Methods for providing safe administration of anti-CD40 antibodies - Patents.com

Abstract

Methods are provided for the clinically proven, safe administration of anti-CD40 antibodies by intravenous administration. Methods are also provided for the clinically proven, safe treatment of advanced solid tumors by intravenous administration of anti-CD40 antibodies.

Description

[Technical Field]

[0001] Reference to an electronically submitted sequence listing This application contains a Sequence Listing having a size of 10 kb, which has been submitted electronically via EFS-Web as an ASCII Sequence Listing with the file name "Sequence Listing_688097.0808" created on May 22, 2019. The Sequence Listing submitted via EFS-Web is a part of the present specification and is incorporated herein by reference in its entirety.

[0002] Background of the Invention CD40, a 48-kilodalton transmembrane cell-surface glycoprotein, is a costimulatory receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily (Elgueta R, et al. Immunol Rev., 2009, 229(1):152(-172)). Constitutive expression of CD40 is variable, and this receptor can be detected on the surface of antigen-presenting cells (APCs), including dendritic cells (DCs), B lymphocytes, and macrophages. Furthermore, CD40 is expressed on granulocytes, endothelial cells, smooth muscle cells, fibroblasts, and epithelial cells (Korniluk, et al. Tumor Biol., 2014, 35(10):9447-9457; Peters et al. Semin Immunol., 2009, 21(5):293-300).

[0003] Consistent with its widespread expression on normal cells, CD40 is also present on the membranes of a wide range of malignant cells, including non-Hodgkin's and Hodgkin's lymphomas, myelomas, and several carcinomas, including those of the nasopharynx, bladder, cervix, kidney, and ovary (Eliopoulos AG & Young LS., Curr. Opin. Pharmacol., 2004, 4(4):360-367). CD40 interacts with a single ligand, CD40L (or CD154), a transmembrane protein expressed by activated T lymphocytes, B lymphocytes, platelets, mast cells, macrophages, basophils, natural killer (NK) cells, and nonhematopoietic cells (smooth muscle cells, endothelial cells, and epithelial cells). Binding of CD40 to its sole ligand, CD40L, as part of a cell-cell interaction activates an intracellular signaling pathway involving a series of adaptor molecules known as TNF receptor activators (or TRAFs). To initiate this intracellular signaling, multiple CD40 receptors must form clusters on the cell membrane (Peters et al. Semin Immunol., 2009, 21(5):293-300). This CD40 clustering allows the assembly of a supramolecular signaling complex consisting of multiple TRAFs, which then leads to the activation of downstream transcription factors, including nuclear factor kappa B (NF-κB) (Kornbluth et al. Int. Rev. Immunol., 2012, 31(4):279-288).

[0004] The molecular consequences of CD40 signaling depend on the cell type expressing CD40 and the microenvironment in which the CD40 signal is provided (Vonderheide et al. ClinCancerRes., 2013, 19(5):1035-1043). CD40 ligation and cross-linking are required for the licensing of adaptive immune responses by APCs and, in particular, DCs, by inducing the upregulation of membrane costimulatory molecules and MHC molecules and the production of proinflammatory cytokines. Thus, CD40 is involved in the functional maturation of APCs and, consequently, the activation of antigen-specific T lymphocytes (Long et al. CancerDiscov., 2016, 6(4):400-13; Moran et al. Curr. Opin. Immunol., 2013, 25(2):230-237). CD40 also plays a role in humoral immunity by activating resting B lymphocytes and increasing their antigen-presenting function (Vonderheide et al. Clin Cancer Res., 2013, 19(5):1035-1043; Wolchok et al. Clin. Cancer Res., 2009, 15(23):7412-7420). Furthermore, CD40 is involved in the induction of innate immunity by stimulating cytotoxic myeloid cells such as NK cells, macrophages, and granulocytes (Rakhmilevich et al. Int. Rev. Immunol., 2012, 31(4):267-278). The opposing roles of CD40 / CD450L in promoting both tumor progression and tumor cell apoptosis have been attributed to the CD40 / CD450L pathway in various neoplastic diseases (Korniluk et al. Tumour Biol., 2014, 35(10):9447-9457).

[0005] These important CD40 / CD40L-mediated pathways play dual roles in both promoting tumor progression and inducing apoptosis of tumor cells in various neoplastic diseases (Beatty GL, et al. Science, 2011, 331(6024):1612-1616). However, systemic administration of CD40 antibodies has been associated with adverse side effects, such as shock syndrome and cytokine release syndrome (van Mierlo et al., 2002, Proc. Natl. Acad. Sci. USA, 99:5561-5566; van Mierlo et al., 2004, J Immunol 173:6753-6759). Examples of other anti-CD40 antibodies and their production are described, for example, in U.S. Pat. No. 9,676,862.

[0006] In view of the above, there remains a need for improved anti-tumor therapies, in particular anti-CD40 agonist antibodies suitable for clinical use.

[0007] Brief Summary of the Invention The present invention relates to the clinically proven and safe administration of anti-CD40 antibodies to subjects, including the clinically proven and safe treatment of advanced solid tumors.

[0008] In one general aspect, the invention provides a method for providing a clinically proven and safe administration of an anti-CD40 antibody to a human subject in need thereof, the method comprising intravenously administering to the subject a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier, preferably the antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, or sequences with at least 95% (or at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region comprises the amino acid sequences of light chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 4, 5, and 6, respectively. the total dose of the antibody administered is 50 μg / kg to 2500 μg / kg, preferably 75 μg to 2000 μg / kg, and optionally 100 μg / kg to 1800 μg / kg, 200 μg / kg to 1500 μg / kg, 300 μg / kg to 1400 μg / kg, 400 μg / kg to 1300 μg / kg, 500 μg / kg to 1200 μg / kg, 600 μg / kg to 1100 μg / kg, 700 to 1000 μg / kg, or 800 to 900 μg / kg of the subject's body weight per administration.

[0009] In one embodiment, the human subject has been diagnosed with an advanced solid tumor.

[0010] In one embodiment, the anti-CD40 antibody comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO:7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:8.

[0011] In one embodiment, the anti-CD40 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO:9 and a light chain (LC) having the amino acid sequence of SEQ ID NO:10.

[0012] In some embodiments, the total dose of anti-CD40 antibody administered per administration is 50 μg / kg, 75 μg / kg, 100 μg / kg, 200 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1000 μg / kg, 1100 μg / kg, 1200 μg / kg, 1300 μg / kg, 1400 μg / kg, 1500 μg / kg, 1800 μg / kg, 2000 μg / kg, or 2500 μg / kg per kg of subject body weight, or any dose therebetween.

[0013] In one embodiment, the total dose of the pharmaceutical composition is administered intravenously to a human subject over a period of 0 minutes to 3 hours, preferably 5 minutes to 150 minutes, 10 minutes to 2 hours, 15 minutes to 90 minutes, 20 minutes to 1 hour, 25 minutes to 55 minutes, 30 minutes to 50 minutes, or 35 minutes to 45 minutes, or 40 minutes to 45 minutes, for example, about 0 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 90 minutes, about 2 hours, about 150 minutes, or about 3 hours. Preferably, the pharmaceutical composition is administered intravenously to a human subject repeatedly, i.e., two or more times, over a period of one day, one week, one month, six months, one year, two years or more, more preferably once daily, once weekly, once every two weeks, once monthly, once every six months, etc.

[0014] In one embodiment, the method further comprises administering a therapeutic agent to the human subject before, after, or simultaneously with administration of the anti-CD40 antibody, preferably the therapeutic agent is selected from the group consisting of corticosteroids, antihistamines, antipyretics, H2-antagonists, and antiemetics.

[0015] In one embodiment, the pharmaceutical composition comprises 1 mg / mL to 100 mg / mL of an anti-CD40 antibody, preferably 10 mg / mL to 90 mg / mL, 20 mg / mL to 80 mg / mL, 30 mg / mL to 70 mg / mL, 40 mg / mL to 60 mg / mL, or 40 mg / mL to 50 mg / mL, for example, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, or 100 mg / mL of an anti-CD40 antibody and a pharmaceutically acceptable carrier.

