Application of anti-RSV antibody in prevention and treatment of RSV

Abstract

The invention provides an application of an anti-RSV antibody in preventing and treating RSV. The anti-RSV antibody can provide enough anti-RSV infection protection for infants entering the first RSV epidemic season.

Description

Technical Field

[0001] This disclosure relates to the fields of medicine and immunology, and more specifically, to the use of respiratory syncytial virus (RSV)-specific binding antibodies in the prevention and treatment of RSV infection. Background Technology

[0002] Human respiratory syncytial virus (RSV) is widely distributed worldwide and is one of the most common viral pathogens causing lower respiratory tract illness (LRI) in infants, the elderly, and immunocompromised adults. Almost all children experience one or more infections by age 2, with peak infection rates between 2 and 8 months. RSV is the leading cause of lower respiratory tract infections in infants and young children, and also the leading cause of hospitalization for respiratory illnesses in young children. Among hospitalized infants, 40%–50% of bronchiolitis and 25% of pneumonia are caused by RSV infection. Furthermore, multiple studies have shown that severe infections in infants are a high-risk factor for developing asthma later in life, with a severity far exceeding that of other microbial pathogens.

[0003] Natural RSV infection does not produce sufficient immunity to generate lasting immunity. Therefore, a significant characteristic of RSV infection is that antibodies produced in the body from previous infections cannot provide permanent protection. Different subtypes of RSV can cause reinfection in the same epidemic season. Even if multiple natural RSV infections occur, they cannot induce lifelong immune protection against viral infection in the respiratory tract. Therefore, reinfection is very common. Summary of the Invention

[0004] To address the aforementioned technical problems, this disclosure first provides a pharmaceutical unit composition comprising 50 to 400 mg of an anti-RSV antibody or its antigen-binding fragment and a pharmaceutically acceptable carrier; the anti-RSV antibody includes a light chain variable region and a heavy chain variable region.

[0005] The heavy chain variable region includes: (1) CDR1 of the amino acid sequence shown in SEQ ID NO: 1 or a functional active CDR variant with equivalent function; (2) CDR2 of the amino acid sequence shown in SEQ ID NO: 2 or a functional active CDR variant with equivalent function; and (3) CDR3 of the amino acid sequence shown in SEQ ID NO: 3 or a functional active CDR variant with equivalent function.

[0006] The light chain variable region includes: (1) CDR1 of the amino acid sequence shown in SEQ ID NO: 4 or a functional active CDR variant with equivalent function; (2) CDR2 of the amino acid sequence shown in SEQ ID NO: 5 or a functional active CDR variant with equivalent function; and (3) CDR3 of the amino acid sequence shown in SEQ ID NO: 6 or a functional active CDR variant with equivalent function.

[0007] In some embodiments, the anti-RSV antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR1, which consists of the amino acid sequence of SEQ ID NO: 1, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 2, and (iii) CDR3, which consists of the amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprises: (i) CDR1, which consists of the amino acid sequence of SEQ ID NO: 4, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 5, and (iii) CDR3, which consists of the amino acid sequence shown in SEQ ID NO: 6.

[0008] In some embodiments, the anti-RSV antibody or its antigen-binding fragment comprises a heavy chain variable region VH and / or a light chain variable region VL, wherein:

[0009] The heavy chain variable region comprises or consists of an amino acid sequence having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or higher with SEQ ID NO: 7;

[0010] The light chain variable region comprises or consists of an amino acid sequence having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or higher with SEQ ID NO: 8.

[0011] In some embodiments, the aforementioned anti-RSV neutralizing antibody or its antigen-binding fragment further comprises heavy chain and / or light chain constant region sequences derived from human antibody germline common sequences. The aforementioned light chain constant region is preferably a human-derived κ or λ chain constant region. The heavy chain constant region can be a γ, μ, α, δ, or ε chain constant region; in some embodiments, the aforementioned heavy chain constant region is a human-derived IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD, and IgE isotype. Each heavy chain and light chain type is characterized by a specific constant region having a sequence well known in the art.

[0012] In some implementations, the constant region is preferably a human IgG constant region, such as a constant region of human IgG1, IgG2, IgG3 or IgG4 isotypes;

[0013] Preferably, the light chain of the anti-RSV antibody disclosed herein may be κ or λ type.

[0014] Furthermore, the heavy chain of the antibody or its antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO:9; the light chain of the antibody or its antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO:10.

[0015] Furthermore, the combination of the heavy chain and light chain of the antibody or its antigen-binding fragment is SEQ ID NO:9-10.

[0016] In some embodiments, the composition comprises 80 to 160 mg of an anti-RSV antibody or its antigen-binding fragment, such as 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg or 160 mg, preferably 120 mg.

[0017] In some embodiments, the concentration of the anti-RSV antibody or its antigen-binding fragment in the composition is 80-120 mg / mL; preferably 100 mg / mL.

