and the PD-L1 antagonist are administered separately.

[0014] In some embodiments, the PD-L1 antagonist is a PD-L1 antibody. In some embodiments, the PD-L1 antibody is selected from the group consisting of atezolizumab, manelimab, avelumab, cosibelimab, durvalumab, envafolimab, socazolimab, BGB-A333, CK-301, CS-1001, FAZ-053, APL-502, MDX-1105, IMC-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12 and KY-1003. In some embodiments, the PD-L1 antibody is atezolizumab. In some embodiments, atezolizumab is administered to a subject at a fixed dose of 1200 mg once every three weeks (Q3W).

[0015] In another aspect, the present application provides a use of a CD73 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a solid tumor in a subject in need thereof, wherein the medicament is administered to the subject at a dose of about 2 to about 20 mg / kg body weight.

[0016] In another aspect, the present application provides an article of manufacture comprising: (1) a CD73 antibody or an antigen-binding fragment thereof, and (2) a package insert suggesting administration of the CD73 antibody or an antigen-binding fragment thereof to a subject in need thereof at a dose of about 2 to about 20 mg / kg body weight.

[0017] It should be understood that one, some or all of the various embodiments described herein may be combined to form other embodiments of the present disclosure. For those skilled in the art, these and other aspects of the present disclosure are apparent. The following detailed description will further describe these and other embodiments of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 demonstrated that uliledlimab adopts a unique intradimer binding mode via the C-terminus of CD73, such as The cryo-EM structure (top) of uliledlimab Fab in complex with CD73 dimer (shown in the bottom).

[0019] Figure 2 Shown is the dose response of uliledlimab or oleclumab on inhibition of soluble CD73 enzymatic activity as measured by Cell Titer Gloassay.

[0020] Figure 3 The clinical study design is presented.

[0021] Figure 4 Serum PK of uliledlimab after single and multiple doses is presented (mean ± SD).

[0022] Figure 5 Uliledlimab administered QW or Q3W demonstrated a sustained decrease in free soluble CD73 (mean ± SD).

[0023] Figure 6 Saturated CD73 target occupancy on peripheral B cells is shown (mean ± SD).

[0024] Figure 7 The duration of treatment for Uliledlimab and exemplary PD-L1 antibody combination therapy is shown.

[0025] Figure 8 The best change from baseline is demonstrated for the uliledlimab and exemplary PD-L1 antibody combination therapy.

[0026] Fig. 9 Demonstrated a confirmed PR in anti-PD-L1 refractory NSCLC.

[0027] Fig.10 CD73, A2AR, and PD-L1 staining of baseline archival tumor tissue is shown. DETAILED DESCRIPTION definition

[0028] Before describing the embodiments in detail, it should be understood that the present disclosure is not limited to specific compositions or biological systems, which, of course, can vary. It should also be understood that the terms used in the present application are only for the purpose of describing specific embodiments and are not intended to be restrictive.

[0029] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the content clearly dictates otherwise. Thus, for example, reference to "a molecule" may optionally include a combination of two or more such molecules, and so forth.

[0030] The term "about" used in this application refers to the usual error range of each numerical value known to those skilled in the art. "About" a value or parameter mentioned in this application includes (and describes) embodiments for the value or parameter itself.

[0031] It should be understood that various aspects and embodiments of the present disclosure include "comprising / including" various aspects and embodiments, "consisting of various aspects and embodiments", and "consisting essentially of various aspects and embodiments.

[0032] As used herein, the term "antibody" is used in the broadest sense and specifically covers intact antibodies (such as full-length antibodies), antibody fragments (including but not limited to Fab, F(ab')2, scFv, scFv-Fc, single domain antibodies, single heavy chain antibodies and single light chain antibodies), monoclonal antibodies and polyclonal antibodies, so long as they exhibit the desired biological activity (such as epitope binding).

[0033] As used herein, the term "isolated" antibody may refer to an antibody that is substantially free of other cellular material. In one embodiment, an isolated antibody is substantially free of other proteins from the same species. In another embodiment, an isolated antibody is expressed by cells from a different species and is substantially free of other proteins from the different species. In some embodiments, an "isolated" antibody refers to an antibody that has been identified and separated and / or recovered from components of its natural environment, wherein contaminating components of its natural environment refer to substances that interfere with the diagnostic or therapeutic use of the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. The antibody may be isolated using protein purification techniques well known in the art such that the antibody is substantially free of naturally associated components (or components associated with the cellular expression system used to produce the antibody). In some embodiments, the antibody will be purified: (1) greater than 75% by weight of the antibody as determined by the Lowry method, and most preferably greater than 80%, 90%, 95%, or 99% by weight; or (2) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.