[0016] In another general aspect, the invention provides a method for providing a clinically proven and safe administration of an anti-CD40 antibody to a human subject in need thereof, the method comprising intravenously administering to the subject a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier, preferably wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region having heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 identical to the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, or at least 95% (or at least 96%, at least 97%, at least 98%, the light chain variable region comprises the amino acid sequences of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively, or sequences that have at least 95% (or at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NOs: 4, 5, and 6, respectively; the total dose of the antibody administered is about 600 μg / kg to 900 μg / kg of the subject's body weight per administration; and preferably, the human subject has been diagnosed with non-small cell lung cancer (NSCLC), pancreatic cancer, or cutaneous melanoma.

[0017] In one embodiment, the anti-CD40 antibody comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO:7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:8.

[0018] In one embodiment, the anti-CD40 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO:9 and a light chain (LC) having the amino acid sequence of SEQ ID NO:10.

[0019] In one embodiment of the present invention, there is provided an anti-CD40 antibody as described in the previous embodiment for use in medicine.

[0020] In further embodiments of the present invention, there are provided anti-CD40 antibodies as described in the preceding embodiments for use in the treatment of advanced solid tumors, including, but not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, kidney cancer, oral cancer, liver cancer, melanoma (including cutaneous melanoma), mesothelioma, non-small cell lung cancer, non-melanoma skin cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, small cell lung cancer, and thyroid cancer.

[0021] In further embodiments of the present invention, there is provided an anti-CD40 antibody as described in the preceding embodiments for use in the manufacture of a medicament for the treatment of advanced solid tumors, including but not limited to bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, kidney cancer, oral cancer, liver cancer, melanoma (including cutaneous melanoma), mesothelioma, non-small cell lung cancer, non-melanoma skin cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, small cell lung cancer, and thyroid cancer.

[0022] Preferably, in these two embodiments, treating an advanced solid tumor comprises administering an anti-CD40 antibody as defined above to a human subject diagnosed with an advanced solid tumor, comprising intravenously administering to the subject a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier, wherein the total dose of the antibody administered is 50 μg / kg to 2500 μg / kg, preferably 75 μg / kg to 2000 μg / kg, of the subject's body weight per administration.

[0023] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will be apparent from the following detailed description and the appended claims. [Brief explanation of the drawings]

[0024] The foregoing Summary of the Invention and the following Detailed Description of the Invention will be better understood when read in conjunction with the accompanying drawings. It should be understood that the invention is not limited to the precise embodiments shown in the drawings.

[0025] This patent or application file contains at least one color-printed drawing. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Figure 1] 1 is a diagrammatic representation of the study design for the clinical trial in Example 1. IV = intravenous, NSCLC = non-small cell lung cancer, q14d = every 14 days, RP2D = recommended Phase II dose. [Figure 2] FIG. 1 shows the study design and cohorts with and without corticosteroid pre-infusion. [Figure 3] Graph of incidence of infusion-related reactions (IRRs) per assigned dose, censored by dose escalation. [Figure 4] Graph showing mean serum concentrations over time cycles 1 and 2. [Figure 5] 1 is a graph showing dose-normalized AUC0-24h. [Figure 6] A-C are graphs showing the percentage of B cells (A), T cells (B), and NK cells (C) in peripheral blood after infusion of antibody A, normalized to pre-infusion levels (no corticosteroid cohort). [Figure 7] A-I are graphs showing cytokine / chemokine levels in peripheral blood after infusion of antibody A (no corticosteroid cohort): MCP-1 (A), IP-10 (B), MIP-1β (C), IFN-γ (D), MIP-1α (E), IL-8 (F), TNF-α (G), IL-6 (H), and IL12p70 (I). [Figure 8]A-D are graphs showing the expression of activation / maturation markers in peripheral blood B lymphocytes: HLA-DR (A), CD54 (B), CD80 (C), and CD86 (D). Symbols and lines represent each individual patient from Cohort 6B expansion (see Figure 2). Note: The fold change in staining intensity (24 h post-infusion of antibody A vs. pre-infusion) was calculated for each marker and converted to the Log2 scale. Of the six patients in the final cohort (1200 μg / kg without corticosteroids), four patients had usable data and were graphed accordingly.

[0026] Detailed Description of the Invention Various publications, articles, and patents are cited or described in the Background and throughout this specification. Each of these references is incorporated herein by reference in its entirety. Any discussion of documents, operations, materials, devices, articles and the like which has been included in the specification is for the purpose of providing a context for the present invention. Such discussion is not an admission that any or all of these items constitute part of the prior art to any invention disclosed or claimed.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise defined, specific terms used herein have the meanings set forth herein. All patents, published patent applications, and publications cited herein are incorporated by reference as if set forth herein in their entireties.

[0028] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0029] Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0030] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise" and variations such as "comprises" and "comprising" will be understood to mean the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. As used herein, the word "comprising" can be replaced with the terms "containing" or "including," or, as sometimes used herein, can also be replaced with the term "having."

[0031] As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. When used herein in connection with aspects or embodiments of the present invention, any of the above terms "comprising," "containing," "including," and "having" can be substituted with the terms "consisting of" or "essentially consisting of" to vary the scope of the disclosure.

[0032] As used herein, the connective term "and / or" between multiple listed elements is understood to encompass both individual and combined alternatives. For example, when two elements are connected by "and / or," the first alternative refers to the first element being applicable without the second element. The second alternative refers to the second element being applicable without the first element. The third alternative refers to the first and second elements being applicable together. Any one of these alternatives is understood to be within the meaning and, therefore, meets the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the alternatives is also understood to be within the meaning and, therefore, meets the requirements of the term "and / or."

[0033] As used herein, the term "subject" refers to a mammalian subject, preferably a human, diagnosed with or suspected of having cancer, who will be or is being administered an anti-CD40 antibody according to the methods of the invention. Diagnosis of cancer can be made by a clinician according to a clinical diagnostic test, a physical examination of the subject, or any other accepted method for diagnosing a subject with a particular disease.

[0034] As used herein, CD40 refers to a cell surface glycoprotein that belongs to the tumor necrosis factor receptor (TNFR) superfamily and plays a central role in the immune system. CD40 is expressed on various immune cells, such as B cells, dendritic cells, monocytes, and macrophages, and professional APCs are activated when CD40-mediated signaling occurs (reviewed by Tasci et al., Cell. Mol. Life. Sci., 2001, (58): 4-43). CD40 expression occurs on many normal cells as well as tumor cells, such as B lymphomas, solid tumors, melanomas, and carcinomas. It is well established that CD40 activation is effective in eliciting antitumor responses and contributes to the impairment of tumor growth at least through mechanisms of immune activation, a direct apoptotic effect on CD40-positive tumors, and stimulation of humoral responses that lead to antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

[0035] As used herein, "CD40" includes any naturally occurring or synthetic protein that has structural and / or functional identity to the human CD40 protein and / or naturally occurring variants thereof, as defined herein. Preferably, the CD40 is human CD40, such as UniProt Accession No. P25942 and GenBank Accession No. AAH12419.

[0036] As used herein, "anti-CD40 antibody" refers to an agonistic human monoclonal antibody (mAb) of the IgG1 subtype that binds to and enhances the effect of the natural ligand CD40L, or an antigen-binding fragment thereof. The agonistic CD40 antibodies of the present invention can induce (1) direct anti-tumor effects by binding to the CD40 receptor expressed on tumor cells, (2) indirect anti-tumor effects by "licensing" DCs and activating cytotoxic T cells (CTLs), and (3) activating cytotoxic myeloid cells such as NK cells or tumor macrophages. In a preferred embodiment, the anti-CD40 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, or sequences with at least 95% (or at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region comprises the amino acid sequences of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively, or sequences with at least 95% (or at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NOs: 4, 5, and 6, respectively. In another preferred embodiment, the anti-CD40 antibody comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8. In another preferred embodiment, the anti-CD40 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO:9 and a light chain (LC) having the amino acid sequence of SEQ ID NO:10.

