WO2024058289A1 - Composition pharmaceutique, pour la prévention ou le traitement d'un néoplasme neuroendocrinien, contenant un anticorps qui se lie de manière spécifique à pd-1 en tant que principe actif - Google Patents

Composition pharmaceutique, pour la prévention ou le traitement d'un néoplasme neuroendocrinien, contenant un anticorps qui se lie de manière spécifique à pd-1 en tant que principe actif Download PDF

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WO2024058289A1
WO2024058289A1 PCT/KR2022/013832 KR2022013832W WO2024058289A1 WO 2024058289 A1 WO2024058289 A1 WO 2024058289A1 KR 2022013832 W KR2022013832 W KR 2022013832W WO 2024058289 A1 WO2024058289 A1 WO 2024058289A1
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neuroendocrine
seq
treatment
antibody
pharmaceutical composition
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PCT/KR2022/013832
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English (en)
Korean (ko)
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윤재봉
임혜림
천성혜
이송하
전은영
김성일
이상헌
이한승
장우익
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주식회사 와이바이오로직스
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention or treatment of neuroendocrine neoplasms comprising an antibody that specifically binds to PD-1 as an active ingredient.
  • the first generation chemical anticancer drugs and second generation targeted anticancer drugs that are currently widely used have problems such as side effects due to the toxicity of the anticancer drugs and a high risk of drug resistance.
  • Immunoanticancer drugs called third-generation anticancer drugs that overcome these problems, act on the signaling pathway of immune cells to activate immune cells and attack cancer cells, producing a therapeutic effect.
  • PD-1 (also named CD279) is a 55 kD receptor protein related to the CD28/CTLA4 Co-stimulatory/inhibitory receptor family (Blank et al., 2005 Cancer Immunol Immunother 54:307- 314).
  • PD-1 The gene and cDNA encoding PD-1 were cloned to examine its characteristics in mice and humans (Ishida et al., 1992 EMBO J 11:3887-3395; Shinohara et al., 1994 Genomics 23:704-706).
  • Full-length PD-1 contains 288 amino acid residues (NCBI accession number: NP_005009).
  • the extracellular domain consists of 1–167 amino acid residues, and the cytoplasmic C-terminal tail contains residues 191–288, which contain two hypothetical immuno-regulatory motifs, the immunoreceptor tyrosine-based inhibition motif (ITIM; Vivier et al. ., 1997 Immunol Today 18:286-291) and an immunoreceptor tyrosine switch motif (ITSM; Chemnitz et al., 2004 J Immunol 173:945-954).
  • ITIM immunoreceptor tyrosine-based inhibition motif
  • ITMS immunoreceptor
  • PD-1 PD-1 protein-specific kinase kinase kinase
  • T-cells T-cells
  • B-cells B-cells
  • monocytes NK cells
  • NK natural killer cells
  • high levels of PD-1 expression are often associated with the activation of immune cells.
  • PHA Phytohaemagglutinin
  • phorbol ester (12-O-tetradecanoylphorbol-13-acetate or TPA
  • Neuroendocrine neoplasms is a general term for tumors originating from gastrointestinal neuroendocrine cells, previously called carcinoid tumors.
  • Neuroendocrine tumors have been called carcinoid tumors because the characteristic shape and arrangement of tumor cells are similar to those of typical carcinomas, and are classified into atypical carcinoids and malignant carcinoids depending on their biological characteristics.
  • the suffix ‘tumor’ was applied to a benign disease and did not fit the biological characteristics of neuroendocrine tumors. Therefore, after 2010, WHO adopted the name Neoplasm instead of the name Tumor.
  • Neuroendocrine neoplasms are classified into well differentiated neuroendocrine tumor, well differentiated neuroendocrine carcinoma, and poorly differentiated neuroendocrine carcinoma, and are classified into grades and It is classified according to location.
  • the present inventors confirmed that an antibody that specifically binds to PD-1 is particularly effective in treating neuroendocrine neoplasms, and completed the present invention.
  • One aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of neuroendocrine neoplasms, comprising an antibody that specifically binds to PD-1 or an antigen-binding fragment thereof as an active ingredient.
