Application of combination of anti-human VEGF antibody and chemical medicine in preparation of medicine for treating ovarian cancer

Abstract

The invention relates to an application of a combination of an anti-human VEGF antibody and a chemical drug in preparation of a drug for treating ovarian cancer, in particular to a combination of the anti-human VEGF antibody and a chemotherapeutic drug, an ovarian cancer treatment method and an application of the combination in preparation of the drug for treating the ovarian cancer. The invention is beneficial to increasing the choices of ovarian cancer patients, improving the treatment effect of ovarian cancer, and benefiting more ovarian cancer patients.

Description

[0001] Related cross-references

[0002] This invention is a divisional application of Chinese application CN202110742169.4 filed on July 1, 2021. Technical Field

[0003] The present invention relates to the field of medicine, and in particular to the use of an anti-human VEGF antibody in combination with a chemical drug in the preparation of a drug for treating ovarian cancer. Background Art

[0004] Ovarian cancer is a malignant tumor that originates in the epithelium and includes epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. It is the second most common gynecological malignancy and has the highest mortality rate. Ovarian cancer lacks specific tumor markers, making early diagnosis difficult and often diagnosed at a late stage. Therefore, the prognosis of ovarian cancer is poor (Chen W. et al., Cancer statistics in China, 2015. CA Cancer J Clin, 2016. 66(2): p. 115-32).

[0005] The recognized standard treatment for ovarian cancer is cytoreductive surgery and postoperative chemotherapy based on platinum and paclitaxel. Despite the high response rate to first-line chemotherapy, up to 70-75% of patients will still relapse (Luigi Rossi et al., Oncotarget, 2016.8: p.12389-12405). Ovarian cancer patients who relapse within 6 months after treatment with platinum-containing drugs are defined as platinum-resistant. After the first relapse, approximately 25% of patients will develop platinum resistance, and eventually almost all relapsed patients will develop platinum resistance. In this case, there are very few effective treatment options and the prognosis is poor. Therefore, new treatment strategies are needed to improve their clinical prognosis (Pujade-Lauraine, E., et al., J Clin Oncol, 2014.32(13): p.1302).

[0006] Vascular endothelial growth factor (VEGF) is a multifunctional cytokine and the most potent and specific angiogenic factor known. It participates in the development and progression of solid tumors by promoting tumor angiogenesis, increasing vascular permeability, and downregulating host anti-tumor immune responses. Studies have shown that anti-human VEGF antibodies can inhibit the growth of solid tumors.

[0007] BD0801 antibody is a humanized rabbit anti-human VEGF monoclonal antibody. Researching and exploring the use of BD0801 antibody in the treatment of ovarian cancer will help increase patient options, improve the treatment effect of ovarian cancer, and benefit more ovarian cancer patients.

[0008] In view of this, the present invention is proposed. Summary of the Invention

[0009] The present invention provides a combination of an anti-human VEGF antibody and a chemotherapy drug, and a method for treating ovarian cancer or an application thereof in preparing a drug for treating ovarian cancer.

[0010] In a first aspect, the present invention provides use of a combination of an anti-human VEGF antibody and a chemotherapy drug in the preparation of a medicament for treating ovarian cancer, wherein the chemotherapy drug is selected from a taxane compound or a camptothecin compound, and the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein:

[0011] The sequence of the HCDR1 is shown in SEQ ID NO: 5;

[0012] The sequence of the HCDR2 is shown in SEQ ID NO: 8;

[0013] The sequence of the HCDR3 is shown in SEQ ID NO: 11;

[0014] The sequence of the LCDR1 is shown in SEQ ID NO: 13;

[0015] The sequence of the LCDR2 is shown in SEQ ID NO: 15; and

[0016] The sequence of the LCDR3 is shown in SEQ ID NO: 17.

[0017] In some specific embodiments, the sequence of the heavy chain variable region is shown in SEQ ID NO: 1, and the sequence of the light chain variable region is shown in SEQ ID NO: 3.

[0018] In some specific embodiments, the antibody further includes a heavy chain constant region, the sequence of which is shown in SEQ ID NO: 2, and the antibody further includes a light chain constant region, the sequence of which is shown in SEQ ID NO: 4.

[0019] In some embodiments, the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0020] In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer.

[0021] In some embodiments, the pathological type of the ovarian cancer is serous adenocarcinoma, clear cell adenocarcinoma, or mixed epithelial carcinoma.

[0022] In some specific embodiments, the taxane compound is paclitaxel, and the camptothecin compound is topotecan hydrochloride.

[0023] In some specific embodiments, the effective administration amount of the anti-human VEGF antibody is 0.5-2 mg / kg.

[0024] In some embodiments, the effective amount of the anti-human VEGF antibody administered is 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2 mg / kg.

[0025] In some embodiments, the anti-human VEGF antibody is in a single-dose dosage form, each dose containing an amount of the antibody that can be effectively administered to a patient.

[0026] In some embodiments, the single-dose dosage form contains 25-150 mg of the anti-human VEGF antibody.

[0027] In some embodiments, the single-dose dosage form contains 25 mg, 50 mg, 80 mg, 100 mg, or 150 mg of the anti-human VEGF antibody.

[0028] In some specific embodiments, the effective administration amount of paclitaxel is 80 mg / m2; the effective administration amount of topotecan hydrochloride is 4 mg / m2.

[0029] In a second aspect, the present invention provides use of a combination of an anti-human VEGF antibody and a chemotherapy drug in the preparation of a medicament for treating ovarian cancer, wherein the chemotherapy drug is selected from a taxane compound or a camptothecin compound, and the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein:

[0030] The HCDR1 is selected from the sequence shown in any one of SEQ ID NOs: 5-7;

[0031] The HCDR2 is selected from the sequence shown in any one of SEQ ID NOs: 8-10;

[0032] The HCDR3 is selected from the sequence shown in any one of SEQ ID NOs: 11-12;

[0033] The LCDR1 is selected from the sequence shown in any one of SEQ ID NOs: 13-14;

[0034] The LCDR2 is selected from the sequence shown in any one of SEQ ID NOs: 15-16; and

[0035] The LCDR3 is selected from the sequence shown in SEQ ID NO:17.

[0036] In some embodiments, the heavy chain variable region has a sequence as shown in SEQ ID NO:1, or a sequence with at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1; the light chain variable region has a sequence as shown in SEQ ID NO:3, or a sequence with at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3.

[0037] In some specific embodiments, the antibody further comprises a heavy chain constant region having a sequence as shown in SEQ ID NO: 2, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2; the antibody further comprises a light chain constant region having a sequence as shown in SEQ ID NO: 4, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4.

[0038] In some embodiments, the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0039] In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer.

[0040] In some embodiments, the pathological type of the ovarian cancer is serous adenocarcinoma, clear cell adenocarcinoma, or mixed epithelial carcinoma.

[0041] In some specific embodiments, the taxane compound is paclitaxel, and the camptothecin compound is topotecan hydrochloride.

[0042] In some specific embodiments, the effective administration amount of the anti-human VEGF antibody is 0.5-2 mg / kg, preferably 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg or 2 mg / kg.

[0043] In some specific embodiments, the dosage form of the anti-human VEGF antibody is a single-dose dosage form, each dose containing an amount of the antibody that can be effectively administered to a patient. Preferably, the single-dose dosage form contains 25 to 150 mg of the anti-VEGF antibody, more preferably 25 mg, 50 mg, 80 mg, 100 mg or 150 mg.

[0044] In some embodiments, the effective amount of paclitaxel is 80 mg / m 2 .

[0045] In some embodiments, the effective dosage of topotecan hydrochloride is 4 mg / m 2 .

[0046] In a third aspect, the present invention also provides a method for treating ovarian cancer, comprising administering to an ovarian cancer patient an effective amount of a combination of an anti-human VEGF antibody and a chemotherapy drug, wherein the chemotherapy drug is selected from a taxane compound or a camptothecin compound, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein:

[0047] The HCDR1 is selected from the sequence shown in any one of SEQ ID NOs: 5-7;

[0048] The HCDR2 is selected from the sequence shown in any one of SEQ ID NOs: 8-10;

[0049] The HCDR3 is selected from the sequence shown in any one of SEQ ID NOs: 11-12;

[0050] The LCDR1 is selected from the sequence shown in any one of SEQ ID NOs: 13-14;

[0051] The LCDR2 is selected from the sequence shown in any one of SEQ ID NOs: 15-16; and

[0052] The LCDR3 is selected from the sequence shown in SEQ ID NO:17.

[0053] In some embodiments, the heavy chain variable region has a sequence as shown in SEQ ID NO:1, or a sequence with at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1; the light chain variable region has a sequence as shown in SEQ ID NO:3, or a sequence with at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3.

[0054] In some specific embodiments, the antibody further comprises a heavy chain constant region having a sequence as shown in SEQ ID NO: 2, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2; the antibody further comprises a light chain constant region having a sequence as shown in SEQ ID NO: 4, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4.

[0055] In some embodiments, the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0056] In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer.