[0037] Additional anti-CD40 antibodies or antigen-binding fragments thereof that can be used in the present invention include those described in US Pat. No. 9,676,862, which is incorporated herein by reference.

[0038] Anti-CD40 antibodies can be prepared by any method known in the art in light of the present disclosure for preparing monoclonal antibodies, including, but not limited to, hybridoma production. For example, anti-CD40 antibodies can be produced in mammalian cell lines (e.g., Chinese Hamster Ovary (CHO) cell lines) using recombinant DNA technology. Methods for producing anti-CD40 antibodies particularly useful in the present invention are further described, for example, in U.S. Patent No. 9,676,862, which is incorporated herein by reference.

[0039] The term "safety," in the context of a dose, dosing regimen, treatment, or method using an anti-CD40 antibody, refers to a favorable risk:benefit ratio, i.e., an acceptable frequency and / or severity of treatment-emergent adverse events (also referred to as AEs or TEAEs), compared with the standard of care or another comparator drug in accordance with the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. §§ 321-392). In particular, safety associated with a dose, dosing regimen, or treatment with an anti-CD40 antibody of the present invention refers to an acceptable frequency and / or acceptable severity of adverse events associated with the administration of the antibody, when the adverse events are considered possible, likely, or highly likely to be due to the use of the anti-CD40 antibody. Safety is often measured by toxicity studies that determine the maximum tolerated dose or optimal dose of the active pharmaceutical ingredient required to achieve the desired effect. Safety studies also seek to identify any potential adverse effects that may result from exposure to the drug.

[0040] As used herein, unless otherwise specified, the term "clinically proven" (used independently or to modify the term "safe") means proven by clinical trials, which meet the approval standards of the U.S. Food and Drug Administration, the European Medicines Evaluation Agency (EMEA), or the corresponding national regulatory body. In the present invention, the clinical trial is a Phase I, open-label study of the safety, pharmacokinetics, and pharmacodynamics of Antibody A, an agonistic human monoclonal antibody targeting CD40, in patients with advanced solid tumors.

[0041] As used herein, the phrases "adverse event," "treatment-emergent adverse event," and "adverse reaction" refer to any adverse, unfavorable, unintended, or undesirable symptom or outcome associated with or resulting from the administration of a pharmaceutical composition or therapeutic agent. However, abnormal values ​​or observations are not reported as adverse events unless deemed clinically significant by the investigator. As used herein, when referring to an adverse event, "clinically evident" means clinically significant as determined by a physician or investigator using criteria accepted by those skilled in the art. If the adverse or undesirable consequences of an adverse event reach such a level of severity, a regulatory authority may determine that the pharmaceutical composition or therapeutic agent is unacceptable for its proposed use. Examples of adverse events or reactions when used in the context of intravenous administration of an anti-CD40 antibody include, but are not limited to, the following: Infections and infestations such as rhinitis, shingles, and bullous myringitis; respiratory, thoracic, and mediastinal disorders such as cough, pharyngeal irritation, and oropharyngeal pain; gastrointestinal disorders such as diarrhea and flatulence; nervous system disorders such as headache and dizziness; blood and lymphatic system disorders such as anemia and lymphadenopathy; back pain, premature labor, infusion reactions, local injection site reactivity, malignancy, and anaphylaxis or serum sickness-type reactions.

[0042] As used herein, "treatment" or "treating" refers to therapeutic treatment. Individuals in need of treatment include subjects diagnosed with a disorder or symptoms of a disorder. Subjects who may be treated also include those prone to or susceptible to a disorder in which such a disorder may be prevented. Beneficial or desired clinical outcomes include alleviation of symptoms, whether detectable or undetectable, reduction in the extent of disease, a stable (i.e., non-worsening) disease state, a delay or slowing of disease progression, improvement or alleviation of the disease state, and remission (whether partial or total) in the treated subject. Beneficial clinical outcomes include, for example, reduced proliferation of B cells or dendritic cells, reduction in inflammatory cytokines, adhesion molecules, proteases, immunoglobulins, or combinations thereof, increased production of anti-inflammatory proteins, reduction in the number of autoreactive cells, enhanced immune tolerance, inhibition of survival of autoreactive cells, and / or reduction in one or more symptoms mediated by CD40 / CD40L-mediated pathways in the treated subject. Clinical response may be assessed using screening techniques such as magnetic resonance imaging (MRI) scans, fluoroscopy, computed tomography (CT) scans, flow cytometry or fluorescence-activated cell sorter (FACS) analysis, histology, macroscopic findings, and blood chemistry methods, including, but not limited to, changes detectable by ELISA, RIA, and chromatography.

[0043] The terms "efficacy" and "effective," as used herein in the context of a dose, dosing regimen, treatment, or method, refer to the effectiveness of a particular dose, administration, or treatment regimen. Efficacy can be measured based on changes over the course of a disease in response to an agent of the invention. For example, an anti-CD40 antibody of the invention (e.g., antibody A) is administered to a subject in an amount and for a time sufficient to cause an improvement, preferably a sustained improvement, in at least one indicator reflecting the severity of the disorder being treated. To determine whether the amount and duration of treatment are sufficient, various indicators reflecting the extent of the subject's illness, disease, or condition can be assessed. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the subject's disorder. The degree of improvement is assessed overall by a physician, who can make this assessment based on signs, symptoms, biopsies, or other test results, or by administering a questionnaire to the subject, such as a quality-of-life questionnaire developed for a given disease. For example, an anti-CD40 antibody of the invention can be administered to achieve improvement in a subject's condition associated with an advanced solid tumor.

[0044] Disease assessment for advanced solid tumors includes computed tomography (CT) or magnetic resonance imaging (MRI) for all subjects and bone scans for subjects with prostate cancer. Disease response will be assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune-related response criteria (irRC). Prostate Cancer Clinical Trials Working Group (PCWG3) criteria 35 will be used to assess disease response for subjects with prostate cancer.

[0045] As used herein, an advanced solid tumor refers to a malignant solid neoplasm that has spread widely to other anatomical sites or no longer responds to treatment. As used herein, accumulation refers to the amount of anti-CD40 antibody in the circulation, as measured by pharmacokinetic measurements, which accumulates and increases with repeated administration of the anti-CD40 antibody.

[0046] As used herein, a dose of an anti-CD40 antibody in "μg / kg" refers to the amount of anti-CD40 antibody in micrograms per kilogram of body weight of the subject to which the antibody is administered.

[0047] In one general aspect, the present invention relates to a method of providing a clinically proven and safe intravenous administration of an anti-CD40 antibody to a subject, preferably a human subject, in need thereof. Preferably, the subject has been diagnosed with any type of advanced or refractory solid malignant tumor, whether metastatic or unresectable. Examples of such diseases include, but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, kidney cancer, oral cancer, liver cancer, melanoma (including cutaneous melanoma), mesothelioma, non-small cell lung cancer, non-melanoma skin cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, small cell lung cancer, and thyroid cancer.

[0048] In one embodiment, a method for providing clinically proven safe administration of an anti-CD40 antibody to a subject and / or safe treatment of an advanced solid tumor in a subject, preferably a human subject, comprises intravenously administering to the subject a pharmaceutical composition comprising an anti-CD40 antibody and a pharmaceutically acceptable carrier, wherein the total dose of the anti-CD40 antibody administered is 50 μg / kg to 2500 μg / kg, preferably 75 μg / kg to 2000 μg / kg, mg / kg, optionally 100 μg / kg to 1800 μg / kg, 200 μg / kg to 1500 μg / kg, 300 μg / kg to 1400 μg / kg, 400 μg / kg to 1300 μg / kg, 500 μg / kg to 1200 μg / kg, 600 μg / kg to 1100 μg / kg, 700 to 1000 μg / kg, or 800 to 900 μg / kg of the subject's body weight per administration.