  • Another aspect of the present invention provides a method for preventing or treating neuroendocrine neoplasms, comprising administering to a subject an antibody or antigen-binding fragment thereof that specifically binds to PD-1.
  • the antibody or antigen-binding fragment thereof that specifically binds to PD-1 of the present invention can bind to PD-1 and inhibit the activity of PD-1, such as inhibiting the interaction between PD-1 and PD-L1. It is useful in the development of immunotherapeutics for various neuroendocrine neoplasms.
  • Figure 1 is a graph showing C max for each patient group.
  • Figure 2 is a graph showing AUC ss,6wk for each patient group.
  • One aspect of the present invention is a pharmaceutical for the prevention or treatment of neuroendocrine neoplasm (NEN) comprising an antibody or antigen-binding fragment thereof that specifically binds to PD-1 (Programmed Cell Death 1) as an active ingredient.
  • NNN neuroendocrine neoplasm
  • a composition is provided.
  • neuroendocrine neoplasm collectively refers to tumors arising from epithelial cells that have both neurological and endocrine functions.
  • the neuroendocrine neoplasm is also called a carcinoid tumor or carcinoid tumor.
  • the neuroendocrine neoplasms can be classified according to the degree of cell differentiation. Specifically, neuroendocrine neoplasms are classified according to histologic features (size, lymphatic invasion, mitotic count, Ki-67 labeling index, adjacent organ invasion, presence of metastases, and presence of hormone production). Specifically, they can be classified using the degree of differentiation, mitotic rate (number of mitoses/2 mm2), and Ki-67 index. For classification and definitions of neuroendocrine neoplasms, refer to the full text of the 2019 WHO classification (2019 World Health Organization (WHO) classification).
  • the neuroendocrine neoplasms can be classified according to the degree of differentiation into well differentiated neuroendocrine tumor, well differentiated neuroendocrine carcinoma, and poorly differentiated neuroendocrine carcinoma. .
  • the highly differentiated neuroendocrine tumor is neuroendocrine tumor (NET);
  • Well-differentiated neuroendocrine carcinoma refers to neuroendocrine carcinoma;
  • poorly differentiated neuroendocrine carcinoma may mean MiNEN (Mixed neuroendocrine-non-neuroendocrine tumor).
  • the neuroendocrine neoplasms include neuroendocrine tumor (NET), neuroendocrine carcinoma (NEC), mixed neuroendocrine-non-neuroendocrine tumor (MiNEN), and adenocarcinoma ex-goblet cell (AGCC). It may be one or more selected from the group consisting of carcinoid).
  • the neuroendocrine neoplasms can be classified as G1 (Grade 1), G2 (Grade 2), or G3 (Grade 3) depending on tumor grade.
  • the neuroendocrine tumor may be classified as G1 NET, G2 NET, or G3 NET.
  • the AGCC may be classified as G1 AGCC, G2 AGCC, or G3 AGCC.
  • the neuroendocrine neoplasm may be a NET or NEC of G3.
  • the neuroendocrine carcinoma may be small cell neuroendocrine carcinoma (SCNEC) or large cell neuroendocrine carcinoma (LCNEC) depending on the type of cell.
  • SCNEC small cell neuroendocrine carcinoma
  • LNEC large cell neuroendocrine carcinoma
  • the neuroendocrine neoplasms can be classified according to the location of onset.
  • the site of occurrence of the neuroendocrine neoplasm may be one or more selected from the group consisting of the pituitary gland, thyroid gland, parathyroid gland, thymus, lung, gastrointestinal tract, peripheral nervous system, pancreas, skin, reproductive system, adrenal gland, urinary system, and breast. It is not limited to this.
  • the neuroendocrine neoplasms include: Neuroendocrine tumor of the anterior pituitary, Neuroendocrine thyroid tumors, Parathyroid tumors, Thymus carcinoid tumors, Mediastinal carcinoid tumors, Pulmonary neuroendocrine tumors, Gastroenteropancreatic neuroendocrine tumors (GEP-NET), Peripheral nervous system tumors, Pheochromocytoma , Merkel cell carcinoma of skin, trabecular cancer, and urinary tract carcinoid tumor.