[0057] In some embodiments, the pathological type of the ovarian cancer is serous adenocarcinoma, clear cell adenocarcinoma, or mixed epithelial carcinoma.

[0058] In some specific embodiments, the taxane compound is paclitaxel, and the camptothecin compound is topotecan hydrochloride.

[0059] In some specific embodiments, the effective administration amount of the anti-human VEGF antibody is 0.5-2 mg / kg, preferably 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg or 2 mg / kg.

[0060] In some embodiments, the effective amount of paclitaxel is 80 mg / m 2 .

[0061] In some embodiments, the effective dosage of topotecan hydrochloride is 4 mg / m 2 .

[0062] In some embodiments, the anti-human VEGF antibody is administered once every 2 weeks.

[0063] In some embodiments, the administration frequency of paclitaxel is once a week.

[0064] In some specific embodiments, the frequency of administration of topotecan hydrochloride is 3 times every 4 weeks, preferably once a week in the first 3 weeks.

[0065] In some specific embodiments, the administration cycle of the combination is 28 days, the anti-human VEGF antibody is administered once on day 1 and day 15, the paclitaxel is administered once on day 1, day 8, day 15 and day 22, and the topotecan hydrochloride is administered once on day 1, day 8 and day 15.

[0066] In a fourth aspect, the present invention also provides a combination of an anti-human VEGF antibody and a chemotherapy drug for treating ovarian cancer, wherein the chemotherapy drug is selected from a taxane compound or a camptothecin compound, and the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein:

[0067] The HCDR1 is selected from the sequence shown in any one of SEQ ID NOs: 5-7;

[0068] The HCDR2 is selected from the sequence shown in any one of SEQ ID NOs: 8-10;

[0069] The HCDR3 is selected from the sequence shown in any one of SEQ ID NOs: 11-12;

[0070] The LCDR1 is selected from the sequence shown in any one of SEQ ID NOs: 13-14;

[0071] The LCDR2 is selected from the sequence shown in any one of SEQ ID NOs: 15-16; and

[0072] The LCDR3 is selected from the sequence shown in SEQ ID NO:17.

[0073] In some specific embodiments, the heavy chain variable region has a sequence as shown in SEQ ID NO:1, or a sequence with at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1; the light chain variable region has a sequence as shown in SEQ ID NO:3, or a sequence with at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3.

[0074] In some specific embodiments, the antibody further comprises a heavy chain constant region having a sequence as shown in SEQ ID NO: 2, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2; the antibody further comprises a light chain constant region having a sequence as shown in SEQ ID NO: 4, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4.

[0075] In some embodiments, the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0076] In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer.

[0077] In some embodiments, the pathological type of the ovarian cancer is serous adenocarcinoma, clear cell adenocarcinoma, or mixed epithelial carcinoma.

[0078] In some specific embodiments, the taxane compound is paclitaxel, and the camptothecin compound is topotecan hydrochloride.

[0079] In some specific embodiments, the effective administration amount of the anti-human VEGF antibody is 0.5-2 mg / kg, preferably 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg or 2 mg / kg.

[0080] In some specific embodiments, the dosage form of the anti-human VEGF antibody is a single-dose dosage form, each dose containing an amount of antibody that can be effectively administered to a patient. Preferably, the single-dose dosage form contains 25 to 150 mg of the anti-VEGF antibody, more preferably 25 mg, 50 mg, 80 mg, 100 mg or 150 mg.

[0081] In some specific embodiments, the effective administration amount of paclitaxel is 80 mg / m 2 .

[0082] In some specific embodiments, the effective dosage of topotecan hydrochloride is 4 mg / m 2 .

[0083] Definitions and Explanations of Terms

[0084] Unless otherwise defined herein, scientific and technical terms related to the present invention shall have the meanings that are understood by those of ordinary skill in the art.

[0085] Furthermore, unless otherwise indicated herein, singular terms shall include pluralities and plural terms shall include the singular. More specifically, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless expressly indicated otherwise.

[0086] The terms "include," "comprising," and "having" are used interchangeably herein and are intended to indicate the inclusiveness of a solution, meaning that the solution may contain other elements in addition to the listed elements. It should also be understood that the use of "include," "comprising," and "having" in this document also provides a "consisting of" solution.

[0087] The term "and / or" as used herein includes the meanings of "and," "or," and "all or any other combination of elements linked by the associated term."

[0088] The term "antibody" is used in the broadest sense herein and refers to a polypeptide or combination of polypeptides that contains sufficient sequence from the variable region of the immunoglobulin heavy chain and / or sufficient sequence from the variable region of the immunoglobulin light chain to be able to specifically bind to an antigen. "Antibodies" herein encompass various forms and various structures, as long as they exhibit the expected antigen binding activity, illustratively including complete antibodies and antibody fragments with antigen binding activity. "Expected antigen binding activity" referred to herein means, for example, that antibodies typically specifically bind to antigens and substantially the same antigens with high affinity, but do not bind to unrelated antigens with high affinity. Affinity is typically reflected in terms of equilibrium dissociation constants (KD), where lower KD indicates higher affinity. For example, high affinity typically refers to an antibody with an affinity of about 10 -7 M or lower, about 10 -8 M or lower, about 1×10 -9 M or lower, about 1×10 -10 M or less, 1×10 -11 M or lower or 1×10 -12 The KD is calculated as follows: KD = Kd / Ka, where Kd represents the off-rate and Ka represents the on-rate. The equilibrium dissociation constant, KD, can be measured using methods known in the art, such as surface plasmon resonance (e.g., Biacore) or equilibrium dialysis.

[0089] The term "antibody" herein includes a typical "four-chain antibody," which is an immunoglobulin composed of two heavy chains (HC) and two light chains (LC). The heavy chain refers to a polypeptide chain that, from the N-terminus to the C-terminus, consists of a heavy chain variable region (VH), a heavy chain constant region CH1 domain, a hinge region (HR), a heavy chain constant region CH2 domain, and a heavy chain constant region CH3 domain. Furthermore, when the full-length antibody is of the IgE isotype, it optionally also includes a heavy chain constant region CH4 domain. The light chain is a polypeptide chain that, from the N-terminus to the C-terminus, consists of a light chain variable region (VL) and a light chain constant region (CL). Heavy chains are linked to each other and to each other through disulfide bonds, forming a "Y"-shaped structure. Due to the different amino acid composition and arrangement order of the constant regions of the heavy chains of immunoglobulins, their antigenicity also varies. Based on this, "immunoglobulins" as used herein can be divided into five classes, or isotypes, namely IgM, IgD, IgG, IgA, and IgE. Their corresponding heavy chains are μ, δ, γ, α, and ε, respectively. Igs within the same class are further divided into subclasses based on the amino acid composition of their hinge regions and the number and location of disulfide bonds in their heavy chains. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4, and IgA can be divided into IgA1 and IgA2. Light chains are classified as either kappa or lambda chains based on differences in their constant regions. Each of the five Ig classes can have either kappa or lambda chains.

[0090] The "antibodies" herein may be derived from any animal, including but not limited to humans and non-human animals, which may be selected from primates, mammals, rodents, and vertebrates, such as camelids, llamas, cassowaries, alpacas, sheep, rabbits, mice, rats, or cartilaginous fish (e.g., sharks).

[0091] The term "humanized antibody" herein refers to a non-human antibody that has been genetically engineered and whose amino acid sequence has been modified to increase homology with the sequence of a human antibody. Generally speaking, all or part of the CDR region of a humanized antibody comes from a non-human antibody (donor antibody), and all or part of the non-CDR region (e.g., variable region FR and / or constant region) comes from a human immunoglobulin (recipient antibody). Humanized antibodies generally retain or partially retain the expected properties of the donor antibody, including but not limited to, antigen specificity, affinity, reactivity, ability to increase immune cell activity, ability to enhance immune response, etc.

[0092] The term "variable region" herein refers to the region of an antibody heavy or light chain that is involved in binding the antibody to an antigen. "Heavy chain variable region" is used interchangeably with "VH" and "HCVR," and "light chain variable region" is used interchangeably with "VL" and "LCVR." The variable domains of the heavy and light chains of native antibodies (VH and VL, respectively) generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). See, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity.