[0049] Intravenous administration refers to administration directly into a vein. Intravenous administration can be by injection (e.g., using a syringe at higher pressure) or by infusion (e.g., using gravity pressure). Intravenous administration is typically the most rapid method for delivering a drug or therapeutic agent throughout the body because the drug or therapeutic agent is carried by the blood circulation. When an anti-CD40 antibody is administered intravenously, it may be administered by intravenous infusion or injection, preferably via infusion. For example, the total dose of anti-CD40 antibody administered to a subject per administration can be administered by intravenous infusion over a period of about 30 to 180 minutes, such as 30, 60, 90, 120, 150, or 180 minutes, preferably 60 to 120 minutes, optionally 90 to 120 minutes. Optionally, the total dose can be administered by intravenous infusion over a period of 0 minutes to 3 hours, preferably 5 minutes to 150 minutes, 10 minutes to 2 hours, 15 minutes to 90 minutes, 20 minutes to 1 hour, 25 minutes to 55 minutes, 30 minutes to 50 minutes, or 35 minutes to 45 minutes, or 40 minutes to 45 minutes, e.g., about 0 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 90 minutes, about 2 hours, about 150 minutes, or about 3 hours.

[0050] The total dose of anti-CD40 antibody per administration is selected to provide safe administration and / or safe treatment by intravenous administration as determined in clinical trials. According to embodiments of the present invention, when the pharmaceutical composition is administered intravenously, the total dose of anti-CD40 antibody administered per administration is, for example, 50 μg / kg, 75 μg / kg, 100 μg / kg, 200 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1000 μg / kg, 1100 μg / kg, 1200 μg / kg, 1300 μg / kg, 1400 μg / kg, 1500 μg / kg, 1800 μg / kg, or 2000 μg / kg, or any dose therebetween.

[0051] The total dose of anti-CD40 antibody can be administered daily, weekly, biweekly, monthly, six months, yearly, two years or longer, and can be administered once a day, once a week, once every two weeks, once a month, once every six months, etc. For example, a total dose of 75 μg / kg to 2000 μg / kg of anti-CD40 antibody may be administered by a single intravenous injection per administration (e.g., once a day for at least one day), i.e., for a period of 0 minutes to 3 hours, preferably 5 minutes to 150 minutes, 10 minutes to 2 hours, 15 minutes to 90 minutes, 20 minutes to 1 hour, 25 minutes to 55 minutes, 30 minutes to 50 minutes, 35 minutes to 45 minutes, or 40 minutes to 45 minutes, for example, about 0 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 90 minutes, about 2 hours, about 150 minutes, or about 3 hours. Multiple doses of anti-CD40 antibody, each at a total dose of 75 μg / kg to 2000 μg / kg, can be administered to a subject in need thereof.

[0052] Pharmaceutical compositions suitable for use in the methods of the present invention are formulated for intravenous administration. Examples of formulations suitable for intravenous administration include, but are not limited to, solutions, suspensions, emulsions, and dry products that can be dissolved or suspended in a pharmaceutically acceptable carrier for injection or infusion. In a preferred embodiment, pharmaceutical compositions comprising anti-CD40 antibodies for use in the methods of the present invention are formulated as liquids.

[0053] The concentration of the anti-CD40 antibody contained in the pharmaceutical composition used in the present invention may vary. Typically, the concentration of the anti-CD40 antibody is 1 mg / mL to 100 mg / mL, preferably 10 mg / mL to 90 mg / mL, 20 mg / mL to 80 mg / mL, 30 mg / mL to 70 mg / mL, 40 mg / mL to 60 mg / mL, or 40 mg / mL to 50 mg / mL, for example, 1 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, or 100 mg / mL, or any concentration therebetween. In one embodiment, the concentration of the anti-CD40 antibody is 10 mg / mL to 30 mg / mL, for example, 20 mg / mL. In one embodiment, the concentration of the anti-CD40 antibody is preferably 20 mg / mL to 60 mg / mL, for example, 40 mg / mL.

[0054] Pharmaceutical compositions for use in the present invention further comprise one or more pharmaceutically acceptable carriers, such as those commonly used in the field of pharmaceutical manufacturing, particularly antibody pharmaceutical manufacturing. As used herein, the term "carrier" refers to any excipient, diluent, buffer, stabilizer, or other material well known in the art of pharmaceutical formulation. In particular, a pharmaceutically acceptable carrier should be non-toxic and not interfere with the efficacy of the active ingredient. Pharmaceutically acceptable carriers include excipients and / or additives suitable for use in pharmaceutical compositions known in the art, such as those listed in "Remington: The Science & Practice of Pharmacy," 19th ed., Williams & Williams, (1995) and "Physician's Desk Reference," 52nd ed., Medical Economics, Montvale, NJ (1998), the entire disclosures of which are incorporated herein by reference.

[0055] According to embodiments of the present invention, pharmaceutical compositions for use in the present invention comprise an anti-CD40 antibody and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises one or more amino acids, such as L-histidine and / or glycine, one or more carbohydrates, such as lactose, maltose, sucrose, or trehalose, one or more surfactants, such as polysorbate 20 or polysorbate 80, and one or more alcohols, such as D-sorbitol. Preferably, the pharmaceutical composition has a pH of 5 to 6, preferably 5.1 to 5.9, 5.2 to 5.8, 5.3 to 5.7, 5.4 to 5.6, or 5.4 to 5.5, e.g., 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0, or any value therebetween.

[0056] In some embodiments, pharmaceutical compositions for use in the present invention include one or more amino acids, such as L-histidine and glycine, which may be present at a concentration of 1 mM to 40 mM, 1 mM to 20 mM, 5 mM to 35 mM, 10 mM to 30 mM, 15 mM to 25 mM, or 20 mM to 40 mM, or 0.50% to 2.00% (weight / volume) (w / v), preferably 0.75% to 1.75% (w / v), 1.00% to 1.50% (w / v), or 1.00% to 1.25% (w / v). For example, the pharmaceutical composition may contain L-histidine or glycine at 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, or 40 mM, or any concentration therebetween. In another example, the pharmaceutical composition may contain L-histidine or glycine at 0.50% (w / v), 0.75% (w / v), 1.00% (w / v), 1.25% (w / v), 1.50% (w / v), 1.75% (w / v), or 2.00% (w / v), or any concentration therebetween.

[0057] In some embodiments, pharmaceutical compositions for use in the present invention comprise at least one sugar, such as sucrose, glucose, cellobiose, or trehalose, at a concentration of 1% to 10% (weight / volume) (w / v), 5% to 10% (w / v), 8% to 9% (w / v), 1.5% to 9.5% (w / v), 2% to 9% (w / v), 2.5% to 8.5% (w / v), 3% to 8% (w / v), 3.5% to 7.5% (w / v), 4% to 7% (w / v), 4.5% to 6.5% (w / v), 5% to 6% (w / v), or 5% to 5.5% (w / v). For example, the pharmaceutical composition may contain sucrose, cellobiose, and / or trehalose at 1% (w / v), 1.5% (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v), 5% (w / v), 5.5% (w / v), 6% (w / v), 6.5% (w / v), 7% (w / v), 7.5% (w / v), 8% (w / v), 8.5% (w / v), 9% (w / v), 9.5% (w / v), or 10% (w / v), or any concentration therebetween.

[0058] In some embodiments, pharmaceutical compositions for use in the present invention comprise at least one surfactant, such as polysorbate 80 (PS80) or polysorbate 20 (PS20), at a concentration of 0.01% (w / v) to 0.10% (w / v), 0.01% (w / v) to 0.08% (w / v), 0.02% (w / v) to 0.05% (w / v), 0.02% (w / v) to 0.09% (w / v), 0.03% (w / v) to 0.08% (w / v), 0.04% (w / v) to 0.07% (w / v), or 0.05% (w / v) to 0.06% (w / v). For example, the concentration of polysorbate 20 and / or polysorbate 80 may be 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1% (w / v), or any concentration therebetween.