  • GEP-NET Gastroenteropancreatic neuroendocrine tumors
  • PD-1 programmed cell death protein 1
  • PD-1 expressed on T cells binds to PD-L1, a ligand expressed on cancer cells within the tumor microenvironment, which activates the PD-1 signaling pathway and ultimately leads to inactivation of T cells.
  • antibody that specifically binds to PD-1 refers to an antibody that can bind to PD-1, and may be used interchangeably with “anti-PD-1 antibody” herein. .
  • the form of the antibody may be a whole antibody or antigen binding fragments.
  • antibody refers to an immunoglobulin (Ig) molecule that reacts immunologically with a specific antigen, and refers to a protein molecule that acts as a receptor that specifically recognizes the antigen, and refers to the entire ( It may be a whole) antibody or antigen binding fragment.
  • Ig immunoglobulin
  • the antibodies or antigen-binding fragments thereof that specifically bind to PD-1 include monoclonal antibodies, polyclonal antibodies, single domain antibodies, single chain antibodies, and polyclonal antibodies. Multispecific antibody, human antibody, humanized antibody, chimeric antibody, intrabody, Fv, scFv, Fv linked by disulfide bond (di-scFv), Fab fragment, F( ab') 2 fragment and any of the above epitope binding fragments, but is not limited thereto.
  • the antibody may be a monoclonal antibody or a polyclonal antibody.
  • the heavy and light chains of immunoglobulins may each include a constant region and a variable region.
  • heavy chain refers to a full-length heavy chain comprising a variable region (VH) and three constant regions, CH1, CH2, and CH3, sufficient to confer specificity for an antigen and its antigen. It is meant to include all combined fragments.
  • VH variable region
  • CH1, CH2, and CH3 constant regions
  • light chain refers to both a full-length light chain and an antigen-binding fragment thereof comprising a variable region (VL) and a constant region (CL) sufficient to confer specificity for an antigen. It means.
  • CDR complementarity determining region
  • the light and heavy chain variable regions of the immunoglobulin include three hypervariable regions called complementarity determining regions (CDRs) and four framework regions (FRs).
  • the CDR mainly functions to bind to the epitope of the antigen.
  • the CDRs of each chain are typically called CDR1, CDR2, and CDR3 sequentially starting from the N-terminus, and are identified by the chain on which the specific CDR is located.
  • the FRs of each chain are typically called FR1, FR2, FR3 or FR4 sequentially, starting from the N-terminus, and are identified by the chain on which the particular FR is located.
  • the antibody or antigen-binding fragment thereof that specifically binds to PD-1 has a heavy chain variable region comprising the heavy chain CDR1 of SEQ ID NO: 1, the heavy chain CDR2 of SEQ ID NO: 2, and the heavy chain CDR3 of SEQ ID NO: 3. ; and a light chain variable region including light chain CDR1 of SEQ ID NO: 4, light chain CDR2 of SEQ ID NO: 5, and light chain CDR3 of SEQ ID NO: 6.
  • the heavy chain variable region of the antibody consists of the amino acid sequence of SEQ ID NO: 7 and about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about It may comprise or consist of an amino acid sequence having a sequence identity of at least 97%, at least about 98%, at least about 99%, or 100%.
  • the light chain variable region of the antibody is about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, and about 96% or more of the amino acid sequence of SEQ ID NO: 8. , may comprise or consist of an amino acid sequence having a sequence identity of at least about 97%, at least about 98%, at least about 99%, or 100%.
  • the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 7;
  • the light chain variable region may consist of the amino acid sequence of SEQ ID NO: 8.
  • the heavy chain of the antibody is about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more of the amino acid sequence of SEQ ID NO: 9. It may include or consist of an amino acid sequence having sequence identity of at least about 98%, at least about 99%, or 100%.
  • the light chain of the antibody is about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more of the amino acid sequence of SEQ ID NO. It may comprise or consist of an amino acid sequence having a sequence identity of at least 97%, at least about 98%, at least about 99%, or 100%.
  • the heavy chain consists of the amino acid sequence of SEQ ID NO: 9;
  • the light chain may consist of the amino acid sequence of SEQ ID NO: 10.