[0093] The terms "complementarity determining region" and "CDR" are used interchangeably herein and generally refer to the hypervariable region (HVR) of the heavy chain variable region (VH) or light chain variable region (VL). This region is also called the complementarity determining region because it forms precise complementarity with the antigen epitope in terms of spatial structure. The heavy chain variable region CDR can be abbreviated as HCDR, and the light chain variable region CDR can be abbreviated as LCDR. The terms "framework region" or "FR region" are used interchangeably herein and refer to the amino acid residues in the heavy chain variable region or light chain variable region of an antibody, excluding the CDRs. A typical antibody variable region is generally composed of four FR regions and three CDR regions in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0094] For further description of CDRs, see Kabat et al., J. Biol. Chem., 252:6609-6616 (1977); Kabat et al., U.S. Department of Health and Human Services, "Sequences of proteins of immunological interest" (1991); Chothia et al., J. Mol. Biol. 196:901-917 (1987); Al-Lazikani B. et al., J. Mol. Biol., 273:927-948 (1997); MacCallum et al., J. Mol. Biol. 262:732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008); Lefranc et al., J. Mol. Biol. 196:901-917 (1987); Al-Lazikani B. et al., J. Mol. Biol., 273:927-948 (1997); MacCallum et al., J. Mol. Biol. 262:732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008); Lefranc et al., J. Mol. MP et al., Dev. Comp. Immunol., 27:55-77 (2003); and Honegger and Plückthun, J. Mol. Biol., 309:657-670 (2001). "CDRs" herein can be annotated and defined by methods known in the art, including but not limited to the Kabat numbering system, the Chothia numbering system, or the IMGT numbering system, and the tool websites used include but are not limited to the AbRSA website (http: / / cao.labshare.cn / AbRSA / cdrs.php), the abYsis website (www.abysis.org / abysis / sequence_input / key_annotation / key_annotation.cgi), and the IMGT website (http: / / www.imgt.org / 3Dstructure-DB / cgi / DomainGapAlign.cgi#results).

[0095] Illustratively, the CDRs of the VH or VL sequence represented by SEQ ID NO: 1 or 3 are shown in the following table: wherein Kabat and Chothia use the abYsis website, and IMGT uses the IMGT website.

[0096] Table 1 Anti-human VEGF antibody heavy chain and light chain CDR region amino acid sequence list

[0097]

[0098] The term "heavy chain constant region" herein refers to the carboxyl-terminal portion of an antibody heavy chain, which is not directly involved in antibody-antigen binding but exhibits effector functions, such as interactions with Fc receptors. It has a more conserved amino acid sequence than the variable domains of antibodies. A "heavy chain constant region" comprises at least: a CH1 domain, a hinge region, a CH2 domain, a CH3 domain, or variants or fragments thereof. "Heavy chain constant regions" include "full-length heavy chain constant regions" and "heavy chain constant region fragments." The former has a structure substantially similar to that of a native antibody constant region, while the latter only comprises "a portion of a full-length heavy chain constant region." For example, a typical "full-length antibody heavy chain constant region" consists of a CH1 domain-hinge region-CH2 domain-CH3 domain; when the antibody is an IgE, it also includes a CH4 domain; when the antibody is a heavy chain antibody, it does not include the CH1 domain. For example, a typical "heavy chain constant region fragment" can be selected from the CH1, Fc, or CH3 domains.

[0099] The term "light chain constant region" herein refers to the carboxyl terminal portion of the antibody light chain, which is not directly involved in binding the antibody to the antigen, and the light chain constant region can be selected from a constant kappa domain or a constant lambda domain.

[0100] The term "Fc" herein refers to the antibody carboxyl terminal portion formed by papain hydrolysis of an intact antibody, typically comprising the CH3 and CH2 domains of an antibody. The Fc region includes, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary slightly, the Fc region of a human IgG heavy chain is typically defined as extending from the amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. The C-terminal lysine (residue 447 according to the Kabat numbering system) in the Fc region can be, for example, removed during production or purification of the antibody, or by recombinant engineering of the nucleic acid encoding the heavy chain of the antibody, and therefore, the Fc region may or may not include Lys447.

[0101] The term "identity" as used herein can be calculated in the following manner: to determine the percent "identity" of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of the first and second amino acid sequences or nucleic acid sequences for optimal alignment, or non-homologous sequences can be discarded for comparison purposes). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide at the corresponding position in the second sequence, then the molecules are identical at that position.

[0102] The percent identity between the two sequences will vary depending on the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0103] The term "drug" herein refers to a substance for preventing, treating and diagnosing a disease, including a "pharmaceutical composition" or a "drug combination". Exemplarily, the drug also includes a cell therapy agent, such as a CAR-T cell or a CAR-NK cell for treatment. A "pharmaceutical composition" refers to a preparation that exists in a form that allows the biological activity of the active ingredient contained therein to be effective, and does not contain other ingredients that have unacceptable toxicity to the subject to whom the pharmaceutical composition is administered. The term "combination" or "drug combination" as used herein refers to a non-fixed combination, wherein the active agent and at least one other active agent can be administered separately at the same time or at time intervals, particularly when these time intervals allow the combination partner to show a cooperative (e.g., synergistic) effect. The term "non-fixed combination" means that the active ingredients (e.g., an active agent and at least one other active agent) are all administered to the patient as separate entities simultaneously or sequentially without specific time limits, wherein such administration provides a therapeutically effective level of the two compounds in the patient's body.

[0104] The term "treatment" herein refers to surgical or pharmaceutical treatment, the purpose of which is to prevent, slow down (reduce) undesirable physiological changes or pathological changes in the treatment subject, such as the progression of cancer or tumors. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, weakening of the disease extent, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, and relief (whether partial relief or complete relief), whether detectable or undetectable. Objects in need of treatment include objects already suffering from a disease or disease, objects susceptible to a disease or disease, or objects intended to prevent a disease or disease. When referring to terms such as slowing down, alleviating, weakening, alleviating, and alleviating, their meanings also include situations such as elimination, disappearance, and non-occurrence.

[0105] As used herein, the term "patient" or "subject" refers to an organism that is being treated for a particular disease or condition as described herein. Examples of "patients" or "subjects" include mammals, such as humans, primates (e.g., monkeys), or non-primate mammals, that are being treated for a disease or condition.

[0106] The term "effective amount" herein refers to the amount of a therapeutic agent that is effective in preventing or alleviating a disease condition or the progression of the disease when administered alone or in combination with another therapeutic agent to a cell, tissue, or subject. "Effective amount" also refers to an amount sufficient to alleviate symptoms, such as to treat, cure, prevent, or alleviate related medical conditions, or to treat, cure, prevent, or alleviate these conditions at an increased rate of a compound or therapeutic cell (e.g., CAR-T cells, CAR-NK cells). When an active ingredient is administered alone to an individual, a therapeutically effective dose refers solely to that ingredient.

[0107] The term "cancer" herein refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Both benign and malignant cancers are included in this definition. The terms "tumor" or "neoplasm" herein refer to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer" and "tumor" as used herein are not mutually exclusive.

[0108] As used herein, the term "patient" or "subject" refers to an organism that is being treated for a particular disease or condition as described herein. Examples of "patients" or "subjects" include mammals, such as humans, primates (e.g., monkeys), or non-primate mammals, that are being treated for a disease or condition. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Figure 1 .The anti-tumor effects of BD0801, Avastin and Paclitaxel in the human ovarian cancer OVCAR-8 nude mouse xenograft tumor model.

[0110] Figure 2 .The anti-tumor effects of BD0801, Avastin and Paclitaxel alone and in combination in the human ovarian cancer OVCAR-8 nude mouse xenograft tumor model.

[0111] Figure 3 .The anti-tumor effects of BD0801, Avastin and Paclitaxel alone and in combination in the human ovarian cancer SK-OV-3 nude mouse xenograft tumor model.

[0112] Figure 4 .Objective response rate (ORR) of subjects in the BD0801 combined with PTX group.

[0113] Figure 5 .Stratified analysis of the objective response rate (ORR) and BD0801 AUC in ovarian cancer patients treated with BD0801 combined with PTX group / TOPO group.

[0114] Figure 6.Graph of the overall median progression-free survival (PFS) of the subjects.

[0115] Figure 7 .Relationship between BD0801 combined with PTX exposure and the percentage reduction of the sum of the longest diameters of the tumor (SLD). DETAILED DESCRIPTION

[0116] The present invention will be further described below with reference to specific examples, and the advantages and features of the present invention will become more apparent as the description proceeds. Where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer were used. Reagents or instruments used, where the manufacturer is not specified, are commercially available conventional products.

[0117] The embodiments of the present invention are merely exemplary and do not limit the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, and such modifications and replacements shall fall within the scope of protection of the present invention.

[0118] The BD0801 antibody used in the following examples was produced and provided by Shandong Xiansheng Biopharmaceutical Co., Ltd. and stored at 2-8° C. The sequence information of the BD0801 antibody is shown below.

[0119] Heavy chain variable region (SEQ ID NO: 1):

[0120] EVQLVESGGGLVKPGGSLRLSCAASGFSFSNNDVMCWVRQAPGKGLEWIGCIMTTDV VTEYANWAKSRFTVSRDSAKNSVYLQMNSLRAEDTAVYFCARDSVGSPLMSFDLWGPGTL VTVSS;

[0121] Heavy chain constant region (SEQ ID NO: 2):

[0122] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK;

[0123] Light chain variable region (SEQ ID NO: 3):

[0124] DIQMTQSPSSSLSASVGDRVTINCQASQSIYNNNELSWYQQKPGKPPKLLIYRASTLASG VPSRFSGSGSGTDFTLTISSLQPEDVATYYCGGYKSYSNDGNGFGGGTKVEIK;

[0125] Light chain constant region (SEQ ID NO: 4):

[0126] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.