[0018] In some embodiments, the composition is used for single intramuscular injection administration; preferably, the composition comprises a single intramuscular injection formulation packaged in a container (such as an ampoule).

[0019] The second aspect of this disclosure provides the use of an anti-RSV antibody or an antigen-binding fragment thereof in the preparation of a medicament for the prevention or treatment of RSV infection or related symptoms or diseases, wherein the medicament is formulated in a single-dose formulation of 50 to 400 mg, and the monoclonal anti-RSV antibody or antigen-binding fragment thereof is as described in the first aspect of this disclosure;

[0020] In some embodiments, the drug is formulated as a single intramuscular injection in doses of 80 to 160 mg, such as 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg or 160 mg, preferably 120 mg.

[0021] In some embodiments, the RSV infection includes subtype A and / or subtype B infection; in some embodiments, the RSV infection includes upper respiratory tract RSV infection and / or lower respiratory tract RSV infection; the symptoms or diseases associated with the RSV infection include fever, cough, sore throat, runny nose and difficulty breathing, bronchitis or pneumonia caused by RSV infection.

[0022] In some implementations, the single administration is an intramuscular injection.

[0023] A third aspect of this disclosure provides a method for preventing or treating symptoms or diseases associated with RSV infection, comprising administering an anti-RSV antibody or an antigen-binding fragment thereof in 50 to 400 mg to a subject in need, said anti-RSV antibody or antigen-binding fragment thereof as described in the first aspect of this disclosure;

[0024] In some implementations, the anti-RSV antibody is administered to the subject in need by a single intramuscular injection of 80 to 160 mg, such as 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg or 160 mg, preferably 120 mg.

[0025] In some implementations, the subjects in need include infants under 1 year of age, as well as toddlers, children, or other individuals with weakened or impaired immune systems.

[0026] In some implementations, the subjects in need include preterm or full-term infants, such as high-risk infants with a birth weight of less than 2,000 grams, a gestational age of <35 weeks, and congenital heart disease (CHD), chronic lung disease (CLD), or / and immunodeficiency.

[0027] In some implementations, the administration is a single intramuscular injection.

[0028] The fourth aspect of this disclosure provides an anti-RSV antibody or antigen-binding fragment thereof for the prevention or treatment of symptoms or diseases associated with RSV infection, said prevention or treatment comprising administering the anti-RSV antibody or antigen-binding fragment thereof at a dose of 50 to 400 mg to a subject in need, said anti-RSV antibody or antigen-binding fragment thereof as described in the first aspect of this disclosure;

[0029] In some embodiments, the anti-RSV antibody or its antigen-binding fragment is administered to a subject in need via a single intramuscular injection of 80 to 160 mg, such as 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg or 160 mg, preferably 120 mg.

[0030] In some implementations, the subjects in need include infants under 1 year of age, as well as toddlers, children, or other individuals with weakened or impaired immune systems.

[0031] In some implementations, the subjects in need include preterm or full-term infants, such as high-risk infants with a birth weight of less than 2,000 grams, a gestational age of <35 weeks, and congenital heart disease (CHD), chronic lung disease (CLD), or / and immunodeficiency.

[0032] In some implementations, the administration is a single intramuscular injection.

[0033] Beneficial technical effects

[0034] This disclosure provides the use of an anti-RSV antibody in the prevention and treatment of RSV, which can provide adequate protection against RSV infection for infants entering the first RSV epidemic season. Attached Figure Description

[0035] Figure 1 The PopPK model predicted that on day 150, the serum concentration of TRN1021 in infants of different weights and at different dosages would not be lower than that of lung tissue A2 strain virus and lung tissue B9320 strain EC virus. 90 percentage of the population

[0036] Figure 2 Pharmacokinetic results of 80mg-160mg anti-RSV antibodies Detailed Implementation

[0037] the term:

[0038] Before this disclosure is described in detail below, it should be understood that this disclosure is not limited to the specific methodologies, procedures, and reagents described herein, as these can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of this disclosure, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0039] For the purpose of interpreting this specification, the following definitions will be used, and terms used in the singular may also include plural forms, where appropriate. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be restrictive.

[0040] As used herein and unless otherwise stated, the terms “about” or “approximately” mean within 10% of a given value or range. Where an integer is required, the term means within 10% of a given value or range, rounded up or down to the nearest integer.

[0041] The term “about” when used in conjunction with a numeric value means to cover a range of numeric values ​​that have a lower limit of 5% less than the specified numeric value and an upper limit of 5% greater than the specified numeric value.

[0042] The term “and / or” should be understood to mean either one of the options or both of the options.

[0043] As used herein, the terms “comprising” or “including” mean to include the elements, integers, or steps described herein, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, the situation consisting of the described elements, integers, or steps also applies.

[0044] For example, when referring to an antibody variable region that "contains" a specific sequence, it is also intended to encompass antibody variable regions composed of that specific sequence.