  • the antibody may be referred to as YBL-006.
  • Immunoglobulin heavy chain constant regions exhibit different amino acid compositions and sequences and therefore possess different types of antigenicity. Therefore, immunoglobulins can be divided into five categories and referred to as immunoglobulin isotypes, namely IgM, IgD, IgG, IgA and IgE.
  • the corresponding heavy chains are ⁇ chain, ⁇ chain, ⁇ chain, ⁇ chain and ⁇ chain, respectively.
  • the same type of immunoglobulin can be classified into different subtypes. For example, IgG can be classified as IgG1, IgG2, IgG3, and IgG4.
  • Light chains can be classified as ⁇ or ⁇ chains depending on their different constant regions. Each of the five types of IgG can have either a ⁇ or ⁇ chain.
  • the PD-1-specific antibody of the present invention may include a constant region derived from IgG, IgA, IgD, IgE, IgM, or a partial hybrid thereof.
  • the antibody may include a heavy chain constant region of SEQ ID NO: 11, SEQ ID NO: 14, and/or SEQ ID NO: 15, or a light chain constant region of SEQ ID NO: 12.
  • the antibody may include the hinge of SEQ ID NO: 13.
  • steady state refers to a state in which the drug's entry rate into the body and the elimination rate are equal and are in equilibrium due to repeated administration of the drug.
  • AUC and C max are pharmacokinetic measures of systemic exposure to a drug (e.g. YBL-006) following administration of the drug in humans. The AUC and C max may be driving factors of drug efficacy.
  • AUC refers to the area under the curve of a graph showing blood concentration and time of an administered drug.
  • C max refers to the maximum or highest drug concentration observed after drug administration.
  • AUC ss,6wk refers to the AUC observed at steady state approximately 4 to 6 weeks after the first drug administration.
  • treatment of neuroendocrine neoplasms means inhibiting the growth of cells or tissues of neoplasms arising in the neuroendocrine system or preventing the occurrence of such neoplasms, compared to when treated or not treated.
  • the concept also includes reducing cell growth and metastasis and reducing drug resistance to increase the therapeutic effect.
  • prevention refers to all actions that inhibit the development of neoplasms or delay their onset by administering the pharmaceutical composition.
  • the pharmaceutical composition for preventing or treating neuroendocrine neoplasms of the present invention may be included in any amount (effective amount) depending on the use, formulation, purpose of formulation, etc.
  • “effective amount” refers to the amount of active ingredient that can induce a therapeutic effect. Such effective amounts can be determined experimentally within the scope of the ordinary ability of those skilled in the art.
  • the pharmaceutical composition of the present invention contains the antibody or antigen-binding fragment thereof as an active ingredient in an amount of about 0.1% to about 90% by weight, specifically about 0.5% by weight to about 75% by weight, more specifically about 0.1% by weight to about 90% by weight, based on the total weight of the composition. It may contain from 1% by weight to about 50% by weight.
  • the pharmaceutical composition may be administered to an individual in a total amount of about 100 mg to about 500 mg of the antibody or antigen-binding fragment thereof every 1 day to 4 weeks.
  • the pharmaceutical composition containing the antibody or antigen-binding fragment thereof is effective for 1 day to 4 weeks, 2 days to 4 weeks, 3 days to 4 weeks, 4 days to 4 weeks, 5 days to 4 weeks, and 6 days to 4 days. weeks, 1 to 4 weeks, 2 to 4 weeks, 2 to 3 weeks, 3 to 4 weeks, 1 day to 3 weeks, 1 day to 2 weeks, 1 day to 1 week, 1 day to 6 days, It may be administered every 1 to 5 days, 1 to 4 days, 1 to 3 days, or every 1 to 2 days.
  • the antibody or antigen-binding fragment thereof is administered in an amount of about 100 mg to about 450 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 150 mg. mg to about 500 mg, about 150 mg to about 450 mg, about 150 mg to about 400 mg, about 150 mg to about 350 mg, about 180 mg to about 320 mg, about 200 mg to about 500 mg, about 200 mg to It may be administered in an amount of about 400 mg, or about 200 mg to about 300 mg. Preferably, it can be administered in an amount of about 200 mg to about 300 mg every 2 to 3 weeks.