[0127] Example 1 Evaluation of the therapeutic effect of BD0801 on human ovarian cancer xenograft tumor model in nude mice

[0128] 1.1 Experimental Materials and Tumor Assessment Methods (Unless otherwise specified, this example uses the experimental materials and tumor assessment methods described in 1.1)

[0129] Test drug:

[0130] BD0801 was produced and provided by Shandong Simcere Biopharmaceutical Co., Ltd.;

[0131] Bevacizumab (Avastin) was purchased from Roche;

[0132] Paclitaxel was purchased from Beijing Union Medical College Hospital.

[0133] Drug preparation method: All drugs were prepared and diluted with sterile saline (purchased from Jiangsu Huaian Shuanghe Pharmaceutical Co., Ltd.).

[0134] OVCAR-8 cells: National Institutes of Health (NIH).

[0135] SK-OV-3 cells: Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences.

[0136] Reagents: RPMI1640: Gibco, catalog number: C22400500BT;

[0137] Fetal bovine serum: Gibco, catalog number: 10099-141C;

[0138] PBS:Hyclone, catalog number:SH30256.01;

[0139] Matrigel: Corning, Cat. No. 354234.

[0140] Tumor Assessment Methods:

[0141] Tumor volume V = 0.5 × a × b 2 , where a is the long diameter of the tumor and b is the short diameter of the tumor;

[0142] Relative tumor volume RTV = V t / V0, where V0 is the tumor volume of the animal at the time of grouping; V t is the tumor volume of the animal after treatment.

[0143] Relative tumor growth rate T / C (%) = T RTV / C RTV × 100%, where T RTV is the average RTV of the treatment group; C RTV is the average RTV of the negative control group.

[0144] Tumor growth inhibition rate TGI (%) = (1-T / C) × 100%.

[0145] 1.2 Evaluation of the efficacy of BD0801 in the human ovarian cancer OVCAR-8 nude mouse xenograft model (single agent)

[0146] Experimental animals: BALB / c nude female mice, 6–8 weeks old, weighing 18.5–25.5 g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., production license number: SCXK(Su)2018-0008, animal qualification certificate number: 201911201. Housing environment: SPF grade.

[0147] OVCAR-8 cells were cultured in RPMI1640 medium containing 10% fetal bovine serum. Cells in the exponential growth phase were collected and 1×10 7 OVCAR-8 cells were resuspended in PBS and Matrigel (1:1) (0.1 ml / mouse) and inoculated subcutaneously in experimental mice. 3 Mice were randomly divided into 8 groups (n=8) for dosing, with the day of dosing defined as day 0 (D0). Each group received normal saline (vehicle), the test drug BD0801 at 0.8 mg / kg, 2.5 mg / kg, or 7.5 mg / kg, the control drug Avastin at 0.8 mg / kg, 2.5 mg / kg, or 7.5 mg / kg, or the positive control drug Paclitaxel at 15 mg / kg via the tail vein. BD0801 and Avastin were administered twice weekly for approximately 6 weeks, while Paclitaxel was administered once every four days for a total of 4 doses. Tumor volume was measured twice weekly, and mice were weighed. Data were recorded and changes in tumor size and weight were statistically analyzed over approximately 6 weeks. These results indicate that in the human ovarian cancer OVCAR-8 nude mouse xenograft tumor model, BD0801 at 2.5 mg / kg and 7.5 mg / kg significantly inhibited tumor growth, with superior tumor inhibition compared to Avastin.

[0148] On the 38th day after administration, the tumor volume of the 0.8mg / kg BD0801 group was not statistically different from that of the Vehicle control group, and the tumor volume of the 2.5mg / kg and 7.5mg / kg BD0801 groups showed significant tumor inhibitory effects compared with the control group. There was no statistical difference in the tumor volume of the 0.8mg / kg, 2.5mg / kg and 7.5mg / kg Avastin groups compared with the Vehicle control group. At the same dose, the tumor inhibitory effect of BD0801 was better than that of Avastin, and there were statistical differences at the two doses of 0.8mg / kg and 2.5mg / kg. No animal weight loss or other obvious toxic reactions were observed at different doses of BD0801 and Avastin. 15mg / kg Paclitaxel also produced a significant tumor inhibitory effect, but the drug had obvious toxic reactions, and 2 of the 8 mice died. See Table 2 and for details. Figure 1 The results showed that in the human ovarian cancer OVCAR-8 nude mouse xenograft tumor model, BD0801 at 2.5 mg / kg and 7.5 mg / kg could significantly inhibit tumor growth, and its tumor inhibition effect was better than Avastin.

[0149] Table 2 Antitumor effects of the test substances on OVCAR-8 xenograft tumor model

[0150]

[0151] Note: a. Data shown are mean ± standard deviation (SD).

[0152] bP values ​​were obtained by analyzing relative tumor volumes using two-way ANOVA. The P values ​​shown are the values ​​compared between each group and the vehicle control group.

[0153] c. Two tumor-bearing mice in the Paclitaxel 15 mg / kg group were found dead on days 5 and 12, respectively. These two mice were not included in the tumor volume and corresponding calculations on day 38.

[0154] 1.3 Evaluation of the efficacy of BD0801 on human ovarian cancer OVCAR-8 xenografts in nude mice - combined with chemotherapy

[0155] Experimental animals: BALB / c nude female mice, 6–8 weeks old, weighing 16.2–21.5 g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., production license number: SCXK(Su)2018-0008, animal qualification certificate number: 202002168. Housing environment: SPF grade.

[0156] OVCAR-8 cells were cultured in RPMI1640 medium containing 10% fetal bovine serum. Cells in the exponential growth phase were collected and 1×10 7 OVCAR-8 cells were resuspended in PBS and Matrigel (1:1) (0.1 ml / mouse) and inoculated subcutaneously in experimental mice. 3 The day of group administration was defined as day 0 (D0). Mice were randomly divided into 6 groups (n=8). Each group of mice was administered normal saline (Vehicle), 2.5 mg / kg test drug BD0801, 2.5 mg / kg control drug Avastin, 10 mg / kg positive control drug Paclitaxel, 2.5 mg / kg BD0801 combined with 10 mg / kg Paclitaxel, or 2.5 mg / kg Avastin combined with 10 mg / kg Paclitaxel via the tail vein. BD0801 and Avastin were administered twice weekly for 4 weeks, and Paclitaxel was administered once every four days for a total of 4 doses. Tumor volume was measured twice weekly, and the mice were weighed. The data were recorded and the changes in tumor size and mouse weight were statistically analyzed over approximately 4 weeks.

[0157] On the 24th day after administration, either 2.5mg / kg BD0801 or 2.5mg / kg Avastin could significantly inhibit tumor growth, and the tumor inhibition effect was comparable. The combination of 2.5mg / kg Avastin and 10mg / kg Paclitaxel did not show a significantly enhanced tumor inhibition effect compared to the Avastin monotherapy group; while the combination of 2.5mg / kg BD0801 and 10mg / kg Paclitaxel showed a significantly enhanced tumor inhibition effect compared to both monotherapy groups, and the tumor inhibition effect of the combination group tended to be better than the Avastin and Paclitaxel combination group. Tumor-bearing mice were able to tolerate treatment with BD0801 at a dose of 2.5mg / kg, Avastin at a dose of 2.5mg / kg, and Paclitaxel at a dose of 10mg / kg, as well as BD0801 2.5 mg / kg combined with Paclitaxel 10mg / kg, and Avastin 2.5mg / kg combined with Paclitaxel 10mg / kg. See Table 3 and for details. Figure 2 The results showed that in the human ovarian cancer OVCAR-8 nude mouse xenograft tumor model, 2.5mg / kg BD0801 monotherapy had a significant tumor inhibitory effect. When combined with 10mg / kg Paclitaxel, it showed a significantly enhanced tumor inhibitory effect compared with both single-drug groups, and showed a trend of significantly superior anti-tumor efficacy to the same-dose combination of Avastin and Paclitaxel.

[0158] Table 3 Antitumor effects of the test substances on OVCAR-8 xenograft tumor model

[0159]

[0160] Note: a. Data shown are mean ± SD.

[0161] bP values ​​were obtained by analyzing relative tumor volumes using two-way ANOVA. The P values ​​shown are the values ​​compared between each group and the vehicle control group.

[0162] 1.4 Evaluation of the efficacy of BD0801 on human ovarian cancer SK-OV-3 nude mouse xenografts in combination with chemotherapy

[0163] Experimental animals: BALB / c nude female mice, 6–8 weeks old, weighing 18.0–23.5 g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., production license number: SCXK(Su)2018-0008, animal qualification certificate number: 202002168. Housing environment: SPF grade.