[0034] As used in this application, the terms "natural antibodies and immunoglobulins" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains (L) and two identical heavy chains (H). Each light chain is connected to the heavy chain by one covalent disulfide bond (also called a "VH / VL pair"), while the number of disulfide bonds between the heavy chains of different immunoglobulin isotypes varies. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at one end, followed by a number of constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the variable domain of the light chain is aligned with the variable domain of the heavy chain. It is believed that specific amino acid residues form an interface between the light chain and heavy chain variable domains. See, for example, Chothia et al., J. Mol. Biol., 186:651 (1985); Novotny and Haber, Proc. Natl. Acad. Sci. USA, 82:4592 (1985).

[0035] As used herein, the term "variable" refers to the fact that some parts of the variable domains have great differences in sequence between antibodies and are used for the binding and specificity of each specific antibody to its specific antigen. However, variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called complementary determining regions (CDRs) or hypervariable regions in both the light chain and heavy chain variable domains. The more conservative part of the variable domain is called framework (FR). The variable domains of natural heavy and light chains each contain four FR regions, most of which adopt a β sheet structure, connected by three CDRs, which form a loop connecting the β sheet structure, and in some cases constitute a part of the β sheet structure. The CDRs on each chain are kept together in close proximity by the FR region, and together with the CDRs on the other chain, contribute to the formation of the antigen binding site of the antibody. For example, see Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Maryland, (1991). The constant domains are not directly involved in the binding of an antibody to an antigen, but exhibit various effector functions, such as participation in antibody-dependent cellular cytotoxicity. Variable region sequences of interest include humanized variable region sequences of CD47 antibodies described in detail elsewhere in this application.

[0036] The term "hypervariable region (HVR)" or "complementarity determining region (CDR)" may refer to a subdomain of a VH and VL domain characterized by enhanced sequence variability and / or forming defined loops. These include three CDRs (H1, H2, and H3) in the VH domain and three CDRs (L1, L2, and L3) in the VL domain. H3 is considered to be key to conferring good binding specificity, while L3 and H3 show the highest levels of diversity. See Johnson and Wu, in Methods in Molecular Biology 248: 1-25 (Lo ed., Human Press, Totowa, NJ, 2003).

[0037] Many descriptions of CDR / HVR are known. Kabat complementarity determining regions (CDRs) are based on sequence variability and are the most commonly used complementarity determining regions (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, Maryland (1991)). Chothia refers to the position of structural loops (Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987)). AbM HVR represents a compromise between Kabat HVR and Chothia structural loops and is adopted by Oxford Molecular's AbM antibody modeling software. "Contact" HVRs are based on analysis of existing complex crystal structures. The residues of each of these HVR / CDRs are recorded as follows: "framework" or "FR" residues refer to those variable domain residues other than HVR / CDR residues.

[0038] Also known are "extended" HVRs: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL, 26-35 (H1), 50-65 or 49-65 (H2), and 93-102, 94-102 or 95-102 (H3) in VH (Kabat numbering).

[0039] "Numbering according to Kabat" may refer to the numbering system used for the heavy chain variable domain or light chain variable domain compiled by Kabat et al. above. The actual linear amino acid sequence may contain fewer or additional amino acids, corresponding to the shortening of the FR or HVR of the variable domain or the insertion of the FR or HVR of the variable domain. The Kabat numbering of the residues of a given antibody can be determined by comparing the homologous region of the antibody sequence with the "standard" Kabat numbering sequence. Typically, when referring to the residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain), Kabat numbering is used, and when referring to the residues in the heavy chain constant region, the EU numbering system or index (such as the EU index in Kabat, according to the numbering of EU IgG1) is generally used.

[0040] As used herein, the term "antibody fragment" and all grammatical variants thereof are defined as a portion of an intact antibody that contains the antigen binding site or variable region of the intact antibody and, in some cases, does not contain the constant heavy chain domains (i.e., CH2, CH3, and / or CH4, depending on the antibody isotype) of the Fc region of the intact antibody. Examples of antibody fragments include Fab, Fab', Fab'-SH, F(ab')2, and Fv fragments; diabodies; any antibody fragment of a polypeptide having a primary structure consisting of an uninterrupted sequence of continuous amino acid residues (referred to herein as a "single-chain antibody fragment" or "single-chain polypeptide"), including but not limited to (1) single-chain Fv (scFv) molecules, (2) a single-chain polypeptide containing only one light chain variable domain or a fragment thereof containing the three CDRs of the light chain variable domain without the associated heavy chain portion, and (3) a single-chain polypeptide containing only one heavy chain variable region or a fragment thereof containing the three CDRs of the heavy chain variable region without the associated light chain portion; and multispecific or multivalent structures formed by antibody fragments. In antibody fragments comprising one or more heavy chains, the heavy chain may comprise any constant domain sequence found in the non-Fc region of an intact antibody (such as CH1 in IgG isotypes), and / or may comprise any hinge region sequence found in an intact antibody, and / or may comprise a leucine zipper sequence fused to or located within a hinge region sequence or a constant domain sequence of a heavy chain.