  • the pharmaceutical composition of the present invention may contain a conventional, non-toxic pharmaceutically acceptable carrier that is formulated into a preparation according to a conventional method.
  • the pharmaceutically acceptable carrier may be any carrier that is a non-toxic material suitable for delivery to a patient. Distilled water, alcohol, fats, waxes and inert solids may be included as carriers. Pharmacologically acceptable adjuvants (buffers, dispersants) may also be included in the pharmacological composition.
  • the term “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not irritate living organisms and does not inhibit the biological activity and properties of the administered compound.
  • Acceptable pharmaceutical carriers in compositions formulated as liquid solutions include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and One or more of these ingredients can be mixed and used, and other common additives such as sweeteners, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, antioxidants, preservatives, lubricants, fillers, buffers, and bacteriostatic agents are added as needed. can do.
  • compositions of the present invention can be prepared in a variety of formulations for parenteral administration (e.g., intramuscular, intravenous, or subcutaneous injection).
  • parenteral administration e.g., intramuscular, intravenous, or subcutaneous injection.
  • the pharmaceutical composition of the present invention can be formulated in the form of injections, transdermal administration, nasal inhalation, and suppositories along with a suitable carrier according to methods known in the art.
  • injectable preparations include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • injectables may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, etc.
  • the antibody, antigen-binding fragment thereof, or composition containing them of the present invention may be administered to a patient in a therapeutically effective or pharmaceutically effective amount.
  • administration means introducing a predetermined substance into an individual by an appropriate method, and the composition can be administered through any general route as long as it can reach the target tissue.
  • the route of administration may include, but is not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, topical administration, intranasal administration, and intrarectal administration.
  • therapeutically effective amount refers to the amount of a compound or composition effective in preventing or treating the target disease, which is sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment. It refers to an amount that does not cause side effects.
  • the level of the effective amount is determined by factors including the patient's health status, type and severity of the disease, activity of the drug, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, combination or concurrent use of drugs, and It may be determined based on other factors well known in the medical field.
  • a therapeutically effective amount refers to an amount of drug that is effective in treating cancer.
  • the effective amount of the antibody or antigen-binding fragment thereof of the present invention may vary depending on the patient's age, gender, and weight, but generally, the antibody or antigen-binding fragment thereof is administered in an amount of about 100 mg to about every 1 day to 4 weeks. Administration may be repeated to achieve a total dose of 500 mg. However, since it may increase or decrease depending on the route of administration, severity of disease, gender, weight, age, etc., the scope of the present invention is not limited thereto.
  • the term "individual” refers to an object to which the composition of the present invention can be applied (prescribed), and may be a mammal such as a monkey, dog, cat, rat, mouse, or other livestock, including humans. Preferably, it may be a human, but is not limited thereto.
  • the antibody, antigen-binding fragment thereof, or pharmaceutical composition containing the same of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. there is. Additionally, it may be formulated in the form of a combination preparation with other therapeutic agents.
  • the other therapeutic agent may include any compound or natural extract whose safety has already been verified and which is known to have therapeutic activity or anti-cancer activity for neuroendocrine neoplasms in order to increase or reinforce therapeutic activity.
  • Another aspect of the present invention provides the use of the antibody or antigen-binding fragment thereof that specifically binds to PD-1 of the present invention for preparing a medicament for the prevention or treatment of neuroendocrine neoplasms.
  • PD-1 antibodies, antigen-binding fragments, neuroendocrine neoplasms, prevention and treatment are the same as described above.
  • Another aspect of the present invention provides the use of the antibody or antigen-binding fragment thereof that specifically binds to PD-1 of the present invention for the prevention or treatment of neuroendocrine neoplasms.
  • the antibodies and antigen-binding fragments thereof, neuroendocrine neoplasms, prevention and treatment are the same as described above.
  • Another aspect of the present invention is the prevention or treatment of neuroendocrine neoplasms, comprising administering an antibody or antigen-binding fragment thereof that specifically binds to PD-1, or a pharmaceutical composition containing the same, to an individual in need thereof.