[0045] The term "respiratory syncytial virus" or "RSV" refers to a single-stranded, negative-sense RNA virus belonging to the Paramyxoviridae family and the Pneumovirus genus. It is named respiratory syncytial virus (RSV) because it can induce a unique cell fusion in cultured cells. Based on differences in surface antigens, RSV can be divided into two subtypes: RSV-A and RSV-B. This virus is transmitted through airborne droplets and close contact. RSV contains 10 genes encoding 11 proteins, among which the surface glycoprotein fusion protein (F protein) and the attachment protein (G protein) are the most important viral antigens that stimulate the body to produce protective antibodies. Because the G protein varies considerably between subtypes, while the F protein is highly conserved, and because the F protein directly mediates viral fusion with cells, viral penetration, and syncytial formation, it is the main target protein for stimulating the body to produce protective antibodies. In this document, "respiratory syncytial virus" or "RSV" refers to any respiratory syncytial virus or RSV molecule known to those skilled in the art. For example, RSV can include any of the aforementioned subtypes; RSV can originate from mammals; and RSV can originate from humans.

[0046] The term "antibody that specifically binds to respiratory syncytial virus (RSV)" refers to a monoclonal anti-RSV antibody that specifically binds to respiratory syncytial virus (RSV), wherein the RSV antibody includes a variant of the parent antibody. In a particular aspect, this document provides antibodies that specifically bind to respiratory syncytial virus (e.g., human respiratory syncytial virus). In a specific aspect, the anti-RSV antibody provided herein is a neutralizing antibody. The term "neutralizing antibody" refers to an antibody that reduces or inhibits at least one biological activity of the F protein. For example, blocking the fusion of RSV with host cells, preventing syncytial formation, and preventing primary disease caused by RSV. Alternatively, the neutralizing antibody of this disclosure can improve at least one symptom of RSV infection.

[0047] The term “antibody” is used in the broadest sense herein and encompasses a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, provided they exhibit the desired antigen-binding activity. A complete antibody will typically contain at least two full-length heavy chains and two full-length light chains, but in some cases may include fewer chains, such as antibodies naturally occurring in camels that may contain only heavy chains. Antibodies can be humanized or human antibodies and single-domain antibodies, such as VH, VHH, or VL. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, single-chain Fv (scFv), Fv, dsFv, biantibodies, Fd and Fd' fragments, and other fragments, including modified fragments (e.g., Methods in Molecular Biology, Vol 207: Recombinant Antibodies for Cancer Therapy Methods and Protocols (2003); Chapter 1; p3-25, Kipriyanov). The aforementioned fragments may include multiple chains linked together, for example, through disulfide bonds and / or peptide linkers. Antibody fragments generally contain at least or about 50 amino acids, and typically at least or about 200 amino acids.

[0048] As used herein, the term "monoclonal antibody" or "mAb" refers to an antibody derived from a single copy or clone of, for example, a eukaryotic, prokaryotic, or phage clone; that is, the individual antibodies constituting the aforementioned group are identical and / or bind to the same epitopes, except that they are typically present in small amounts as possible variant antibodies (e.g., those containing natural mutations or variant antibodies generated during the production of monoclonal antibody products). The modifier "monoclonal" indicates that the antibody is derived from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology such as CDR grafting, or combinations of such or other techniques known in the art.

[0049] The term "natural antibody" refers to naturally occurring immunoglobulin molecules with different structures. A "natural sequence Fc domain" contains the same amino acid sequence as an Fc domain found in nature. Natural sequence human Fc domains include, for example, the natural sequence human IgG1 Fc domain (non-A and A allotypes); the natural sequence human IgG2 Fc domain; the natural sequence human IgG3 Fc domain; and the natural sequence human IgG4 Fc domain; and their naturally occurring variants.

[0050] The term "human antibody" refers to an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell or derived from a non-human source, utilizing a human antibody library or other human antibody coding sequences. The term "human antibody" explicitly excludes humanized antibodies containing non-human antigen-binding residues.

[0051] The term "neutralizing antibody" refers to an antibody that reduces or inhibits at least one biological activity of the F protein. For example, it may block the fusion of RSV with host cells, prevent syncytial formation, or prevent primary disease caused by RSV. Alternatively, the neutralizing antibody of this disclosure may improve at least one symptom of RSV infection. The reduction in biological activity may be partial or complete. The degree to which an antibody neutralizes RSV is called its neutralizing potency. The neutralizing potency of an antibody can be determined or measured using one or more tests known to a person skilled in the art and / or mentioned herein, including but not limited to competitive binding assays, direct and indirect sandwich assays, immunoprecipitation assays and enzyme-linked immunosorbent assays (ELISA), plaque reduction assays, micro-neutralization assays, fixed antiserum-dilution virus assays, fixed virus-dilution antiserum assays, and pseudovirus neutralization assays.

[0052] The term "complementarity-determining region" or "CDR region" or "hypervariant region" refers to the amino acid region in the antibody's variable region that is primarily responsible for binding to antigenic epitopes. The CDRs of the heavy and light chains are usually referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus.