[0041] The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. The Fab' fragment differs from the Fab fragment by the addition of several residues to the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines in the antibody hinge region. Fab'-SH herein refers to Fab' in which the cysteine ​​residues of the constant domains carry free thiol groups. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0042] As used herein, the term "monoclonal antibody" (mAb) refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies constituting the population are identical except for a small amount of possible naturally occurring mutations. Monoclonal antibodies are highly specific and are directed only to a single antigenic site. Each mAb is directed to a single determinant on the antigen. In addition to its specificity, the advantage of monoclonal antibodies is that they can be synthesized by hybridoma culture without being contaminated by other immunoglobulins. The modifier "monoclonal" indicates that the characteristic of the antibody is obtained from a substantially homogeneous antibody population, and should not be construed as requiring the production of antibodies by any particular method. For example, the monoclonal antibodies used according to the disclosure of the present application can be made in immortalized B cells or their hybridomas, or can also be made by DNA recombination methods.

[0043] The monoclonal antibodies in the present application include hybrid antibodies and recombinant antibodies produced by splicing the variable (including hypervariable) domains of CD47 antibodies with constant domains (e.g., "humanized" antibodies), or splicing light chains with heavy chains, or splicing chains from one species with chains from another species, or fusion with heterologous proteins, regardless of their species of origin or immunoglobulin class or subclass designations, as well as antibody fragments (e.g., Fab, F(ab')2, and Fv), as long as they exhibit the desired biological activity.

[0044] The monoclonal antibodies in the present application specifically include chimeric antibodies (immunoglobulins) in which a portion of the heavy chain and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they exhibit the desired biological activity.

[0045] As used in this application, the term "treatment" refers to a clinical intervention intended to change the natural course of the treated individual or cell in the clinical pathological process. The ideal therapeutic effect includes reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. For example, if one or more symptoms related to cancer are alleviated or eliminated, including but not limited to reducing the proliferation of cancer cells (or eliminating cancer cells), reducing the symptoms caused by the disease, improving the quality of life of individuals with the disease, reducing the dosage of other drugs required for treating the disease, and / or extending the survival period of the individual, then the individual has successfully obtained "treatment". In some embodiments, "treating" a disease (such as cancer) refers to delaying the development of the disease, that is, postponing, hindering, slowing down, delaying, stabilizing and / or delaying the development of a disease (such as cancer). This delay time varies in length, depending on the disease and / or the medical history of the individual being treated. As is apparent to those skilled in the art, sufficient or significant delays can actually include prevention, which is that the individual will not have disease development, for example, advanced cancer (such as metastasis) may be postponed.

[0046] As used herein, the term "subject" for purposes of treatment refers to any animal classified as a mammal, including humans, livestock and farm animals, and zoo, sport or pet animals, such as dogs.

[0005] As used herein, the term "advanced solid tumor" refers to a solid tumor that cannot be cured or grows beyond the original site of origin, whether locally advanced or metastatic. In some embodiments, advanced solid tumors include but are not limited to solid tumors in stage III or stage IV.

[0006] As used herein, the term "metastatic" or "metastasis" refers to the spread of a tumor from its initial or primary site to different or secondary sites in a subject's body. It is generally distinguished from cancer invasion, which refers to the direct spread and infiltration of cancer cells into adjacent tissues.

[0007] As used herein, the term "refractory" refers to a disorder, disease or condition that has not responded to prior treatment, which may include one or more lines of therapy. CD73 Antibody

[0008] CD73, cluster of differentiation 73, also known as 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase, is an enzyme used to convert AMP to adenosine. CD73 catalyzes the formation of extracellular adenosine, which contributes to the immunosuppressive tumor environment. CD73 is overexpressed in stromal cells and multiple types of tumor cells, as well as Treg, M2 and myeloid-derived suppressor cells (MDSC).

[0047] Any CD73 antibody known in the art can be used in the present application. In some embodiments, the CD73 antibody is selected from the group consisting of a full-length antibody, Fab, Fab', F(ab')2, scFv, and sdAb. In some embodiments, the CD73 antibody is a full-length antibody.

[0048] In some embodiments, the CD73 antibody comprises HCDR1, HCDR2, and HCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 in the heavy chain variable region (VH) as shown in SEQ ID NO: 1, wherein CDR1, CDR2, and CDR3 are according to the Kabat numbering scheme. In some embodiments, the CD73 antibody comprises: (1) HCDR1 comprising the amino acid sequence as shown in SEQ ID NO: 3 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 3; (2) HCDR2 comprising the amino acid sequence as shown in SEQ ID NO: 4 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 4; and (3) HCDR3 comprising the amino acid sequence as shown in SEQ ID NO: 5 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 5.

[0049] In some embodiments, the CD73 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as shown in SEQ ID NO:1, or an amino acid sequence that is at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:1.

