Treatment methods for advanced or metastatic solid tumors using anti-CD47 antibodies

Abstract

A treatment method for solid tumors using anti-CD47 antibodies is provided.

Description

[Technical Field]

[0001] This patent application claims priority to Korean Patent Application No. 10-2024-0066776, filed with the Korean Intellectual Property Office on 22 May 2024, and the disclosures of the said patent application are incorporated herein by reference. The present invention relates to a method for treating patients with advanced or metastatic cancer using an anti-CD47 antibody.

[0002] Array List This application includes a sequence list, which has been submitted electronically in XML format and is included in its entirety by reference. A copy of the said sequence list, created on October 15, 2024, is named KC24163.xml and has a size of 10.3 kilobytes. [Background technology]

[0003] CD47 is a transmembrane protein expressed on the surface of cancer cells that transmits a "don't-eat-me" signal to signal regulatory protein α (SIRPα), a receptor found on macrophages and predatory cells such as dendritic cells. When CD47 binds to SIRPα, phosphorylation of the immune receptor tyrosine-based inhibitory motif in the cytoplasmic domain of SIRPα is induced, leading to the aggregation of Src homologous phosphate-degrading enzymes 1 and 2 (SHP-1, SHP-2) and suppression of phagocytic signaling (Oldenborg 2013). This CD47 inhibition mechanism is frequently overexpressed in various cancer cells, including hematological malignancies and solid tumors. Blockade of CD47 / SIRPα in various animal models has been shown to induce phagocytic activity by macrophages against cancer cells, thereby promoting antitumor activity (Tseng D, et al. 2013; Majeti R, et al. 2009). In particular, CD47 blockade induces an antitumor T cell response by causing dendritic cells to cross-present cancer antigens after phagocytosis of cancer cells (Liu X, et al. 2015). Furthermore, combining CD47 / SIRPα with chemotherapy or immunomodulatory agents such as PD-1 (programmed cell death protein 1) and PD-L1 (programmed deathligand 1) enhances the anticancer effect (Gordon SR, et al. 2017; Liu X, et al. 2018; Lian S, et al. 2019).

[0004] Currently, various anticancer drugs targeting CD47 / SIRPα are in the preclinical or clinical development stages. According to the relevant website (Clinicaltrials.gov), 12 drugs are currently under development as anticancer agents. Maglolimab (Hu5F9-G4, an anti-CD47 monoclonal antibody) has been reported to be effective as monotherapy in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and certain solid tumors (clear cell ovarian carcinoma, fallopian tube carcinoma). However, in recent years, serious safety concerns have led to the suspension of clinical trials for hematological malignancies and the suspension of recruitment of clinical trial subjects for solid tumors. Thus, there is a pressing need for anticancer drugs that are safe, tolerable, and effective, especially for patients with advanced or metastatic cancer for whom there are no approved or established therapeutic alternatives.

[0005] IMC-002, an anti-CD47 antibody, is a human IgG4 antibody that prevents Fab substitution due to the presence of the S228P mutation, which stabilizes the hinge. IMC-002 targets CD47 and inhibits the interaction between CD47 and SIRPα, thereby enhancing macrophage phagocytosis against cancer cells in vitro and suppressing tumor growth in vivo (xenograft model). Because IMC-002 does not readily bind to red blood cells, it did not cause anemia in in vitro hemagglutination tests or in vivo studies. These test results suggest that IMC-002 has the potential to be a safe, tolerable, and effective anticancer agent. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Korean Registered Patent Publication No. 10-2625835 [Non-patent literature]

[0007] [Non-Patent Document 1] Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication no. 91-3242, 1991 [Non-Patent Document 2] Lefranc et al, Dev. Comp. Immunol. 29:185-203; 2005 [Non-Patent Document 3] Honegger and Pluckthun, J. Mol. Biol. 309(3):657-670; 2001 [Non-Patent Document 4] Tseng D, et al. 2013, Majeti R, et al. 2009 [Non-Patent Document 5] Gordon SR, et al. 2017 Liu X, et al. 2018, Lian S, et al. 2019 [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The purpose of this invention is to solve all of the problems of the prior art described above. One objective of the present invention is to provide a method, pharmaceutical composition, and kit for administering an anti-CD47 antibody to treat tumors in patients with solid cancers or to suppress tumor growth. The objectives of the present invention are not limited to those stated above. The objectives of the present invention will become clearer in the following description and will be achieved by the means and combinations thereof described in the claims. [Means for solving the problem]

[0009] A typical configuration of the present invention for achieving the above objective is as follows. One aspect of the present invention provides a pharmaceutical composition for treating tumors or suppressing tumor growth in patients with progressive or metastatic solid tumors, comprising an effective amount of an anti-CD47 antibody that specifically binds to CD47 and includes HCDR1, HCDR2, and HCDR3 contained in the medium-chain variable region (HCVR) of SEQ ID NO: 1, and LCDR1, LCDR2, and LCDR3 contained in the light-chain variable region (LCVR) of SEQ ID NO: 2, wherein the antibody is administered to the patient at a dose of approximately 5 mg / kg to approximately 30 mg / kg every approximately 2 to 3 weeks without priming.

[0010] One aspect of the present invention provides a method for treating a tumor or inhibiting tumor growth, comprising the steps of (a) selecting patients with advanced or metastatic solid tumors; and (b) administering an anti-CD47 antibody or a pharmaceutical composition disclosed herein to the selected patients without priming at doses of about 5 mg / kg to about 30 mg / kg every about 2 to about 3 weeks, wherein the antibody specifically binds to CD47 and comprises HCDR1, HCDR2 and HCDR3 contained in the medium chain variable region of SEQ ID NO: 1, and LCDR1, LCDR2 and LCDR3 contained in the light chain variable region of SEQ ID NO: 2.

[0011] Another aspect of the present invention provides a kit comprising an anti-CD47 antibody, along with instructions for use of the anti-CD47 antibody for treating or inhibiting tumor growth in patients with solid tumors, wherein the instructions for use include instructions for a therapeutic or inhibitory method disclosed herein, which involves administering the antibody to the patient without priming at doses of approximately 5 mg / kg to approximately 30 mg / kg every approximately 2 to approximately 3 weeks, and the antibody specifically binds to CD47 and comprises HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region of SEQ ID NO: 1, and LCDR1, LCDR2 and LCDR3 contained in the light chain variable region of SEQ ID NO: 2. In some embodiments, the antibody may be a fully human anti-CD47 antibody (e.g., IMC-002 antibody).

[0012] In some embodiments, the heavy chain variable region of the antibody can include HCDR1 of SEQ ID NO: 5, HCDR2 of SEQ ID NO: 6, and HCDR3 of SEQ ID NO: 7, and the light chain variable region can include LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 9, and LCDR3 of SEQ ID NO: 10. In some embodiments, the heavy chain variable region of the antibody can include the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, and the light chain variable region can include the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2.

[0013] In some embodiments, the antibody can be capable of not inducing significant levels of hemagglutination or anemia in a patient. In some embodiments, the composition can include about 10 - 30 mM sodium phosphate, about 80 - 120 mM sodium chloride, about 50 - 80 mM mannitol, and about 0.01 - 0.1% polysorbate 80, and can have a pH of about 4 - 7. In some embodiments, the composition can include about 20 mM sodium phosphate, about 100 mM sodium chloride, about 65.9 mM mannitol, and 0.05% polysorbate 80, and can have a pH of about 5.5. In some embodiments, the composition can be in a liquid dosage form for intravenous injection or infusion.