[0059] In some embodiments, pharmaceutical compositions for use in the present invention comprise at least one polyol, such as mannitol, xylitol, or D-sorbitol, at a concentration of between 0.01% (w / v) and 0.10% (w / v), between 0.01% (w / v) and 0.08% (w / v), between 0.02% (w / v) and 0.05% (w / v), between 0.02% (w / v) and 0.09% (w / v), between 0.03% (w / v) and 0.08% (w / v), between 0.04% (w / v) and 0.07% (w / v), or between 0.05% (w / v) and 0.06% (w / v). For example, the concentration of mannitol, xylitol, or D-sorbitol may be 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / v), or any concentration therebetween.

[0060] Pharmaceutical compositions containing anti-CD40 antibodies for use in the present invention can be prepared by any method known in the art in light of the present disclosure. For example, an anti-CD40 antibody can be mixed with one or more pharmaceutically acceptable carriers to obtain a solution. The solution can be stored as a frozen liquid at a controlled temperature ranging from -40°C ± 10°C to -70°C ± 20°C (minus 40°C ± 10°C to minus 70°C ± 20°C) in an appropriate vial, protected from light, until administration to a subject.

[0061] According to embodiments of the present invention, supportive care, such as pre-infusion and post-infusion supportive care, may be used in addition to administration of an anti-CD40 antibody to treat advanced solid tumors. In some embodiments, the human subject receives pre-infusion medication before administration of the anti-CD40 antibody. In some embodiments, the human subject receives post-infusion medication after administration of the anti-CD40 antibody. In some embodiments, the human subject receives supportive care medication simultaneously with administration of the anti-CD40 antibody. Examples of these medications include, but are not limited to, corticosteroids, antihistamines, antipyretics, H2-antagonists, and antiemetics. Preferably, the subject receives all of a corticosteroid, antihistamine, antipyretic, H2-antagonist, and antiemetic. Optionally, the subject receives an antihistamine, antipyretic, H2-antagonist, and antiemetic. Further optionally, the subject receives one or more selected from a corticosteroid, an antihistamine, an antipyretic, an H2-antagonist, and an antiemetic.

[0062] Examples of suitable corticosteroids include dexamethasone and methylprednisolone. Dexamethasone may be administered at 20 mg, and methylprednisolone at 80 mg. Examples of suitable antihistamines include diphenylhydramine and cetirizine. Cetirizine may be administered at 10 mg. An example of a suitable antipyretic is acetaminophen (paracetamol). Acetaminophen may be administered at a dose of 650 to 1000 mg. An example of a suitable H2-antagonist is ranitidine. Ranitidine may be administered at 50 mg. An example of a suitable antiemetic is ondansetron. Ondansetron may be administered at 8 mg.

[0063] According to embodiments of the invention, various factors can be analyzed to determine whether a particular dose of an anti-CD40 antibody provides safe intravenous administration through clinical trials such as those described herein. For example, the safety of a particular dose of an intravenously administered anti-CD40 antibody can be determined through immunogenicity studies (e.g., measuring the production of antibodies against the anti-CD40 antibody), by determining dose-limiting toxicity (DLT) in subjects, by protein profiling to determine effects on blood biomarkers such as serum proteins (e.g., cytokines, chemokines, and inflammatory proteins), and by pharmacokinetic studies (e.g., area under the concentration time curve (AUC) and observed maximum concentration (C). max The safety of intravenously administered anti-CD40 antibodies can also be monitored by physical examination of the subject; evidence of local injection site reactions, systemic injection-related reactions, and other allergic reactions; electrocardiograms; laboratory tests; vital signs; and monitoring of other adverse events, such as infusion-related reactions (IRRS).

[0064] In some embodiments, the clinically proven safe administration of an anti-CD40 antibody and / or the clinically proven safe treatment of an advanced solid tumor is determined by measuring the amount of antibodies to the anti-CD40 antibody in a sample obtained from the subject. The amount of antibodies to the anti-CD40 antibody can be measured by any method known in the art in light of the present disclosure, for example, by ELISA.

[0065] In some embodiments, the clinically proven safe administration of an anti-CD40 antibody and / or the clinically proven safe treatment of an advanced solid tumor is measured by terminal half-life, target saturation, area under the concentration-time curve (AUC), and maximum observed concentration (C maxThe serum sample is analyzed to determine the concentration of the anti-CD40 antibody by any method known in the art in light of the present disclosure. The pharmacokinetic parameters are then analyzed, for example, by non-compartmental analysis (NCA), to determine pharmacokinetic parameters, such as AUC, C max , terminal half-life (T 1 / 2 ), total systemic clearance (CL) after intravenous administration, and terminal volume of distribution (V z ), total systemic clearance over bioavailability (CL / F), and terminal volume of distribution over bioavailability (V z Calculate the formula:

[0066] In some embodiments, the clinically proven safe administration of anti-CD40 antibodies and / or the clinically proven safe treatment of advanced solid tumors exhibits target-mediated drug disposition with rapid decline in serum concentration, e.g., the half-life of the anti-CD40 antibody is about 10-16 hours, preferably about 13 hours, when the total dose of anti-CD40 antibody administered per administration is about 600 μg / kg of subject body weight, or about 20-28 hours, preferably 24 hours, when the total dose of anti-CD40 antibody administered per administration is 1200 μg / kg or more of subject body weight.

[0067] In some embodiments, clinically proven safe administration of anti-CD40 antibodies and / or clinically proven safe treatment of advanced solid tumors achieves target saturation at a concentration of 1000 μg / kg to 1400 μg / kg, 1050 μg / kg to 1350 μg / kg, 1100 μg / kg to 1300 μg / kg, 1150 μg / kg to 1250 μg / kg, or 1150 μg / kg to 1200 μg / kg per kg of subject body weight. For example, the saturation concentration can be 1000 μg / kg, 1050 μg / kg, 1100 μg / kg, 1150 μg / kg, 1200 μg / kg, 1250 μg / kg, 1300 μg / kg, 1350 μg / kg, or 1400 μg / kg, or any dose therebetween.

[0068] According to an embodiment of the present invention, the average C max and AUC 0~24h The increase in CD40 receptor occupancy is greater than dose-proportional at doses below 1200 μg / kg and dose-proportional at doses equal to or greater than 1200 μg / kg. In some embodiments, the clinically proven safe administration of anti-CD40 antibodies and / or the clinically proven safe treatment of advanced solid tumors is determined by assessing CD40 receptor occupancy. For example, the percentages of B cells, T cells, and NK cells in peripheral blood after infusion of an anti-CD40 antibody are measured normalized to pre-infusion levels. According to embodiments of the invention, dose-independent margination of B cells, T cells, and natural killer (NK) cells is achieved after infusion of an anti-CD40 antibody, while dose-dependent B cell recovery is achieved, consistent with observations with competing anti-CD40 agonist antibodies. NK cells and T cells are reduced in number in peripheral blood after infusion, with full recovery of T cells and natural killer (NK) cells tested later.

[0069] In some embodiments, the clinically proven safe administration of anti-CD40 antibodies and / or the clinically proven safe treatment of advanced solid tumors is assessed by measuring a panel of serum cytokines and chemokines, including, but not limited to, MCP-1, IP-10, MIP-1β, MIP-1α, IFN-γ, TNF-α, IL12p70, IL-2, IL-6, IL-8, and IL-12. These data complement flow cytometry studies of B cell, T cell, myeloid, and NK compartments to demonstrate PD changes in cell numbers and / or activation status after anti-CD40 antibody infusion. According to embodiments of the invention, after anti-CD40 antibody infusion, peripheral chemokines (MCP-1, IP-10, and MIP-1β) are prominent in the peripheral blood, peaking 1-4 hours after infusion. This is consistent with myeloid cell activation, and cytokines (IFN-γ, TNF-α, and IL12p70) and chemokines (MIP-1α and IL-8) were also observed to a lesser extent, whereas levels of IL-6, which have been associated with the induction of cytokine storms by other CD40 agonist antibodies, were not significant after infusion.

[0070] In some embodiments, the clinically proven safe administration of anti-CD40 antibodies and / or the clinically proven safe treatment of advanced solid tumors is assessed by measuring APC / DC licensing and combined B and T cell subset activation in blood samples using appropriate methodology, such as, but not limited to, flow cytometry of cell surface activation markers such as HLA-DR, CD54, CD80, and CD86. According to embodiments of the invention, these activation markers are increased in activated B cells and monocytes after infusion of anti-CD40 antibodies.