[0050] In some embodiments, the CD73 antibody comprises LCDR1, LCR2, and LCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 in the light chain variable region (VL) shown in SEQ ID NO:2, wherein CDR1, CDR2, and CDR3 are according to the Kabat numbering scheme. In some embodiments, the CD73 antibody comprises: (1) LCDR1 comprising the amino acid sequence as shown in SEQ ID NO:6 or an amino acid sequence having one or more substitutions compared to SEQ ID NO:6; (2) LCDR2 comprising the amino acid sequence as shown in SEQ ID NO:7 or an amino acid sequence having one or more substitutions compared to SEQ ID NO:7; and (3) LCDR3 comprising the amino acid sequence as shown in SEQ ID NO:8 or an amino acid sequence having one or more substitutions compared to SEQ ID NO:8.

[0051] In some embodiments, the CD73 antibody comprises a light chain variable region (VL) comprising an amino acid sequence as shown in SEQ ID NO:2, or an amino acid sequence that is at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2.

[0052] In some embodiments, the CD73 antibody comprises: (1) HCDR1, HCDR2 and HCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2 and CDR3 in the heavy chain variable region (VH) as shown in SEQ ID NO:1, and (2) LCDR1, LCR2 and LCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2 and CDR3 in the light chain variable region (VL) as shown in SEQ ID NO:2, wherein CDR1, CDR2 and CDR3 are according to the Kabat numbering scheme. In some embodiments, the CD73 antibody comprises: (1) HCDR1 comprising the amino acid sequence as shown in SEQ ID NO:3, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:3; (2) HCDR2 comprising the amino acid sequence as shown in SEQ ID NO:4, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:4; (3) HCDR3 comprising the amino acid sequence as shown in SEQ ID NO:5, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:5; (4) LCDR1 comprising the amino acid sequence as shown in SEQ ID NO:6, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:6; (5) LCDR2 comprising the amino acid sequence as shown in SEQ ID NO:7, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:7; and (6) LCDR3 comprising the amino acid sequence as shown in SEQ ID NO:8, or an amino acid sequence having one or more substitutions compared to SEQ ID NO:8.

[0053] In some embodiments, the CD73 antibody comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 1, or an amino acid sequence at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1, and (2) a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO:2, or an amino acid sequence at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2.

[0054] In some embodiments, the CD73 antibody is selected from the group consisting of uliledlimab (I-Mab Biopharma), oleclumab (AstraZeneca), CPI-006 (Corvus Pharma), BMS-986179 (Bristol-Myers Squibb), AB-680 (Arcus Biosciences), NZV-930 (SRF373, Surface Oncolohgy / Novartis), JAB-BX102 (Jacobio), AK119 (Akesobio), Sym024 (Symphogen), IBI325 (Innovent), BR101 (Hisun BioRay), and LY3475070 (Eli Lilly). In some embodiments, the CD73 antibody is uliledlimab (I-Mab Biopharma) or oleclumab (AstraZeneca). PD-L1 antagonists

[0009] Any suitable PD-L1 antagonist known in the art may be used in the present application. In some embodiments, the PD-L1 antagonist includes a small molecule inhibitor of PD-L1 signaling. In some embodiments, the PD-L1 antagonist includes an antibody or an antigen-binding fragment thereof, such as a PD-L1 antibody or an antigen-binding fragment thereof.

[0010] Exemplary anti-PD-L1 antibodies that can be used in the methods of the present application include, but are not limited to, polyclonal antibodies, monoclonal antibodies, Fab, scFv, diantibodies, triantibodies, miniantibodies, VHHs, and sdAbs. Exemplary anti-PD-L1 antibodies include, but are not limited to, Manelimab, atezolizumab, avelumab, Cosibelimab, durvalumab, Envafolimab, Socazolimab, BGB-A333, CK-301, CS-1001, FAZ-053, APL-502, MDX-1105, IMC-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12, and KY-1003. In some embodiments, the anti-PD-L1 antibody is atezolizumab. method

[0055] In one aspect, a method of treating a solid tumor is provided, comprising administering a CD73 antibody or an antigen-binding fragment thereof to a subject in need thereof at a dose of about 2 to about 50 mg / kg body weight. In one aspect, a method of treating a solid tumor is provided, comprising administering a CD73 antibody or an antigen-binding fragment thereof to a subject in need thereof at a dose of about 2 to about 20 mg / kg body weight.

[0056] In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 40 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 40 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 35 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 15 to about 35 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 15 to about 30 mg / kg body weight. In some embodiments of the methods of the present application, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 20 to about 30 mg / kg body weight.

[0057] In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 3 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 4 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 5 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 6 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 7 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 8 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 9 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 10 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 11 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 12 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 13 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 14 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 15 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 16 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 17 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 18 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered at a dose of about 19 to about 20 mg / kg body weight.

[0058] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 13 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 12 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 11 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 10 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 9 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 8 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 7 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 6 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 2 to about 5 mg / kg body weight.

[0059] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 13 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 12 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 11 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 10 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 9 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 8 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 7 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 6 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 3 to about 5 mg / kg body weight.