[0053] In some embodiments, the monoclonal anti-RSV antibody or its antigen-binding fragment mentioned herein further comprises heavy chain and / or light chain constant region sequences derived from human antibody germline common sequences. The aforementioned light chain constant regions are preferably human κ or λ chain constant regions. Heavy chain constant regions may be γ, μ, α, δ, or ε chain constant regions; in some embodiments, the aforementioned heavy chain constant regions are human IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD, and IgE isotypes. Each heavy chain and light chain type is characterized by a specific constant region having sequences well known in the art.

[0054] In some implementations, the constant region is preferably a human IgG constant region, such as a constant region of human IgG1, IgG2, IgG3 or IgG4 isotypes.

[0055] Preferably, the light chain of the monoclonal antibody disclosed herein may be κ or λ type.

[0056] In a preferred embodiment, the light chain is of the λ type. The light chain can be a naturally occurring chain, including naturally rearranged, genetically modified, or synthetic light chain types.

[0057] The heavy chain of the monoclonal antibody disclosed herein can be selected from: isotype IgM, IgA, or IgG, preferably IgG. In a preferred embodiment, the heavy chain of the monoclonal antibody is of the IgG type.

[0058] It should be understood that sequence variants of these constant region domains can also be used, for example, those containing one or more amino acid modifications, where the amino acid sites are identified by the EU indexing system of Kabat et al. (1991). These sites can be selected from 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 279, 280, 281, 282D, 283, 284, 285, 286, 287, 288S, 305, 30 6, 307, 308, 309, 310, 311, 312, 313, 315, 317, 339, 340, 341, 374, 376, 378, 380, 382, ​​383, 384, 385, 386, 387, 389, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 440, and 443. Optionally, the Fc region may include non-naturally present amino acid residues at additional and / or alternative sites, as known to those skilled in the art (examples include U.S. Patents 5,624,821; 6,277,375; 6,586,207; 6,737,056; 7,083,784; 7,317,091; 7,217,797; 7,276,585; 7,355,008; 2002 / 0147311; 2004 / 0002587; 2005 / 0215768; 2007 / 0135620; 2007 / 0224188; 2008 / 0089892; WO94 / 29351; WO99 / 58572; WO 98 / 48032; WO03 / 073238; WO05 / 35727A2; WO05 / 74524A2; JWChin et al., (2002), Journal of the American Chemical Society 124: 9026-9027; JWChin and PGSchultz, (2002), ChemBioChem 11: 1135-1137; JWChin et al., (2002), PICAS United States of America 99: 11020-11024; and L.Wang and PGSchultz, (2002), Chem. 1-10).

[0059] In some implementations, to prevent the glycosylation of the aforementioned antibodies, modifications are made, for example, in the constant region of human IgG. Such modifications may be N297A or N297Q (Sazinsky, PNAS (2008), 105(51):20167-20172).

[0060] In some implementations, in order to alter Fc receptor interactions, modifications may be made, for example, in the human IgG constant region, such modifications may be L234A and / or L235E or L235A.

[0061] In some implementations, in order to prevent or reduce chain exchange, modifications are made, for example, in the human IgG constant region, such modifications may be S228P (Angal, S. Mol Immunol (1993), 30: 105-108).

[0062] In some implementations, to alter antibody-dependent cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), modifications are made, for example, in the human IgG constant region. Such modifications are known (including, but not limited to: Natsume et al., Cancer Res (2008), 68(10):3863-72; Idusogie et al., J. Immunol (2001), 166(4):2571-5; Moore et al., mAbs (2010), 2(2):181-189; Lazar et al., PNAS (2006), 103(11):4005-4010; Shields et al., J. Biol. Chem. (2001), 276(9):6591-6604; Stavenhagen. Cancer Res (2007), 67(18):8882-8890; Alegre et al., J. Immunol (1992) 148:3461-3468.; Kaneko, Niwa et al., Biodrugs (2011), 25(1):1-11.).

[0063] In some implementations, heterodimerization can also be induced by T366W modification and optionally further by introducing disulfide bonds via S354C and Y349C modification on the opposing CH3 domains (Carter, Journal of Immunological Methods (2001), 248:7-15).

[0064] The term "pharmaceutical carrier" refers to one or more nontoxic materials that are administered with a therapeutic agent without interfering with the bioactivity of the active ingredient, including but not limited to buffers, preservatives, compatible carriers, diluents, adjuvants (e.g., Freund's adjuvants (complete and incomplete)), excipients, mediators, and optionally other additives or encapsulating substances. Pharmaceutical carriers suitable for use in this disclosure can be conventional pharmaceutical excipients; and compositions and formulations suitable for delivering the disclosed neutralizing antibodies.