[0071] Abbreviation: β-hCG β-human ciliary gonadotropin ADA anti-drug antibodies ADCC antibody-dependent cell-mediated cytotoxicity AE (treatment-emergent) adverse events ALT alanine transaminase Anti-HCV anti-hepatitis C antibody APC antigen presenting cells AST aspartate transaminase AUC Area under the serum concentration versus time curve BLRM Bayesian logistic regression model CI confidence interval C max Maximum observed serum concentration CR complete response CRF(s) Case Record Form(s) (paper or electronic format as appropriate for this study) CRS cytokine release syndrome CT Computed Tomography CTCAE Common Terminology Criteria for Adverse Events DC dendritic cells DLT dose-limiting toxicity DOR duration of response ECG electrocardiogram ECOG Eastern Cooperative Oncology Group eDC Electronic Data Capture EWOC Escalation with Overdose Control FcγR Fcγ receptor FSH follicle-stimulating hormone GCP: Standards for conducting clinical trials of pharmaceuticals Good Laboratory Practice (GLP) HBsAg Hepatitis B surface antigen hCD40tg human CD40-transgenic HIV human immunodeficiency virus ICF Informed Consent Form ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IEC Independent Ethics Committee IRB Institutional Review Board irCR immune-related complete response irRC Immune-Related Response Criteria IRRs Infusion-related reactions (IRRS) IT intratumoral IV (intravenous) LLOQ Lower limit of quantification MAD maximum dose mCRM revised continuous revaluation method MRI Magnetic Resonance Imaging MTD maximum capacity NCI National Cancer Institute NK Natural Killer NSCLC non-small cell lung cancer ORR Objective Response Rate PCWG Prostate Cancer Clinical Trials Working Group PD Pharmacodynamics PFS Progression-free survival PK Pharmacokinetics Verification of POM mechanism of action PQC Product Quality Complaint PR partial response RBC red blood cells RECIST Response Evaluation Criteria in Solid Tumors RP2D Phase II recommended dose SC subcutaneous SET Safety Assessment Team SUSAR Suspected unexpected serious adverse reaction TEAE Treatment-emergent adverse events T max Time to maximum observed serum concentration TRAF Tumor necrosis factor receptor activator Vd distribution volume WBC white blood cell [Example]

[0072] Example 1: A Phase I, Open-Label Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Antibody A in Patients with Advanced Solid Tumors Antibody A is an agonistic human monoclonal (IgG1) antibody targeting CD40 that is being investigated for the treatment of advanced solid tumors. This Phase 1, open-label study is designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of Antibody A administered as an IV infusion in patients with advanced solid tumors and to establish a recommended Phase 2 dose (RP2D) and schedule. In the second part of the study, additional safety data will be generated, and the therapeutic efficacy of Antibody A will be investigated in an expansion cohort of subjects with non-small cell lung cancer (NSCLC), pancreatic cancer, and cutaneous melanoma who have failed or are ineligible for approved effective therapies.

[0073] Study design overview Part 1, Dose Escalation: Escalating doses of antibody A, starting at 75 μg / kg, will be investigated in a modified continual reassessment method (mCRM) design in subjects with advanced solid tumors to determine the recommended Phase II dose (RP2D). Doses will be increased by no more than half-logarithmic (3.2-fold) dose increments. Dose escalation will continue until the maximum-tolerated dose (MTD) and / or RP2D of antibody A are defined, or the maximum-administered dose (MAD) is reached.

[0074] The MTD is the highest dose of antibody A that emerges from the evaluation of PK / PD and safety data guided by a statistical model (BLRM) using the EWOC principle during the DLT evaluation period. · The MAD is defined as the maximum dose of antibody A administered. The RP2D will be determined after review of all available PK / PD, safety, and efficacy data according to a Bayesian Logistic Regression Model (BLRM).

[0075] Part 2, Dose Expansion: Antibody A will be administered at the RP2D in expansion cohorts of approximately 30 subjects to further characterize the safety and PK / pharmacodynamic (PD) properties, and to evaluate the efficacy of this agent in subjects with NSCLC, pancreatic cancer, and cutaneous melanoma, respectively.

[0076] Part 2 (dose expansion) will begin after the RP2D is determined and will (1) collect additional information on the safety and PK / PD characteristics of Antibody A in selected disease populations and (2) evaluate the clinical activity of the study drug in subjects with NSCLC, pancreatic cancer, and cutaneous melanoma. Expansion cohorts will consist of approximately 30 subjects each.

[0077] Biomarker Substudy: Additional biomarkers will be evaluated to define the impact of Antibody A on the innate and adaptive immune responses in tumors.

[0078] Figure 1 shows a diagram of the study design.

[0079] subject Subjects must be 18 years of age or older and have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0080] Part 1: Subjects with any type of advanced or refractory solid malignant tumor that is metastatic or unresectable are eligible for enrollment in Part 1. Subjects have received all standard treatment options or are no longer eligible for additional standard treatment options.

[0081] Part 2: Subjects with histologically or cytologically confirmed NSCLC, pancreatic cancer, or cutaneous melanoma are eligible for enrollment in Part 2. Subject cohorts include, for example:

[0082] Cohort 2A: Histologically or cytologically confirmed NSCLC Stage IV disease Patients must have received at least two prior approved systemic therapies, one of which must be a platinum-containing regimen. At least one measurable tumor lesion by RECIST v1.1

[0083] Cohort 2B: Histologically or cytologically confirmed adenocarcinoma of the pancreas Unresectable, locally advanced (Stage III), or metastatic (Stage IV) disease Prior treatment with at least one approved systemic therapy At least one measurable tumor lesion by RECIST v1.1

[0084] Cohort 2C: Histologically or cytologically confirmed cutaneous melanoma Unresectable (stage III) or metastatic (stage IV) disease Prior treatment with at least one approved systemic therapy At least one measurable tumor lesion by RECIST v1.1

[0085] The second part of the trial is underway.

[0086] Test drug Antibody A is supplied as a lyophilized cake or as a frozen liquid. The formulations contain 20 mg / mL or 40 mg / mL of Antibody A.

[0087] Dosage and Administration Doses will be titrated from a starting dose of 75 μg / kg. Administration will be by IV infusion. The initial schedule of administration will be every 14 days (Q14d) (Days 1 and 15) of a 28-day cycle. Administration will initially be by IV infusion over 2 hours.

[0088] Recommended supportive care before and after infusion Prior to each infusion of Antibody A, subjects will receive pre-infusion medication as described in Table 1.

[0089] [Table 1] IV = intravenous a Optional unless expressly mandated by the Safety Evaluation Team (SET)

[0090] The study design and cohorts with and without corticosteroid pre-infusion are shown in Figure 2 .

[0091] After each infusion of Antibody A, subjects who experienced Antibody A-related toxicity during or after the previous dose must take post-infusion medication as described in Table 2.

[0092] [Table 2] IV = intravenous a In the absence of symptoms of JNJ-64457107-related toxicity, post-infusion medication may be given for up to 48 hours after the end of the infusion. bInvestigators should use their clinical judgment if further corticosteroid support is needed. c Oral or IV administration begins 12 hours after the first dose of study drug. It is recommended to limit administration to 48 hours after JNJ-64457107 administration.

[0093] evaluation Safety evaluation Safety assessments are based on medical review of adverse event reports and results of clinical laboratory tests, electrocardiograms (ECGs), vital sign measurements, physical examinations, ECOG performance scores, and other safety assessments at each time point.

[0094] Pharmacokinetics and immunogenicity For all subjects participating in the study, blood or serum samples were used to evaluate PK and the immunogenicity of Antibody A. Venous blood will be collected for measurement of serum concentrations of Antibody A (approximately 5 mL measurement) and assessment of anti-Antibody A antibodies (approximately 7.5 mL for combined PK and immunogenicity samples, 5 mL for other immunogenicity samples alone). Venous blood samples will be collected and, if both PK and immunogenicity samples are collected, each serum sample will be split into three equal aliquots (one each for PK, anti-Antibody A antibodies, and a backup) for each time point; otherwise, if only PK samples are collected, each serum sample will be split into two equal aliquots for each time point.