[0014] In some embodiments, the solid cancer can be liver cancer (e.g., hepatocellular carcinoma), breast cancer (e.g., triple negative breast cancer), or gallbladder cancer. In some embodiments, the patient can be a patient for whom standard treatment is impossible or who has failed standard treatment. In some embodiments, the antibody can be administered to the patient every about two weeks or every about three weeks. In some embodiments, the antibody can be administered to the patient at a dose of about 20 mg / kg or about 30 mg / kg. In some embodiments, the patient can have received at least one systemic treatment prior to administration of the anti - CD47 antibody. In some embodiments, the patient may be a stage 4 patient with multiple distant metastases or a locally advanced patient.

[0015] In some embodiments, the antibody can be administered in combination with other anti-cancer agents. In some embodiments, the antibody can be administered in combination with lenvatinib. In some embodiments, the antibody can be administered in combination with paclitaxel. In some embodiments, the antibody can be administered in combination with gemcitabine, carboplatin, or a combination thereof. In some embodiments, the antibody can be administered simultaneously, sequentially, or in reverse order with other anti-cancer agents used in combination, with a time interval required for treatment.

[0016] In some embodiments, lenvatinib can be administered daily. In some embodiments, paclitaxel can be administered on the first day of the antibody administration cycle. In some embodiments, gemcitabine and carboplatin can be administered on the first and eighth days of the antibody administration cycle.

[0017] In some embodiments, the method of treatment or inhibition can further include measuring the density of CD47-positive macrophages in a biological sample obtained from the patient before or after administration of the anti-CD47 antibody. In one aspect of the invention, a pharmaceutical composition for treating a tumor or suppressing tumor growth in a patient with progressive or metastatic hepatocellular carcinoma, comprising an effective amount of the IMC-002 antibody, wherein the antibody is administered to the patient at a dose of about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, or about 30 mg / kg every about two weeks or about three weeks without a priming dose.

[0018] In some embodiments, in patients with advanced or metastatic hepatocellular carcinoma, a pharmaceutical composition for treating the tumor or inhibiting tumor growth may be administered to the patient in combination with lenvatinib. In one embodiment of the present invention, a pharmaceutical composition is provided for treating a tumor or inhibiting tumor growth in a patient with advanced or metastatic gallbladder cancer, comprising an effective amount of IMC-002 antibody, wherein the antibody is administered to the patient at doses of approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, or approximately 30 mg / kg every approximately two or three weeks without priming.

[0019] In one embodiment of the present invention, a pharmaceutical composition is provided for treating a tumor or inhibiting tumor growth in a patient with advanced or metastatic breast cancer, comprising an effective amount of IMC-002 antibody, wherein the antibody is administered to the patient at doses of approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, or approximately 30 mg / kg every approximately two or three weeks without priming. In some embodiments, in patients with advanced or metastatic breast cancer, a pharmaceutical composition for treating the tumor or inhibiting tumor growth may be administered to the patient in combination with paclitaxel or a combination of gemcitabine and carboplatin. [Effects of the Invention]

[0020] The anti-CD47 antibody IMC-002 induces macrophage phagocytosis of cancer cells, potently suppressing tumor growth in patients with advanced or metastatic cancer. In patients with advanced or metastatic solid tumors who had failed standard treatment, IMC-002 was administered at doses of approximately 5 mg / kg to 30 mg / kg every 2 to 3 weeks without priming, demonstrating an excellent safety profile and efficacy. [Brief explanation of the drawing]

[0021] [Figure 1] The mechanism of action of the anti-CD47 antibody (IMC-002) according to one embodiment of the present invention is shown. [Figure 2]A schematic diagram of a dose-escalation study and an expansion study based on a clinical trial design of one embodiment of the present invention is shown. [Figure 3] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the change in hemoglobin levels with the administered dose of IMC-002 in a dose-escalation study. [Figure 4] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the change in neutrophil counts with the dose of IMC-002 administered in a dose-escalation study. [Figure 5] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the change in platelet counts with the dose of IMC-002 administered in a dose-escalation study. [Figure 6] This is the result of a clinical trial according to one embodiment of the present invention, showing a swimmer plot of tumor response over time in a dose-escalation study. In the swimmer plot, the symbol "●" indicates SD (Stable Disease), "+" indicates PD (Progressive Disease), and "→" indicates continued treatment. [Figure 7] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the rate of change in the tumor burden of the target lesion in a dose-escalation study. [Figure 8A] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the CD47-positive macrophage density and CD47-negative macrophage density in patients who received clinical benefit (CBR) and patients who did not receive clinical benefit (Non-CBR). [Figure 8B] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the CD47-positive macrophage density and CD47-negative macrophage density in patients who received clinical benefit (CBR) and patients who did not receive clinical benefit (Non-CBR). [Figure 9] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the simulated pharmacokinetic (PK) profile of IMC-002 after intravenous infusion every three weeks. [Figure 10] This shows the results of a clinical trial according to one embodiment of the present invention, comparing the PK profile based on the administered dose. [Figure 11]This shows the results of a clinical trial according to one embodiment of the present invention, indicating the PK serum concentration after initial administration. [Figure 12] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the change in hemoglobin levels depending on the dose of IMC-002 administered in the expanded study. [Figure 13] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the change in neutrophil counts depending on the IMC-002 dose administered in the expanded study. [Figure 14] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the change in platelet counts based on the IMC-002 dosage in an expanded study. [Figure 15] This is the result of a clinical trial according to one embodiment of the present invention, showing a swimmer plot of tumor response over time in an expanded trial. In the swimmer plot, the symbol "▲" represents PR (Partial Response), "●" represents SD (Stable Disease), "+" represents PD (Progressive Disease), and "→" represents continued treatment. [Figure 16] This shows the results of a clinical trial according to one embodiment of the present invention, illustrating the rate of change in tumor burden of the target lesion in an expanded study. [Modes for carrying out the invention]

[0022] The detailed description of the present invention, as described below, will be written with reference to specific drawings (if drawings are available) with respect to specific embodiments in which the present invention can be implemented, but the present invention is not limited thereto and is limited only to the appended claims with respect to all scope identical or equivalent to that described in the claims. It should be understood that the various embodiments / examples of the present invention are different from each other but do not need to be mutually exclusive. For example, specific shapes, structures and characteristics described herein can be realized by changing one embodiment / example to another, or by combining multiple embodiments / examples, without departing from the technical idea and scope of the present invention. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as those commonly used in the art to which the present invention belongs. In case of any conflict, this specification, including the definitions, shall prevail. The definitions of terms described herein are for the purpose of interpreting this specification, and a term expressed in the singular form should be interpreted as referring to the plural form (i.e., at least one) and vice versa, unless otherwise inappropriate in context.

[0023] definition As used herein, the term “about” refers to the normal range of error for each value known to a person of the ordinary skill in the art. Furthermore, unless otherwise explicitly stated, all numbers, values ​​and / or expressions used herein to describe components, conditions, compositions, quantities, etc., should be understood to be modified by the term “about,” as such numbers are essentially approximations that reflect various uncertainties in the measurement that arise, in particular, when obtaining such values. For example, this may include cases where the value is within ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.5% of a given numerical value.

[0024] The term "cancer" refers to a range of diseases characterized by the uncontrolled growth of abnormal cells within the body. "Cancer" or "cancer tissue" can include tumors. The term "progressive" is used in relation to cancer and refers to cancer that has progressed locally and has not been completely removed or controlled by surgery. "Progressive cancer" is cancer that has reached at least stage IIIB. The term "metastatic" is used in relation to cancer to refer to a condition in which cancer cells leave the place where they were first formed and travel, for example, through the blood or lymphatic system, or form tumors (metastatic tumors) in other parts of the body. "Metastatic cancer" is cancer that has reached at least stage IV.