[0060] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 13 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 12 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 11 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 10 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 9 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 8 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 7 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 6 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 4 to about 5 mg / kg body weight.

[0061] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 13 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 12 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 11 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 10 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 9 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 8 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 7 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 5 to about 6 mg / kg body weight.

[0062] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 13 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 12 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 11 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 10 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 9 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 8 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 7 mg / kg body weight.

[0063] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 7 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 7 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 6 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 7 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 7 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 7 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 7 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 7 to about 13 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 7 to about 12 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 7 to about 11 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 7 to about 10 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 7 to about 9 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 7 to about 8 mg / kg body weight.

[0064] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 13 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 12 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 11 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 10 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 8 to about 9 mg / kg body weight.

[0065] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 13 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 12 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 11 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 9 to about 10 mg / kg body weight.

[0066] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 to about 13 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 10 to about 12 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 10 to about 11 mg / kg body weight.

[0067] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 11 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 11 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 11 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 11 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 11 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 11 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 11 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 11 to about 13 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 11 to about 12 mg / kg body weight.

[0068] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 12 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 12 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 12 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 12 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 12 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 12 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 12 to about 14 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 12 to about 13 mg / kg body weight.

[0069] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 13 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 13 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 13 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 13 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 13 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 13 to about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 13 to about 14 mg / kg body weight.

[0070] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 14 to about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 14 to about 19 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 14 to about 18 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 14 to about 17 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 14 to about 16 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 14 to about 15 mg / kg body weight.

[0071] In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 15 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 15 to about 19 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 15 to about 18 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 15 to about 17 mg / kg body weight. In some embodiments, the CD73 antibody or its antigen-binding fragment is administered to the subject at a dose of about 15 to about 16 mg / kg body weight.

[0072] In some embodiments, the CD73 antibody or antigen binding fragment thereof is administered to the subject at a dose of about 16 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or antigen binding fragment thereof is administered to the subject at a dose of about 16 to about 19 mg / kg body weight. In some embodiments, the CD73 antibody or antigen binding fragment thereof is administered to the subject at a dose of about 16 to about 18 mg / kg body weight. In some embodiments, the CD73 antibody or antigen binding fragment thereof is administered to the subject at a dose of about 16 to about 17 mg / kg body weight.

[0073] In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 17 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 17 to about 19 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 17 to about 18 mg / kg body weight.

[0074] In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 18 to about 20 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 18 to about 19 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 19 to about 20 mg / kg body weight.

[0075] In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 15.5, about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 19.5, or about 20 mg / kg body weight. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 22, about 22.5, about 23, about 23.5, about 24, about 24.5, about 25, about 25.5, about 26, about 226.5, about 27, about 27.5, about 28, about 28.5, about 29, about 29.5, about 30, about 30.5, about 31, about 31.5, about 32, about 32.5, about 33, about 33.5, about 34, about 34.5, about 35, about 35.5, about 36, about 36.5, about 37, about 37.5, about 38, about 38.5, about 39, about 39.5, or about 40 mg / kg body weight.

[0076] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 20 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 25 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 30 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 35 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 40 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 15 mg / kg body weight. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of about 10 mg / kg body weight.

[0077] In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to the subject once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), or once a month. In some embodiments, the CD73 antibody or antigen-binding fragment thereof is administered to the subject once every three weeks (Q3W).

[0011] In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of 20 mg / kg once every three weeks (Q3W). In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of 25 mg / kg once every three weeks (Q3W). In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of 30 mg / kg once every three weeks (Q3W). In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of 35 mg / kg once every three weeks (Q3W). In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of 40 mg / kg once every three weeks (Q3W). In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of 15 mg / kg once every three weeks (Q3W). In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered to a subject at a dose of 10 mg / kg once every three weeks (Q3W). In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered intravenously to a subject. In some embodiments, a CD73 antibody or an antigen-binding fragment thereof is administered intravenously to a subject once every three weeks (Q3W) at a dose of 20 mg / kg. In some embodiments, the CD73 antibody is uliledlimab, and uliledlimab is administered intravenously to a subject once every three weeks (Q3W) at a dose of 20 mg / kg. In some embodiments, the CD73 antibody is oleclumab, and oleclumab is administered intravenously to a subject once every three weeks (Q3W) at a dose of 20 mg / kg.

[0012] In some embodiments, the solid tumor is selected from the group consisting of acute lymphoblastic leukemia, multiple myeloma, glioma, mesothelioma, ovarian cancer, sarcoma, cervical cancer, bladder cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymphoma, melanoma, skin cancer (basal cell carcinoma), pancreatic cancer, prostate cancer, uterine cancer and thyroid cancer. In some embodiments, lung cancer includes non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

[0013] In some embodiments, the solid tumor is an advanced solid tumor. In some embodiments, the solid tumor is a metastatic solid tumor. In some embodiments, the solid tumor is a refractory solid tumor. In some embodiments, the solid tumor is in stage III or stage IV.