[0065] The term "treatment" refers to the slowing, improvement, relief, cessation, or reduction of the progression, severity, and / or duration of upper and / or lower respiratory tract RSV infection or associated symptoms or respiratory symptom (e.g., asthma, wheezing, or a combination thereof). In some embodiments, the term refers to a reduction or inhibition of RSV replication, inhibition or reduction of RSV spread to other tissues or subjects (e.g., lower respiratory tract spread), inhibition or reduction of cellular RSV infection, or improvement of one or more symptoms associated with upper and / or lower respiratory tract RSV infection.

[0066] The term “prevention” means preventing or suppressing the development or onset of upper and / or lower respiratory tract RSV infection or related respiratory symptoms in a subject; preventing or suppressing the progression of upper and lower respiratory tract RSV infection or related respiratory symptoms caused by the administration of a therapy (e.g., a prophylactic or therapeutic agent); preventing the symptoms of upper and / or lower respiratory tract RSV infection or related respiratory symptoms; or administering a combination of therapies (e.g., a combination of prophylactic or therapeutic agents).

[0067] The term "subject" or "individual" refers to a primate (e.g., a human or a non-human primate such as a monkey). In some embodiments, the individual or subject is a human; in other embodiments, the subject is a premature or full-term infant.

[0068] The specific methods for population pharmacokinetics (PopPK) in Examples 1 and 2 are as follows:

[0069] Raw data processing for the antibody TRN1021PopPK was performed in SAS (v9.4, SAS Institute Inc., NC, US). The data analyzed included, but were not limited to: demographic and physiological / biochemical indicators, dosing information, sample collection information and test results, and efficacy results.

[0070] 1. Analytical Methods

[0071] 1.1 Modeling Software and Strategies

[0072] Data was prepared using SAS (v9.4), and population modeling was performed using NONMEM (Non-linear mixed effects modeling, v7.5.0, ICON Development Solutions, MD, US). PsN (perl-speaks-nonmem v4.8.1, Uppsala, Sweden) was used as an auxiliary software for running NONMEM. R (v4.1.3, R Core Team

[2022] , R Foundation for Statistical Computing, Vienna, Austria) was used for exploratory data analysis, data preparation, and model result charting. The PopPK model was executed using the built-in ADVAN module in the PREDPP subroutine of NONMEM, and the model parameter estimation method was the First-Order Conditional Evaluation with Interactions (FOCEI). The exposure-treatment ER model was analyzed using a proportional hazards model (Cox model), executed using the built-in "ADVAN6" module of the PREDPP subroutine in NONMEM. The model parameters were estimated using the FOCEI method and the Laplace method. Graphical analysis was performed using R (v4.1.3).

[0073] 1.2 PopPK Model Analysis

[0074] This PopPK analysis will proceed with model development according to the following steps: 1) Basic structure model development; 2) Random effects model development; 3) Covariate modeling; 4) Model suitability assessment; 5) Model predictive performance evaluation (validation). In covariate modeling, graphical methods and linear correlation tests are first used to preliminarily screen covariates that may affect PK parameters. Then, the stepwise covariate method (SCM) is used to conduct a detailed evaluation of the covariate modeling of the initially screened covariates or those of interest in the study. SCM includes two processes: a forward addition step and a backward elimination step. The criteria for the forward addition step are p < 0.05, and the criteria for the backward elimination step are p < 0.001. The goodness of fit of the model will be evaluated using the following methods: changes in the objective function (OFV), visualization of various diagnostic methods, and the accuracy and reasonableness of parameter estimation. Visualized prediction test (pcVPC) or visualized prediction test (VPC) for corrected predictive values ​​is used to evaluate the model's predictive performance on the observed data.

[0075] 1.3 Simulation based on the final PopPK model

[0076] Based on the established PopPK final model, the PK characteristics of infants and young children after intramuscular injection of different doses of antibody TRN1021 under different weights and ages (generated based on the age-adjusted distribution of 504 infant subjects in the antibody TRN1021 group [PAGE1]) were simulated. The blood concentrations of antibody TRN1021 under different dosing regimens were calculated to be higher than the EC50 obtained in animal experiments. 90 (i.e., lung tissue A subtype A2 strain virus EC) 90 The concentration was 2.09 μg / mL, and the EC count of 9320 strains of subtype B virus in lung tissue was [missing information]. 90 The percentage of subjects with a concentration of 2.53 μg / mL.

[0077] 2. Antibody TRN1021 and its preparations

[0078] CDR sequence of antibody TRN1021:

[0079]

[0080] The heavy chain variable region sequence and light chain variable region sequence of antibody TRN1021:

[0081]

[0082] The heavy chain (SEQ ID NO:9) and light chain (SEQ ID NO:10) of antibody TRN1021:

[0083]

[0084] Antibody production and formulation: Antibody TRN1021 is produced by transfecting mammalian cell lines with a vector containing the antibody sequence. The antibody-producing cells are grown in a controlled bioreactor in suspension. Cells are harvested and the antibody is purified using a series of chromatographic steps. The purification process includes multiple inactivation and impurity removal steps to ensure the absence of viral, retroviral, and bacterial contamination. Antibody TRN1021 is then formulated in a buffer solution. Antibody TRN1021 is used as a single-use, sterile, clear liquid formulation.