[0025] The term “standard treatment” means a generally accepted treatment method that is appropriate for the treatment of a particular type of cancer, preferably a particular type of solid tumor, as determined by medical professionals. “Standard treatment” may be the same or different for different tumor types. “Standard treatment” may include primary or secondary treatment methods, such as surgery, radiation therapy, chemotherapy, and immunotherapy. “Standard treatment” may be approved by various regulatory agencies, such as the U.S. Food and Drug Administration.

[0026] The term “antibody” includes monoclonal antibodies (including full-length antibodies) of any isotype such as IgG, IgM, IgA, IgD, and IgE, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibody fusions (e.g., fusions of antibodies with (poly)peptides or antibodies with compounds), and antibody fragments (including antigen-binding fragments). In this specification, the prefix “anti-” means that, when associated with an antigen, the antibody is reactive with that antigen. Antibodies that react with a particular antigen can be produced by synthetic and / or recombinant methods, such as the selection of recombinant antibody libraries from phages or similar vectors, or by immunization of animals using the antigen or antigen-coding nucleic acids, but are not limited to these. A typical IgG antibody consists of two identical heavy chains and two identical light chains linked by disulfide bonds. Each medium and light chain contains an invariant region and a variable region. The medium-chain variable region (HVR) and the light-chain variable region (LVR) each contain three sections referred to as "complementarity-determining regions" ("CDRs") or "hypervariable regions," which are primarily involved in binding to the antigen epitope. These are numbered sequentially from the N-terminus and are usually referred to as CDR1, CDR2, and CDR3. Of the variable regions outside the CDRs, the better-conserved regions are referred to as "skeleton regions" ("FRs"). In this specification, the antibody may be, for example, an animal antibody, a chimeric antibody, a humanized antibody, or a human antibody.

[0027] The term “monoclonal antibody” or “mAb” refers to a substantially homogeneous population of antibodies, where the antibody molecules constituting the population are identical in amino acid sequence, except for possible spontaneous mutations that may be present in trace amounts. In contrast, typical (polyclone) antibody preparations typically contain a number of different antibodies, each having different amino acid sequences in variable domains specific to different epitopes, particularly in the CDR sequence. “Monoclonal” refers to the characteristic of an antibody being obtained from a substantially homogeneous population of antibodies and should not be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies used in therapeutic methods, pharmaceuticals, and disclosed uses can be produced by the hybridoma method first described in the literature [Kohler et al. (1975) Nature 256: 495] or by the recombinant deoxyribonucleic acid (DNA) method. Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, in the literature [Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597]. See also the literature [Presta (2005) J. Allergy Clin. Immunol. 116:731].

[0028] The term "priming" refers to initial antigen stimulation administered before the initiation of treatment. Priming is used to activate the immune system or maximize the effectiveness of treatment. For example, in certain immunotherapies, priming administration activates T cells, allowing subsequent treatments to work more effectively. Priming refers to primary antigen stimulation, which induces an immune response to a specific antigen and then recalls (remembers) a high level of immune response to that specific antigen through subsequent re-immunization with the same antigen. The term "pharmaceutical composition" or "pharmaceutical dosage form" refers to a combination of an active ingredient and an inactive or active carrier and / or excipient.

[0029] The term "effective dose" refers to the amount of a compound (including macromolecules such as antibodies) or composition (e.g., the compound or composition of the present invention) sufficient to achieve a favorable or desired result. An effective dose may be administered in one or more doses, applications, or applications and is not intended to be limited to a specific dosage form or route of administration. The terms “patient,” “subject,” “subject,” or “subject” refer to a single subject that is in need of a therapy or treatment, or is participating in a clinical trial, epidemiological study, or is used as a control group, and include human and mammalian veterinary patients, e.g., cattle, horses, dogs, and cats.

[0030] The term “administration” refers to the physical delivery of a therapeutic agent to a subject using any variety of methods and delivery systems known to the ordinary technician. Exemplary routes of administration include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration. Parenteral routes of administration may be, for example, injection or infusion (e.g., intravenous infusion). When administered orally, the active ingredient may be formulated with pharmaceutically acceptable excipients into pills, capsules, sachets, tablets, etc. As used herein, the term “parenteral administration” generally means, but is not limited to, methods of administration other than intestinal and topical administration, generally by injection, and includes intravenous, intramuscular, intra-arterial, intra-spinal, intralymphatic, intra-lesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as intracellular electroporation. Therapeutic agents may be administered parenterally or orally. Other parenteral routes of administration include topical, cutaneous, or mucosal routes, such as intranasal, intravaginal, rectal, sublingual, or topical administration. Administration may be, for example, once, multiple times, and / or over an extended period of one day or more.

[0031] The term "combined administration" refers to the administration of two or more therapeutic agents. Each type of therapeutic agent can be administered to an individual simultaneously, sequentially, or individually. Simultaneous administration means administering each type of therapeutic agent at once through the same or different administration methods. Sequential administration means administering each type of therapeutic agent separately and continuously at regular intervals, but with the intervals being the shortest possible time. Individual administration means administering each type of therapeutic agent at regular time intervals. Such administration methods can be appropriately selected by a skilled technician, taking into account the patient's therapeutic efficacy and side effects. The number of administrations can also be appropriately selected, along with the dosage, taking into account the patient's condition and therapeutic efficacy, and may be, for example, one or more times, and may be carried out over one or more extended periods.

[0032] The term "biological sample" includes clinical samples, as well as tissues obtained by surgical excision, tissues obtained by biopsy, cultured cells, conditioned medium, cell lysates, tissue samples, organs, bone marrow, blood, plasma, serum, etc. A "biological sample" includes a sample that contains or is suspected of containing target cells or normal control cells, or such cells or biological fluids derived therefrom (e.g., cancerous cells, infected cells, etc.), for example, a sample containing polynucleotides and / or polypeptides obtained from such cells (e.g., cell lysates or other cell extracts containing polynucleotides and / or polypeptides). A biological sample containing cells that cause a patient's disease may also contain cells that do not cause the disease.

[0033] The terms "phagocytic cell" and "phagocyte" are used interchangeably in this invention to refer to cells capable of phagocytosis. There are three main categories of phagocytes: macrophages, mononuclear cells (histiocytes and mononuclear cells); polymorphonuclear leukocytes (neutropenic cells); and dendritic cells.

[0034] Treatment method In one embodiment of the present invention, a method for treating a patient with an effective dose of an anti-CD47 formulation is provided. The present invention is based on clinical confirmation that both safety and efficacy can be ensured without priming when an anti-CD47 antibody (particularly IMC-002) is administered to patients with advanced or metastatic solid tumors in specific doses and cycles. In some embodiments, the cancer may be an advanced or metastatic solid tumor. Specifically, the solid tumor may be one or more selected from lung cancer, pancreatic cancer, colorectal cancer, gallbladder cancer, biliary tract cancer, stomach cancer, liver cancer, brain tumor, breast cancer, thyroid cancer, bladder cancer, esophageal cancer, ovarian cancer, melanoma, head and neck cancer, skin cancer, prostate cancer, hepatocellular carcinoma, fibrosarcoma, and cervical cancer. More specifically, the solid tumor may be liver cancer (e.g., hepatocellular carcinoma), breast cancer (e.g., triple-negative breast cancer), or gallbladder cancer.

[0035] In some embodiments, the patient may be one for whom standard treatment is not possible or has failed standard treatment. Specifically, standard treatment may be a treatment method generally recognized by medical professionals as appropriate for the treatment of a particular cancer, preferably a particular solid tumor. Specifically, standard treatment may include first- or second-line treatment measures, such as surgery, radiotherapy, chemotherapy, immunotherapy, or a combination thereof. Failure to respond to standard treatment may mean that recurrence / refractory / disease progression has been observed after standard treatment.