[0095] Serum samples will be analyzed by or under the supervision of the sponsor to determine the concentration of Antibody A using a validated, specific, and sensitive assay. Detection and characterization of antibodies to Antibody A will be performed by or under the supervision of the sponsor using a validated MescoScale Discovery (MSD) Platform assay. All samples collected to detect antibodies to Antibody A will also be evaluated for serum concentrations of Antibody A to enable interpretation of the antibody data.

[0096] Biomarkers Biomarkers will be evaluated to explore the molecular mode of action of Antibody A and to explore biomarkers that may be predictive of response to therapy. Biomarker objectives for this study include testing of CD40 receptor occupancy, innate immune responses, CD40 activation markers, Fc-dependent effector function, and CD40 expression on tumor tissue. An optional biomarker substudy will use pre-drug and post-drug biopsies to assess immune cell changes following CD40 engagement with the goal of identifying drug combination opportunities incorporating Antibody A.

[0097] Efficacy evaluation Efficacy assessments will include computed tomography (CT) or magnetic resonance imaging (MRI) for all subjects and bone scans for subjects with prostate cancer. Disease response will be assessed according to Response Evaluation in Solid Tumors (RECIST) v1.1 criteria and according to immune-related response criteria (irRC). Disease response will be assessed for subjects with prostate cancer using Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. The relationship between PK, including receptor occupancy, and PD will be investigated and reported in a separate report.

[0098] statistical methods Data will be summarized using descriptive statistics. Continuous variables will be summarized using number of observations, mean, standard deviation, median, and range as appropriate. Categorical values ​​will be summarized using number of observations and percentages as appropriate. Distributions of time-to-event endpoints will be estimated using the Kaplan-Meier method.

[0099] result Demographics and Breakdown: Ninety-five patients, ages 18-80 years (median 59), were enrolled in seven cohorts with corticosteroids (n=50, 75 μg / kg-2000 μg / kg) and five cohorts without corticosteroids (n=45, 75 μg / kg-1200 μg / kg) and received 1-26 (median 3) cycles of antibody A (Figure 2). Most patients discontinued due to progressive disease (n=62, 76%).

[0100] Safety Results As shown in Table 3, the majority of adverse events (AEs) were grade 1 (G1) or 2 (G2), and the number of patients with grade 3 (G3) or higher AEs was limited.

[0101] [Table 3]

[0102] As shown in Figure 3, infusion-related reactions (IRRs) were reported in 51% of patients (G1-G2: 50%, G3: 1%). The most common IRRs (>10%) were pruritus (31%), rash (15%), chills (13%), and flushing (12%). Based on the high incidence of pruritus, a new premedication regimen was implemented. Cetirizine and montelukast were administered as premedication / postmedication from 3 days before to up to 3 days after each antibody A infusion and were shown to significantly reduce IRRs, with no pruritus reported.

[0103] Two dose-limiting toxicities (DLTs) were reported: a 5-day continuous G3 headache at 1200 μg / kg with corticosteroids, and a G3 increase in ALT / AST plus G2 bilirubin at 1200 μg / kg without corticosteroids.

[0104] Pharmacokinetic results Preliminary PK of Antibody A appeared to indicate target-mediated drug disposition with rapid decline in serum concentrations (half-life: approximately 13 hours at 600 μg / kg and approximately 24 hours at doses ≥ 1200 μg / kg) (Figure 4). No accumulation was observed after multiple biweekly dosing. Based on limited data, target saturation was observed at approximately 1200 μg / kg. Mean C max and AUC 0~24h The increase in IgG (Figure 5) was greater than dose-proportional at doses below 1200 μg / kg and dose-proportional at doses ≥ 1200 μg / kg. Immunogenicity data showed a low incidence of antibodies to antibody A (approximately 10.5%).

[0105] Pharmacodynamic results Dose-dependent margination of B cells, T cells, and natural killer (NK) cells was observed after infusion of Antibody A, with a dose-dependent recovery of B cells consistent with that observed with a competing anti-CD40 agonist antibody. NK cells and T cells were reduced in peripheral blood after infusion at all doses tested except the lowest dose (75 μg / kg), with both levels fully recovering by study day 8. See Figures 6A-6C.

[0106] Peripheral chemokines (MCP-1, IP-10, and MIP-1β) were prominent in the peripheral blood, peaking 1 to 4 hours after infusion, consistent with myeloid cell activation. Cytokines (IFN-γ, TNF-α, and IL12p70) and chemokines (MIP-1α and IL-8) were also observed, albeit to a lesser extent. IL-6 levels, which have been associated with the induction of cytokine storm by other CD40 agonist antibodies, were not significant after antibody A infusion. See Figures 7A-7I.

[0107] Phenotypic staining of peripheral B cells showed increased fluorescence intensity of activation / maturation markers (HLA-DR, CD54, CD80, and CD86) consistent with data from other agonist antibodies (Figures 8A-8D).

[0108] Clinical Activity Results Early signs of clinical activity included partial responses in patients with renal cell carcinoma and 10 patients with long-term stable disease for 6 months or more.

[0109] Consideration CD40 agonist Antibody A has a manageable safety profile with favorable PK and PD properties. Preliminary PK of Antibody A was linear and dose-proportional at doses above 1200 μg / kg with moderate variability. Antibody A resulted in increased levels of selected chemokines, particularly MCP-1 and IP-10, and margination of B cells, T cells, and NK cells after infusion, with subsequent recovery. Residual peripheral B cells showed an increase in activation / maturation markers.

[0110] Those skilled in the art will appreciate that changes could be made to the embodiments described above without departing from the broad inventive concept. It is understood, therefore, that the invention is not limited to the particular embodiments disclosed, but is intended to cover modifications within the spirit and scope of the invention as defined by the specific description. The following aspects may be included. [1] A method for providing a clinically proven and safe administration of an anti-CD40 antibody to a human subject diagnosed with an advanced solid tumor, comprising intravenously administering to the subject a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region comprising the amino acid sequences of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively, and the total dose of the antibody administered is 50 μg / kg to 2500 μg / kg, preferably 75 μg to 2000 μg / kg, per kg of the subject's body weight per administration. [2] The method described in [1] above, wherein the antibody comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8. [3] The method described in [1] or [2] above, wherein the antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10. [4] The method according to any one of [1] to [3] above, wherein the total dose of the anti-CD40 antibody administered per administration is 75 μg / kg, 200 μg / kg, 400 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1000 μg / kg, 1100 μg / kg, 1200 μg / kg, 1300 μg / kg, 1400 μg / kg, 1500 μg / kg, 1800 μg / kg, or 2000 μg / kg, or any dose therebetween, per kg of the subject's body weight. [5] The method according to any one of [1] to [4] above, wherein the total dose of the pharmaceutical composition is administered intravenously to the human subject over a period of about 2 hours, and preferably the pharmaceutical composition is administered intravenously to the human subject repeatedly, more preferably once every two weeks. [6] The method further comprises administering a therapeutic agent to the human subject before or after the administration of the anti-CD40 antibody, preferably the therapeutic agent being a corticosteroid, antihistamine, antipyretic, H 2 The method according to any one of [1] to [5] above, wherein the anti-inflammatory drug is selected from the group consisting of anti-inflammatory drugs, ... [7] The method according to any one of [1] to [6] above, further comprising reducing an infusion-related reaction (IRRS) or a pruritic reaction by administering to the subject an effective amount of at least one of cetirizine and montelukast in combination with the anti-CD40 antibody, preferably cetirizine and montelukast being administered within 3 days before and within 3 days after the administration of the anti-CD40 antibody. [8] The method according to any one of [1] to [7] above, wherein the anti-CD40 antibody has an in vivo half-life of about 10 to 16 hours, preferably about 13 hours, when the total dose of the anti-CD40 antibody administered per administration is 600 μg / kg per kg of the subject's body weight, or the anti-CD40 antibody has an in vivo half-life of about 20 to 28 hours, preferably 24 hours, when the total dose of the anti-CD40 antibody administered per administration is 1200 μg / kg or more per kg of the subject's body weight. [9] The method according to any one of [1] to [8] above, wherein when the pharmaceutical composition is repeatedly administered intravenously to the human subject, the human subject does not accumulate the anti-CD40 antibody.