[0014] In some embodiments, the method further comprises administering a PD-L1 antagonist to the subject.Any suitable PD-L1 antagonist known in the art can be used in the present application.

[0015] In some embodiments, the PD-L1 antagonist is a PD-L1 antibody. In some embodiments, the PD-L1 antagonist is a PD-L1 antibody as described in the present application. In some embodiments, the PD-L1 antibody is selected from the group consisting of atezolizumab, manelimab, avelumab, cosibelimab, durvalumab, envafolimab, socazolimab, BGB-A333, CK-301, CS-1001, FAZ-053, APL-502, MDX-1105, IMC-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12 and KY-1003.

[0016] In some embodiments, the PD-L1 antibody is atezolizumab. In some embodiments, atezolizumab is administered to the subject at a fixed dose of 1200 mg once every three weeks (Q3W).

[0017] In some embodiments, the method comprises administering to the subject intravenously a dose of 20 mg / kg of uliledlimab once every three weeks (Q3W) and a fixed dose of 1200 mg of atezolizumab once every three weeks (Q3W). In some embodiments, the method comprises administering to the subject intravenously a dose of 20 mg / kg of oleclumab once every three weeks (Q3W) and a fixed dose of 1200 mg of atezolizumab once every three weeks (Q3W).

[0018] In some embodiments, the antibody or antigen-binding fragment thereof and the PD-L1 antagonist are administered simultaneously. In some embodiments, the antibody or antigen-binding fragment thereof and the PD-L1 antagonist are administered separately.

[0019] In some embodiments, the method comprises administering to the subject intravenously at a dose of 20 mg / kg of uliledlimab once every three weeks (Q3W) and a fixed dose of 1200 mg of atezolizumab once every three weeks (Q3W). In some embodiments, the method comprises administering to the subject intravenously at a dose of 20 mg / kg of oleclumab once every three weeks (Q3W) and a fixed dose of 1200 mg of atezolizumab once every three weeks (Q3W).

[0020] In another aspect, the present application provides a use of a CD73 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a solid tumor in a subject in need thereof, wherein the medicament is administered to the subject at a dose of about 2 to about 20 mg / kg body weight. Products

[0021] In another aspect, the present application provides an article of manufacture comprising: (1) a CD73 antibody or an antigen-binding fragment thereof, and (2) a package insert suggesting that the CD73 antibody or the antigen-binding fragment thereof be administered to a subject in need thereof at a dose of about 2 to about 20 mg / kg body weight.

[0078] All publications and patent applications cited in this specification are incorporated herein by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Example

[0079] The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of how to make and use the disclosure of the present application, and are not intended to limit the scope of what the inventors regard as their disclosure, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure the accuracy of the numbers used (e.g., quantities, temperatures, etc.), but some experimental errors and deviations should also be taken into account. Unless otherwise indicated, parts are by weight, molecular weights are weight average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure. Example 1. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy of the combination of differentiated CD73 antibody uliledlimab and PD-L1 antibody in patients with advanced cancer

[0080] CD73 has emerged as a promising immuno-oncology target and has been implicated in tumor resistance to checkpoint immunotherapy (CPI). Figure 1), Uliledlimab is a differentiated anti-CD73 antibody that works through the intra-dimer binding mode of the C-terminal domain. Compared with other CD73 antibodies, Uliledlimab can achieve complete inhibition of CD73 activity without a hook effect ( Figure 2 ).

[0081] The current phase 1 clinical trial was designed to evaluate the safety, pharmacokinetic and pharmacodynamic (PK / PD) relationships, and tumor biomarker analyses associated with clinical activity of uliledlimab as monotherapy (3-week run-in) followed by combination therapy with atezolizumab in patients with solid tumors. Study Design

[0082] The trial is an open-label, Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of uliledlimab in subjects with advanced or refractory solid tumors. Figure 3 As shown, this is a 3+3 dose-escalation study: doses of 5, 10, or 15 mg / kg once weekly (QW), or 15 or 20 mg / kg once every 3 weeks (Q3W) were administered intravenously as monotherapy in the first cycle, followed by combination therapy with atezolizumab (1200 mg, Q3W) starting in the second cycle (week 4). result Patient Demographics

[0083] Twenty patients with advanced, relapsed, or refractory solid tumors were enrolled. Their baseline characteristics are shown in Table 1. Table 1. Baseline characteristics Security

[0084] No dose-limiting toxicity (DLT) was observed, and the MTD (maximum tolerated dose) was not reached. All TRAEs were grade 1 or 2 (Table 2). Most IRRs occurred after the first infusion and were all well controlled. Table 2. Treatment-related adverse events (TRAEs) by cohort Note: Grade (GR); All toxicities were graded using CTCAE v5.0, and TRAEs occurring in ≥10% of patients are shown. Any adverse event that indicated an association with an IRR, such as chills, nausea, and vomiting, was considered an IRR and reported separately in this table. Pharmacokinetics

[0022] Uliledlimab showed a linear PK profile at doses ≥10 mg / kg, indicating target saturation. Figure 4 Serum concentrations of uliledlimab after a single dose of monotherapy (left) and two cycles of combination therapy with atezolizumab (right) are shown. The effective half-life was estimated to be 19 days by the population PK model, supporting a Q3W dosing interval. Confirmed ADA positivity in three patients did not appear to have an impact on safety or PK. Pharmacodynamics

[0023] Sustained reductions in free soluble CD73 levels were achieved in all patients treated with uliledlimab, both as monotherapy and in combination with atezolizumab ( Figure 5 ).