[0036] In some embodiments, the patient may be a stage 4 patient with multiple distant metastases or a locally advanced patient. A stage 4 patient with multiple distant metastases or a locally advanced patient refers, for example, to a patient with histologically or cytologically documented metastatic or locally advanced liver cancer (e.g., hepatocellular carcinoma), breast cancer (e.g., triple-negative breast cancer), or gallbladder cancer.

[0037] In some embodiments, the method of the present invention does not include a priming step for the anti-CD47 formulation. Specifically, the absence of a priming step means that a preparatory step for activating the immune system in the early stages of cancer treatment is omitted. Omitting priming can simplify the treatment process, which may be advantageous, especially for elderly patients or patients with other health problems. Omitting priming can reduce the side effects of cancer treatment. In some embodiments, the anti-CD47 formulation of the present invention may be an anti-CD47 antibody, specifically a fully human anti-CD47 monoclonal antibody. The fully human antibody of the present invention is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by / or made by a human or made using any technique for producing human antibodies.

[0038] In some embodiments, the anti-CD47 antibody of the present invention is an IgG4 antibody. Specifically, the anti-CD47 antibody is an IgG4 kappa isotype antibody. More specifically, the anti-CD47 antibody is composed of a glycosylated tetramer consisting of two identical heavy gamma chains and two identical kappa light chains linked by disulfide bonds. In some embodiments, the anti-CD47 antibody of the present invention has an S228P mutation as a hinge region mutation, thus preventing Fab substitution. The S228P mutation reduces Fab arm exchange. In some embodiments, the anti-CD47 antibody may include HCDR1, HCDR2, and HCDR3 contained in the medium-chain variable region of SEQ ID NO: 1, and LCDR1, LCDR2, and LCDR3 contained in the light-chain variable region of SEQ ID NO: 2.

[0039] In some embodiments, the heavy chain variable region of the anti-CD47 antibody may contain, or be, an amino acid sequence that is 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more identical to the amino acid sequence of SEQ ID NO: 1, or the sequence described in SEQ ID NO: 1. In some embodiments, the light chain variable region of the anti-CD47 antibody may contain, or be, an amino acid sequence that is 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more identical to the amino acid sequence of SEQ ID NO: 2 or the sequence described in SEQ ID NO: 2.

[0040] In some embodiments, the anti-CD47 antibody may include the heavy chain variable region of SEQ ID NO: 1 and / or the light chain variable region of SEQ ID NO: 2. In some embodiments, the anti-CD47 antibody may include the heavy chain of SEQ ID NO: 3 and / or the light chain of SEQ ID NO: 4. In some embodiments, the anti-CD47 antibody may be an antibody named IMC-002. IMC-002 is a fully human anti-CD47 antibody of IgG4 containing a heavy chain variable domain with the amino acid sequence described in SEQ ID NO: 1 and a light chain variable domain with the amino acid sequence described in SEQ ID NO: 2. IMC-002 contains the S228P mutation as a hinge region mutation. See Table 1 below for the amino acid sequence information of IMC-002.

[0041] [Table 1]

[0042] [Table 2]

[0043] IMC-002 is a selection of antibodies from among the various anti-CD47 antibodies described in Korean Registered Patent No. 10-2625835 (International Patent Application No. PCT / US2016 / 020980) that showed low hemagglutination in in vitro hemagglutination tests, and is the C47B10-H3-D4 clone antibody described in the aforementioned document. The entire contents of the aforementioned document are included as references in this specification.

[0044] In some embodiments, the dose of anti-CD47 antibody may vary depending on the age and weight of the individual being administered, the target disease, the pathological condition, the route of administration, etc. When anti-CD47 antibody is used to treat or inhibit the growth of solid tumors, it can be administered in single or multiple doses. The frequency and duration of treatment can be adjusted according to the severity of the disease. In some embodiments, the anti-CD47 antibody may be administered to the tumor of an individual in a therapeutically effective dose one or more times, for example, one, two, three, four, five, six, seven, eight, nine, or ten or more times. For example, a therapeutic administration regimen may include one or more doses of the anti-CD47 antibody administered at intervals of about one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, or four weeks. In some embodiments, the anti-CD47 antibody may be administered every two to three weeks. In some embodiments, the anti-CD47 antibody may be administered every two or three weeks.

[0045] In some embodiments, each dose of anti-CD47 antibody may be about 5 to about 30 mg / kg. For example, each dose of anti-CD47 antibody may be about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 mg / kg. In some embodiments, each dose of anti-CD47 antibody may be about 20 to about 30 mg / kg. In some embodiments, each dose of anti-CD47 antibody is about 20 mg / kg or about 30 mg / kg. In some embodiments, the minimum effective concentration of anti-CD47 antibody in the treatment of solid tumors may be about 20 to about 30 μg / mL. In some embodiments, the minimum effective concentration of anti-CD47 antibody in the treatment of solid tumors may be about 24 μg / mL. The minimum effective concentration is the minimum concentration of the drug that must be maintained in the serum for the treatment of solid tumors. In some embodiments, by administering the pharmaceutical composition of the present invention, the serum concentration of the drug may be about 20 to about 30 μg / mL or higher, which is the minimum effective concentration. In some embodiments, by administering the pharmaceutical composition of the present invention, the serum concentration of the drug may be about 24 μg / mL or higher, which is the minimum effective concentration.

[0046] Pharmaceutical compositions In other embodiments of the present invention, the anti-CD47 formulations disclosed herein can be provided as pharmaceutical compositions suitable for therapeutic use, for example, human treatment. In some embodiments, the anti-CD47 antibody disclosed herein can be formed with one or more carriers and / or excipients and provided as a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprising the anti-CD47 antibody disclosed herein and one or more carriers and / or excipients is provided. Specifically, a therapeutic dosage form containing an anti-CD47 antibody can be prepared for storage by mixing an anti-CD47 antibody of a desired degree of purity with a selectively physiologically acceptable carrier, excipient, or stabilizer in the form of a lyophilized dosage form or aqueous solution. For carriers, excipients, stabilizers, etc., see Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). The preferred form of the composition depends on the intended administration method and therapeutic application. In some embodiments, the composition may also include a pharmaceutically acceptable, non-toxic carrier or diluent, defined as a vehicle typically used to formulate a pharmaceutical composition for animal or human administration, depending on the desired dosage form. The diluent is selected so as not to affect the biological activity of the combination. Examples of diluents include distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. The pharmaceutical composition or dosage form may also include other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0047] Typically, the pharmaceutical composition is prepared as an injectable liquid solution or suspension, and a solid form suitable for solution or suspension in a liquid vehicle can also be prepared before injection. Furthermore, as previously stated, the formulation can be emulsified or encapsulated in liposomes or microparticles, such as polylactic acid, polyglycolides, or copolymers, for enhanced adjuvant effects. The formulation of the present invention can be administered in the form of depot injection or implantable formulations, which can be dosage-formed in a manner that allows for sustained or pulsatile release of the active ingredient. The pharmaceutical composition is generally sterile, substantially isotonic, and dosage-formed in full compliance with all U.S. Food and Drug Administration Good Manufacturing Practice (GMP) regulations.