[10] The method according to any one of [1] to [9] above, wherein the administration of the anti-CD40 antibody results in target saturation when the total dose of the anti-CD40 antibody administered per administration is approximately 1000 to 1400 μg / kg of the subject's body weight, preferably 1200 μg / kg of the subject's body weight.

[11] The method according to any one of [1] to

[10] above, wherein the administration of the anti-CD40 antibody causes margination of one or more cells selected from the group consisting of B cells, T cells, and natural killer (NK) cells in the peripheral blood of the human subject, and subsequent recovery of the cells.

[12] The method according to any one of [1] to

[11] above, wherein the administration of the anti-CD40 antibody achieves an increase in one or more chemokines selected from the group consisting of MCP-1, IP-10, MIP-1β, MIP-1α, and IL-8 in the peripheral blood of the human subject.

[13] The method according to any one of [1] to

[12] above, wherein the administration of the anti-CD40 antibody achieves an increase in one or more cytokines selected from the group consisting of IFN-γ, TNF-α, and IL12p70 in the peripheral blood of the human subject.

[14] The method according to any one of [1] to

[13] above, wherein the administration of the anti-CD40 antibody results in an increase in one or more activation markers on peripheral blood B lymphocytes, and the activation markers are selected from the group consisting of HLA-DR, CD54, CD80, and CD86.

[15] The method according to any one of [1] to

[14] above, wherein the human subject has at least a partial response or has long-term stable disease for at least 6 months.

[16] A method for providing clinically proven and safe administration of an anti-CD40 antibody to a human subject diagnosed with an advanced solid tumor, comprising intravenously administering to the subject a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region comprising the amino acid sequences of light chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 4, 5, and 6, respectively. The method of the present invention further comprises administering to a subject a human subject having a human body that has been diagnosed with non-small cell lung cancer (NSCLC), pancreatic cancer, or cutaneous melanoma, a total dose of the antibody administered per administration, the total dose comprising the amino acid sequences of complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3, of about 600 μg / kg to about 1200 μg / kg, e.g., 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1000 μg / kg, 1100 μg / kg, or 1200 μg / kg, of the subject.

[17] The method described in

[16] above, wherein the antibody comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8.

[18] The method described in

[16] or

[17] above, wherein the antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.

[19] A pharmaceutical composition comprising an anti-CD40 antibody and a pharmaceutically acceptable carrier, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region comprising the amino acid sequences of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively, and the total dose of the antibody administered per administration is 50 μg / kg to 2500 μg / kg, preferably 75 μg / kg to 2000 μg / kg, per kg of subject body weight.

[20] An anti-CD40 antibody for use in medical treatment, the antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region comprising the amino acid sequences of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively, and the total dose of the antibody administered per administration is 50 μg / kg to 2500 μg / kg, preferably 75 μg / kg to 2000 μg / kg, per kg of subject body weight.

[21] An anti-CD40 antibody for use in treating advanced solid tumors, the antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region comprises the amino acid sequences of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively, and the total dose of the antibody administered is 50 μg / kg to 2500 μg / kg, preferably 75 μg / kg to 2000 μg / kg, per kg of subject body weight per administration.

Claims

1. A pharmaceutical composition for use in a method of providing clinically proven, safe administration of an anti-CD40 antibody to a human subject diagnosed with an advanced solid tumor for the treatment of the advanced solid tumor, the pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier, the method comprising intravenously administering the pharmaceutical composition to the subject, the antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively. wherein the light chain variable region comprises the amino acid sequences of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively; the total dose of the antibody administered is 50 μg / kg to 2500 μg / kg of the subject's body weight per administration; and the method further comprises reducing an infusion-related reaction (IRRS) or a pruritic reaction by administering to the subject an effective amount of at least one of cetirizine and montelukast in combination with the anti-CD40 antibody.

2. The pharmaceutical composition of claim 1 , wherein the antibody comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:

8.

3. The pharmaceutical composition of claim 1 or 2, wherein the antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO:

10.

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the total dose of the anti-CD40 antibody administered per administration is 75 μg / kg, 200 μg / kg, 400 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1000 μg / kg, 1100 μg / kg, 1200 μg / kg, 1300 μg / kg, 1400 μg / kg, 1500 μg / kg, 1800 μg / kg, or 2000 μg / kg, or any dose therebetween, per kg of the subject's body weight.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the total dose of the pharmaceutical composition is administered intravenously to the human subject over a period of about 2 hours.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is administered intravenously to the human subject repeatedly.

7. 7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is administered once every two weeks.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the method further comprises administering a therapeutic agent to the human subject before or after the administration of the anti-CD40 antibody.

9. The therapeutic agent may be a corticosteroid, an antihistamine, an antipyretic, a H ２ 9. The pharmaceutical composition of claim 8, wherein the anti-inflammatory agent is selected from the group consisting of: anti-inflammatory drugs, ...

10. 10. The pharmaceutical composition of claim 1, wherein cetirizine and montelukast are administered within 3 days before and 3 days after the administration of the anti-CD40 antibody.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the anti-CD40 antibody has an in vivo half-life of about 10 to 16 hours when the total dose of the anti-CD40 antibody administered per administration is 600 μg / kg per kg of the subject's body weight, or the anti-CD40 antibody has an in vivo half-life of about 20 to 28 hours when the total dose of the anti-CD40 antibody administered per administration is 1200 μg / kg or more per kg of the subject's body weight.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the human subject does not have an accumulation of the anti-CD40 antibody when the pharmaceutical composition is repeatedly administered intravenously to the human subject.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the administration of the anti-CD40 antibody results in target saturation when the total dose of the anti-CD40 antibody administered per administration is about 1000-1400 μg / kg of the subject's body weight.

14. The administration of the anti-CD40 antibody results in the following in the peripheral blood of the human subject: (a) margination of one or more cells selected from the group consisting of B cells, T cells, and natural killer (NK) cells, and the subsequent recovery of said cells; (b) an elevation of one or more chemokines selected from the group consisting of MCP-1, IP-10, MIP-1β, MIP-1α, and IL-8; (c) an increase in one or more cytokines selected from the group consisting of IFN-γ, TNF-α, and IL12p70; and / or (d) an increase in one or more activation markers on peripheral blood B lymphocytes, wherein said activation markers are selected from the group consisting of HLA-DR, CD54, CD80, and CD86. The pharmaceutical composition according to any one of claims 1 to 13,

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the human subject has at least a partial response or long-term stable disease for six months or more.

16. 2. The pharmaceutical composition of claim 1, wherein the total dosage of the antibody administered is about 600 μg / kg to about 1200 μg / kg, such as 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1000 μg / kg, 1100 μg / kg, or 1200 μg / kg, per kg of the subject's body weight, per administration.

17. 17. The pharmaceutical composition of claim 16, wherein the human subject has been diagnosed with non-small cell lung cancer (NSCLC), pancreatic cancer, or cutaneous melanoma.

18. (a) the antibody comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8; and / or (b) the antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO:

10.

19. 1. A pharmaceutical composition for use in treating an advanced solid tumor, the pharmaceutical composition comprising an anti-CD40 antibody, the antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequences of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region comprising the amino acid sequences of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively, wherein a total dose of the antibody administered is 50 μg / kg to 2500 μg / kg of the subject's body weight per administration, and the treatment further comprises reducing an infusion-related reaction (IRRS) or a pruritic reaction by administering to the subject an effective amount of at least one of cetirizine and montelukast in combination with the anti-CD40 antibody.

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