[0024] With the QW or Q3W dosing regimen, the occupancy of CD73 receptor on peripheral CD19+ B cells was Full saturation of uliledlimab was achieved throughout the dosing period ( Figure 6 Complete saturation was observed in every dose cohort at or above 10 mg / kg. Efficacy

[0025] Among the 13 efficacy-evaluable patients at a dose of ≥10 mg / kg, complete response (CR=1) and partial response (PR=2) were observed in 3 patients (ORR=23%), and 3 patients had stable disease (SD) (DCR=46%) ( Figure 8 The treatment duration for the 6 patients (CR, PR, and SD) ranged from 187 to 485 days ( Figure 7 ). A PD-(L)1-naive patient with ovarian clear cell carcinoma (OCCC) achieved a CR at 10 mg / kg and maintained it for at least 15 months on the study. Two patients with NSCLC achieved a PR at doses of 15 mg / kg QW and 20 mg / kg Q3W ( Fig. 9 ). One patient had failed nivolumab, and the other had not received prior PD-(L)1 therapy. Biomarker analysis

[0026] The expression levels of CD73, A2AR, and PD-L1 in baseline tumor biopsy specimens from 13 efficacy-evaluable patients who received a dose of ≥10 mg / kg were analyzed ( Fig.10 All 3 patients considered as responders (CR and PR) showed higher co-expression of CD73 (78%) and PD-L1 (mean TPS = 52%) in tumor cells compared with non-responders (CD73 positivity 22% and mean TPS of PD-L1 4%) ( Fig.10 , right). Almost all patients (12 of 13) showed strong and highly prevalent A2AR staining, with no significant difference in expression levels between responders and non-responders.

[0027] Uliledlimab was safe and well tolerated up to 20 mg / kg Q3W and 15 mg / kg QW as monotherapy or in combination with atezolizumab 1200 mg Q3W. No DLTs were observed and the MTD was not reached. Complete saturation of circulating and cell-bound CD73 was achieved at doses ≥10 mg / kg. After a single dose, a linear PK profile was observed at doses ≥10 mg / kg. The PK profile of uliledlimab supports Q3W dosing. In this Phase I study, there was evidence of clinical activity in both PD-(L)1-naïve and PD-(L)1-refractory cancer patients after treatment with uliledlimab and atezolizumab (1 CR, 2 PRs, and 3 SDs). Higher tumor CD73 and PD-L1 co-expression was found in all responders compared with nonresponders, suggesting a potential correlation that warrants further investigation.

[0085] The present technology has been described to include the preferred mode of the present technology practice according to the specific embodiments found or proposed by the inventors. It will be appreciated by those skilled in the art that, according to the disclosure of the present application, a large number of modifications and changes can be made to the specific embodiments of the examples without departing from the expected scope of the present technology. For example, due to codon redundancy, potential DNA sequences can be changed without affecting the protein sequence. In addition, for the consideration of biological function equivalence, the protein structure can be changed without affecting its biological effect in kind or quantity. All these modifications are expected to be included in the scope of the appended claims. Sequence Listing

Claims

1. A method for treating solid tumors, comprising administering a CD73 antibody or an antigen-binding fragment thereof to a subject in need thereof at a dose of about 2 to about 50 mg / kg body weight.

2. The method according to claim 1, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 5 to about 40 mg / kg body weight.

3. The method according to claim 1, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 10 to about 35 mg / kg body weight.

4. The method according to claim 1, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 15 to about 30 mg / kg body weight.

5. The method according to claim 1, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 15 to about 25 mg / kg body weight.

6. The method according to claim 1, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 15 to about 20 mg / kg body weight.

7. The method according to claim 1, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 2, about 5, about 10, about 15, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg or about 35 mg / kg body weight.

8. About 20 mg / kg method, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 20 mg / kg body weight.

9. The method according to any one of claims 1 to 8, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), or once a month.

10. The method according to claim 9, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject once every three weeks (Q3W).

11. The method according to claim 9, in, The CD73 antibody or antigen-binding fragment thereof is administered to the subject at a dose of 20 mg / kg once every three weeks (Q3W), 25 mg / kg once every three weeks (Q3W), or 30 mg / kg once every three weeks (Q3W).