[0164] SK-OV-3 cells were cultured in McCoy's 5a medium (McCoy's 5a: Gibco, Catalog No.: 12330-031) containing 10% fetal bovine serum (Ecocell, Catalog No.: FND500). Cells in the exponential growth phase were collected and 1×10 7 SK-OV-3 cells were resuspended in PBS and Matrigel (1:1) (0.1 ml / mouse) and inoculated subcutaneously in experimental mice. 3 Mice were randomly divided into 8 groups (n=8) and administered via the tail vein. The day of group administration was defined as day 0 (D0). Each group received normal saline (vehicle), 2.5 mg / kg or 7.5 mg / kg of the test drug BD0801, 2.5 mg / kg or 7.5 mg / kg of the control drug Avastin, 10 mg / kg of the positive control drug Paclitaxel, 10 mg / kg Paclitaxel combined with 2.5 mg / kg BD0801, or 10 mg / kg Paclitaxel combined with 2.5 mg / kg Avastin. BD0801 and Avastin were administered twice weekly for 4 weeks, while Paclitaxel was administered every four days for a total of 4 doses. Tumor volume was measured twice weekly, and mouse weights were weighed. Data were recorded and statistically analyzed for changes in tumor size and mouse weight over approximately 4 weeks.

[0165] On the 24th day after administration, all the treatment groups showed significant activity in inhibiting tumor growth compared with the control group. The test drug BD0801 showed very good dose dependence, while the control drug Avastin had a slightly weaker dose dependence. The tumor inhibition effect of BD0801 was comparable to that of Avastin at a dose of 2.5 mg / kg, while at a dose of 7.5 mg / kg, the tumor inhibition effect of BD0801 was significantly better than that of Avastin at the same dose. The combination of 2.5 mg / kg Avastin and 10 mg / kg Paclitaxel did not show a significantly enhanced tumor inhibition effect compared with the Avastin monotherapy group; while the combination of 2.5 mg / kg BD0801 and 10 mg / kg Paclitaxel showed a significantly enhanced tumor inhibition effect compared with both monotherapy groups. Tumor-bearing mice were able to tolerate treatment with BD0801 at doses of 2.5 mg / kg and 7.5 mg / kg, Avastin at doses of 2.5 mg / kg and 7.5 mg / kg, and Paclitaxel at doses of 10 mg / kg, as well as BD0801 at doses of 2.5 mg / kg combined with Paclitaxel at doses of 10 mg / kg, and Avastin at doses of 2.5 mg / kg combined with Paclitaxel at doses of 10 mg / kg. Figure 3The results showed that both BD0801 and Avastin had significant tumor inhibitory effects in the SK-OV-3 nude mouse xenograft model of human ovarian cancer. BD0801 demonstrated a very good dose-response relationship, while Avastin had a slightly weaker dose-response relationship. At a high dose of 7.5 mg / kg, BD0801 exhibited significantly superior tumor inhibition compared to Avastin at the same dose. Furthermore, when combined with paclitaxel at a dose of 2.5 mg / kg, BD0801 significantly enhanced the tumor inhibition effect compared to either single-agent group.

[0166] Table 4 Tumor inhibition effect of the test substances on SK-OV-3 xenograft tumor model

[0167]

[0168] Note: a. Data shown are mean ± SD.

[0169] bP values ​​were obtained by analyzing relative tumor volumes using two-way ANOVA. The P values ​​shown are the values ​​compared between each group and the vehicle control group.

[0170] Example 2 Clinical trial of BD0801 combined with chemotherapy in patients with ovarian cancer

[0171] Study Objectives

[0172] To evaluate the safety and tolerability, pharmacokinetic characteristics, and antitumor efficacy of BD0801 monoclonal antibody combined with chemotherapy in patients with platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

[0173] Study Design

[0174] A multicenter, open-label, dose-escalation study was conducted to treat patients with platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer using a BD0801 monoclonal antibody combined with chemotherapy.

[0175] The trial is divided into two parts: the first phase is the dose escalation phase, in which the dose of BD0801 monoclonal antibody is designed to be 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, and 2 mg / kg, administered once every 2 weeks. The dose escalation is based on the occurrence of dose-limiting toxicities (DLTs) within two dosing cycles (two BD0801 monoclonal antibody combined with chemotherapy, generally 28 days, and no longer than 56 days). Blood samples are collected during this period for drug concentration determination. The chemotherapy drugs selected for combination are paclitaxel (administered once a week) or topotecan hydrochloride (administered 3 times every 4 weeks). After the end of treatment, the efficacy is evaluated. Subjects who have clinically benefited can continue to take the drug at the original dose and frequency until the disease progresses or intolerable adverse reactions occur, or informed consent is withdrawn / lost to follow-up, or new anti-tumor treatment is started.

[0176] The second phase is the expansion enrollment phase to further investigate the safety and efficacy of this product. If no DLT is observed in the first three subjects of each dose group at the end of the first two treatment cycles (week 4) or only one subject is observed in the first six subjects at the end of the first two treatment cycles (week 4), then enrollment is allowed to continue to 8-12 subjects. In addition, after discussion between the researchers and the sponsor, a specific dose group can be selected to expand to a maximum of 40 subjects. The medication method and blood collection method are the same as those for the subjects already enrolled in the dose group.

[0177] Dose escalation and termination criteria:

[0178] No dose escalation will be performed within individual subjects. Dose escalation between groups will be guided by the occurrence of dose-limiting toxicity (DLT) after completing two dosing cycles (two doses of BD0801 monoclonal antibody, generally 28 days, and no longer than 56 days). Dose escalation will be performed using the traditional "3+3" approach. Each dose group will first enroll one subject, and after completing one dose of BD0801 monoclonal antibody (d14), if no DLT occurs, two more subjects will be enrolled. At least three subjects in each dose group will complete the first and second cycles of treatment and evaluation and can be used for DLT evaluation. Dose escalation to the next dose will only be possible if no DLT occurs. If one patient in the first three cases develops DLT, another three patients will be enrolled in that dose group. If ≥2 / 6 subjects develop DLT, dose escalation will be stopped. If two patients in the first three cases develop DLT, dose escalation will be stopped.

[0179] The MTD (maximum tolerated dose) is defined as the highest dose at which fewer than one-third of subjects experience a DLT within a specified timeframe. The MTD is determined based on the occurrence of DLTs within two dosing cycles (two doses of BD0801 monoclonal antibody, typically 28 days apart and no longer than 56 days).

[0180] Subject population

[0181] Patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer.

[0182] Inclusion criteria:

[0183] 1. Age: ≥18 years old;

[0184] 2. Histologically or cytologically confirmed platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, including the following types: nonspecific adenocarcinoma (NOS), clear cell adenocarcinoma, endometrial adenocarcinoma, malignant Brunner's tumor, mixed epithelial carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, transitional cell carcinoma, and undifferentiated carcinoma;

[0185] 3. At least one measurable tumor lesion (according to RECIST 1.1);

[0186] 4. ECOGPS score 0-1;

[0187] 5. Subjects must have adequate organ function and meet all of the following laboratory test results before enrollment:

[0188] a) Bone marrow reserve is basically normal (no blood transfusion or blood products within 14 days before screening, no use of G-CSF or other hematopoietic stimulating factors for correction): ANC ≥ 1.5 × 10 9 / L, HB≥90g / L, PLT≥100×10 9 / L;

[0189] b) Normal liver function: TBIL ≤ 1.5 × ULN, AST ≤ 2.5 × ULN, alkaline phosphatase ≤ 2.5 × ULN;

[0190] c) Normal renal function: serum creatinine ≤ ULN or GFR (glomerular clearance) ≥ 60 mL / min, calculated according to the Cockroft-Gault formula: GFR for men = (140-age)*BW / (Scr*72); GFR for women = M*0.85;

[0191] d) Normal coagulation function: INR ≤ 1.5 (if the patient is receiving a stable dose of warfarin to manage venous thrombosis, the INR range should be between 2-3), APTT ≤ 1.2 × ULN;

[0192] 6. Disease progression within 6 months after completing at least 4 cycles of platinum-containing treatment;

[0193] 7. Expected survival time ≥ 12 weeks;

[0194] 8. The last chemotherapy should be at least 4 weeks old. If anti-tumor biological products have been received, a washout period of at least 4 half-lives is required;

[0195] 9. Toxic side effects caused by previous treatment need to be restored to ≤ Grade 1 (NCI CTC4.03);

[0196] 10. Subjects must provide informed consent to this study before the trial and voluntarily sign a written informed consent form;

[0197] 11. The subjects are able to communicate well with the researchers and complete the study in accordance with the research regulations.