[0048] In some embodiments, the pharmaceutical composition may be an aqueous solution. In some embodiments, the pharmaceutical composition may contain, along with the anti-CD47 antibody of the present invention, approximately 10-30 mM sodium phosphate, approximately 80-120 mM sodium chloride, approximately 50-80 mM mannitol, and approximately 0.01-0.1% polysorbate 80, which are phosphate buffers. In some embodiments, the pharmaceutical composition may contain, along with the anti-CD47 antibody of the present invention, about 20 mM sodium phosphate, about 100 mM sodium chloride, about 65.9 mM mannitol, and about 0.05% polysorbate 80. In some embodiments, the pH of the pharmaceutical composition may be about 4 to 7, more specifically about 5 to 6, and more specifically about 5.5. In some embodiments, the pharmaceutical composition may contain the anti-CD47 antibody of the present invention at a concentration of about 40 to 60 mg / mL, specifically about 50 mg / mL.

[0049] In some embodiments, the anti-CD47 antibody of the present invention can be provided as a liquid in a 10 mL sterile glass vial. Anti-CD47 preparations can be administered by any suitable route and method, including oral or parenteral administration. In some embodiments, anti-CD47 preparations are administered parenterally. Parenteral administration refers to administration by means of other than intestinal and topical administration, generally by injection, and includes epidermal, intravenous, intramuscular, intraarterial, intravertebral, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural, and intrasternal injections and infusions. In some embodiments, the route of administration of anti-CD47 preparations is intravenous injection or infusion. In some embodiments, the route of administration of anti-CD47 preparations is intravenous infusion.

[0050] Concomitant administration In one embodiment of the present invention, the anti-CD47 antibody of the present invention can be administered in combination with other anticancer agents. For example, the other anticancer agents may include, but are not limited to, one or more of the following substances: chemotherapeutic agents (e.g., carboplatin, gemcitabine, paclitaxel, or a combination thereof), tyrosine kinase inhibitors (e.g., lenvatinib, regorafenib, cabozantinib, or a combination thereof). In some embodiments, the anti-CD47 antibody of the present invention may be administered in combination with a tyrosine kinase inhibitor, preferably lenvatinib, regorafenib, cabozantinib, or a combination thereof, more preferably lenvatinib. In some embodiments, the anti-CD47 antibody of the present invention may be administered in combination with a chemotherapeutic agent, preferably paclitaxel, carboplatin, gemcitabine, or a combination thereof, more preferably with paclitaxel, or in combination with carboplatin and gemcitabine.

[0051] In some embodiments, an anti-CD47 antibody can be administered in combination with lenvatinib to patients with hepatocellular carcinoma. In some embodiments, when administered in combination, lenvatinib can be administered once daily. In some embodiments, when administered in combination, lenvatinib may be administered at a dose of 4-8 mg (e.g., 8 mg) once daily (body weight < 60 kg) or at a dose of 4-12 mg (e.g., 12 mg) once daily (body weight ≥ 60 kg). In some embodiments, anti-CD47 antibodies can be administered in combination with paclitaxel to patients with triple-negative breast cancer. In some embodiments, when administered in combination, paclitaxel may be administered on days 1 to 3 of each cycle, preferably on day 1 of each cycle. In some embodiments, when administered in combination, paclitaxel is administered at a dose of 100 to 250 mg / m² on days 1 to 3 of each cycle. 2 It may also be administered intravenously. For example, paclitaxel may be administered at a dose of 175 mg / m² on day 1 of each cycle. 2 It may be administered intravenously. In some embodiments, an anti-CD47 antibody can be administered in combination with gemcitabine and carboplatin to patients with triple-negative breast cancer. In some embodiments, when administered in combination, gemcitabine and carboplatin may each be administered once to three times, preferably twice, per cycle. In some embodiments, when administered in combination, gemcitabine and carboplatin may each be administered on days 1 to 3 and days 6 to 10 of each cycle. In some embodiments, when administered in combination, gemcitabine and carboplatin may each be administered on days 1 and 8 of each cycle. In some embodiments, gemcitabine may be administered at a dose of 800 to 1,200 mg / m² on days 1 to 3 and days 6 to 10 of each cycle. 2 It may be administered intravenously, and carboplatin may be administered intravenously with an AUC of 1.5 to 2.5. For example, gemcitabine may be administered at 1,000 mg / m² on days 1 and 8 of each cycle. 2 It may be administered intravenously, and carboplatin may also be administered intravenously with an AUC of 2.

[0052] kit In other embodiments of this method, a kit for using the anti-CD47 pharmaceutical compositions disclosed herein is provided. The kit comprises the anti-CD47 formulations disclosed herein. In some embodiments, the kit comprises two or more anti-CD47 formulations. In some embodiments, the anti-CD47 formulation is provided in a dosage form (e.g., a therapeutically effective dosage form). In some embodiments, the anti-CD47 formulation is provided in two or more different dosage forms (e.g., two or more different therapeutically effective dosage forms). In some embodiments, the anti-CD47 formulation can be provided in liquid or solid form in any convenient packaging (e.g., stick pack, dose pack, etc.). In some embodiments, the kit may further include instructions for carrying out the method. These instructions are the therapeutic or inhibitory methods disclosed herein. These instructions may be present in the kit in multiple forms, one or more of which may be present in the kit. One form in which such instructions may be present is information printed on a suitable medium or substrate, e.g., a piece of paper or fragment on which the information is printed, the kit packaging, a packaging insert, etc. Another form of such instructions may be a computer-readable medium on which the information is recorded, e.g., a diskette, a compact disc (CD), a flash drive, etc. Yet another form of such instructions may be a website address that can be used to access the information from a site removed via the Internet. All patents and references cited herein are included herein by reference in their entirety.

[0053] The present invention will be described in more detail below with reference to the following examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited to these examples. [Examples]

[0054] Example 1. A Phase 1 dose-escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics, and clinical activity of IMC-002 in patients with advanced and metastatic solid tumors. This example describes a dose-escalation and expansion cohort study of the anti-CD47 antibody IMC-002 conducted in patients with metastatic or locally advanced solid tumors that were not treatable with standard therapy or were histologically or cytologically confirmed after standard therapy.

[0055] 1.1. Background and Rationale Pharmacological data for IMC-002 demonstrated its potential as an anticancer agent, and nonclinical safety, pharmacokinetic, and pharmacodynamic data were used to determine the starting dose for clinical trials. Furthermore, clinical trial results in patients with metastatic or locally advanced solid tumors suggested that IMC-002 is safe and tolerable when administered weekly or bi-weekly. CD47 is a transmembrane glycoprotein that is ubiquitously expressed on the surface of various cell tumors and overexpressed in various cancer cells. IMC-002 is a fully human IgG4 antibody that targets CD47 and lacks function as an Fc regulator, including complement-dependent cell-mediated cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). IMC-002 binds to various cancer cells such as MDA-MB-231 (EC50 = 5.73 μg / mL) and Raji (EC50 = 4.77 μg / mL), but unlike other CD47 blockers, it does not bind to red blood cells up to a concentration of 300 μg / mL, thus preventing hemagglutination. In vitro phagocytic analysis was used to confirm whether IMC-002 could induce antibody-dependent cell phagocytosis (ADCP). As a single formulation, IMC-002 induced phagocytosis in a dose-dependent manner against various cancer cell lines derived from hematological malignancies as well as solid tumors.