  • PD-1 antibodies, antigen-binding fragments, pharmaceutical compositions, neuroendocrine neoplasms, administration, treatment and prevention are the same as described above.
  • the subject may be a mammal, preferably a human. Additionally, the individual may be a patient or have a high risk of suffering from neuroendocrine neoplasm.
  • Another aspect of the present invention provides an antibody or antigen-binding fragment thereof that specifically binds to PD-1 for use in the prevention or treatment of neuroendocrine neoplasm (NEN).
  • NNN neuroendocrine neoplasm
  • PD-1 antibodies, antigen-binding fragments, pharmaceutical compositions, neuroendocrine neoplasms, treatment and prevention are the same as described above.
  • YBL-006 is an antibody containing the amino acid sequence shown in Table 1 below. For specific details about YBL-006, refer to the full text of WO 2018-026248.
  • YBL-006 was produced by preparing a vector containing DNA or RNA encoding the amino acid sequence shown in Table 1, then transfecting it into host cells and expressing it. Afterwards, the purification process was performed and completed.
  • the method for producing antibodies is not limited to this, and various methods known to those skilled in the art can be used. For examples of methods for producing antibodies, see the full text of Korean Patent Nos. 10-1093717, 10-2250234 or WO 2018-026248.
  • Table 1 below shows the heavy chain, light chain, heavy chain CDR (HCDR), light chain CDR (LCDR), and heavy chain variable domain (VH) of YBL-006. ), light chain variable domain (VL), heavy chain constant domain (CH), and light chain constant domain (CL).
  • the treatment period to confirm the treatment effect of YBL-006 consisted of a 14-day (cohort B1 and B3) or 21-day (cohort B2) cycle.
  • the B1 and B3 cohorts were administered 200 mg every 2 weeks (Q2W), and the B2 cohort was administered 300 mg every 3 weeks (Q3W).
  • YBL-006 was administered once intravenously on Day 1 of each cycle. Tumor response evaluation was performed every 6 weeks. Specifically, for cohorts B1 and B3, it was conducted at the end of every 3 cycles (i.e., 3rd, 6th, and 9th cycles, etc.), and for cohort B2, it was conducted at the end of every 2 cycles (i.e., 2nd, 4th, and 6th cycles, etc.) did. The duration of treatment for patients who responded to therapy was up to 1 year for both the dose escalation and dose expansion phases.
  • Archival tumor tissue is available and agrees to provide archived tumor for retrospective biomarker analysis or agrees to perform fresh tumor biopsy during screening. Patients who do not have an existing (archived) tumor specimen and do not wish to undergo a biopsy may be enrolled with prior approval from the sponsor.
  • At least one measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Previously irradiated lesions may be considered target lesions if they are well defined, measurable, and have objective evidence of increase in size.
  • Central nervous system (CNS) metastases must have no evidence of progressive neurological symptoms and require increased corticosteroid doses to control CNS disease for more than 4 weeks. If the patient requires corticosteroids for the management of CNS disease, the dose should be stable at a low dose (less than 10 mg/day of prednisone or equivalent steroid dose) for at least 2 weeks prior to C1D1.
  • Immunosuppressive administration of systemic drugs such as steroids should be discontinued at least 2 weeks prior to IP administration.
  • Hemoglobin ⁇ 9.0 g/dL may have received a blood transfusion
  • AST Aspartate aminotransferase ⁇ 2.5 ⁇ ULN (for liver metastases, AST ⁇ 5 ⁇ ULN)
  • ALT Alanine aminotransferase
  • Bilirubin ⁇ 1.5 ⁇ ULN (for patients with Gilbert's syndrome, total bilirubin ⁇ 3.0 mg/dL must be).
  • WOCBP childbearing potential
  • NSCLC - Metastatic non-small cell lung cancer
  • ALK anaplastic lymphoma kinase
  • FISH fluorescence in situ hybridization
  • MSI-H testing has previously been completed, no additional testing is required. However, if the subject did not undergo this test, additional testing must be completed at a local facility.