[0198] Exclusion criteria:

[0199] 1. Patients have received more than 2 anti-tumor treatment regimens in the past;

[0200] 2. The patient has platinum-refractory disease, which is defined as disease progression during previous platinum-containing treatment;

[0201] 3. Ovarian tumors with low malignant potential, such as borderline tumors;

[0202] 4. The patient has an invasive malignant tumor (except non-melanoma skin cancer) or previous malignant tumor treatment is contraindicated by the current treatment plan;

[0203] 5. The patient has received any pelvic or abdominal radiotherapy;

[0204] 6. The patient has severe unhealed wounds, ulcers or fractures;

[0205] 7. Patients with a history of intestinal obstruction (including occlusive disease), abdominal fistula, gastrointestinal perforation, or abdominal abscess. Patients with rectal and sigmoid colon invasion during the screening period, or intestinal invasion found on CT scan, or with clinical symptoms of intestinal obstruction;

[0206] 8. Severe infections may require intravenous antibiotics or hospitalization;

[0207] 9. History of thromboembolism or bleeding disease within 6 months before enrollment;

[0208] 10. CNS diseases unrelated to tumors, symptomatic brain metastases;

[0209] 11. Clinically significant cardiovascular disease:

[0210] a) Uncontrolled hypertension (systolic blood pressure ≥150 mmHg and / or diastolic blood pressure ≥90 mmHg);

[0211] b) history of myocardial infarction or unstable angina within 6 months before enrollment;

[0212] c) Congestive heart failure or New York Heart Association (NYHA) class II heart failure;

[0213] d) Severe arrhythmias requiring drug treatment, excluding asymptomatic atrial fibrillation with controllable heart rate;

[0214] 12. Left ventricular ejection fraction is lower than the lower limit of normal;

[0215] 13. Previous neuropathy ≥CTCAE grade 2 (limited to the paclitaxel + BD0801 monoclonal antibody group);

[0216] 14. Known severe allergy to the therapeutic drugs or excipients used in the regimen;

[0217] 15. Pregnant or breastfeeding women;

[0218] 16. Patients with proteinuria (urine protein >1+ during screening examination, or proteinuria of 1+ that does not return to normal after retesting within 24 hours);

[0219] 17. Patients who have previously received anti-VEGF protein drugs such as bevacizumab and BD0801 monoclonal antibody;

[0220] 18. Patients undergoing major surgery or planning to undergo surgery:

[0221] a) Underwent major surgical operation or obvious trauma within 28 days before enrollment;

[0222] b) Major surgical procedures are expected during the study, including but not limited to abdominal surgery (open or laparoscopic) before disease progression;

[0223] c) Open biopsy within 7 days before enrollment;

[0224] 19. Currently or within 30 days before enrollment, receiving treatment with other study drugs.

[0225] Test drug

[0226] BD0801 antibody was produced and provided by Shandong Xiansheng Biopharmaceutical Co., Ltd. and stored at 2-8°C.

[0227] Paclitaxel injection: Manufacturer: Beijing Union Pharmaceutical Factory.

[0228] Topotecan Hydrochloride for Injection: Manufacturer: Jiangsu Aosaikang Pharmaceutical Co., Ltd.

[0229] Dosage

[0230] BD0801 monoclonal antibody dosing regimen: specific doses (0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg) are administered once every 2 weeks (14 days).

[0231] Paclitaxel: 80 mg / m 2 , administer once on days 1, 8, 15, and 22 of a 28-day dosing cycle. Use according to the instructions.

[0232] Topotecan hydrochloride: 4 mg / m 2 Intravenous infusion, once on days 1, 8, and 15 of a 28-day dosing cycle. Use according to the instructions.

[0233] Dosing order: Administer according to the respective dosing cycles. If BD0801 and chemotherapy are administered on the same day, BD0801 should be infused first.

[0234] Trial Groups

[0235] BD0801 monoclonal antibody + paclitaxel group: BD0801 monoclonal antibody was administered every 2 weeks (14 days) as a dosing cycle, and paclitaxel was administered once on the 1st, 8th, 15th, and 22nd days of the 28-day dosing cycle. If both were administered on the same day, BD0801 monoclonal antibody was infused first.

[0236] BD0801 monoclonal antibody + topotecan hydrochloride group: BD0801 monoclonal antibody was administered every 2 weeks (14 days) as a dosing cycle, and topotecan hydrochloride was administered once on the 1st, 8th, and 15th days of the 28-day dosing cycle. If both were administered on the same day, BD0801 monoclonal antibody was infused first.

[0237] Treatment continued until disease progression or intolerable adverse reactions occurred or other treatment termination criteria were met.

[0238] Research indicators and evaluation criteria

[0239] Safety indicators: DLT, adverse events, clinical safety laboratory tests, electrocardiogram, vital signs, echocardiography, etc.

[0240] Efficacy endpoints: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).

[0241] Pharmacokinetic indicators: Cmax, Tmax, AUC (TAU) 、Accumulation Ratio(AR),C trough .

[0242] Statistics and Analysis

[0243] Analyze the dataset:

[0244] Full Analysis Set (FAS): All enrolled subjects who received study drug and had at least one tumor assessment after baseline.

[0245] Safety Data Set (SS): All subjects enrolled and received study drug. DLT Assessment Analysis Set: The DLT Assessment Set includes subjects who completed at least one BD0801 monoclonal antibody treatment during the dose escalation phase and completed the DLT assessment observation period (e.g., 28 days from the first dose) or withdrew due to DLT during the observation period.

[0246] PK concentration set (PKCS): All subjects who were enrolled, received the study drug, and had at least one valid blood drug concentration data during the trial.

[0247] PK Parameter Analysis Set (PKPS): All subjects enrolled, receiving study drug, and with at least one valid PK parameter during the trial. Subjects excluded from the PKPS include: a) subjects whose enrollment was due to serious protocol violations, which affected PK parameter results or made it impossible to estimate parameters; and b) subjects who took concomitant medications during the trial that affected PK parameters.

[0248] Security Analysis:

[0249] Analyze the SS / DLT assessment analysis set. Determine the DLT and MTD. Adverse events, laboratory values, vital signs, and electrocardiograms were analyzed using descriptive statistics. The incidence of adverse events, adverse reactions, major adverse events, serious adverse events, and adverse events leading to discontinuation were summarized by dose group.

[0250] Pharmacokinetic analysis:

[0251] Descriptive statistics were summarized for BD0801 monoclonal antibody plasma concentrations by dose level and planned duration; descriptive statistics were analyzed for PK parameters by dose level. Concentration-time curves for each subject and the mean concentration-time curve were plotted based on the plasma concentration-time data measured for each subject.

[0252] Immunogenicity analysis:

[0253] The frequency and rate of positive immunogenicity reactions were summarized, and the corresponding titer values ​​were tabulated by subject and study date. The possible impact of immunogenicity on the pharmacokinetics and safety of BD0801 monoclonal antibody was also explored.

[0254] Efficacy analysis:

[0255] Objective response rate (ORR) and disease control rate (DCR), along with their 95% confidence intervals, were calculated based on the full analysis set (FAS). Kaplan-Meier survival curves were estimated for progression-free survival (PFS) and overall survival (OS), and survival curves were plotted. Descriptive statistics were also collected for changes in tumor size.

[0256] Objective response rate (ORR): ORR and its 95% confidence interval were calculated (Clopper-Pearson exact method).

[0257] ORR=(CR+PR) / (CR+PR+SD+PD+NE)×100%

[0258] Confirmed and unconfirmed CR and PR results were analyzed simultaneously.

[0259] Disease Control Rate (DCR): DCR and its 95% confidence interval were calculated (Clopper-Pearson exact method).

[0260] DCR=(CR+PR+SD) / (CR+PR+SD+PD+NE)×100%

[0261] Analyze both confirmed and unconfirmed results.

[0262] Progression-free survival (PFS) is the time from the start of study drug treatment to the first documented PD or death, whichever occurs first. If no disease progression is observed, the censoring date should be the date of the last tumor measurement before the receipt of a new anti-cancer drug. PFS was summarized graphically using the Kaplan-Meier test, with censoring rates, quartiles, and 95% CIs (Brookmeyer-Crowley method) presented. PFS rates at different times and their 95% CIs were estimated (log-log transformation).

[0263] PFS (months) = (date of first disease progression or death or date of last tumor measurement – ​​date of first dose + 1) / 30.4375

[0264] Overall survival (OS) was defined as the time from the start of study drug treatment to the date of death (from any cause). If no death was observed, the last known living date was used as the censoring date. OS was summarized graphically using the Kaplan-Meier test, with censoring rates, quartiles, and 95% CIs presented (Brookmeyer-Crowley method). Survival rates at different times and their 95% CIs were estimated (log-log transformation).

[0265] OS (months) = (date of death or last follow-up date – date of first administration + 1) / 30.4375

[0266] Tumor Size Change: Descriptive statistics were generated for the change from baseline in the sum of the longest diameters (SLD) of the measurable tumors. A waterfall plot was created to show the maximum percentage reduction in SLD compared to the screening period for each patient. Additionally, the change from baseline in SLD at each tumor assessment after treatment was also presented.

[0267] result

[0268] 1. Subject population

[0269] A total of 29 subjects participated in this trial and received at least one dose of study drug. Among these 29 subjects, the average disease duration was approximately 28.19 months. The majority of these subjects had epithelial ovarian cancer (25 patients, 86.2%), with 2 patients each having primary peritoneal cancer and fallopian tube cancer (6.9%). The pathological diagnosis was primarily serous adenocarcinoma (25 patients, 86.2%), followed by clear cell adenocarcinoma in 2 patients (6.9%), mixed epithelial carcinoma in 1 patient (3.4%), and other types in 1 patient (3.4%). See Table 5 for details.

[0270] Table 5 History of tumor

[0271]

[0272] All 29 subjects had target lesions, with the maximum sum of target lesions being 195.54 mm, the minimum being 12 mm, and the average being 71.342 mm.

[0273] All enrolled subjects had received chemotherapy before, but none had received radiotherapy. One subject (3.4%) had received PARP inhibitor treatment, and eight subjects (27.6%) had received other treatments.