[0056] The in vivo efficacy of IMC-002 was evaluated in mouse xenograft models. Efficacy studies using the MDA-MB-231 xenograft model showed that administration of 3 mg / kg or higher at weekly intervals significantly controlled cancer cell growth and extended survival. In the MDA-MB-231 orthotopic xenograft model, the in vivo efficacy of IMC-002 was confirmed at a dose of 10 mg / kg three times weekly. No drug-induced weight loss or abnormal clinical signs were observed in either study model. The pharmacokinetic (PK) characteristics of IMC-002 were evaluated in mice and monkeys. C57BL / 6 mice and sinomorgus monkeys were intravenously injected with IMC-002 at doses ranging from 0.4 to 10.0 mg / kg. IMC-002 generally showed dose-proportional systemic exposure. The steady-state volume of distribution (Vdss) was 75.1–83.8 mL / kg in mice and 137.9–200.3 mL / kg in monkeys. Total intracellular clearance (CL) was 0.2–0.3 mL / hr / kg in mice and 0.7–1.1 mL / hr / kg in monkeys. Serum concentrations decreased in a polyphasic pharmacokinetic pattern, and the terminal elimination half-life (t1 / 2) was 224.9–240.9 hours in mice and 114.8–171.6 hours in monkeys.

[0057] In a 15-day preliminary toxicity study conducted in monkeys, intravenous administration of 100 mg / kg of IMC-002 three times at one-week intervals was well tolerated, with only minimal decreases in red blood cell and platelet counts. In a 4-week repeated toxicity study conducted in monkeys, 10, 30, and 100 mg / kg of IMC-002 were administered intravenously at one-week intervals for four weeks, followed by an assessment of reversibility after a four-week recovery period. No abnormalities were observed in clinical signs, general behavior and neurological function, body weight, food intake, eyes, electrocardiogram, respiratory rate, blood pressure, urinalysis results, clinical chemistry, cytokine analysis results, autopsy results, organ weight, and histopathology. Although drug-related changes were observed in blood tests and peripheral blood immunophenotyping, they were of low toxicological significance, with individual values ​​within the normal range or only slightly deviating, and no related changes were observed in clinicopathological or histopathological analysis. As a result, the maximum no-observed-adverse-effect level (NOAEL) for IMC-002 was confirmed to be 100 mg / kg. In vivo safety pharmacology studies evaluated the adverse effects of IMC-002 on the central nervous system, respiratory system, and cardiovascular system in a 4-week toxicity study in monkeys. No adverse nervous, respiratory, or cardiovascular changes associated with the study drug were observed.

[0058] 1.2. IMC-002 formulation The active pharmaceutical ingredient is IMC-002, a fully human anti-CD47 monoclonal antibody of the IgG4 kappa isotype. IMC-002 is composed of a glycated tetramer linked by disulfide bonds, consisting of two identical 446-amino acid heavy chains (gamma chains) and two identical 216-amino acid kappa light chains. The IMC-002 drug product is provided in liquid dosage form for IV infusion. IMC-002 is provided as a liquid in a 10 mL sterile glass vial containing 500 mg / 10 mL (50 mg / mL) of antibody in a dosage form of phosphate buffer (20 mM sodium phosphate, 100 mM sodium chloride, 65.9 mM mannitol, 0.05% polysorbate 80, pH 5.5). IMC-002 was diluted with 5% glucose injection solution and then injected into test subjects. The drug substance (DS) for IMC-002 was manufactured by Samsung Biologics (South Korea), and the drug product (DP) was manufactured by Vetter Pharma (US).

[0059] During the first four doses, all subjects received an antihistamine and paracetamol (e.g., 25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] intravenous injection or an equivalent oral formulation) approximately 30-60 minutes before each dose (or in accordance with national standards). The investigator then decided whether to continue administering pre-treatment drugs to subjects who did not experience infusion-related reactions. The administered drugs were modified according to national treatment standards and guidelines.

[0060] 1.3. Design of Clinical Trials This clinical trial was conducted to evaluate the safety, tolerability, pharmacokinetics, and clinical activity of IMC-002 in patients with advanced cancer who had failed standard treatment. As shown in Figure 2, it was conducted in two phases: a dose-escalation study (Part 1) and an expansion study (Part 2). In the expansion study, patients received combination therapy with other anticancer agents that had not been previously administered, along with IMC-002.

[0061] 1.3.1. Dose-escalation study (Part 1) Hepatic dose-limiting toxicity (DLT) over 21 days was evaluated using a conventional 3+3 design, with four doses of IMC-002 (5, 10, 20, and 30 mg / kg) administered. IMC-002 was infused intravenously for 3 hours (±30 minutes) (i.e., 150–210 minutes) every two weeks until disease progression or the occurrence of unacceptable toxicity. Tumor assessments were performed every six weeks according to RECIST 1.1 criteria.

[0062] Patients were selected who were unable to receive standard treatment or who had metastatic or locally advanced solid tumors histologically or cytologically confirmed after standard treatment. Additionally, patients were selected who had one or more measurable lesions according to the Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 and an ECOG performance status of 0–1. RECIST is a well-known solid tumor evaluation response criterion as described by Eisenhauer et al. (European J. Cancer 45: 228-247 (2009)). The Eastern Cooperative Oncology Group (ECOG) performance status index can be used to evaluate or select subjects for treatment, e.g., subjects with poor performance from prior therapies (see, e.g., Oken et al., (1982) Am J Clin Oncol. 5:649-655). The ECOG performance status scale describes the patient's functional level in terms of self-management ability, daily living activities, and physical abilities (e.g., walking, working, etc.). Twelve refractory patients meeting the aforementioned criteria (9 with hepatocellular carcinoma, 2 with breast cancer, and 1 with gallbladder cancer) were selected, with an average age of 57 years (48-73 years). Three patients were enrolled in each dose level 1-3 (5 mg / kg, 10 mg / kg, 20 mg / kg), and no DLTs were observed. A total of four patients were enrolled in dose level 4 (30 mg / kg) because one patient was ineligible and not included in the DLT population. The analysis was performed on the DLT population. Of these, 11 patients were stage 4 patients with multiple distant metastases and a high tumor burden. The median number of previous systemic therapies was 3 (range 1-3), and 4 patients received anti-PD-(L)1 antibodies. The median interval from the last dose of previous treatment to IMC-002 administration was 1 month (range 1-4). The criteria for the selected patients are summarized in Table 2 below.

[0063] [Table 3]

[0064] 1.3.2. Expanded Study: Concomitant Therapy (Part 2) The study included nine patients with hepatocellular carcinoma (HCC) and one patient with triple-negative breast cancer (TNBC), eight of whom had a prior history of anti-PD-(L)1 treatment. In the expanded trial, patients were treated with a combination therapy of IMC-002 and an anticancer drug they had not previously received. In the hepatocellular carcinoma cohort, lenvatinib was used in combination therapy, while in the triple-negative breast cancer cohort, gemcitabine plus carboplatin was used in combination therapy. All study subjects received 20 mg / kg of the study drug IMC-002 IV every three weeks (Q3W). In the first cycle, IMC-002 was administered over 3 hours (±30 minutes). If the initial infusion was tolerable, subsequent infusions were administered over 1–1.5 hours (±10 minutes). Standard care (SOC, Standard of Care, lenvatinib, paclitaxel, or gemcitabine + carboplatin) was initiated after 1 hour of safety monitoring for IMC-002 was completed. IMC-002 was administered for up to 2 years (34 cycles) until progressive disease (PD) or unacceptable toxicity occurred.

[0065] In the hepatocellular carcinoma cohort, lenvatinib was administered once daily at the clinically approved dose of 8 mg (two 4 mg capsules) for subjects weighing less than 60 kg, or 12 mg (three 4 mg capsules) for subjects weighing 60 kg or more. Lenvatinib was administered for up to two years (34 cycles) until progression of disease or unacceptable toxicity occurred. In the triple-negative breast cancer cohort, participants received gemcitabine plus carboplatin for up to two years (34 cycles) until progression of disease (PD) or unacceptable toxicity occurred. Gemcitabine 1,000 mg / m² was administered on days 1 and 8 of each cycle. 2 After the administration of gemcitabine, carboplatin was administered intravenously with an AUC of 2. The dosage of carboplatin was determined according to the following formula. Gemcitabine was administered over approximately 30 minutes, and carboplatin was administered over approximately 30 to 60 minutes. Carboplatin dose (mg) = AUC × (GFR + 25) GFR: Glomerular filtration rate (not converted to body surface area) The criteria for the selected patients are summarized in Table 3 below.