[0085] Example

[0086] Example 1: A study of anti-RSV fully human monoclonal antibody injection in healthy adult subjects.

[0087] This study evaluated the safety and pharmacokinetic characteristics of a single dose of antibody TRN1021 in healthy adult subjects (hereinafter referred to as the "101 trial"). The investigational drug was administered in two phases. Phase 1 included six dosage groups: 50 mg, 150 mg, 400 mg, 900 mg, 1500 mg, and 2500 mg, with eight subjects enrolled in each group (antibody TRN1021 to placebo ratio 3:1). Phase 2 included one dosage group: 300 mg, enrolling 80 subjects (antibody TRN1021 to placebo ratio 3:1). All doses were administered via a single intramuscular injection.

[0088] The specific experimental design is shown in Table 1 below:

[0089] Table 1 Research Plan for Experiment "101"

[0090]

[0091]

[0092] PK: Pharmacokinetics; PD: Pharmacodynamics; IM: Intramuscular injection; Placebo: Placebo; HVs: Healthy adult subjects; Infants: Infant subjects; ADA: Anti-drug antibody; NAbs: Neutralizing antibody;

[0093] RSV: Respiratory syncytial virus; CHD: Congenital heart disease; CLD: Chronic lung disease; LRTI: Lower respiratory tract infection.

[0094] a: In the second phase, the first 20 subjects were subjected to PK-intensive sampling, and the remaining subjects were subjected to sparse sampling.

[0095] b: The first phase of the visit will be scheduled for D180, and the second phase of the visit will be scheduled for D150.

[0096] Based on data from the 101 trial, including PK, PD, ADA, and participant demographic information (such as height, weight, and age), rolling PopPK analyses were conducted during and at the end of the 101 trial to predict PK characteristics in infant participants given 20–200 mg doses, and compared with EC obtained from animal studies. 90 Comparisons are made to support the selection of subsequent dosage ranges.

[0097] like Figure 1As shown, the results indicated that at the predicted dose of 80 mg, the protection rate for infants with a maximum weight (10 kg) was less than 90%; at doses below 80 mg (e.g., 50 mg), infants weighing over 4 kg did not receive adequate protection (90% protection rate). A medium dose of 120 mg ensured a protection rate of over 90% for all infant subjects (2–10 kg). Considering the significant variability among infant subjects, in the subsequent 201 trial, a low dose of 80 mg was chosen, and a higher dose of 160 mg was selected to ensure that all infant subjects received protection.

[0098] Example 2

[0099] This study evaluated the safety, tolerability, and pharmacokinetic characteristics of a single dose of antibody TRN1021 in healthy preterm and full-term infants (hereinafter referred to as the "201" trial). Three administration groups and a placebo control group were set up, with doses of 80 mg, 120 mg, and 160 mg in each group. Eight subjects in the investigational drug group and two subjects in the placebo group were included in each group, with a single intramuscular injection administered. The specific study design is shown in Table 2 below:

[0100] Table 2 Research Plan for Experiment "201"

[0101]

[0102] Note: DOSE: Dosage

[0103] T max Peak time; AUC inf Area under the drug-time curve from 0 to ∞; AUC 150 Area under the curve within 150 days of drug administration; C max Peak concentration; C 150 : Blood drug concentration of antibody TRN1021 150 days after administration; t 1 / 2 Half-life; CL / F: apparent distribution volume of the central chamber; Vc / F: apparent distribution volume of the central chamber.

[0104] Data in the table excluding T max Except for the median (minimum - maximum), all other parameters are presented as the arithmetic mean (coefficient of variation %).

[0105] result:

[0106] Except for the 80 mg dosing group, one subject (1 / 6) had a blood drug concentration lower than EC50 at 150 days. 90 In addition, the plasma concentrations in the other two treatment groups (120 and 160 mg) were higher than EC50 at 150 days. 90 This is largely consistent with the PopPK simulation results (see...). Figure 2 ).

[0107] PopPK analysis results:

[0108] Based on the final PopPK model of antibody TRN1021, the individual PK parameters (where clearance rate incorporates the maturation process that varies with age) and dosing information of the subjects included in the PopPK analysis were obtained. The blood drug concentration of each subject was simulated according to the actual dosing regimen and after injection of 120 mg antibody TRN1021. The exposure parameters were calculated by non-compartmental analysis methods. The results are summarized in Table 3.

[0109] Table 3. Summary of PK parameters of antibody TRN1021 estimated by each study and dosage group based on the PopPK final model.

[0110]

[0111] Note: DOSE: dosage; STUDY: 201 refers to the antibody TRN1021-201 study.