[0274] Most of the 29 subjects (26, 89.7%) had an ECOG score of 0 at enrollment, and 3 subjects (10.3%) had a score of 1.

[0275] All 29 subjects had a history of major surgery.

[0276] The most common concomitant diseases were hypertension (5 cases, 17.2%) and diabetes (5 cases, 17.2%), and the most common concomitant medications were systemic antibiotics (2 cases, 6.9%).

[0277] A total of 22 of the 29 subjects (75.9%) received subsequent chemotherapy anti-tumor treatment after the end of study treatment, including 2 in the 0.5 mg / kg dose group, 11 in the 1 mg / kg dose group, and 9 in the 1.5 mg / kg dose group.

[0278] 2. Security

[0279] There were no DLT events in this study, and the MTD was not reached. The recommended dose is 1.5 mg / kg Q2W.

[0280] By the end of the study, 29 subjects (100%) experienced adverse events. There were no differences in the frequency of adverse events across dose groups or chemotherapy regimens, with hematologic toxicity being the most common. Grade 3 or higher adverse events with an incidence greater than 5% included decreased neutrophil count (51.72%), decreased white blood cell count (41.38%), decreased platelet count (17.24%), anemia (17.24%), increased gamma-glutamyltransferase (10.34%), vomiting (10.34%), hypertension (10.34%), and hypertriglyceridemia (6.90%).

[0281] A total of 27 subjects (93.10%) experienced adverse events related to BD0801 monoclonal antibody. The incidence of drug-related adverse events was similar in the three dose groups. According to PT classification, the most common drug-related adverse reaction was decreased white blood cell count (24.14%).

[0282] There was one fatal SAE, an intracranial hemorrhage in the 1.5 mg / kg dose group (combined with topotecan hydrochloride). The researchers believe this SAE was likely unrelated to the trial drug and the combined chemotherapy. A total of 11 subjects experienced 15 post-treatment SAEs. The most common SAE, according to PT classification, was decreased neutrophil count (6.9%).

[0283] A total of 26 subjects (89.66%) experienced adverse events leading to dose reduction or suspension of BD0801 monoclonal antibody, with the highest incidence being decreased neutrophil count (44.83%). A total of 3 subjects (10.34%) experienced adverse events leading to permanent discontinuation of BD0801 monoclonal antibody after taking the drug, including 2 cases in the 1.5 mg / kg dose group, decreased platelet count and proteinuria, and 1 case in the 1.0 mg / kg dose group, abdominal pain.

[0284] Adverse events of particular interest in this study included gastrointestinal perforation or fistula, hypertension, proteinuria, embolic and thrombotic events, and various types of bleeding. Details of their occurrence are shown in Table 6. By SOC classification, the most common AESI was renal and urinary system disorders (11 cases / 37.93%), followed by various investigations (9 cases / 31.03%), vascular and lymphatic disorders (7 cases / 24.14%), and respiratory, thoracic, and mediastinal disorders (3 cases / 10.34%). By PT classification, the most common AESI was proteinuria (11 cases / 37.93%), followed by urine protein detection (7 cases / 24.14%) and hypertension (6 cases / 20.69%).

[0285] Table 6 Subsystem analysis of adverse events of special concern after medication (SS)

[0286]

[0287]

[0288] Analysis of grade 3 and above adverse events

[0289] A total of 25 subjects (86.21%) experienced adverse events of Grade 3 or higher severity following treatment, with the incidence rates in the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg groups being 100%, 91.67%, and 78.57%, respectively. Grade 3 or higher adverse events with an incidence of 5% or more included decreased neutrophil count (51.72%), decreased white blood cell count (41.38%), decreased platelet count (17.24%), anemia (17.24%), increased gamma-glutamyltransferase (10.34%), hypertension (10.34%), decreased neutrophil percentage (6.90%), vomiting (10.34%), and hypertriglyceridemia (6.90%). See Table 7 for details.

[0290] Table 7 Subsystem analysis (SS) of adverse events ≥ grade 3 after medication

[0291]

[0292]

[0293] The incidence of grade ≥3 adverse events related to BD0801 was 37.93%. The incidence in the 1.5 mg / kg group was 57.14%, slightly higher than the 1.0 mg / kg group (25.0%). The incidence in the paclitaxel subgroup was slightly higher than that in the topotecan hydrochloride subgroup (45.45% vs. 33.33%). Grade ≥3 adverse events related to BD0801 with an incidence of ≥5% included decreased white blood cell count (10.34%), decreased neutrophil count (10.34%), hypertension (10.34%), increased gamma-glutamyltransferase (6.90%), and decreased platelet count (6.90%). See Table 8 for details. There were no grade ≥3 adverse events related to BD0801 and unrelated to chemotherapy after administration.

[0294] Table 8 Subsystem analysis (SS) of adverse events related to BD0801 monoclonal antibody with grade ≥3 after administration

[0295]

[0296] 3. Pharmacokinetics / pharmacodynamics

[0297] The pharmacokinetic parameters of BD0801 monoclonal antibody after administration of different doses are detailed in Table 9-1, Table 9-2 and Table 9-3. 1 / 2The main exposure parameters (C max , AUC 0-t , AUC 0-inf ) increases with increasing dose and shows a good linear relationship. After multiple administrations, within the dose range of 0.5-1.5 mg / kg, T 1 / 2 The main exposure parameters (C max , AUC 0-t , AUC 0-inf ) increased with increasing dose, showing a good linear relationship. The steady-state AUC was similar to the AUC after the first dose, indicating no significant accumulation of BD0801 after repeated dosing.

[0298]

[0299] Note: *T max Use median (range) description; AR, accumulation coefficient, AR = AUC 0-t (Steady state) / AUC 0-t (first).

[0300] Table 9-2 Pharmacokinetic parameters of BD0801 monoclonal antibody after administration (Mean±SD)

[0301]

[0302] Note: *T max Use median (range) description; AR, accumulation coefficient, AR = AUC 0-t (Steady state) / AUC 0-t (first).

[0303] Table 9-3 Pharmacokinetic parameters of BD0801 monoclonal antibody after administration (Mean±SD)

[0304]

[0305]

[0306] Note: *T max Use median (range) description; AR, accumulation coefficient, AR = AUC 0-t (Steady state) / AUC 0-t (first).

[0307] Immunogenicity

[0308] A total of 29 subjects were enrolled in immunogenicity analysis of the BD0801 monoclonal antibody in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. Nine patients tested positive for ADA (anti-drug antibodies) in their sera after BD0801 administration compared to baseline levels, with a positive ADA detection rate of 31.0% (9 / 29).

[0309] 4. Effectiveness

[0310] (1) Analysis of the overall best therapeutic effect of tumor lesions (confirmation)

[0311] The overall objective response rate (ORR) was 31%, with 20 subjects achieving a clinical benefit, for a clinical benefit rate (DCR) of 69.0%. One subject (3.4%) achieved a CR as the best overall response, in the 1.0 mg / kg paclitaxel group. Eight subjects (27.6%) achieved a PR as the best response, including one (33.3%) in the 0.5 mg / kg group, three (25.0%) in the 1 mg / kg group, and four (28.6%) in the 1.5 mg / kg group. Eleven subjects (37.9%) achieved a SD as the best response, including six (50.0%) in the 1 mg / kg group and five (35.7%) in the 1.5 mg / kg group. A detailed analysis of the overall best response by dose group is shown in Table 10.

[0312] In the BD0801 combined with paclitaxel subgroup, 7 of 11 patients experienced a response, resulting in an overall objective response rate of 63.6%, 8 patients experiencing clinical benefit, and a DCR of 72.7%. The ORRs for the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg dose groups were 50.0%, 66.7%, and 66.7%, respectively.

[0313] In the BD0801 monoclonal antibody combined with topotecan hydrochloride group, 2 of 18 subjects experienced remission, with an overall objective response rate of 11.1%. 12 subjects achieved clinical benefit, with a DCR of 66.7%.

[0314] The ORRs of the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg dose groups were 0, 22.2%, and 0, respectively.

[0315] Table 10 Comprehensive analysis of the best overall efficacy (confirmation) of tumor lesions (FAS)

[0316]

[0317]

[0318] Note: Best efficacy refers to the best efficacy recorded from the start of treatment to disease progression / recurrence.

[0319] Objective response rate (ORR) = n1 / N, n1 = CR + PR;

[0320] Clinical benefit rate (DCR) = n2 / N, n2 = CR + PR + SD;

[0321] Conditions that could not be classified as CR, PR, SD, or PD were classified as NE (not evaluable).

[0322] Confirmed: Patients with CR or PR must be re-examined 4 weeks after the initial evaluation of CR or PR to confirm the efficacy.

[0323] (2) Comprehensive analysis of the best overall therapeutic effect of tumor lesions (unconfirmed)

[0324] The unconfirmed overall objective response rate was 37.9%, and the clinical benefit rate was 69.0%. One subject (3.4%) achieved a CR (best overall response) in the 1.0 mg / kg dose group. Ten subjects (34.5%) achieved a PR (best overall response), including one (33.3%) in the 0.5 mg / kg dose group, three (25.0%) in the 1.0 mg / kg dose group, and six (42.9%) in the 1.5 mg / kg dose group. A detailed analysis of the best overall response by dose group is shown in Table 11.