[0066] [Table 4]

[0067] 1.4. Safety Results 1.4.1. Dose-escalation study (Part 1) No dose-limiting toxicities (DLTs) were observed at any of the four dose levels. The majority of treatment-related adverse events (TRAEs) were grade 1–2 (92%), and the majority of these reactions occurred in the first cycle (95%). TRAEs observed in two or more patients included transient floaters, skin rash, anemia, and nausea. No infusion-related reactions, thrombocytopenia, or neutropenia were reported. The proportions of treatment-related adverse events in the safe population are summarized in Table 4 below.

[0068] [Table 5]

[0069] After IMC-002 administration, hemoglobin, neutrophil, and platelet counts were measured. Hemoglobin levels decreased slightly after initial exposure to IMC-002, but subsequently recovered without evidence of hemolytic anemia. Recovery was delayed in the 30 mg / kg cohort compared to the 20 mg / kg cohort. Therefore, 20 mg / kg was administered in the expanded study (Part 2). Neutropenia and thrombocytopenia, specific side effects of anti-CD47 agents, were not observed after initial exposure. Figures 3-5 show that hemoglobin, platelet, and neutrophil counts were maintained above the lower limit of normal (LLN) after IMC-002 administration.

[0070] 1.4.2. Expansion Test (Part 2) In a total of 10 patients, administered the drug in 3-week therapy and combination therapy, one patient reported anemia as a specific side effect of the anti-CD47 agent. Skin rash and floaters were observed at lower rates compared to the dose-escalation study (Part 1). The rates of treatment-related adverse reactions in the safety population are summarized in Table 5 below.

[0071] [Table 6]

[0072] Hemoglobin, neutrophil, and platelet counts were measured after IMC-002 administration. No grade 2 anemia was observed during the 3-week therapy regimen. After initial exposure, anemia, neutropenia, and thrombocytopenia, which are specific side effects of anti-CD47 agents, were not observed. Figures 12-14 show that hemoglobin, platelet, and neutrophil counts were maintained above the lower limit of normal (LLN) after IMC-002 administration.

[0073] 1.5. Results of effectiveness 1.5.1. Dose-escalation study (Part 1) Serum exposure (Cmax and AUC) of IMC-002 increased with dose, and the lowest predicted concentration when administered at doses of 10 mg / kg or higher every two weeks exceeded the lowest effective concentration of IMC-002. Of the 12 patients for whom efficacy could be evaluated, 6 showed stability with a median treatment duration of 11 cycles (range 6-28) (Disease Control Rate 50%), and 4 maintained stability for more than 6 months (Clinical Benefit Rate 30%). Of these, 5 had hepatocellular carcinoma and 1 had breast cancer. Refer to Figure 6 for the swimmer plot of tumor response over time. Figure 7 shows the percentage change in tumor burden from the baseline to the lowest point relative to the target lesion. Referring to the waterfall plot in Figure 7, it can be seen that a reduction in tumor size (up to -20%) was observed in 3 out of 12 patients.

[0074] Among the 12 patients for whom efficacy could be evaluated, the disease control rate was 50.0%, the Clinical Benefit Rate (CBR; stable disease during a treatment period of 6 months or more) was 33.3%, and the median treatment period was 10 months. CD47 immunohistochemistry (IHC) images were analyzed using an artificial intelligence-based analysis tool (Lunit SCOPE) that can distinguish staining positivity and cell type at the single-cell level. Specifically, the Lunit SCOPE uIHC v.2 model was used as the AI-based analysis tool. In artificial intelligence analysis of CD47 IHC, the density of CD47-positive macrophages tended to be higher in cases with clinical benefit compared to cases without (average CD47+ macrophage density: 71.0 vs 44.3 cells / mm³). 2 The proportion of tumor cells expressing CD47 was similar between the two groups (mean CD47+ tumor cells: 3289.3 vs 4098.4 cells / mm³). 2 Figures 8A and 8B show the CD47-positive macrophage density and CD47-negative macrophage density in patients who experienced clinical benefit and those who did not. The group of patients who experienced clinical benefit showed a higher density of CD47-positive macrophages. Table 6 below shows the analysis results for four patients who showed clinical benefit.

[0075] [Table 7]

[0076] 1.5.2. Dosage determination using PK modeling Population pharmacokinetic (PK) analysis was performed using NONMEM (version 7.5, ICON Development Solution, Ellicott City, MD, USA) with the support of PsN (version 3.0.0, Perl-speaks-NONMEM, Uppsala, Sweden). A total of 213 unbound IMC-002 serum concentration samples from patients were analyzed for model development. First-order conditional estimation by interaction (FOCE-I) was used for parameter estimation, and model selection was performed according to numerical (e.g., statistically significant reduction in objective function value (OFV)) and visual (e.g., goodness-of-fit (GOF) plots and visual predictive tests (VPC, n=1000)) criteria. Bootstrapping (n=1000) was performed to evaluate nonparametric models. As structural models, we explored general compartment models (e.g., 1, 2, 3 compartment models) and targeted drug-mediated drug delivery (TMDD) models via neonatal Fc receptor (FcRn) recycling, and performed stepwise covariate modeling (SCM) to identify clinically relevant covariates. Simulation studies were conducted on the final models under various scenarios to optimize doses for clinical trials.

[0077] Based on numerical and visual criteria, the TMDD model, which includes IgG FcRn recycling, was selected as the final model because it adequately explains the pharmacokinetics of IMC-002. Furthermore, physiological model parameters (e.g., CD47 degradation rate, total FcRn receptor volume) and target binding affinity (e.g., CD47 binding affinity, FcRn binding affinity, drug-CD47 complex dissociation rate) were fixed in the final model based on literature and in vitro observations. No covariate effects of IMC-002 on PK were observed. Simulations were performed using the final model for the appropriate dose, considering the lowest effective concentration (MEC, 24 μg / mL) obtained in nonclinical efficacy studies. As a result, the 3-week dosing regimen (Q3W) was considered an equivalent efficacy regimen compared to the 2-week dosing regimen (Q2W) used in previous clinical trials. Key steady-state parameters for evaluating equivalent efficacy regimens are shown in Table 7 and Figure 9. In Table 7, AUC taumeans the area under the serum concentration curve during the dosing interval, MEC means the minimum effective concentration, and C trough means the minimum serum concentration of the drug. Figure 9 shows the simulated pharmacokinetic (PK) profile of IMC-002 after intravenous (IV) injection every three weeks (Q3W). The solid line means the median of the PK profile, the shaded area means the PK profile from the 5th to the 95th percentile, and the dashed line means the minimum effective concentration (MEC, 24 μg / mL). Figure 10 shows the comparison results of the PK profiles after intravenous administration every three weeks according to the administered dose. Figure 11 shows the PK serum concentration after the initial administration. Table 7 shows the PK simulation results for the three-week therapy in the 5th cycle (cycle 5) when the steady state was confirmed.