[0112] T max Peak time; AUC inf Area under the drug-time curve from 0 to ∞; AUC 150 Area under the curve within 150 days of drug administration; C max Peak concentration; C 150 : Blood drug concentration of antibody TRN1021 150 days after administration; t 1 / 2 Half-life; CL / F: Apparent distribution volume of the central ventricle; V c / F: Apparent distribution volume of the central chamber.

[0113] Data in the table excluding T max Except for the median (minimum - maximum), all other parameters are presented as the arithmetic mean (coefficient of variation %).

[0114] To further confirm the effective dosage, the subsequent 301 trial (Example 3) selected the dosage based on the plasma drug concentration (C0) on day 150 after administration in more than 90% of the population. 150 ) Remains in EC 90 The above amounts. In a pharmacodynamic study of rat challenge, antibody TRN1021 showed EC50 against A2 and 9320 virus strains in lung tissue. 90The concentrations were 2.09 and 2.53 μg / mL, respectively. Based on the PK data from the above studies (including PK data from healthy adults and PK data from healthy preterm and full-term infants up to 30 days after administration), a PopPK model was established to simulate the PK characteristics of subjects in the 301 trial. According to this model, a single intramuscular injection of antibody TRN1021 120 mg is likely effective, with most infants achieving serum concentrations (C0) on day 150 after administration. 150 ) will remain in EC 90 The above dosage of antibody TRN1021 will provide protection against RSV infection for infants entering the first RSV epidemic season.

[0115] Example 3

[0116] This study evaluated the efficacy and safety of antibody TRN1021 injection in preventing lower respiratory tract infection (LRTI) caused by respiratory syncytial virus (RSV) in infants under 1 year of age (hereinafter referred to as the "301 study"). In this study, 751 subjects were enrolled, and all subjects were randomized in a 2:1 ratio to receive either antibody TRN1021 120 mg or placebo via a single intramuscular injection. The specific experimental design is shown in Table 4 below:

[0117] Table 4 Research Plan for "301" Experiment

[0118]

[0119] Notes: PK: Pharmacokinetics; PD: Pharmacodynamics; IM: Intramuscular injection; Placebo: Placebo; HVs: Healthy adult subjects; Infants: Infant subjects; ADA: Anti-drug antibody; NAbs: Neutralizing antibody;

[0120] RSV: Respiratory syncytial virus; CHD: Congenital heart disease; CLD: Chronic lung disease; LRTI: Lower respiratory tract infection.

[0121] c: All subjects requiring respiratory secretion collection will also have additional serum samples collected for analysis of PK, anti-RSV neutralizing antibodies, and immunogenicity. If relevant PK, anti-RSV neutralizing antibody, and ADA specimens collected at LRTI are within the time window of the routine collection point or within 10 days (whichever is longer), only one collection is required.

[0122] result:

[0123] Trial 301 showed that after infant subjects were given 120 mg of antibody TRN1021, almost all subjects had blood drug concentrations higher than ECG levels at 150 days. 90 This is basically consistent with PopPK's simulation results.

[0124] Although this disclosure has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, such modifications or improvements made without departing from the spirit of this disclosure are all within the scope of protection claimed by this disclosure.

Claims

1. A pharmaceutical unit composition comprising 50 to 400 mg of an anti-RSV antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier, said anti-RSV antibody comprising a light chain variable region and a heavy chain variable region: The heavy chain variable region includes: (1) CDR1 with the amino acid sequence shown in SEQ ID NO: 1 or a functional active CDR variant with equivalent function; (2) CDR2 with the amino acid sequence shown in SEQ ID NO: 2 or a functional active CDR variant with equivalent function; (3) CDR3 with the amino acid sequence shown in SEQ ID NO: 3 or a functional active CDR variant with equivalent function. The light chain variable region includes: (1) CDR1 of the amino acid sequence shown in SEQ ID NO: 4 or a functional active CDR variant with equivalent function; (2) CDR2 of the amino acid sequence shown in SEQ ID NO: 5 or a functional active CDR variant with equivalent function; and (3) CDR3 of the amino acid sequence shown in SEQ ID NO: 6 or a functional active CDR variant with equivalent function.

2. The pharmaceutical unit composition of claim 1, wherein the anti-RSV antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR1, which consists of the amino acid sequence of SEQ ID NO: 1, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 2, and (iii) CDR3, which consists of the amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprises: (i) CDR1, which consists of the amino acid sequence of SEQ ID NO: 4, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 5, and (iii) CDR3, which consists of the amino acid sequence shown in SEQ ID NO: 6; Preferably, the anti-RSV antibody or its antigen-binding fragment comprises a heavy chain variable region VH and / or a light chain variable region VL, wherein, The heavy chain variable region comprises or consists of an amino acid sequence having at least 76%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or higher with SEQ ID NO: 7; The light chain variable region comprises or consists of an amino acid sequence having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or higher with SEQ ID NO:

8. Preferably, the above-mentioned anti-RSV neutralizing antibody or its antigen-binding fragment further comprises a heavy chain and / or light chain constant region sequence derived from the human antibody germline common sequence; Preferably, the heavy chain constant region is selected from the constant region of human IgG1, IgG2, IgG3 or IgG4 subtypes; Preferably, the light chain constant region is selected from the κ type or the λ type; Preferably, the heavy chain of the antibody or its antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO:9; the light chain of the antibody or its antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO:

10. More preferably, the combination of the heavy chain and light chain of the antibody or its antigen-binding fragment is SEQ ID NO:9-10.