  • Non-clear cell renal cell carcinoma RCC
  • anal squamous cell carcinoma aSCC
  • cervical cancer cutaneous squamous cell carcinoma
  • cSCC cutaneous squamous cell carcinoma
  • endometrial cancer high tumor mutation burden (TMB-H) tumor
  • penile epithelial tumor Histologic confirmation of squamous cell carcinoma or adenocarcinoma
  • neuroendocrine tumor any origin, pancreatic or non-pancreatic
  • nasopharyngeal carcinoma nasopharyngeal carcinoma.
  • TMB-H Test registration is possible if TMB ⁇ 10 mutations/megabase is confirmed in the local (testing institution) laboratory.
  • HNSCC head and neck squamous cell carcinoma
  • Anti-PD-1, anti-PD-L1, anti-PD-L2, anti-cytotoxic T lymphocyte associated protein 4 (anti-CTLA-4) antibodies or other antibodies or drug-specific T cell costimulation or immune checkpoints Previous therapy using the route.
  • hepatitis B e.g. HBs antigen reactivity
  • hepatitis C infection e.g. hepatitis C infection
  • HAV human immunodeficiency virus
  • ILD Active interstitial lung disease
  • Congestive heart failure grade 3 to 4 according to the New York Heart Association (NYHA) classification Clinically significant uncontrolled cardiovascular disease, such as myocardial infarction or unstable angina within the previous 6 months, which may cause uncontrolled hypertension or QT prolongation Patients with clinically significant uncontrolled arrhythmias, such as bradyarrhythmias (e.g., type 2 second-degree atrioventricular block or third-degree atrioventricular block).
  • NYHA New York Heart Association
  • Example 2 the blood concentration of YBL-006 administered to the patient group was investigated, and the results and NONMEM® (Boeckmann, A. J., Sheiner, L. B., Beal, S. L. (2020). NONMEM Users Guide - Part V. ICON plc., version 7.5.1) was used to conduct pharmacokinetic analysis.
  • NONMEM® Boeckmann, A. J., Sheiner, L. B., Beal, S. L. (2020). NONMEM Users Guide - Part V. ICON plc., version 7.5.
  • Cohort B1 B2 B3 Dose 200mg Q2W 300mg Q3W 200mg Q2W C max,est (mg/L) 59.02 ⁇ 15.60 68.37 ⁇ 19.87 53.87 ⁇ 10.22 AUC ⁇ ,est (mgh/L) 12549 ⁇ 4903 15821 ⁇ 5117 11571 ⁇ 2369 AUC ss,6wk (mgh/L) 38703 ⁇ 8123 39839 ⁇ 8956 37234 ⁇ 6980
  • the maximum concentration was the group administered 300 mg every 3 weeks (300mg Q3W) (Cohort B2) and the group administered 200 mg every 2 weeks (200mg Q2W) (Cohort It was measured slightly higher than B1, B3). This is within the error range of cohorts B1 and B3, and there was no significant difference even when comparing the C max.est of each experimental group divided by the administered dose (C max,est /Dose).
  • the drug concentration maintained in the body until 6 weeks after administration is the group administered 200 mg every 2 weeks (200mg Q2W) and the group administered 300 mg every 3 weeks (300mg Q3W). It was confirmed that this was at a similar level.
  • Example 3 Through the results of Example 3 and Example 4, it was confirmed that there was no significant difference between 200mg Q2W and 300mg Q3W in the administration method of YBL-006 for cancer treatment.
  • ORR means the objective response rate
  • DCR means the disease control rate.
  • ORR was determined as the ratio of patients with complete response (CR) and partial response (PR) compared to the total number of patients
  • DCR was determined as the ratio of patients with complete response (CR), partial response (PR), and stable lesion (SD) among the total number of patients. Judgment was made.
  • the ORR of the NET patient group was 22.2% and the DCR was 66.7%, confirming that YBL-006 has a therapeutic effect on NET.
  • the ORR was 28.6% and the DCR was 71.4%.
  • the two patients in whom partial remission was observed were patients with duodenal NEC (large cell) and ampulla of vater NEC, and both were confirmed to have NEC disease of the digestive system.