[0078]

Table 8

[0079] IMC-002 is an engineered full human IgG4 monoclonal antibody. Since IgG has a longer half-life characteristic compared to other immunoglobulins due to the recycling process of the neonatal Fc receptor (FcRn) in the blood and lymph circulation, similar characteristics to endogenous IgG were observed in IMC-002. Such a phenomenon involves the non-linear PK of the drug and is the reason for selecting the mechanism-based TMDD model as the final model. Since IMC-002 is administered at a body weight-based dose and all tested covariates (e.g., body weight, age, gender) may be correlated with body weight, it could be predicted that no statistically significant covariates would be found. According to the simulation results, considering the plasma concentration retention time and the maximum tolerated dose (MTD) for the MEC observed in non-clinical and clinical trials, a 20 mg / kg Q3W therapy was presented as an effective and safe equivalent dosing regimen. Also, the half-life of IMC-002 was estimated to be about 4 to 5 days, which has the advantage of being able to synchronize the dosing frequency with other anti-cancer drugs in a clinical setting. Generally, chemotherapy sets one cycle to three weeks, and it is shown that if the half-life of the drug is about 4 to 5 days, systemic exposure can be maintained constantly without accumulation.

[0080] 1.5.3. Expansion Test (Part 2) In a combination therapy regimen, IMC-002 was administered at a dose of 20 mg / kg every three weeks. Of the nine patients with liver cancer, one showed a partial response, five remained stable, and the disease control rate was 67%. Three of these patients maintained a partial response or stable condition for more than six months, resulting in a clinical benefit rate of 33%. See Figure 15 for a swimmer plot of tumor response over time. Figure 16 shows the percentage change in tumor burden from the baseline to the lowest point relative to the target lesion. Referring to the waterfall plot in Figure 16, a reduction in tumor size (up to -31%) was observed in six out of ten patients. In the case of triple-negative breast cancer patients (Figure 16 (A)), a 12% reduction in tumor size was also observed.

[0081] conclusion Through dose-escalation studies, IMC-002 demonstrated a superior safety profile when administered at doses up to 30 mg / kg every two weeks for a maximum treatment period of 18 months, confirming preliminary efficacy in patients with advanced or metastatic solid tumors whose disease has progressed after standard treatment. Based on PK modeling and safety data, a dose of 20 mg / kg every three weeks was determined to be the optimal dose, and this dosing regimen was considered to allow for easier combination administration.

[0082] IMC-002 monotherapy was found to have a significant clinical benefit in advanced or metastatic solid tumors, particularly refractory HCC. Furthermore, the density of CD47-positive macrophages was found to be higher in CBR patients compared to non-CBR patients. Through expanded studies, it was confirmed that IMC-002 showed enhanced efficacy in terms of safety and clinical activity when administered at a dose of 20 mg / kg every three weeks. IMC-002 demonstrated a superior safety profile when administered at a dose of 20 mg / kg every three weeks, and its combination with other drugs such as lenvatinib, paclitaxel, or gemcitabine + carboplatin showed increased clinical benefit.

Claims

1. A pharmaceutical composition for treating tumors or suppressing tumor growth in patients with advanced or metastatic solid tumors, comprising an effective amount of a fully human anti-CD47 antibody that specifically binds to CD47 and contains HCDR1, HCDR2, and HCDR3 contained in the medium-chain variable region (HCVR) of SEQ ID NO: 1, and LCDR1, LCDR2, and LCDR3 contained in the light-chain variable region (LCVR) of SEQ ID NO:

2. The antibody is administered to the patient at a dose of approximately 5 mg / kg to approximately 30 mg / kg every approximately 2 to 3 weeks without priming. Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the medium-chain variable region comprises HCDR1 of SEQ ID NO: 5, HCDR2 of SEQ ID NO: 6, and HCDR3 of SEQ ID NO: 7, and the light-chain variable region comprises LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 9, and LCDR3 of SEQ ID NO:

10.

3. The pharmaceutical composition according to claim 1, wherein the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, and the light chain variable region includes the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

2.

4. The pharmaceutical composition according to claim 1, wherein the antibody does not induce significant levels of hemagglutination or anemia in the patient.

5. The pharmaceutical composition according to claim 1, comprising about 10 to 30 mM sodium phosphate, about 80 to 120 mM sodium chloride, about 50 to 80 mM mannitol, and about 0.01 to 0.1% polysorbate 80, and having a pH of about 4 to 7.

6. The pharmaceutical composition according to claim 1, comprising about 20 mM sodium phosphate, about 100 mM sodium chloride, about 65.9 mM mannitol, and 0.05% polysorbate 80, and having a pH of about 5.

5.

7. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a liquid drug for intravenous infusion.

8. The pharmaceutical composition according to claim 1, wherein the solid tumor is liver cancer, breast cancer, or gallbladder cancer.

9. The pharmaceutical composition according to claim 1, wherein the solid tumor is hepatocellular carcinoma.

10. The pharmaceutical composition according to claim 1, wherein the solid tumor is triple-negative breast cancer.

11. The pharmaceutical composition according to claim 1, wherein the patient is a patient for whom standard treatment is impossible or who has failed to receive standard treatment.

12. The pharmaceutical composition according to claim 1, wherein the antibody is administered to the patient approximately every two weeks or every three weeks.

13. The pharmaceutical composition according to claim 1, wherein the antibody is administered to the patient in a dose of approximately 20 mg / kg or approximately 30 mg / kg.

14. The pharmaceutical composition according to claim 1, wherein the patient received at least one systemic treatment prior to the administration of the anti-CD47 antibody.

15. The pharmaceutical composition according to claim 1, wherein the patient is a stage 4 patient with multiple distant metastases or a locally advanced patient.

16. The pharmaceutical composition according to claim 1, wherein the antibody is administered in combination with other anticancer agents.

17. The other anticancer drugs mentioned above are lenvatinib, paclitaxel, gemcitabine, carboplatin, or a combination thereof. The pharmaceutical composition according to claim 16.

18. The lenvatinib is administered once daily, according to claim 17.

19. The pharmaceutical composition according to claim 17, wherein the paclitaxel is administered on day 1 of the antibody administration cycle.

20. The pharmaceutical composition according to claim 17, wherein the gemcitabine and carboplatin are administered on day 1 and day 8 of the antibody administration cycle.

21. A method of treating a tumor or inhibiting its growth. (a) the stage of screening patients with advanced or metastatic solid tumors; and (b) The step of administering anti-CD47 antibodies to the patient without priming at doses of approximately 5 mg / kg to approximately 30 mg / kg every approximately 2 to 3 weeks, The antibody specifically binds to CD47 and contains HCDR1, HCDR2, and HCDR3 contained in the medium-chain variable region of SEQ ID NO: 1, and LCDR1, LCDR2, and LCDR3 contained in the light-chain variable region of SEQ ID NO:

2. method.

22. The further step includes measuring the CD47-positive macrophage density in a biological sample obtained from a patient before or after administration of the anti-CD47 antibody. The method according to claim 21.

23. (c) Further comprising the step of administering another anticancer agent before, after, or simultaneously with the administration of the antibody, The method according to claim 21.

24. The aforementioned other anticancer agent is administered once daily, or on day 1 of the antibody administration cycle, or on days 1 and 8 of the antibody administration cycle. The method according to claim 23.

25. A kit containing an anti-CD47 antibody, along with instructions for use of the anti-CD47 antibody to treat or inhibit tumor growth in patients with solid tumors. The instructions for use include providing the antibody to the patient without priming at a dose of approximately 5 mg / kg to approximately 30 mg / kg every approximately 2 to 3 weeks, The antibody specifically binds to CD47 and contains HCDR1, HCDR2, and HCDR3 contained in the medium-chain variable region of SEQ ID NO: 1, and LCDR1, LCDR2, and LCDR3 contained in the light-chain variable region of SEQ ID NO:

2. kit.

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