12. The method of any one of claims 1-11, wherein the CD73 antibody or antigen-binding fragment thereof is administered intravenously to the subject.

13. The method according to any one of claims 1-12, wherein the CD73 antibody or antigen-binding fragment thereof is selected from the group consisting of: full-length antibody, Fab, Fab', F(ab')2, scFv and sdAb.

14. The method of claim 13, wherein the CD73 antibody or antigen-binding fragment thereof is a full-length antibody.

15. The method of any one of claims 1-1, wherein the CD73 antibody or antigen-binding fragment thereof comprises: (1) HCDR1, HCDR2 and HCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2 and CDR3 in the heavy chain variable region (VH) as shown in SEQ ID NO: 1, and (2) LCDR1, LCDR2 and LCDR3, which respectively comprise the amino acid sequences of CDR1, CDR2 and CDR3 in the light chain variable region (VL) as shown in SEQ ID NO: 2, CDR1, CDR2 and CDR3 are numbered according to the Kabat scheme.

16. The method of any one of claims 1-15, wherein the CD73 antibody or antigen-binding fragment thereof comprises: (1) HCDR1 comprising the amino acid sequence shown in SEQ ID No: 3, (2) HCDR2 comprising the amino acid sequence shown in SEQ ID No: 4, (3) HCDR3 comprising the amino acid sequence shown in SEQ ID No: 5, (4) LCDR1, comprising the amino acid sequence shown in SEQ ID No: 6, (5) LCDR2, comprising the amino acid sequence shown in SEQ ID No: 7, and (6) LCDR3, which comprises the amino acid sequence shown in SEQ ID No:

8.

17. The method of claim 16, wherein the CD73 antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence as shown in SEQ ID NO: 1 or an amino acid sequence having at least 90% identity to SEQ ID NO: 1, and (2) a light chain variable region (VL) comprising the amino acid sequence as shown in SEQ ID NO:2 or an amino acid sequence having at least 90% identity with SEQ ID NO:

2.

18. The method according to any one of claims 1-17, wherein the CD73 antibody or antigen-binding fragment thereof is selected from the group consisting of uliledlimab (I-Mab Biopharma), oleclumab (AstraZeneca), CPI-006 (Corvus Pharma), BMS-986179 (Bristol-Myers Squibb), AB-680 (Arcus Biosciences), NZV-930 (SRF373, Surface Oncolohgy / Novartis), JAB-BX102 (Jacobio), AK119 (Akesobio), Sym024 (Symphogen), IBI 325 (Innovent), BR 101 (Hisun BioRay), and LY3475070 (Eli Lilly).

19. The method of any one of claims 1-18, wherein the solid tumor is selected from the group consisting of acute lymphoblastic leukemia, multiple myeloma, glioma, mesothelioma, ovarian cancer, sarcoma, cervical cancer, bladder cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymphoma, melanoma, skin cancer (basal cell carcinoma), pancreatic cancer, prostate cancer, uterine cancer, and thyroid cancer.

20. The method according to any one of claims 1-19, wherein the lung cancer comprises non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

21. The method of any one of claims 1-20, wherein the solid tumor is an advanced solid tumor.

22. The method of any one of claims 1-21, wherein the solid tumor is a metastatic solid tumor.

23. The method of any one of claims 1-22, wherein the solid tumor is a recurrent solid tumor.

24. The method of any one of claims 1-23, wherein the solid tumor is a refractory solid tumor.

25. The method of any one of claims 1-24, wherein the solid tumor is at stage III or stage IV.

26. The method according to any one of claims 1-25, wherein the method further comprises administering to the subject a PD-L1 antagonist.

27. The method according to claims 1-26, in, The CD73 antibody or antigen-binding fragment thereof and the PD-L1 antagonist are administered simultaneously.

28. The method according to claims 1-26, in, The CD73 antibody or antigen-binding fragment thereof and the PD-L1 antagonist are administered separately.

29. The method according to claim 26, in, The PD-L1 antagonist is a PD-L1 antibody.

30. The method according to claim 29, in, The PD-L1 antibody is selected from the group consisting of atezolizumab, manelimab, avelumab, cosibelimab, durvalumab (durvalumab), envafolimab, socazolimab, BGB-A333, CK-301, CS-1001, FAZ-053, APL-502, MDX-1105, IM C-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12 and KY-1003.

31. The method of claim 30, wherein the PD-L1 antibody is atezolizumab.

32. The method of claim 31, wherein atezolizumab is administered to the subject at a fixed dose of 1200 mg once every three weeks (Q3W).

33. Use of a CD73 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a solid tumor in a subject in need thereof, in, The drug is administered to the subject at a dose of about 2 to about 50 mg / kg body weight.

34. A product, include: (1) a CD73 antibody or an antigen-binding fragment thereof, and (2) a package insert recommending administration of the CD73 antibody or antigen-binding fragment thereof to a subject in need thereof at a dose of about 2 to about 50 mg / kg body weight.

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