3. The pharmaceutical unit composition according to claim 1 or 2, wherein the composition comprises 80 to 160 mg of an anti-RSV antibody or an antigen-binding fragment thereof, such as 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg or 160 mg, preferably 120 mg.

4. The pharmaceutical unit composition according to any one of claims 1-3, wherein the concentration of the anti-RSV antibody or its antigen-binding fragment in the composition is 80-120 mg / mL; preferably 100 mg / mL.

5. The pharmaceutical unit composition according to any one of claims 1-4, wherein the composition is for single intramuscular injection administration; preferably, the composition comprises a single intramuscular injection formulation packaged in a container (such as an ampoule).

6. Use of an anti-RSV antibody or an antigen-binding fragment thereof in the preparation of a medicament for the prevention or treatment of RSV infection or related symptoms or diseases, wherein the medicament is formulated in a single-dose formulation of 50 to 400 mg, and the monoclonal anti-RSV antibody or the antigen-binding fragment thereof is as described in claim 1 or 2.

7. The use as described in claim 6, wherein the drug is formulated in the form of a single intramuscular injection at a dose of 80 to 160 mg, such as 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg or 160 mg, preferably 120 mg.

8. The use as described in claim 6 or 7, wherein the RSV infection includes subtype A and / or subtype B infection; and / or, the RSV infection includes upper respiratory tract RSV infection and / or lower respiratory tract RSV infection; and / or, the symptoms or diseases associated with the RSV infection include fever, cough, sore throat, runny nose and difficulty breathing, bronchitis or pneumonia caused by RSV infection.

9. The use as described in any one of claims 6-8, wherein the single administration is an intramuscular injection.

10. A method for preventing or treating symptoms or diseases associated with RSV infection, comprising administering an anti-RSV antibody or an antigen-binding fragment thereof at a dose of 50 to 400 mg to a subject in need, said anti-RSV antibody or antigen-binding fragment thereof as described in claim 1 or 2.

11. The method of claim 10, wherein the anti-RSV antibody is administered to a subject in need by a single intramuscular injection of 80 to 160 mg, such as 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg or 160 mg, preferably 120 mg.

12. The method of claim 10 or 11, wherein the subjects in need include infants under 1 year of age, as well as toddlers, children, or other individuals with weakened or impaired immune systems; Preferably, the subjects in need include preterm or full-term infants, such as high-risk infants with a birth weight of less than 2,000 grams, a gestational age of less than 35 weeks, and congenital heart disease (CHD), chronic lung disease (CLD), or / and immunodeficiency.

13. The method of any one of claims 10-12, wherein the administration is a single intramuscular injection.

14. An anti-RSV antibody or antigen-binding fragment thereof for the prevention or treatment of symptoms or diseases associated with RSV infection, said prevention or treatment comprising administering an anti-RSV antibody or antigen-binding fragment thereof at a dose of 50 to 400 mg to a subject in need, said anti-RSV antibody or antigen-binding fragment thereof as described in claim 1 or 2.

15. The anti-RSV antibody or antigen-binding fragment thereof for the prevention or treatment of RSV infection or related symptoms or diseases as described in claim 14, wherein the anti-RSV antibody or antigen-binding fragment thereof is administered to a subject in need by a single intramuscular injection of 80 to 160 mg, such as 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg or 160 mg, preferably 120 mg.

16. The anti-RSV antibody or antigen-binding fragment thereof for the prevention or treatment of RSV infection or related symptoms or diseases as described in claim 14 or 15, wherein the subject in need includes infants under 1 year of age and toddlers, children or other immunocompromised or impaired individuals; Preferably, the subjects in need include preterm or full-term infants, such as high-risk infants with a birth weight of less than 2,000 grams, a gestational age of less than 35 weeks, and congenital heart disease (CHD), chronic lung disease (CLD), or / and immunodeficiency.

17. The anti-RSV antibody or antigen-binding fragment thereof for the prevention or treatment of RSV infection or related symptoms or diseases as described in any one of claims 14-16, wherein the RSV infection includes subtype A and / or subtype B infection; and / or, the RSV infection includes upper respiratory tract RSV infection and / or lower respiratory tract RSV infection; and / or, the RSV infection-related symptoms or diseases include fever, cough, sore throat, runny nose and dyspnea, bronchitis or pneumonia caused by RSV infection.

18. The anti-RSV antibody or antigen-binding fragment thereof for the prevention or treatment of RSV infection or related symptoms or diseases as described in any one of claims 14-17, wherein the administration is a single intramuscular injection.

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