  • AUC ⁇ ,est Estimated area under the concentration-time curve, for dosing interval tau
  • AUC ss,6wk Area under the concentration-time curve at steady state, estimated for a period of 6 weeks
  • IgG4 Immunoglobulin G4
  • NEC Neuroendocrine carcinoma
  • NEN Neuroendocrine neoplasm
  • PD-1 Programmed cell death-1
  • Vc Central volume of distribution in the central compartment
  • Vp Peripheral volume of distribution in peripheral compartment
  • Vss Volume of distribution at steady state
  • VH Heavy chain variable region
  • VL Light chain variable region

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Abstract

Un anticorps selon la présente invention qui se lie de manière spécifique à PD-1, ou un fragment de liaison à l'antigène de l'anticorps, peut inhiber l'activité de PD-1, par exemple par liaison à PD-1 et inhiber l'interaction entre PD-1 et PD-L1, et est ainsi utile dans le développement d'agents immunothérapeutiques pour divers néoplasmes neuroendocriniens.
PCT/KR2022/013832 2022-09-15 2022-09-15 Composition pharmaceutique, pour la prévention ou le traitement d'un néoplasme neuroendocrinien, contenant un anticorps qui se lie de manière spécifique à pd-1 en tant que principe actif WO2024058289A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180016321A (ko) * 2016-08-05 2018-02-14 주식회사 와이바이오로직스 프로그램화된 세포 사멸 단백질 리간드-1 (pd-l1)에 대한 항체 및 이의 용도
CN113248612A (zh) * 2020-02-13 2021-08-13 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗神经内分泌瘤中的用途
KR20210124993A (ko) * 2019-02-03 2021-10-15 지앙수 헨그루이 메디슨 컴퍼니 리미티드 항-pd-1 항체, 이의 항원-결합 단편 및 이의 약학적 용도
WO2022022660A1 (fr) * 2020-07-31 2022-02-03 江苏恒瑞医药股份有限公司 Composition pharmaceutique d'anticorps anti-pd -1 et son utilisation
US11248048B2 (en) * 2016-08-05 2022-02-15 Y-Biologics Inc. Antibody to programmed cell death 1 (PD-1) and use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180016321A (ko) * 2016-08-05 2018-02-14 주식회사 와이바이오로직스 프로그램화된 세포 사멸 단백질 리간드-1 (pd-l1)에 대한 항체 및 이의 용도
US11248048B2 (en) * 2016-08-05 2022-02-15 Y-Biologics Inc. Antibody to programmed cell death 1 (PD-1) and use thereof
KR20210124993A (ko) * 2019-02-03 2021-10-15 지앙수 헨그루이 메디슨 컴퍼니 리미티드 항-pd-1 항체, 이의 항원-결합 단편 및 이의 약학적 용도
CN113248612A (zh) * 2020-02-13 2021-08-13 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗神经内分泌瘤中的用途
WO2022022660A1 (fr) * 2020-07-31 2022-02-03 江苏恒瑞医药股份有限公司 Composition pharmaceutique d'anticorps anti-pd -1 et son utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LEE K-W., PARK J., OH D-Y., KIM S.H., SABANATHAN D., KIM T.M., KIM M., YOON J., LEE H., PARK S., PAENG K., OCK C-Y.: "977P Interim results of phase I dose escalation study of YBL-006: A novel anti-PD-1 monoclonal antibody in advanced solid tumors", ANNALS OF ONCOLOGY, ELSEVIER, vol. 32, no. S5, 16 September 2021 (2021-09-16), pages S838, XP009553623, ISSN: 0923-7534, DOI: 10.1016/j.annonc.2021.08.1361 *
OH, D.-Y. et al. Safety and efficacy of YBL-006, an anti-PD-1 monoclonal antibody in advanced solid tumors : A phase 1 study. 2022 ASCO Annual Meeting 1, Meeting Abstract. 02 June 2022, abstract no. : e14557. *
YOON, J. ET AL. : "Preclinical characterization of YBL-006, a fully human anti-PD-1 antibody being ready for clinical studies", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 80, no. 16, Suppl., 15 August 2020 (2020-08-15), US, pages 3367, XP009553619, ISSN: 0008-5472, DOI: 10.1158/1538-7445.AM2020-3367 *

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