[0325] In the BD0801 combined with paclitaxel subgroup, 8 of 11 subjects achieved an objective response (ORR) of 72.7%. The ORRs for the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg doses were 50.0%, 66.7%, and 83.3%, respectively. A total of 8 subjects achieved clinical benefit, with a DCR of 72.7%. The DCRs for the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg doses were 50.0%, 66.7%, and 83.3%, respectively.

[0326] In the BD0801 combined with topotecan hydrochloride subgroup, 3 of 18 subjects achieved an objective response (ORR) of 16.7%. ORRs were 0%, 22.2%, and 12.5% ​​in the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg doses, respectively. A total of 12 subjects achieved clinical benefit, with a DCR of 66.7%. DCRs were 0%, 88.9%, and 50.0% in the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg doses, respectively.

[0327] Table 11 Comprehensive analysis of the best overall therapeutic effect (unconfirmed) of tumor lesions (FAS)

[0328]

[0329]

[0330] Note: Best efficacy refers to the best efficacy recorded from the start of treatment to disease progression / recurrence.

[0331] Objective response rate (ORR) = n1 / N, n1 = CR + PR;

[0332] Clinical benefit rate (DCR) = n2 / N, n2 = CR + PR + SD;

[0333] Conditions that could not be classified as CR, PR, SD, or PD were classified as NE (not evaluable).

[0334] Unconfirmed: Unconfirmed CR or PR (calculated without considering the next tumor assessment confirmation).

[0335] (3) Analysis of progression-free survival (months)

[0336] A total of 27 (93.1%) of the 29 subjects experienced a PFS event. Two subjects in the 1.5 mg / kg dose group were censored, both in the paclitaxel subgroup. The median PFS was 5.4 months, compared with 1.9 months in the 0.5 mg / kg, 5.9 months in the 1.0 mg / kg, and 4.6 months in the 1.5 mg / kg groups. The 3-month, 6-month, and 1-year PFS rates were 65.5%, 40.3%, and 4.0%, respectively. Detailed PFS analysis is provided in Tables 12-13.

[0337] In the BD0801 plus paclitaxel subgroup, 9 of 11 patients (81.8%) experienced a PFS event, with a median PFS of 5.3 months. The median PFS in the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg groups was 5.2 months, 5.3 months, and 5.7 months, respectively. The 3-month, 6-month, and 1-year PFS rates were 72.7%, 43.6%, and 14.5%, respectively.

[0338] All 18 subjects (100%) in the BD0801 combined with topotecan hydrochloride subgroup experienced a PFS event, with a median PFS of 5.5 months. The median PFS in the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg groups were 1.0 month, 6.1 month, and 4.0 months, respectively. The 3-month, 6-month, and 1-year PFS rates were 61.1%, 38.9%, and 0%, respectively.

[0339] Table 12 Analysis of disease progression-free survival (months) (FAS)

[0340]

[0341] Note: 95% CI was calculated using the Brookmeyer-Crowley method.

[0342] Table 13 Progression-free survival rate (%) (FAS) at different time (months)

[0343]

[0344] Note: 95% CI was calculated using log-log transformation.

[0345] (4) Analysis of overall survival (months)

[0346] As of October 20, 2020, with a median follow-up of 12.8 months, 15 patients (51.7%) experienced OS events, with 14 censored (10 alive, 4 lost to follow-up). The median OS was 14.9 months. The mOS was not reached in the 0.5 mg / kg dose group, while the median OS was 13.5 months and 18.9 months in the 1.0 mg / kg and 1.5 mg / kg dose groups, respectively. The 6-month overall survival rate was 86.2%, the 1-year overall survival rate was 71.0%, and the 2-year overall survival rate was 31.2%. Detailed overall survival and survival analysis is shown in Tables 14-15.

[0347] In the BD0801 combined with paclitaxel subgroup, 4 (36.4%) subjects achieved OS (OS) events. Both subjects in the 0.5 mg / kg dose group did not reach OS. Median OS was 14.2 months in the 1.0 mg / kg and 18.9 months in the 1.5 mg / kg and 1.5 mg / kg dose groups, respectively. Six-month survival rates were 100%, 100%, and 83.3%, respectively, and one-year overall survival rates were 100%, 66.7%, and 83.3%, respectively, in the 0.5 mg / kg, 1.0 mg / kg, and 1.5 mg / kg dose groups.

[0348] Eleven of the 18 patients (61.1%) treated with BD0801 combined with topotecan hydrochloride experienced an OS event, with a median OS of 12.8 months. The median OS was 3.5 months for the 0.5 mg / kg, 12.8 months for the 1.0 mg / kg, and 15.1 months for the 1.5 mg / kg dose groups, respectively. The 6-month, 1-year, and 2-year OS rates were 83.3%, 65.7%, and 24.6%, respectively.

[0349] Table 14 Overall survival (months) analysis (FAS)

[0350]

[0351] Table 15 Overall survival rate (%) (FAS) at different time (months)

[0352]

[0353]

[0354] (4) Analysis of the relationship between exposure and efficacy

[0355] Eleven patients received BD0801 monoclonal antibody combined with paclitaxel (PTX) chemotherapy, and the ORR was 7 / 11 (63.6%). Further analysis was conducted to divide the 11 PTX group subjects into groups according to the dose, and to analyze the dose-effect relationship between the subjects' best overall efficacy objective response rate (ORR) and the dose. Figure 4 .

[0356] In the chemotherapy regimen of BD0801 monoclonal antibody combined with paclitaxel (PTX) or topotecan hydrochloride, the subjects' AUCs were ranked from low to high and divided into three strata. A dose-effect relationship analysis was performed between the ORR of the subjects with the best overall efficacy and drug exposure (AUC). There was a certain positive correlation between ORR and BD0801 monoclonal antibody exposure. In contrast, there was no obvious correlation between ORR and exposure of BD0801 monoclonal antibody combined with topotecan hydrochloride (TOPO). Figure 5 .

[0357] There was no significant correlation between progression-free survival (PFS) and dose at different doses in the overall population. Figure 6 .

[0358] The relationship between the exposure of BD0801 monoclonal antibody combined with paclitaxel (PTX) and the percentage reduction of the sum of the longest diameter of the tumor (SLD) is shown in detail. Figure 7 It can be seen that the exposure of BD0801 monoclonal antibody is positively correlated with tumor shrinkage.

Claims

1. Use of a combination of an anti-human VEGF antibody and a chemotherapy drug in the preparation of a drug for treating ovarian cancer, characterized in that: The chemotherapy drug is selected from taxane compounds or camptothecin compounds, the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3, wherein, The sequence of the HCDR1 is shown in SEQ ID NO: 5; The sequence of the HCDR2 is shown in SEQ ID NO: 8; The sequence of the HCDR3 is shown in SEQ ID NO: 11; The sequence of the LCDR1 is shown in SEQ ID NO: 13; The sequence of the LCDR2 is shown in SEQ ID NO: 15; and The sequence of the LCDR3 is shown in SEQ ID NO:

17.

2. The use according to claim 1, characterized in that The sequence of the heavy chain variable region is shown in SEQ ID NO: 1, and the sequence of the light chain variable region is shown in SEQ ID NO:

3.

3. The use according to claim 2, characterized in that The antibody further includes a heavy chain constant region, the sequence of which is shown in SEQ ID NO:

2. The antibody further includes a light chain constant region, the sequence of which is shown in SEQ ID NO:

4.

4. The use according to any one of claims 1 to 3, characterized in that The ovarian cancer is epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

5. The use according to claim 4, characterized in that The ovarian cancer is platinum-resistant recurrent ovarian cancer.

6. The use according to claim 4, characterized in that The pathological type of the ovarian cancer is serous adenocarcinoma, clear cell adenocarcinoma or mixed epithelial carcinoma.

7. The use according to any one of claims 1 to 3, characterized in that The taxane compound is paclitaxel, and the camptothecin compound is topotecan hydrochloride.

8. The use according to any one of claims 1 to 3, characterized in that: The effective administration amount of the anti-human VEGF antibody is 0.5 to 2 mg / kg.

9. The use according to claim 8, characterized in that The effective administration amount of the anti-human VEGF antibody is 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg or 2 mg / kg.

10. The use according to claim 8, characterized in that The dosage form of the anti-human VEGF antibody is a single-dose dosage form, and each dose contains an amount of the antibody that can be effectively administered to a patient.

11. The use according to claim 10, characterized in that The single-dose dosage form contains 25 to 150 mg of the anti-human VEGF antibody.

12. The use according to claim 11, characterized in that The single-dose dosage form contains 25 mg, 50 mg, 80 mg, 100 mg or 150 mg of the anti-human VEGF antibody.

13. The use according to claim 7, characterized in that The effective dosage of paclitaxel is 80 mg / m 2 The effective dosage of topotecan hydrochloride is 4 mg / m 2 .

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